Outline and argumentative paper
Book Review
A Guide to Understanding Dietary Supplements
Shawn M. Talbott, PhD. The Haworth Press, Inc., Binghamton, NY, 2003, 713 plus xxv pages, $34.95 softcover/$79.95 hardcover.
Dietary supplements are a group of products, as defined by the 1994 Dietary Supplement Health and Education Act (DSHEA), intended to supplement the diet and which contain at least 1 ingredient that is a vitamin, mineral, amino acid, herb or other botanical, or a combination thereof. An estimated 40% to 55% of Americans regularly use dietary supplements of one type or another for any number of reasons. Given the limited regulatory authority over these products, many consumers (and health care professionals) might be misled by marketing hyperbole into using 1 or more dietary supplements without a full understanding of the benefits and potential risks from individual ingredients or mul- ticomponent products. Nutrition support clinicians feel comfortable with the more common nutrient ingredients of dietary supplements but may be less likely to feel competent in providing clinically useful information regarding the plethora of nonnutrient dietary supplements on the market.
Several paper and electronic reference sources have become available over the last few years. Some cover dietary supplements in general, whereas oth- ers are more specific to herbal medicine or other nonnutrient dietary supplements. These resources vary in their target audience and in their level of scientific content. A Guide to Understanding Dietary Supplements is an attempt to provide a broad, user friendly, quick reference on dietary supplements that can appeal to both consumers and health care professionals.
The author, trained in exercise physiology and nutritional biochemistry, holds a position in the dietary supplement industry. Because he under- stands the balance between the business objective of the industry and the scientific needs of the health care professional and their patients, the book seeks to provide a balanced viewpoint on the value of dietary supplements. The author states that the book is intended to educate consumers about dietary supplements and to be a part of the effort to encour- age consumers to “assert their open-minded skepti- cism” and demand that dietary supplement products
meet scientific safety and efficacy standards. Despite referring in the forward to dietary supple- ments as “nutritional” supplements that can improve the diet, supplements from all categories are included in this book.
The book contains a total of 17 chapters. The first 3 chapters provide an overview of the DSHEA, the product development process, and the critical eval- uation of dietary supplements. These provide a good summary for the uninitiated, with useful insights and examples that set the background for the remainder of the book. The following 14 chapters are then organized by primary use or “indication,” and each provides a collection of monographs on individ- ual supplement ingredients. These chapter topics include use of dietary supplements for weight loss, ergogenic aids, and boosting energy level, and those used for the health of bone, joints, brain, heart, immune system, eyes, and gastrointestinal tract. Additional chapters cover gender-specific health and dietary supplements used for cancer and for patients with diabetes. In the process, well over 100 individ- ual supplement ingredients are covered, necessarily leaving thousands of others unmentioned. Each of the chapters on specific uses starts with an intro- duction to the topic, which in some cases includes basic exercise or nutrition guidelines, and an over- view of the supplements before the sequence of specific monographs. Each monograph is organized in similar fashion: description of the supplement ingredient, its claims, the theory behind those claims, and scientific support, safety, value, and dosage. Most chapters have at least 1 table summa- rizing the ingredients discussed. A chart at the end of the book summarizes primary and secondary indications of the over 100 supplements discussed. The book includes a useful index as well.
The writing style is direct and easy to follow. Interesting information is included on protein and amino acid supplements, several vitamins and minerals, coenzyme Q10, and lycopene in a reasonably fair and balanced manner. There are some shortcomings of the book. It would be more meaningful to the consumer if a statement by the author at the end of each monograph described the clinical value of the ingredient, even simply stating that the benefit outweighs risk or that the risk outweighs benefit. From a clinician’s per- spective, the lack of citations within the text of each monograph is a significant drawback, although a useful Works Consulted section is included at the end of each monograph. Virtually no discussion of poor product quality is offered, a critical and relevant issue once a decision is made to use a particular supplement. One of the excep-
0884-5336/03/1805-0440$03.00/0 Nutrition in Clinical Practice 18:440–441, October 2003 Copyright © 2003 American Society for Parenteral and Enteral Nutrition
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tions occurs in the monograph on ma huang/ ephedra. Little mention is made of allergic reac- tions to natural products or of interactions between dietary supplements and medications or other supplements. White willow is mentioned in several places in the book, but even in the safety discussion no mention is made of the potential allergenicity to this substance in those with an aspirin allergy. At about 700 pages, the paper- back is not likely to endure much punishment
from constant use as it might get in a drug information center. These limitations aside, this remains a useful book.
Although not as comprehensive or as clinically valuable as some other resources, it can serve the purpose of a quick reference in common language for busy nutrition support clinicians or students, and for lay persons, at a reasonable price.
Joseph Boullata, PharmD, BCNSP Philadelphia, PA
October 2003 441UNDERSTANDING DIETARY SUPPLEMENTS
at SAGE Publications on November 11, 2014ncp.sagepub.comDownloaded from
Themed Section: Principles of Pharmacological Research of Nutraceuticals
REVIEW ARTICLE
Probiotics, fibre and herbal medicinal products for functional and inflammatory bowel disorders
Correspondence Diego Currò, Institute of Pharmacology, School of Medicine, Catholic University of the Sacred Heart, L.go F. Vito, 1, I-00168 Rome, Italy. E-mail: diego.curro@unicatt.it
Received 15 June 2016; Revised 11 August 2016; Accepted 13 September 2016
Diego Currò1, Gianluca Ianiro2, Silvia Pecere2, Stefano Bibbò3 and Giovanni Cammarota2
1Institute of Pharmacology, School of Medicine, Catholic University of the Sacred Heart, L.go F. Vito 1 00168 Rome, Italy, 2Department of Internal
Medicine, School of Medicine, Catholic University of the Sacred Heart, L.go F. Vito 1 00168 Rome, Italy, and 3Department of Clinical and Experimental
Medicine, University of Sassari, V.le S. Pietro, 8 07100 Sassari, Italy
Functional bowel disorders (FBD), mainly irritable bowel syndrome (IBS) and functional constipation (FC, also called chronic idiopathic constipation), are very common worldwide. Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease, although less common, has a strong impact on patients’ quality of life, as well as being highly expensive for our healthcare. A definite cure for those disorders is still yet to come. Over the years, several therapeutic approaches complementary or alternative to traditional pharmacological treatments, including probiotics, prebiotics, synbiotics, fibre and herbal medicinal products, have been investigated for the management of both groups of diseases. However, most available studies are biased by several drawbacks, including small samples and poor methodological quality. Probiotics, in particular Saccharomyces boulardii and Lactobacilli (among which Lactobacillus rhamnosus), synbiotics, psyllium, and some herbal medicinal products, primarily peppermint oil, seem to be effective in ameliorating IBS symptoms. Synbiotics and fibre seem to be beneficial in FC patients. The probiotic combination VSL#3may be effective in inducing remission in patients with mild-to-moderate ulcerative colitis, in whom Escherichia coliNissle 1917 seems to be as effective as mesalamine in maintaining remission. No definite conclusions can be drawn as to the efficacy of fibre and herbal medicinal products in IBD patients due to the low number of studies and the lack of ran- domized controlled trials that replicate the results obtained in the individual studies conducted so far. Thus, further, well-designed studies are needed to address the real role of these therapeutic options in the management of both FBD and IBD.
LINKED ARTICLES This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc
Abbreviations ACG, American College of Gastroenterology; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; CFTR, cystic fibrosis transmembrane conductance regulator; CIC, chronic idiopathic constipation; DC, dendritic cell; DSS, dextran sulphate sodium; ECCO, European Crohn’s and Colitis Organisation; ECN 1917, Escherichia coli Nissle 1917; FBD, functional bowel disorder; FC, functional constipation; FFA, free fatty acid; FOS, fructo-oligosaccharides; GBF, germinated barley foodstuff; GOS, galacto-oligosaccharides; HDAC, histone deacetylase; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; IBS-C, irritable bowel syndrome with predominant constipation; IBS-D, irritable bowel syndrome with predominant diarrhoea; iNOS, inducible NOS; mPGES, microsomal prostaglandin E2 synthase; MPO, myeloperoxidase; NNT, number needed to treat; OR, odds ratio; PHGG, partially hydrogenated guar gum; RCT, randomized controlled trial; RR, relative risk; SCFA, short-chain fatty acid; TNBS, 2,4,6-trinitrobenzenesulfonic acid; UC, ulcerative colitis; WHO,World Health Organization
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DOI:10.1111/bph.13632 © 2016 The British Pharmacological Society
Introduction The two most important functional bowel disorders (FBD), irritable bowel syndrome (IBS) and functional constipation (FC, also known as chronic idiopathic constipation [CIC]), have high worldwide prevalence in adults, between 5.8% and 17.5%, depending on the geographical areas (Sperber et al., 2016), and approximately 14% (Suares and Ford, 2011) respectively. Their diagnosis is based on well-defined clinical criteria, established with the Rome III consensus, that have been very recently revised (Lacy et al., 2016). The main inflammatory bowel diseases (IBD), ulcerative colitis (UC) and Crohn’s disease (CD), have a prevalence in the Western countries much lower than that of IBS and FC (between 0.25% and 0.5%) (Ye et al., 2015) and are diagnosed based on clinical, biochemical, endoscopic and histopathological criteria (Baumgart and Sandborn, 2012; Ordás et al., 2012). However, although they are less common than FBD, they are similarly very important diseases, for their strong impact on patients’ quality of life, as well as the high costs of patient treatments for our healthcare systems.
Different options of pharmacological treatment are available for FBD. FC is usually treated with laxatives, pro- secretory agents and prokinetic drugs. All these therapeutic options are also used to treat IBS patients with predominant constipation (IBS-C). Anti-diarrheal drugs, bile salt sequestrants and antibiotics can be used to treat IBS patients with predominant diarrhoea (IBS-D). In all IBS patients, anti- spasmodic drugs and antidepressants can also be used, primarily to relieve abdominal pain (Lacy et al., 2016). Aminosalicylates, corticosteroids, immunosuppressive drugs and monoclonal antibodies to TNF-α are well established
pharmacological therapies for IBD. However, current treat- ment options suffer from some limitations. Several drugs used to treat IBS patients show low therapeutic gain with respect to placebo and some of them, in particular antispas- modic drugs and antidepressants, have poor profiles of toler- ability (Barboza et al., 2014). Systemic corticosteroids are still a first-line therapeutic option for IBD patients with severe disease or those not responding to aminosalicylates (or budesonide for ileocaecal CD), but they induce important short- and long-term adverse effects. Immunosuppressive drugs, that is thiopurines and methotrexate, and antibodies to TNF-α are currently the most important pharmacother- apies for IBD patients who do not maintain remission with aminosalicylates or those with severe disease not responding to corticosteroids. However, high percentages of patients do not achieve remission or discontinue treatment, at various times due to loss of response or adverse effects (Krishnareddy and Swaminath, 2014). That is why new therapeutic options are continuously sought and consideration has been also given to approaches alternative to traditional medicines.
In this review, we focus on probiotics, fibre and herbal medicinal products that provide other, not negligible, thera- peutic options in the setting of FBD and IBD (Magge and Wolf, 2013; Holtmann and Talley, 2015). We have chosen to deal with such a wide range of disorders and these thera- peutic options for several reasons. First of all, we wanted to compare the alternative therapies used in functional disor- ders with those used in organic diseases of the colon, to high- light differences and similarities. Probiotics and fibre could positively affect both categories of bowel disorders via the gut microbiota. In fact, the acknowledgment of the pathophysiological role of alterations in bowel microbiota
Tables of Links
TARGETS
Other ion channelsa Enzymesd
Ca2+-activated chloride channels
COX-2
CFTR Histone deacetylases (HDACs)
GPCRsb Inducible nitric oxide synthase (iNOS)
5-HT4 receptor Microsomal prostaglandin E synthase (mPGES)
Adenosine A2A receptor Myeloperoxidase (MPO)
Free fatty acid (FFA) receptors
Cathepsin G
M3 receptor Catalytic receptors e
Opioid receptors Toll-like receptor (TLR) family
Voltage-gated ion channelsc
Nuclear hormone receptorsf
Transient receptor potential (TRP) channels
Peroxisome proliferator- activated receptor-γ
LIGANDS
Acetate IL-2 Propionate
Acetylcholine IL-4 Serotonin
Apigenin IL-8 TNF-α
Bradykinin IL-10
Butyrate IL-12
β-Catenin IL-18
Curcumin LTB4 Histamine Menthol
IFN-γ Mesalamine
IL-1β PGE2
These Tables list key protein targets and ligands in this article that are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Southan et al., 2016), and are permanently archived in the Concise Guide to PHARMACOLOGY 2015/16 (a,b,c,d,e,fAlexander et al., 2015a,b,c,d,e,f).
Probiotics and nutraceuticals for IBS, CIC and IBD BJP
British Journal of Pharmacology (2017) 174 1426–1449 1427
in IBS and IBD and the possibilities that probiotics, prebiotics and synbiotics offer to restore a functionally normal gut mi- crobial environment is becoming increasingly important (Cammarota et al., 2015, 2016; Spiller, 2016). On the other hand, some fibres are fermented by colonic bacteria, with the formation of short-chain fatty acids (SCFAs, mainly acetate, butyrate and propionate), which have anti- inflammatory effects (Cammarota et al., 2015; Sivaprakasam et al., 2016) and improve the propulsive colonic function (Soret et al., 2010), mechanisms throughwhich they could in- duce beneficial effects in inflammatory and FBD respectively. In addition, the therapeutic importance of fibre is attested by the advice generally given to IBS and FC patients to adopt life- style changes, including an adequate fluid intake (1.5–2 L per day), the increase in fibre intake with the diet (at least 25 g per day) and physical activity (Lee, 2014; Chey et al., 2015). Con- stipation is a common clinical feature of both FC and IBC-C patients; consequently, fibre, acting as bulk-forming laxa- tives, can be effective in both types of constipated patients. Another reason is that the use of alternative medicines, mainly herbal products, is widespread among patients with IBS and IBD, as they are not completely satisfied with tradi- tional drug therapies and consider them safe, even though pertinent data are generally not conclusive (Ng et al., 2013; Grundmann and Yoon, 2014), and related adverse events have been sometimes observed (De Smet, 2004).
Irritable bowel syndrome
Probiotics, prebiotics and synbiotics Probiotics. In 2001, the Food and Agriculture Organization of the United Nations and the World Health Organization (WHO) defined probiotics as live microorganisms which, if administered in an adequate amount, confer a health benefit to the host. Theoretically, probiotics might be able to exert beneficial influences on several pathogenetic pathways of IBS, including the restoration of altered gut microbiota, by increasing the number of beneficial bacteria (Bifidobacteria and Lactobacilli among others) and reducing the number of pathogens because of competition, and consequently the decrease of inflammation associated with the proliferation of pathogenic bacteria (Scully et al., 2013), changes in the metabolism of biliary salts (Joyce et al., 2014) and the restoration of a normal colonic fermentation (King et al., 1998). In addition, probiotics were shown to decrease visceral hypersensitivity in several mouse models (Ait-Belgnaoui et al., 2006; Kamiya et al., 2006; Verdu et al., 2006; Eutamene et al., 2007). Furthermore, the finding of a low-grade inflammation or immune dis-reactivity in patients with IBS, with both an increase in inflammatory cells in the colonic mucosa and an increase of pro- inflammatory cytokines and Toll-like receptors (TLRs) (Talley and Butterfield, 1996; Scully et al., 2010; Brint et al., 2011), has been the pathophysiological support of the usefulness of probiotics, which are well known for their immunoregulatory effects (Cammarota et al., 2015).
There is a relevant heterogeneity among different trials of probiotics in patients with IBS, in terms of subjects enrolled, design, outcomes and kind and dosage of probiotics used,
which jeopardize the several systematic reviews and meta- analyses published on this topic. In particular, a series of meta-analyses pooled together studies evaluating different probiotic species/strains (Table 1). A meta-analysis by Hoveyda et al. (2009) found 14 randomized controlled trials (RCTs) of probiotics compared with placebo for IBS and showed a little amelioration of overall symptoms. One year later, Moayyedi et al. (2010) released a systematic review of 19 RCTs. Although the trials showed overall satisfactory qual- ity, and the meta-analysis showed a significant benefit of probiotics in ameliorating IBS symptoms, the authors con- cluded that the real therapeutic importance of probiotics and the best probiotic strain/s are yet to be identified due to the heterogeneity of studies. A further meta-analysis, despite being released 4 years later, and including 35 RCTs, was af- fected by the same drawbacks, and reached, therefore, similar conclusions (Ford et al., 2014b). Finally, Didari et al. (2015) pooled together 15 heterogeneous RCTs and they concluded that probiotics were better over placebo in reducing overall symptoms and abdominal pain after 8–10 weeks of therapy.
Nevertheless, pooling together the data on different probiotics has been claimed to be methodologically inappro- priate, in that different strains may exert different actions on the human organism (Szajewska, 2014). The efficacy of spe- cific probiotic strains in patients with IBS has also been eval- uated through focused meta-analyses. One of them investigated the role of Saccharomyces boulardii (S. boulardii) for gastrointestinal diseases in adult patients; the authors found only one RCT, which evaluated patients with IBS, in which the probiotic group experienced, after 4 weeks of treatment, a significant relief in the daily number of bowel movements (McFarland, 2010). Another meta-analysis inves- tigated the role of Lactobacillus rhamnosus (L. rhamnosus) GG in the relief of pain related to functional gastrointestinal dis- orders in children. In particular, among the retrieved studies, authors found three RCTs of patients with IBS, which showed, when pooled together, a significant reduction in the intensity and in the frequency of abdominal pain (Horvath et al., 2011). Recently, a meta-analysis evaluated the effect of Lactobacillus species and strains in IBS. The authors found six RCTs, without heterogeneity among them; probiotic therapy with Lactobacilli achieved a significant relative risk (RR) of clinical improvement of 7.69 overall (Tiequn et al., 2015).
Prebiotics. Prebiotics are defined as non-digestible, fermentable dietary components that exert beneficial effects on the host through the modulation of composition or activity of gut microbiota (Roberfroid et al., 2010; see below the ‘Fibre’ section for more information). So far, only a few studies have investigated the efficacy of prebiotics in patients with IBS, with contrasting results. In a RCT with placebo, short-chain fructo-oligosaccharides (FOS) were shown to significantly improve digestive comfort and daily activities of patients with FBD according to Rome II criteria (Paineau et al., 2008). In another RCT of patients with Rome II IBS, a trans-galacto-oligosaccharide prebiotic was significantly better than placebo in increasing the number of faecal Bifidobacteria and improving several symptoms, including stool consistency, flatulence, bloating, subjective global assessment and anxiety (Silk et al., 2009).
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Table 1 Probiotics, prebiotics, synbiotics, fibre and herbal medicinal products in irritable bowel syndrome
Reference Study type Disease Intervention Number of patients Results
Probiotics, prebiotics and synbiotics
Hoveyda et al., 2009
Meta-analysis (14 RCTs)
IBS (no restriction for subtypes)
Probiotics 1225 Probiotics may have a role in alleviating some symptoms of IBS. OR was 1.6 for dichotomous data from seven trials; SMD was 0.23 for continuous data from six trials.
Moayyedi et al., 2010
Meta-analysis (19 RCTs)
IBS (no restriction for subtypes)
Probiotics 1650 Probiotics were significantly better than placebo (RR of IBS not improving =0.71) with NNT = 4.
Ford et al., 2014b
Meta-analysis (probiotics, 35 RCTs; synbiotics, two RCTs)
IBS (no restriction for subtypes)
Probiotics and synbiotics
3452 (probiotics) and 198 (synbiotics)
The significant RR of IBS symptoms persisting with probiotics versus placebo was 0.79. There were no significant effects of synbiotic in reducing symptoms.
Didari et al., 2015
Meta-analysis (24 RCTs)
IBS (no restriction for subtypes)
Probiotics 1793 Probiotics improved abdominal pain (two trials, RR 1.96), global symptom score (two trials, RR 2.43), general symptoms (seven trials, RR 2.14), and an IBS severity score evaluating distension, bloating and flatulence (three trials, SMD 2.57).
Horvath et al., 2011
Meta-analysis (three RCTs)
Children with abdominal pain- related functional gastrointestinal disorders
L. rhamnosus GG 290 L. rhamnosus GG supplementation was associated with a significantly higher rate of treatment responders (RR 1.31, NNT 7)
Tiequn et al., 2015
Meta-analysis (six RCTs)
IBS (no restriction for subtypes)
Lactobacillus spp. 440 (273 adults and 167 children)
Lactobacilli induced therapeutic benefit with a significant RR of 7.69 (adults, 17.62; children, 3.71).
Fibre
Ford et al., 2008
Meta-analysis (12 RCTs)
IBS (no restriction for subtypes)
Fibre (bran or psyllium)
591 Fibre induced no clinical improvement with respect to placebo or a low fibre diet (RR 0.87). Bran had no significant effect (RR of persistent symptoms 1.02). Psyllium was significantly effective (RR of persistent or unimproved symptoms 0.78).
Ruepert et al., 2011
Meta-analysis (12 RCTs)
IBS (no restriction for subtypes)
Fibre 621 No beneficial effect of fibre over placebo for improvement of abdominal pain (SMD 0.03), global assessment of symptoms (RR 1.10), or symptom score (SMD �0.00). Subgroup analyses for insoluble and soluble fibres also showed no significant benefit.
Moayyedi et al., 2014
Meta-analysis (14 RCTs)
IBS (no restriction for subtypes)
Fibre (soluble and insoluble)
921 Significant clinical benefit of fibre (RR = 0.86), that was confirmed in RCTs on soluble fibre (RR = 0.83,
(Continues)
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British Journal of Pharmacology (2017) 174 1426–1449 1429
Nevertheless, in two RCTs, neither oligofructose nor FOS induced any therapeutic benefit in ameliorating IBS symptoms, which were even worsened at the beginning of the treatment with FOS (Hunter et al., 1999; Olesen and Gudmand-Hoyer, 2000). Additionally, a diet rich in fermentable carbohydrates increased breath hydrogen and worsened gastrointestinal symptoms in patients with IBS (Ong et al., 2010). According to these results, prebiotic treatment may be considered a double-edged sword for patients with IBS, as high dosages of prebiotics can exacerbate symptoms rather than improve them, through their fermentation by microbiota and the consequent increase in the quantity of gas in the large bowel (Whelan, 2011). This evidence laid the groundwork for the development of a diet poor in fermentable oligo-, di-, monosaccharides and polyols (FODMAP), which was shown in several studies to achieve a higher control of symptoms with respect to standard dietary advice in patients with IBS (Rao et al., 2015; Thomas and Quigley, 2015). However, an
RCT of patients with IBS showed no therapeutic benefit of low-FODMAP diet over traditional dietary advice (Bohn et al., 2015). Furthermore, a low-FODMAP diet decreased microbial abundance, particularly the number of Bifidobacteria, and diversity (Staudacher et al., 2012; Halmos et al., 2015), which are considered indices of the well-being of the gut microbiota. The low FODMAP diet has been considered effective in relieving symptoms in selected patients with IBS in the systematic review by Rao et al. (2015). Nevertheless, authors advocated the need for further, thorough studies, to assess the long-term efficacy and safety of low FODMAP diet, especially on gut microbiota homeostasis (Rao et al., 2015).
Synbiotics. Synbiotics are dietary supplements which combine prebiotics and probiotics, to increase the levels and activity of beneficial microbes in the gut. Only few RCTs investigated the efficacy of synbiotics in patients with IBS, to date. Bacillus coagulans combined with FOS led to a
Table 1 (Continued)
Reference Study type Disease Intervention Number of patients Results
NNT = 7), but not in those on bran (RR = 0.90)
Everitt et al., 2013
RCT IBS (no restriction for subtypes)
Mebeverine versus methylcellulose versus placebo or self-management website for 6 weeks
135 No significant difference in IBS symptom severity scale or IBS-QOL scores between medication or website groups at 12 weeks, or in medication groups at 6 weeks, or IBS-QOL in website groups at 6 weeks
Toskes et al., 1993
Crossover study IBS (no restriction for subtypes)
Polycarbophil 6 g per day versus placebo for 6 months
23 15 patients chose polycarbophil over placebo for relief of the symptoms (71%)
Herbal medicinal products
Liu et al., 2006 Systematic review (75 trials)
IBS (no restriction for subtypes)
Herbal medicines were compared with placebo or conventional pharmacological therapy
7957 Improvement of symptoms with 6 and 22 herbal medicines compared with placebo or conventional therapy respectively; 29 herbal medicines were not significantly different from conventional therapy.
Madisch et al., 2004
RCT IBS (no restriction for subtypes)
STW 5 (iberogast), STW 5-II, bitter candytuft mono- extract or placebo for 4 weeks
208 STW 5 and STW 5-II were significantly better than placebo in reducing the total abdominal pain score and IBS symptom score.
Ford et al., 2008
Meta-analysis (four RCTs)
IBS (no restriction for subtypes)
Peppermint oil 392 26% of patients randomized to peppermint oil had persistent symptoms compared with 65% of those receiving placebo (RR 0.43)
Khanna et al., 2014
Meta-analysis (nine studies)
IBS (no restriction for subtypes)
Peppermint oil 726 Improvement of global symptoms (RR 2.23) and abdominal pain (RR 2.14) with peppermint oil with respect to placebo
IBS-QOL, IBS quality of life; SMD, standardized mean differences
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significantly higher improvement of abdominal pain and diarrhoea over placebo both in adult (Rogha et al., 2014) and paediatric (Saneian et al., 2015) patients with IBS. A synbiotic preparation, containing Lactobacillus acidophilus, Lactobacillus helveticus and Bifidobacteria in a medium enriched with phytoextracts, led to a significant amelioration of pain and bloating, in comparison with the heat-inactivated synbiotic, in patients with Rome II IBS (Tsuchiya et al., 2004). Finally, a combination of cellulose, l-leucine and 29 probiotic species was more effective than placebo in improving some symptoms in a small trial of IBS patients (Bittner et al., 2005). According to a recent meta- analysis, synbiotics appear to be significantly effective in improving IBS symptoms, but data are too few to draw any definitive conclusion (Ford et al., 2014a, b).
Fibre Generalities. The commonmeaning of the term ‘fibre’ is that of carbohydrates that are not digested or absorbed in the small intestine and thus reach the large intestine unchanged (Eswaran et al., 2013). In an effort to standardize the various definitions of fibre which had been given by different national authorities, the Codex Alimentarius Commission has defined in 2010 dietary fibre as ‘carbohydrate polymers with ten or more monomeric units, which are not hydrolysed by the endogenous enzymes in the small intestine of humans’ (Jones, 2014). The definition has a footnote that leaves up to national authorities the decision on whether to include carbohydrates of 3 to 9 monomeric units. Since then, several national authorities have adopted the entire Codex definition, including short- chain carbohydrates. The Codex Commission categorizes dietary fibre as carbohydrate polymers that are: (i) edible, naturally occurring in the food as consumed; (ii) obtained from food raw material by physical, enzymatic or chemical means; or (iii) synthetic. The last two categories must have been shown to have physiological effects of benefit to health. Dietary fibre includes long-chain carbohydrates, such as cellulose, hemicelluloses, β-glucans, fructans, among which inulins, pectins, dextrins, gums and resistant starch, and short-chain carbohydrates, such as FOS and galacto-oligosaccharides (GOS). Fibres are usually classified on the basis of some characteristics, such as solubility, viscosity and fermentability by colonic microbiota. The latter feature leads to the production of SCFAs and gases (fermentable fibre). SCFAs are the preferred energy source for colonic mucosa cells, have anti-inflammatory and immunoregulatory activities (Cammarota et al., 2015) and induce beneficial effects on myenteric neurons and colonic motility, improving peristalsis (Soret et al., 2010). Viscous fibre can form a gel (‘mucilage’) in the intestinal tract. More or less widely commercially available dietary fibre are FOS, GOS, inulin, wheat dextrin, partially hydrogenated guar gum (PHGG) and resistant starch (soluble, highly fermentable fibre); oat bran (soluble, intermediate fermentable fibre); and wheat bran (insoluble, very little fermentable fibre) (Eswaran et al., 2013). As discussed previously and subsequently in the sections on ‘Prebiotics’, various highly fermentable fibres, including FOS, GOS and inulin, have been studied as components of the category of prebiotics, in that they are an energy source for some gut
bacteria and positively affect the composition and function of gut microbiota (Cammarota et al., 2015). As already mentioned, it is thought that many beneficial effects of these prebiotic fibres are attributable to the SCFAs. acetate, propionate and butyrate, formed by their fermentation (Cammarota et al., 2015). SCFAs have been shown to strengthen the intestinal barrier function (Corrêa-Oliveira et al., 2016) and reduce neutrophil recruitment and inflammation in experimental models of colitis (Sivaprakasam et al., 2016). SCFAs induce their effects by interacting with several molecular targets, among which important are the histone deacetylases (HDACs) and the metabotropic receptors free fatty acid 2 and 3 (FFA2 and 3; Bolognini et al., 2016; Sivaprakasam et al., 2016). Butyrate and propionate are inhibitors of the isoforms 1 and 3 of HDACs; this activity leads to the increase in histone acetylation, changes in the interaction between histones and DNA and modulation of the transcription of specific genes that affect cell processes such as apoptosis and cell cycle (Sivaprakasam et al., 2016). In the gut, FFA2 and 3 receptors are expressed in enteroendocrine, immune and epithelial cells, and in enteroendocrine cells and enteric neurons, respectively (Sivaprakasam et al., 2016). They are considered to be a link between dietary fibre and intestinal homeostasis through the gut microbiota (Sivaprakasam et al., 2016). In particular, the activation of FFA2 receptors on dendritic cells (DCs) leads on one hand to the differentiation of naïve lymphocytes T into regulatory lymphocytes T and on the other hand, to the inhibition of the differentiation of naïve lymphocytes T into T helper 17 cells; in addition, the stimulation of FFA2 receptors expressed in dendritic and epithelial cells induces the production of the cytokines IL-10 and IL-18, respectively (Corrêa-Oliveira et al., 2016; Sivaprakasam et al., 2016). All these are well-known anti-inflammatory effects.
Fibres used for medical purposes, mainly for their laxative effects, can be separated into two broad classes, natural and synthetic (Gonzalez-Martinez et al., 2014). The most com- monly used natural fibres are psyllium and gum Karaya (sterculia; Eswaran et al., 2013). Other less widely used natu- ral fibres are kelp (Kim and Bhatnagar, 2011), agar gum (Kim and Bhatnagar, 2011), and tragacanth (Fu et al., 2014). The most popular synthetic fibres are methylcellulose and cal- cium polycarbophil.
Natural fibre. The terms ‘psyllium’ or ‘ispaghula’ usually refer to the seed husk of the plant genus Plantago, mainly Plantago ovata. The husk is the mucilaginous portion of the seed coat; it contains soluble, viscous and intermediate fermentable fibre that is mainly able to retain water, swell and form a gelatinous mass which softens and increases the volume of stool, helping to stimulate the peristaltic movements (Eswaran et al., 2013; Slavin, 2013). It is believed that additional actions contribute to the therapeutic effects of psyllium: the induction of beneficial microbiota changes, the increase in microbiota growth and faecal biomass and the production of SCFAs through fermentation. Wheat bran is the hard outer layers of wheat grain. It is composed for approximately 45–50% of fibre, mainly cellulose and hemicelluloses that is insoluble and minimally fermentable (Eswaran et al., 2013; Slavin, 2013).
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Differently from psyllium, bran has a low water holding capacity; it is thought that its laxative effects are primarily due to the increase in faecal mass and mechanical stimulation of the intestinal mucosa (Tomlin and Read, 1988).
Several RCTs investigated the effects of psyllium and wheat bran in patients with IBS; two meta-analyses, pub- lished by Ford et al. in 2008 and Ruepert et al. in 2011, selected the same number of eligible studies (12, 11 of which were the same studies), but came to different results. In fact, soluble fibre (psyllium) was found to be significantly more effective than placebo or no treatment in the first meta-analysis (Ford et al., 2008), whereas no statistically significant benefits were found for either soluble or insoluble fibre (wheat bran) in the second meta-analysis (Ruepert et al., 2011) (Table 1). In the discussion of the latter meta-analysis, the authors attributed the attainment of different conclusions to the choice of analysing different outcomes: they analysed separately improvement of abdominal pain, global assessment of symp- toms and IBS symptom score, whereas Ford et al. (2008) pooled together these different outcomes; in addition, Ford et al. (2008) did not use an intention to treat analysis. An update of the meta-analysis of Ford et al. (2008) was pub- lished by Moayyedi et al. (2014); the authors added two RCTs to their previous meta-analysis and confirmed the superiority of psyllium over placebo for improving IBS symptoms or ab- dominal pain (Table 1).
Synthetic fibre. Methylcellulose is a derivative of cellulose in which some of the hydroxyl groups are substituted with methoxide groups and it should be considered more properly a semisynthetic fibre. It is soluble, viscous and non-fermentable fibre. Calcium polycarbophil is the Ca2+
salt of a highly branched, very hydrophilic fibre, formed by polyacrylic acid crosslinked with divinyl glycol. Once in the stomach, Ca2+ ions are replaced by H+ ions, giving rise to polycarbophilic acid, which is able to bind water molecules, markedly increasing its volume.
The therapeutic effects of methylcellulose were compared in an exploratory double-blind RCTwith those of mebeverine and placebo. Patients with IBS fulfilling Rome III criteria were treated for 6 weeks and evaluated at 6 and 12 weeks; primary outcomes were the change in the IBS Symptom Severity Scale and Quality of Life questionnaire scores from baseline to 12 weeks. There were no significant differences among the three groups at 12 weeks, but the number of recruited patients was low (11, 14 and 15 for mebeverine, methylcellu- lose and placebo arms respectively) (Everitt et al., 2013). The effects of calcium polycarbophil, compared with those of pla- cebo, were investigated in a double-blind, crossover RCT in 23 patients with IBS-C or IBS withmixed bowel habits. In this trial, calcium polycarbophil was rated better than placebo in monthly global response to therapy and for the relief of vari- ous symptoms, including pain (Toskes et al., 1993).
Herbal medicinal products A Cochrane Library systematic review published by Liu et al. in 2006 found 75 RCTs comparing 71 different herbal medi- cines, including single herbal extracts or combination of plant extracts, to placebo or conventional pharmacological treatments in IBS patients. However, the methodological
quality of 72 of these trials was assessed to be poor. A few herbal products showed efficacies significantly higher than placebo in improving global symptoms, including iberogast, Padma Lax (a Tibetan herbal medicine), the traditional Chinese preparation Tongxie Yaofang, a standard Chinese herbal formula, an individualized Chinese herbal medicine, and an Ayurvedic preparation (Liu et al., 2006). In addition, 72 herbal products, most of which were traditional Chinese medicine formulas, significantly improved symptoms of IBS when compared with standard drug treatments (Table 1). Very recently, berberine, a benzylisoquinoline alkaloid iso- lated from several plants, in particular from Coptis chinensis, a plant used for a very long time in China for medical pur- poses, has shown therapeutic efficacy in patients affected by IBS-D in a RCT with placebo (Chen et al., 2015b). On the basis of the findings of a study in a murine model of IBS-D, it has been proposed that berberine induces its beneficial effects through stimulation of μ and δ opioid receptors (Chen et al., 2015a). The herbal products most known in the Western countries for their beneficial effects in IBS patients are undoubtedly iberogast and peppermint oil. Strangely, the latter was not taken into account in the Cochrane systematic review on herbal medicines, but was included among the antispasmodic agents in another Cochrane systematic review evaluating the efficacies of bulking agents, antispasmodics and antidepressants for the treatment of IBS (Ruepert et al., 2011). We will focus our discussion on these two herbal medicinal products; the readers can refer to recent reviews for a general overview on this topic (Rahimi and Abdollahi, 2012) or the detailed discussion of traditional Chinese herbal medicines (Li et al., 2013; Xiao et al., 2015).
Iberogast. Iberogast, also termed STW 5, is a proprietary combination, in a liquid formulation, of hydroethanolic extracts of nine plants: bitter candytuft (Iberis amara L.) planta totalis, caraway (Carum carvi L.) fructus, chamomile (Matricaria recutita L.) flos, peppermint (Mentha piperita L.) folium, lemon balm (Melissa officinalis) folium, liquorice (Glycyrrhiza glabra L.) radix, angelica (Angelica archangelica L.) radix, greater celandine (Chelidonium majus L.) herba and milk thistle (Silybum marianum L.) fructus; a preparation without last three components (STW 5-II) is also available. Iberogast owes its name to its main constituent, the extract of Iberis amara L. STW 5 and STW 5-II were compared with placebo for their efficacy and safety in IBS patients in a double-blind, multicentre RCT. Both significantly decreased the IBS symptom score and the total abdominal pain score in an intention-to-treat analysis after 4 weeks of treatment (Madisch et al., 2004). Iberogast is well tolerated and the incidence of adverse effects, usually mild, has been estimated to be 0.04% and hypersensitivity reactions occur very rarely (Ottillinger et al., 2013).
Many mechanisms of action have been reported that could underlie the therapeutic efficacy of iberogast (Cremonini, 2014). STW 5 reduces the afferent nerve discharge activated by mechanical (pressure increases) or pharmacological (serotonin and bradykinin) stimulation from the rat small intestine in vivo (Liu et al., 2004), whereas STW 5-II decreases the afferent sensitivity to bradykinin only (Mueller et al., 2009). In addition, iberogast depolarizes the resting membrane potential of circular smooth muscle cells
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in the small and large intestine, decreases amplitude and fre- quency of small intestinal slow waves and reduces fast and slow inhibitory junction potentials in the colon of the mouse (Storr et al., 2004; Sibaev et al., 2006). In the guinea pig ileum, it induces small longitudinal smooth muscle contractions and, on the other hand, importantly antagonizes the contrac- tions produced by histamine or acetylcholine in a concentration-dependent manner (Ammon et al., 2006; Heinle et al., 2006). Iberogast also affects intestinal secretory function, as it dose-dependently increases Cl� ion secretion from the mucosa of human small and large intestine by acti- vating submucosal neurons and through mechanisms involving cystic fibrosis transmembrane conductance regula- tor and Ca2+-activated chloride channels (Krueger et al., 2009). It was later shown that iberogast-induced pro- secretory effects are mainly attributable to the angelica extract, with minor contributions from peppermint and lemon balm extracts (Allam et al., 2015). As regards the molecular drug targets that may underlie these actions, it has been shown that phytochemicals contained in iberogast bind with good affinity to acetylcholine M3, 5-HT4, opioid and adenosine A2A receptors (Simmen et al., 2006; Michael et al., 2012). Iberogast contains over 350 substances, mainly belonging to the following five groups: coumarins, flavo- noids, phenol carboxylic acids, terpenes and volatile oils (Wegener and Wagner, 2006). Sixty-two of these compounds have been shown to induce effects on gut contractility, mainly inhibitory (spasmolytic) (Wegener and Wagner, 2006). These compounds are the most probable active sub- stances responsible for the predominant spasmolytic actions of iberogast, which are likely to contribute to its beneficial effects in IBS patients. As far as we know, no single compo- nent of iberogast has been evaluated for possible effects on intestinal afferent nerve firing or secretion.
Peppermint oil. The oil extracted from peppermint, an herb also contained in iberogast, is well known for its therapeutic efficacy in IBS patients. The first study investigating the effects of peppermint oil in IBS was a double-blind crossover RCT published by Rees et al. in 1979. Sixteen patients were treated with peppermint oil 0.2–0.4 mL tid or placebo for 3 weeks. The overall symptom score was significantly lower in patients taking peppermint oil than in those treated with placebo. A multicentre trial followed this first study 5 years later (Dew et al., 1984), and then several other studies were published that confirmed the therapeutic efficacy of peppermint oil in both adult and paediatric IBS patients (Liu et al., 1997; Kline et al., 2001; Vejdani et al., 2006; Cappello et al., 2007; Merat et al., 2010). In three recent meta-analyses, peppermint oil was found to be significantly more effective than placebo in improving global assessment of symptoms or IBS symptom score (Ruepert et al., 2011), these two outcomes pooled together (Ford et al., 2008; Khanna et al., 2014) or abdominal pain (Khanna et al., 2014) (Table 1). Overall, peppermint oil is a safe herbal preparation and no serious adverse effects were noted in RCTs (Ford et al., 2008). The most frequently reported adverse effect is heartburn, very probably due to lower esophageal sphincter relaxation (Khanna et al., 2014).
The main component of peppermint oil is menthol, a chemical compound belonging to the class of
monoterpenes, which has long been known for its relaxant effects on gut smooth muscle (Hawthorn et al., 1988). This substance binds to TRP ion channels and in particular, it activates the TRPM8 channels and blocks the TRPA1 channels. The latter play important roles in intestinal mechanosensation and pathophysiological mechanisms of visceral hypersensitivity (Brierley et al., 2009; Brierley et al., 2011). The activation of TRPM8 channels by menthol is responsible for the occurrence of the typical sensation of freshness when peppermint oil is inhaled or applied to the skin or oral mucosa. TRPM8 channels have been localized on colonic afferent neurons, where their activation inhibit chemo- and mechanosensory signalling due to TRPV1 and TRPA1 channel activation (Harrington et al., 2011). Overall, these inhibitory actions of menthol on visceral chemo- and mechanosensation could contribute to its therapeutic efficacy in the setting of IBS.
Functional constipation Therapeutic approaches other than those most frequently used, have been attempted to alleviate the symptoms of this condition, including probiotics, prebiotics, synbiotics, fibre and botanical medicines (Suares and Ford, 2011; Ford et al., 2014a,b; Cirillo and Capasso, 2015; Rao et al., 2015). Their role has been addressed by several RCTs, which have been pooled together through many systematic reviews and meta-analyses. Overall, these meta-analyses are biased by many drawbacks, such as either the paucity of included studies, or their poor quality and heterogeneity, according to several of them.
Probiotics, prebiotics and synbiotics In a recent meta-analysis, Ford et al. (2014b) showed that probiotics are beneficial in FC, with a mean increase in weekly number of stools of 1.49; nevertheless, these findings came out from only two RCTs. Data on prebiotics, instead, were few, impeding any conclusions, whereas synbiotics overall exerted a beneficial effect, with a 22% decrease of the RR of failure to respond to treatments. Authors con- cluded that the efficacy of all three treatments in patients with FC is still uncertain (Ford et al., 2014b) (Table 2). In another meta-analysis of 14 RCTs, probiotics significantly improved whole intestinal transit time, stool frequency and consistency. Nevertheless, at subgroup analysis, only Bifidobacterium lactis was confirmed to be significantly effec- tive. Moreover, authors found high heterogeneity among studies, as well as high risk of attrition and reporting bias; therefore, such results should be considered with prudence (Dimidi et al., 2014) (Table 2). Based on this evidence, the American College of Gastroenterology (ACG) recently stated that there is insufficient evidence to recommend probiotics for FC, as considered trials were few, heterogeneous, and with a risk of bias ranging from unclear to high. Neverthe- less, some synbiotics may improve stool frequency in those patients (Ford et al., 2014a).
Fibre The increase in dietary fibre or the use of supplementary fibre is generally recommended to patients affected by FC.
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Table 2 Probiotics, prebiotics, synbiotics, fibre and herbal medicinal products in FC
Reference Study type Intervention Number of patients Aim Results
Probiotics, prebiotics and synbiotics
Ford et al., 2014b
Meta-analysis (probiotics, three RCTs; prebiotics, one RCT; and synbiotics, two RCTs)
Prebiotics, probiotics, and synbiotics
245 (probiotics), 198 (synbiotics), 60 (prebiotics)
To evaluate the global clinical response
Two trials on probiotics reported about dichotomous outcomes; both trials demonstrated a clinical benefit, but pooled data were not statistically significant (RR of failure to respond to therapy 0.29). Two trials on probiotics reported a significant increase in the mean number of bowel movements per week (1.49). Synbiotics appeared beneficial on FC symptoms (significant RR of failure to respond to therapy =0.78; NNT =5). The trial on prebiotic (inulin and PHGG) reported no difference in satisfaction in relief of constipation in prebiotic group versus placebo (32% vs 31%); also the mean number of bowel movements per week was not significantly different.
Dimidi et al., 2014
Meta-analysis (14 RCTs)
Probiotics 1182 To investigate the effect of probiotics on gut transit time, stool output, and constipation symptoms
Probiotics significantly reduced the whole gut transit time by 12.4 h and increased stool frequency by 1.3 bowel movements per week; the latter was significant for B. lactis (WMD: 1.5 bowel movementsper week), but not for L. casei Shirota (WMD: �0.2 bowel movements per week). Probiotics improved stool consistency (SMD: +0.55), and this was significant for B. lactis (SMD: +0.46), but not for L. casei Shirota (SMD: +0.26)
Fibre
Ford et al., 2014a
Meta-analysis (six RCTs)
Soluble fibre 293 To investigate the mean increase in stool frequency
Formal meta-analysis was conducted with 3 RCTs, which concluded that soluble fibre has therapeutic superiority over placebo with NNT of 2
Christodoulides et al., 2016
Meta-analysis (seven RCTs)
Fibre (including prebiotic)
287 To investigate the effects on global symptom response and stool output
Patients assigned to fibre responded to therapy (RR of success to respond 1.71). Fibre significantly increased stool frequency (SMD = 0.39), and softened stool consistency (SMD = 0.35). Flatulence was significantly higher with fibre (SMD = 0.56)
Herbal medicinal products
Cheng et al., 2011
RCT Hemp seed pill versus placebo for 8 weeks
120 To assess the efficacy and safety of Hemp seed pill
Response rates for the Hemp seed pill and placebo groups were significantly different (43.3% and 8.3% respectively)
Jia et al., 2010
RCT Yun-chang capsule versus placebo tid for 2 weeks
140 To assess the changes in main symptom score and cumulative symptom score
Beneficial effects, assessed as significant reductions in main and cumulative symptom scores, with Yun-chang
B. lactis, Bifidobacterium lactis; L. casei Shirota, Lactobacillus casei Shirota; SMD, standardized mean differences; WMD, weighted mean differences
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A recent monograph of the ACG on the treatment of IBS and CIC ranks this recommendation as ‘strong’, even though it classifies the quality of evidence as ‘low’ (Ford et al., 2014a). The authors of this monograph found six parallel- group RCTs comparing the effects of fibre to those of pla- cebo or no therapy in adult patients with FC diagnosed by any of the Rome criteria or clinical evaluation. They con- ducted a formal meta-analysis with three of these studies, all of which investigated the effects of soluble fibre (two of them used psyllium, the third a combination of inulin and a resistant maltodextrin), which concluded that soluble fibre has therapeutic superiority over placebo with the number needed to treat (NNT) of 2 (Table 2). A more recent meta- analysis found seven RCTs with parallel-group or crossover design, in which the effects of fibre were compared with those of placebo or control interventions in adult patients with FC diagnosed by clinical or Rome criteria, or self-report. A formal meta-analysis included the four studies that reported dichotomous data on the response to therapy eval- uated as symptomatic improvement; the authors underlined the considerable variability of the studies as for fibre type (psyllium, wheat bran, inulin plus PHGG and inulin plus resistant maltodextrin respectively) and dose used, and duration of treatment (2 to 4 weeks) (Christodoulides et al., 2016). Also, in this meta-analysis, it has been found that fibre determines symptomatic improvement in a proportion of patients significantly higher than that of placebo (77 vs 44% respectively; RR = 1.71, NNT = 3) (Table 2). However, it was recognized once again that the overall quality of the studies is low. A possible weakness of these two meta- analyses is that they have grouped together studies with soluble bulk-forming fibre (psyllium) and studies with highly fermentable fibre (inulin plus resistant maltodextrin or PHGG, all of which are considered prebiotics) and/or insoluble fibre (wheat bran). Subgroup analyses performed in the second meta-analysis indicate that there is evidence for therapeutic efficacy for psyllium but not for prebiotics (Christodoulides et al., 2016).
Herbal medicinal products Stimulant laxatives of plant origin have been commonly used for a long time for the treatment of constipation. The most popular of them are senna, cascara, frangula, aloe and rhu- barb, obtained from the dried leaves and pods of some Cassia species, the dried barks of Rhamnus purshiana or Rhamnus frangula, the latex contained in the leaves of some Aloe species and the dried rhizome of some Rheum species respec- tively (Cirillo and Capasso, 2015). Senna and cascara are the most used; they contain some anthraquinone drugs, known as sennosides and cascarosides, which are glycoside deriva- tives of hydroxyanthracene. These glycosides arrive intact to the colon, where the glycosidases produced by the micro- biota break the glycoside bond and release the active substances, mainly rhein and rhein-anthrone. The latter stimulate the colonic peristalsis through activation of the secretory and motor functions, mediated by the increase in the synthesis and release of PGs and other autacoids (Cirillo and Capasso, 2015). Despite being widely used and effective laxatives, no RCT has been, however, carried out with them in patients affected by FC.
Two herbal medicinal products, the proprietary medicines Hemp seed pill and Yun-chang, both Chinese, have been investigated and found to be effective in RCTs of patients with FC. Significantly more patients treated for 8 weeks with the Hemp seed pill, a mixture of six herbs (Cannabis fructus [hemp seed], Rheum rhizoma, Paeonia alba radix, Prunus armeniaca semen, Citrus aurantium fructus immaturus and Magnolia officinalis cortex) attained the primary outcome (a mean increase of complete sponta- neous bowel movement ≥1 per week compared with their baselines) than those treated with placebo (43.3 vs 8.3%) (Cheng et al., 2011). A statistically significant difference in rates of the primary outcome was also observed during the 8-week follow-up period. In addition, the hemp seed pill improved the global assessment of symptoms and the sensation of straining, with respect to baseline levels, significantly more than placebo. Yun-chang, a herbal mix- ture containing seven herbs, only five of which were disclosed (Aloe, Panax ginseng, Polygoni multiflori radix, Citrus aurantium fructus immaturus and Asini corii colla) showed beneficial effects, assessed as significant reductions in main and cumulative symptom scores, in a 2-week RCT (Jia et al., 2010).
Inflammatory bowel disease
Probiotics, prebiotics and synbiotics One of the pathogenetic pathways of IBD is represented by an imbalanced immune response to microbes, together with an impairment of gut microbiota, in individuals with genetic susceptibility (Ewaschuk and Dieleman, 2006). Probiotics, prebiotics and synbiotics may restore the intestinal microbial balance, thus enhancing gut barrier function and improving local immune response (Cammarota et al., 2015; Wasilewski et al., 2015).
Probiotics. In recent years, several studies have investigated the effects of probiotics in IBD, suggesting that certain microbial strains could be useful in the management of the disease. The therapeutic effects of probiotics have been related to several cytoprotective mechanisms, different for each probiotic strain. Oral administration of VSL#3, a probiotic combination composed of three Bifidobacterium species, four Lactobacillus species and Streptococcus thermophilus, was shown to modulate intestinal DCs, that mediate the recognition of microbes and induce the response of T lymphocytes. Oral VSL#3 decreased TLR-2 expression, increased IL-10 production, and down-regulated IL-12p40 levels in DC of UC patients (Ng et al., 2010). Moreover, Petrof et al. (2004) showed that VSL#3 produces soluble factors that decrease the chymotrypsin-like activity of proteasome in enterocytes, inhibits NF-κB, and stimulates the enterocyte production of cytoprotective heat shock proteins, pointing out the anti-inflammatory and cytoprotective pathways as novel mechanisms of microbial- epithelial interaction. Lactobacilli are known to act mainly on the cascade of pro-inflammatory cytokines. When administered to IL-10 knockout mice, L. reuteri and L. casei attenuated the severity of Helicobacter hepaticus-induced
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colitis, decreasing colonic levels of TNF-α and IL-12 (Pena et al., 2005). Moreover, Braat et al. (2004) demonstrated that a different Lactobacillus species, L. rhamnosus, influenced DC maturation, leading to a decrease in T lymphocyte proliferation and cytokine release (mainly IL-2, IL-4 and IL-10). In addition, they reported that peripheral CD4+ T cells obtained from healthy volunteers after a 2 wk oral supplementation with L. rhamnosus produced less IL-4 than lymphocytes isolated before the treatment, whereas peripheral CD4+ T cells isolated from CD patients after the same treatment produced less IFN-γ and IL-2. These findings indicate that probiotics induce their beneficial effects through anti-inflammatory mechanisms, by direct or indirect, via antigen presenting cells, actions on both Th1 and Th2 lymphocytes, and suggest that peripheral T-cell hypo-responsiveness might be an important mechanism of the beneficial effects of probiotic treatment in vivo. Probiotics may also induce their beneficial effects by counteracting the activity of pathogenic bacteria, through the inhibition of their growth and proliferation, via the reduction of bowel luminal pH and the synthesis of defensins, and mechanisms that inhibit their adherence to and translocation across the epithelium (Wasilewski et al., 2015; Durchschein et al., 2016). In addition, probiotics have been shown to strengthen the gut barrier function by modulating the secretion of mucus and chloride and the expression of the proteins that make the tight junctions, and reducing apoptosis of the epithelial cells (Wasilewski et al., 2015; Durchschein et al., 2016).
When translated into clinical practice, those interesting results were not always confirmed, although a large body of evidence is available both for single probiotic strains and for probiotic combinations. Among single strains, E. coli Nissle 1917 (ECN 1917), a nonpathogenic E. coli, is the most exten- sively investigated. In three RCTs, oral ECN 1917 showed ef- ficacy and safety comparable to those of mesalamine in maintaining remission in patients with quiescent UC (Kruis et al., 1997; Rembacken et al., 1999; Kruis et al., 2004). Addi- tionally, rectal administration of ECN 1917 was more effec- tive than placebo in inducing remission of patients with distal mild-to-moderate active UC (Matthes et al., 2010). L. rhamnosus GG showed a significantly longer relapse-free time with respect to mesalamine in patients with quiescent UC (Zocco et al., 2006). Moreover, an 8-week-rectal administra- tion of L. reuteri ATCC 5573 obtained significantly higher rates of clinical remission than placebo in children with active UC (Oliva et al., 2012). Among probiotic combina- tions, VSL#3 provides the most relevant evidence. In several RCTs, it was effective in the induction of remission in patients with mild-to-moderate UC, together with conven- tional treatment (Tursi et al., 2004, 2010), or alone (Sood et al., 2009). In a recent meta-analysis of RCTs of patients with active UC, VSL#3 probiotics, given as adjuvant therapy to mesalamine or immunomodulators, was significantly more effective than conventional therapy alone in inducing both remission [odds ratio (OR) = 2.4] and response (OR = 3.03; NNT: 3–4) (Mardini and Grigorian, 2014) (Table 2). Other probiotic combinations, based mainly on Bifidobacteria and Lactobacilli, did not replicate the reliable results of VSL#3 (Ishikawa et al., 2003; Kato et al., 2004; Wildt et al., 2011).
Many systematic reviews and meta-analyses evaluated the effect of probiotics in patients with UC, with discor- dant results. In a systematic review from a Cochrane group, probiotics were not more effective than placebo or active comparators in inducing remission of patients with active UC (Mallon et al., 2007). Further reports confirmed such findings (Zigra et al., 2007; Sang et al., 2010; Jonkers et al., 2012). Nonetheless, in a recent meta-analysis of RCTs, probiotics showed a significant advantage over pla- cebo in inducing remission in patients with active UC (RR 1.80) (Shen et al., 2014), although this finding was confirmed only for VSL#3 at subgroup analysis (RR 1.74) (Table 3). In another systematic review from the Cochrane Library, probiotics were not effective in maintaining remis- sion in patients with quiescent UC (Naidoo et al., 2011). On the contrary, probiotics were shown to be able to pre- vent pouchitis in a meta-analysis of RCTs (Elahi et al., 2008). As for IBS, the heterogeneity of studies, as well as the inclusion of different strains, dosages and therapy lengths, jeopardizes the findings of available meta-analyses. Based on this consideration, guidelines for the treatment of IBD kept a very limited role for probiotics. The latest European Crohn’s and Colitis Organisation (ECCO) guide- lines do not support the use of probiotics in the achieve- ment of remission, although recognizing a certain role for VSL#3. Moreover, ECN 1917 was suggested as a comparable treatment to mesalamine to maintain remission of patients with quiescent UC (Dignass et al., 2012). In ECCO- ESPGHAN paediatric guidelines, VSL#3 and ECN 1917 are prudently suggested as single treatment in children with mildly active UC who do not tolerate mesalamine, or as ad- juvant treatment in children who do not achieve complete remission with standard therapy (Turner et al., 2012).
While available data on the efficacy of probiotics in UC are discordant, the majority of studies performed on CD patients reported no significant advantages for probiotics with respect to placebo, both in adults and in children (Prantera et al., 2002; Schultz et al., 2004; Bousvaros et al., 2005). No benefit with probiotic therapy was shown either for the prophylaxix of CD recurrences after surgical resection, as reported by Prantera et al. (2002), who investigated the effects of 1 year administration of LGG, and recent studies that evaluated the effects of L. johnsonii (Marteau et al., 2006; Van Gossum et al., 2007). The only study that reported positive effects of probiotics on clinical outcomes in CD patients is the one published by Guslandi et al. in 2000. In this study, 32 patients with CD in remission were randomized to receive for 6 months either mesalamine 1 g tid or mesalamine 1 g bid plus S. boulardii. In the group treated with the combination mesalamine plus S. boulardii, significantly fewer patients relapsed compared with the mesalamine alone group (6.25 vs. 37.5%, p< 0.05). These results were not, how- ever, confirmed in a larger study, in which S. boulardii did not significantly reduce the rate of CD relapse at 52 weeks com- pared with placebo in patients not receiving any other pro- phylactic therapy (Bourreille et al., 2013). Finally, probiotics did not show any advantage over placebo, either for the induction or for the maintenance of remission in CD, accord- ing two systematic reviews from the Cochrane Library (Rolfe et al., 2006; Butterworth et al., 2008). Therefore, the latest ECCO guidelines do not support the use of probiotics for
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pa ti en
ts co
nc om
it an
tl y re ce iv in g
m es al am
in e an
d /o r
im m un
om od
ul at or s
31 9
In du
ct io n of
re m is si o n
Th e re sp on
se ra te
w as
53 .4 %
in VS
L# 3-
tr ea
te d p at ie nt s ve
rs us
29 .3 %
in pa
ti en
ts g iv en
pl ac eb
o (P
< 00
01 ;O
R, 3. 03
; N N T = 3–
4) .
Th e re m is si o n ra te
w as
43 .8 %
in VS
L# 3-
tr ea
te dp
at ie n ts
ve rs us
24 .8 %
in pa
ti en
ts g iv en
pl ac eb
o (P
= 00
07 ;O
R, 2. 4;
N N T = 4–
5) .
Sh en
et al .,
20 14
M et a- an
al ys is
w ith
23 RC
Ts A ct iv e U C ,C
D ,
an d po
uc hi ti s
Pr ob
io tic
s ve
rs us
pl ac eb
o 17
63 In du
ct io n an
d m ai n te na
nc e
of re m is si on
Th e re m is si o n ra te s w er e si gn
ifi ca nt ly
hi gh
er in
p at ie nt s w ith
ac ti ve
U C tr ea
te d
w it h p ro b io ti cs
th an
in th os e tr ea
te d
w it h p la ce bo
(R R = 1. 80
). VS
L# 3 (R R = 0. 18
) si gn
ifi ca
nt ly
re d uc
ed th e cl in ic al
re la ps e ra te s fo r m ai nt ai ni ng
re m is si on
in pa
ti en
ts w ith
po uc
hi ti s.
Ra h im
ie t al .,
20 08
M et a- an
al ys is
w it h se ve
n RC
Ts C D
Pr ob
io tic
s (L .j oh
ns on
ii, L. rh am
no su s, EC
N 19
17 ,S
.b ou
la rd ii)
ve rs us
p la ce bo
32 0
M ai n te na
nc e
of re m is si on
Po ol in g of
da ta
fo r th e ou
tc om
e of
cl in ic al
re la ps e yi el de
d an
O R of
0. 92
(9 5%
co n fi de
nc e in te rv al
of 0. 52
– 1. 62
). Th
e O R w it h th re e st ud
ie s fo r th e ou
tc om
e of
en d os co
pi c re la p se
w as
0. 97
(9 5%
co n fi de
nc e in te rv al
of 0. 54
– 1. 78
).
Be nj am
in et
al .,
20 11
RC T w ith
pl ac
eb o
A ct iv e C D
15 g pe
r d ay
FO S
ve rs us
p la ce bo
10 3
C lin
ic al
re sp on
se :
fa ll in
C D A Io
f ≥7
0 po
in ts
Th er e w er e no
si gn
ifi ca n t di ff er en
ce s in
th e
nu m b er
of pa
ti en
ts ac hi ev
in g a cl in ic al
re sp
on se
be tw
ee n th e FO
S an
d p la ce bo
g ro up
s
St ee
d et
al .,
20 10
RC T w ith
pl ac
eb o
A ct iv e C D
Sy nb
io ti c in cl ud
in g
B. lo ng
um an
d Sy
ne rg y 1
24 C lin
ic al
re m is si o n
as se ss ed
b y C D A I
to < 15
0 or
a dr op
in C D A Io
f> 75
fr om
ba se lin
e; re du
ct io n
in m uc
os al
TN F- α
In th e sy nb
io ti c gr ou
p th er e w er e si gn
ifi ca nt
re d uc
ti on
s in
C D A I, hi st ol og
ic al
sc or e,
an d
TN F- α ex
p re ss io n at
3 m on
th s
Fu jim
o ri et
al .,
20 09
RC T
Q ui es ce
n t or
m ild
ac ti ve
U C
Sy nb
io ti c fo rm
ul at io n
of on
e d ai ly
ca p su le
of B.
lo ng
um 2 x 10
9
C FU
+ 8. 0 g d ai ly
of ps yl liu
m ve
rs us
pr eb
io ti c
al on
e ve
rs us
pr ob
io tic
al on
e
12 0
Im p ro ve
m en
t of
IB D Q s sc or es
In d iv id ua
ls co
re s si gn
ifi ca nt ly
im p ro ve
d as
fo llo
w s: p ro bi ot ic s, em
ot io na
lf un
ct io n;
p re bi ot ic s, bo
w el
fu nc
ti on
,a n d sy nb
io ti cs ,
sy st em
ic an
d so ci al
fu nc
ti on
s
Is hi ka w a et
al .,
20 11
RC T w ith
pl ac
eb o
M ild
-t o- m od
er at e
U C
B. br ev e an
d G O S
41 Im
p ro ve
m en
t of
en do
sc op
ic sc or e
(M at ts
cl as si fi ca tio
n)
Th e m ea
n en
do sc op
ic sc or e of
pa ti en
ts re ce iv in g sy nb
io ti cs
w as
si g ni fi ca nt ly ( C on
tin ue
s)
Probiotics and nutraceuticals for IBS, CIC and IBD BJP
British Journal of Pharmacology (2017) 174 1426–1449 1437
Ta b le
3 (C
on ti n ue
d )
R ef
er en
ce St
u d y ty
p e
D is ea
se In te
rv en
ti o n
N . o f p a ti en
ts A im
R es
u lt s
d ec
re as ed
co m p ar ed
w it h th at
be fo re
tr ea
tm en
t
Fi b re
H al le rt et
al ., 19
91 RC
T w ith
pl ac
eb o
Q ui es ce
n t U C
Ps yl liu
m 29
Re lie ve
of ga
st ro in te st in al
sy m pt om
s
G ra di ng
of sy m p to m s ju dg
ed ps yl liu
m to
be si g ni fi ca nt ly
su pe
ri or
to p la ce bo
Fe rn an
d ez -B an
ar es
et al ., 19
99 RC
T Q ui es ce
n t U C
Ps yl liu
m (1 0 g b id .)
ve rs us
m es al am
in e
(5 00
m g ti d) ,v
er su s
ps yl liu
m + m es al am
in e
10 5
M ai n te na
nc e
of re m is si on
Ps yl liu
m m ig h t b e as
ef fe ct iv e as
m es al am
in e to
m ai n ta in
re m is si on
H er b al
m ed
ic in al
pr od
uc ts
H ol tm
ei er
et al .,
20 11
RC T w ith
pl ac
eb o
Q ui es ce
n t C D
Bo sw
el lia
se rr at a (3
× 2
ca ps ul es
pe r da
y; 40
0 m g ea
ch )
10 8
M ai n te na
nc e
of re m is si on
Th e m ea
n ti m e to
d ia gn
os is of
re la p se
w as
17 1 da
ys fo r th e ac
ti ve
gr ou
p an
d 18
5 d ay
s fo r th e pl ac
eb o g ro up
(P = 0. 6 9) .
Th e tr ea
tm en
t gr ou
p sh ow
ed no
ad va
nt ag
e in
m ai n ta in in g re m is si on
co m p ar ed
w ith
p la ce bo
H an
ai et
al ., 20
06 RC
T w it h
pl ac
eb o
Q ui es ce
n t U C
C ur cu
m in
2 g pe
r d ay
19 D ec re as e of
U C D A I
an d en
do sc op
ic in de
x
C ur cu
m in
si gn
ifi ca nt ly
im p ro ve
d b ot h
U C D A Ia
n d th e en
do sc op
ic in de
x
G er h ar d t et
al .,
20 01
RC T
A ct iv e C D
Bo sw
el lia
se rr at a ex
tr ac t
H 15
ve rs us
m es al am
in e
83 C h an
ge of
C D A I
Th e th er ap
y w ith
H 15
w as
no t
si g ni fi ca nt ly
in fe rio
r to
m es al am
in e
La ng
m ea
d et
al .,
20 04
a RC
T w ith
pl ac
eb o
M ild
-t o- m od
er at e
U C
Al oe
ve ra
44 In du
ct io n of
re m is si o n
Si gn
ifi ca n tl y hi gh
er ra te s of
cl in ic al
re m is si on
,i m pr ov
em en
t an
d re sp on
se oc
cu rr ed
in th e tr ea
tm en
t gr ou
p co
m p ar ed
w ith
p la ce bo
H an
ai et
al .,
20 06
RC T
Q ui es ce
n t U C
C ur cu
m in
2 g pe
r d ay
pl us
su lfa
sa la zi n e or
m es al am
in e ve
rs us
pl ac eb
o pl us
su lfa
sa la zi n e
or m es al am
in e
89 Pr ev
en ti on
of re la ps e
Re la p se
ra te s: 4. 65
% in
th e tr ea
tm en
t g ro up
ve rs us
20 .5 1%
in th e pl ac eb
o g ro up
(P = 0. 04
0)
O m er
et al .,
20 07
RC T w ith
pl ac
eb o
A ct iv e C D
Ar te m is ia
ab si nt hi um
40 St er oi d -s p ar in g
ef fe ct
C lin
ic al
re m is si on
w as
ob se rv ed
in 65
% of
pa ti en
ts tr ea
te d w ith
Ar te m is ia
an d
no ne
of th e pa
ti en
ts re ce iv in g pl ac eb
o. 10
% of
pa tie
nt s ha
d to
re -s ta rt st er oi ds
in th e tr ea
tm en
t g ro up
ve rs us
80 %
of p at ie nt s re ce iv in g pl ac eb
o
Sa nd
bo rn
et al .,
20 13
RC T
A ct iv e U C
An dr og
ra ph
is pa
ni cu la ta
ex tr ac t (H
M PL
-0 0 4)
12 00
ve rs us
18 00
m g pe
r d ay
ve rs us
p la ce bo
22 4
C lin
ic al
re sp on
se 45
% an
d 60
% of
pa ti en
ts re ce iv in g
An dr og
ra ph
is pa
ni cu la ta
12 00
an d
18 00
m g d ai ly ,r es p ec
ti ve
ly ,w
er e in
cl in ic al
re m is si on
at w ee
k 8,
co m p ar ed (C on
tin ue
s)
BJP D Currò et al.
1438 British Journal of Pharmacology (2017) 174 1426–1449
the maintenance of remission in patients with CD (Dignass et al., 2010).
Prebiotics and synbiotics. The use of prebiotics and synbiotics in IBD has been little investigated. A systematic review of RCTs found only two studies investigating prebiotics and other two studies investigating synbiotics in patients with CD (Ghouri et al., 2014). Neither FOS nor lactulose showed any efficacy in patients with CD (Hafer et al., 2007; Benjamin et al., 2011). Lactulose did not improve clinical activity index, endoscopic score or immunohistochemical parameters in patients with UC, in whom, however, it improved the quality of life (Hafer et al., 2007). A synbiotic consisting of B. longum and Synergy 1, an inulin/ oligofructose mixture, was compared with placebo in a small randomized trial of patients with active CD, showing a significant improvement in Crohn’s Disease Activity Index (CDAI) score over placebo (Steed et al., 2010) (Table 3). Moreover, Synbiotic 2000, a combination of several probiotics and four prebiotics, showed no advantage over placebo in improving CDAI score, endoscopic and biochemical parameters (Chermesh et al., 2007).
In another RCT of patients with active UC, the combina- tion of B. longum and the prebiotic Synergy 1 provided a sta- tistically significant decrease of the inflammatory markers, together with a non-significant improvement of endoscopy features, with respect to placebo (Furrie et al., 2005). In an RCT, Fujimori et al. (2009) compared psyllium, B. longum and their synbiotic combination for the effects on quality of life and C-reactive protein levels in patients with quiescent or mildly active UC; the patients in the synbiotic group obtained a significant advantage over those in the other two groups for the improvement of quality-of-life scores and achieved a statistically significant reduction in C-reactive protein levels, but the study had many drawbacks, including high drop-out percentages, short duration of treatment and absence of endoscopic or histological assessments. Finally, another synbiotic, constisting of B. breve strain Yakult and GOS, showed significant efficacy over placebo in improving the clinical status of patients with mildly-to-moderately active UC (Ishikawa et al., 2011).
Fibre Dietary fibres showed, both in pre-clinical studies inmice and in clinical studies with humans, beneficial effect on IBD. In a mouse model of experimental colitis provoked by 2,4,6-trinitrobenzenesulfonic acid (TNBS), psyllium decreased, respectively, intestinal inflammation, and levels of TNF-α and inducible NOS (Rodriguez-Cabezas et al., 2002). In two RCTs of patients with quiescent UC, psyllium was shown both to relieve symptoms better than placebo (Hallert et al., 1991), and to maintain the remission at rates similar to those of mesalamine (Fernandez-Banares et al., 1999) (Table 3).
In a mouse model of dextran sulphate sodium (DSS) coli- tis, germinated barley foodstuff (GBF), a preparation rich in protein and fibre made by milling and sieving brewer’s spent grain (Kanauchi and Agata, 1997), was able to prevent the damage of the mucosa (Kanauchi et al., 1998). Furthermore, in a pilot study, GBF supplementation improved clinical activity and endoscopic scores in patients with mild-Ta
b le
3 (C
on ti n ue
d )
R ef
er en
ce St
u d y ty
p e
D is ea
se In te
rv en
ti o n
N . o f p a ti en
ts A im
R es
u lt s
w it h 40
% of
th os e re ce iv in g pl ac
eb o
(P = 0. 5 92
4 fo r 12
00 m g an
d P = 0. 01
83 fo r 18
00 m g )
Ta n g et
al ., 20
11 RC
T M ild
-t o- m od
er at e
U C
12 00
m g pe
r d ay
An dr og
ra ph
is pa
ni cu la ta
ex tr ac t (H
M PL
-0 0 4)
ve rs us
45 00
m g pe
r d ay
sl ow
re le as e m es al am
in e
12 0
C lin
ic al
re m is si o n
an d re sp
on se
Th er e w er e no
si gn
ifi ca n t di ff er en
ce s
b et w ee
n th e tw
o tr ea
tm en
t gr ou
p s
La ng
ho rs t et
al .,
20 13
RC T
In ac ti ve
U C
H er b al
p re pa
ra ti on
of m yr rh ,c
h am
om ile
an d
co ff ee
ch ar co
al ve
rs us
m es al am
in e
96 M ai n te na
nc e
of re m is si on
N o si gn
ifi ca n t di ff er en
ce s be
tw ee
n th e tw
o tr ea
tm en
t gr ou
ps
N af ta li et
al .,
20 13
RC T w ith
pl ac
eb o
A ct iv e C D
11 5 m g of
Δ 9 -
te tr ah
yd ro ca n na
b in ol
(T H C )
21 C lin
ic al
re sp on
se A cl in ic al
re sp
on se
(d ec re as e in
C D A I
sc or e of
> 10
0) w as
ob se rv ed
in 10
of 11
su bj ec ts
in th e ca nn
ab is g ro up
an d 4 of
10 in
th e pl ac
eb o g ro up
, P = 0. 02
8
B. br ev e,
Bi fi do
ba ct er iu m
br ev e;
C I, co
n fi de
nc e in te rv al s; IB D Q s, In fl am
m at o ry
Bo w el
D is ea
se Q ue
st io n na
ir es ;L
.j oh
ns on
ii, La ct ob
ac ill us
jo hn
so ni i; U C D A I, ul ce ra ti ve
co lit is d is ea
se ac
tiv it y in d ex
Probiotics and nutraceuticals for IBS, CIC and IBD BJP
British Journal of Pharmacology (2017) 174 1426–1449 1439
to-moderately activeUC (Mitsuyama et al., 1998). Finally, GBF supplementation was able to taper corticosteroids and to lengthen remission in subjects with UC (Hanai et al., 2004).
Nevertheless, according to a recent questionnaire-based survey, subjects with IBD usually avoid high-fibre diets, irre- spective of the activity of the disease (Zallot et al., 2013). Prac- tical recommendations include the consumption of a regular diet in the case of mild or moderate activity of both UC and CD, and that fibres should be avoided only in specific cases, including acute relapse of the disease, small intestinal bacte- rial overgrowth, gastrointestinal stenosis and selected surgi- cal interventions (Brown et al., 2011).
Herbal medicinal products Herbal products may be of help for IBD through different pathways, for example by modulating the immune system, inhibiting LTB4 synthesis, NF-κB or platelets (Gilardi et al., 2014; Somani et al., 2015). Several herbal products have been shown to be effective in IBD patients (Holtmann and Talley, 2015; Langhorst et al., 2015; Table 3).
In experimental models of intestinal inflammation, an extract of Boswellia serrata reduced the interplay between endothelium and white blood cells and attenuated the inflammatory process (Krieglstein et al., 2001; Hartmann et al., 2014). It has been suggested that the anti-inflammatory effects of this plant extract are due to the inhibition of micro- somal prostaglandin E2 synthase (mPGES) and the serine pro- tease cathepsin G by β-boswellic acid (Abdel-Tawab et al., 2011). In a double-blind RCT, an extract of Boswellia serrata resin induced remission of disease in a percentage of patients with active CD similar to that of mesalamine (Gerhardt et al., 2001). Nevertheless, in a RCT of 108 outpatients with quies- cent CD, an extract of this plant resin did not show any advantage over placebo in maintaining remission (Holtmeier et al., 2011).
Several therapeutic pathways of curcumin, the major con- stituent of Curcuma longa, have been found in mouse models of IBD. First, it decreases levels of pro-inflammatory cytokines (e.g. IFN-γ, TNF-α, IL-1β and IL-12) (Sugimoto et al., 2002; Jian et al., 2004, 2005; Jiang et al., 2006; Zhang et al., 2006a, b; Camacho-Barquero et al., 2007), then regulates several tran- scription factors and signal pathway molecules, such as β-catenin, NF-κB, signal transducer and activator of transcrip- tion, activator protein 1, PPAR-γ (Jian et al., 2005) and finally, it down-regulates the activity of COX-2 (Camacho-Barquero et al., 2007), and decreases both iNOS and myeloperoxidase (MPO) activity (Ukil et al., 2003; Zhang et al., 2006a; Camacho-Barquero et al., 2007; Deguchi et al., 2007). Few clinical studies have investigated the potential of curcumin in IBD. Curcumin, administered by enema to patients with mild-to-moderate distal UC taking mesalamine, was more effective than placebo in inducing endoscopic improvement and remission of the disease (Singla et al., 2014). In a RCT of 89 patients with quiescent UC treated with sulfasalazine or mesalamine, curcumin showed higher efficacy than placebo in maintaining remission (Hanai et al., 2006).
Wheat grass, a preparation obtained from the cotyledons of Triticum aestivum, the common wheat plant, has shown significantly higher efficacy than placebo in reducing, after 4 weeks, an overall disease activity index in patients with active distal UC (Ben-Arye et al., 2002). The beneficial
clinical activity of wheat grass probably relates to its antioxi- dant properties, due to the high content of phenolic and fla- vonoid substances, the down-regulation of mPGES, COX-2 and iNOS, and the inhibition of the synthesis of pro- inflammatory cytokines by its main component, apigenin (Marquez-Flores et al., 2016).
The central pulp of Aloe vera leaves has been known for centuries for its medicinal effects, above all for the treatment of skin disorders. The gel extracted from this pulp has been shown to ameliorate the colitis produced by DSS in rats, by down-regulating the expression of pro-inflammatory media- tors, including TNF-α and IL-1β, and the activity of MPO (Park et al., 2011), and to reduce the synthesis of PGE2 and IL-8 and the production of ROS in human colorectal mucosa in vitro (Langmead et al., 2004b). The main active substances contained in this gel, aloesin, aloin and aloe-emodin, mimicked the gel-induced effects in the inflamed rat colon (Park et al., 2011). The Aloe vera gel has been investigated for its therapeutic effects in a double-blind RCT of 44 patients with mild-to-moderate active UC. It induced significantly higher rates of disease remission, improvement and response with respect to placebo after a 4-week treatment (Langmead et al., 2004a).
An RCT of CD patients treated with a stable daily dose of corticosteroids suggested that the herb Artemisia absinthium, commonly known as wormwood, has corticosteroid sparing effects. In this trial, 40 patients were randomized to receive the herbal extract or a placebo for 10 weeks during which the corticosteroid daily doses were tapered until discontinu- ation. Remission of the disease was observed in 65% of patients treated with Artemisia and none of the patients receiving placebo. The remission was maintained in the 10weeks following the end of treatment, and only two pa- tients in the Artemisia arm had to re-start the therapy with corticosteroids, which, on the contrary, were re-started in 80% of patients receiving placebo (Omer et al., 2007). The anti-inflammatory effects of Artemisia are very probably due to its flavonoid components; in fact, 5,6,3′,5′- tetramethoxy 7,4′-hydroxyflavone, a flavonoid isolated from Artemisia, has been shown to inhibit the activation of NF-κB and reduce the expression of COX-2 and iNOS in a macrophage cell line stimulated with LPS (Lee et al., 2004). Another substance isolated from Artemisia, cardamonin, also reduces the expression of iNOS in macrophage cell lines in- cubated with LPS by inhibiting NF-κB DNA-binding (Hatziieremia et al., 2006).
HMPL-004, a proprietary extract of Andrographis paniculata, induced a clinical response at week 8 in a percent- age of patients withmild-to-moderate UC significantly higher than that of patients treated with placebo, in a double-blind RCT in which approximately 60% of patients were taking concomitantly mesalamine (Sandborn et al., 2013). This trial followed a double-blind RCT published by Tang et al. in 2011, in which HMPL-004 had shown an efficacy not signifi- cantly different from that of mesalamine, at week 8, in pa- tients with mild-to-moderate UC (Tang et al., 2011). In a T-cell-driven model of murine intestinal inflammation, HMPL-004 was able to prevent the development of colitis by inhibiting the proliferation of CD4+ T lymphocytes and their differentiation into Th1/Th17 cells (Michelsen et al., 2013). These anti-inflammatory effects of Andrographis paniculata
BJP D Currò et al.
1440 British Journal of Pharmacology (2017) 174 1426–1449
were mimicked by its main component, andrographolide, in mice with TNBS-induced colitis (Liu et al., 2014).
A double-blind, double-dummy RCT of patients with qui- escent UC investigated the efficacy of a proprietary combina- tion of myrrh, chamomile extract and coffee charcoal for the maintenance of the remission; the non-inferiority of the herbal mixture with respect to mesalamine was evaluated by the mean Clinical Colitis Activity Index (Langhorst et al., 2013). After 12 months of treatment, the relapse rate in the herbal product arm (53%) was not significantly different from that in the mesalamine arm (45%), indicating its use as a pos- sible alternative to mesalamine for the maintenance of remission.
Finally, conflicting results come from studies of Cannabis sativa (the marijuana plant) in patients with CD. Twenty-one patients with active CD not responding to ste- roids, immunosuppressants and/or biological agents, were randomized to cannabis or placebo, as cigarettes, for 8 weeks. Although the difference in clinical remission rates was not significant between the two groups, the clinical response rate (defined as a reduction in CDAI score of more than 100 points) was significantly higher in the cannabis group (Naftali et al., 2013). In a following survey of 313 patients with CD, nearly 18% of them used cannabis to improve symptoms (mainly diarrhoea, abdominal pain and joint pain). Neverthe- less, a chronic (>6 months) use of cannabis predicted the fur- ther need for surgery (OR = 5.03) (Storr et al., 2014).
Safety of probiotics, fibre and herbal medicinal products Probiotics are generally available without the need of a med- ical prescription, as they are mostly considered as food sup- plements. Moreover, both the U.S. FDA and the WHOclassed probiotics to be generally safe (Mattia and Merker, 2008). However, defining a safety profile for probiotics has become a paramount need for the medical community (Shanahan, 2012). Some systematic reviews of the literature have tried to address it and they agreed that probiotics can be considered partially, but not totally, safe (Whelan and Myers, 2010; Didari et al., 2014). The most rele- vant safety concerns on probiotics include the infectious ad- verse events (mainly sepsis), imbalance of the immune system and transmission of antibiotic resistance genes to pathogenic bacteria (Boyle et al., 2006). Therefore, probiotics should be avoided, or used with great care, in critically ill pa- tients, in subjects with immunodeficiency, immune dysregu- lation, or taking immunosuppressant and/or antineoplastic drugs, patients with central venous catheters, those with car- diac valve diseases, replacement or history of endocarditis, premature infants, and in subjects with altered gastrointesti- nal barrier (e.g. graft-versus-host disease, or radiation enteri- tis, or severe acute pancreatitis), at high risk of bacterial translocation (Boyle et al., 2006; Williams, 2010; Doron and Snydman, 2015). In particular, probiotics were associated with increased mortality rates in patients with severe acute pancreatitis (Besselink et al., 2008); moreover, S. boulardii was responsible for more than a half of total events of fungal sepsis in France (Enache-Angoulvant and Hennequin, 2005). Therefore, the FDA has recently stated that probiotics should
be considered as food supplements only when used in healthy subjects, whereas they should be considered as drugs when used in ill subjects (Venugopalan et al., 2010).
Fibres do not generally pose important safety problems (Eswaran et al., 2013; Moayyedi et al., 2014). The herbal prod- ucts deserve, instead, a more thorough discussion. The wide- spread use of plants as medicines or dietary supplements is mainly attributable to the fact that everything is natural is generally considered safe. Actually, this assumption does not exactlymatch the reality.Many pharmacologically active sub- stances are contained in plants and they can induce adverse events as can traditional drugs. A recent multicentre retro- spective study based on data from selected poisons centres as part of the PlantLIBRA project funded by the European Community aimed to investigate the incidence of adverse events related to the intake of plants as food or food supple- ments in the years 2006–2010 (Lüde et al., 2016). Overall, 75 cases from 10 centres met the inclusion criteria of the study and the observed adverse events affected more frequently the nervous and gastrointestinal systems and only five were severe. Thus, the toxicity of plants ingested for health reasons seems to be infrequent and generally not severe. A recent sys- tematic review on the adverse events caused by 66 plants ingested as food supplements or botanical preparations has come to similar conclusions (Di Lorenzo et al., 2014). This work showed that reports of adverse events related to the in- gestion of botanicals are many in the literature, but those with an adequate evidence of causal link, according to the WHO Causality Assessment Criteria, are much less (Di Lorenzo et al., 2014). The plants causally associated with adverse events were 39 out of the 66 considered, and a mini- mum number of papers regarded as significant by the authors (at least 10), was found only for 14 of them, which were re- sponsible for 86.6% of all adverse events. Four plants, namely, in decreasing order of importance, Glycine max (soybean), Glycyrrhiza glabra (liquorice), Camellia sinensis (green tea) and Ginkgo biloba (ginkgo) caused approximately 50% of all adverse events (Di Lorenzo et al., 2014). A recent overview of systematic reviews on the adverse events associated with the use of herbal medicines also concluded that these latter are reasonably safe and the adverse events they may cause are usually mild, even though some of them can induce severe health problems (Posadzki et al., 2013). Therefore, on the ba- sis of these possible serious adverse events reported in the lit- erature and the increasing use of herbal products, it has been suggested that constant attention is required to herbal prod- ucts both in terms of the regulation and in terms of the healthcare consequences (Izzo et al., 2016; Lüde et al., 2016).
Discussion Over the years, several therapeutic approaches complemen- tary or alternative to traditional pharmacological treatments, including probiotics, prebiotics, synbiotics, fibre and herbal medicinal products, have been investigated for the manage- ment of FBD and IBD. Due to increasing consumer spending on nutritious and healthy dietary supplements globally, their market has shown consistent growth during the past few years. On the basis of the present medical evidence, a few conclusions can be summarized. Probiotics, in particular
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S.boulardii and Lactobacilli (among which L. rhamnosus), synbiotics, psyllium, and some herbal medicinal products, primarily peppermint oil, seem to be effective in ameliorating IBS symptoms. Synbiotics and fibre seem to be beneficial in FC patients. The probiotic combination VSL#3 may be effec- tive in inducing remission in patients with mild-to-moderate UC, in whom ECN 1917 seems to be as effective as mesalamine in maintaining remission. As for the efficacy of fibre and herbal medicinal products in IBD patients, although several RCTs showed beneficial effects with different prepara- tions, no definite conclusions can be drawn due to the low number of studies and the lack of RCTs that replicate the re- sults obtained in the individual studies conducted so far.
Few considerations can be made from these conclusions. Interventions aimed to affect the gut microbiota seem to in- duce therapeutic effects in both functional and organic bowel diseases, giving support to the hypothesis that perturbations of a healthy microbiota may have a pathogenic role in both categories of colonic disorders. We do not know exactly yet what happens to the gut microbiota when we administer probiotics. A recent meta-analysis based on seven studies sug- gests that probiotics do not modify the composition of gut microbiota in healthy subjects (Kristensen et al., 2016). How- ever, these findings do not exclude the possibility that probiotics affect the function or the homeostasis, that is the ability to resist to or recover from the perturbations induced by different stressors, of gut microbiota (Sanders, 2016). In addition, it is possible that some probiotics exert beneficial ef- fects on composition and/or function and/or homeostasis of the gut microbiota in subjects with gut dysbiosis, such as IBS and IBD patients, with amelioration of gastrointestinal symptoms (McFarland, 2014). Fibres seem to be effective in the treatment of both IBS and FC patients. Most evidence is available for psyllium, a soluble, viscous and intermediate fer- mentable fibre. It is probable that its efficacy in ameliorating symptoms in patients with IBS-C and FC is mainly attribut- able to the bulk-forming property, that is the ability to form a mucilage that increases the faecal mass and stimulate the colonic propulsive activity, thus relieving constipation. How- ever, it cannot be ruled out that psyllium fermentation by the microbiota, and the consequent beneficial effects of fermen- tation products on the microbiota itself, epithelium and im- mune cells, can importantly contribute to its therapeutic effects, particularly in IBS patients. The efficacy of psyllium in relieving symptoms and maintaining remission in UC pa- tients shown in two RCTs and the results of some studies showing the therapeutic efficacy of prebiotics in IBS patients may support this possibility. Very few RCTs investigating the effects of prebiotics in patients affected by functional or in- flammatory bowel disorders have been done so far; thus, it would be desirable that other RCTs are conducted, in particu- lar with intermediate fermentable fibre or low doses of highly fermentable prebiotics, to avoid the production of high levels of gases that could worsen the symptoms. The real contrast between functional and inflammatory colonic disorders con- cerns the herbal medicinal products that have been shown to be effective in RCTs. It seems now proven that iberogast and peppermint oil are therapeutic in IBS patients. Their thera- peutic efficacy is very probably due to their ability to reduce the afferent nerve discharge activated by various stimuli, and thus, the visceral hypersensitivity and the smooth
muscle spasms that have been hypothesized to be among the most important pathophysiological mechanisms under- lying the abdominal pain in IBS patients. In contrast, in line with expectations, all herbal medicinal products that pro- duce clinical improvement in IBD patients have been shown to act on molecular mechanisms involved in the inflamma- tory process. Unfortunately, confirmatory RCTs are missing for all of them.
In summary, probiotics, prebiotics, synbiotics, fibre and herbal medicinal products are, for some aspects, at the same time both current and promising therapeutic approaches for the management of FBD and IBD. Nevertheless, available studies on probiotics and synbiotics are biased by several drawbacks. Most meta-analyses included trials differing each other in strains, dosages and duration of probiotic or synbiotic treatment; moreover, most trials included subjects from different populations, differing for gender, age, BMI and other features. This ‘one-size-fits-all’ approach risks to flatten different findings on probiotics or synbiotics. Addi- tionally, the good fortune of most probiotic and synbiotic tri- als has been hampered by their small sample size, and by the enormous number of species/strains investigated, either alone or in combination. Finally, as suggested in the very re- cent Rome IV Foundation report, future trials on probiotics should include microbiota analysis to check their presence in the gutmicrobiota of a representative subset of exposed pa- tients, and should undergo the same rigorous methodology applied to clinical trials of traditional drugs (Irvine et al., 2016). Prebiotics seem to be promising therapeutic options in both functional and inflammatory bowel disorders, but more studies are necessary, in particular with low doses and larger numbers of enrolled patients. Finally, confirmatory studies for the therapeutic efficacy of herbal medicinal prod- ucts in IBD patients are awaited.
Conflict of interest The authors declare no conflicts of interest.
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Review article: herbal and dietary supplement hepatotoxicity C. Bunchorntavakul*,† & K. R. Reddy†
*Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand. †Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Correspondence to: Dr K. R. Reddy, 2 Dulles, 3400 Spruce Street, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA. E-mail: rajender.reddy@uphs.upenn. edu
Publication data Submitted 26 August 2012 First decision 18 September 2012 Resubmitted 2 October 2012 Accepted 6 October 2012 EV Pub Online 5 November 2012
This commissioned review article was subject to full peer-review.
SUMMARY
Background Herbal and dietary supplements are commonly used throughout the World. There is a tendency for underreporting their ingestion by patients and the magnitude of their use is underrecognised by Physicians. Herbal hepatotox- icity is not uncommonly encountered, but the precise incidence and mani- festations have not been well characterised.
Aims To review the epidemiology, presentation and diagnosis of herbal hepato- toxicity. This review will mainly discuss single ingredients and complex mixtures of herbs marketed under a single label.
Methods A Medline search was undertaken to identify relevant literature using search terms including ‘herbal’, ‘herbs’, ‘dietary supplement’, ‘liver injury’, ‘hepatitis’ and ‘hepatotoxicity’. Furthermore, we scanned the reference lists of the primary and review articles to identify publications not retrieved by electronic searches.
Results The incidence rates of herbal hepatotoxicity are largely unknown. The clini- cal presentation and severity can be highly variable, ranging from mild hep- atitis to acute hepatic failure requiring transplantation. Scoring systems for the causality assessment of drug-induced liver injury may be helpful, but have not been validated for herbal hepatotoxicity. Hepatotoxicity features of commonly used herbal products, such as Ayurvedic and Chinese herbs, black cohosh, chaparral, germander, greater celandine, green tea, Herbalife, Hydroxycut, kava, pennyroyal, pyrrolizidine alkaloids, skullcap, and usnic acid, have been individually reviewed. Furthermore, clinically significant herb–drug interactions are also discussed.
Conclusions A number of herbal medicinal products are associated with a spectrum of hepatotoxicity events. Advances in the understanding of the pathogenesis and the risks involved are needed to improve herbal medicine safety.
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Alimentary Pharmacology and Therapeutics
INTRODUCTION With historical background on use, the use of herbal medicine can be traced back as far as 2100 BC in ancient China and India.1 Despite their largely unproven thera- peutic potential through systematic and rigorous investi- gations, herbal therapy has been increasingly used for the treatment of various diseases, not only in the Eastern World but also in the Western World. In the US, herbal and dietary supplements (HDS) represent a $180 billion market and their use was reported by 18.9% individuals in 2004, and this had doubled from the previous decade.2, 3 Interestingly, 30–40% of patients admitted that they did not disclose the use of HDS to their Physi- cians.3 The list of the ten most commonly used herbal preparations for various conditions, included echinacea, garlic, ginko biloba, saw palmetto, ginseng, grape seed extract, green tea, St. John’s wort, bilberry and aloe.4
Notably, the use of HDS is particularly common in indi- viduals with chronic liver disease, as was reported by 30–62% of patients who ingested silymarin (milk this- tle).3 This population is theoretically more susceptible for hepatotoxicity as well as more likely to develop severe hepatic adverse consequences.
HERBAL PRODUCTS AND THEIR REGULATIONS Herbal products used for treating disease exist as both crude and commercial preparations. Crude herbal prod- ucts (come as roots, leaves, seeds or teas) are more often used in less developed countries. They are sometimes formulated as a mixture (i.e. Chinese and Thai herbal medicine, and Indian ayurvedic medicine), where often all constituents are not known and may contain harmful contaminants, such as heavy metals (i.e. lead, mercury and arsenic), corticosteroids nonsteroidal anti-inflamma- tory drugs and benzodiazepines.5 Commercial herbal products (as tablets or capsules) are more commonly used in developed countries. They often vary in content and concentration of chemical constituents from batch- to-batch and also come from different manufacturers. Even with standardisation for the known active com- pounds, there may be variation in other constituents, resulting in differences in bioavailability and pharmaco- logical activity in humans.2, 5, 6 In the US, these com- mercial herbal products are expected to adhere to the regulations of the Dietary Supplement and Health Education Act (DSHEA), issued in 1994, and the Final Rule for Current Good Manufacturing Practices for Dietary Supplements, issued in 2007. These regulations require for the manufacturers to determine the safety of herbal products before marketing, to define dietary
ingredients as vitamins, minerals, herbs, amino acids (and any concentrate, metabolite, extract thereof), to provide standards in identification and purity and as well as to ensure that claims made regarding the product are accurate and not misleading.2, 5 However, this does not always guarantee good manufacturing practices and the manufacturers are not bound to register their products before distribution.2, 5 Thus, there is no aspect of the law to give the US Food and Drug Administration (FDA) authority to review and approve herbal products for safety and effectiveness.2
EPIDEMIOLOGY The true prevalence of herbal product use and incidence of herbal hepatotoxicity are unknown. Unlike modern prescription medications, current regulations for herbal products do not mandate systematic surveillance or reporting of adverse events by the manufacturer to the FDA. Therefore, the data regarding herbal hepatotoxicity are derived largely from anecdotal case reports, case ser- ies, retrospective databases and, more recently, from pro- spective registries of drug-induced liver injury (DILI), such as the US DILI Network and the Spanish DILI Reg- istry. Notably, some of these DILI reports have excluded patients with herbal hepatotoxicity. Based on available data of DILI cohorts from the US and Europe, herbal products are implicated as a cause of hepatotoxicity in 2–11% of patients with DILI,7–9 and in 5–10% of patients with drug-induced acute liver failure (ALF),10, 11
although a single-centre experience has implicated HDS in up to 70% of patients with ALF.12 These numbers reflect the magnitude of herbal hepatotoxicity in clinical practice, and it should again be emphasised that this prevalence is likely to be underestimated. As traditional herbal medications are widely used in China and India, as well as in many other countries in Southeast Asia, Africa and Central America, one can speculate that her- bal hepatotoxicity is encountered commonly in these parts of the World. While the data from such areas are scant, prospective DILI studies from Korea and Singa- pore do support this assumption by reporting a high prevalence of herbal hepatotoxicity, among all cases of DILI, of 73% and 71% respectively.13, 14 Surprisingly, a low prevalence of herbal hepatotoxicity (1.3%) was reported from India, where the use of herbal remedies and ayurvedic compounds are quite common.15
Although the exact reasons remain unclear, the authors speculated that ayurvedic compounds in India are often taken after the development of a hepatitis like illness and the high rate of heavy metal contamination in the
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remedies result in a more dominant nonhepatic organ involvement that may overshadow hepatitis, which may be insignificant and overlooked and thus, underreported15
(Table 1). The incidence of idiosyncratic liver injury among per-
sons who use HDS is variable. Based on limited data, the incidence of hepatotoxicity from Chinese herbs appears to be low (less than 1%).16, 17 Melchart et al. reported a study of 1507 consecutive inpatients treated with tradi- tional Chinese medicine wherein 1% developed more than 2-fold elevation of serum alanine aminotransferase (ALT), and only 2 patients were symptomatic.16 Further- more, a prospective, observational study from Korea
reported that significant changes in hepatic biochemical tests were not observed among 122 patients who took herbal medicine.17 However, relatively high incidence of hepatotoxicity has been reported in a randomised controlled trial of Tinospora crispa as an adjunctive therapy for diabetes mellitus (N = 40), wherein signifi- cant ALT elevations (>200 IU/L) occurred in 10% of patients.18 Although it is difficult to quantitate the exact amount of active herbal ingredients ingested, dose-dependent pattern of hepatotoxicity can be seen with several herbs, such as pyrrolizidine alkaloids (PA), greater celandine and Atractylis gummifera.
Table 1 | Herbal and dietary supplement hepatotoxicity: Prevalence and clinical features among drug-induced liver injury in different reports
Reference Countries and patient characteristics
Prevalence of HDS hepatotoxicity
Clinical features and prognosis of cases identified as HDS hepatotoxicity
Ibunez et al.9 Spain (1993–1998) N = 103; DILI Population-based, prospective
11% 64% hepatocellular injury 18% mixed injury 18% cholestasis injury
Andrade et al.7 Spain (1994–2004) N = 446; DILI Multi-centre, prospective
2% 89% hepatocellular 11% cholestasis 56% needed hospitalisation 11% death
Chalasani et al.8 USA (2003–2008) N = 300; DILI Multi-centre, prospective
9% 63% hepatocellular 17% cholestasis 21% mixed injury 41% needed hospitalisation 6% ALF 9% chronic DILI
Suk et al.13 Korea (2005–2007) N = 371; DILI Multi-centre, prospective
73% (40% herbs, 14% dietary supplement, 19% folk remedies)
~78% hepatocellular ~10% cholestasis ~12% mixed injury 1.5% death or LT
Wai et al.14 Singapore (2004–2006) N = 31; DILI Multi-centre, prospective
71% 74% hepatocellular 19% cholestasis 7% mixed injury
Devarbhavi et al.15 India (1997–2008) N = 313; DILI Single-centre, retrospective
1.3% 50% mortality
Estes et al.12 USA (2001–2002) N = 20, ALF Single-centre, retrospective
50% 60% underwent LT
Russo et al.11 USA (1990–2002) N = 270; ALF from drug Retrospective, UNOS data
5.1% All underwent LT
Reuben et al.10 USA (1998–2007) N = 133; ALF from drug Multi-centre, prospective
10% >90% hepatocellular injury 21% spontaneous recovery 50% underwent LT 29% death
ALF, acute liver failure; DILI, drug-induced liver injury; HDS, herbal and dietary supplement; LT, liver transplantation; UNOS, United Network for Organ Sharing.
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PRESENTATION The clinical presentation of herbal hepatotoxicity varies from asymptomatic abnormal hepatic biochemical test abnormalities indicating mild self-limiting liver injury, to severe ALF requiring LT. In symptomatic individuals, the manifestation often begins with nonspecific constitu- tional symptoms, followed by jaundice.19 Due to the variety and complexity of herbal regimens, it is difficult to summarise the clinical manifestations of herbal hepa- totoxicity in general. In 28 patients with DILI from herbs and dietary supplements in the US DILI Network, the median duration from exposure to DILI recognition was 54 days (IQR 36–109); 50% were female and the mean age was 45 (±12) years. Pattern of liver injury was hepa- tocellular in 63%, cholestatic in 17% and 21% were mixed, with a mean bilirubin of 14.7 (±13.0) mg/dL. The severity was mild–moderate in 88% of patients, whereas 12% have severe–fatal DILI; 3.5% of patients underwent LT and chronic DILI developed in 9%.8 A prospective nationwide study of DILI in Korea reported 270 patients with HDS-related hepatotoxicity; most patients were female with median age of 48–53 years.13 Hepatocellular pattern of injury was noted in the majority of cases (~78%) with a median ALT of 566–796 IU/L and a med- ian bilirubin of 5.4–7.0 mg/dL. Median hospital stay was 7–9 days; most patients spontaneously recovered with 2 deaths and 2 requiring LT.13
DIAGNOSIS AND CAUSALITY ASSESSMENT As with DILI, an early and high-index of suspicion of herbal hepatotoxicity is paramount. The use of herbal products should always be a part of history taking in patients presenting with any form of acute liver injury or in those with acute on chronic liver disease. Further details on all herbal preparations used, dose and dura- tion and concomitant medications are essential. In some instances, it can be helpful to examine the label of the herbal products, which sometimes contains a long list of ingredients mixed in the preparation. Prompt recognition of common culprit herbs and their hepatotoxicity pat- terns (some of them may have a ‘signature’) reported previously in the literature (see below) is very important. Currently, there is no gold standard, even with a liver biopsy, for the diagnosis of herbal hepatotoxicity. The diagnosis, therefore, depends greatly on the exclusion of other causes of liver disease by a thorough clinical assessment, as well as laboratory testing. A list of essen- tial diagnostic elements for the exclusion of other causes of hepatic dysfunction and to increase the reliability of the diagnosis of DILI has been suggested and this could
increase the quality and clinical utility of the publications on drug toxicity.20 Acute hepatitis E has accounted for some cases of suspected DILI (up to 13% in developed countries, and possibly much higher in developing coun- tries),21, 22 and therefore testing for hepatitis E antibody should be performed, particularity if clinical features resemble acute viral hepatitis.22 The possibility of herbal hepatotoxicity superimposed on pre-existing liver disease should also be considered, especially because many her- bal remedies are used by patients with chronic liver dis- eases, and in this situation, it is more challenging to make a clear-cut diagnosis. Liver histology often is non- specific, but may be helpful in some cases. Uncommon histological patterns of liver injury should trigger the suspicion of herbal hepatotoxicity, and these include zonal necrosis, necrotic lesions with steatosis or bile duct injury, and vascular injury, particularly veno-occlusive disease (VOD).19
Several scoring systems have been proposed for aiding in the causality assessment of DILI, such as the Roussel Uclaf Causality Assessment Method (RUCAM) by the Council for the International Organization of Medical Sciences (CIOMS)23 and the clinical scale by Maria and Victorino.24 Among these scoring systems, the CIOMS scale is perhaps the most widely used in the litera- ture.8, 23 This scale applies numerical weighting to key features in 7 different domains: chronology (latency and dechallenge), risk factors, concomitant drug use, exclu- sion of other causes, previous information on drug’s hep- atotoxicity potential and response to rechallenge. The score given to each domain is summed up to generate a total score that reflects the causality probability of DILI; definite, very likely, probable, possible, unlikely or excluded.23 The CIOMS scale, when initially validated, demonstrated acceptable reproducibility and perfor- mance, with 93% positive predictive value and 78% nega- tive predictive value.25 However, subsequent validations have questioned the reliability of this method, and there have been several pitfalls in applying the score in clinical practice.26, 27
Although the CIOMS scale has been utilised as a diag- nostic tool in most of the literature pertaining to herbal hepatotoxicity, the performance of this method in causal- ity assessment of herbal hepatotoxicity remains unde- fined. Herbals and dietary supplements are less likely to be well characterised with regard to hepatotoxicity infor- mation of the active ingredients. This may compromise the CIOMS score for herbal products as no points are given for agents without existing information on hepato- toxicity. A recent study from Hong Kong Herb-induced
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Liver Injury Network evaluated the performance of CIOMS scale and a multidisciplinary approach (consist- ing of expert opinion by a hepatologist, clinical toxicolo- gist, analytic toxicologist and Chinese medicine pharmacist) in 27 patients with suspected herbal hepato- toxicity. The concordance for causality assessment was moderate, either between the hepatologist and clinical toxicologist (weight k = 0.48), or between the multidisci- plinary team and the CIOMS scale (weight k = 0.51).28
The diagnostic algorithm for the causality assessment of drugs and dietary supplements, consisting of a pretest (qualitatively oriented for hepatocellular injury and/or cholestasis), a main-test (CIOMS scale) and a posttest (exclusion of other liver diseases not considered in the CIOMS) procedure, has also been proposed by Tes- chke.29 More recently, a group of experts from the US DILI Network has developed a novel causality assessment tool specifically for HDS (HDS-CAT), which needs further investigation and validation.30
HERBAL PRODUCTS THAT HAVE BEEN LINKED TO HEPATOTOXICITY
Ayurvedic herbal products Ayurvedic medicine is the science of a plant-based sys- tem of healing applicable to a spectrum of disorders that originated is ancient India. It generally consists of numerous plants, but metals may also be present due to the practice of ‘Rasa shastra’ (combining herbs with met- als, minerals and gems).31 Notably, 20–22% of both US- and Indian-manufactured Ayurvedic medicines randomly purchased via the Internet in 2005 contain detectable lead, mercury or arsenic.31 Although cases of heavy metal poisoning associated with Ayurvedic medicine have been continuously reported, this form of treatment is still utilised by the majority in rural India (1.1 billion people) and worldwide by the South Asian diaspora and others.31, 32 Interestingly, despite being widely used, hep- atotoxicity from Ayurvedic medicine has been rarely reported in the literature. Severe hepatitis has been docu- mented in a woman who had treated herself for 9 months with various Indian Ayurvedic herbal products for her vitiligo, in which the key implicated ingredient was believed to be Psoralea corylifolia.33 Centella asiatica (Gotu kola, Mandukaparni, Kannada), an ayurvedic medicine used mainly for leprosy, has been reported to be associated with granulomatous hepatitis and cirrho- sis.34, 35 Additionally, in the European RCT of Ayurvedic herbal combination, Liv.52 which contains capers, wild chicory, arjuna, black nightshade, yarrow, and others, for
the treatment of alcoholic cirrhosis (N = 188), no effect on survival was seen in Child class A/B patients, but substantially increased liver-related mortality was observed in those with Child class C (2-year survival: 40% vs. 81% in those who adhered to treatment, P = 0.02), suggesting a potential detrimental effect of this Ayurvedic preparation.36
Atractylis gummifera and Callilepsis laureola (Impila) Atractylis gummifera is a thistle located in the Mediterra- nean regions, where more than 26 species have been identified. These plants secrete a whitish glue-like sub- stance often used by children as chewing gum, and also used as an antipyretic, antiemetic, abortifacient and a diuretic.5 Ingestion of A. gummifera continues despite its well-known toxicity attributed to atractyloside and carb- oxyatractyloside, which are concentrated in the root of the plant.5, 37 These two diterpenoid glucosides are capa- ble of inhibiting mitochondrial oxidative phosphorylation by interaction with a mitochondrial protein, the adenine nucleotide translocator.37 More than hundred cases of liver and renal injury associated with A. gummifera ingestion have been reported, and they frequently involved children.38, 39 In addition, toxicity is reported with the cutaneous application.40 The onset of toxicity usually begins within few hours after ingestion, and is characterised by headache, anxiety, vomiting, abdominal pain, diarrhoea, and convulsion, which then often leads to acute liver and renal failure, neurovegetative state and death.38–41 There is no specific pharmacological treat- ment for A. gummifera intoxication available and all the current therapeutic approaches are only symptomatic, with LT being an option. In vitro experiments noted that some compounds such as verapamil, or dithiothreitol could protect against the toxic effects of atractyloside by blocking ADP-ATP conversion through inhibition of P450 cytochrome, but only if administered before atract- yloside exposure.37, 41 New therapeutic approaches could come from immunotherapy research; efforts to develop polyclonal antibodies against the toxic components of A. gummifera are in progress.37, 41
Callilepsis laureola (Impila), is a plant indigenous to the Natal region of South Africa, and has been used as a traditional remedy, mainly by the Zulu Tribe. Similar to A. gummifera, C. laureola also contains the toxic atracty- loside.42 Several cases of acute liver and renal failure have been reported with a mortality rate greater than 90% by 5 days.43, 44 Interestingly, C. laureola-induced cytotoxicity in Hep G2 cells involves depletion of cellular glutathione and preventing glutathione depletion by
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supplementing cells with N-acetylcysteine to reduce its cytotoxicity potential has been demonstrated.45
Chaparral Chaparral (Larrea tridentate) is made from the leaves of a desert shrub, known as the creosote bush or grease- wood, found in Southwestern United States and Mexico.5
It has been used for the treatment of various conditions, such as pain, bronchitis, skin conditions, cancer, and also as an alternative medicine for AIDS.52, 53 Currently, chaparral comes in the form of a tea, and as capsules, tablets and salves.5, 53 It is perceived to have antimicro- bial and antioxidant activities and its active ingredient is nordihydroguiaretic acid, a potent inhibitor of lipoxy- genase and cyclooxygenase pathways.5, 19
Several reports on hepatotoxicity associated with ingestion of chaparral leaf, including acute and subacute hepatocellular injury, and cholestatic hepatitis, have been published.54–57 Sheikh et al. reviewed 13 cases of chapar- ral-induced hepatotoxicity in 1997.53 Most patients presented with jaundice with a marked increase in ALT within 3–52 weeks after ingestion, which often resolved 1–17 weeks after discontinuing the product. However, 2 patients developed ALF requiring LT, and 4 patients eventually evolved onto cirrhosis.53 Histological findings ranged from biliary changes and cholestasis to massive hepatic necrosis, particularly in zone 3.19, 53–57
Chinese herbal medicines Numerous herbs from China have been used for centu- ries as traditional medicine. Chinese herbal medicines, while being quite popular in the East, have also become highly popular among Western countries as a form of ‘natural’ alternative medicine; they are perceived to be free of side effects. Most traditional Chinese medicines are blends of 4–6 different herbs, but there is typically a primary pharmacologically active component referred to as the ‘King herb’. The remaining constituents are believed to function as modifiers of toxicity, act synergis- tically with the King herb, improve the immune function or strengthen certain aspects of actions, and such con- glomeration of constituents makes the identification and assignment of causative hepatotoxic compounds extre- mely difficult.6 In addition, adulteration by synthetic drugs and heavy metals has also been reported.58–60
Jin Bu Huan (Lypocodium serratum) has been widely used as a sedative and analgesic, as it contains levo-tetra- hydropalmatine, a potent neuroactive substance. In North America, it was marketed as ‘anodyne tablets’ in the 1990s, and subsequently was banned due to convincing
reports of toxicity (i.e. central nervous system and respi- ratory depression, cardiovascular collapse, and hepato- toxicity) after both acute and chronic use.61–64 In a series of 7 cases of Jin Bu Huan-associated liver injury, acute hepatitis occurred after 7–52 weeks (mean 20 weeks) of ingestion and usually resolved within 2–30 weeks (mean 8 weeks).64 Liver biopsy specimens noted mild hepatitis, moderate fibrosis and micro vesicular steatosis, with or with- out eosinophilic infiltrates.64 In addition, chronic hepatitis with bridging fibrosis has also been described.63 The mecha- nism of hepatotoxicity is unclear, but an immune-mediating process might play a role based on the development of fever, rash and eosinophilia in many individuals.5, 64
Ma huang (Ephedra sinica) is used as a nasal decon- gestant and bronchodilator, as well as to aid weight loss. In a meta-analysis, it was noted to promote modest short-term weight loss (not sufficient data regarding long-term weight loss and the contribution from athletic performance), but was associated with increased rate of psychiatric and autonomic system issues, gastrointestinal symptoms and heart palpitations.65 Liver injury, including severe hepatitis, ALF, and as fulminant exacerbation of AIH, has been described in association with ma huang inges- tion,66, 67 as well as with the use of multiple different commercial weight-loss herbal products containing ma huang.68, 69
Dai-saiko-to (Sho-saiko-to, TJ-19, Da-chai-hu-tang, Xiao-chai-hu-tang) is a Chinese herbal medicine that has been used widely in Japan for the treatment of liver dis- eases and is part of the Japanese Kampo medical sys- tem.5, 38 Dai-saiko-to differs from Sho-saiko-to only in the proportion of herbal constituents and which contains bupleuri, pinelliae, scutellaria, ginseng, ginger, glycyrrhiza and jujube fruits.5, 38 Several in vitro and in vivo studies suggested that this product may be effective in prevent- ing hepatic inflammation, fibrosis and hepatocellular car- cinoma.3 There have been, however, reports of liver injury attributed to these products.70–72 Itoh et al. reported 4 cases of acute hepatitis following a latency period of 1.5–3 months after ingestion of Sho-saiko-to, which improved with cessation and recurred with rechal- lenge.71 The liver histology revealed centrilobular conflu- ent necrosis or spotty necrosis, micro vesicular fatty change, acidophilic degeneration, and a granuloma.71
Kamiyama et al. reported a case of AIH, which possibly was triggered by Dai-saiko-to and this was based on the development of fatigue, fever, ALT elevation,, and ANA titre of 1:2560 after 2 weeks of treatment. Alanine aminotransferase returned to normal after treatment with prednisolone.72
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Geniposide is one of the major iridoid glycosides in Gardenia fruit (Gardenia jasminoides) and is used in several Chinese and Kampo herbal medicines (i.e. Shui- Zhi-Zi, Sansisi) to treat various conditions, such as febrile conditions, liver diseases and cancers. In rat livers, acute hepatotoxicity of geniposide at high doses was pre- dictable and likely to be linked to oxidative stress.73
Interestingly, a case series and review of case reports from Japan suggested that long-term use of geniposide- containing herbal medicines appears to be associated with mesenteric phlebosclerosis.74 The mechanism is not well understood, but possibly is due to biotransformation of geniposide by intestinal microflora into more toxic metabolite, genipin, that is cytotoxic and can induce cross-link formation in collagen.74
Sporadic cases of liver toxicity attributed to other Chinese herbs containing Paeonia spp. (commonly used for eczema)6, 75 and Polygonum multiflorum (Shou-wu- pian)76–78 have also been described.
Germander The blossoms of Germander (Teucrium chamaedrys), a plant found in Europe and the Middle East, have been used for thousands of years for a variety of conditions, such as dyspepsia, hypertension, gout, diabetes and obes- ity.5, 6 It is available as tea, capsules and as an addition to liquor.6 Many reports (mostly from France) of liver injury have been documented, and these include presen- tations as acute, chronic hepatitis and as ALF.79–83 Most cases of hepatotoxicity occurred after 2 months of intake at the manufacturer’s recommended doses (600– 1600 mg/day).79–83 Symptoms were nonspecific (anor- exia, nausea, abdominal pain and jaundice) and were accompanied by a marked elevation of ALT. After with- drawal, jaundice generally disappeared within 8 weeks; however, the development of cirrhosis and relapse fol- lowing accidental exposure have also been anecdotally reported.80 Germander contains saponins, glycosides, flavonoids and furan-containing diterpenoids. Furan- containing diterpenoids are well-known to be cytotoxic and carcinogenic.84–86 In rat studies, these constituents are oxidised by cytochrome P450 3A4 to reactive metab- olites that bind to proteins, deplete cellular glutathione and protein thiols, and ultimately induce membrane dis- ruption and hepatocyte apoptosis.84–86
Apart from the instances of hepatitis from T. cha- maedrys, there have been anecdotal case reports involv- ing other herbs in the same genus (Teucrium), including T. polium,87–89 T. capitatum90 and T. viscidum.91 These herbal products are often used as hypoglycaemic agents
to aid in treatment of diabetes. Notably, acute severe cholestasis, cholestatic hepatitis and ALF requiring LT can be associated with T. polium ingestion.87, 92–94 Based on chemical analysis, hepatotoxic neo-clerodane diterpe- noids have also been isolated from other species of Teuc- rium, including T.alpestre, T. cuneifolium, T. divarication subsp. villosum and T. flavum subsp. hellenicum.95
Greater celandine Greater celandine (Chelidonium majus) is a plant found mainly in Europe and contains at least 20 different alka- loids, such as berberine, coptisine, chelerythrine and chelidonine. Its extracts have been used for the treatment of biliary disorders and irritable bowel syndrome.5, 6 Sev- eral reports, mostly from Germany, where commercial drug preparations containing Greater celandine are widely available, described liver injury associated with this herb.96–99 In the largest case series of 10 patients, all were women presenting with moderate elevation of ALT and ALP, which began often around 3 months after ingestion.96 Marked cholestasis was observed in 5 patients, but liver failure did not occur. Most of the liver biopsies showed portal inflammation and eosinophilic infiltrates, and in all patients, discontinuation of greater celandine treatment led to normalisation of hepatic bio- chemical tests in 2–6 months. Interestingly, low titre of antinuclear and smooth muscle autoantibodies were noted in 8 cases, which may indicate low-grade autoim- munity.96 Additional 40 cases of hepatic injury from C. majus have been reported to the German regulatory authorities. Based on these data, C. majus has been banned from oral use in Germany and other European countries, while the Australian Complementary Medi- cines Evaluation Committee has recently recommended that all oral products containing C. majus have a warn- ing label and be used under professional healthcare supervision.100
Green tea (Camellia sinensis) Green tea is very popular worldwide and is also a fre- quent ingredient in various dietary supplements used predominantly for weight loss.2 Several reports of hepa- totoxicity, including ALF, following the ingestion of numerous and different green tea preparations have been published since 1999.101–106 A review of 34 published case reports and 2 unpublished cases suggests a causal association between green tea and liver damage. Majority of cases were judged as ‘possible’ according to the CIOMS score and a positive rechallenge occurred in 7 cases.106 Patterns of liver injury were hepatocellular in
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most cases, but cholestasis and a mixed pattern were also observed. Liver histology examination revealed inflam- matory reactions, cholestasis, occasional steatosis and necrosis.106–108 In addition, a case with features mimick- ing AIH (elevation of ALT, hyperglobulinemia, transient presence of antismooth-muscle antibodies and necroin- flammation with interface hepatitis on liver histology) following green tea infusion has also been described.109
The mechanism of hepatotoxicity is incompletely under- stood, but components responsible are probably catechins and their gallic acid esters, particularly epigallocatechin-3- gallate, which, under certain conditions such as fasting, can induce reactive oxygen species formation, and affect mitochondrial membrane potential. Although there is reason to be concerned regarding green tea-induced liver injury, a systematic review of 34 such cases (27 were categorised as possible causality and 7 as probable causality) performed by the US Pharmacopoeia has not uncovered a major safety issue and therefore a warning on the label of the product has not been implemented.104
While there is concern of hepatotoxicity, significant amount of data from both experimental and clinical studies have suggested the role of green tea in hepatoprotection and cancer prevention, as well as in ‘optimizing’ general health.107, 108, 110, 111 Although heterogeneity among studies exists, a systematic review of 10 studies, including 4 RCTs, showed a significant protective role of green tea against various liver diseases.110 Whether the potential risk of hepatotoxicity from green tea outweighs their benefits remains unclear.
Herbalife products Herbalife products (Los Angeles, CA, USA) are distrib- uted as herbal and dietary supplements in the form of drinks, tablets, capsules and energy bars for weight con- trol, cosmetics, nutritional support and improvement in well-being, via online marketing and through indepen- dent sale agents. It is one of the largest weight manage- ment and nutritional supplement companies in the World, with activity in almost 60 countries, and sales of over 3 billion US dollars.108 Since 2007, there have been several published reports of Herbalife hepatotoxicity from different countries (i.e. Argentina, Iceland, Israel, Spain and Switzerland) describing more than 34 cases.108, 112–116 Pattern of liver injury was hepatocellular in the majority of cases, but mixed and cholestatic patterns were also observed. Severity ranged from mild- to-severe liver damage and included cases that developed cirrhosis and ALF requiring LT.108, 115, 116 Causality relationship was assessed by various widely used scores,
and it was considered ‘probable’ in most cases, although ‘certain’ (with positive rechallenge) cases were also reported.108, 113, 115 The exact mechanism of liver injury has not been established, but Elinav et al. hypothesised that immune-mediated injury could be a possible explanation, based on their observation of plasma cell infiltrates and occasional transient presence of autoanti- bodies in some cases.113 More recently, Stickel et al. reported on 2 cases of severe hepatotoxicity associated with consumption of Herbalife products contaminated with Bacillus subtilis. Causality according to CIOMS was scored as ‘probable’ in both cases, and histology showed cholestatic and lobular/portal hepatitis with cirrhosis in one patient, and biliary fibrosis with ductopenia in the other. The authors further demonstrated that culture supernatants of the Bacillus subtilis isolated from the products induced dose-dependent leakage of LDH from HepaG2 cells, which they interpreted as the basis for the liver injury, thus raising concern for the possibility of adulteration of Herbalife products with hepatotoxin-pro- ducing bacterial strains. Therefore, it seems quite likely that hepatotoxicity does occur among some people who receive these products, but the precise mechanism or the responsible agent in the products is uncertain, in part because, to date, the complete listing of the ingredients of these products is not known and the manufacturer apparently is unwilling to provide the needed informa- tion.117 Besides, Herbalife representatives have so far challenged the causal relationship between consumption of their products and DILI, as well as confirming good quality control for ingredients and contaminants in their production lines.118, 119
Hydroxycut Hydroxycut is a popular dietary supplement consisting of a variety of herbal mixtures that claim to enhance the ability to lose weight. Several cases of hepatotoxicity associated with Hydroxycut have been reported.120–122
Most patients exhibited a hepatocellular pattern of injury with marked elevation of ALT, but some patients had a more insidious and usually cholestatic course.120–122
Notably, cases of AIH-like features and ALF requiring liver transplantation have also been described.120, 121 The responsible toxic ingredient is not entirely certain, but may be the consequence of Camellia sinensis present in the product.121 In May 2009, the FDA issued a warning to stop using Hydroxycut products, which was followed by a voluntary recall of all its products by the manufac- turer.108, 121 Subsequently, a new formulation of Hydroxycut has been developed and is being sold.108
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Kava Kava (Piper methysticum) is a plant indigenous to the South Pacific Islands, including Hawaii, Vanuatu, Poly- nesia, Melanesia and some parts of Micronesia, where an extract from its rhizome is commonly used to prepare a traditional beverage for social and recreational pur- poses.123, 124 In Western countries, dietary supplements containing kava are promoted as an agent to relieve stress, anxiety, and tension, as well as for sleeplessness and menopausal symptoms.123, 124 Its efficacy for the treatment of anxiety is supported by a Cochrane meta- analysis.125 Numerous reports of severe hepatotoxicity have been described in the US and Europe, and some of which have been confirmed by structured, quantitative and liver-specific causality assessment methods.5, 6, 29, 38, 126–128
In an analysis of 36 cases of kava hepatotoxicity, the pat- tern of injury was both hepatocellular and cholestasis; majority of the patients were women, the cumulative dose and latency were highly variable, and ALF devel- oped in 9 patients and 8 of whom underwent LT.126 The US-FDA began advising consumers on the potential risk of severe liver injury associated with the use of kava-con- taining dietary supplements in the year 2002 and the products have been banned from the markets of some countries in Europe, although they are still available in the US, Canada, Australia, New Zealand and South Paci- fic Islands, as well as via the Internet.124
The mechanism of hepatotoxicity has not been clearly elucidated; however, several potential hepatotoxic constit- uents (i.e. pipermethystine, flavokavain B and mould hepatotoxins) and co-factors (i.e. alterations in hepatic microsomal cytochrome P450, cyclooxygenase inhibition, P-glycoprotein and glutathione) have been extensively reviewed by Teschke.123, 129 The author suggested that kava hepatotoxicity is partly preventable by quality con- trol, prescription adherence and avoidance of co-medica- tions, since it occurs primarily due to daily overdose (exceeding 250 mg of kava lactones), prolonged treat- ment and the use of the kava plant’s aerial parts, which may contain the hepatotoxic alkaloid pipermethysticin, and contaminated kava raw material.123, 124, 129
Pennyroyal Pennyroyal (squawmint oil) is an herb containing pule- gone and a smaller amount of other monoterpenes, which often is in a form of oil.5, 19 It has long been used as an abortifacient despite its potentially lethal hepatotoxic and neurotoxic effects.130 Pennyroyal’s toxicity is believed to be mainly from menthofuran, a metabolite of pulegone, which is oxidised by cytochrome P450. In addition,
pulegone markedly depletes glutathione as measured in both liver tissue and plasma.131 Therefore, drugs inhibit- ing cytochrome P450 (i.e. cimetidine and disulfuram) and/or replacement of glutathione with N-acetylcysteine may theoretically alleviate or prevent pennyroyal hepato- toxicity.19, 131, 132 Anderson et al. published a report with a literature review of 22 cases of hepatotoxicity associated with pennyroyal oil.130 Patients often developed severe gastrointestinal upset and central nervous system effects within 1–2 h following ingestion of the oil. Severe/fatal hepatic necrosis and multiorgan failure seemed to occur when more than 15 mL was ingested.130 One patient was successfully treated by N-acetylcysteine.130
Pyrrolizidine alkaloids Pyrrolizidine alkaloids (PA) are found in more than 350 plant species worldwide. These alkaloids have been well- recognised in causing hepatotoxicity for over 70 years, particularly with Senecio, Heliotropium, Crotalaria, and Symphytium (Comfrey) species.19, 133–137 The key pattern of liver injury is VOD, newly termed sinusoidal obstruc- tion syndrome (SOS), which was first reported in Jamai- can children who drank bush tea for their illness.133
Subsequently, several cases of VOD associated with an ingestion of PA-containing plants (most often as herbal tea) have been reported mainly from the Southern US, Africa, and Asia, as well as sporadically from Western Countries.19, 134–138
PA-associated VOD typically presents with ascites, oe- dema and hepatomegaly. The clinical onset and severity are variable. In the acute form, abdominal pain develops suddenly, often with jaundice and markedly elevated ALT levels, and with rapid deterioration ending in death.19, 133–138
The pathogenic process begins with damage to sinusoid endothelial cells that leads to partial obstruction of the sinusoidal lumens, thereby causing obstruction to the sinusoidal blood flow.38 Liver histology is characterised by nonthrombotic occlusion of small terminal hepatic venules, leading to sinusoidal dilatation and, eventually, haemorrhagical centrilobular necrosis.19, 133–138 Acute VOD is fatal in 15–20% of patients, with it being worse in adults as compared with children.133 Complete recov- ery has been observed in about half of the patients, whereas approximately 15% of patients may have a pro- tracted course of liver injury, characterised by perivenu- lar and bridging fibrosis, and some may die from decompensated liver disease several years later.19, 133–138
A smaller proportion of patients may have subacute or chronic onset of illness, which may insidiously progress to cirrhosis and portal hypertension.19 In animal models,
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the hepatotoxicity of PA seems to be related to the bio- transformation by cytochrome P450 3A4 into unstable toxic metabolites (pyrrole derivatives) that may act as al- kylating agents and this depends on the type and total dose of PA ingested, along with susceptibility to the alka- loids.139–141 Notably, herb–drug or herb–herb interac- tions involving cytochrome P450 are likely to affect PA- associated VOD susceptibility and severity, as toxicity can be amplified by concomitant use of phenobarbital via the induction of cytochrome P450.6, 141 Acute VOD may result from a short time exposure to high doses, whereas chronic liver injury may be caused by prolonged exposure to even small doses of PA.139–141
The management of PA-associated VOD is mainly supportive. Defibrotide, a polydisperse oligonucleotide with local antithrombotic, anti-ischaemic and anti- inflammatory activity, appears to be effective for severe VOD following haematopoietic stem cell transplant;142
however, its role in the treatment of PA-associated VOD is unknown. As soon as acute or chronic liver failure appears imminent, LT may be the only effective therapy.6
Other herbal and dietary supplements Numerous other herbal products, including camphor oil (Cinnamomum camphora, Vicks VapoRub),38, 143 black
cohosh,46–51 saw palmetto (Serrenoa repens),144Noni juice (Morinda citrifolia),145–148 Cascara (Cascara sagra- da),38, 149 mistletoe (Viscus album),150–152 skullcap (Scu- tellaria),153, 154 valerian (Valeriana officinalis),155 senna (Cassia angustifolia and C. acutifolia),156–158 usnic acid,159–161 Margosa oil (Antelaea azadirachta, Aza- dirachta indica)6, 38 and Aloe vera,162, 163 as well as die- tary supplements, including vitamin A have been described to cause hepatotoxicity.108, 164–166 Furthermore, preparations containing anabolic steroids108, 167, 168 have also been linked to liver injury and are summarised in Table S1.
HERB–DRUG INTERACTIONS In addition to the potential for direct hepatotoxicity, some of these herbs may have interactions with certain prescription medications by various mechanisms leading to adverse events, including potentiation of risk for hepa- totoxicity, renal toxicity, abnormal bleeding, graft rejec- tion and cardiovascular collapse.169–171 Many herbs have been identified as substrates, inhibitors, and/or inducers of various cytochrome P450 enzymes, such as St. John’s wort, garlic, pepper, licorice, flavonoids, triterpenoids and anthraquinones.172 For example, St. John’s wort is a potent inducer of CYP3A4, mediated by activation of the
Table 2 | Herb–drug interactions relevant to hepatology [Adapted from Ref. (38)]
Medications Herbs Interactions and potential consequences
Warfarin and aspirin Danshen (S. miltiorrhiza) Increased INR ? bleeding risk Dong quai (A. sinensis) Increased INR ? bleeding risk Garlic Increased INR ? bleeding risk Papaya Increased INR ? bleeding risk Tamarind Increased aspirin level ? bleeding risk Feverfew Platelet dysfunction ? bleeding risk Gingko biloba Platelet dysfunction ? bleeding risk Ginseng Decreased INR ? clotting risk St. John’s wort Decreased INR ? clotting risk Devil’s claw (H. cumbens) Purpura
CYP34A drugs Pyrrolizidines CYP3A4 induction ? hepatotoxicity Germander CYP3A4 induction ? hepatotoxicity
Cyclosporine St. John’s wort CYP3A4 induction ? rejection risk Grape fruit juice CYP3A4 induction ? rejection risk
Methotrexate St. John’s wort Increased methotrexate level and toxicity Echinacea Increased hepatotoxicity ?
Prednisolone Ginseng Possible additive effect Glycyrrhizin (licorice root) Reduced clearance ? hypokalemia Sho-saiko-to Altered clearance ? low prednisolone level
Protease inhibitors St. John’s wort CYP3A4 induction ? suboptimal antiviral activity Garlic CYP3A4 induction ? suboptimal antiviral activity
Spironolactone Glycyrrhizin (licorice root) Mineralocorticoid ? low spironolactone level Benzodiazepines Kava Increased sedative effects
CYP, cytochrome P450; INR, international ratio.
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pregnane X receptor, which can then potentiate the intrinsic hepatotoxicity of other substances, such as ger- mander and acetaminophen, by way of an increased con- version to toxic metabolites.19, 172 It also enhances plasma clearance of a number of drugs, such as cyclo- sporine and protease inhibitors, which can complicate the management of posttransplant immunosuppression, as well as HIV and hepatitis C therapy.169, 170, 172, 173 In addition, coadministration of St. John’s wort significantly increased the systemic exposure and toxicity of metho- trexate in a rat model.174 Several herbs, including Dan- shen, Dong quai, garlic, papaya, tamarind, feverfew, and Gingko biloba, have been associated with an increased risk of bleeding in patients who are on warfarin and/or aspirin. Other herb–drug interactions that may result in hepatotoxicity or significantly affect practice are sum- marised in Table 2.
CONCLUSION As herbal products continue to be used widely around the World, herbal hepatotoxicity will continue to be observed. Such events are not necessarily unique to her- bal medications as they can be seen with prescription medications such as antibiotics, anticonvulsants, etc. It is therefore imperative that the recognition and reporting of herbal hepatotoxicity be held to the same standards as prescription medications. Liver injury is mostly hepato- cellular, but mixed and cholestatic patterns can also occur, and the severity ranges from mild injury to ALF,
as well as with evolution to chronicity. The diagnosis of herbal hepatotoxicity depends on a proper knowledge of the available literature on hepatotoxicity with the spec- trum of herbal preparations ingested and also on a heightened awareness for such hepatotoxic events. Advances in the understanding of the frequency, the pathogenesis, the clinical manifestations and outcomes are needed to be able to improve herbal medicine safety.
AUTHORSHIP Guarantor of the article: K. R. Reddy. Author contributions: C. Bunchorntavakul conceptua- lized, searched and reviewed the literature, and drafted the manuscript. K. R. Reddy conceptualized and critically reviewed the manuscript. All authors approved the final version of the manuscript.
ACKNOWLEDGEMENT Declaration of personal and funding interests: None.
SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article: Table S1. Herbal and dietary products associated with
liver injury: application, toxic mechanism and clinical features.
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REVIEW - SPONSORED
Cardiovascular disease and omega-3s: Prescription products and fish oil dietary supplements are not the same Adina S. Gutstein,MSN, CRNP, CLS, FPCNA1 & Tina Copple, DNP, APRN, CLS, FNP-BC, ADM, CDE2
1Cardiovascular Medical Associates, P.C., Philadelphia, Pennsylvania 2Diabetes & Glandular Disease Clinic, San Antonio, Texas
Keywords cardiovascular risk; dyscalculia; dyslipidemia;
hyperlipidemia; low-density lipoprotein
cholesterol; statins.
Correspondence Adina S. Gutstein MSN, CRNP, CLS, FPCNA,
Cardiovascular Medical Associates, P.C., 818
Chestnut Street, Philadelphia, PA 19107.
Tel: 215-825-5917; Fax: 267-644-1073;
E-mail: adina.gutsteincrnp@gmail.com
Received: 14 July 2017;
revised: 10 November 2017;
accepted: 13 November 2017
doi: 10.1002/2327-6924.12535
Disclosures Medical writing and editorial assistance were
provided by Katie Singh, PharmD, Elizabeth
Daro-Kaftan, PhD, and Jim Wood of Peloton
Advantage, Parsippany, NJ, and funded by
Amarin Pharma Inc., Bedminster, NJ. Medical
scientific reference checks and associated
assistance were provided by Sephy Philip, RPh,
PharmD of Amarin Pharma Inc.
Abstract
Background and purpose: Despite achievement of optimal low-density lipoprotein cholesterol (LDL-C) control with statin therapy, patients with ele- vated triglycerides (TGs) and residual cardiovascular risk are commonly encoun- tered in clinical practice.
Methods: We present information from completed and ongoing clinical trials examining Rx omega-3s for TG-lowering and omega-3 dietary supplements to highlight important differences affecting patient management for nurse practi- tioners.
Conclusions: Rx omega-3s demonstrate robust reductions in TGs and may have a role in reducing residual cardiovascular risk. Products containing docosa- hexaenoic acid (DHA) may raise LDL-C and should not be substituted for Rx eicosapentaenoic acid (EPA)-only icosapent ethyl, which does not raise LDL-C. Omega-3 dietary supplements (e.g., fish oils containing EPA and DHA) may be used for general health promotion; however, they are not regulated as medica- tions and concerns regarding quality, purity, safety, and variability of content exist. It is important to advise patients that omega-3 dietary supplements are not medications and should not be substituted for Rx omega-3s. Large-scale car- diovascular outcomes studies are underway for Rx omega-3s in statin-treated patients.
Implications for practice: Nurse practitioners can take an active role in re- ducing residual cardiovascular risk and educating patients about important dif- ferences between Rx omega-3s and fish oil supplements.
Introduction
Despite achieving optimal low-density lipoprotein cholesterol (LDL-C) control with statin therapy, patients may still be at risk for cardiovascular events because of factors such as elevated triglycerides (TGs) and nonhigh- density lipoprotein cholesterol (non-HDL-C). Such pa- tients are commonly encountered in clinical practice, and the importance of this residual cardiovascular risk are now a well-recognized factor in their care (Fruchart et al., 2014). Treatment with an adjunctive lipid-modifying agent may help to reduce residual cardiovascular risk (Cannon et al., 2015). Recent epidemiological evidence has documented the first uptick in cardiovascular disease- related mortality in the modern statin era (Benjamin et al., 2017; Xu, Murphy, Kochanek, & Arias, 2016), and thus
nurse practitioner awareness of residual cardiovascular risk and strategies to reduce this risk are at the front lines of reducing cardiovascular risk and mortality.
Elevated TGs are independently associated with in- creased incidence of cardiovascular events, and recent data report that TG-rich lipoproteins play a causal role in the development and progression of atherosclerosis via multi- ple direct and indirect mechanisms (Figure 1) (Toth, 2016; Watts, Ooi, & Chan, 2013). Given their substantial TG- lowering effects, prescription (Rx) omega-3 fatty acids rep- resent an important option to potentially reduce resid- ual cardiovascular risk when used in addition to statin therapy. The long-chain polyunsaturated omega-3s eicos- apentaenoic acid (EPA) and docosahexaenoic acid (DHA) are important nutrients with roles in a range of health areas including aging, brain health and development,
791Journal of the American Association of Nurse Practitioners 29 (2017) 791–801 C©2017 American Association of Nurse Practitioners
Rx omega-3s and fish oil supplements A. S. Gutstein & T. Copple
Figure 1 Overviewof role of hypertriglyceridemia and TGs in cardiovascular disease.Within the lumenof the blood vessel, TG-rich particles (lipoproteins and remnants) induce atherosclerosis by generating mediators of inflammation, coagulation, and endothelial dysfunction and induce the activation of platelets
and adhesion of monocytes. After crossing the vessel wall, activated monocytes differentiate into macrophages in the vessel intima. TG-rich particles also
cross the vessel wall and are taken up by macrophages, causing the formation of foam cells in the vessel intima. Foam cell accumulation induces plaque
formation and progression, which ultimately leads to thrombosis, rupture, and cardiovascular events. TGs, triglycerides. Adapted with permission from
Watts et al. (2013).
cardiovascular health, and eye health (Arterburn, Hall, & Oken, 2006; Connor, 2000; Jump, Depner, & Tripa- thy, 2012; Manku, 2015; Mozaffarian & Wu, 2011; Siri- wardhana, Kalupahana, & Moustaid-Moussa, 2012). As a means of supporting good health, intake of 500 mg of omega-3s (EPA and DHA combined) daily is recom- mended by dietetic/nutrition organizations as part of a 2000-calorie diet for adults (Kris-Etherton & Innis, 2007; Vannice & Rasmussen, 2014).
It is important to recognize that while omega-3 dietary supplements such as fish oils can be used for general health promotion, these supplements are not medica- tions. Omega-3 dietary supplements are not approved or indicated for the treatment of any disease or condition and thus should not be used as such. In contrast, Rx omega-3s are currently approved as an adjunct to diet for the treatment of adults with severe hypertriglyc- eridemia (TGs �500 mg/dL) and are under investigation for potential benefits in reducing residual cardiovascular risk/events in large randomized clinical trials (discussed later) (Epanova [package insert], 2017; Lovaza [package insert], 2015; Omtryg [package insert], 2014; STRENGTH study; REDUCE-IT study, 2017, December 12; Vascepa [package insert], 2017). This review describes important differences between Rx omega-3s and omega-3 dietary supplements and discusses the potential role of Rx omega- 3s in the treatment of cardiovascular disease for nurse practitioners in primary care practice in the context of completed and ongoing clinical studies, some of which are very long term and may not have final results for several years.
Overview of omega-3 dietary supplements
Omega-3 dietary supplements lack strict regulatory oversight
Dietary supplements are not over-the-counter (OTC) drugs (there are, in fact, no approved OTC omega-3 drugs) and, unlike Rx and OTC drugs, supplements are not required to demonstrate efficacy and/or safety prior to marketing (Cohen, 2014; Lopez & Ito, 2010; Dietary Supplement Health and Education Act of 1994). Un- fortunately, patients, pharmacists, and even healthcare providers may mistakenly equate the omega-3 dietary supplements with OTC drugs and may have the impres- sion that dietary supplements are subject to the same or similar rigorous regulatory standards of safety, effi- cacy, and good manufacturing practices required for OTC medications.
Quality, purity, and safety concerns with omega-3 dietary supplements
Omega-3 dietary supplements widely available at retail stores nationwide are derived from a variety of sources, in- cluding fish (i.e., fish oil), krill, and algal sources. Nearly all contain both EPA and DHA and very few are avail- able that claim to contain only EPA. Furthermore, multiple publications have raised concerns regarding the variabil- ity of omega-3 content in dietary supplements as well as the quality and purity of these products (Kleiner, Cladis, & Santerre, 2015; Mason & Sherratt, 2017; Shim, San- terre, Burgess, & Deardorff, 2003; Truong, Johnson, &
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A. S. Gutstein & T. Copple Rx omega-3s and fish oil supplements
Gabriel, 2007; Tur, Bibiloni, Sureda, & Pons, 2012; Weitz, Weintraub, Fisher, & Schwartzbard, 2010; Zargar & Ito, 2011). For example, studies have shown that the actual concentrations of DHA and/or EPA in omega-3 supple- ments may be far below or far in excess of the labeled amounts (Albert et al., 2015; Kleiner et al., 2015; Shim et al., 2003; Yi et al., 2014). In addition, omega-3 di- etary supplements are not “pure” and may contain con- taminants and/or harmful/unwanted ingredients such as high concentrations of cholesterol, saturated fats, lipid per- oxides, and oxidation products (Albert et al., 2015; Jack- owski et al., 2015; Mason & Sherratt, 2017; Ritter, Budge, & Jovica, 2013; Truong et al., 2007; Tur et al., 2012; Weitz et al., 2010; Zargar & Ito, 2011). The presence of some of these ingredients may interfere with the intended health benefits of omega-3 dietary supplements (Mason & Sher- ratt, 2017). There are some high-dose omega-3 dietary supplement products that claim purity; however, these products are still not subject to the stringent level of reg- ulatory oversight required for medications. Overall, the variability in quality and omega-3 quantity between dif- ferent products and between different batches of the same product may be because of the lack of regulatory oversight afforded to dietary supplements, and thus consumers and healthcare providers ultimately have no way of knowing exactly what is contained in omega-3 dietary supplements.
Overview of Rx omega-3s
Several Rx omega-3 products containing combinations of both DHA and EPA and one product containing high- purity EPA have been approved by the United States Food and Drug Administration (FDA) (Table 1). The indica- tion for each of these Rx omega-3s is the same: for use as an adjunct to diet to reduce TGs in adults with se- vere hypertriglyceridemia (TGs �500 mg/dL) (Epanova [package insert], 2017; Lovaza [package insert], 2015; Omtryg [package insert], 2014; Vascepa [package in- sert], 2017). Notably, among approved Rx omega-3 prod- ucts, only Vascepa (icosapent ethyl; Amarin Pharma Inc., Bedminster, NJ, USA), Lovaza (omega-3-acid ethyl es- ters; GlaxoSmithKline, Research Triangle Park, NC, USA), and Lovaza generics are commercially available; Omtryg (omega-3-acid ethyl esters A; Trygg Pharma, Inc., Arling- ton, VA, USA) and Epanova (omega-3-carboxylic acids; AstraZeneca Pharmaceuticals, Wilmington, DE, USA) are not. The omega-3-carboxylic acids are in a free fatty acid form, which has been suggested to have higher bioavail- ability than products containing ethyl esters (Siscovick et al., 2017); however, bioavailability data from short-term studies may not be reflective of long-term clinical out- comes from chronic treatment.
Table 1 Omega-3 products (Epanova [package insert]; Lovaza [package insert]; Omtryg [package insert]; Vascepa [package insert])
FDA-approved products
Rx omega-3s: combination products containing high-purity DHA and EPA � Lovaza: omega-3-acid ethyl esters (GlaxoSmithKline, Research
Triangle Park, NC) and genericsa � Omtryg: omega-3-acid ethyl esters A (Trygg Pharma, Inc.,
Arlington, VA; not commercially available) � Epanova: omega-3-carboxylic acids (AstraZeneca
Pharmaceuticals, Wilmington, DE; not commercially available)
Rx omega-3: high-purity EPA-only product � Vascepa: icosapent ethyl (Amarin Pharma, Inc., Bedminster, NJ)b
Dietary supplements
Are not OTC drugs: no FDA-approved OTC omega-3s � Purity, quality, and quantity of EPA and DHA is highly variable � Not approved by the FDA to treat disease � Hundreds of fish, algal, and krill oil products available without Rx
DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; FDA, Food and
Drug Administration; OTC, over-the-counter; Rx, prescription. aGeneric formulations of omega-3-acid ethyl esters are approved by the
FDA. bA high-purity formulation of the ethyl ester of EPA.
Impact of Rx omega-3s on lipid profiles
Multiple randomized, blinded, placebo-controlled trials have evaluated the impact of Rx omega-3s on lipid pa- rameters (Ballantyne et al., 2012; Bays et al., 2011; David- son et al., 2007; Harris et al., 1997; Kastelein et al., 2014; Maki et al., 2013; Pownall et al., 2017). Table 2 summa- rizes the findings for the 4 g/day dose of Rx omega-3s in patients with very high baseline TGs (�500 mg/dL) and in patients with residually high TGs (�200 to <500 mg/dL) despite statin therapy. All Rx omega-3s demonstrate ro- bust reductions in TGs and non-HDL-C (Ballantyne et al., 2012; Bays et al., 2011; Davidson et al., 2007; Epanova [package insert], 2017; Harris et al., 1997; Kastelein et al., 2014; Lovaza [package insert], 2015; Maki et al., 2013; Omtryg [package insert], 2014; Pownall et al., 2017; Vas- cepa [package insert], 2017). Differences in the degree of TG reduction are likely driven by baseline TGs, with higher TGs at baseline being associated with greater TG reductions (Jacobson, Glickstein, Rowe, & Soni, 2012; Nieman, Dick- lin, Bell, Rains, & Maki, 2014).
A notable difference in lipid effects between Rx omega- 3s is that increases in LDL-C have been observed after treatment with products containing both DHA and EPA, but have not been associated with EPA-only treatment (icosapent ethyl) (Ballantyne et al., 2012; Bays et al., 2011; Davidson et al., 2007; Harris et al., 1997; Kastelein et al., 2014; Maki et al., 2013; Pownall et al., 1999). DHA has
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Table 2 Impact of Rx omega-3s containingDHA+EPAandEPA-only on lipid parameters (Ballantyne et al., 2012; Bays et al., 2011; Davidson et al., 2007;
Epanova [package insert]; Kastelein et al., 2014; Lovaza [package insert];
Maki et al., 2013; Omtryg [package insert]; Vascepa [package insert])
Rx omega-3 (4 g/day)
Impact on lipid profile
Products containing
both DHA and EPAa EPA-only product
(icosapent ethyl)b
Baseline TGs �500 mg/dL
TGs −12 to −52%c −33% TC −7 to −9% −16% Non-HDL-C −9 to −10% −18% ApoB +2% −9% LDL-C +15 to +49% −2%
Baseline TGs 200 to 499 mg/dL
TGs −23% −22% TC −3% −12% ApoB −2% −9% Non-HDL-C −7% −14% LDL-C +4% −6%
ApoB, apolipoprotein B; DHA, docosahexaenoic acid; EPA, eicosapen-
taenoic acid; LDL-C, low-density lipoprotein cholesterol; non-HDL-C,
nonhigh-density lipoprotein cholesterol; TC, total cholesterol; TGs, triglyc-
erides.
Values represent median % differences versus placebo. aLovaza (omega-3-acid ethyl esters), Lovaza generics, Epanova (omega-3-
carboxylic acids), Omtryg (omega-3-acid ethyl esters A). Only Lovaza and its
generics are currently commercially available. bVascepa. cLarge range of TG reduction because of wide variation in baseline TGs
between studies.
been found to raise LDL-C levels through multiple mecha- nisms (Jacobson et al., 2012; Wei & Jacobson, 2011). This differential effect on LDL-C underlies a key distinction in the respective product labels: periodic monitoring of LDL- C during therapy is required for the products containing DHA (Epanova [package insert], 2017; Lovaza [package insert], 2015; Omtryg [package insert], 2014) but not for the product containing high-purity EPA (Vascepa [pack- age insert], 2017). The potential LDL-C increase associ- ated with DHA-containing products may complicate pa- tient management and interfere with the attainment of LDL-C goals.
As the primary lipoprotein found in atherogenic cholesterol-carrying particles, apolipoprotein B (ApoB) is an important marker of atherosclerosis (Brown, Sacks, & Sniderman, 2015). In clinical trials, EPA-only treatment has been shown to significantly reduce ApoB compared with placebo in patients with both high or very high TGs (Ballantyne et al., 2012; Bays et al., 2011). However, prod- ucts containing both EPA and DHA have variable results with respect to ApoB changes in clinical trials, with neutral effects or increases in ApoB in patients with very high TGs
and modest, but statistically significant, decreases in pa- tient populations with high TGs on statin therapy (David- son et al., 2007; Kastelein et al., 2014; Maki et al., 2013).
Safety of Rx omega-3s
Rx omega-3s have a well-established and longstanding record of safety. The FDA-approved Rx omega-3s are safe and well tolerated, with a low incidence of adverse events (AEs). For Rx products containing both DHA and EPA, the most commonly reported AEs include gastrointestinal ef- fects such as eructation, dyspepsia, nausea, diarrhea, and taste perversion (reported in �3% of patients and at a higher rate than placebo) (Epanova [package insert], 2017; Lovaza [package insert], 2015; Omtryg [package insert], 2014). For icosapent ethyl, arthralgia is the most com- monly reported AE (reported in �2% of patients and at a higher rate [2.3%] than placebo [1.0%]) (Vascepa [pack- age insert], 2017).
The potential for bleeding risk with omega-3s has been the subject of extensive review, with collective data sup- porting that omega-3s are not associated with an in- creased risk of clinically significant bleeding, even in patients on antiplatelet or antithrombotic treatments (Bays, 2007; Begtrup, Krag, & Hvas, 2017; Harris, 2007; Wachira, Larson, & Harris, 2014; Watson, Joy, Nkonde, Hessen, & Karalis, 2009). For Rx omega-3s, the prescribing information notes that prolongation of bleeding time re- ported with omega-3s has not exceeded normal limits and has not produced clinically significant bleeding episodes (Lovaza [package insert], 2015; Vascepa [package insert], 2017). It is recommended that patients who are treated with Rx omega-3s and other drugs that affect coagulation be monitored periodically. Of interest, a drug–drug inter- action study of icosapent ethyl with warfarin in healthy adults found no effect on anticoagulation pharmacody- namics (Braeckman, Stirtan, & Soni, 2014).
Pleiotropic effects of omega-3s
Beyond the lipid profile effects observed in clinical tri- als, omega-3s also have other potential cardiovascular benefits including anti-arrhythmic, anti-thrombotic, anti- atherosclerotic, anti-hypertensive, and anti-inflammatory effects (Endo & Arita, 2016; Mozaffarian & Wu, 2011). In particular, EPA has beneficial effects at multiple steps in atherosclerosis (Borow, Nelson, & Mason, 2015) that may help to slow its development and progression. These effects include improved endothelial and vascu- lar function, reduced monocyte migration/differentiation and development into foam cells, reduced inflamma- tion (reduced pro-inflammatory cytokine levels and in- creased anti-inflammatory cytokines), and reduced plaque
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A. S. Gutstein & T. Copple Rx omega-3s and fish oil supplements
volume and carotid intima-media thickness (which sug- gests inhibition of plaque formation and progression) (Ando et al., 2015; Cawood et al., 2010; Dangardt et al., 2010; Grenon et al., 2012; Katoh & Ikeda, 2011; Mita et al., 2007; Niki et al., 2012; Nishio et al., 2014; Sasaki, Miwa, & Odawara, 2012; Satoh-Asahara et al., 2012; Shintani & Kawasaki, 2012; Thies et al., 2003; Toyama et al., 2014; Wakita, Wakida, Itou, & Mizuno, 2013). Furthermore, omega-3s have been shown to reduce platelet aggrega- tion, which may help to limit thrombus formation follow- ing plaque rupture (Gajos, Rostoff, Undas, & Piwowarska, 2010).
Rx omega-3s versus omega-3 dietary supplements
Important differences between omega-3 dietary supple- ments and Rx omega-3s are summarized in Figure 2. The lack of strict regulatory oversight for dietary supplements as a class raises dual concerns regarding the lack of proven efficacy and the potential for serious safety issues. In re- cent years, these concerns have been the subject of reports in prominent medical journals such as the Journal of the American Medical Association (Cohen, 2016; Kantor, Rehm, Du, White, & Giovannucci, 2016) and the New England Journal of Medicine (Geller et al., 2015) and have been fea- tured in high-profile mainstream media such as the New York Times (Brody, 2016a,b; O’Connor, 2015). The authors of these articles and other experts have called for increased regulatory oversight of the supplement industry.
Key points for patient education
Fish oil products are among the most commonly con- sumed dietary supplements in the United States (Clarke, Black, Stussman, Barnes, & Nahin, 2015), and thus there are frequent opportunities for patient education in clini- cal practice. Specifically, it is important that patients un- derstand that dietary supplements should not be mistaken for medications, as they are not approved or appropriate for the treatment of any disease. In contrast to omega- 3 dietary supplements, Rx omega-3s have demonstrated robust TG reductions in rigorous clinical trials that led to their approval by the FDA. Likewise, there are myriad con- cerns with dietary supplements in terms of quality, con- tent variability, and unwanted ingredients, whereas the safety and tolerability profile of Rx omega-3s is well es- tablished and the contents of Rx omega-3s are well con- trolled, regulated, and frequently checked. It should be made clear that although Rx omega-3 drugs may be de- rived from fish oils, they are not “fish oil,” and, although omega-3 dietary supplements such as fish oil products con- tain omega-3s, these supplements are not equivalent to or interchangeable with the Rx products. The bottom line
is that patients should not substitute an omega-3 dietary supplement for their Rx omega-3. Another consideration is that some Rx omega-3 and fish oil products are associ- ated with a fishy taste/taste perversion that may impact pa- tient adherence; this is less of an issue with Rx high-purity EPA.
Cost considerations and Rx omega-3 product substitution
Concerns about the cost of Rx omega-3s may some- times lead to inappropriate substitution of omega-3 dietary supplements for Rx products. Another issue is that pa- tients and/or healthcare providers may assume generic Rx omega-3s are less expensive than brand-name Rx omega- 3s; however, the costs are often comparable. In addition, potential cost savings with supplements may be offset when attempting to achieve a prescription-strength dose, and the risk of adverse lipid consequences that have been associated with supplements may be increased when used in higher doses (Mason & Sherratt, 2017; Rundblad, Hol- ven, Ottestad, Myhrstad, & Ulven, 2017; Zargar & Ito, 2011).
For some patients, costs of Rx products can be a barrier to the management of hypertriglyceridemia. Patient dis- count/savings programs are available for some Rx omega- 3s and may help address this concern (GSK for You, 2017; Vascepa Savings Program, 2017). In addition, among Rx omega-3s, pure EPA has no “therapeutic equivalent” by FDA standards (Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations, 2017). There- fore, Rx products containing both DHA and EPA should not be substituted for the EPA-only product. From a clin- ical point of view, the potential effects on ApoB and LDL- C increases associated with switching from the EPA-only product to a combination DHA+EPA product could com- plicate patient lipid management (Crandell, Tartaglia, & Tartaglia, 2016; Kedia & Lynch, 2015).
Overview of omega-3 outcomes studies
Overview of omega-3 cardiovascular outcomes data
There is a need to address the residual cardiovascu- lar risk in statin-treated patients, and addition of Rx omega-3 treatment may be an option for achieving this goal; however, the results of omega-3 cardiovascular outcomes clinical trials have been inconsistent (GISSI Prevenzione Investigators, 1999; GISSI HF Investigators, 2008; Kromhout, Giltay, & Geleijnse, 2010; Risk and Pre- vention Study Collaborative Group, 2013; ORIGIN Trial Investigators, 2017; Rauch et al., 2010; Yokoyama et al., 2007). Potential explanations for the lack of observed risk
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Figure 2 Key differences and shared features of OM3s. aLovaza (omega-3-acid ethyl esters), Lovaza generics, Epanova (omega-3-carboxylic acids), Omtryg (omega-3-acid ethyl esters A). Only Lovaza and its generics are currently commercially available. DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid;
FDA, Food and Drug Administration; GI, gastrointestinal; LDL-C, low-density lipoprotein cholesterol; OM3, omega-3 fatty acid; OTC, over-the-counter; Rx,
prescription; TGs, triglycerides; Tx, treatment.
reduction include omega-3 doses that were too low and patient populations that were not appropriate for observ- ing significant risk reduction. For example, none of the completed studies investigated patients with high-baseline TGs and not all studies investigated Rx omega-3s (some investigated omega-3 dietary supplements).
A notable consequence of the inconsistent findings from omega-3 outcomes studies to date is inconsistent rec- ommendations by various health guidelines, with many turning away from recommending low-dose omega-3 di- etary supplements (Hilleman & Smer, 2016). The Amer- ican Diabetes Association recommends eating foods rich in omega-3 fatty acids, but does not recommend omega- 3 dietary supplements for cardiovascular disease preven- tion in patients with diabetes, stating that evidence does not support a beneficial role for these supplements (Amer-
ican Diabetes Association, 2017). Similarly, the Interna- tional Atherosclerosis Society states that low-dose omega- 3 dietary supplementation does not reduce risk in rou- tine secondary prevention of dyslipidemia (International Atherosclerosis Society, 2014). The American Associa- tion of Clinical Endocrinologists recommends prescription omega-3s (2–4 g daily) for treatment of severe hyper- triglyceridemia (TGs �500 mg/dL), noting that dietary supplements are not approved by FDA for treatment of hy- pertriglyceridemia and generally are not recommended for this purpose (Jellinger et al., 2017).
The 2017 Science Advisory from the American Heart Association (AHA) on omega-3 supplementation and the prevention of clinical cardiovascular disease found that supplementation was not reasonable for the following five conditions: primary prevention of coronary heart disease
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A. S. Gutstein & T. Copple Rx omega-3s and fish oil supplements
(CHD) in the general population, primary prevention of heart failure, prevention of cardiovascular disease mortal- ity in patients with diabetes, or primary and secondary prevention of stroke and atrial fibrillation (Siscovick et al., 2017). There was a lack of consensus regarding preven- tion of CHD among patients at high risk of cardiovascu- lar disease and secondary prevention of CHD and sudden cardiac death among patients with prevalent CHD (Siscov- ick et al., 2017). Notably, the AHA acknowledged that re- cent randomized controlled trials raise questions regarding the benefits of omega-3 supplements, but stood by their recommendation of 1 g of omega-3 supplements daily (in consultation with a physician) for secondary prevention of CHD in patients with a recent CHD event (e.g., post- myocardial infarction) as a reasonable approach; another group in whom the AHA considered supplements to be reasonable were patients with heart failure with reduced left ventricular function. The AHA points out that, com- pared with 15–20 years ago, the risk of recurrent events in patients with CHD who are treated with currently rec- ommended guideline-based therapy is relatively low, and thus the role of omega-3 supplements in such patients is not well established.
While dietary supplements may have a place for gen- eral wellness in healthy consumers wishing to increase their omega-3 intake, these guideline updates underscore that the use of omega-3 dietary supplements for dis- ease management or treatment is complex and often not recommended or appropriate (Hilleman & Smer, 2016). Cardiovascular guidelines regarding prescription-strength omega-3s currently focus on efficacy of these products for TG lowering (Jacobson et al., 2015; Jellinger et al., 2017; Miller et al., 2011; Stone et al., 2014). The results of on- going outcomes studies described in the next section will help determine the role of Rx omega-3s in patients at high risk of cardiovascular disease.
New omega-3 cardiovascular outcomes studies
In contrast to some of the matters discussed in the previous section regarding past cardiovascular outcomes studies, new Rx omega-3 trials have been designed to employ higher doses (4 g/day) and to target high-risk pa- tients with high TGs (200–500 mg/dL). These new omega- 3 CV outcomes studies are expected to provide important insight as to whether these products can reduce resid- ual CV risk in statin-treated patients (Bhatt et al., 2017; STRENGTH study; REDUCE-IT study, 2017, December 12). The REDUCE-IT study (NCT01492361) is investi- gating the EPA-only product, icosapent ethyl, in statin- treated patients with established cardiovascular disease or at high risk of cardiovascular disease (Bhatt et al., 2017; REDUCE-IT study, 2017, December 12). The
STRENGTH study (NCT02104817) (2017, December 12) is investigating the DHA+EPA combination product, omega-3-carboxylic acids, in patients with atheroscle- rotic cardiovascular disease or at high risk of a future cardiovascular event. Additional large ongoing studies are evaluating relatively low doses of omega-3s, which are comparable with dietary supplements. These include VITAL (NCT01169259), ASCEND (NCT00135226), and OMEMI (NCT01841944), which are assessing omega-3s (DHA+EPA) with vitamin D in the general population, omega-3s (DHA+EPA) with aspirin in patients with dia- betes, and omega-3s (DHA+EPA) in elderly patients post- myocardial infarction, respectively (ASCEND study, 2015, December 2; Laake et al., 2014, 2016; VITAL study, 2017, December 12). Collectively, these trials will cover over 60,000 patients, underscoring the importance and interest in omega-3 treatment. REDUCE-IT will be the only cardio- vascular outcomes study conducted with high-dose, pure EPA in a prescription form in patients with persistently ele- vated TGs despite statin treatment; REDUCE-IT is expected to complete in early 2018 with results expected to be re- ported in Q3 2018.
Reducing residual risk with add-on therapy to statins
Several studies support the benefits of using pure EPA as an anti-atherosclerotic agent in addition to statins for reducing residual cardiovascular risk. In the JELIS study, Japanese patients with hypercholesterolemia who were treated with high-purity EPA plus statin had significantly reduced major coronary events compared with patients treated with statin therapy alone (relative risk reduction of 19% with EPA, P = 0.011) (Yokoyama et al., 2007). The ongoing RESPECT-EPA study in Japan has been designed to confirm the results of JELIS in a secondary prevention population (RESPECT-EPA study, 2017, January 9). In an- other Japanese study of 241 patients, EPA reduced the ab- solute risk of cardiovascular events by 11% (P = 0.02) in the 1-year period following percutaneous coronary inter- vention (Nosaka et al., 2017). Also of interest are data sug- gesting that use of EPA with a statin can stabilize vulner- able plaques more effectively than statin treatment alone (Nishio et al., 2014). It should be noted that findings from these studies of Japanese patients may not be generalizable to other populations.
The concept that the addition of other lipid-lowering agents to statins can reduce residual cardiovascular risk is also supported by recent clinical trials of ezetim- ibe (IMPROVE-IT) (Cannon et al., 2015) and the pro- protein convertase subtilisin–kexin type 9 (PCSK9) in- hibitor evolocumab (FOURIER) (Amgen press release, 2017; Bonaca et al., 2017). The data anticipated from the ongoing large-scale and long-term cardiovascular
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outcomes studies of high-dose Rx omega-3s (REDUCE- IT and STRENGTH) will provide important information regarding the ability of Rx omega-3s to reduce residual cardiovascular risk, enabling nurse practitioners to more definitively address the needs of this patient population.
Summary and conclusions
Reduction of residual cardiovascular risk is an impor- tant goal in the management of statin-treated patients in clinical practice. Mounting evidence supports that TGs and TG-rich lipoproteins play an important and causal role in cardiovascular disease. High-dose Rx omega-3s effectively lower TGs and represent a potential option to reduce resid- ual cardiovascular risk in statin-treated patients. Omega-3s are available as Rx drugs and dietary supplements such as fish oils. The enormously popular fish oil (omega-3) di- etary supplements may be misconstrued by patients and healthcare professionals as a solution to the problem of residual cardiovascular risk. Although fish oil supplements may contain omega-3s, these products are not defined as medications by the FDA, but rather as foods to sup- plement the diet. Omega-3 dietary supplements are not FDA-approved OTC products, are not nearly as highly reg- ulated as OTC or prescription omega-3 products, and have been shown to contain variable levels of EPA and DHA as well as other fats, cholesterol, and potentially harmful ox- idized contaminants. Thus, omega-3 dietary supplements are not appropriate for disease treatment and should not be substituted for Rx omega-3s. In contrast, Rx omega- 3s are high-purity, FDA-approved products, and as such are subject to rigorous regulation and supported by robust clinical safety and efficacy studies. Rx and dietary supple- ment omega-3 products that contain DHA may raise LDL- C and have mixed effects on ApoB. They should not be substituted for Rx EPA-only icosapent ethyl, which did not raise LDL-C and decreased ApoB compared with placebo in clinical trials. Results of ongoing large cardiovascular out- comes studies designed to assess the efficacy of high-dose Rx omega-3s for cardiovascular risk reduction in statin- treated patients are highly anticipated. Nurse practitioners are on the front lines of treating patients with cardiovascu- lar risk and can play an important role in the better under- standing and appropriate use of the wide range of omega- 3 products available today. Key points and misperceptions regarding omega-3 products need to be widely appreciated and understood, especially in cases where patients are at risk of progressive disease.
Author contributions
Adina S. Gutstein and Tina Copple had full editorial con- trol of the subject matter and planning of the manuscript,
provided critical revision and review of the manuscript, and approved the final draft for submission.
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Other Reviewobr_599 475..486
Effect of calcium from dairy and dietary supplements on faecal fat excretion: a meta-analysis of randomized controlled trials
R. Christensen1, J. K. Lorenzen2, C. R. Svith1,2, E. M. Bartels1,3, E. L. Melanson4, W. H. Saris5, A. Tremblay6 and A. Astrup2
1The Parker Institute, Musculoskeletal
Statistics Unit, Frederiksberg Hospital,
Frederiksberg, Denmark; 2Department of
Human Nutrition, Centre for Advanced Food
Studies, Faculty of Life Sciences, University of
Copenhagen, Frederiksberg, Denmark; 3Copenhagen University Library,
Copenhagen, Denmark; 4Division of
Endocrinology, Metabolism, and Diabetes,
University of Colorado Denver, Aurora, CO,
USA; 5Nutrition and Toxicology Research
Institute Maastricht, Department of Human
Biology, Maastricht University, Maastricht, The
Netherlands; 6Division of Kinesiology (PEPS),
Department of Social and Preventive
Medicine, Laval University, Québec, Canada
Received 28 October 2008; revised 16 March
2009; accepted 17 March 2009
Address for correspondence: Professor A
Astrup, Department of Human Nutrition, LMC,
Faculty of Life Sciences, University of
Copenhagen, DK-1958 Frederiksberg,
Denmark. E-mail: ast@life.ku.dk
Summary Observational studies have found that dietary calcium intake is inversely related to body weight and body fat mass. One explanatory mechanism is that dietary calcium increases faecal fat excretion. To examine the effect of calcium from dietary supplements or dairy products on quantitative faecal fat excretion, we performed a systematic review with meta-analysis. We included randomized, controlled trials of calcium (supplements or dairy) in healthy subjects, where faecal fat excretion was measured. Meta-analyses used random-effects models with changes in faecal fat excreted expressed as standardized mean differences, as the studies assessed the same outcome but measured in different ways.
An increased calcium intake resulted in increased excretion of faecal fat by a standardized mean difference of 0.99 (95% confidence intervals: 0.63–1.34; P < 0.0001; expected to correspond to ~2g day-1) with moderate heterogeneity (I2 = 49.5%) indicating some inconsistency in trial outcomes. However, the dairy trials showed homogeneous outcomes (I2=0%) indicating consistency among these trials. We estimated that increasing the dairy calcium intake by 1241 mg day-1 resulted in an increase in faecal fat of 5.2 (1.6–8.8) g day-1. In conclusion, dietary calcium has the potential to increase faecal fat excretion to an extent that could be relevant for prevention of weight (re-)gain. Long-term studies are required to establish its potential contribution.
Keywords: Dairy products, dietary calcium, faecal fat excretion, meta-analysis.
obesity reviews (2009) 10, 475–486
Introduction
An inverse association between dietary calcium intake and body weight was first reported in the mid-1980s based on data from the first National Health and Nutritional Exami- nation Survey in the US. (1). Since then, similar associations between calcium intake, or intake of dairy products, and body weight and body fat mass have been found in several observational studies (2–6), but not in all (7,8). A number of randomized intervention studies examining the effect of calcium supplements or dairy calcium have not produced a
clear answer as to whether calcium may have a role in energy balance. In several studies, Zemel and colleagues have found that subjects randomized to a high-calcium intake achieve a significantly greater reduction in body weight and body fat during energy restriction than those with a low-calcium intake (9–11). However, a recent meta-analysis of interven- tion studies that examined the effect of calcium on weight loss showed that the results of the available trials are het- erogeneous – with contradictory results (12).
The mechanism responsible for the potential effect of increased calcium intake on energy balance is not clear, but
obesity reviews doi: 10.1111/j.1467-789X.2009.00599.x
475© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
a number of different mechanisms have been suggested. Zemel and colleagues have advocated a hypothesis that calcium intake plays a regulatory role in lipid metabolism by influencing intracellular calcium levels via hormonal regulation (13). According to this hypothesis, an increase in dietary calcium would result in increased lipolysis and decreased de novo lipogenesis, thereby stimulating loss of body weight and fat (13). However, the hypothesis is mainly supported by animal studies, while recent human studies do not indicate that adipocyte and whole body fat metabolism are affected by dietary calcium intakes (14– 17). Although it has been suggested that high-calcium intake may increase fat oxidation under conditions of acute energy deficit, a number of studies have failed to detect any consistent effect of calcium on energy expenditure during energy balance (14,15,18–20). However, a reduction in body fat stores cannot occur without either affecting energy intake, faecal energy loss, or increasing energy expenditure. It has recently been suggested that supplementation with a calcium plus vitamin D in subjects with a habitual low intake of calcium results in a decrease in ad libitum intake of energy and fat (21). More research is needed to establish if and how calcium intake affects human appetite regula- tion. Another mechanism, suggested by a number of studies in both humans and animals, is that dietary calcium inter- feres with fat absorption in the intestine by forming insoluble calcium soaps with fatty acids (FAs) and/or binding of bile acids, resulting in a decrease in the digestible energy of the diet (15,18,22–25).
We carried out a quantitative systematic review on ran- domized, controlled trials to determine the effectiveness of calcium supplementation – from either dairy products or dietary supplements – on changes in faecal fat excretion. A secondary aim was to explore whether an increased faecal fat loss could be explained by typical bias items, such as blinding and randomization, affecting individual trials’ internal validity (26,27). Finally, we examined whether the effect could be explained by the amount of calcium admin- istered, and whether the level of protein in the diet could modify any effect of dietary calcium on faecal fat excretion (15,18).
Methods
Study selection, assessment of eligibility criteria, data extraction and statistical analysis were performed based on a predefined protocol according to the Cochrane Collabo- ration guidelines (28). This article was prepared in accor- dance with the Quality of Reporting of Meta-analyses statement (29).
Literature search
The following databases were searched: Medline (Mid- 1950s to May 2008), EMBASE (1980 to May 2008), Web
of Science (1945–54 to May 2008), BiosisPreviews (1980 to May 2008), Scifinder (1907 to May 2008), Agricola (1970 to May 2008), Food Science Technical Abstracts [FSTA] (1969 to May 2008), CAB Abstracts (1973 to May 2008), Cochrane Central Register of Controlled Trials (until May 2008). The search strategy contained the fol- lowing: (calcium* OR milk* OR dairy*) AND (lipid* OR fat*) AND (faeces* OR feces* OR faecal* OR fecal* OR stool*) AND human*. There were no limits on language or publication type. As a supplement to the systematic litera- ture search, two reviewers (J. K. L. & A. A.) contacted (via email) other known experts in the field (including all first authors of the papers retrieved). Searching for potentially unpublished data was supervised by three experts in the field (E. L. M., W. H. S., A. T.). The reference lists of relevant reviews or potentially eligible papers were also checked for other possible eligible trials. Finally the Global Dairy Platform (Chicago, US) was contacted in order to reveal any extra data not already available in the public domain.
Selection criteria
All randomized and quasi-randomized controlled trials were considered eligible if they (i) Enrolled healthy partici- pants, whether adults, adolescents or children more than 6 years of age; (ii) Examined the effect of intake of calcium from dairy products or dietary supplements and (iii) Reported changes in faecal fat – i.e. either as total fat or as FAs. There was no upper limit to the duration of trials considered eligible. In order to ensure adequate methodol- ogy, studies were eligible for inclusion if the time from starting the intervention to the measurement of the faecal fat excretion was at least 3 days. Studies with a crossover design were considered eligible for inclusion in the meta- analysis as the risk of carry-over effect was considered minimal (30). The preliminary literature search for poten- tially eligible studies (conducted by J. K. L. & C. R. S.) was supervised by an experienced research librarian (E. M. B.). Two investigators (J. K. L. & C. R. S.) concluded the literature search by eliminating/including studies according to the agreed eligibility criteria, and obtained approval of the result via a consensus call with the other content expert reviewers (E. L. M., W. H. S., A. T., and A. A.).
Data extraction and quality assessment
The included studies were scrutinized and reviewed (without blinding of reviewers). Data were extracted using a customized form (Microsoft Excel® spreadsheet) pro- vided by a fourth reviewer (R. C.), including (i) Character- istics of included studies; (ii) The Cochrane Collaboration’s tool for assessing risk of bias and (iii) Outcome mea- sures applicable for the subsequent data analyses. Two
476 Calcium and faecal fat excretion R. Christensen et al. obesity reviews
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
investigators (R. C. & J. K. L.) were responsible for the assessment and extraction of data. The extracted outcome was the difference between the intervention and control groups (i.e. the paired mean difference in crossover studies), and the variance measure was obtained for each trial according to a standardized procedure using a data abstraction form. Data were collected on trial design (par- allel vs. crossover), duration of the trial, type of calcium (dairy product, dietary supplement), calcium dosage applied compared with the control group (mg) and the estimated average level of protein intake in the study. Fur- thermore, data were extracted on sample size and charac- teristics of the study population, including the subjects’ average age and sex (proportion of men).
In order to apply the Cochrane Collaboration’s tool for assessing risk of bias, two reviewers (R. C., J. K. L.) inde- pendently assessed whether each of the following domains would be considered adequate – i.e. presumably with a low risk of bias (i) ‘Adequate sequence generation’; (ii) ‘Alloca- tion concealment’; (iii) ‘Blinding’; (iv) ‘Incomplete outcome data addressed’; (v) ‘Free of selective reporting’ and (vi) ‘Free of other biases’ (published as a peer-reviewed paper). Each of these key components of methodological quality was assessed on a Yes/Unclear/No basis, handled as A, B and C, respectively (http://www.cochrane-handbook.org/). Any differences between reviewers were resolved at a subsequent consensus meeting (with A. A.).
Data synthesis and analysis
For crossover trials lacking data on standard errors (SEs) for paired differences (SED), the pooled SE was estimated assuming a correlation at a conservative level of 0 between intervention and control periods (r = 0.0) in crossover trials (30). We anticipated that the type of outcome
measurement would vary across individual studies, so the standardized mean difference (SMD including Hedges’s adjustment for small sample bias (31)) was used as the summary statistic in the meta-analysis – assessing the same outcome measured in a variety of ways (32). The SMD expresses the size of the treatment effect relative to the variability observed in that trial ([mCalcium - mControl]/s), using slightly different calculi for parallel or crossover trial designs (31,33). To combine the individual study results, we performed meta-analyses using SAS software (PROC MIXED version 9.1.3; SAS Institute Inc., Cary, NC, USA), applying a restricted maximum likelihood (REML) method to estimate the between-study variance (i.e. t2) and the combined efficacy (34). We examined heterogeneity between trials with a standard Q-test statistic (35), and we present the I2 value (36), which can be interpreted as the amount of inconsistency in the reported results between the individual studies (37). We performed a number of pre- defined sensitivity analyses, subgroup analyses stratifying the available trials according to calcium from dairy products vs. dietary supplements, and analyses of varying degrees of risk of bias according to the Cochrane Collabo- ration’s tool for assessing risk of bias. REML-based (i.e. random-effects) meta-regression analysis (38) was applied in order to answer the specific question raised by the sec- ondary hypothesis – whether the amount of extra calcium could predict the quantitative changes in faecal fat loss.
Results
Results of the search
We identified more than 300 studies in the database searches, of which 62 studies were potentially relevant and therefore read in full text (Fig. 1). Of these, a total of 45
Figure 1 Quality of Reporting of Meta-analyses (QUOROM) flowchart.
obesity reviews Calcium and faecal fat excretion R. Christensen et al. 477
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
studies were immediately excluded: 10 studies did not report original research (reviews, etc.); one was an in vitro study; 16 studies did not include a separate calcium or dairy intervention and the isolated contrast associated with supplementation could therefore not be evaluated; 12 had no measurement of faecal fat excretion but only measured fat in a single stool; one study only measured the fat content in faecal water; one study was judged methodologi- cally insufficient because of problems with separation of stools from the two intervention periods; and five studies focused on patients or subjects with previous or current gastrointestinal diseases. This left 17 potentially eligible studies. However, four of these studies were not random- ized in any way and were therefore excluded. The remain- ing 13 studies were deemed eligible for inclusion in the systematic review (15,18,39–49). Two of these studies could be handled as having a factorial design (15,40), resulting in a final total of 15 substudies included in the meta-analysis.
Description of studies
The average characteristics of the included studies are shown in Table 1. The trials were published between 1964 and 2008, and varied in participant size. The majority of trials were crossover trials. A total of 168 participants were assessed (focusing solely on the individuals included in the analyses) – receiving extra calcium, an appropriate control, or both. The length of the trials varied from 3 days to 1 month. The studies had more or less the same primary end point – either total fat excreted via faeces or a specific focus on free FAs (Table 1). In two of the included studies, the time from starting the intervention to the measurement of the faecal fat excretion was less than 3 days (45,49). In the study by Bendsen et al., the intervention started 2 days before the faecal collection was started (49): in this study the mean transit time was estimated by non-absorbable faecal markers to be ~40 h and it was therefore included. In the study by Murata et al., the subjects were given two different oral trace markers, one at the beginning and one at the end of the diet period (45). Excretion of these trace markers was used to determine when to begin and when to end faecal collection.
Effect of intervention
Calcium supplementation resulted in an increased excre- tion of faecal fat and FAs compared with control groups, with a SMD of 0.99 (95% confidence intervals [CI]: 0.63– 1.34; z = 5.44, P < 0.0001; Fig. 2). There was no evidence to indicate a difference between the calcium supplements and calcium from dairy products (1.04 vs. 0.90, respec- tively; z = 0.30, P = 0.76). Assuming an average (�SD) fat excretion in the population of 5.4 (�2.0) g day-1 (43), we
estimate that applying extra calcium (with a range from 800 to 6000 mg day-1) would result in an increase of 2.0 (95% CI: 1.3–2.7) g faecal fat excreted (37% increase) each day. The meta-analysis was based on studies showing a moderate degree of heterogeneity (I2 = 49.5%), support- ing the use of a random-effects meta-analysis. As a sensi- tivity analysis, the same meta-analysis based on a fixed- effects model resulted in a combined SMD of 0.80 (95% CI: 0.55–1.04, P < 0.0001). When the studies were divided into studies using calcium supplementation and studies using dairy calcium, a relatively high degree of heterogene- ity (I2 = 58.5%) was found among the studies using calcium supplements. In contrast, the dairy calcium studies showed homogeneity (I2 = 0%). We therefore conducted a meta-analysis with the faecal fat excretion expressed as gram per day as all the dairy trials used the same outcome measure. An increased dairy calcium intake of 1241 mg day-1 increased faecal fat excretion by 5.2 g day-1 com- pared with low-calcium (<700 mg day-1) dairy diet (95% CI: 1.6–8.8; see Fig. 3). One of the inclusion criteria was that the time from starting the intervention to measurement of faecal fat excretion was at least 3 days. However, as mentioned previously, two studies departed somewhat from this condition (44,49). In a sensitivity analysis, we therefore grouped these two studies as potentially inad- equate compared with the other studies (see Table 1). There was no significant difference between the two subgroups (z = 1.07, P = 0.28), although the studies indexed as being adequate showed a less pronounced efficacy (SMD = 0.91 [SE = 0.19]) when compared with those categorized as potentially inadequate (SMD = 1.56 [SE = 0.57]).
Risk of bias in included studies Table 2 presents results from stratified analyses. Estimates of effect sizes varied to some degree depending on the quality of the trials. When meta-analysing the trials, with explicit focus on the adequacy of random and concealed allocation, the studies indexed as adequate had the least pronounced effect size compared with those indexed as inadequate. The same pattern applied for handling of incomplete outcome data, free of selective outcome report- ing, and whether or not the study had been presented in a peer-reviewed journal. In contrast, the adequately double- blinded trials seemed to have a more pronounced effect than those with an unclear risk of bias (not significant, P = 0.78).
Association between intake and size of faecal fat excretion We found no relationship between amounts of extra calcium applied in the individual trials (see Fig. 4A) and the increase in faecal fat excretion expressed as SMD, as the slope was not significantly different from null (z = 0.37, P = 0.71). Accordingly the overall efficacy associated with
478 Calcium and faecal fat excretion R. Christensen et al. obesity reviews
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
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obesity reviews Calcium and faecal fat excretion R. Christensen et al. 479
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
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C on
tro lle
d d
ie t
w ith
: C
a( +)
hi g
h ca
lc iu
m fro
m d
ai ry
p ro
d uc
ts C
a( -)
lo w
ca lc
iu m
C ro
ss ov
er :
tw o-
g ro
up co
m p
ar is
on
47 4*
,† †
To ta
lf at
(g d
ay -1
) 14
.2 �
6† 6.
0 �
2 1
w ee
k 3
d ay
s ~1
0 00
0† †
15 C
ro ss
ov er
: N
= 8
N A
N A
B oo
n et
al .
(D ai
ry )
20 07
N et
he rla
nd s
H ea
lth y
m en
an d
w om
en C
on tro
lle d
d ie
t w
ith :
C a(
+) hi
g h
ca lc
iu m
fro m
d ai
ry p
ro d
uc ts
C a(
-) lo
w ca
lc iu
m
C ro
ss ov
er :
2 ¥
1 p
se ud
o fa
ct or
ia l
d es
ig n
34 8
� 28
†† To
ta lf
at (g
d ay
-1 )
7. 2
� 3.
5 4.
8 �
2. 5
1 w
ee k
3 d
ay s
~1 0
00 0†
† 20
C ro
ss ov
er :
N =
10 5
(5 0%
) 28
� 6
B en
d se
n et
al .
20 08
D en
m ar
k H
ea lth
y m
en an
d w
om en
C on
tro lle
d d
ie t
w ith
: C
a( +)
hi g
h ca
lc iu
m fro
m d
ai ry
p ro
d uc
ts C
a( -)
lo w
ca lc
iu m
C ro
ss ov
er :
tw o-
g ro
up co
m p
ar is
on
69 8
� 15
3† †
To ta
lf at
(g d
ay -1
) 11
.5 �
4. 6†
5. 4
� 1.
7 1
w ee
k 5
d ay
s ~1
2 50
0† †
15 C
ro ss
ov er
: N
= 11
5 (4
5% )
33 (r an
g e
25 –4
7)
Va lu
es ar
e M
ea ns
� S
D un
le ss
ot he
rw is
e st
at ed
. *S
D no
t st
at ed
in th
e p
ap er
. † S
ig ni
fic an
t d
iff er
en t
fro m
C a(
-) (P
< 0.
05 ).
‡ T he
su b
je ct
s ha
d co
ns um
ed a
d ie
t si
m ila
r to
th e
ex p
er im
en ta
ld ie
t fo
r at
le as
t on
e ye
ar p
rio r
to th
e st
ud y.
§ S ta
nd ar
d se
rv in
g of
co nt
ro lle
d d
ie t.
In ta
ke ad
ju st
ed ac
co rd
in g
to in
d iv
id ua
le ne
rg y
re q
ui re
m en
t b
y re
m ov
in g
or ad
d in
g ca
rb oh
yd ra
te fo
od .
¶ O
nl y
m aj
or fa
tty ac
id s
(1 4
:0 ,
16 :0
, 18
:0 an
d 18
:1 )
w er
e in
cl ud
ed .
** S
ub je
ct s
w er
e g
iv en
tw o
d iff
er en
t or
al tr
ac e
m ar
ke rs
, on
e in
th e
b eg
in ni
ng an
d on
e in
en d
of th
e d
ie t
p er
io d
. E
xc re
tio n
of th
es e
tr ac
e m
ar ke
rs w
er e
us ed
to d
et er
m en
t w
he n
to b
eg in
an d
w he
n to
en d
fa ec
al co
lle ct
io n.
†† M
ea n
in ta
ke .
In ta
ke ad
ju st
ed ac
co rd
in g
to in
d iv
id ua
le ne
rg y
re q
ui re
m en
t.
480 Calcium and faecal fat excretion R. Christensen et al. obesity reviews
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
-3.5 -2.5 -1.5 -0.5 0.5 1.5 2.5 3.5 Favours calciumFavours placebo/control
Subtotal: supplements
Jacobsen (2005)
Bendsen (2008) Boon (2007)
Subtotal: dairy products
Pooled standardized mean difference
Welberg (1994)
Murata (1998)
Lutwak (1964) Bhattacharyya (1969): PUFA Bhattacharyya (1969): SFA Saunders (1988) Denke (1993)
Govers (1996)
Shahkhalili (2001A) Shahkhalili (2001) Ditscheid (2005) Boon (2007)
Supplements
Dairy products
1.15 (-0.03 to 2.33)
1.14 (0.12 to 2.17) 0.51 (-0.35 to 1.37)
0.64 (-0.34 to 1.62)
2.55 (0.69 to 4.41)
1.64 (0.60 to 2.67) 0.50 (-0.32 to 1.33) 2.33 (0.68 to 3.99) 1.42 (0.10 to 2.73) 0.50 (-0.27 to 1.27)
0.96 (0.07 to 1.85)
2.44 (1.01 to 3.88) 3.29 (0.98 to 5.59) 0.26 (-0.23 to 0.74) 0.38 (-0.45 to 1.22)
1.04 (0.62 to 1.47)
0.90 (0.07 to 1.73)
0.99 (0.63 to 1.34)
Test for homogeneity: χ2 = 26.49, P = 0.005, I 2 = 58.5%
Test for homogeneity: χ2 = 1.16, P = 0.56, I2 = 0.0%
Test for homogeneity: χ2 = 27.71, P = 0.02, I2 = 49.5%
Standardized mean difference
(95% CI)
Test for overall effect: z = 5.44, P < 0.0001
Figure 2 Effects of calcium supplementation on faecal fat excretion; presented as supplements or dairy products. Every square represents the individual study’s SMD with 95% CI indicated by horizontal lines; square sizes are directly proportional to the precision of the estimate.
-2.0 0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0
Extra faecal fat excreted (g day–1)
Dairy products
Jacobsen (2005)
Boon (2007)
Bendsen (2008)
Pooled mean difference
8.2 (3.8 to 12.6)
1.9 (-0.9 to 4.7)
6.1 (3.2 to 9.0)
5.2 (1.6 to 8.8)
Mean difference
(95% CI)
Figure 3 Amount of faecal fat excreted among the homogeneous studies following extra calcium from dairy products. Every square represents the individual study’s mean difference with 95% CI indicated by horizontal lines; square sizes are directly proportional to the precision of the estimate.
obesity reviews Calcium and faecal fat excretion R. Christensen et al. 481
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
Ta b
le 2
R es
ul ts
of th
e st
ra tifi
ed m
et a-
an al
ys es
: st
an d
ar d
iz ed
m ea
n d
iff er
en ce
in fa
ec al
fa t
ex cr
et ed
fo llo
w in
g ex
tr a
ca lc
iu m
op p
os ed
to co
nt ro
li nt
er ve
nt io
n
S tu
d y
D es
ig n
D os
e (C
a: m
g d
ay -1
) R
an d
om al
l1 C
on ce
al ed
al l2
D ou
b le
b lin
d in
g 3
In co
m p
le te
O D
4 Fo
S O
R 5
Fo B
6
S up
p le
m en
ts Lu
tw ak
et al
. (1
96 4)
P G
99 1
C C
B B
A A
B ha
tta ch
ar yy
a et
al .
(1 96
9) C
O 20
00 A
B B
B A
A B
ha tta
ch ar
yy a
et al
. (1
96 9)
C O
20 00
A B
B B
A A
S au
nd er
s et
al .
(1 98
8) C
O 60
00 A
B A
B B
A D
en ke
et al
. (1
99 3)
C O
18 00
B B
A B
B A
W el
b er
g et
al .
(1 99
4) P
G 20
00 B
B A
B A
A G
ov er
s et
al .
(1 99
6) C
O 10
80 B
B A
B B
A M
ur at
a et
al .
(1 99
8) C
O 11
50 B
B A
B B
A S
ha hk
ha lil
ie ta
l. (2
00 1A
) P
G 10
00 B
B A
B B
C S
ha hk
ha lil
ie ta
l. (2
00 1)
C O
90 0
B B
A B
A A
D its
ch ei
d et
al .
(2 00
5) C
O 10
60 B
B A
B A
A B
oo n
et al
. (2
00 7)
C O
80 0
A A
B A
A A
D ai
ry p
ro d
uc ts
Ja co
b se
n et
al .
(2 00
5) C
O 13
00 A
A B
A A
A B
oo n
et al
. (2
00 7)
C O
80 0
A A
B A
A A
B en
d se
n et
al .
(2 00
8) C
O 16
00 A
A B
A A
C C
O :
0. 85
(0 .4
9– 1.
22 )
(S ee
Fi g
ur e
4) A
: 0.
91 (0
.3 6–
1. 45
) A
: 0.
75 (0
.0 6–
1. 44
) A
: 1.
07 (0
.5 3–
1. 60
) A
: 0.
75 (0
.0 5–
1. 45
) A
: 0.
86 (0
.4 4–
1. 29
) A
: 0.
87 (0
.5 2–
1. 22
) P
G :
1. 43
(0 .6
5– 2.
21 )
B :
1. 01
(0 .4
6– 1.
57 )
B :
1. 06
(0 .5
9– 1.
53 )
B :
0. 96
(0 .4
1– 1.
50 )
B :
1. 12
(0 .6
7– 1.
57 )
B :
1. 28
(0 .6
3– 1.
93 )
B )
N A
C :
1. 64
(0 .2
1– 3.
06 )
C :
1. 64
(0 .2
1– 3.
07 )
C :
N A
C :
N A
C :
N A
C :
1. 64
(0 .6
4– 2.
64
Va lu
es ar
e H
ed g
es ’s
st an
d ar
d iz
ed m
ea n
d iff
er en
ce s
(9 5%
co nfi
d en
ce in
te rv
al s)
st ra
tifi ed
ac co
rd in
g p
ot en
tia lr
is k
of b
ia s,
an d
re g
re ss
ed vs
. ex
tr a
ca lc
iu m
d os
ag e
ap p
lie d
. 1:
ra nd
om al
lo ca
tio n,
2: co
nc ea
le d
al lo
ca tio
n, 3:
d ou
b le
b lin
d in
g ,
4: in
co m
p le
te ou
tc om
e d
at a,
5: fre
e of
se le
ct iv
e ou
tc om
e re
p or
tin g
, 6:
fre e
of ot
he r
b ia
s’ (i.
e. p
ub lis
he d
in a
p ee
r- re
vi ew
ed jo
ur na
l) A
: ad
eq ua
te (i.
e. lo
w ris
k of
b ia
s) .
B :
un cl
ea r
(i. e.
un cl
ea r
ris k
of b
ia s)
. C
: in
ad eq
ua te
(i. e.
hi g
h ris
k of
b ia
s in
th e
an al
ys is
). In
t: in
te rc
ep t
w ith
th e
y- ax
is (i.
e. ca
lc iu
m d
os e
= 0
m g
); S
lp :
S lo
p e
(i. e.
in cr
em en
t in
ef fe
ct si
ze w
ith 1
m g
of C
a ad
d ed
). C
O :
cr os
so ve
r tr
ia l;
P G
: p
ar al
le lg
ro up
d es
ig n;
N A
, no
t av
ai la
b le
.
482 Calcium and faecal fat excretion R. Christensen et al. obesity reviews
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
use of extra calcium was best explained by applying the intercept, being a consequence of allocation to ‘extra calcium’ per se – opposed to control of 0.90 (95% CI: 0.27–1.53; z = 2.82, P = 0.0048). On a post hoc level, examining the impact of the concomitant level of protein intake (Table 1) showed no significant slope effect (z = 1.46, P = 0.14), although data might support a poten- tial inverse association between faecal fat excreted and energy intake from protein in the concomitant diet (see Fig. 4B).
Discussion
The major result of this meta-analysis is that dietary calcium impairs the absorption of dietary fat and increases faecal fat excretion. Although the effect was statistically highly significant, its importance for the daily energy balance and body-weight regulation may be minor. The additional daily excretion of 2.0 g fat (~18 kcal) is equiva- lent to ~0.7 kg body fat or ~1 kg body weight on an annual basis, providing that no adaptation or counter regulatory mechanism offsets the effect. However, the heterogeneity of the trials (I2 = 49.5%) suggests that the outcome of the meta-analysis could be confounded by study characteris- tics, such as differences in study design, methods used for fat analyses, study population, calcium sources, matrix in which calcium is provided, habitual diet and interaction with other nutrients in the food matrix. In particular, high- protein intake could interfere with the calcium soap forma- tion and consequently with fat excretion (15,18). As the dairy trials showed homogeneity (I2 = 0%) the estimate from the meta-analysis including only these studies may be more certain than the pooled estimate from the meta- analysis including all trials. The meta-analysis of these trials showed that a weighted-average increase in dairy calcium by 1241 mg day-1 produced an increase in faecal fat excretion of 5.2 g day-1, although based on a relatively small sample (n = 29 participants). This is equivalent to 47 kcal day-1 or 1.9 kg body fat or 2.2 kg body weight over 1 year. Without further studies to produce more robust data, we estimate that increasing dietary calcium intake has the potential to increase faecal fat excretion by 2–5.2 g day-1, which corresponds to a change in body weight of -1 to -2.2 kg over 1 year. In comparison, orlistat, a gas- trointestinal lipase inhibitor reducing dietary fat absorption (50), has been shown to increase the amount of excreted fat by 16.13 (SD: 7.27) g day-1 (51). This amount of extra faecal fat corresponds to a SMD of 2.2. Orlistat therefore seems at least twice as efficacious as extra calcium (Fig. 2). Some studies have found the effect of a high-calcium diet on body-weight loss to be more pronounced than can be explained by an increase in fat excretion, indicating that there may be an additional relation between calcium and body weight (9–11). Major et al. found recently that supplementation with a calcium plus vitamin D supplement decreases energy and fat intake in women with a low habitual calcium intake (21). However, more research is needed to establish whether calcium affects human appetite regulation.
We failed to establish a clear dose–response relationship between intake of calcium and faecal fat excretion, which makes it difficult to make quantitative estimates of its importance for energy balance, and to translate the findings into importance for dietary guidelines. The failure to find a dose–response relationship between calcium intake and
(a)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0 1000 2000 3000 4000 5000 6000 7000
Extra calcium applied (mg day–1)
S ta
n d
ar d
iz ed
m ea
n d
if fe
re n
ce
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
0 5 10 15 20 25
Average protein content in the diet (E%)
S ta
n d
ar d
iz ed
m ea
n d
if fe
re n
ce
(b)
Intercept (α) = 0.90 ± 0.32
Slope (β) = 0.00006 ± 0.0002
Intercept (α) = 2.33 ± 1.01
Slope (β) = -0.09 ± 0.06
Figure 4 Meta-regression analysis: The size of the circles is proportional to the precision of the estimate used in the meta-regression. The line indicates the predicted effects (regression line). Values are given as the estimate � SE. Effect sizes on the vertical axis are plotted against (a) the estimated group mean difference in calcium dose, and (b) the average protein content (energy%) in the diet.
obesity reviews Calcium and faecal fat excretion R. Christensen et al. 483
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
faecal fat excretion might be due to the small number of trials, few participants in each trial and the observed het- erogeneity of the trials. Furthermore, scatter plots of treat- ment effect against the amount of extra calcium applied should be compatible with there being no effect of no extra calcium, and so a simple regression line should intercept the vertical axis at zero treatment effect (27). In this case, with the scatter plot indicating an effect independent of the calcium dose, bias could be a possible explanation. Finally, if subjects’ adherence to a treatment varied across trials, a corresponding variation in treatment effects will occur. It is therefore probable that some of the studies included in this meta-analysis underestimated the true ability of calcium to impair fat absorption, as the lack of adherence to the prescribed calcium intake will tend to reduce the effect size. However, many of the studies used faecal and urinary calcium excretion as a compliance marker, and demon- strated at least some adherence.
Normally the quantitative importance for body weight would be assessed by large, controlled, randomized trials, providing high- vs. low-calcium intakes over at least 1 year in order to detect a change in body weight, but it is difficult to maintain strict adherence to specific diets over such a long period. In future trials, compliance should be moni- tored by measuring faecal and urinary calcium excretion, and the effect size should be adjusted to optimal compli- ance. Good adherence to calcium intakes with low vs. high intakes might be easier to achieve using calcium supple- ments, but we would still question whether this can be achieved and a meaningful efficacy assessment can be made without the use of biological adherence markers. Further- more, if calcium is to affect fat digestibility, it is a condition that fat and calcium are present in the intestine at the same time. Therefore the time of ingestion of calcium and perhaps also the matrix in which calcium is provided (dairy products, tablet, fortified food, etc.) is crucial. In the Women’s Health Initiative trial on calcium supplementa- tion (1000 mg elementary calcium plus 400 IU of cholecal- ciferol [vitamin D] vs. placebo) 36 282 post-menopausal were treated for 7 years (52). Women receiving calcium vs. placebo had a consistently favourable difference in weight change of -0.13 kg (-0.21 to -0.05; P = 0.001) (52). After 3 years of follow-up, women with daily calcium intakes less than 1200 mg at baseline who were randomized to supple- ments were 11% less likely to experience small weight gains (1–3 kg) and 11% less likely to gain more moderate amounts of weight (>3 kg). However, the true effect of calcium is very likely to have been underestimated in this study because of lack of compliance (only 55–63% of the subjects consumed 80% or more of the supplements) (52). As no biological markers of calcium intake were monitored in this study, the true effect size remains an open question.
Boon et al. showed, in a 23-year follow-up cohort study, that longitudinal calcium intake only had a positive effect
on body composition below an intake level of <800 mg day-1 (53). No relation was found in the group with a calcium intake of 800–1200 mg day-1 or in the group >1200 mg day-1, suggesting a threshold of approximately 800 mg day-1 below which the effect of dietary calcium on body composition is most pronounced (53). It has been suggested that the effect of increased calcium intake on body weight and composition is most pronounced in sub- jects with a low habitual intake (54). Furthermore, the majority of the studies included in this meta-analysis, which found a significant effect of increased calcium intake on faecal fat excretion, compared a high intake of dietary calcium with a relatively low intake of dietary calcium (Table 2). Thus it is likely that subjects with a low habitual calcium intake will benefit more from an increased calcium intake than subjects with a high habitual calcium intake.
In conclusion, dietary calcium intake has the potential to increase faecal fat excretion to an extent that could be relevant for prevention of weight (re-) gain, and may poten- tially accentuate weight loss if no compensation occurs. The effect may be most pronounced in subjects with a low habitual dietary calcium intake. There is a need for studies of a longer duration to establish long-term effectiveness.
Conflict of Interest Statement
R. C. is a statistical editor in the Cochrane Collaboration (CMSG and PHRG); this is not a Cochrane Review.
A. A. is a scientific member of the Global Dairy Plat- form, and has received research funding from Arla and the Danish Dairy Foundation.
Acknowledgements
We thank the personal and scientific support of Professor Henning Bliddal (from The Parker Institute, Frederiksberg Hospital, Denmark) and the linguistic support of Tina Cuthbertson. We gratefully acknowledge financial support from Global Dairy Platform (Chicago, USA), The Oak Foundation, Frederiksberg Hospital and University of Copenhagen.
The study was funded by an unrestricted grant from Global Dairy Platform LLC, Chicago, USA, and the Oak Foundation, who provide support to The Parker Institute. The funding sources had no influence on the study, and did not approve the manuscript before submission.
Contributions of authors
R. C. participated in the study conception and design, the acquisition of data, the analysis/interpretation of data, drafting and revision of the manuscript and the statistical analyses. J. K. L. participated in the study conception and design, the acquisition of data, the analysis/interpretation
484 Calcium and faecal fat excretion R. Christensen et al. obesity reviews
© 2009 The Authors Journal compilation © 2009 International Association for the Study of Obesity. obesity reviews 10, 475–486
of data and drafting of the manuscript. C. R. S. participated in the study conception and design. E. M. B. coordinated the literature search, participated in the acquisition of data and critical revision of the manuscript. E. L. M., W. H. S. and A. T. participated in the study conception, interpreta- tion of data, critical revision of the manuscript and super- vision of the study. A. A. generated the idea and took the initiative to conduct the study – participated in the study conception and design, the acquisition of data, the interpretation of data, and drafting and revision of the manuscript. All authors have seen and approved the final version of the manuscript.
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calcium intake on faecal fat excretion, energy metabolism and adipose tissue mRNA expression of lipid-metabolism related pro- teins. Int J Obes (Lond) 2007; 31: 1704–1712. 16. Bortolotti M, Rudelle S, Schneiter P, Vidal H, Loizon E, Tappy L, Acheson KJ. Dairy calcium supplementation in overweight/ obese individuals; its effect on markers of fat metabolism. Am J Clin Nutr 2008; 88: 877–885. 17. Astrup A. The role of calcium in energy balance and obesity: the search for mechanisms. Am J Clin Nutr 2008; 88: 873–874. 18. Jacobsen R, Lorenzen JK, Toubro S, Krog-Mikkelsen I, Astrup A. Effect of short-term high dietary calcium intake on 24-h energy expenditure, fat oxidation, and fecal fat excretion. Int J Obes (Lond) 2005; 29: 292–301. 19. Melanson EL, Donahoo WT, Dong F, Ida T, Zemel MB. Effect of low- and high-calcium dairy-based diets on macronutri- ent oxidation in humans. Obes Res 2005; 13: 2102–2112. 20. Melanson EL, Sharp TA, Schneider J, Donahoo WT, Grunwald GK, Hill JO. Relation between calcium intake and fat oxidation in adult humans. Int J Obes Relat Metab Disord 2003; 27: 196–203. 21. Major GC, Alarie FP, Doré J, Tremblay A. Calcium plus vitamin D supplementation and fat mass loss in female very low- calcium consumers: potential link with a calcium-specific appetite control. Br J Nutr 2008; 101: 659–663. 22. Papakonstantinou E, Flatt WP, Huth PJ, Harris RB. High dietary calcium reduces body fat content, digestibility of fat, and serum vitamin D in rats. Obes Res 2003; 11: 387–394. 23. Gacs G, Barltrop D. Significance of Ca-soap formation for calcium absorption in the rat. Gut 1977; 18: 64–68. 24. Govers MJ, Termont DS, Van Aken GA, Van der MR. Char- acterization of the adsorption of conjugated and unconjugated bile acids to insoluble, amorphous calcium phosphate. J Lipid Res 1994; 35: 741–748. 25. Govers MJ, Van der MR. Effects of dietary calcium and phos- phate on the intestinal interactions between calcium, phosphate, fatty acids, and bile acids. Gut 1993; 34: 365–370. 26. Juni P, Altman DG, Egger M. Systematic reviews in health care: assessing the quality of controlled clinical trials. BMJ 2001; 323: 42–46. 27. Sterne JA, Egger M, Smith GD. Systematic reviews in health care: investigating and dealing with publication and other biases in meta-analysis. BMJ 2001; 323: 101–105. 28. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6. [updated September 2006]. John Wiley & Sons, Ltd: Chichester, 2006. 29. Moher D, Cook DJ, Eastwood S, Olkin I, Rennie D, Stroup DF. Improving the quality of reports of meta-analyses of ran- domised controlled trials: the QUOROM statement. Quality of Reporting of Meta-analyses. Lancet 1999; 354: 1896–1900. 30. Elbourne DR, Altman DG, Higgins JP, Curtin F, Worthington HV, Vail A. Meta-analyses involving cross-over trials: method- ological issues. Int J Epidemiol 2002; 31: 140–149. 31. Hedges LV. Distribution theory for glass’s estimator of effect size and related estimators. J Educ Stat 1981; 6: 107–128. 32. Normand SL. Meta-analysis: formulating, evaluating, com- bining, and reporting. Stat Med 1999; 18: 321–359. 33. Curtin F, Altman DG, Elbourne D. Meta-analysis combining parallel and cross-over clinical trials. I: continuous outcomes. Stat Med 2002; 21: 2131–2144. 34. Christensen R, Kristensen PK, Bartels EM, Bliddal H, Astrup A. Efficacy and safety of the weight-loss drug rimonabant: a meta- analysis of randomised trials. Lancet 2007; 370: 1706–1713. 35. Cochran WG. The combination of estimates from different experiments. Biometrics 1954; 10: 101–129.
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36. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21: 1539–1558. 37. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560. 38. Thompson SG, Higgins JP. How should meta-regression analyses be undertaken and interpreted? Stat Med 2002; 21: 1559– 1573. 39. Lutwak L, Laster L, Gitelman HJ, Fox M, Whedon GD. Effects of high dietary calcium and phosphorus on calcium, phos- phorus, nitrogen and fat metabolism in children. Am J Clin Nutr 1964; 14: 76–82. 40. Bhattacharyya AK, Thera C, Anderson JT, Grande F, Keys A. Dietary calcium and fat. Effect on serum lipids and fecal excretion of cholesterol and its degradation products in man. Am J Clin Nutr 1969; 22: 1161–1174. 41. Saunders D, Sillery J, Chapman R. Effect of calcium carbonate and aluminum hydroxide on human intestinal function. Dig Dis Sci 1988; 33: 409–413. 42. Denke MA, Fox MM, Schulte MC. Short-term dietary calcium fortification increases fecal saturated fat content and reduces serum lipids in men. J Nutr 1993; 123: 1047–1053. 43. Welberg JW, Monkelbaan JF, de Vries EG, Muskiet FA, Cats A, Oremus ET, Boersma-van Ek W, van Rijsbergen H, van der Meer R, Mulder NH, Kleibeuker JH. Effects of supplemental dietary calcium on quantitative and qualitative fecal fat excretion in man. Ann Nutr Metab 1994; 38: 185–191. 44. Govers MJ, Termont DS, Lapre JA, Kleibeuker JH, Vonk RJ, Van der MR. Calcium in milk products precipitates intestinal fatty acids and secondary bile acids and thus inhibits colonic cytotoxicity in humans. Cancer Res 1996; 56: 3270–3275. 45. Murata T, Kuno T, Hozumi M, Tamai M, Takagi T, Kamiwaki T, Itoh Y. Inhibitory effect of calcium (derived from eggeshell)-supplemented chocolate on absorption of fat in human males. J Jpn Soc Nutr Food Sci 1998; 51: 165–171.
46. Shahkhalili Y, Murset IM, Acheson K. Calcium and magne- sium supplementation of chocolate as a mean to reduce the digest- ible energy value of chocolate in man. Abstract presented in the 17th International Congress of Nutrition 27–30 August 2001, Vienna, Austria 2001; (abstr). 47. Shahkhalili Y, Murset C, Meirim I, Duruz E, Guinchard S, Cavadini C, Acheson K. Calcium supplementation of chocolate: effect on cocoa butter digestibility and blood lipids in humans. Am J Clin Nutr 2001; 73: 246–252. 48. Ditscheid B, Keller S, Jahreis G. Cholesterol metabolism is affected by calcium phosphate supplementation in humans. J Nutr 2005; 135: 1678–1682. 49. Bendsen NT, Hother AL, Jensen SK, Lorenzen JK, Astrup A. Effect of dairy calcium quantitative and qualitative fecal fat excre- tion: a randomized cross-over trial. Int J Obes (Lond) 2008; 32: 1816–1824. 50. Padwal RS, Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet 2007; 369: 71–77. 51. Guerciolini R, Radu-Radulescu L, Boldrin M, Dallas J, Moore R. Comparative evaluation of fecal fat excretion induced by orlistat and chitosan. Obes Res 2001; 9: 364–367. 52. Caan B, Neuhouser M, Aragaki A, Lewis CB, Jackson R, LeBoff MS, Margolis KL, Powell L, Uwaifo G, Whitlock E, Wylie- Rosett J, LaCroix A. Calcium plus vitamin D supplementation and the risk of postmenopausal weight gain. Arch Intern Med 2007; 167: 893–902. 53. Boon N, Koppes LL, Saris WH, Van MW. The relation between calcium intake and body composition in a Dutch popu- lation: The Amsterdam Growth and Health Longitudinal Study. Am J Epidemiol 2005; 162: 27–32. 54. Thompson WG, Rostad HN, Janzow DJ, Slezak JM, Morris KL, Zemel MB. Effect of energy-reduced diets high in dairy prod- ucts and fiber on weight loss in obese adults. Obes Res 2005; 13: 1344–1353.
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The history of efforts to regulate dietary supplements in the USA John P. Swann*†
This review examines the emergence of dietary supplements and how the Food and Drug Administration (FDA) attempted to regulate these, beginningwith the arrival of vitamins and how theseweremanaged under the 1906 Food andDrugs Act, and ending with the seismic influence of the 1994 Dietary Supplement Health and Education Act (DSHEA). Included are the impact ofmajor laws, key court decisions, and the construction of the FDA’s supplement actions and rules from the 1920s to the 1990s for products that were neither drugs nor typical foods. Stiff resistance to the regulations by supplementmanufacturers, trade associations, politicians, and especially the public at large is an important part of this story. The paper closes with the passage of DSHEA and how it literally changed the definition and parameters of control of dietary supplements. Copyright © 2015 John Wiley & Sons, Ltd.
Keywords: regulation; FDA; supplements; history; vitamins; botanicals
Introduction, origin of vitamins, and early regulatory interest in supplements
This paper examines the long history of the engagement of the US Food and Drug Administration (FDA) with dietary supplements.[1]
Of course, that engagement unfolded through a complex of interactions and relationships between the FDA and consumers, manufacturers, trade organizations, other associations, all levels of the federal judicial system, politicians, health practitioners, scien- tists, and others. Complicating the story as well is the fact that the very nature of these commodities posed a scientific and regulatory challenge throughout the period under study and beyond: products largely rooted in the food supply but employed beyond the purpose of sustenance. Here it is worth noting that this paper focuses on supplements per se rather than the development and regulation of fortified foods. There is an obvious overlap between the two, but the principal concern of the papers in this special issue address vitamins, minerals, botanicals, and amino acids formulated for separate use, whether by themselves or in combination with other supplements. Regardless, the name of this group of products itself seemed to capture the challenge: literally they are additions to the food supply, but in practice they came to be understood by many as supplements to the therapeutic armamentarium. More- over, though the early interest of the consuming public and regula- tors emphasized vitamins andminerals, botanicals and amino acids eventually also joined the litany of dietary supplements— certainly as this category was defined in the Dietary Supplement Health Education Act (DSHEA) of 1994. This expansion of supplements, in fact the very embrace and impassioned defense of supplements by the public, flourished not coincidentally as later twentieth- century patients assumed a greater role in their healthcare. Dietary supplements were very much part of their search for greater autonomy in healthcare decision-making, within or without the traditional patient-health care provider relationship.
Regulating these commodities was made no less difficult by the science — or lack thereof — surrounding them. The movement from an understanding of macronutrients in nutrition
and health to a discernment of their components and their basic functions proceeded somewhat slowly. But once the initial food fac- tors were identified, others followed in relatively short order in the early twentieth century. While science yielded greater understanding in the subsequent decades, much still remained to be known about how these factors actually worked, their untoward effects, appropri- ate and concerning dosage, and other properties. Once isolated, commercial and consumer interest in the products accelerated rapidly, which in turn created more regulatory attention to their safe and accurately labelled use— essential concerns for both food and drugs since the early twentieth century — to the extent science allowed and public health required. However, while controls relied to a great extent on the best science available about supplements, those who consumed them were not necessarily so encumbered. That is, consumption could and did outpace science and regulation.
The story of supplement regulation in the USA does not begin until the early twentieth century, in part because federal regulation of consumer commodities did not materialize — despite longstanding efforts — until 1906, and in part because the discoveries of specific, marketable factors in food responsible for health and nutrition did not arrive until the first two decades of the twentieth century. Several eighteenth- and nineteenth-century workers had helped clarify the connection between certain diseases— beri beri, scurvy, rickets, and pellagra – and diet. Analyz- ing that connection, however, was done within the entrenched concept of nutrition that boiled down to the tripartite pillars of the field: proteins, carbohydrates, and fats. Particularly influential
* Correspondence to: John P. Swann, History Office, White Oak Bldg. 1, Rm. 1206, 10903 New Hampshire Ave., Silver Spring, MD 20993, FDA. E-mail: john.swann@fda.hhs.gov
† The author is indebted to three anonymous referees for their many comments and suggestions.
History Office, Office of Communications, Office of External Affairs, Office of the Commissioner, FDA
Drug Test. Analysis 2016, 8, 271–282 Copyright © 2015 John Wiley & Sons, Ltd.
Review Drug Testing and Analysis
Received: 15 May 2015 Revised: 6 October 2015 Accepted: 7 October 2015 Published online in Wiley Online Library: 23 November 2015
(www.drugtestinganalysis.com) DOI 10.1002/dta.1919
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in the study of food, its composition, and its physiological role was German chemist Justus Liebig, whose book, Animal Chemistry (1842),[2] dealt to a large extent with the metabolic utilization of nitrogen-rich protein, carbohydrates, and fats. By the turn of the century the purposes of food were still largely considered to be generation of energy and tissue development and maintenance. Though he is owed a great debt for his physiological investigations of food, deeper inquiries into foodstuffs and their role in disease prevention were delayed because of the continued dominance of Liebig’s ideas, the prevailing germ theory of disease that looked first to pathogenesis as a causation, and for other reasons.[3,4] Some scientists nevertheless began to realize there were answers beyond the macronutrients, which themselves had begun to be broken down by the early nineteenth century with William H. Wollaston’s isolation of the amino acid, cystine. Cambridge biochemist Frederick Gowland Hopkins, who isolated
tryptophan in 1900, learned from feeding studies on mice that unknown, refined food factors beyond the well-known gross categories had an important role in the diet.[5] Studies by others yielded similar conclusions. In 1912, Hopkins labelled these unknowns as ‘accessory food factors’. The same year, Casimir Funk, who had discovered that protein fractions from rice polishings could prevent a beri-beri-like disease in birds, chose to call such nutrient factors capable of preventing deficiency diseases, ‘vitamines’.[4] In the next several years researchers at Wisconsin, Yale, Cambridge, in corporate laboratories, and other institutions began to isolate ‘fat soluble A’, vitamins D and C, the first of the B complex vitamins, biotin, pantothenic acid, and other nutrients.[6] These discoveries were readily adapted into mainstream commerce. That these latest advances in nutrition were commercialized and
embraced by the public so quickly should come as no surprise, given how so many other commodities — linked in fact or in advertising to scientific progress — swept the American mindset and marketplace. The public fascination with the discovery of radium in 1898 and its therapeutic potential led to some marketed commodities that may or may not have included the actual deadly element. Thus, within about a decade of Marie Curie’s announce- ment, St Louis physician Rupert Wells introduced Radol to cure cancer, and other products followed: Radiozone, Radium Rings, Radium Radia, Radiumite, Magical Mineral Radium Water, Radium Ore Revigator, Radithor, and so on.[7–10] William Radam’s Microbe Killer, a late nineteenth-century addition to the public dispensary, professed to further the microbiological advances of Louis Pasteur, Robert Koch, and others through this widely available patent medicine.[11] Medical devices of all manner followed on from such technological advances as electricity, electrification, and radio, though construction of individualized theories of energy and matter could be invoked as well to promote devices like the Electropoise, Oxydonor, Electro-Chemical Ring, Oscilloclast, Radioclast, the Sanden Electric Company belt, and countless more.[12–16] Clinicians in the 1890s reported in themedical literature beneficial results in reducing their overweight patients with desic- cated thyroid, though they also broadcast concern to their colleagues for close oversight of this therapy. Nonetheless, a host of thyroid preparations came on the market to cultivate a self- medicating population that was growing increasingly interested in weight loss. Marmola was perhaps among the most successful preparations and, despite the efforts of the Post Office and the Federal Trade Commission (FTC), remained on the market for decades.[17,18] Those two agencies had limited authority to interdict problem products. Postal fraud laws of the late nineteenth century enabled the Post Office to prevent the use of themail under false or
fraudulent pretences. The enabling legislation of the FTC provided for the prosecution of firms that engaged in advertising practices that promoted unfair trade.[12,19]
Another federal agency, the Bureau of Chemistry, predecessor of the FDA, had been in existence since the appointment of the first chemist to the Department of Agriculture in 1862. It became ‘the most conspicuous laboratory in Washington’ and ‘the locus of gov- ernment chemical activity’,[20] and thus other agencies such as the Post Office and the FTC often turned to the Bureau for counsel in scientific and medical matters, such as their concerns with some of the products mentioned. The Bureau’s responsibilities changed immensely in 1906, when the quarter-century-long battle to pass a national law to control food and drugs culminated in the passage of the Federal Food and Drugs Act, marking the Bureau’s emer- gence as the first federal agency charged with the primary purpose of consumer protection.[21] The law prohibited interstate and foreign commerce in adulterated and misbranded food and drugs, and called for seizure and prosecution as the principal tools of en- forcement. Drugs — defined as substances used to cure, mitigate, or prevent disease — had to abide by the standards of strength, quality, and purity in either the US Pharmacopoeia (USP) or the National Formulary (NF).[22] Foods — any article for food, drink, confectionary, or condiment — did not have to meet standards as drugs did. However, the law prohibited the substitution of some- thing for the labelled food, concealing damage or inferiority, adding ingredients to render the product injurious to health, or selling filthy or decomposed food. The law did not require ingredi- ent listing generally, but both food and drugs had to list 11 partic- ular ingredients, including alcohol, morphine, opium, cocaine, and cannabis. In addition, the law prohibited food or drug labelling that was false ormisleading in any particular. Essentially, the 1906 law— a Progressive Era repudiation of the caveat emptor marketplace— used the label (among other devices, and with many limits that would be addressed in subsequent years) as a tool to empower consumers to have a much better conception of what they were putting into their bodies. For example, it did not prohibit the 11 dangerous ingredients; but it maintained that the purchaser had a right to know what they were using.
There were instances in the early years of the enforcement of the 1906 Act where the boundaries between food and drug were blurred, for example, where a substance traditionally used as a food might be labelled for the treatment of a disease. However, as Peter Hutt argues, foods with health claims appeared to subside after passage of the law — with some exceptions — and certainly the Bureau’s interests were more focused on drug labelling in this respect.[1,23,24] In the wake of the Food and Drugs Act and the Trade Commission Act and their prohibition of bogus and unfair labelling and advertising , more and more food company ads appeared to rely less on appeals to the health properties of their products and more on the flavour and, eventually, the convenience of their products.[23] It was quite different with vitamins. By the 1920s vitamins and their role in health, many having been isolated and elaborated by this time, occupied a noticeable part of the consciousness of the public, the Bureau of Chemistry, and other groups. Pharmaceutical companies at this time were advertising various vitamin preparations in popular magazines such as Good Housekeeping and Parent’s Magazine, calling attention to their importance in the formation of bones and teeth in children, as well as their ability to help children resist infections.[25] By the early 1920s the American Medical Association (AMA) began voicing concern with the proliferation of vitamins. This was not much of a stretch for the AMA, folding vitamins into the legion of patent
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medicines against which they had railed for decades— both types of products having removed or at least decreased the self- medicator’s contact with a physician; not that there was a level of scientific uncertainty attendant to many of the claims made for them. The AMA’s journal carried a report from a University of Illinois researcher whose analysis of vitamin studies led him to the conclu- sion that, in the absence of a vitamin deficiency, the ‘benefit from an excess of any [vitamins] seems most improbable, and we lack proof that such is the case’.[26] The association criticized the ‘irresponsible’ and ‘distorted’ advertising for vitamins in popular magazines,[27] and reminded their readership of ‘the recent form of quackery that has used the remarkable story of the vitamins in physiology as a device to promote the sale of nostrums’.[16,28] It was the beginning of a battle that would last the rest of the century.
Though the 1906 Act of course did not address these products directly, the Bureau of Chemistry first inquired into vitamins as a potential regulatory concern in the early 1920s, a first step in a journey that would continue to the present. That the legal compendial standards – the USP and the NF— did not offer insight into the quality, purity, or strength of any of these ‘medicinal agents’ until 1926 (at that time the USP listed only vitamin A)[29,30]
left a void that the Bureau had to negotiate; were the labelled claims accurate insofar as the law required, and did products that reputedly contained these supplements actually have the vitamins, and in the amounts stated? At the minimum it called for refined analytical procedures, research into which the Bureau would soon initiate. In February 1922 the Bureau began assembling basic infor- mation about vitamins— their manufacture, the ingredients used, labelling, and advertising— ’to establish the standing, as a medic- inal agent, of this type of product’.[31]
The labelling and advertising that the Bureau received from its field offices promoted vitamins for deficiency diseases; periods of stress associated with pregnancy, lactation, and convalescence; bone and dentition promotion as well as general growth in children; loss of appetite; a possible application in tuberculosis; other wasting diseases; infantile diarrhea; and other therapeutic applications.[32–34] From 1921 through the remainder of the decade, the Bureau’s in-house investigations into vitamins and minerals were centred in the Protein Laboratory, and the principal concern was to study a variety of foods to learn if their vitamin content was below the labelled amount. This group, headed by chemist D. Breese Jones, examined the effect of bleaching on the vitamin content of flour, the extent to which vitamin A diminished due to long term cold storage of eggs, and the nutrients in a variety of foods, including oleomargarine, lentils, and infant foods.[35–38]
Jones, his colleagues, and chemist Hazel Munsell — Jones’s counterpart in the Nutrition Studies Section of the USDA Bureau of Home Economics — also launched an investigation of cod liver oils and analytical procedures for determining their vitamin content around 1926, a precursor to anticipated regulatory work addressing the large number of these products on the market. Indeed, the Bureau of Chemistry began moving against adulterated and misbranded cod liver oil, tablets thereof, and other products before the end of the decade.[39–44] Such investigations were important, according to Assistant Chief Chemist Paul Dunbar, because vitamins ‘opened a wide field for the food manufacturer whose enthusiasm in advertising his product exceeds the bounds of propriety’.[45]
The interest of the FDA (as the agency was known by then)[46] in the study and regulation of vitamins grew in the next decade. In July 1931, the agency announced plans to establish a laboratory dedicated to the study of vitamins, which it did by February of
the next year.[47,48] The prominence of these commodities can be further seen in the establishment of a Vitamin Division by August 1935, headed by Elmer M. Nelson, the US delegate to the Conference on Vitamin Standardization of the League of Nations Health Committee— the committee’s formation itself a testament to the global impact of vitamins and minerals by this time.[49] This committee, comprised of international experts on vitamins and minerals, first met in June 1931 to promote the standardization of vitamins, beginning with vitamins A, B1, C, and D.
[50,51] Concerns previously expressed by Dunbar quickly grew into a fairly clear statement of regulatory philosophy under the 1906 Act. In a 1930 speech to two food associations, Dunbar lamented the fact that, despite the advancing knowledge of vitamins and nutrition, a considerable gap still existed between what experimental studies revealed and the health-giving claims some manufacturers were expressing. So, the FDA would be particularly attentive to both claims on food products that they actually possessed the vitamins so labelled, and the allusion to health imparting properties:
. . . labeling of food products with claims implying that they possess curative, health-giving, healing qualities, when, as a matter of fact, they merely possess those wholesome, nutritive qualities which a food of that particular description should possess, is a misbranding within the meaning of the food and drugs act and subjects the product so labeled to the penalties imposed by that act. In like manner, extreme and unwarranted vitamin claims must be classed as illegal.[52–54]
The FDA proceeded with several actions against vitamins pro- moted for broad therapeutic indications and other problems. For example, the manufacturer of garlic tablets rich in vitamins A, B, C, and several minerals did not contest the agency’s misbranding charge on the basis that the tablets claimed to treat diphtheria, tuberculosis, hypertension, rheumatism, whooping cough, and other diseases.[55,56] The court found in favour of the government when the FDA challenged Commanders vitamin capsules, ostensi- bly consisting of six essential vitamins in amounts equivalent to specific volumes of yeast and other foods, for falling below its claimed strength and quality.[57,58] The San Francisco Station detained over 2200 gallons of imported cod liver oil due to hypopotent levels of vitamin D.[59,60] Geba Tablets professed through its name and literature to be an excellent source of vitamins G (later identified as B2, or riboflavin), E, B, and A, and it was labelled as a product to promote health and a vigorous and robust mind and body; build resistance against colds and bacterial infections of the eyes, ears, sinuses, and throat; stimulate growth among all ages; empower the reproductive organs; and other claims. That manufacturer pled guilty, as did the proprietor of Neu-Life, a product that combined five vitamins and at least eight minerals to treat glandular weakness and nervousness. Analysis revealed Neu-Life lacked one of the vitamins and it misled the user into believing that it could effect the physiological actions claimed.[61–64] The manufacturer of a ‘vitamized’ veterinary vitamin and mineral compound lost its case, in which the FDA charged Occo Compounds for sheep, hogs, and poultry with either subpo- tent or completely absent ingredients.[65,66] A case against Royal Lee’s Catalyn multiple vitamin tablets, initiated in 1933, dragged on through the end of the decade. Labelled as a preparation of vitamins A, C, D, B, and G, analysis showed that it lacked any of the first three, and it was substantially subpotent in the last two vitamins. Moreover, the government challenged the claims— even if the tablets had contained the labelled vitamins — that Catalyn
History of efforts to regulate dietary supplements
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effectively treated over 50 ailments other than deficiency diseases, including arteriosclerosis, hyper- and hypotension, insomnia and lack of energy, and Bright’s disease.[67–70] As the agency pursued these cases Congress was debating and eventually passed a new consumer protection statute.
Special dietary foods and the first regulations
The 1938 Food, Drug, and Cosmetic Act replaced the 1906 Act, a New Deal endeavour that broadened the scope of consumer products to be brought under the FDA’s oversight and enhanced the protections over those commodities that were part of the old law. Among its provisions, the new statute prohibited the misbranding and adulteration of cosmetics and medical devices. In addition, new drugs had to be shown safe before entering the marketplace, and foods had to abide by standards of identity. Of particular interest to the history of supplement regulation were two changes from the earlier law. First, the definition of a drug now included ‘articles (other than food) intended to affect the structure or any function of the body of man or other animals’.[71]
In discussions of this definition during hearings leading up to the law, the FDA indicated that this language would address the exis- tence of some problematical commodities that claimed to treat dis- eases, products not ordinarily considered drugs such as remedies for obesity, which some had long likened to cosmetics. Congress’s sense was that the intended use of the thing was more important for classification purposes than anything else: ‘If it contains nutritive ingredients but is sold for drug use only, as clearly shown by the labelling and advertising, it will come within the definition of drug, but not that of food.’[1] In other words, the claim was more impor- tant than the source of the product, and that should dictate how the product should be regarded. Second, the food misbranding provisions introduced the
following prohibition that would have a significant impact on the regulation of vitamins and other products. A food would be consid- ered misbranded ‘if it purports to be or is represented for special dietary uses, unless its label bears such information concerning its vitamin, mineral, and other dietary properties as the Secretary determines to be, and by regulations prescribes as, necessary in order fully to inform purchasers as to its value for such uses’.[71]
Not surprisingly, the law itself did not define foods for special dietary uses, but during the long deliberations that eventually led to the 1938 law, Congress understood that special dietary foods included but were not limited to foods for infants, for invalids, and for those wishing to reduce or gain weight; foods for those, in other words, who had special or particular dietary needs, as opposed to general dietary requirements. The framers of the law recognized that the concept of special dietary foods could be broadened given the state of nutritional science. According to the law’s chief sponsor, Sen. Royal Copeland:
. . . there are being offered to the consumer an increasing number of preparations alleged to contain this or that vitamin, or mineral salt, mysterious combinations of these, with special proteins, carbohydrates, and the like. . . . It is essential to the well-being of the public that provisions be made to keep abreast of these developments and to require informative labeling . . .[1]
The FDA issued proposed rules in September 1940 to address foods for special dietary uses, and the following month held public
hearings; final regulations appeared one year later. Recognizing that infants, young children, and older children and adults have different nutritional requirements, the FDA established minimum daily requirements (MDRs) that were defined as the amount of vita- mins andminerals needed to prevent deficiency diseases. Labelling of these required the proportion of the MDR that each vitamin and mineral represented, as well as adequate directions for use. Any additional substances for special dietary use, including vitamins and minerals beyond those supplements identified in the regula- tions, required a statement indicating (1) that the need for such substances has not been established, (2) the quantity of each substance present, and (3) directions for use. Though adequate directions for use requirement was in the law as a labelling require- ment for drugs, the agency elected to regulate vitamins and minerals as special dietary foods under these regulations. Years later the agency’s general counsel at this time reflected that this designation required full disclosure of all ingredients (inert or other- wise) in the preparation— unlike the case with drugs, it accommo- dated the use of MDRs, and the agency simply had more experience at regulating foods at this time.[71–74] In announcing these regulations, the Secretary of the Federal Security Agency (the FDA’s executive branch department by this time) also announced that advertising as well as labelling would be taken into account. The FTC still oversaw food advertising, but advertising special dietary uses absent labelling that abided by these regula- tions constituted misbranding under the 1938 Act; if a product’s advertising suggested a special dietary use, then its labelling was required to be in accord with the rules for special dietary foods.[75]
Though several efforts were made to change them, the special dietary food regulations remainedmore or less in place for the next three decades.
The FDA actively engaged violative vitamin and mineral prepara- tions over the next decade, so many actions that in September 1942 Notices of Judgment, the published summaries of cases brought by the FDA, started to group together vitamin andmineral actions as a discrete category.[76] A study of vitamin and special di- etary food cases from 1947 to 1952 indicated that about 43% of the violations dealt with false andmisleading labelling,[77] and indeed a pivotal case emerged in this period. In 1948, the FDA conducted nationwide multiple seizures of Nutrilite, a family of preparations that featured multiple vitamin and mineral food supplements distributed by ‘potentates’, ‘high potentates’, or ‘exalted potentates’ (depending on their volume of sales) through door-to-door sales. Promotions were based in large part on company-issued literature entitled ‘How to Get Well and Stay Well’, which drew clear connec- tions between Nutrilite and a wide variety of diseases and illnesses. Procedural challenges and appeals prolonged the case. However, the two sides settled on a wide-ranging consent decree in April 1951.[78–80] This outcome spared both sides what promised to be a very long trial, it helped the government avoid disclosure of what would have been an embarrassing difference of opinion between FDA policy and past statements made by Federal Security Agency Secretary Oscar Ewing about typical nutritional deficiencies faced by Americans, and it provided a resolution to Nutrilite for a massive inventory tied up in the legal system.[81]
The Nutrilite decree addressed particulars of this case, but also it established parameters for a new regulatory approach to food supplements. For example, the decree recognized the relationship between the absence of particular vitamins and minerals and par- ticular pathological conditions: deficiencies of vitamin A and night blindness, vitamin C and dental caries, vitamin K and excessive bleeding from wounds, iodine and goiter, and calcium and blood
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coagulation. Statements relating to over 30 different conditions would be allowed, with the understanding that:
If a claim is made that a symptommay be due to a sub-clinical vitamin or mineral deficiency, there shall be associated with the claim a qualification that Nutrilite Food Supplement would be of benefit only if the symptom resulted from a deficiency of one or more of the vitamins or minerals contained in Nutrilite Food Supplement.[80]
The decree provided for future additions to the list of allowable representations that abided by the requirements of the 1938 Act as long as they were grounded in generally accepted nutritional science. Moreover, representations could be made, even if not reflective of the consensus of scientific opinion, as long as there was reliable scientific opinion behind them. In such cases the statements would have to be qualified with an explanation that reliable scientific opinion differed on such claims.[80]
As FDA General Counsel William Goodrich observed, this case helped him to understand that people look at vitamins as tonics; they’re usually not toxic, readily available, and people feel good if they take them, whether or not they do any good; at least they’re usually not doing much harm.[74] However, the decree prohibited a large number of claims the FDA had discovered were used at the point of sale by Nutrilite representatives and/ or indicated in the promotional literature, including arthritis, rheumatism, diabetes, cancer, and impotence. Likewise, the de- cree forbade the use of over a dozen statements about science, health, and nutrition — and their connection to food supple- ments — that the FDA insisted also were used in Nutrilite promotions. Finally, the decree permitted the use of testimonials as long as these did not deviate from the terms of the decree, and it provided for modification by either side should future laws, facts, or scientific opinions so dictate.[80,81] The terms of the Nutrilite decree affected the agency’s regulation of supple- ments for the next decade, and charges were drawn not only from the 1938 Act’s prohibitions against food misbranding but from drug misbranding as well.[1,82]
Nutritional quackery and rulemaking revisited
Of the hundreds of cases developed against vitamin and mineral supplement products in the ensuing years, many dealt with health fraud — quackery — in which manufacturers or their sales agents made unscientific and often outrageous therapeutic claims.[12, 83-86]
This was not new, certainly not in therapeutics generally nor in the sale of vitamins specifically. As noted previously, the AMA had been railing against nutritional fraud operating under the veil of vitamins since the early 1920s, and the Bureau of Chemistry was well aware of the potential to ‘exceed the bounds of propriety’ in vitamin labelling. However, cases grew in the wake of the Nutrilite decree, and in June 1957, FDA field offices around the country held press conferences on nutritional quackery, with members of state and local public health departments, medical societies, Better Business Bureaus, and others appearing with agency representatives before the local media.[12,87] Also, the AMA and the FDA collaborated on the first of two National Congresses on Medical Quackery in 1961. A feature of these events was exposure of how ‘food faddists and nutritional quacks’ were flouting the law, exposure that would help challenge them
. . . in the courts, in the press, in our educational institutions, or wherever they or their pseudo-scientific theories appear. . . . we believe that exposure is the most effective tool, particularly exposure in the courts where the quacks do not want to be and where their batting average is zero. It is our firm conviction that consumers understand and accept the judgments of Federal judges and juries, and that there is no substitute for successful court action supplemented by publicity and public information . . .[88,89]
Though the batting average of supplement manufacturers was probably a bit better than ‘zero’, there is no doubt that the FDA had significant success in its court proceedings — most of which did not even involve litigation.[1] To be sure, it may have been the business strategy in at least some of these cases to plead guilty, pay the applicable fines, make changes as necessary, and move on with the commercial enterprise with as little delay as possible. Nevertheless, court work— particularly for numerous and ongoing problems in an industry— was time consuming and not the most efficient means of bringing violations of the law under better control.[1,90] Thus, the agency took a more systematic approach by revisiting the 1941 regulations, and in so doing experienced a public recoil unprecedented in FDA rulemaking, and by no means the last time this would happen. In June 1962, the agency issued proposed regulations to overhaul the special dietary food regula- tions. The agency was concerned with ‘shotgun preparations’ containing not only vitamins and minerals known to have a role in nutrition but many additional ingredients whether or not there was evidence to support their inclusion.[91] So, the regulations identified 12 nutrients — 8 vitamins and 4 minerals — ‘only those nutrients recognized by competent authorities as essential and of significant dietary-supplement value’. Any label claiming to provide nutritional supplementation could bear only these ingredients. As for other vitamins and minerals, according to the regulations there was ‘no convincing evidence’ that the ordinary diet required their supplementation. Also, the regulations replaced ‘minimum daily requirements’ with ‘daily requirements’, which were based on the Recommended Dietary Allowances (RDAs) long developed by the Food and Nutrition Board of the National Academy of Sciences.[1,90,92,93]
According to General Counsel Goodrich, the FDA received over 54 000 communications regarding the proposed rules from scien- tists, non-scientists, health practitioners, and many other citizens, in addition to pharmaceutical firms, and especially from the National Health Federation, a group whose origins dated back to 1955 when it formed to help make Harry Hoxsey’s contentious multi-herbal cancer remedy available to themasses.[12] Most simply vented, and less than 1% of the comments actually addressed how to improve the regulations.[91] With the agency consumed by the implementation of the 1962 Drug Amendments, Food and Drug did not promulgate revised regulations until June 1966. This version used RDAs explicitly because of concern that the old term, minimal daily requirements, suggested to purchasers that more than the minimum would be beneficial to health — certainly the opposite of the case with fat soluble vitamins.[94] The regulations identified required and optional vitamins and minerals for inclusion if an article were to be called a multivitamin or multimineral supple- ment. In all there were five more allowable nutrients than in 1962. The identity standard for vitamins and minerals indicated an established range of minimum and maximum daily amounts for these entities — an issue that would attract considerably more attention when it resurfaced a few years later. More significantly,
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though, was the requirements that the labelling had to include the following statement: ‘Vitamins and minerals are supplied in abun- dant amounts by the foods we eat. The Food and Nutrition Board of the National Research Council recommends that dietary needs be satisfied by foods. Except for persons with special medical needs, there is no scientific basis for recommending routine use of dietary supplements.’[95] Hundreds of objections — particularly to that so- called ‘crepe label’[96] to be applied to all supplements — led the FDA to schedule administrative hearings, which lasted from 1968 to 1970. While the FDA was digesting the nearly 32 000-page transcript
from these hearings, an investigation contracted by the agency was winding down and nearing publication, the Study of Health Practices and Opinions (1972), an analysis of a massive survey that yielded results that may or may not have been surprising, but also suggested where the public reaction to supplement regulation, at least in part, was coming from. Half of those surveyed had used nutritional supplements, and three-quarters of those interviewed believed taking vitamins andminerals beyond the RDAs gave them greater energy and made them healthier. Twenty percent said that some serious diseases, such as cancer and arthritis, were at least somewhat linked to nutrient deficiencies; about one-quarter said they had arthritis or a related condition, and too few to register reported that they had cancer. The public relied on retailers and industry for what information they possessed about supplements, perhaps according to the authors because there was an assumption by those surveyed that the industry was regulated to the extent that their promotions and labels had to be accurate. Also, many of those interviewed did not make decisions necessarily based on a particular belief system, but rather stemming from the proposi- tion that ‘anything is worth a try,’ and thus they made decisions about their health on a trial and error basis.[90,97]
The nature of health decision-making, in fact, had been changing for many and would continue to shift, thanks to a confluence of trends. Tilting to some extent against the onwardmarch of technol- ogy in general and traditional drug therapy in particular was a distrust seeded by atomic fear, thalidomide, Silent Spring, DES/ diethylstilbestrol, the Dalkon Shield, phenformin, Bhopal, Cherno- byl, and fen-phen. Communist witch hunts, Vietnam, Watergate, and the wide coverage of the indiscretions of a legion of highly placed officials were among the developments that contributed to the erosion of the trust many had in government. Perhaps, then, it was not such a huge surprise that patients began to turn in in- creasing numbers towards unorthodoxy: naturopathic medicine, chiropractic, homeopathy, and as one critic noted according to historian James Whorton, the whole ‘holistic hodgepodge’.[98] In fact, as seen below, Congress itself assigned the National Institutes of Health an Office of Dietary Supplements. Patients were taking matters into their own hands. Well-women health clinics were rejecting traditional medical paternalism in favour of informed lay caregivers, and the nascent women’s health network upended the medical establishment (and at least one Congressional hearing) to secure informative patient labelling for the oral contraceptive.[99,100]
Patients and their supporters developed a ground swell of interest to convince Congress to pass a law, the Orphan Drug Act, to provide the necessary financial incentives to convince the pharmaceutical industry to research and develop treatments for rare diseases.[101]
AIDS activists worked tirelessly through very visible protests and in face-to-face policy development meetings to convince government agencies— including the FDA— to createmore treatments for AIDS, make investigational therapies more widely available, and evaluate medicines more rapidly. Thus, while recognizing there were
commercial and political interests served bymorewidely available di- etary supplements, the public’s embrace of supplements — and its recoil at the notion of restricting access to these—was inmanyways a distillation of the social climate in the last decades of the century.
Towards an unprecedented ‘retrogressive step’
In 1973, 32 years after publishing regulations on foods for special dietary uses, the FDA proposed an overhaul of the rules, beginning with several dozen findings derived from the exhaustive hearings, findings that were as wide ranging as one might expect from a hearing that lasted for years and accumulated a transcript of more than 30 000 pages.[102] The label would be considered in its entirety, which included promotional and advertising material, though that had been the case since the time of the 1941 regulations. Reversing a long trend that certainly was stoked under the Nutrilite decree, the FDA stipulated that there was ‘no rationale for allowing or encouraging the promotion and sale of dietary supplements of vitamins and/or minerals to the general American population for the purpose of treating, preventing, or curing disease or symptoms’. The findings also dispensed with what the agency had long consid- ered recurring myths associated with vitamins and minerals: there was no rationale for the concept of sub-clinical nutritional deficiency; soil quality did not adversely affect the quantity of nutrients in foods; and storage, transport, and processing did not significantly affect the level of nutrients in food. The number of essential vitamin and minerals grew to 12 and 13, respectively, and the official US Recommended Daily Allowance (USRDA) for these would be based on the RDAs of the National Academy of Sciences, the same organization to which the agency had turned just a few years earlier for expertise in dealing with effectiveness questions of thousands of new drugs introduced between 1938 and 1962. Because of the ‘bewildering combinations now found in the marketplace, for which there is neither medical support nor consumer understanding’, the rules continued the requirement that a multi-component supplement would have to have all the essential vitamins and/or minerals, though provision was made to petition for additions to the complement.
The most controversial element that came out of the proposed regulations for vitamins and minerals addressed limits on the amount of nutrients. This was designed to counter the ‘nutritionally irrational’ levels of some supplements with amounts arrived at through ‘a sound scientific basis’. The rapid excretion of some nutri- ents (thereby limiting a benefit to the consumer) as well as the toxicity associated with other nutrients that had the opposite problem, such as fat soluble vitamins, would figure prominently in these determinations. If a supplement contained more than the listed upper limit of the USRDA (150% of the allowance) it would be deemed a drug and handled as part of the over-the-counter drug review under way.[103] The agency received over 20 000 letters objecting to these proposals, though reputedly none offeredmean- ingful reasons to stay the order. The final order basically included what had been proposed, most notably the implementation of ceilings on the strength of nutrients.[104] The final order would trigger a paroxysm of public backlash unseen in agency history and, some claimed, unseen anywhere in the federal government. It also provided an entrée for a long-awaited legislative attack on the regulation of dietary supplements.
As these developments were in the works, though, another supplement trade association, the National Nutritional Foods Association, challenged the new regulations and secured a decision
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on appeal that struck down the agency’s attempt to define as drugs supplements that exceeded the stated threshold. The court disagreed with the agency’s claim that the hearing record did not demonstrate any known food or nutritional use of nutrients in such high levels. The decision furthermore enjoined the enforcement of identity standards that barred certain nutrients; these nutrients had been recognized in the regulations as essential and even would be allowed in infant formulas and some other uses, yet they had no established RDAs. The appellate court thus stayed the regulations in their entirety.[105] At the same time, the FDA, Congress, and the White House were pummelled by communications of outrage over the proposed regulations. An aide to Sen. Edward Kennedy, who was chairing hearings on the regulation of vitamins, claimed their office received more mail about vitamins than what was witnessed during the Watergate hearings.[25] Opponents included expected parties, such as the supplement trade associations, manufacturers, and citizens — as the case with protested regulations in the 1960s — from all walks of life, but also some groups traditionally aligned with the FDA, such as the Association of Food and Drug Officials. While many consumer groups such as the American Association of Retired Persons and the Health Research Group supported the regulations, masses of consumers themselves clearly did not.[25]
Perhaps the most influential player was the senior senator from Wisconsin, a vitamin enthusiast himself who did not suffer what he considered government waste. William Proxmire, convinced that the FDA had sufficient power to remove toxic or misbranded supplement products from the market without infringing on the public’s right of access to vitamins and minerals, led the way in passing the Vitamin-Mineral Amendments of 1976.[25] First and foremost, the law prohibited the FDA from limiting the potency of vitamins or minerals, and it prevented the classification of any vitamin or mineral exceeding an agency-established threshold as a drug. Also, it prevented the government from limiting any combi- nation of vitamins or minerals or other food ingredients. Exceptions weremade for supplements used to treat diseases in children or for use by pregnant or lactating women. The FDA retained the ability to pursue false or misleading labelling of supplements and to classify as drugs supplements represented to treat or prevent diseases. As partial recompense for authorities removed under the amendments, the agency could enforce false or misleading advertising of vitamins or minerals, though only if the FTC first declined to act.[106,107] The 1976 law changed the landscape of food supplements and the FDA’s place in it in a manner that historian James Harvey Young characterized as taking ‘the first retrogressive step in federal legislation respecting self-treatment wares since enactment of the initial Food and Drugs Act in 1906’.[25]
The FDA had already begun to redraw its regulations to conform to the 1974 appellate court ruling, and in 1976 incorporated the changes wrought by the Vitamin-Mineral Amendments. However, the National Nutritional Foods Association again took the agency to court and secured a ruling that these regulations were issued im- properly; the FDA took no further action on the vitamin-mineral regulations.[90,105] However, in 1979 the OTC Drug Review, a project to determine the safety and effectiveness of over-the-counter (OTC) drugs that began in 1972,[105,108] appeared to serve as a vehicle to study vitamins and minerals for their possible reclassification as drugs, depending on what they claimed to do. The advisory panel on vitamin andmineral drugs, following a long study of these prod- ucts used as drugs, found that eight vitamins and three minerals were safe and effective as dietary supplements. Still, with concerns that this would constitute an FDA end-run around statutory and
court decisions on supplements, public protest ensued once again. The idea of folding supplements into the OTC monograph system was dropped two years later.[90,105]
The terrain changes: from the NLEA to DSHEA
Through the 1980s, and as the political climate in Washington shifted to regulatory reform vis-à-vis the state of the business environment, food labelling becamemore and more cluttered with confusing serving sizes, nebulous descriptors and nutrient claims, and health messages that pushed the boundaries of established facts.[109] Approaching the end of the decade, Congress was mov- ing more and more towards legislating some clarity out of the con- fusion. Of course, much of that would depend on the FDA’s role in developing regulations to interpret what the lawmeant in everyday life, and of course that track record over the past quarter-century had been frustrating all around, at least with respect to supple- ments. Nevertheless, Congress passed the Nutrition Labeling and Education Act of 1990 (NLEA). Among its provisions, the law charged the FDA with translating the current food label into a meaningful guide to promoting more informed and healthier eating. Regulations would need to establish definitions for such rampant food label terms as ‘free’, ‘low’, ‘light or lite’, ‘reduced’, ‘less’, and ‘high’.[110] With respect to vitamins, minerals, herbs (apparently the first appearance for these products), and other similar nutritional substances, within 24 months of passage of the law, the FDA had to promulgate final rules to establish the validity of health claims made by these products. The law specified the need for validation of the claimed relationship between folic acid and neu- ral tube defects, zinc and immune function in the elderly, antioxidant vitamins and cancer, and omega-3 fatty acids and heart disease.[90,110]
Herbs, or botanicals, had a particularly interesting history in this context. These were the heart and soul of traditional therapeutics that antedated Galen, yet hundreds of these types of medicines remained official for many editions of the USP — most eventually dispatched out of desuetude with the arrival of powerful new (and heavily advertised) therapeutic agents. Yet these phytomedicines also had a long tradition of popular use, witnessed in part by the cultivation of herbals for the literate masses, from John Gerard’s Herball (1597) and Nicolas Culpeper’s The English Physician (1652) and many others before, to Maude Grieve’s A Modern Herbal (1931). Medical botany was as much the province of the public as it was a field for pharmacognosists. Yet, as the case with themodern chemotherapeutic agents that supplanted them, those who would market these medicinal agents — and to be sure herbs from the foodworld were among them—were expected to providemodern evidence behind their therapeutic claims. That was a potentially expensive proposition that few were willing to risk.[111]
As the NLEAwas winding its way through Congress, a serious pub- lic health problem involving a dietary supplement was unfolding, a grim reminder of the potential hazards even among those innoc- uous products that prompted the respondents to the Health Practices study to remark that, ‘anything is worth a try’. Late in 1989, three patients in New Mexico experienced severe myalgia and peripheral eosinophilia, a debilitating and potentially fatal neurological illness with pain, swelling, rash, and other symptoms affecting the extremities rather suddenly and lasting for an ex- tended period.[112] The syndrome developed after having taken the amino acid tryptophan as a food supplement. The law did not provide the FDA recall authority in such situations. However, the power of conducting multiple seizures through district court
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orders served as the basis for the FDA to issue— fairly frequently — requests for firms to recall their products as the situation required.[113–115] Thus, in November, the FDA requested a volun- tary recall of tryptophan supplements, and urged those taking this OTC supplement to stop; it had been used for sleep disorders, premenstrual syndrome, stress, depression, appetite suppression, and alcohol and drug abuse. By this time there were 287 cases across 37 states. Retail trace-back eventually connected the supplements to a new strain of bacteria that had found its way into production at a Japanese manufacturer. Subsequent evidence indi- cated pre-1989 instances of eosinophilia outbreaks linked to other sources of the amino acid. Regardless, by October 1990 more than 1500 Americans had suffered tryptophan-induced eosinophilia- myalgia syndrome, and 38 eventually died.[116–120] The FDA subse- quently commissioned the Federation of American Societies for Experimental Biology to investigate the safety of amino acids on the market as dietary supplements, and the authors determined that, of the 24 substances studied, no safe level of consumption existed, and there were significant risks possible with consuming these in high dosages.[90]
The 1990 labelling act prompted another round of massive public protest by those who feared their supplement sales or supplement consumption would be jeopardized by the FDA regulations, and Congress passed a law to stave off the FDA’s statutory deadline to develop regulations under the NLEA. How- ever, under the Dietary Supplement Act of 1992 (DSA), the FDA certainly was free in the meantime to approve health claims for vitamins, minerals, or herbs. In addition, the Comptroller General was tasked with conducting an investigation of the practices and procedures used by the FDA to regulate dietary supplements — how it determined if a product were adulterated or misbranded, how it determined the staffing levels to devote to these problems, and ‘the means by which the Food and Drug Administration makes a determination that a substance poses a risk to public health and safety that justifies the expenditure of resources by the agency’.[121]
This law was passed, of course, in the wake of the eosinophilia- myalgia syndrome epidemic linked to tryptophan supplements. The same year saw the appearance of the report of the FDA’s
Dietary Supplements Task Force, formed by Commissioner David Kessler in 1991 to look anew at the regulation of dietary supple- ments with a focus on the public health. The task force acknowl- edged the American public’s ‘strong desire’ to have access to supplements and for the agency to ensure their freedom of choice as much as possible. Safety of the products — both their contents and their labelling — should be the agency’s foremost concern and the burden for ensuring that should fall on the manufacturer. Among its recommendations for supplement controls were appli- cation of good manufacturing practices; strengthened adverse event reporting; regulation of amino acids sold singly or asmixtures as drugs; and since the safety of a number of herbs had not been established and little was known about their untoward reactions, the FDA’s Center for Food Safety and Applied Nutrition and the Center for Drug Evaluation and Research would collaborate to re- solve issues with their safety and labelling.[122] The FDA had been ramping up a collaborative system of reporting adverse events associated with medical products since the 1950s, prompted largely by the disclosure of rare but fatal blood dyscrasias con- nected to the antibiotic, chloramphenicol. The American Society of Hospital Pharmacists, the Association of Medical Record Librar- ians, and a pilot group of five general hospitals participated with the FDA. The 1962 Drug Amendments required manufacturers to report serious drug reactions immediately to the FDA, but in terms
of reports from practitioners, the FDA was still trying to facilitate communications of untoward effects. In 1993, the FDA had launched a programme—MedWatch— that remains in operation, and initially focused on health practitioners but eventually enabled patients as well to report problems to the agency.[123–127]
Under the NLEA, the regulations that the FDA proposed in November 1991 and July 1992 automatically became final under terms of the law at the conclusion of the 24-month period, on 8 November 1992. However, the FDA soon thereafter announced its intention to issue regulations in the near future based on public comments it had received on its proposed rules. Nevertheless, about a week prior to the mandatory finalization of the NLEA rules, with the approval of the DSA, implementation of the NLEA insofar as it applied to dietary supplements was prohibited until at least 15 December 1993. So what was supposed to have been finalized on 8 November was not to be, at least for a while.[128,129] What one law gave, another took away. After the DSA-mandatedmorato- rium ended, the FDA indeed developed proposed regulations that addressed supplements, including amino acids. However, at the time the regulations appeared, Congress was at work on a law that would make those rules null and void, and even more significantly it would change dietary supplements and their regulation like no statute, regulation, or court decision ever had.
Driven principally by Sen. Orrin G. Hatch, Republican senator from Utah, and Bill Richardson, a Democratic representative from New Mexico, the Dietary Supplement Health Education Act (DSHEA) was passed on 25 October 1994. The statute recognized up front the place of dietary supplements in the economy: these were commodities used by half the population, which was spending annually about 4 billion on 4000 products sold by 600 manufacturers. While the government was expected to move swiftly against unsafe and adulterated (and presumably misbranded) supplements, otherwise regulators should stay out of the way of these products. By definition, dietary supplements contained one or more vitamin, mineral, herb, or other botanical, amino acid, or another substance taken to increase one’s total dietary intake. As for the safety of supplements, the law required the government to ‘bear the burden of proof to show that a dietary supplement is adulterated’. This was somewhat novel and unlike the approach taken for either drugs or foods at that time, grandfathering of pre-law products notwithstanding. The rationale for the placement of burden no doubt included the sense that an historical familiarity with supplements and the corresponding predictive track record was an important consideration in the assessment of a supplement’s safety. Moreover, the framers proba- bly believed the risk-benefit calculus of the potential harm caused by withholding the supplement judged against the potential bene- fit of their use justified a rapid assimilation into the marketplace. Still, premarket clearance for drugs and for food additives had been a requirement under the law since 1938 and 1958, respectively.[130]
Literature used ‘in connection with’ the sale of a supplement would not be considered labelling as long as it was not false ormisleading, did not promote a specific product or manufacturer, was displayed with similar matter to present a ‘balanced view’ of scientific infor- mation on a supplement, and was displayed apart from the supplement. Again the burden of proof would fall on the govern- ment to establish that any such arrangements above were false or misleading.[131]
DSHEA allowed for statements of so-called nutritional support, and these would not cause the supplement to be classified as a drug. In this way, a supplement could claim to benefit a deficiency disease (and indicate the prevalence of such a disease in the USA), it
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could describe a nutrient’s role in affecting the structure or function in humans and the mechanism whereby such structure or function was maintained, but the firm would need to have ‘substantiation’ that the statements above were truthful and not misleading.[132]
A manufacturer would notify the government within 30 days after marketing a product with one of these claims. Finally, if a label bore such a claim, it would also have to include the prominent notifica- tion: ‘This statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.’ In a sense, this boilerplate announce- ment was reminiscent— though in a starkly different way— of the proposed 1966 regulations and the labelled statement that informed the purchaser there was no scientific basis behind the routine use of dietary supplements. It was also reminiscent of the labelling approach inherent in the FDA’s 1906 enabling legislation, that the consumer had a right to be informed of certain realities about a product — for example, that it contained a dangerous ingredient — and left it to the user to decide whether or not to go forward. That philosophy of course shifted in the coming decades. In any event, the manufacturer could not juxtapose to the boilerplate any claim to treat or prevent any specific disease or class of diseases.[131]
Petitions could be filed with the FDA to market in dietary supple- ments new dietary ingredients, i.e., those not already marketed prior to 15 October 1994, and the agency would issue conditions under which this new ingredient would be reasonably expected to be safe under the labelled conditions of use. However, this provision applied only to new ingredients; there was no provision for premarket review of any pre-1994 ingredients in dietary supple- ments. The FDA’s proposed rules under the NLEA would be withdrawn under the new supplement law. Also, DSHEA provided for the issuance of good manufacturing practices for supplements, modeled after those established for foods. Finally, the new law called for the creation of two entities, one short lived with a specific charge, and the other to be a permanent fixture within the federal government’s preeminent medical research institution. First, a Commission on Dietary Supplement Labels, consisting of seven sci- entifically qualified members appointed by the President, would develop a report on how supplement labelling would best convey to the public valid scientific information to help consumers make better informed healthcare decisions.[133] The government would then promulgate regulations relating to the Commission’s recom- mendations. Second, an Office of Dietary Supplements would be established within the National Institutes of Health to study these commodities and their role in maintaining health and preventing disease.[131]
DSHEA thus changed the terrain of supplement regulation in a substantial way. Supplements were allowed certain health support claims if they had on file substantiation of such claims. The FDA’s lack of input into the veracity of those claimswould be so stipulated on the label, and the claims themselves would not cause supple- ments to be considered as drugs— and thus they would not have to abide by the level of evidence required of those therapeutic commodities. Manufacturers of supplements employing new (i.e., post-DSHEA) ingredients had to provide to the FDA advanced notification of their intent to market such ingredients and provide evidence to establish ‘a reasonable expectation of safety’.[134]
Otherwise, there would be no premarket review for supplements that included a vitamin, botanical, etc., that had been around before the law was passed. If there were problems then it was up to the government to prove that the supplement was unsafe. As DSHEA made clear, ‘the Federal Government should not take any
actions to impose unreasonable regulatory barriers limiting or slowing the flow of safe products and accurate information to consumers.’[131]
For nearly three-quarters of a century, the regulation of dietary supplements travelled a circuitous path to get to this point. The public was takenwith vitamins from the very beginning. Retail sales grew from $700,000 in 1925 to over $32 million ten years later. By the end of the 1930s Americans spent nearly $83 million on vitamins.[25] The figure for all dietary supplements by 1994 reached $4 billion. Efforts to deal with these never-before-seen commodities witnessed regulatory fits and starts all along the way, perhaps because the scientific understanding of these nutrients and their role in health lagged a bit. Certainly one observer saw the limits of science as a reasonwhy therewere suchmarked differences over supplement regulation.[25] Perhaps the fact that supplements seemed to straddle commodity classifications confused the issue. From the beginning, the Bureau of Chemistry wanted to learn more about vitamins and their standing as ‘medicinal agents’, and of course various regulations after that invoked both food and drug classifications. And perhaps the FDA underestimated the depth of the public’s devotion to dietary supplements, which is not to deny that this was stoked somewhat by those with vested economic or political interests in supplements. But when the vox populi on a fairly narrow regulatory issue achieves comparison with a cultural touchstone such as Watergate, it is probably a good idea to pay at- tention. The FDA had a glimpse of this through its Study of Health Practices and Opinions. However, by the time of that report, public sentiment had already started to overwhelm the regulatory pro- cess. So, given the chequered past with efforts to regulate dietary supplements, it is all themore important to learn about the problems that have been encountered with some of these products, and this special issue (and many others) of Drug Testing and Analysis will go a longway towards that end. As regulatory history has taught us with so many other commodities, the problems we faced often helped stimulate improvements in public health.
References [1] P. B. Hutt. Government regulation of health claims in food labeling
and advertising. Food Drug Cosmet. Law J. 1986, 41, 5–6 9-25 (Copeland’s remarks on S. 2800, from 16 May 1934, are quoted on p. 23), 53-55 (contrast 55 n. 333 with [Apple, Vitamania, 127]), 60. FDA certainly is not the only federal agency with a responsibility to oversee dietary supplements.
[2] J.v. Liebig. Die Organische Chemie in Ihrer Anwendung auf Physiologie und Pathologie. F. Vieweg, Braunschweig, 1842.
[3] A. J. Ihde, S. L. Becker. Conflict of concepts in early vitamin studies. J. Hist. Biol. 1971, 4, 12.
[4] A. J. Ihde. The Development of Modern Chemistry, Harper & Row, New York, 1964, pp. 261–264 (Liebig’s impact on chemistry in general is hard to overestimate. He was a gifted and innovative analytical chemist, but his influence was extended even more so by his students, legends in their own right: Kekulé, von Hoffmann, Pettenkoffer, Fresenius, Gibbs, and many others), 644-648 (the ‘e’ was dropped when it became clear that these substances, contrary to Funk’s original belief, were not necessarily amines).
[5] M. Stephenson. Obituary notice: Frederick Gowland Hopkins, 1861–1947. Biochem. J. 1948, 42, 160.
[6] S. L. Becker, in Chemistry andModern Society: Historical Essays in Honor of Aaron J. Ihde, (Eds: J. Parascandola, J.C. Whorton). American Chemical Society, Washington, DC. 1983, 61–83.
[7] Samuel Hopkins Adams reported on these in his famous series, “The Great American Fraud,” which appeared in Collier’s magazine in 1905 and 1906, republished as S.H. Adams The Great American Fraud: Collier’s Exposé of the Patent Medicine Fraud, Nostalgic American Research Foundation, Denver, 1978, pp. 91–93.
History of efforts to regulate dietary supplements
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[8] American Medical Association. Nostrums and Quackery, 2nd ed., American Medical Association, Chicago, 1912, pp. 68–75.
[9] R. d F. Lamb. American Chamber of Horrors: The Truth About Food and Drugs, Farrar and Rinehart, New York, 1936, pp. 74–79.
[10] S. Walker. Permissible Dose: A History of Radiation Protection in the Twentieth Century, University of California Press, Berkeley, 2000, pp. 3–6. Most of these products contained no radium, but Radithor unfortunately did.
[11] J. H. Young. The Toadstool Millionaires: A Social History of Patent Medicines in America before Federal Regulation, Princeton University Press, Princeton, 1961, pp. 144–162.
[12] J. H. Young. TheMedical Messiahs: A Social History of Health Quackery in Twentieth-Century America, Princeton University Press, Princeton, 1967, pp. 66–67, 333-359, 368-369, 383.
[13] J. H. Young. American Health Quackery: Collected Essays by James Harvey Young, Princeton University Press, Princeton, 1992, pp. 187–198.
[14] B. McCoy. Quack! Tales of Medical Fraud from the Museum of Questionable Medical Devices, Santa Monica Press, Santa Monica, 2000.
[15] A. J. Cramp. Nostrums and Quackery, Vol. 2, American Medical Association, Chicago, 1921, pp. 689–725.
[16] A. J. Cramp. Nostrums and Quackery and Pseudo-Medicine, Vol. 3, American Medical Association, Chicago, 1936, pp. 112–119, 213–214.
[17] P. A. Cohen, A. Goday, J. P. Swann. The return of rainbowdiet pills. Am. J. Public Health. 2012, 102, 1677.
[18] J. Swann.Marmola and the battle over authority in obesity treatment in the early twentieth century. Speech presented at the History of the Health Sciences Lecture Series, Claude Moore Health Sciences Library, University of Virginia Health System, Charlottesville, Virginia, 16 March 2005.
[19] Federal Trade Commission Act, Public Law 63-203, 38 US Stat. 717, 26 September 1914.
[20] A. Thackray, J. L. Sturchio, P. T. Carroll, R. Bud. Chemistry in America, 1876-1976, D. Reidel, Dordrecht, 1985, p. 129.
[21] Federal Food andDrugs Act, Public Law 59-384, 34 US. Stat. 768, 30 June 1906.
[22] G. Sonnedecker, in The Early Years of Federal Food and Drug Control, American Institute of the History of Pharmacy, Madison, 1982, 34–36. A variation clause in Section 7 allowed manufacturers to indicate different standards as long as they were plainly labelled; the product nonetheless would have to meet whatever its labelled standards were.
[23] L. A. Grossman. Food, drugs, and droods: a historical consideration of definitions and categories in American food and drug law. Cornell Law Rev. 2008, 93, 1113 Plots the relative decline of newspaper advertisements featuring health benefits associated with various foods after the 1906 Act.
[24] J. P. Swann, in The Inside Story of Medicines, (Eds: G.J. Higby, E.C. Stroud). American Institute of the History of Pharmacy, Madison, 1997, 231–232. Of course, the greater concern of the Bureau was in dealing with the 1911 Supreme Court decision overruling its ability to pursue therapeutic claims under the misbranding provisions of the law.
[25] R. D. Apple. Vitamania: Vitamins in American Culture, Rutgers University Press, New Brunswick, 1996, pp. 8–32.
[26] L. E. Holt. The Practical Application of the Results of Vitamin Studies. J. Am. Med. Assoc. 1922, 79, 129.
[27] Vitamin theories. J. Am. Med. Assoc. 1922, 79, 381. [28] A Study of Commercial Vitamin Preparations. J. Am. Med. Assoc. 1922,
79, 1846. [29] The Pharmacopoeia of the United States of America. 10th rev, J.B.
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[31] Chief, Central District to Chiefs of Stations, 16 February 1922, FDA History Office files.§
[32] Coco-Vitamin Lilly: A Standardized Vitamin Preparation. n.pub., n. place, ca 1922.
[33] Metagen: Concentrated Vitamines for Therapeutic Administration. Parke, Davis, and Company, [Detroit], ca 1922, attached to H. Walters,
Assistant to Chief, Central District, FDA, to Chief, Bureau of Chemistry, 6 April 1922, FDA History Office files.§ Note that this and the Coco- Vitamin booklets likely were intended for a professional audience rather than for broad, popular dissemination.
[34] Food Drug Rev. March 1923, 7, 7: The manufacture of vitamine preparations was investigated in January by several stations.
[35] Protein investigation. Food Drug Rev. 1921, 5, 18. [36] The vitamine content and digestibility of vegetable oil oleomargarine.
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gov/fdanj/handle/123456789/5068 [9 May 2015]. [44] Notices of Judgment No. 16411. Available at: http://archive.nlm.nih.
gov/fdanj/handle/123456789/50685 [9 May 2015]. [45] P. B. Dunbar. Chemistry and food regulation. Food Drug Rev. 1928, 12, 4. [46] FDA. Federal Food, Drug, and Cosmetic Law: Administrative Reports,
1907-1949. Commerce Clearing House, Chicago, 1951, pp. 645-648, 679, 713, and 957. The title of the agency changed from the Bureau of Chemistry to the Food, Drug, and Insecticide Administration in 1927, as several of the Bureau’s research functions were transferred elsewhere in the Department of Agriculture (a Department that largely concentrated on the promotion of agricultural interests, whereas the Bureau of Chemistry’s post-1906 responsibility was to regulate many industries—including many of those based in agriculture). The agency name changed again on 1 July 1930 to the Food and Drug Administra- tion. Both changes were implemented as part of appropriation bills. FDA remained in the Department of Agriculture until 30 June 1940, when it was transferred to the new Federal Security Agency.
[47] Federal Pure Food Law is 25 years old. Food Drug Rev. 1931, 15, 230. [48] F. J. Cullen. The purpose of the Federal Food and Drugs Act. Food Drug
Rev. 1932, 16, 57. [49] Food and drug research expanded to study vitamins and pharmacol-
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www.indiana.edu/~league/1931.htm [28 September 2015]. [51] Vitamin Standardization and the International Pharmacopoeia. Avail-
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[52] P. B. Dunbar. Government attitude on health claims for foods. Food Drug Rev. 1930, 14, 41.
[53] When does a food become a drug? Food Drug Rev. 1929, 13, 155. [54] USDA. Beware of so-called “health foods” say U. S. food law officials. US
Department of Agriculture press release, 22May 1929. FDAHistory files.§
[55] Salad oils figure prominently in seizures. Food Drug Rev. 1935, 19, 43. [56] Notices of Judgment No. 24682. Available at: http://archive.nlm.nih.gov/
fdanj/bitstream/123456789/64601/3/FDNJ24682.pdf [28 September 2015].
[57] Omaha firm fined for false vitamin claims. Food Drug Rev. 1936, 20, 232. [58] Notices of Judgment No. 26734. Available at: http://archive.nlm.nih.
gov/fdanj/bitstream/123456789/63156/4/FDNJ26734.pdf [28 September 2015].
[59] San Francisco stationdetains violative imports. FoodDrug Rev.1937, 21, 4. [60] Notices of Judgment No. 30956. Available at: http://archive.nlm.nih.
gov/fdanj/bitstream/123456789/58678/3/FDNJ30956.pdf [28 September 2015].
[61] Fine assessed for false and fraudulent vitamin claims. Food Drug Rev. 1937, 21, 177.
[62] Notices of Judgment No. 27353. Available at: http://archive.nlm.nih.gov/ fdanj/bitstream/123456789/62083/4/FDNJ27353.pdf [28 September 2015].
[63] Neu-Life shipper fined. Food Drug Rev. 1939, 23, 80. [64] Notices of Judgment No. 30622. Available at: http://archive.nlm.nih.gov/
fdanj/bitstream/123456789/59252/3/FDNJ30622.pdf [28 September 2015].
[65] Drugs and ‘patents’ seized. Food Drug Rev. 1935, 19, 17.
§Any unpublished matter cited can be obtained by contacting the author. Public release of all FDA press releases is forthcoming.
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[66] Notices of Judgment No. 24031. Available at: http://archive.nlm.nih.gov/ fdanj/bitstream/123456789/65369/4/FDNJ24031.pdf [28 September 2015].
[67] Catalyn shipper assessed over $4000 for prosecution costs. Food Drug Rev. 1939, 23, 45.
[68] Notices of Judgment No. 21213. Available at: http://archive.nlm.nih.gov/ fdanj/bitstream/123456789/58721/10/FDNJ30999.pdf [28 September 2015].
[69] Notices of Judgment No. 30999. Available at: http://archive.nlm.nih.gov/ fdanj/bitstream/123456789/68251/6/FDNJ21213.pdf [28 September 2015].
[70] Notices of Judgment No. 821. Available at: http://archive.nlm.nih.gov/ fdanj/bitstream/123456789/9762/10/ddnj00821.pdf [28 September 2015]. Lee, trading as Vitamin Products, lost in District Court, lost on appeal, and the Supreme Court denied his request for a hearing.
[71] Federal Food, Drug, and Cosmetic Act, Public Law 75-717, 52 US Stat. 1040, 25 June 1938, Sec. 201(g)(3), 403(j), 502(f).
[72] 5 Fed. Reg. 3565-3566, 5 September 1940. [73] 6 Fed. Reg. 5921-5926, 22 November 1941. [74] W.W. Goodrich. Interview by R.T. Ottes and F.L. Lofsvold, 15 October
1986. Transcript, 10, 109-110. Available at: http://www.fda.gov/ downloads/AboutFDA/WhatWeDo/History/OralHistories/Selected OralHistoryTranscripts/UCM372999.pdf [5 October 2015].
[75] Regulations promulgated on food for special dietary uses. FDA press re- lease, 22 Nov. 1941. FDA History Office files.§
[76] For example, see Notices of Judgment, Nos. 2819-2822, 2986-2991, 3221-3222, and 4242-4250). After July 1944 these cases were gathered as ‘vitamin preparations and foods for special dietary uses’.
[77] L.H. Boss. An analysis of the notices of judgment under the Federal Food, Drug, and Cosmetic Act. M. A. thesis, Western Michigan College of Education, 1953, 20-21, 50.
[78] Notices of Judgment, No. 3381. Available at: https://ceb.nlm.nih.gov/ fdanj/bitstream/123456789/72344/3/FFNJ03381.pdf [28 October 2015].
[79] Notices of Judgment, No. 3382. Available at: https://ceb.nlm.nih.gov/ fdanj/bitstream/123456789/72344/3/FFNJ03381.pdf [28 October 2015].
[80] Notices of Judgment, No. 3383 Available at: https://ceb.nlm.nih.gov/ fdanj/bitstream/123456789/72344/3/FFNJ03381.pdf [28 October 2015] (quote from p. 373).
[81] L. L. Lev. The Nutrilite consent decree. Food Drug Cosmet. Law J. 1952, 7, 57.
[82] Of course, as theNotices of Judgment indicate, many actions had been taken against vitamin andmineral preparations based on Section 502 charges for years.
[83] Food and Drug Administration. Annual Reports, 1950-1974. G.P.O, Washington, D. C., n.d., pp. 70 (1952), 99 (1953), 127 (1954), and 201 (1957).
[84] Recent Enforcement Actions in Federal Courts Involving Food Supplements, 13 January 1959, attached to Statement by Arthur S. Flemming. FDA press release, 13 January 1959. FDA History Office files.§
[85] Recent Enforcement Actions in Federal Courts Involving Food Supple- ments, 15 September 1959-15 September 1960, attached to State- ment by Arthur S. Flemming. FDA press release, 22 September 1960. FDA History Office files.§
[86] Recent Enforcement Actions in Federal Courts Involving Food Supplements, 1 November 1961-30 September 1963. FDA History Office files.§
[87] District Chiefs expose food supplement quackery. Food Drug Rev. 1957, 41, 119 129.
[88] K. L. Milstead. Food fads and nutritional quackery from the viewpoint of the Food and Drug Administration. Speech presented to the Joint Meeting of the Great Lakes Section of the Institute of Food Technologists and the Nutrition Foundation, Kellogg Center, Michigan State University, East Lansing, Michigan, 13 October 1961, 3 (quote). FDA History Office files.§
[89] W. Janssen. Interview by J.H. Young, F.L. Lofsvold, R.G. Porter, 30-31 January 1984. Transcript, 71-74. Available at: http://www.fda.gov/ downloads/AboutFDA/WhatWeDo/History/OralHistories/ SelectedOralHistoryTranscripts/UCM265184.pdf [5 October 2015].
[90] M. A. Kassel. From a history of near misses: the future of dietary supplement regulation. Food Drug Law J. 1994, 49, 237–238 241–243, 254–255, 258–261.
[91] W.W. Goodrich. The coming struggle over vitamin-mineral pills. Speech presented to the Division of Food, Drug, and Cosmetic Law, Section on Corporation, Banking, and Business Law, American Bar Association, New York, 12 August 1964, 5. FDA History Office files.§
[92] 27 Fed. Reg. 5815- 5818, 20 June 1962 (quotes). [93] FDA press release, 20 June 1962. FDA History Office files.§
[94] Fact Sheet: Recommended Dietary Allowances. attached to FDA press release, 17 June 1966. FDA History Office files.§
[95] 31 Fed. Reg. 8521-8527, 18 June 1966. [96] S.R. White. Chemistry and Controversy: Regulating the Use of Chemicals
in Foods, 1883-1959. PhD dissertation. Emory University, 1994, 259. The name derives from the traditional association of crepe with mourning clothing and funereal accoutrements, and thus presumably the suggestion of an association with doom. As one precedent of a crepe label, under the McNary-Mapes Amendment of 1930, substandard canned foods had to be labeled as falling below the US standard, of low quality, but not necessarily illegal.
[97] FDA. National Analysts. A Study of Health Practices and Opinions: Final Report. June 1972, FDA Contract no. 66-193, i-xviii. Available at http:// www.chsourcebook.com/articles/health_practices_and_opinions.pdf [13 May 2015].
[98] J. C. Whorton. Nature Cures: The History of Alternative Medicine in America, Oxford University Press, Oxford, UK, 2002, pp. 271–295.
[99] J.A. Houck, in Prescribed: Writing, Filling, Using, and Abusing the Prescription in Modern America, (Eds: J.A. Greene, E.S. Watkins). Johns Hopkins University Press, Baltimore, 2012, pp. 134–156.
[100] E. S. Watkins. On the Pill: A Social History of Oral Contraceptives, 1950-1970. Johns Hopkins University Press, Baltimore, 1998, p. 107 ff.
[101] L. R. Basara, M. Montagne. Searching for Magic Bullets: Orphan Drugs, Consumer Activism, and Pharmaceutical Development, Pharmaceutical Products Press, Binghamton, 1994.
[102] The complete hearing record, including the Hearing Examiner’s re- port, was deposited with the agency’s Hearing Clerk under docket number FDC-78 on 25 January 1971.
[103] 38 Fed. Reg. 2144, 2147 (first quote), 2152-2162 (second quote at 2158, and third and fourth quotes at 2154), 19 January 1973. Modifications to the regulations appeared two months later.
[104] 38 Fed. Reg. 20708-20718, 2 August 1973. [105] P. B. Hutt, R. A. Merrill. Food and Drug Law: Cases and Materials,
Foundation Press, Westbury, 1991, pp. 215–221 223-228, 588 ff. [106] Vitamin-Mineral Amendments, Public Law 94-278, 90 U. S. Stat. 410, 22
April 1976. [107] H. Hopkins. Regulating vitamins and ninerals. FDA Consum. 1976,
10, 10. [108] J. H. Moxley III, G. L. Yingling, C. C. Edwards. The Food and Drug
Administration’s Over-the-Counter Drug Review: Why review OTC drugs? Fed. Proc. 1973, 32, 1435.
[109] P. Rogers. Capitol clutter: Washington awash in labeling legislation. Dairy Foods. 1990, 91, 40.
[110] Nutrition Labeling and Education Act, Public Law 101-535, 104 U. S. Stat. 2353, 8 Nov. 1990, Sec. 3(b)1(A)iii (104 U. S. Stat. 2361), Sec. 3(b)1(A)x (104 U. S. Stat. 2361).
[111] V. E. Tyler. The Honest Herbal: A Sensible Guide to the Use of Herbs and Related Remedies, 3rd ed. Pharmaceutical Products Press/Haworth Press, Binghamton, 1993 Purdue pharmacognosist Varro E. Tyler was a long-time champion of a less cumbersome regulatory path for many botanical remedies, and held up Germany’s handling of such products as a model, though he also recognized many problem products as well.
[112] T. A. Medsger Jr. Tryptophan-induced eosinophilia-myalgia syndrome. NEJM. 1990, 322, 926.
[113] 37 Fed. Reg. 6938-6940, 6 April 1972. FDA issued proposed and final rules in the early 1970s removing amino acids (including L-tryptophan) from the Generally Recognized as Safe (GRAS) list, since “the mere natural presence of an amino acid in unprocessed foods in free or combined (as protein) form does not qualify it as safe for addition in a pure form as a component of a formulated or processed food. A risk to health exists when a free amino acid produces toxic or other adverse effects.” The agency then promul- gated the conditions for the safe use of these substances, namely, as nutrients to protein-containing food.
[114] 38 Fed. Reg. 20036-20039, 26 July 1973. [115] For a perspective on this rule given subsequent developments,
including the L-tryptophan disaster, see Malcolm Gladwell. 72 diet-pill ban ignored until recent deaths. Washington Post. 5 September 1990, A1.
[116] L. A. Swygert, E. F. Maes, L. E. Sewell, L. Miller, H. Falk, E. M. Kilbourne. Eosinophilia-myalgia syndrome: results of national surveillance. JAMA. 1990, 264, 1698.
[117] FDA press release, 11 November 1989. FDA History Office files.§
[118] FDA press release, 17 November 1989. FDA History Office files.§
[119] FDA press release, 22 March 1990. FDA History Office files.§
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[120] F.R. Shank (Director, Center for Food Safety and Nutrition, FDA). Statement to the Subcommittee on Human Resources and Intergovernmental Relations, Committee on Government, 20 July 1993, 9. FDA History Office files.§
[121] Dietary Supplement Act of 1992, Public Law 102-571, 106 U. S. Stat. 4500, 29 Oct. 1992, Sec.205(b)1 (quote).
[122] Dietary Supplements Task Force: Final Report, May 1992, 262–264. FDA History Office files.§
[123] I. Kerlan. Reporting adverse reactions to drugs. Bull. Am. Soc. Hosp. Pharmacists. 1956, 13, 311.
[124] J.L. Goddard. Interview by J.H. Young, 30 April to 19 June 1969. Transcript, 224 ff. Available at: http://www.fda.gov/ downloads/AboutFDA/WhatWeDo/History/OralHistories/Selected OralHistoryTranscripts/UCM264188.pdf [5 October 2015].
[125] D. A. Kessler, S. Natanblut, D. Kennedy, E. Lazar, P. Rheinstein, C. Anello, D. Barash, I. Bernstein, R. Bolger, K. Cook, M. P. Couig, J. Donlon, J. Johnson, C. Lorraine, T. McGinnis, J. Nazario, S. Nightingale, C. Peck, M. Pendergast, S. Rastogi, C. Reynolds, R. Schapiro, L. Tollefson, A. Wion. Introducing Medwatch: A new approach to reporting medication anddevice adverse effects andproduct problems. JAMA.1993, 269, 2765.
[126] T. Maeder. Adverse Reactions, William Morrow, New York, 1994. [127] Exhibit 67: Tabulation of August 31, 1962, by Food and Drug
Administration of Information Furnished Under Adverse Reaction
Program—July 1961 to June 1962. U. S. Senate, Committee on Govern- ment Operations, Subcommittee on Reorganization and International Organizations. Agency Coordination Study, 87th Congress, 2nd Sess., Part 2, 1 and 9 August 1962. GPO, Washington, D. C., 1963, 399-406, presents an interesting example of the outcome of the drug event reporting program.
[128] 57 Fed. Reg. 56347-56348k, 27 November 1992. [129] 58 Fed. Reg. 33690 ff, 18 June 1993. [130] Notwithstanding the waiver provided for products generally recog-
nized as safe by qualified experts. [131] Dietary Supplement Health and Education Act, Public Law 103-417, 108
U. S. Stat. 4325, 25 October 1994, Sec. 2-13. [132] Recall that part of the definition of a drug under the 1938 Act was a
substance that affected the structure or function of the body—other than a food.
[133] M. C. Nesheim, A. Dickinson, N. Farnsworth, M. Gilhooley, S. Kumanyika, R. S. McCaleb, A. Podesta. Report of the Commission on Dietary Supplement Labels, 24 November 1997. Available at: http://web.health.gov/dietsupp/final.pdf [28 October 1997].
[134] P. A. Cohen. Assessing supplement safety—The FDA’s controversial proposal. NEJM. 2012, 366, 389, which cites figures for the growth of new supplement ingredients vis-à-vis all other supplements that came on the market since 1994.
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Ad ve
rt is
em en
t
International Journal of Clinical Practice / Volume 66, Issue 11
REVIEW ARTICLE Free Access
Evaluation of documented drug interactions and contraindications associated
with herbs and dietary supplements: a systematic literature review
H.‐H. Tsai , H.‐W. Lin … See all authors
First published: 16 October 2012 https://doi-org.proxygw.wrlc.org/10.1111/j.1742-1241.2012.03008.x Cited by: 62
Serials Solutions
Hsiang‐Wen (Margaret) Lin, PhD School of Pharmacy and Graduate Institute, College of Pharmacy, China Medical University No. 91 Hsueh‐Shih Road, Taichung 40402, Taiwan Tel.: 886‐4‐22053366 ext 5151 Fax: 886‐4‐22078083 Email: hsiangwl@mail.cmu.edu.tw, hsiangwl@yahoo.com
Disclosures: None.
Linked Comment: Ernst. Int J Clin Pract 2012; 66: 1019‐20.
Summary
Background and Aims: The use of herbs and dietary supplements (HDS) alone or concomitantly with medications can potentially increase the risk of adverse events experienced by the patients. This review aims to evaluate the documented HDS‐drug interactions and contraindications.
Methods: A structured literature review was conducted on PubMed, EMBASE, Cochrane Library, tertiary literature and Internet.
Results: While 85 primary literatures, six books and two web sites were reviewed for a total of 1,491 unique pairs of HDS‐drug interactions, 213 HDS entities and 509 medications were involved. HDS products containing St. John’s Wort, magnesium, calcium, iron, ginkgo had the greatest number of documented interactions with medications. Warfarin, insulin, aspirin, digoxin, and ticlopidine had the greatest number of reported interactions with HDS. Medications affecting the central nervous system or cardiovascular system had more documented interactions with HDS. Of the 882 HDS‐ drug interactions being described its mechanism and severity, 42.3% were due to altered pharmacokinetics and 240 were described as major interactions. Of the 152 identified HDS contraindications, the most frequent involved gastrointestinal (16.4%), neurological (14.5%), and renal/genitourinary diseases (12.5%). Flaxseed, echinacea, and yohimbe had the largest number of documented contraindications.
Conclusions: Although HDS‐drug interactions and contraindications primarily concerned a relatively small subset of commonly used medications and HDS entities, this review provides the summary to identify patients, HDS products, and medications that are more susceptible to HDS‐drug interactions and contraindications. The findings would facilitate the health‐care professionals to communicate these documented interactions and contraindications to their patients and/or caregivers thereby preventing serious adverse events and improving desired therapeutic outcomes.
Review criteria We conducted a structured literature search on tertiary literature, web resources and primary literature, which were focusing on MEDLINE (via PubMed), EMBASE and the Cochrane Library. All evidence related to drug interactions or contraindications for herbal remedies and dietary supplements were selected and all relevant data were extracted using standardised checklists. Possible mechanisms and severity ratings of documented HDS–drug interactions were identified using MicroMedex and Natural Medicines Comprehensive®
®
Database .®
Message for the clinic Some HDS ingredients have potentially harmful drug interactions that are predominately moderate in their severity. HDS products containing St John’s Wort, magnesium, calcium, iron and ginkgo had the greatest number of documented interactions with other medications. Drugs affecting the central nervous system and cardiovascular system were documented to have more interactions with HDS. Herbal remedies were more likely to have documented drug interactions and contraindications than other dietary supplements.
Introduction The marketing and consumer use of herbs and dietary supplements (HDS) has risen dramatically in the USA over the past two decades (1, 2). It is estimated that > 50% of patients with chronic diseases or cancers ever use HDS (3), and nearly one‐fifth of patients take HDS products concomitantly with prescription medications (4, 5). Despite their widespread use, the potential risks associated with combining HDS with other medications are poorly understood by these consumers. Although many HDS users believe that HDS are safe (6), HDS products have been reported to be associated with mild‐to‐severe adverse effects such as heart problems, chest pain, abdominal pain and headache (2, 7, 8). Because a majority of patients often fail to disclose that they have taken HDS products to their healthcare providers, e.g. one study estimated only 30% disclosure (9), patient‐provider communication concerning the risks and benefits of HDS is critically important.
A major challenge for healthcare providers in counselling patients about HDS is that the available clinical evidence may be ambiguous and sometimes conflicting for HDS adverse events and drug interactions (10, 11). Also, there are often practice‐based barriers to identifying the evidence on HDS–drug interactions (12), including lack of familiarity or access to HDS‐related textbooks and databases (13, 14). In general, fewer and less rigorous studies are available for HDS than that of prescription drugs, particularly with respect to randomised controlled clinical trials (15). Many available references for HDS list numerous ‘potential HDS–drug interactions’ with little clinical significance or risk. Many reference books are replete with errors that serve only to confuse healthcare practitioners or consumers. The aim of this review was to provide healthcare professionals with a resource that concisely summarises the scientific evidence for HDS–drug interactions and contraindications from 2000 to 2010.
Methods
Evidence resources and literature search This review of HDS–drug interactions and contraindications focused on the evidence in the primary literature and tertiary literature (i.e. textbooks) related to HDS or drug interactions (16-21). Important online resources about HDS, including the website of National Center for Complementary and Alternative Medicine (NCCAM) (22), and Office of Dietary Supplements (23) were also included. The definition of HDS used for this study was the official definition of dietary supplements as stated in the Dietary Supplement Health and Education Act of 1994 (DSHEA) (24). HDS refers to any herbal product or dietary supplement product containing one of the following ingredients: vitamin, mineral, other botanical, amino acid, or other dietary substance. Thus, traditional foods or fruit products, not listed in the definition (e.g. avocado, grapefruit, and onion, etc.), were not included in this review.
The primary literature was obtained by searching databases, i.e. MEDLINE (via PubMed), EMBASE and Cochrane Library. Search terms included, but were not limited to the medical subject headings (MeSH terms) or key words that encompassed ‘herb drug interactions’, ‘dietary supplements’ OR ‘vitamins’ OR ‘minerals’ OR ‘amino acids’ OR ‘botanical’ OR ‘herbal medicine’ OR ‘phytotherapy’ combined with ‘contraindications’ OR ‘drug interactions’. The searches were performed in English only for the period of January 2000 to December 2010. The articles were selected based on the titles and abstracts and reviewed independently by two authors (HHT, HWL). Literature without related information, including studies regarding efficacy of HDS, regulation of HDS or methods of assay, was excluded. All relevant articles were selected without restriction for animal studies, clinical trials, observational studies (including case reports) or review articles.
Data extraction and synthesis Two standardised data abstraction checklists were developed and used to perform the review (one for the HDS–medication interactions and the other for HDS contraindications). All pairs of HDS–drug interactions documented in the retrieved literature sources (except for those interaction pairs with consequences that may benefit to users) were extracted. Because most HDS products or ingredients are not recommended for use during pregnancy or lactation (25), documented contraindications for these conditions were not further reviewed. All relevant data were extracted, compiled and classified all by one qualified reviewer, and then validated by another. Any disagreements related to the abstraction of data were resolved by consensus.
We grouped HDS products/ingredients into three categories: herb/botanical, vitamin/mineral/amino acid (VMA) and others. The most common drugs were grouped
according to the Anatomical Therapeutic Chemical (ATC) classification system (26). Possible mechanisms and the severity ratings of each pair of interactions were retrieved using the Interactions database in MicroMedex (27) and ‘Natural Product/Drug Interaction Checker’ in Natural Medicines Comprehensive Database (NMCD ) (28). We categorised the mechanisms for pairs of interactions into four types: pharmacokinetics, pharmacodynamics, both (pharmacokinetics plus pharmacodynamics) and unknown. The severity of each documented interaction was categorised as contraindicated, major, moderate and minor based upon MicroMedex , and major, moderate and minor based upon NMCD , respectively. The definitions of ‘major’, ‘moderate’ and ‘minor’ were similar in these two databases. For instance, a major interaction may cause life‐threatening damage and/or serious adverse effect(s), and a minor interaction would result in a negligible effect(s). However, contraindicated interactions were rated as ‘major’ severity in NMCD . The types of contraindications were categorised based on Goldman: Cecil Medicine (29). All data were compiled and managed using an Excel spreadsheet. Descriptive analyses to define the frequency or proportion of the evidence associated with the interaction pairs, the corresponding mechanisms and severity ratings of interactions and the types of contraindications for certain populations or patients was performed.
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Results Literature search Finally, 461 articles of primary literature were initially identified. Eighty‐five articles with full text, including 54 review articles, other than the 6 books and 2 web sites were selected for further review (Figure 1). The summaries of the animal studies, observational studies and clinical trials to retrieve information about HDS–drug interactions and contraindications for the original studies are listed in Tables 1–3, respectively. The summaries of the retrieved books and reviewed articles to retrieve information about HDS–drug interactions and contraindications were listed in Appendices 1 and 2, respectively. Among the original studies (n = 31), more than half (n = 16) were clinical trials. All of these articles contained information about HDS–drug interactions (12, 30-113), but only five articles provided descriptive information about HDS contraindications (55-57, 59, 102).
Figure 1
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Flow chart of primary literature search
Table 1. Summary of the included animal studies to retrieve information about HDS–drug interactions
Reference HDS Medication Animal
model
(number)
Study
design
Outcome
measures
Dose
dependent
Chiang
et al. (61)
Water extract
of crude
Pueraria lobata
(oral)
Methotrexate
(oral and
intravenous)
Rats (7 in
each
group)
Parallel
design
Pharmacokinetic
parameters
Yes
Jan et al. 1. Extract of Theophylline Rats (6 in Randomised Pharmacokinetic Yes
(67) dry Evodia
rutaecarpa
(Wu‐Chu‐Yu)
2. Commercial
herbal extract
preparation of
Wu‐Chu‐Yu‐
Tang
(gastrogavage).
(intravenous) each
group)
parallel
design
parameters
Tang et al.
(83)
Commercial
extract of
Ginkgo biloba
(oral)
Theophylline
(oral and
intravenous)
Rats (6 in
each
group)
Randomised
parallel
design
Pharmacokinetic
parameters
Yes
Okonta
et al. (94)
Extract of
fresh ginger
(oral)
Metronidazole
(oral)
Rabbit (5) Crossover
study
Pharmacokinetic
parameters
No data
Chang
et al. (100)
Silymarin,
silibinin
dissolved in
ethanol and
PEG2000 (oral)
Trazodone
(intravenous)
Rats (6 in
each
group)
Randomised
parallel
design
Pharmacokinetic
parameters
Biliary excretion
Yes
Chien Extract of Theophylline Rats (9 in Randomised Pharmacokinetic Yes
HDS, herbs and dietary supplements; AUC, area under concentration curve.
Table 2. Summary of the included observational studies to retrieve information about HDS– drug interactions
et al. (109) crude
Andrographis
paniculata and
major
components
(oral)
(intravenous) control
group
and 6 in
each
studied
group)
parallel
design
parameters.
Major
component of
HDS.
Reference HDS Medication Study
design
Population
(number of
participants)
Outcome
measures
Evidence
resources of
interactions
Barone
et al. (34)
St John’s
wort
Cyclosporine Case
report
Transplant
recipients (n = 2)
_ No mention
Rogers
et al. (38)
Herbs General Survey Emergency
department
patients with
heart disease,
diabetes,
psychiatric
disorders and/or
hypertension (n =
944)
Prevalence
and
occurrence
of sever
herb–drug
interactions
No mention
Dergal
et al. (40)
Herbal
medicines
Prescription
and over‐
the‐counter
Survey Older adults (≧65
years) attending a
memory clinic (n
The
frequency of
potential
Book, medical
literature
identified in
drugs = 195) interactions
between
herbal
medicines
and
conventional
drug
therapies
MEDLINE
Ly et al.
(41)
Dietary
supplements
Prescription
drugs
Survey Veterans ≧65
years (n = 285)
The
frequency of
dietary
supplement
use and to
identify
potential
interactions
No mention
Peng et al.
(52)
Dietary
supplements
Prescription
drugs
Survey Veteran
outpatients (n =
458)
The
incidence
and severity
of potential
interactions
between
prescription
medications
and dietary
supplements
Tertiary
references,
newsletters,
textbooks,
internet web
pages and
medical
literature
Sood et al.
(96)
Dietary
supplements
Prescription
drugs
Cross‐
sectional,
point‐of‐
care
survey
Patients in 6
different specialty
clinics (n = 1818)
The
frequency of
clinically
significant
interactions
between
dietary
supplements
and
prescription
MEDLINE
database,
Natural
Medicines
Comprehensive
Database,
published
textbook
HDS, herbs and dietary supplements; CAM, complementary and alternative medicine; MAOI,
monoamine oxidase inhibitors.
Table 3. Summary of the included clinical trials to retrieve information about HDS–drug interactions
medication
Goldman
et al. (101)
Vitamins Prescribed
or over‐the‐
counter
medications
Cross‐
sectional
study
(survey)
Children aged 0–
18 years (n =
1804)
The
frequency
and types of
potential
interactions
between
vitamins and
medications
PubMed
database,
MEDLINE Plus,
Drug digest
and the
database of the
University of
Maryland
Medical Center
Lapi et al.
(104)
Herbal drugs
and dietary
supplements
Synthetic
drugs
Cross‐
sectional
study
(survey)
Patients during
preoperative
anaesthesiological
visit (n = 478)
The
predictors of
potential
interactions
among
drugs, HDS
and/or other
CAM
medications
No mention
Simmons
and
Schneir
(113)
Commercial
supplement
products
(Atrophex )
Phenelzine Case
report
24‐Year‐old male
with hypertension
(n = 1)
_ No mention
Reference HDS Dose
schedule
Medication Study
design
Country Population
(number of
Outcome
measures
®
of HDS participants)
Wang et al.
(44)
Commercial
product of
St John’s
wort (oral)
Single
dose and
long
term for
14–15
days
Fexofenadine
(oral)
Open‐label,
fixed‐
schedule
study
USA Healthy
subjects (n =
12)
Pharmacokinetics
(C , T
Gurley et al.
(49)
Commercial
products of
Citrus
aurantium,
Echinacea
purpurea,
Milk thistle,
Saw
palmetto
(oral)
28 days Midazolam,
caffeine,
chlorzoxazone,
debrisoquin
(oral)
Randomised
open‐label
study
USA Healthy
subjects (n =
12)
Phenotypic ratio
Yin et al.
(53)
Commercial
Ginkgo
biloba
product
(oral)
12 days Omeprazole
(oral)
Open‐label
sequential
study
Hong
Kong
Healthy
subjects
genotyped
for CYP2C19
(n = 18)
Pharmacokinetics
(C , T
Yoshioka
et al. (54)
Commercial
product of
Ginkgo
biloba (oral)
Single
dose
Nifedipine
(oral)
Randomised
crossover
study
Japan Healthy
subjects (n =
8)
Pharmacokinetics
(C , T
Pharmacodynamics
(blood pressure).
Gurley et al.
(62)
Commercial
products of
St John’s
wort, garlic
oil, Panax
ginseng and
Ginkgo
biloba (oral)
28 days Midazolam,
caffeine,
chlorzoxazone
and
debrisoquine
(oral)
Randomised
open‐label
study
USA Healthy older
subjects who
were
extensive
metabolisers
of CYP2D6 (n
= 12)
Phenotypic
metabolic ratios,
serum
concentration
max
max
max
Gurley et al.
(63)
Commercial
products of
goldenseal,
kava kava,
black
cohosh and
valerian
(oral)
28 days Caffeine,
midazolam,
chlorzoxazone,
debrisoquin
(oral)
Randomised
open‐label
study
USA Healthy
subjects who
were
extensive
metabolisers
of CYP2D6 (n
= 12)
Phenotypic ratio
Gurley et al.
(71)
Commercial
products of
milk thistle,
black
cohosh
(oral)
14 days Digoxin (oral) Randomised
open‐label
study
USA Healthy
young adults
(n = 16)
Pharmacokinetic
analysis, ABCB1
(MDR1) genotyping
Jiang et al.
(73)
Commercial
products of
St John’s
wort, Asian
ginseng,
Ginkgo
biloba or
ginger
(oral)
7 or 14
days
Warfarin (oral) Two
randomised,
open‐label,
controlled,
crossover
studies
Australia Healthy
subjects (n =
24)
Population
pharmacokinetic
and
pharmacodynamic
parameter
Gurley et al.
(78)
Commercial
products of
goldenseal,
kava kava
(oral)
14 days Digoxin (oral) Randomised
open‐label
study
USA Healthy
subjects (n =
20)
Pharmacokinetic
analysis,
phytochemical
analyses
Fan et al.
(86)
Commercial
product of
baicalin
(oral)
14 days Rosuvastatin
(oral)
Randomised
crossover
study
China Healthy
subjects who
were
CYP2C9*1/*1
with different
OATP1B1
haplotypes
(n = 18)
Plasma
concentration and
pharmacokinetic
parameters
Gurley et al.
(88)
Commercial
products of
goldenseal,
kava kava
(oral)
14 days Midazolam
(oral)
Randomised
open‐label
study
USA Healthy
subjects (n =
16)
Pharmacokinetic
parameters,
phenotypic ratios
Gurley et al.
(89)
Commercial
products of
black
cohosh,
echinacea,
goldenseal,
kava kava,
milk thistle
and St
John’s wort
(oral)
14 days Debrisoquine
(oral)
Randomised
open‐label
design
USA Healthy
subjects who
were
extensive
metabolisers
of CYP2D6 (n
= 16)
Phenotypic ratios,
phytochemical
analysis and
disintegration
times
Gurley et al.
(90)
Commercial
products of
St John’s
wort,
echinacea
(oral)
14 days Digoxin (oral) Randomised
open‐label
study
USA Healthy
young adults
(n = 18)
Pharmacokinetic
parameters,
phytochemical
analysis and
disintegration
times
Mohammed
Abdul et al.
(91)
Commercial
products of
garlic,
cranberry
(oral)
14 days Warfarin (oral) Randomised
open‐label
crossover
study
Australia Healthy
subjects of
known
CYP2C9 and
VKORC1
genotype (n
= 12)
Pharmacokinetic
parameters,
pharmacodynamics
(INR)
Kim et al.
(110)
Commercial
product of
Ginkgo
biloba (oral)
Single
dose
Ticlopidine
(oral)
Randomised
open‐label,
crossover
study
Korea Healthy
subjects (n =
24)
Pharmacokinetic
parameters,
pharmacodynamics
(bleeding times)
Nieminen
et al. (111)
Commercial
product of
15 days Oxycodone
(oral)
Randomised,
balanced,
Finland Healthy
subjects (n =
Pharmacokinetic
parameters,
HDS, herbs and dietary supplements; C , maximum plasma concentration; T , time to reach
C ; CYP, Cytochrome P450; VKORC1, vitamin K epoxide reductase subunit 1; INR, international
normalised ratio.
Quantity of retrieved evidence After excluding the evidence regarding HDS not recommended for human use (i.e. anvirzel, belladonna, chaparral, comfrey, ephedra and pennyroyal) (16, 19, 21-23) and the duplicates, a total of 1491 unique pairs of documented interactions between HDS and individual drugs were identified. Among these pairs, 814 pairs (54.6%) were retrieved from the primary literature, 1018 pairs (68.3%) from books and only 23 pairs of interactions were identified in the two reviewed web sites. Among these interactions, the corresponding mechanism and severity was determined for 507 pairs (34.0%) using MicroMedex and 763 pairs (51.2%) in the NMCD online database. In total, 882 pairs (59.2%) of documented HDS–drug interactions were identified for their potential mechanism and severity. In terms of contraindications, there were 128, 15 and 9 documented HDS contraindications retrieved from books, primary articles and web sites, respectively, for a total of 152.
HDS–drug interactions Among all included interactions between HDS and individual drugs, 166 different herbs/botanical products, 28 VMA and 19 other supplements accounted for 890 pairs (59.7%), 529 pairs (35.5%) and 72 pairs (4.8%) of documented interactions, respectively (Figure 2). The top five herbs/botanical products, which were documented to have the most interactions with individual medications, were St John’s Wort (Hypericum perforatum), ginkgo (Ginkgo biloba), kava (Piper methysticum), digitalis (Digitalis purpurea) and willow (Salix alba). For example, St John’s Wort, magnesium, calcium, iron and ginkgo have been documented to interact with 147, 102, 75, 71 and 51 individual medications, respectively. Furthermore, a total of 509 unique drugs contributed to the 1491 documented pairs of interactions with HDS. The majority of these medications (n = 100) were categorised as treatment for central nervous system (CNS), second were those medications affecting the cardiovascular system and then systemic anti‐infective drugs (n = 90 and 75, respectively) (Figure 3). The
St John’s
wort (oral)
placebo‐
controlled,
crossover
study
12) pharmacodynamics
(behavioural and
analgesic effects);
adverse effects
max max
max
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medications that most contributed to documented interactions with HDS were warfarin, insulin, aspirin, digoxin and ticlopidine. Not surprisingly, warfarin was documented to have interactions with over 100 HDS entities (Figure 4).
Figure 2
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Herbs and dietary supplements tended to have documented interactions with medications in each caterory. VMA, vitamin/mineral/amino acid; DS, dietary supplements; DHEA, dehydroepiandrosterone
Figure 3
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Distribution of medications that might have interactions with herbs and dietary supplements. ATC, anatomical therapeutic chemical. The number of total medications was 509
Figure 4
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Medications with the largest number of interactions with herbs and dietary supplements. HDS, herbs and dietary supplements
Among 882 pairs of interactions with identified mechanisms, a total of 373 pairs (42.3%) were attributable to pharmacokinetic‐related mechanisms, i.e. affected the absorption, distribution, metabolism or excretion of the HDS/drug. Approximately 40.1% of all interaction pairs accounted for pharmacodynamic‐related mechanisms, and 8.5% were attributed to a combination of both mechanisms. No mechanism was identifiable for the remaining 9.1% of pairs. Among the 373 documented HDS interaction pairs that were pharmacokinetic‐related, 87 pairs were associated with St John’s Wort (23.3%), whereas calcium supplements were involved in 47 pairs of documented interactions (12.6%), and iron was involved in 42 pairs of interactions (11.3%). St John’s Wort was documented to reduce the effectiveness of alprazolam, amitriptyline, imatinib, midazolam, nifedipine and verapamil via the CYP (Cytochrome P450) 3A4 pathway, and the plasma levels of fexofenadine and digoxin via PgP (p‐glycoprotein) pathway. Some drugs (i.e. atorvastatin, cyclosporin, indinavir, nevirapine and simvastatin) were documented to interact with St John’s Wort through both pathways (37, 99). Among the 354 documented interactions that were pharmacodynamic‐related, kava accounted for 4.8% pairs of interactions (17 pairs). St John’s
Wort and ginkgo were both involved in 15 pairs of interactions (4.2%). Risk of additive serotonergic effects were increased when St John’s Wort was used concurrently with monoamine oxidase inhibitors (MAOI), selective serotonin reuptake inhibitors (SSRI), or tryptamine‐based drugs causing symptoms of anxiety, dizziness, restlessness, nausea and vomiting (16-18, 20). As a result of their pharmacological actions on the GABA receptor, synergism in CNS adverse events may result from taking barbiturates or benzodiazepines in combination with kava (16, 20, 98). Furthermore, kava may worsen the extrapyramidal effects associated with the use of droperidol, haloperidol, metoclopramide or risperidone because of a dopamine (21, 98).
Among the 507 documented interaction pairs identified with a severity rating in MicroMedex , 69.4% were categorised as the moderate interactions, 17.2% as major interactions, 10.3% as minor interactions and 3.1% were attributable to the contraindications. As for the 763 pairs of documented interactions being identified with the severity rating based on the NMCD , the majority documented interaction pairs were categorised as moderate (69.2%), major (26.5%) and minor (4.3%). Approximately, 240 documented HDS–drug interactions were categorised as major severity in either database (Tables 4 and 5). For example, the following pairs of interactions were considered as being contraindicated for concurrent use in MicroMedex : L‐Tryptophan vs. MAOI (i.e. isocarboxazid, phenelzine and tranylcypromine) or venlafaxine and St John’s wort vs. protease inhibitors (i.e. amprenavir, fosamprenavir and indinavir), irinotecan, rasagiline or voriconazole, respectively. Among the 390 documented interaction pairs having severity ratings in both databases, 41.3% were inconsistent. For example, the combination of alfalfa (Medicago sativa) and warfarin were considered as the minor interaction in MicroMedex ; however, it was rated as the major interaction in NMCD . The combination of St John’s Wort with quetiapine, quinidine, risperidone or sildenafil gave severity ratings major according to NMCD , and no interaction was reported in MicroMedex .
Table 4. The HDS–drug interactions with major severity* (other than St John’s Wort)
HDS Drugs Potential
consequences/reactions†
5‐
Hydroxytryptophan
Fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine
(17)
↑Risk of serotonin syndrome
Acacia Amoxicillin (98) ↓Absorption of amoxicillin
Alfalfa Warfarin (21, 33, 43, 75) ↓The effect of warfarin
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Aloe vera Digoxin (16, 21, 33, 45) ↑Digoxin toxicity
American ginseng Warfarin (16, 70, 75) ↓The effect of warfarin
Arginine Enalapril, nitroglycerin (21) ↑Hypotensive effects
Spironolactone (21) ↑Risk of hyperkalemia
Bitter orange Phenelzine (22, 98) ↑Risk of hypertensive crisis
Cowhage Methyldopa (98) ↑Hypotensive effects
Danshen Aspirin, ticlopidine, warfarin (17, 20, 21, 31, 35, 43, 47, 64-66,
68, 70, 75, 77, 81, 92, 97, 98)
↑Risk of bleeding
Digoxin (20, 21) ↑Digoxin toxicity
Digitalis Bendroflumethiazide, chlorothiazide, chlorthalidone,
hydrochlorothiazide, hydroflumethiazide, indapamide,
methyclothiazide, metolazone, polythiazide,
trichlormethiazide (17, 20)
↑Digoxin toxicity
Digoxin (17) ↑Digoxin toxicity
Dong quai Aspirin, heparin, ticlopidine, warfarin (16, 17, 20, 21, 31, 33,
35, 38, 43, 47, 64-66, 70, 72, 75, 77, 92)
↑Risk of bleeding
Evening primrose Warfarin (18, 75, 98) ↑Risk of bleeding
Garlic Ritonavir (16, 64, 97, 103) ↓The effect of ritonavir
Saquinavir (16, 22, 51, 64, 65, 77, 81, 85, 97, 98, 103) ↓The effect of saquinavir
Warfarin (16-19, 31, 33, 35, 36, 41, 43, 47, 51, 52, 64-66, 68,
75, 77, 80, 81, 85, 87, 96, 98)
↑Risk of bleeding
Ginkgo Aspirin, cilostazol, clopidogrel, dipyridamole, heparin,
ibuprofen, naproxen, ticlopidine, warfarin (12, 16-22, 30, 31,
33-36, 38, 40, 47, 51, 52, 55, 60, 64-66, 68, 75, 77, 80, 81, 85,
87, 98, 103, 105, 110)
↑Risk of bleeding
Risperidone (20, 103) ↑Risk of risperidone adverse
effects
Trazodone (12, 17, 20, 21, 35, 36, 40, 47, 60, 64, 65, 77, 81,
87, 103)
Excessive sedation and
potential coma
Glucosamine Warfarin (20, 75, 96) ↑Risk of bleeding
Green tea Ephedrine (17, 21) ↑Risk of stimulatory adverse
effects
Guarana Ephedrine (16) ↑Risk of stimulatory adverse
effects
Hawthorn Digoxin (16, 21, 33, 98) ↑Digoxin toxicity
Henbane Chlorpheniramine, clemastine, dimenhydrinate,
diphenhydramine, doxylamine, promethazine (17)
↑Risk of anticholinergic side
effects
Kava Alprazolam, chlordiazepoxide, clonazepam, diazepam,
estazolam, flurazepam, lorazepam, midazolam, morphine,
oxazepam, henobarbital, quazepam, temazepam, triazolam
(16-20, 30, 35, 36, 42, 57, 64, 65, 69, 72, 80, 81, 85, 103)
↑Central nervous system
depression
Droperidol (21, 98) ↑Central nervous system
depression
Licorice Warfarin (16, 43, 68, 75) ↑Risk of bleeding
L‐Tryptophan Citalopram, duloxetine, fluoxetine, fluvoxamine,
isocarboxazid, paroxetine, phenelzine, selegiline, sertraline,
sibutramine, tranylcypromine, venlafaxine (17, 20, 51)
↑Risk of serotonin syndrome
Zolpidem (17) ↑Zolpidem‐induced side
effect
Melatonin Zolpidem (21) ↑Sedative effects
N‐acetylcysteine Nitroglycerin (17) Severe hypotension,
intolerable headaches
Niacin Atorvastatin, cerivastatin, lovastatin, rosuvastatin,
simvastatin (19, 20, 82, 84, 112)
↑Risk of myopathy or
rhabdomyolysis
PABA Dapsone, sulfamethoxazole (17, 20) ↓Antibacterial effects
Pleurisy root Digoxin (17) ↑Digoxin toxicity
Potassium Amiloride, benazepril, captopril, enalapril, fosinopril,
indomethacin, lisinopril, moexipril, quinapril, ramipril,
spironolactone, trandolapril, triamterene (17, 19, 20, 52, 82)
↑Risk of hyperkalemia
Red yeast rice Cyclosporin (21, 65, 98) ↑Creatine phosphokinase
values
S‐
adenosylmethionine
Clomipramine (16) ↑Risk of serotonin syndrome
Scotch broom Haloperidol (98) ↑The potential toxicity
Phenelzine (17) ↑Risk of hypertensive crisis
Valerian Alprazolam, phenobarbital (16, 20, 42) ↑Central nervous system
depression
Vitamin A Acitretin, bexarotene, etretinate, isotretinoin, tretinoin (17,
19, 51, 82, 84, 101, 112)
↑Risk of vitamin A toxicity
Vitamin B6 Altretamine (84) ↓Response to altretamine
Vitamin E Dicumarol (84) ↑Risk of bleeding
Vitamin K Warfarin (17, 19, 20, 23, 43, 47, 75, 82, 84, 112) ↓Effect of warfarin
Willow Diclofenac, ibuprofen, naproxen, ticlopidine, warfarin (16,
17, 47, 68, 75)
↑Risk of bleeding
*Any HDS–drug interactions with severity rated as contraindicated or major in either database of
MicroMedex or NMCD were included in this table.
†Potential consequences or reactions were documented according to either aforementioned
database with severity rating as major or contraindicated. ↑, increasing; ↓, decreasing.
Table 5. The St John’s Wort‐drug interactions with major severity*
HDS Drugs Potential
consequences/reactions†
St
John’s
wort
Amiodarone (20, 37) ↓Effect of amiodarone
Benzodiazepine: alprazolam, clonazepam, diazepam, midazolam, triazolam
(20, 36, 37, 49, 59, 62, 64, 65, 76, 77, 80, 81, 87, 93, 97, 99, 103)
↓Benzodiazepine
effectiveness
Bupropion, buspirone, eletriptan, meperidine, trazodone (17, 31, 37, 39, ↑Risk of serotonin syndrome
® ®
65, 69, 99, 103)
MAOI: isocarboxazid, phenelzine, tranylcypromine (17, 33)
SSRI: citalopram, duloxetine, fluoxetine, fluvoxamine, nefazodone,
paroxetine, sertraline, venlafaxine (12, 16-18, 20, 31, 32, 35-37, 47, 52, 59,
64, 65, 69, 72, 77, 81, 87, 99, 103)
TCA: amitriptyline, amoxapine, clomipramine, desipramine, doxepin,
imipramine, nortriptyline, protriptyline, trimipramine (12, 16, 17, 20, 36, 37,
59, 64, 65, 69, 72, 76, 77, 80, 81, 85, 87, 93, 97, 99, 103)
Busulfan (39) ↓Effect of busulfan
Calcium channel blockers: diltiazem, felodipine, nicardipine, nifedipine,
nitrendipine, verapamil (16, 20, 37, 59, 65, 76, 79-81, 99, 102, 103)
↓Effect of calcium channel
blockers
Carbamazepine (32, 37, 99) ↓Effect of carbamazepine
Cyclophosphamide (16, 37, 93) ↓Effect of cyclophosphamide
Cyclosporin (12, 16-18, 20-22, 30-32, 34-37, 47, 49-51, 59, 64, 65, 69, 72, 76,
77, 79-81, 92, 93, 97, 99, 102, 103)
↓Effect of cyclosporine
Dapsone (37) ↓Effect of Dapsone
Dexamethasone (39) ↓Effect of dexamethasone
Digoxin (12, 16-18, 20, 22, 30-32, 34, 36, 37, 47, 51, 59, 64-66, 69, 72, 76, 77,
79-81, 87, 90, 92, 93, 97, 99, 102, 103)
↓Effect of digoxin
Docetaxel (39, 74) ↓Effect of decetaxel
Dolasetron (39) ↓Effect of dolasetron
Doxorubicin (39, 81) ↓Effect of doxorubicin
Erlotinib (20) ↓Effect of erlotinib
Erythromycin (103) ↓Effect of erythromycin
Estrogens/progestogens: estradiol, gestodene, levonorgestrel,
norethindrone (37, 39, 50, 72)
↓Effect of contraceptive
Etoposide (39, 81) ↓Effect of etoposide
Exemestane (20) ↓Effect of exemestane
Fentanyl, Morphine, Oxycodone (21, 37, 99, 111) ↑Sedation
Fexofenadine (20, 44, 59, 64, 65, 76, 77, 79, 80, 93, 97, 99, 103) ↓Effect of fexofenadine
Finasteride (39) ↓Effect of finasteride
Flutamide (32, 39) ↓Effect of flutamide
Gliclazide (103) ↓Effect of gliclazide
Haloperidol (37) ↓Effect of haloperidol
Ifosfamide (39) ↓Effect of ifosfamide
Imatinib (20, 59, 76, 77, 79, 80, 97, 99, 103) ↓Effect of imatinib
Irinotecan (12, 16, 20-22, 49, 59, 64, 65, 76, 77, 80, 81, 97, 103) ↓Effect of irinotecan
Ivabradine (103) ↓Effect of ivabradine
Ixabepilone (20) ↓Effect of ixabepilone
Lapatinib (20) ↓Effect of lapatinib
Lidocaine (37) ↑Risk of cardiovascular
collapse
Loperamide (21, 30, 35, 36, 64, 77, 99, 103) ↓Effect of loperamide
Maraviroc (20) ↓Effect of maraviroc
Mephenytoin (76, 97, 99, 103) ↓Effect of mephenytoin
Methadone (20, 21, 37, 64, 65, 77, 92, 93, 99, 103) ↓Effect of methadone
NNRTI: delavirdine, efavirenz, nevirapine (16, 18, 20, 32, 37, 69, 76, 77, 80,
99, 103)
↓NNRTI concentrations
Omeprazole (17, 20, 65, 76, 77, 80, 92, 93, 103) ↓Effect of omeprazole
Ondansetron (39) ↓Effect of ondansetron
Paclitaxel (37, 39) ↓Effect of paclitaxel
Phenprocoumon (12, 18, 31, 35-37, 47, 65, 66, 77, 80, 81, 97, 103) ↓Effect of phenprocoumon
Phenytoin (32) ↓Effect of phenytoin
Piroxicam, rasagiline, risperidone, tetracycline, tolbutamide, tretinoin (20, ↑Photosensitivity reactions
37, 39, 77, 102, 103)
Propofol, sevoflurane (20, 99, 103) ↑Risk of cardiovascular
collapse
Protease inhibitors: amprenavir, atazanavir, darunavir, fosamprenavir,
indinavir, nelfinavir, ritonavir, saquinavir, tipranavir (12, 16-22, 32, 34, 36,
37, 47, 49, 51, 64, 65, 69, 72, 76, 77, 79-81, 93, 97, 103)
↓Effect of protease inhibitor
Quetiapine (37) ↓Effect of Quetiapine
Quinidine (37) ↓Effect of Quinidine
Sildenafil (37, 50, 93) ↓Effect of Sildenafil
Sirolimus (20) ↓Effect of Sirolimus
Sunitinib (20) ↓Effect of sunitinib
Tacrolimus (12, 16, 20, 37, 59, 64, 65, 76, 77, 79-81, 92, 93, 97, 99, 103) ↓Effect of tacrolimus
Tamoxifen (16, 37, 39) ↓Effect of tamoxifen
Temsirolimus (20) ↓Effect of sirolimus, the
active metabolite of
temsirolimus
Teniposide (39) ↓Effect of teniposide
Tramadol (96) ↓Effect of tramadol
Vinblastin (37, 39, 81) ↓Effect of vinblastin
Vincristine (39) ↓Effect of vincristine
Voriconazole (20, 76, 77, 99, 103) ↓Effect of voriconazole
Warfarin (16-18, 20, 22, 32, 35-37, 43, 47, 51, 59, 64-66, 69, 70, 72, 73, 75-
77, 79-81, 85, 87, 97, 99, 102, 103)
↓Effect of warfarin
*Any HDS–drug interactions with severity rated as contraindicated or major in either database of
MicroMedex or NMCD were included in this table. †Potential consequences or reactions were
documented according to either aforementioned database with severity rating as major or
contraindicated. ↑, increasing; ↓, decreasing. MAOI, monoamine oxidase inhibitors; SSRI, selective
serotonin reuptake inhibitors; TCA, tricyclic antidepressants; NNRTI, non‐nucleoside reverse
® ®
transcriptase inhibitors.
HDS contraindications Fifty‐nine HDS from 152 reports were contraindicated for use among patients with specific disease states. The reports were classified into 19 disease states, including gastrointestinal diseases, neurologic disorders, renal/genitourinary diseases, neoplastic disorders, diseases of the liver/gallbladder/bile ducts and cardiovascular diseases (Figure 5). Flaxseed (Linum usitatissimum), echinacea (Echinacea purpurea) and yohimbe (Pausinystalia yohimbe) had the highest number of documented contraindications. For example, flaxseed was documented to have contraindications associated with gastrointestinal disorders such as acute or chronic diarrhoea, oesophageal stricture, inflammatory bowel disease, hypertriglyceridemia and prostate cancer (21). Echinacea was contraindicated for use among patients with rheumatoid arthritis, systemic lupus erythematosus, leukosis, multiple sclerosis, tuberculosis and HIV infection (16, 18). Yohimbe was contraindicated in patients with anxiety, bipolar disorder, depression, mania and schizophrenia, as well as benign prostate hypertrophy and kidney disease (21, 22).
Figure 5
Open in figure viewer PowerPoint
Common contraindications for HDS use. *Other contraindications of gastrointestinal diseases included fecal impaction for aloe vera and oesophageal stricture for flaxseed. †Other contraindications of neurologic disorders included multiple sclerosis for echinacea and posttraumatic stress disorder for yohimbe. HDS, herbs and dietary supplements
Discussion In this study, we summarised the evidence of HDS–drug interactions and contraindications that have been reported in the primary and tertiary literature. The existing evidence suggests that some HDS products/ingredients have potentially harmful drug interactions that are predominately moderate in their severity. HDS products containing St John’s Wort, magnesium, calcium, iron, and ginkgo had the greatest number of documented interactions with drugs. Medications affecting the CNS and cardiovascular system tended to have more documented interactions with these HDS. Of all listed medications, warfarin was documented to have the greatest number of HDS interactions. HDS products containing herbal remedies were more likely to have documented interactions with medications and the contraindications than vitamins, minerals and other types of dietary supplements.
Some of the commonly used herbal remedies such as echinacea, flaxseed, ginkgo and St John’s Wort have featured more prominently in industry or government sponsored clinical trials, academic studies and official monographs (114, 115). Some of these HDS entities have undergone more rigorous scientific evaluations. The clinical evidences for HDS are often mixed in terms of their support for efficacy and/or effectiveness. The benefits of HDS treatment must be balanced against the potential harmful effects including adverse events,
and the potential for drug interactions or disease state contraindications. Furthermore, there often may be just a self‐medicating ‘indication creep’, where patients who have a certain disease or condition unrelated to the supportive therapy with these HDS. For example, WHO monographs listed that echinacea products could be used in supportive therapy of colds and infections but were contraindicated for patients with autoimmune diseases (116). Even though the evidence to support the immunological effects of echinacea was still controversial (117), 6.4% of patients with arthritis/lupus reportedly used echinacea in the 2002 NHIS (4). Thus, patients need to understand that advantages of using echinacea products are outweighed by the potential harm if they have a specific disease state.
Patients using medications that have a narrow therapeutic range (i.e. warfarin, digoxin) were at greater risk for adverse outcomes because of HDS–drug interactions (20). This was particularly important for patients on anticoagulants (i.e. warfarin) who concomitantly took HDS products that had antiplatelet or anticoagulant effects (e.g. danshen, dong quai, garlic, ginger and ginkgo) (70, 75). In particular, HDS products that contained vitamin K or metabolites related to vitamin K (e.g. coenzyme Q10) had the potential to reduce the effects of warfarin (75). However, some conflicting information regarding warfarin–HDS interactions was observed when the evidence was retrieved from different literature sources. For instance, in a case study, the international normalised ratio (INR) decreased in patients when ginseng was administered with warfarin in some case reports (12, 66, 118), but other in vitro studies demonstrated that several components of Panax ginseng had anticoagulant effects (12). Furthermore, a controlled clinical trial of healthy subjects revealed that there was no significant interaction when ginseng was administered with warfarin (12, 17, 20, 31, 64). This discrepancy may be attributed to the fact that there are several different species of ginseng on the market [i.e. Asian ginseng (Panax ginseng), American ginseng (Panax quinquefolius), Siberian ginseng (Eleutherococcus senticosus)], different extract types and different doses used. Another interesting example is the concomitant use of warfarin with green tea. Some studies suggested that green tea may enhance the anticoagulant effects of warfarin (19, 75). However, much of the literature suggested that the content of vitamin K in green tea might antagonise the effect of warfarin (16, 17, 68, 70, 75). Regardless, it is important to regularly monitor the INR levels of warfarin users who also use HDS products that might influence the anticoagulation effect.
In addition, patients on a digoxin regime who have been taking an HDS should check to ensure that their plasma concentration of digoxin is indeed within the therapeutic ranges. If this is not the case, then the pharmacist usually should recommend to their patients to stop taking these HDS or have their digoxin dose adjusted by their healthcare providers; for example, as digoxin serum concentrations are usually measured by fluorescence
polarisation immunoassay or microparticle enzyme immunoassay, which may be influenced by ginseng and danshen (Salvia miltiorrhiza) (20, 58). False digoxin levels may confuse laboratory results and result in inappropriate patient management. Furthermore, aloe vera (Aloe barbadensis), buckthorn (Rhamnus catartica), cascara (Rhamnus purshiani), licorice (Glycyrrhiza glabra) and senna (Cassia senna) may cause hypokalaemia and result in digoxin toxicity (16, 17, 33, 47). As a result, digoxin users should be told to avoid taking the aforementioned herbal remedies.
In this study, the documented evidence of HDS–drug interactions and contraindications were systematically reviewed from the published literature. This was done because healthcare professionals, in general, use only textbooks, journal and review articles, as well as Internet as their major information source for HDS (119). Although the NCCAM and Office of Dietary Supplements are the two most commonly used, free online resources about HDS (120), only limited information is available related to HDS interactions and contraindications on these sites. Furthermore, only 59% of documented HDS–drug interactions could be identified with either their mechanisms and/or severity in either of the two common drug interaction resources (i.e. MicroMedex and NMCD ). Among them, over 40% of the interactions differed in their severity rating, which is likely to create confusion among healthcare providers about the potential harmful effects associated with a given HDS–drug interactions. Concerns about disagreements across literature resources and databases for drug interactions have been raised before (121), and these increase the difficulty in implementing an evidence‐based clinical practice for HDS products in clinical care. The intention of this review was to evaluate the evidence of HDS interactions and contraindications and to assist clinical practitioners in identifying patients with specific disease states and drug regimens that are more susceptible to these HDS–drug interactions and contraindications.
One of the limitations of this review was that it included all relevant information identified in the literature, regardless of the evidence types or quality of the studies. Although some HDS–drug interactions with little or no clinical significance were included in this study, their severity grading was based upon the available version of MicroMedex and NMCD . In order to reduce any personal bias, only those pairs of interactions with evidence retrieved from the aforementioned two databases were included to categorise the corresponding mechanisms and the severity rating. Consequently, we were unable to evaluate 41% of the interaction pairs for the corresponding mechanisms and severity in this study. Another limitation was the concern of publication bias, which might arise as only HDS products and medications that have been published in the literature on the basis of evidence‐based medicine. Therefore, there are many potential HDS–drug or disease interactions that may
® ®
® ®
Appendices
exist but are simply without documented outcomes. Lastly, only reports, books or articles published in English were included in this review. Those evidence regarding traditional herbal medicine or folk therapies, which were published in other languages (e.g. Chinese, Japanese), might be missing. Thus, it is very likely that the amount of documented HDS–drug interactions and/or contraindications in this review might be under‐reported.
Conclusions This review provides a structured summary of the evidence of the most widely documented HDS interactions and contraindications with medications. Although our findings primarily concern with a relatively small subset of commonly used medications and HDS entities, it is recommended that healthcare professionals should be paid more attention towards those pairs of interactions between any HDS products that contain St John’s Wort, magnesium, calcium, iron and ginkgo, and medications that affect the CNS or the cardiovascular system. These findings should be helpful for healthcare professionals to identify the priority areas where communication regarding HDS usages has the greatest potential to prevent adverse events and to improve patient’s therapeutic outcomes.
Acknowledgements The authors express their gratitude to Jun‐Fon Wang, Yi‐Ling Chen, Ying‐Hung Lu, Po‐Ming Hung, Tang‐Ping Shih, Chung‐Hui Ku, Shan‐Chieh Wu and Yi‐Zhu Chen for their help on data management, and Dr Chao‐Ling (David) Chen, Daniel Lee, Vincent Lee and Matthias C. Lu for their insights and comments for the manuscript. This work was partially supported by the National Science Council (NSC 99‐2320‐B‐039‐031‐MY3), China Medical University Hospital (DMR‐99‐140) and Committee on Chinese Medicine and Pharmacy, Department of Health, Executive Yuan, Taiwan, R.O.C. (CCMP99‐RD‐016).
Author contributions HHT, HWL and ASP participated in designing the review. HHT and HWL searched databases and retrieved the articles. HHT extracted and managed the data, while HWL validated it. HYT helped to resolve the disagreements in evidence abstraction. HHT wrote the manuscript, HWL, ASP, HYT and GBM reviewed and revised the manuscript. All authors read and approved the final manuscript.
Appendix 1 Summary of included books to retrieve information about HDS–drug interactions and contraindications.
Reference Year HDS–drug
interactions
Medication Format Severity
rating of
interactions
Contraindications HDS
Cassileth
(16)
2003 Yes Drug class
or
individual
drug
By HDS No Yes Herbal
remedies,
other dietary
supplements
and non‐
mainstream
producted
promoted as
cancer
treatments
Gaby (17) 2006 Yes Individual
drug
By
drug
and by
HDS
No No Herbs,
deitary
supplements,
foods and
alcohol
Mahady
(18)
2001 Yes Drug class
or
individual
drug
By HDS No Yes Herbs
Mason
(19)
2001 Yes Drug class
and/or
individual
drug
By HDS No Yes Vitamins,
minerals and
natural oils,
natural
substances,
enzymes,
amino acid
Tatro (20) 2010 Yes Drug class
with
individual
drug
By
drug
Yes No Vitamins,
electrolytes
and few
common
used herbs
HDS, herbs and dietary supplements.
Ulbricht
(21)
2005 Yes Drug class
or
individual
drug
By HDS No Yes Herbs and
supplements
Appendix 2 Summary of review articles to retrieve information about HDS–drug interactions and contraindications.
Reference Review
type
HDS Medications Databases Searching
period
Coxeter et al.
(12)
Narrative
review
Herbs General No mention No
mention
Ernst (30) Narrative
review
Herbs Conventional drugs No mention No
mention
Fugh‐Berman
(31)
Narrative
review
Herbs General MEDLINE; EMBASE MEDLINE:
1966–
1998;
EMBASE:
1994–
1999
McIntyre (32) Narrative
review
St John’s wort General No mention No
mention
Semaan (33) Narrative
review
Herbal
medicine
General No mention No
mention
Fugh‐Berman
and Ernst (35)
Systematic
review
Herbs Conventional drugs MEDLINE (via
PubMed), EMBASE,
the Cochrane Library,
CISCOM
Their
inception
to 2000
Izzo and Ernst Systematic Herbal Prescribed drugs MEDLINE (via Their
(36) review medicines PubMed), EMBASE,
Cochrane Library and
Phytobase
inception
to 2000
Markowitz and
DeVane (37)
Narrative
review
St John’s wort General MEDLINE, Current
contents and
PSYCINFO
1966–
2000
Block and
Gyllenhaal (39)
Narrative
review
Natural
inhibitors and
inducers of
CYP450
Cancer
chemotherapy
drugs, adjunctive
drugs
No mention No
mention
Lyons (42) Narrative
review
Herbal
medicine
Drugs used in
anaesthesia
No mention No
mention
Myers (43) Narrative
review
Complementary
medicines
Warfarin No mention No
mention
Buehler (45) Narrative
review
Herbal
products
Conventional
medicines
No mention No
mention
Chavez et al. (46) Narrative
review
Herbs General No mention No
mention
Williamson (47) Narrative
review
Herbs Prescription
medicines
EMBASE, MEDLINE EMBASE:
1980–
2003;
MEDLINE:
1966–
2003
Zhou et al. (48) Narrative
review
Herbs Substrates of CYP
enzymes
No mention No
mention
Huang and
Lesko (50)
Narrative
review
Dietary
supplements
General No mention No
mention
Ohnishi and
Yokoyama (51)
Narrative
review
Dietary
supplements
General No mention No
mention
Bartlett and
Eperjesi (55)
Narrative
review
Ocular
nutritional
General PubMed, Web of
Science
1980–
2004
supplements
Bressler (56) Narrative
review
Saw palmetto Prescription
medications
No mention No
mention
Bressler (57) Narrative
review
Kava Prescription
medications
No mention No
mention
Bressler (58) Narrative
review
Ginseng Prescription
medications
No mention No
mention
Bressler (59) Narrative
review
St John’s wort Prescription
medications
No mention No
mention
Bressler (60) Narrative
review
Ginkgo biloba General
(prescription drugs)
No mention No
mention
Hu et al. (64) Narrative
review
Herbal
medicines
General
(prescription drugs)
MEDLINE, Biological
Abstracts, Cochrane
Library, AMED, Biosis
Previews and EMBASE
Their
inception
to 2005
Izzo (65) Narrative
review
Herbal
remedies
General
(prescription drugs)
No mention No
mention
Izzo et al. (66) Systematic
review
Herbal
medicines
Cardiovascular
drugs
MEDLINE 1966–
2003
Marder (68) Narrative
review
Dietary
supplements
Antithrombotic
agents
No mention No
mention
Singh (69) Narrative
review
Kava and St
John’s wort
General
(prescription drugs)
No mention No
mention
Daugherty and
Smith (70)
Narrative
review
Dietary
supplements
Warfarin No mention No
mention
Haller (72) Narrative
review
Herbal and
dietary
supplements
General No mention No
mention
Meijerman et al.
(74)
Narrative
review
Herbs Anticancer drug No mention No
mention
Nutescu et al. Narrative Herbal and Warfarin No mention No
(75) review dietary
supplements
mention
Venkataramanan
et al. (76)
Narrative
review
Herbal General No mention No
mention
Yang et al. (77) Narrative
review
Herbs General No mention No
mention
Marchetti et al.
(79)
Narrative
review
P‐gp
modulators
(e.g. St John’s
wort)
ABCB1 substrates,
e.g. digoxin,
cyclosporin A,
tacrolimus
No mention No
mention
Nekvindova and
Anzenbacher
(80)
Narrative
review
Dietary
constituents
affecting CYPs
CYP substrates No mention No
mention
Skalli et al. (81) Systematic
review
Common
herbal
General MEDLINE via PubMed,
Allied and
Complementary,
Medicine Database,
Healthstar, AMBASE,
CINHAL, Cochrane
Library
1966–
2006
Sulli and Ezzo
(82)
Narrative
review
Vitamins and
minerals
General No mention No
mention
Yetley (84) Narrative
review
Multivitamin
and
multimineral
dietary
supplements
General No mention No
mention
Cranwell‐Bruce
(85)
Narrative
review
Herbs General No mention No
mention
Gardiner et al.
(87)
Narrative
review
Herbs, vitamins Anticoagulants,
cardiovascular
medications,
psychiatric
No mention No
mention
medications,
laxatives, diabetes
medications or
medications for
human
immunodeficiency
virus (HIV) infection
Nowack (92) Narrative
review
Herbs CYP3A4 and
transport‐protein
dependent drug,
anticoagulants or
antiplatelets,
antidiabetics,
antihypertensive
agents
No mention No
mention
Nowack (93) Narrative
review
Herbs Immunosuppressive
drugs
No mention No
mention
Samuels et al.
(95)
Narrative
review
Herbal
medicine
Antiepileptic drug No mention No
mention
Tomlinson et al.
(97)
Narrative
review
Herbs CYP3A4/P‐gp
substrates
No mention No
mention
Ulbricht et al.
(98)
Systematic
review
Herbs General MEDLINE, EMBASE,
the Cochrane Library,
CINAHL, Napralert,
International
Pharmaceutical
Abstracts, CANCERLIT,
CISCOM, HERBMED
No
mention
Borrelli and Izzo
(99)
Narrative
review
St John’s wort General No mention No
mention
Holcomb (102) Narrative
review
Herbs General No mention No
mention
Izzo and Ernst
(103)
Systematic
review
Herbs General MEDLINE (via
PubMed), EMBASE
Their
inception
and Cochrane Library to 2009
Shord et al. (105) Narrative
review
Herbs General No mention No
mention
Toselli et al.
(106)
Narrative
review
Echinacea CYP450 substrate No mention No
mention
Abad et al. (107) Narrative
review
Ginkgo biloba General No mention 2000–
2008
Cheng et al.
(108)
Narrative
review
Herbs Anticancer drugs Ovid OLDMEDLINE,
Ovid MEDLINE,
Excerpta Medica
Database (EMBASE),
Cochrane Database of
Systematic Reviews
(CDSR), ACP Journal
Club, Database of
Abstracts of Reviews
of Effects (DARE),
Cochrane Central
Register of Controlled
Trials (CCTR), Health
Technol
Until
November
2009
Rogovik et al.
(112)
Narrative
review
Vitamins General MEDLINE/PubMed,
MEDLINE Plus, Drug
Digest, Natural
Medicine
Comprehensive
Database and the
database of the
University of
Maryland
1966–
2009
HDS, herbs and dietary supplements; CYP, Cytochrome P450; P‐gp, P‐glycoprotein.
Appendix 3 PRISMA checklist.
Section/topic No. Checklist item Reported
on page
no.
Title
Title 1 Identify the report as a systematic review, meta‐analysis or both. P1
Abstract
Structured
summary
2 Provide a structured summary including, as applicable: background;
objectives; data sources; study eligibility criteria, participants and
interventions; study appraisal and synthesis methods; results; limitations;
conclusions and implications of key findings; systematic review registration
number
P2
Introduction
Rationale 3 Describe the rationale for the review in the context of what is already known P4
Objectives 4 Provide an explicit statement of questions being addressed with reference to
participants, interventions, comparisons, outcomes and study design (PICOS)
P4
Methods
Protocol and
registration
5 Indicate if a review protocol exists, if and where it can be accessed (e.g. Web
address), and, if available, provide registration information including
registration number
N/A
Eligibility
criteria
6 Specify study characteristics (e.g. PICOS, length of follow‐up) and report
characteristics (e.g. years considered, language, publication status) used as
criteria for eligibility, giving rationale
P5
Information
sources
7 Describe all information sources (e.g. databases with dates of coverage,
contact with study authors to identify additional studies) in the search and
date last searched
P5
Search 8 Present full electronic search strategy for at least one database, including any
limits used, such that it could be repeated
P5
Study
selection
9 State the process for selecting studies (i.e. screening, eligibility, included in
systematic review, and, if applicable, included in the meta‐analysis)
P5
Data
collection
process
10 Describe method of data extraction from reports (e.g. piloted forms,
independently, in duplicate) and any processes for obtaining and confirming
data from investigators
P6
Data items 11 List and define all variables for which data were sought (e.g. PICOS, funding
sources) and any assumptions and simplifications made
P6
Risk of bias in
individual
studies
12 Describe methods used for assessing risk of bias of individual studies
(including specification of whether this was done at the study or outcome
level), and how this information is to be used in any data synthesis
N/A
Summary
measures
13 State the principal summary measures (e.g. risk ratio, difference in means) N/A
Synthesis of
results
14 Describe the methods of handling data and combining results of studies, if
done, including measures of consistency (e.g. I ) for each meta‐analysis
N/A
Risk of bias
across studies
15 Specify any assessment of risk of bias that may affect the cumulative evidence
(e.g. publication bias, selective reporting within studies)
N/A
Additional
analyses
16 Describe methods of additional analyses (e.g. sensitivity or subgroup analyses,
meta‐regression), if done, indicating which were prespecified
N/A
Results
Study
selection
17 Give numbers of studies screened, assessed for eligibility and included in the
review, with reasons for exclusions at each stage, ideally with a flow diagram
P7, P48
(Figure1)
Study
characteristics
18 For each study, present characteristics for which data were extracted (e.g.
study size, PICOS, follow‐up period) and provide the citations
P28–37
(Table 1–
3); P53–
62
(Appendix
1–2)
Risk of bias
within studies
19 Present data on risk of bias of each study and, if available, any outcome level
assessment (see item 12)
N/A
Results of
individual
studies
20 For all outcomes considered (benefits or harms), present, for each study: (a)
simple summary data for each intervention group (b) effect estimates and
confidence intervals, ideally with a forest plot
N/A
Synthesis of
results
21 Present results of each meta‐analysis done, including confidence intervals and
measures of consistency
N/A
2
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Discussion
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P11–14
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P14
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British Journal of Clinical Pharmacology
Br J Clin Pharmacol (2017) 83 172–179 172
REVIEW‐THEMED ISSUE
Adverse effects of herbal or dietary supplements in G6PD deficiency: a systematic review
Correspondence Dr Shaun Wen Huey Lee, School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, 46150 Bandar Sunway, Malaysia. Tel.: +60 35514 5890; Fax: +60 35514 6263; E-mail: shaun.lee@monash.edu
Received 14 January 2016; revised 29 March 2016; accepted 13 April 2016
Shaun Wen Huey Lee1, Nai Ming Lai2, Nathorn Chaiyakunapruk1,3,4,5 and David Weng Kwai Chong6
1School of Pharmacy, Monash University Malaysia, 2School of Medicine, Taylorˈs University, Malaysia, 3Center of Pharmaceutical Outcomes
Research (CPOR), Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand, 4School of
Pharmacy, University of Wisconsin, Madison, USA, 5School of Population Health, University of Queensland, Brisbane, Australia and 6School of
Pharmacy, International Medical University, Malaysia
Keywords glucose-6-phosphate dehydrogenase, herbal medicine, safety, systematic review
AIM Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common genetic disorder, affecting nearly 400 million individuals worldwide. Whilst it is known that a number of drugs, foods and chemicals can trigger haemolysis in G6PD deficient individuals, the association between herbal and dietary supplements and haemolysis is less clear. The objective of this study was to evaluate the association between herbal or dietary supplements and adverse events in G6PD deficient individuals.
METHODS We searched 14 electronic databases from their inception until November 2015 for articles describing the use of herbal or dietary supplements in G6PD deficient individuals. Additional publications were identified from manually searching textbooks, conference abstracts and the grey literature. All study designs were included as long as they contained clinical information. These gathered findings were summarized narratively.
RESULTS Thirty-two publications met inclusion criteria. These reported on 10 herbal and dietary supplements. Overall evidence linking haemolysis to a herbal/dietary supplement was only found for henna. No evidence of harm was observed for vitamin C, vitamin E, vitamin K, Gingko biloba and α-lipoic acid.
CONCLUSIONS The review showed that there was insufficient evidence to contravene the use of most herbal or dietary products at therapeutic doses in G6PD deficient subjects.
Introduction Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a common inherited disorder, affecting nearly 400 million in- dividuals worldwide [1]. It is characterized by an enzyme
DOI:10.1111/bcp.12976
defect that plays an important role in preserving erythrocyte integrity against oxidative stress and damage [2]. This predis- poses G6PD deficient individuals to haemolysis when exposed to certain triggers such as fava beans and oxidant drugs. While most haemolytic attacks are generally self-limiting, they may
© 2016 The British Pharmacological Society
Adverse effects of herbal or dietary supplements in G6PD deficient patients
sometimes result in an increase of bilirubin levels that leads to kernicterus in infants or haemoglubinuria with acute renal failure in adults [3].
The effective management of G6PD deficient individuals includes educating patient and care providers about the known triggers that may increase the risk of haemolysis. Most reviews have largely focused on drugs to be avoided in G6PD deficiency [4, 5]. Similarly, several reviews have suggested that certain foods are known to trigger haemolysis, including legumes, especially fava beans, as well as green tea and its extracts. However, there is scarcity of any evidence that aims to outline the potential of herbs or dietary products in wors- ening the condition of G6PD deficient patients. In this study, we conducted a systematic review to identify and collate evidence on herbal or dietary supplements that should be avoided by G6PD deficient individuals. This is particularly important in a contemporary environment characterized by the widespread use of such supplements.
Methods
Literature search We searched for publications that examined the use of die- tary or herbal supplements in G6PD-deficiency. A supplement was defined as any vitamin, mineral, herb or botanical, amino acid, concentrate, metabolite or extract [6]. We searched 14 electronic databases from inception until No- vember 30 2015. We manually searched the reference lists of retrieved articles, textbooks and conference abstracts. We did not restrict the search by language and obtained full-text translation as required. Original articles of all study designs (clinical trials, cohort studies, case–control studies, case series and case reports) were included as long as they reported clinical information regarding harm. Keywords used included glucose-6-phosphate deficiency, adverse events, side effects, haemolysis, herbal medicine, dietary supplements and alternative medicine. The summary of the protocol can be found on PROSPERO (CRD42016032724).
Two authors (SWHL and NML) screened the title and abstracts using a standardized data extraction form. Publica- tions were further evaluated if they contained original data involving herbal or dietary supplement(s) and reported an outcome of interest such as haemolysis, jaundice, kernicterus or hyperbilirubinaemia in humans. Data abstracted included the exposure period, history of previous exposure to a similar substance, re-challenge test, any laboratory findings, factors affecting the G6PD deficient subjectˈs pharmacokinetic or pharmacodynamic response and the authorsˈ conclusions.
Assessment of outcome, causation and quality of evidence
Outcome classifications Outcomes were classified as major or minor. Major outcomes were death, major life-threatening bleeding or bleeding requiring hospitalization. Minor outcomes were defined as no change in clinical status or status requiring monitoring.
Criteria for the assessment of causation We used criteria adapted from the World Health Organization-Uppsala Monitoring Centre causality catego- ries [7], namely temporal association, risk of bias by other outcomes, prior exposure and outcome objectivity. Causation probability was classed as highly probable, probable, possible or highly improbable. The list of herbal or dietary supplements identified was subsequently classified into one of the three groups as proposed by Youngster and colleagues [4] as follow:
• Herbs/dietary products that should be avoided in patients with G6PD deficiency. These included compounds with a well- established association with haemolysis as evidenced by case reports and laboratory and clinical studies.
• Herbs/dietary products that should be consumed with caution by G6PD deficient patients. These included all compounds that were mentioned by any author or source as causing haemolysis, but insufficient evidence existed to implicate or exclude the administration as the cause of haemolytic anaemia.
• Herbs/dietary products where there was no evidence to con- travene their use by G6PD deficient patients.
Results The search identified 5511unique publications, of which 176 were evaluated as relevant. Of these, 32 publications contain- ing original data on food or herbal use in G6PD deficient individuals met the inclusion criteria (Figure 1). These publi- cations included five controlled studies, 18 case reports and nine case series and involved 10 dietary or herbal substances (Table 1, 2). Most of the adverse events reported were classified as major, with most patients reporting haemolysis requiring hospitalization and even death in four studies [8–11]. However, there was very low certainty for the evidence for harm. This may be due to reporting bias, as most of the data were based on case reports, in which only major events were likely to be reported. A discussion of individual substances is presented below.
Henna (Lawsonia inermis) Henna is a dye derived from the dried leaves of the flowering plant Lawsonia inermis [12]. The dye principally contains 2- hydroxy-1, 4-napthoquinone, but also flavonoids and ste- roids. Henna continues to be widely used in Africa, Asia and the Middle East, to colour or adorn the skin, nails and hair. Its use is often associated with religio-cultural events, includ- ing marriage.
Reports of haemolysis with the topical use of henna have been reported [8, 13–17]. Raupp et al. presented four cases of G6PD deficient individuals who experienced haemolytic crisis following topical henna application. Acute renal failure occurred in one case and the patient died after 2 days of admission [8]. In another study by Kandil and colleagues, the authors reported 15 G6PD deficient individuals who were admitted due to acute haemolysis after 24–72 h post-henna application [13]. Other authors have also reported similar fea- tures after application of henna. Taken together, existing data reviewed showed that henna could increase the risk of haemolysis in infants and children with G6PD deficiency.
Br J Clin Pharmacol (2017) 83 172–179 173
Figure 1 Flow diagram of study search
S. W. H. Lee et al.
Ascorbic acid (vitamin C) Four case reports described episodes of haemolysis in G6PD-deficient individuals following use of high doses of 3 and 40 g ascorbic acid daily [10, 18, 20]. One case re- port described the death of a 68-year-old black male who was given 80 g of ascorbic acid intravenously for burns [10]. In another report by Mehta and colleagues, the au- thors reported two boys in India who developed acute haemolysis after a ‘binge of fizzy drinks’ containing 4– 6 g of ascorbic acid [18]. The third report concerned a G6PD deficient individual with a history of HIV and ma- laria [19]. He was given a course of multivitamins, essen- tial fatty acids, glutathione supplements as well as a course of high dose intravenous antibiotics, 40 g three times weekly supplemented by 20–40 g of oral ascorbic acid daily. Acute haemolysis developed after a dose of 80 g intravenously. Our review found that at therapeutic doses, there is little evidence to preclude the use of vita- min C in G6PD deficient patients.
Vitamin E Similar to vitamin C, vitamin E is a natural antioxidant which acts to protect cells from lysis induced by oxidative stress. Several studies have demonstrated that vitamin E deficiency can contribute to shortened red cell survival
174 Br J Clin Pharmacol (2017) 83 172–179
[21, 22]. Seven studies examined the effects of vitamin E supplementation in G6PD deficient individuals [22–28]. Five of these studies indicated that high doses of vitamin E could reduce the rate of haemolysis in G6PD deficient patients [22–24, 27, 28]. Conversely, no changes in hae- matological status were reported in two other studies [25, 26]. While the role of vitamin E on chronic haemolysis in G6PD deficient individuals remains contra- dictory, all seven studies reported no adverse effects with oral supplementation of vitamin E between 400 iu to 2400 iu daily. Results of these studies suggest that vitamin E is safe to be consumed at doses of up to 800 iu daily.
Vitamin K Vitamin K is a fat soluble vitamin with a key role in the syn- thesis of clotting factors. As vitamin K may decrease glutathi- one concentrations in normal infant erythrocytes, it is suggested that it may trigger haemolysis in G6PD deficient in- fants [29]. Three publications provided limited evidence of harm with use of vitamin K in G6PD deficient subjects [11, 30, 31]. In one of the few randomized controlled studies found in this review, Capps et al.; randomized patients to re- ceive vitamin K or no treatment. Of the 30 G6PD deficient ne- onates, only four treated with vitamin K and two with no treatment became jaundiced. In the other report by Dhillon
Table 1 Summary of key adverse events reported
Herbal supplement: common name Number of studies Adverse effect Number of case(s)
Causality (number of studies)
Lawsonia inermis, Henna 1 Death 1 Possible (1)
5 Haemolysis 20 Probable(5)
Possible(1)
Ayurvedic medicine, Acalypha indica
4 Haemolysis 12 Possible (4)
Ayurvedic medicine, Mentat 1 Haemolysis 1 Highly improbable (1)
Ayurvedic medicine, unspecified
1 Haemolysis 1 Highly improbable (1)
Traditional Chinese medicine, Coptis chinensis 1 Death 1 Possible (1)
1 Hyperbilirubinaemia 1 Possible (1)
Traditional Chinese medicine, unspecified
1 Haemolysis 3 Possible (1)
Ascorbic acid, vitamin C 1 Death 1 Possible (1)
3 Haemolytic anaemia 4 Possible (3)
Vitamin K 1 Death 1 Possible (1)
2 Haemolytic anaemia 5 Possible (1)
Highly improbable (1)
1 Jaundice 1 Possible (1)
Gingko biloba 1 Haemolytic anaemia 1 Highly improbable (1)
Adverse effects of herbal or dietary supplements in G6PD deficient patients
et al. [11], vitamin K could not be ascertained to be the cause of all three cases reported. Taking into account the scarcity of reports and widespread use of vitamin K after birth among infants, it is likely that vitamin K can be administered safely to G6PD deficient individuals.
Gingko biloba Gingko biloba is a commonly used phytomedicine and claims have been made for improvement in cognitive performance, prevention of Alzheimerˈs disease and vascular dementia. Gingko is generally well tolerated, but can increase the risk of bleeding if used combination with warfarin, antiplatelet agents or in subjects with G6PD deficiency [32]. One case re- port discussed a 55-year-old woman with a history of hyper- tension and dementia [33], who was given a 17.5 mg injection of Gingko biloba leaf extract to improve her memory and subsequently developed jaundice. Cessation of therapy improved her condition and she was discharged 5 days later. Taking into consideration the widespread use of this supple- ment and paucity of reports, it is highly improbable that Gingko can lead to haemolysis in G6PD deficiency.
α-lipoic acid α-lipoic acid (LA) is a naturally occurring thiol compound which has potent antioxidant activities. Studies have demon- strated that LA can act to restore intracellular gluthathoine and thus benefit G6PD deficient individuals. One study
examined how LA supplementation regulated the antioxidant capacity in eight G6PD deficient adults and found no adverse events at doses of 600 mg day-1 over a period of 28 days [34]. The authors concluded that LA supplementationmaybe benefi- cial in G6PD deficient individuals due to its antioxidant capac- ity and ability to modulate the blood redox status.
Ayurvedic medicine Ayurvedic medicine is a form of Indian folk medicine which promotes universal connectedness and life forces. Practitioners often individualize treatment and include various compounds and herbs in their treatment. Two studies reported haemolysis following the administration of Ayurvedic medicine in G6PD deficient patients [35, 36]. One study described the harm associated with the use of Mentat, a traditional remedy containing 26 different herbs advocated for enhancingmemory. A previously healthy 21-year-oldmale had taken aMentat tablet twice daily for his incoming examinations for the past 3 days when he complained of dark coloured urine. He subsequently developed jaundice and acute renal failure [35]. The supplement was discontinued and he recovered after 28 days.
Acalypha indica Acalypha indica is a weed found in various parts of Asia, and widely used in Ayurveda for its claimed anti-inflammatory, antimicrobial and antitussive effects [37]. Sellahewa first described Acalypha indica induced haemolysis in four patients
Br J Clin Pharmacol (2017) 83 172–179 175
Table 2 Forms used by consumers experiencing adverse effects
Herbal supplement Botanical parts used, where specified Dosage form Comments
Henna, Lawsonia inermis
Leaves Crude extracts Contains 2-hydroxy-1, 4-napthoquinone, which is chemically similar to 1,4 naphtoquinone, a metabolite of naphthalene
Ayurvedic medicine, Mentat
NA Tablet containing 26 herbs
No mechanism of haemolysis postulated
Ayurvedic medicine, Acalypha indica
Leaves Herbal tonic extract Contains flavonoid, kaempherol, glycosides, mauritianin, clitoria and nictiflorin which has antioxidant activities
Ayurvedic medicine NA Solution containing several agents including Salix caprea
Salix caprea contains salicin, which is metabolized to salicylic acid, an inducer of haemolysis in G6PD deficient patients
Traditional Chinese medicine, Coptis chinensis
NA Herbal tonic Contains berberine, which can displace bilirubin from albumin
Traditional Chinese medicine,
NA Unknown No mechanism of haemolysis postulated
Ascorbic acid NA Fruit juice, injection Only occurs when consumed at high concentrations, exceeding normal recommended daily allowance
Vitamin K NA Injection Vitamin K is thought to be a strong antioxidant
Gingko biloba Leaves Injection Use of gingko has been associated with haemorrhage in adults
NA: Not available
S. W. H. Lee et al.
in Sri Lanka [38]. Since then, three other studies have similar reported incidences of acute haemolysis after ingestion of Acalypha indica [39–41]. In all cases, the authors suggested that consumption of a broth containing Acalypha indica was the cause of haemolysis. Nevertheless, the actual dose and purity of these extracts were not reported. Indeed, toxicity studies from laboratory studies using low to very high doses of Acalypha indica extract in rats found it to be non-toxic to major organs [42]. In view of these contradictory findings, we suggest caution in the consumption of Acalypha indica.
Traditional Chinese medicines TraditionalChinesemedicine (TCM) is a type of Easternmedicine built upon the foundation of Chinese medical practice and in- cludes herbal medicine, acupuncture, moxibustion, dietary ther- apy, exercise and massage. TCM is widely use worldwide for various ailments ranging from common cold to complex diseases such as arthritis and metabolic diseases. Among Asians, Chinese herbs are traditionally consumed by both the mother and child immediately after delivery, potentially endangering the newborn. We found only one study which reported haemolysis due to the use of unspecifiedChineseherbalmedicine in three childrenwith G6PD deficiency [43]. We found only one study which reported haemolysis due to the use of unspecified Chinese herbal medicine in three children with G6PD deficiency [43].
176 Br J Clin Pharmacol (2017) 83 172–179
Coptis chinensis Coptis chinensis is a commonly used herb in TCM for the treat- ment of various ailments including febrile illness as well as hepatobiliary diseases [44]. It contains the alkaloid berberine, which can increase bilirubin formation and thus increase the risk of jaundice especially in infants. Two studies reported death or severe hyperbilirubinaemia in infants with G6PD deficiency following the administration of Coptis chinensis in Singapore [9, 45]. However, another study by Lin and colleagues in Guangxi, China which examined 62 G6PD deficient neonates who were givenCoptis chinensis found that it did not aggravate the incidence of jaundice [46]. Like all reports of herbal medicines, the purity and actual doses were never reported. In view of this, we suggest caution during the consumption of Coptis chinensis.
Discussion
This review aims to provide an overview and critical evalua- tion on the safety of herbal products in relation to their use in G6PD deficient individuals. Most of the adverse events re- ported were major in nature as they required hospitalization or resulted in death. Nevertheless, we found that solid evi- dence associating harm with any herbal/dietary product ex- ists only for henna. Caution should be exercised while consuming the herbal preparations such as Acalypha indica
Adverse effects of herbal or dietary supplements in G6PD deficient patients
and Coptis chinensis as contradictory evidences exists. In the remaining herbal/dietary products reviewed, there was no evidence to contravene its use at therapeutic doses (Table 3).
The need for rigorous safety evaluation of herbs has always been questioned, especially by those who equate ‘natural’ to be equivalent to ‘safe’. In recent years, with the increasing recog- nition of the role of herbal pharmacovigilance, increasing reports have appeared describing the association of herbal/ dietary products with adverse events. The WHO Monitoring Centre has reported that nearly 9000 reports of adverse events over a 30 year period were associated with herbal medicines [33, 34]. In light of this, supplementary studies to spontaneous reporting are needed to establish causality to the herbal/dietary product and better understand the magnitude of the risk involved especially in special populations such as G6PD defi- cient individuals.
Some methodological challenges were noted when conducting this study. Firstly, most of the publications found were primarily case reports and case series, from which it is generally difficult to establish causality but areimportant for assessing safety issues. In all studies especially those address- ing herbal products, the actual dose of active ingredient, source of origin, purity and chemical composition to exclude the presence of contaminants are not reported. Similarly, the lack of regulation of most herbal/dietary products makes the treatment effect and even its adverse events very difficult to measure. Most plants contain a complex mixture of terpenes, alkaloids and other chemicals, which increase the risk of adverse reactions. The existence of contaminants and adulterants can also be pharmacologically active and thus responsible for toxicity. For example, some herbal plants used in Ayurvedic medicine have been known to contain heavy metals such as arsenic and mercury [47].
Strength and limitations The primary strength of the review is the broad search strat- egy adopted, aiming at identifying and retrieving all available published evidence. We systematically searched 14 databases and all primary references available, to enhance the com- pleteness of our search. We had not applied any language
Table 3 Herbal/dietary supplements which should be avoided, cautioned or can be safely consumed by G6PD deficient individuals
Herbs/dietary products that should be avoided by G6PD deficient individuals
Herbs/dietary products in which caution should be exercised during consumption
Herbs/dietary products in which there is no evidence to contravene their use
Henna Acalypha indica Vitamin C
Coptis chinensis Vitamin E
Vitamin K
Gingko biloba
α-lipoic acid
restriction, which allowed us to gather the most updated and relevant information from various journals since publi- cation bias is opposite that of conventional medicine, that is negative studies ares more likely to be published in well- known journals and positive studies in foreign language journals [48]. While we hoped to be able to make robust rec- ommendations and to provide readers with a list of poten- tially harmful herbal products or substances, we found instead a wide knowledge gap in their safety.
This review has several important limitations. The lack of systematic investigation and small reported sample sizes made it difficult, if not impossible, to ascertain the potential for true clinical interaction of any herbal product with G6PD deficiency. Indeed, we found that there was a paucity of evidence especially those related to TCM and Ayurvedic medicine. Similarly, we could not perform a meta-analysis. As such it is impossible to determine if the difference in re- ported harm outcome is due to true pharmacological interac- tion or due to more independent additive effects. While the number of articles published in the literature is low, we be- lieve that the real, clinical impact seen in these case reports and case series highlights the significance of such results.
In the course of this study, we also found several review ar- ticles that have addressed the issue concerning food which needs to be avoided by G6PD deficient individuals. In an article by Frank in 2005, the author advised against the consumption of fava beans, since they are known to be one of the precipitators of haemolysis for several decades [5]. Several other articles have made similar recommendations pertaining to the consumption of fava beans, but fall short in their listing of other food sources [49, 50]. While this is out of the scope of this review, future studies should look into systematically examining the possible list of foods that should be avoided by patients with G6PD deficiency. Finally, the under-reporting of adverse events especially associated with herbal and dietary supplements is generally well docu- mented and it is possible that such adverse events are more prevalent than the current study shows.
Conclusion In summary, we found that evidence linking haemolytic ef- fects in G6PD deficient patients was found only for henna. For most other herbal or dietary supplements, there is no ev- idence to contravene their use at therapeutic doses in G6PD deficient individuals.
Competing Interests All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on re- quest from the corresponding author) and declare no support from any organization for the submitted work, no financial relationships with any organizations that might have an in- terest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have in- fluenced the submitted work.
Br J Clin Pharmacol (2017) 83 172–179 177
S. W. H. Lee et al.
The authors wish to thank Dr Vivienne Mak and Dr Tahir Mehmood Khan for their invaluable input and feedback of the article.
Contributors SWHL conceived the study. SWHL, NML and NC had full ac- cess to all the data and take responsibility for its integrity. SWHL and NML developed and tested the data collection forms and conducted the analysis. SWHL, LNM, NC and DWKC interpreted the data and drafted the manuscript. All authors critically reviewed the manuscript.
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Supporting Information
Additional Supporting Information may be found in the online version of this article at the publisher’s web-site:
http://onlinelibrary.wiley.com/doi/10.1111/bcp.12976/suppinfo.
Appendix S1 Databases used in review
Br J Clin Pharmacol (2017) 83 172–179 179
https://doi.org/10.1177/0884533617721687
Nutrition in Clinical Practice Volume 32 Number 5 October 2017 607 –627 © 2017 American Society for Parenteral and Enteral Nutrition DOI: 10.1177/0884533617721687 journals.sagepub.com/home/ncp
Invited Review
Reportedly, 50% of adults residing in the United States use dietary supplements on a regular basis for a variety of health reasons.1-3 In a recent review by Kantor et al, overall supple- ment use by noninstitutionalized and nonmilitary adults in the United States remained stable from 1999 to 2012, although some differences were noted with adults aged 20–39 years reportedly using fewer supplements of any kind while supple- ment use increased in those aged ≥65 years.3 When evaluating use of specific supplements, Kantor and colleagues found increases in the use of vitamin D (from 5.1% in 1999–2000 to 19% in 2011–2012) and fish oil supplements (from 1.9% in 1999–2000 to 16% in 2011–2012).3 Various differences were also observed, with women and non-Hispanic white adults using supplements the most. Additionally, use was the highest among highly educated individuals as compared with survey responders reporting less than a high school education (65% vs 37%, respectively).3
Reportedly, dietary supplements are used by 20%–85% of individuals after being diagnosed with cancer.4,5 Supplements are most commonly used by breast cancer survivors, followed by patients with prostate, colorectal, and lung cancers, which is not surprising since these are the most common types of cancer diagnosed in adults.6 Improved quality of life, reduced symp- toms related to treatment and/or the disease process, and recom- mendation by medical practitioners are commonly cited reasons; family and friends may also be an influence.7 Controversy, how- ever, surrounds the use of dietary supplements, particularly when patients are undergoing treatment because it is unknown whether supplements affect treatment efficacy.
The results of studies exploring the effect of dietary supple- ments on cancer outcomes are mixed, with some studies report- ing benefits and others finding significant adverse outcomes.2,8
This article discusses the evidence available in the literature regarding selected dietary supplements commonly used by cancer survivors (see Table 1).
Multivitamin/Mineral Supplements
Reportedly, a little over one-third of adults in the United States take a daily multivitamin/mineral (MVM) supplement to pre- vent developing chronic diseases, including cancer, despite the lack of data supporting their efficacy for such purposes.3,5 A variety of MVM supplements are available in the marketplace, with varying levels of vitamins and minerals. While many con- tain 100% of the daily value for ≥1 vitamins and some for miner- als, no supplement contains 100% of the daily value for calcium, magnesium, phosphorus, or potassium. MVM supplements are also produced specifically for individual segments of the popu- lation, as supplements directly formulated for children, women, men, and older adults are widely available. Often, these supple- ments have been designed to provide higher or lower amounts of a particular vitamin and/or mineral for that market segment. For example, some supplements manufactured for women typically contain more iron than that in supplements developed for men.
721687 NCPXXX10.1177/0884533617721687Nutrition in Clinical PracticeMarian research-article2017
From the 1University of Arizona, Tucson, Arizona, USA.
Financial disclosure: None declared.
Conflicts of interest: None declared.
This article originally appeared online on August 16, 2017.
Corresponding Author: Mary J. Marian, DCN, RDN, CSO, FAND, University of Arizona, 6310 N Canon del Pajaro, Tucson, AZ 85750, USA. Email: mmarian@u.arizona.edu
Dietary Supplements Commonly Used by Cancer Survivors: Are There Any Benefits?
Mary J. Marian, DCN, RDN, CSO, FAND1
Abstract Following a cancer diagnosis, dietary supplements are reportedly used by 20%–80% of individuals. Supplements are most commonly used by breast cancer survivors, followed by patients with prostate, colorectal, and lung cancers, which is not surprising since these are the most common types of cancer diagnosed in adults. Reasons cited for such use include improving quality of life, reducing symptoms related to treatment and/or the disease process, and recommendation from medical practitioners; family and friends may also be an influence. However, controversy surrounds the use of dietary supplements, particularly during treatment—specifically, whether supplements affect treatment efficacy is unknown. This article discusses the evidence related to common dietary supplements used to prevent cancer or a recurrence. (Nutr Clin Pract. 2017;32:607-627)
Keywords dietary supplements; oncology; herbal medicine; vitamins; glutamine; omega-3 fatty acids; botanical supplements
608 Nutrition in Clinical Practice 32(5)
Several investigators have examined the relationship between MVM supplements and cancer.9-23 The Physician’s Health Study II—a large prospective double-blind primary prevention trial—randomized middle-age male physicians (N = 14,641) from 1997 to 2011 to either a MVM supplement (Centrum Silver) or placebo.10 The primary study end points evaluated the impact of a daily MVM supplement vs a pla- cebo in regard to total cancer incidence and major cardio- vascular events. Predetermined secondary outcomes included incidence of site-specific cancers. Study results revealed that men taking a multivitamin supplement experienced a modest decrease in total cancer incidence (hazard ratio [HR], 0.92; 95% CI, 0.86–0.998; P = .04), although there was no reduced risk for prostate cancer (the most common type of cancer diagnosed in men) or overall cancer mortality noted. The Vitamins and Lifestyle study reported similar findings regard- ing lung and pancreatic cancers.12,13 Conversely, Dawsey and colleagues reported that use of multivitamins did not reduce the risk for either esophageal or gastric cancers.14 Similarly, several large cohort studies, including the Women’s Health Initiative and the Women’s Healthy Eating and Living, have not found any benefits related to taking multivitamin supple- ments for reducing the risk for cancer, risk for recurrence, or risk for mortality.15,16 Alternatively, the Cancer Prevention II Cohort study noted a decrease in colorectal cancer risk with the use of multivitamin supplements but only after 10 years of use.17 Likewise, the Nurses’ Health Study observed a decrease in colon cancer risk when multivitamin supplements were used for at least 15 years or longer.18 Additionally, a nonsig- nificant weak relationship was seen for breast cancer risk with long-term use (5–9 years) in this study, while an increased risk for fatal non-Hodgkin’s lymphoma was found with multivita- min supplement use for >10 years.
Multiple studies have evaluated whether taking an MVM supplement may provide any advantages to cancer survivors.
Jatoi et al found that survival was longer (4.3 years) for patients with non–small cell lung cancer who used MVM supplements daily vs those who were nonusers.4 After adjusting for vari- ous factors, including tumor stage, treatment, and age, the authors found a relative risk (RR) of death of 0.74 (95% CI, 0.44–0.65; P < .01) in favor of vitamin/mineral use. In breast cancer survivors, multivitamin use prior to diagnosis and extending to postdiagnosis was associated with a nonsignifi- cant decreased risk of recurrence (HR, 0.76; 95% CI, 0.54– 1.06) and total mortality (HR, 0.79; 95% CI, 0.56–1.12). Conversely, the Shanghai breast cancer survivor study reported no positive relationship between multivitamin use and radiation treatment for breast cancer.20 Study investigators, however, have hypothesized that perhaps the dosages may have been insufficient to see protective benefits.
Wassertheil-Smoller et al also reported a 30% reduction in breast cancer mortality in MVM users vs nonusers (HR, 0.70; 95% CI, 0.55–0.91) in postmenopausal women with invasive breast cancer.21 Despite these positive findings, Ng et al found no significant relationship between multivitamin use for survivors with stage III colon cancers after completion of surgery and adjuvant chemotherapy after 6 months of fol- low-up, although a secondary analysis of the data reflected improved disease-free survival for study participants ≤60 years of age, with no benefits noted in those >60.22
The Life After Cancer Epidemiology study also found that breast cancer survivors who were consuming 5.5 servings of vegetables and fruits daily and exercising for approximately 16 h/wk experienced a 60%–70% decrease in dying from any cause when using multivitamins on a regular basis.19 Therefore, it is difficult to sort out whether the multivitamins and/or a healthy lifestyle promoted the beneficial findings, given that using mul- tivitamins was not found to provide any protection to women with unhealthy lifestyle practices, although taking multivitamin supplements was not associated with any risks. Alternatively, in the Iowa Women’s Health study, Inoue-Choi et al found that mortality risk was 2.3 times higher with the use of folic acid supplements and 28% greater among multivitamin users, with a trend toward a greater risk for dying when an increasing number of supplements were used by cancer survivors with poor diet- quality scores.23 A trend for lower mortality risk was observed with higher diet-quality scores and multivitamin use, as well as the use of a greater number of dietary supplements, highlighting perhaps the role of dietary quality in affecting outcomes.
Summary
Given the conflicting study results described here, consumers and cancer survivors should not rely on using MVM supple- ments to prevent cancer. This is supported by leading national cancer organizations, including the American Institute for Cancer Research and the American Cancer Society (see its guidelines for nutrition and cancer prevention), as both recom- mend against using MVM supplements to prevent cancer.24,25 Consuming a prudent healthy diet rich in colorful fruits, vege- tables, nuts, seeds, and whole grains is more likely to provide a
Table 1. Common Dietary Supplements Used for Cancer Prevention and Risk Reduction for Recurrence and Mortality.
Type of Supplement Example
Vitamin/mineral supplements
Botanical supplements
Other
Multivitamin/mineral (standard or specialty; age related or sex specific)
Vitamin C Vitamin D Vitamin E
Astragalus Milk thistle Turmeric Resveratrol Ginger Ginseng
β-carotene ω-3 fatty acids Glutamine Melatonin
Marian 609
variety of anti-inflammatory, anticarcinogenic nutrients than relying on obtaining these from dietary supplements.26 A com- prehensive nutrition assessment should be completed to deter- mine if the patient is exhibiting any signs of micronutrient deficiencies or is at high risk for developing a deficiency before supplements are recommended. The American Cancer Society does recommend that when using a MVM supplement, consumers should not choose those that provide >100% of the daily value for any nutrient.25
Vitamin D
Vitamin D, a fat-soluble vitamin, is commonly referred to as the “sunshine” vitamin, although many nutrition experts think that vitamin D should be classified as a hormone due to its many physiologic functions.27 In addition to sun exposure, vitamin D can be obtained from dietary supplements and foods such as fatty fish, beef, eggs, cheese, cod liver oil, mushrooms, as well as fortified foods such as milk, orange juice, and break- fast cereals; however, endogenous vitamin D production fol- lowing ultraviolet B exposure is the primary contributor to circulating levels.28
A potential role for vitamin D in cancer prevention and treatment has been reported, as preclinical research has revealed that vitamin D possesses antitumorigenic properties (eg, anti-inflammatory, antiproliferative, proapoptotic, and immunomodulatory).27 Additionally, observational studies reflect an inverse association between sunlight exposure and the incidence of many types of cancer.20,27-29 However, the results of epidemiologic studies have been more mixed.
The vitamin D metabolite 25-hydroxycholecalciferol, 25(OH)D, is the biomarker primarily used to assess vitamin D status in studies, since it reflects both dietary and endogenous synthesis. With an estimated half-life of 3 weeks, 25(OH)D is considered a better indicator of status than the activated form of vitamin D, 1,25(OH)2D, which has a half-life of 15 hours.27 Additionally, 1,25(OH)2D is tightly controlled by the parathy- roid hormone, with levels generally not reflecting a decrease until vitamin D deficiency is severe. However, challenges also exist with using 25(OH)D to reflect status, as levels are influ- enced by inflammation, season of the year, body weight, age, sunscreen usage, medications, diet, skin pigmentation, physi- cal activity, and genetic polymorphisms.27,29
A clear inverse association has been reported between cir- culating 25(OH)D levels and incidence of several cancers, including breast, pancreatic, kidney, ovarian, colorectal, lung, and upper gastrointestinal cancers, as well as total cancer inci- dence.29-36 The few prospective randomized trials that have been completed thus far have not consistently supported these findings, however.37-39
Lung Cancer
Studies reflect that lower serum vitamin D levels are prevalent in cancer survivors with lung cancers, which may be concerning
given that higher circulating levels are associated improved sur- vival.40,41 Zhou et al found that patients having tumors resected in summer months did better in terms of recurrence-free survival than patients undergoing surgery in the winter months.40 Collectively, the data from 2 meta-analysis and numerous pro- spective observational studies have reported a lower risk for lung cancer with increasing circulating 25(OH)D levels.40-43 Chen et al noted a statistically significant 5% decreased risk for lung cancer with each 10-nmol/L increase in 25(OH)D values (RR, 0.95; 95% CI, 0.91–0.99) in their meta-analysis evaluat- ing circulating vitamin D levels and lung cancer risk.42 In the second meta-analysis, Zhang et al observed an RR of 0.83 (95% CI, 0.77–0.90) comparing lowest to highest 25(OH)D levels.43 Based on circulating 25(OH)D levels, poorer survival and an increased risk for cancer recurrence have been reported by some investigators, while other studies have found no association.44-48
Supplementation. There have been no studies evaluating the role of vitamin D supplementation for risk reduction regarding lung cancer as the primary study outcome, with the only evi- dence coming from studies that examined overall intake, including supplements. In the Women’s Health Initiative, which enrolled postmenopausal women aged 50–79 years, an inverse statistically significant association was found between vitamin D intake (from diet and supplements) and risk for lung cancer in never smokers.48 A 63% reduction in risk was noted for intakes >800 IU/d (HR, 0.37) when compared with vitamin D intakes <100 IU/d. This suggests that vitamin D may provide additional risk reduction benefits in postmenopausal women in addition to not smoking. In a meta-analysis by Zhang et al, no statistical difference was found between vitamin D intake and lung cancer risk (RR, 0.89; 95% CI, 0.74–1.06; P = .184), although higher intakes (including supplements) were associ- ated with a tendency for a lower risk for developing lung can- cer.43 No studies have been designed evaluating whether vitamin D supplementation can improve survival in this population.
Colorectal Cancer
Several meta-analyses have reported links between serum vita- min D levels and colorectal cancer, which suggests a consistent inverse relationship between serum levels and risk for colorec- tal cancer.49,50 Recently, a possible benefit between serum vita- min levels and survival in patients with metastatic colon cancer has been reported.33,51 In a phase III trial enrolling patients with metastatic colorectal cancers, Facciorusso et al found that study participants (n = 1043) with higher vitamin D levels at baseline experienced a significantly greater overall survival; increasing serum levels also resulted in better progression-free survival.51 Patients in the upper quartile of vitamin D levels (median 25[OH]D level, 27.5 ng/mL) had a median overall survival of 32.6 months, compared with 24.5 months for patients in the lower quartile (median 25[OH]D level, 8 mg/mL). When
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adjusted for season and age, the HR for survival comparing the highest quintile to the lowest was 0.64 (P = .0003). In another study, Zgaga and colleagues reported a strong association between serum 25(OH)D values and colorectal cancer (stage I-III) outcomes related to disease-specific mortality as well as all-cause mortality, with adjusted HRs of 0.68 (95% CI, 0.50– 0.90) and 0.70 (95% CI, 0.55–0.89), respectively for the highest vs lowest tertiles of values.33
Supplementation. Data regarding whether vitamin D supple- ments are associated with primary prevention for colorectal cancer are scarce, with data available from only a few studies. In the Women’s Health Initiative study, no difference for risk was found between women taking 400 IU/d of D3 and 1000 mg/d of calcium and women taking a placebo.52 However, women who were not taking their own calcium or vitamin D supplements upon study entry did experience a 17% nonsig- nificant decline in colorectal cancers with supplementation. In a clinical trial completed in Britain, no reduction in risk for developing or dying from colorectal cancer was found in men and women randomized to receive 100,000 IU/d of vitamin D
3
every 4 months for 5 years.53 Thus far, no studies have been completed evaluating whether vitamin D supplementation affects disease progression or disease-specific mortality related to colorectal cancer.
Breast Cancer
A number of studies have investigated the role of vitamin D and the risk of breast cancer, with inconsistent findings. Several meta-analyses have reported a statistically significant inverse relationship between serum 25(OH)D levels and risk for breast cancer.54-56 However, in review of these studies, there is a clear and distinct difference in outcomes, with case-control studies reflecting a statistically significant decrease in breast cancer risk when circulating levels are higher and with prospective studies noting no significant association between breast cancer and circulating serum vitamin D levels.
In a recent study by Eliassen et al, no overall association was found between plasma 25(OH)D levels and risk for breast can- cer, although a reduced risk was found for women having higher levels when compared with the those in the lowest quintile in the summer (RR, 0.66; 95% CI, 0.46–0.94; P trend = .01).57 More recently, McDonnell et al reported that in women with 25(OH)D levels ≥40 ng/mL, a 67% lower risk of breast cancer was found vs women having serum levels <20 ng/mL (HR, 0.33; 95% CI, 0.12–0.90).58 Whether vitamin D may play a role in the risk for breast cancer recurrence has also been exam- ined.59 Yao and colleagues found in the Pathways Study, a pro- spective cohort study of breast cancer survivors, that serum 25(OH)D levels were reduced in women with advanced-stage tumors; concentrations were also the lowest in premenopausal women with triple-negative cancer.59 Study participants in the highest tertile of serum levels also had a greater overall sur- vival, with the association remaining after controlling for
confounding factors (HR 0.72; 95% CI, 0.54–0.98). Further- more, a meta-analysis evaluated whether higher vitamin D levels at the time of diagnosis were associated with greater sur- vival in women with breast cancer. Mohr and colleagues noted that higher serum levels were linked with a reduced mortality when compared with lower serum levels.60 Meta-analyses by Kim and Je and Vrieling et al also reflect an improvement in survival, with higher 25(OH)D concentrations in breast cancer survivors.61,62
Supplementation. In a recent prospective randomized con- trolled trial (PRCT) of postmenopausal women, Lappe et al failed to find any benefits associated with daily vitamin D supplementation (2000 IU) when taken with calcium (1500 mg/d) vs placebo after 4 years.38 Limitations to the study, however, were that women in the placebo group were allowed to take their own vitamin D supplements. Moreover, mean baseline vitamin D levels were found to be 32.8 ng/mL or within the normal range. These confounders may have possibly affected the lack of beneficial findings, but further research is needed to better determine whether vitamin D supplements are beneficial in primary prevention of breast cancer when serum levels are normal.
In the Women’s Health Initiative trial, no benefit was found regarding a reduction in breast cancer among women taking vitamin D supplementation (400 IU/d), except for the women with very low vitamin D levels at baseline.63 However, there was reportedly poor compliance with subjects consuming sup- plements, and many women were already taking supplements prior to study enrollment.
A retrospective study by Zeichner et al found that women receiving a little over 10,000 IU/week (≈1500 IU/d) of vitamin D while undergoing chemotherapy for breast cancer had a sta- tistically significant improved disease-free survival in com- parison with study participants undergoing the same treatment who were not taking vitamin D supplements.64 Although inves- tigators in these studies generally controlled for confounding variables—such as dietary vitamin D intake, body weight, physical activity levels, and stage of diseases—well-designed double-blind PRCTs are needed to better understand whether vitamin D supplementation can play a role in breast cancer.
Prostate Cancer
The results of studies completed to date with prostate cancer survivors and vitamin D levels are mixed, as some studies reflect no significant correlation, a decreased risk, or an increased in risk for prostate cancer.65-71 A meta-analysis pub- lished in 2014, which included 21 studies, observed a statisti- cally significant association (odds ratio, 1.17; 95% CI, 1.05–1.30) between higher circulating 25(OH)D levels and an increased risk for prostate cancer.70 In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which included healthy men aged ≥50 years, levels ranging from 45 to 70 nmol/L were associated with a decreased risk when compared with levels
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that were low or high, although these findings were greater with Gleason scores of 7–10.68 Findings also varied according to eth- nicity, as no correlation was found with African American study participants and Gleason scores of 2–6, but a statistically sig- nificant decrease in prostate cancer risk was found with scores ranging from 7 to 10 in subjects with serum vitamin D levels >50 nmol/L. This evidence therefore appears to suggest that both very low and very high 25(OH)D levels are associated with an increased risk. These findings have been reported by others indicating that risk may be increased or decreased according to circulating values.66,69 Studies investigating vita- min D levels and morality are likewise equivocal.67,72,73
Supplementation. Whether vitamin D supplementation may be beneficial for prevention of prostate cancer progression has been explored in only 1 clinical trial. Marshall et al investi- gated whether 4000 IU/d of vitamin D
3 for 1 year could pre-
vent disease progression or affect prostate-specific antigen levels in men with low-risk prostate cancer when compared with historical controls.71 While no differences in prostate- specific antigen levels were found between the groups, only 34% of the study participants in the intervention group experi- enced disease progression, as exhibited by increases in their Gleason scores or in the number of positive biopsy cores obtained, vs 63% in the historical control group. While these results suggest that some benefit may be derived from vitamin D supplementation, larger PRCTs are needed to con- firm this finding. Additionally, trials should include a diverse population, as many of the studies completed thus far have pri- marily enrolled non-Hispanic white males. African American men have been found to consistently have lower circulating values of 25(OH)D, which is particularly important since Afri- can American men also have the highest incidence and rate of mortality related to prostate cancer.74,75 Kristal et al recom- mend that men >50 years old who use vitamin D supplements should have their levels monitored to avoid having levels exceeding 70 nmol/d.68
Pancreatic Cancer
Whether an association exists between circulating vitamin D concentrations and risk for pancreatic cancer has been explored. Pooled analysis of data from several large cohort studies noted a significant reduction in the risk for pancreatic cancer with higher concentrations of 25(OH)D.76 An increased risk for pancreatic cancer with higher vitamin D levels has been found among heavy smokers.77 Survivorship has been examined, as a retrospective study completed by McGovern and colleagues did not find any association between vitamin D concentrations and disease progression or survival in patients with pancreatic cancer between the highest and lowest quin- tiles (<20 and >60 ng/mL).78 No studies have been completed examining the role of supplementation and pancreatic cancer risk or outcomes once diagnosed.
Other Cancers
Circulating vitamin D levels and clinical outcomes have been evaluated in other cancers. Hypovitaminosis D has been linked to poorer survival for cancer survivors with lymphoid cancers.56,79 Although no clinical studies have been com- pleted regarding the role for vitamin D supplementation and outcomes in this patient population, the University of Iowa/ Mayo Clinic SPORE trial is currently underway exploring whether maintaining serum vitamin D levels >30 ng/dL can positively affect outcomes.80
In patients with Barrett’s esophagus, no association was found between circulating 25(OH)D levels and incidence of esophageal adenocarcinoma despite a high prevalence of vita- min D deficiency (23.6%) or insufficiency (34.7%).81 However, in another study, patients receiving vitamin D supplements postoperatively for esophageal cancer had a longer disease- free period, although there was no difference in overall survival.82
The evidence regarding the risk for developing other types cancers and vitamin D values is limited, but some data appear to suggest that higher vitamin D levels are associated with a lower risk for developing kidney and bladder cancers.83,84 In contrast, a 2015 meta-analysis found no association between vitamin D values and risk for gastric cancer.85 Additionally, 2 meta-analyses did not find any association between 25(OH)D levels and ovarian cancers.86,87
Summary
In conclusion, although numerous studies have been conducted regarding vitamin D and risk for cancer, the lack of data from PRCT trials investigating whether benefits can be derived from vitamin D supplementation limit our ability to know whether vitamin D
3 supplementation alone or in combination with other
nutrients can prevent cancer, recurrence, and cancer-specific mortality. The only completed PRCT completed thus far with the primary study outcome of all-type cancer incidence (excluding nonmelanoma skin cancers) found no benefit for vitamin D
3 (2000 IU/d) and calcium supplementation (1500
mg/d) vs placebo in healthy postmenopausal women after 4 years of supplementation.38 Unfortunately, this study did not examine whether vitamin D supplementation alone might be beneficial. Moreover, study participants had a mean baseline serum 25(OH)D of 32.8 ng/mL, within the reference range, although post hoc analysis did reveal that with 25(OH)D levels of 30 ng/mL at baseline, the estimated HR for cancer incident with values between 30 and 55 ng/mL was 0.65 (95% CI, 0.44–0.97).
While serum levels >20 ng/mL are recommended for bone health, clarity is needed regarding whether an optimal level exists for the primary prevention of cancer or for reduction in risk of recurrence and morality. Whether lower levels of 25(OH)D are associated with cancer risk or recurrence or are a
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consequence of the disease is also unknown. Vitamin D is con- sidered an acute-phase reactant and thus affected by inflamma- tory status. Hence, it is difficult to know whether increasing serum concentrations in the face of inflammation, which is commonly associated with cancer, can positively affect outcomes, requires further research. However, bone density can be adversely affected by cancer and many oncologic therapies. Vitamin D supplementation is considered safe and affordable and thus should be recommended to avoid hypovi- taminosis D to maintain or promote skeletal health.88
To address the current gaps in research, future studies exploring the impact of vitamin D supplementation on circulat- ing levels and the risk for cancer and cancer recurrence should measure (1) circulating levels in individuals at high risk for developing cancer and (2) levels at various time points, starting with before diagnosis, at the time of diagnosis, and throughout the continuum of survival until death, to better understand if circulating vitamin D levels play any role in promoting sur- vival in the cancer survivor population. Supplementation should be in doses sufficient to achieve levels associated with beneficial effects. Confounding factors—such as dietary and supplement intake, body weight, physical activity patterns, season, skin pigmentation, sunscreen use, and sun exposure— should be taken into consideration, since many of these factors can adversely affect levels. The presence and impact of genetic polymorphisms should be evaluated, given an observed link with outcomes. Studies need to ascertain at which level is cir- culating 25(OH)D ideal for reducing the risk for cancer and recurrence, as well as what doses of supplementation should be prescribed to achieve optimal levels, since no guidelines for vitamin D supplementations for cancer survivors exist. Finally, studies should be designed where cancer prevention or cancer outcomes, such as recurrence and mortality, are the primary outcomes.
Last, reportedly 80% of the U.S. adult population has serum 25(OH)D levels <30 ng/mL, with another 30% having circulating levels <20 ng/mL.38 Since vitamin D is naturally found in few food sources, ultraviolet B exposure is the larg- est contributor to circulating levels. Ultraviolet B radiation is insufficient for vitamin D synthesis from November to early May in latitudes at approximately 40 degrees north and 40 degrees south.89 Given that vitamin D supplementation is generally regarded as safe and affordable, supplementation should be recommended to achieve adequate levels, as estab- lished by clinical practice guidelines, to derive possible ben- efits for risk reduction of cancer as well as for many other chronic diseases.88
To better answer the question regarding if vitamin D sup- plementation can play a role in the primary prevention of can- cer, the Vitamin D and Omega-3 Trial is currently underway. This trial is exploring whether any benefits may be derived from 2000 IU/d of vitamin D
3 supplementation, with and with-
out ω-3 fatty acid supplementation, and risk for cancer and cardiovascular disease.
β-Carotene
β-carotene, a precursor to vitamin A, is a plant phytonutrient found in many red and orange fruits and vegetables. The purported benefits of β-carotene ingestion for chemopreven- tion are associated with its antioxidant and immunostimulant properties. A number of studies have explored whether a higher dietary intake of the carotenoids, particularly β-carotene, from supplements provides health benefits similar to findings of epi- demiologic studies suggesting that lower serum levels of anti- oxidants may be associated with an increased cancer risk.8,90-94 Thus far, the data are inconsistent. In the landmark Alpha- Tocopherol and Beta-Carotene Cancer Prevention Trial, high- dose supplementation with β-carotene significantly increased the incident of lung cancer.8 The key aim of this double-blinded primary prevention PRCT was to investigate whether supple- mentation with β-carotene, alone or with α-tocopherol, would prevent lung cancer in a high-risk population—male smokers. In this trial, 29,133 male Finnish smokers were randomized to 1 of 4 groups: 20 mg/d of β-carotene, 50 mg/d of dl-α- tocopherol, both, or placebo. Supplements were consumed for a range of 5–8 years, with a mean follow-up of 6.1 years. Study results reflected a 16% increase in the incidence of lung cancer (RR, 1.16; 95% CI, 1.02–1.33; P = .02) in study participants and an 8% increase in overall mortality (RR, 1.08; 95% CI, 1.01–1.16; P = .02) in the groups supplemented with β-carotene. These results were a surprise given that ecologic studies had previously indicated a reduced risk for lung cancer with high fruit and vegetable intakes, thereby reflecting a significant dif- ference related to obtaining a nutrient from supplementation vs dietary sources.90,91
These findings were further supported by the U.S. CARET (Beta-Carotene and Retinol Efficacy Trial), which found that supplementation with 30 mg/d of β-carotene plus 25,000 IU/d of retinyl palmitate, in a high-risk population (current smokers, recent smokers, and exposed to asbestos) that included partici- pants of both sex, was associated with a 28% increase in the incidence of lung cancer (RR, 1.28; 95% CI, 1.04–1.57; P = .02) and a 17% increase in all-cause mortality (RR, 1.17; 95% CI, 1.03–1.33; P = .02) after 4 years of follow-up.9 This trial was stopped early due to the increased incidence of lung cancer and mortality demonstrated in the study subjects consuming the β-carotene and retinol supplements. Importantly, in their posttrial follow-up of the initial Alpha-Tocopherol, Beta- Carotene Cancer Prevention (ATBC) study of participants tak- ing β-carotene supplements, Virtamo et al found that the impact of β-carotene lingered and was associated with greater risk for lung cancer throughout the first 4 years posttrial, particularly in heavy smokers (>20 cigarettes per day).92 In both the ATBC and CARET studies, lung cancer incidence was increased in men consuming >11 g/d of alcohol, although the association was null after discontinuation of supplements.8,9
The Vitamins and Lifestyle trial is the most recent pub- lished study to investigated the long-term use of β-carotene
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supplementation and incidence of lung cancer.12 An 18% non- significant increase in the incidence of lung cancer was found with the use of β-carotene supplements for ≥4 years. An increased risk for non–small cell lung cancer was noted for those consuming individual lutein supplements as well as for total lung cancers. Interestingly, no increased risk was found when multivitamin supplements were taken in conjunction with β-carotene supplements.
Other studies have not reported an increased risk for lung cancers with use of β-carotene supplements. Neither the Physicians’ Health Study—where supplementation with 50 mg of β-carotene every other day plus aspirin (325 mg every other day) or β-carotene plus aspirin placebo—nor the Women’s Health Study, where β-carotene supplements (50 mg) were consumed every other day, found any increased risk for lung cancer related to β-carotene supplementations.93,94 However, both studies included low-risk populations.
While the exact mechanisms of how β-carotene promotes lung carcinogenesis are unknown, the prevailing hypothesis is that components in cigarette smoke may induce oxidation of the β-carotene resulting in a pro-oxidant effect.95 In animal studies, the combination of cigarette smoke with β-carotene resulted in a potent proliferative effect on lung tissues.96
In summary, high-dose β-carotene supplementation is associ- ated with adverse effects by increasing the risk for lung cancer in tobacco users; long-term supplementation should especially be avoided by heavy smokers. There is no evidence that β-carotene supplements are harmful for low-risk individuals.94,95 More important, ingestion of high doses of β-carotene from foods has not been associated with any risks.96
Antioxidants
The production of reactive oxygen species (ROS) has been proposed to play a dual role in health, as ROS facilitate cell signaling and communication but can also adversely cause cell damage and alterations in gene expression promoting an oxida- tive environment.97 In normal physiologic homeostasis, bal- ance is achieved by countering ROS production with a variety of endogenous antioxidant defenses. However, excessive ROS synthesis can lead to alterations in redox balance, which in turn may stimulate tumorigenesis through cell signaling pathways that increase cellular proliferation, inhibit apoptosis, and facili- tate cancer cell metabolic adaptation.97 In an effort to decrease the risk for developing a number of chronic diseases, consum- ers, including cancer patients, are drawn to using antioxidant dietary supplements to combat the oxidative stress associated with developing such diseases.
Many chemotherapeutic agents—including commonly used drugs such as anthracyclines, bortezomib, capecitabine, cispla- tin, and cyclophosphamide—act by inducing oxidative stress that leads to cancer cell death. Additionally, radiotherapy pro- duces ROS, which causes cellular damage to healthy cells while destroying cancer cells.96,98 Therefore, controversy exists
whether augmentation of endogenous antioxidant defenses (which are often depleted in cancer patients) with antioxidant supplementation can provide benefits (eg, alleviating ROS damage) and reduce common side effects associated with che- motherapy and radiation therapies.97 Theoretically, it is thought that antioxidants may be advantageous by preventing DNA damage and oxidation while increasing cellular repair, blocking cell proliferation as well as cell transduction and signaling with increased apoptosis.99 In practice, the fear has been that antioxi- dant supplementation may reduce the cytotoxic effects of anti- neoplastic therapies, thereby reducing treatment efficacy.98,100,101 The results of studies, however, show that the impact of antioxi- dant supplementation on cancer cells is dose dependent, with greater doses inhibiting the type of antioxidant and type of can- cer, with some being inhibitory and with others possibly pro- moting cancer growth.98,101
Use for Cancer Prevention
When referring to antioxidants commonly used, most studies have examined if benefits could be derived from supplementa- tion with β-carotene, vitamins C and E, and/or selenium. In 1 of the largest PRCTs, healthy Chinese men and women resid- ing in Linxian, China, who were at risk for developing gastric and esophageal cancers were randomized to receive either a combination of antioxidants, including β-carotene (15 mg/d), α-tocopherol (30 mg/d), and selenium (50 mcg/d), or placebo consumed daily for 5 years.102 Initial study results reflected a reduction in mortality for gastric cancers but not esophageal cancers in study participants receiving supplementation; no reduction in risk for either cancer was found between the groups. Ten years after the trial was stopped, no reduction for risk of death related to either gastric or esophageal cancer was found between supplement users and nonusers.103
The Women’s Health Study, a double-blinded PRCT, found no benefits in incidence of cancer for women taking either 50 mg of β-carotene every other day or placebo.104 No reduction in cancer risks were seen for the women receiving vitamin E supplements (600 IU every other day) on follow-up after an average of 10.1 years.104,105 Additionally, the Women’s Antioxidant Cardiovascular Study, which enrolled approxi- mately 8171 women at high risk for cardiovascular disease, observed no statistically significant benefit for cancer risk reduction with use of vitamin C supplements (500 mg/d), vita- min E supplements (600 IU every other day), or β-carotene (50 mg every other day) after a mean follow-up of 9.4 years when compared with the placebo group.106
The Supplémentation en Vitamines et Minéraux Antioxydants Study results noted no decreased risk on the inci- dence for cancer or all-cause mortality in healthy French study participants taking a combination of antioxidant supplements daily, including vitamin C (120 mg), vitamin E (30 mg), β-carotene (6 mg), selenium (100 mcg), and zinc (20 mg), when compared with the placebo group after an average
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follow-up of 9.4 years of treatment.107 Of note, when the data were analyzed separately, a lower total cancer incidence and a lower all-cause mortality rate were found for men taking the supplements vs women, although this benefit disappeared 5 years after supplementation was stopped. Thus, in totality, there appears to be no benefits associated with taking a variety of antioxidant supplements for the primary prevention of cancer.
Use During Treatment
Studies using β-carotene and vitamin E in patients undergo- ing radiotherapy for head/neck cancers have yielded mixed results (see Table 2).108-110 While supplementation reduced the severity of side effects (eg, mucositis), the study participants receiving supplementation experienced a reduction in sur- vival, although this was later seen in subgroup analysis among only those who smoked. In breast cancer survivors, supple- mentation with β-carotene, niacin, vitamin C, coenzyme Q10, selenium, and possibly zinc in varying doses resulted in a decrease in breast cancer–specific survival and disease-free survival in the supplement group.111 In contrast, a randomized controlled trial completed by Pathak and colleagues found a nonsignificant trend for a slightly greater response rate to chemotherapy and survival in study participants with stage IIIb–IV non–small cell lung cancer receiving a combination supplement (vitamin C, α-tocopherol, and β-carotene) in com- parison with the nonsupplemented group.112 Additionally, an 18% decrease in mortality risk (HR, 0.82; 95% CI, 0.65–1.02) and a 22% reduced recurrence risk (HR, 0.78; 95% CI, 0.63– 0.95) were observed in women residing in Shanghai, China, who used vitamin E, vitamin C, or multivitamins within the first 6 months after being diagnosed with breast cancer, inde- pendent of disease stage, lifestyle factors, sociodemographic status, or whether participants were receiving chemotherapy or not.20 However, a nonsignificant increased risk for mortal- ity or recurrence was found for study participants who either
took or did not take antioxidant supplements while receiving radiation treatment. Last, a systematic review by Block et al in 2007 concluded that there is no interaction between cancer treatment and antioxidants and that antioxidant supplemen- tation can enhance cytotoxic effects and improve patient survival.98 In a more recent systematic review by Yasenda et al, the authors concluded that they could not determine if the use of antioxidant supplements during chemotherapy and/ or radiation affected treatment outcomes or improved the side effects related to treatment.99
In summary, it is unknown whether antioxidant supple- ments may provide any benefits or harm to cancer patients undergoing treatment. Most studies have used a various types and doses of antioxidants and have included patients undergo- ing a variety of treatment regimens with numerous types of cancer, thus making it difficult to determine the true impact of using antioxidant supplements during treatment. Future studies need to investigate the single use of agents, as well as mixtures and standardized dosages, and enroll study participants with the same type of cancer who are undergoing the same treat- ment regimens to better understand the impact of supplementa- tion in this patient population.
It has been suggested that antioxidant supplement use while receiving chemotherapy regimens associated with low oxidative stress production (purine/pyrimidine analogues, antimetabolites, monoclonal antibodies, vinca alkaloids, and corticosteroids) is less likely to be associated with any possible adverse interac- tions between supplements and treatments.98 Caution should be taken, though, when using therapeutic levels of antioxidants dur- ing treatment with other cytotoxic agents, including alkylating, anthracyclines, platinum-based, antiangiogenic, or tyrosine kinase inhibitors.98,99
Vitamin E
Vitamin E, a fat-soluble vitamin, is another nutrient that has generated a lot of interest over the years, as α tocopheryl
Table 2. Antioxidant Supplementation and Radiation.108-110
Study Sample Intervention Outcome
Bairati et al108 N = 540 participants with head/neck cancer undergoing radiation
α-Tocopherol (400 IU/d) or α-tocopherol + 30 mg/d of β- carotene or placebo × 37 mo
↓ 38% in severity of acute side effects; smoking + antioxidants: ↑ disease recurrence (hazard ratio, 2.41; 95% CI, 1.25–4.64)
Meyer et al109 Follow-up to Bairati et al Follow-up of outcomes from Bairati et al study regarding cancer recurrence and mortality
Smoking during radiation + supplementation—hazard ratios: 2.41 (95% CI, 1.25–4.64; P = .03) for recurrence, 2.26 (95% CI, 1.29–3.97) for all-cause mortality, and 3.38 (95% CI, 1.11–10.34) for head/ neck cancer mortality
Ferreira et al110 N = 54 participants with head/neck cancer undergoing radiation
Oral rinse with 400 IU/d of vitamin E or placebo before/ after radiation therapy
↓ 36% in mucositis symptoms; ↓ 2-y overall survival (32% vs 63% placebo)
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succinate in cancer cell culture studies has been shown to reduce cellular proliferation and promote increased cell death.113 Several investigators have examined the impact of vitamin E supplementation in regard to cancer. The Vitamins and Lifestyle study found a small but significant increase in risk for lung cancer among smokers secondary to, on average, a 10-year consumption of vitamin E supplementation for each 100-mg increase in dose (HR, 1.05; 95% CI, 1.00–1.09, P = .033) and every 100-mg/d increase in dose (HR, 1.07; 95% CI, 1.02–1.12; P = .004).12 Similarly, the ATBC study noted a RR of 1.03 (95% CI, 0.91–1.16) between use of vitamin E supplements and risk of lung cancer in heavy smokers.8 Conversely, Roswall et al found no association between vita- min E supplement intake and risk of lung cancer at a median follow-up of 10.6 years, although a protective effect was related to a high dietary vitamin E intake; smoking status did not have any effect on outcomes.114
In an observational trial, Antwi et al investigated whether the use of vitamin E supplements was associated with prostate cancer risk in the North Carolina–Louisiana Prostate Cancer Project.115 Study results showed no association with reported use of vitamin E supplements in the 12 months prior to study enrollment, with varying doses consumed. However, findings were very different with vitamin E supplementation in a PRCT. The SELECT was a PRCT that explored the effect of vitamin E and selenium supplementation on the incidence of prostate cancer in healthy men >50 years old, when taken either alone or together vs placebo. Initially, it was reported that neither vitamin E (400 IU/d) nor selenium (200 mcg/d) supplementation reduced the risk for prostate cancer, although a statistically nonsignificant increase in risk was found with vitamin E supplementation.11 However, Klein et al noted an increased incidence of prostate cancer after 7 years of median follow-up in all supplemented groups (selenium alone, vita- min E alone or vitamin E plus selenium) when compared with the placebo group, although the increase was statistically sig- nificant only in the group receiving vitamin E alone (HR, 1.17; 99% CI, 1.004–1.36; P = .008).116 The increase in risk became apparent with supplement use after 3 years and con- tinued through follow-up. When adjusted for covariates, no significant association with risk was observed with vitamin E and selenium supplements when taken together. In contrast, the Physicians’ Health Study II (PHS II) found no association between vitamin E supplement use and incidence of prostate cancer after approximately 12 years of follow-up.117 The PHS II investigators note that differences in the 2 studies—namely, that vitamin E supplements (400 IU) were taken every other day during the intervention period in the PHS II study—may have made a difference. Risk may have also been increased in the SELECT, as many men were taking vitamin E supple- ments prior to study enrollment. Additionally, the SELECT included men from the general population, while the PHS II study enrolled physicians, who have a higher socioeconomic status and may practice healthier lifestyles. The PHS II trial did not find any benefit or adverse effect of vitamin E and
other site-specific cancers or total cancer. Interesting, the SELECT group reported that study participants with higher α-tocopherol values prerandomization had a statistically sig- nificant increased risk for prostate cancer if they received the selenomethionine supplement either alone or in combination with vitamin E supplementation.118 Further studies are war- ranted to evaluate this finding.
In a double-blind placebo-controlled trial of study partici- pants with head/neck cancers undergoing radiotherapy, vita- min E supplementation as swish-and-swallow mouth rinses did not affect survival.119 Furthermore, vitamin E supplementation reduced the severity of radiation-induced mucositis.
Vitamin E supplementation has been prescribed for reduc- ing chemotherapy-induced neuropathy. Mixed results have been reported regarding supplement use and neurotoxicity in patients receiving vitamin E supplementation while undergo- ing chemotherapy with taxane- or platinum-based agents, with 2 studies reporting no benefits and 2 studies noting significant benefits.120-123
Summary
As described here, trials exploring vitamin E supplementation present conflicting findings in terms of whether it provides any benefits to survivors or for the prevention of cancer. Differences in study outcomes may be related to the dose (typically higher than dietary intake), the type of vitamin E used (eg, α-tocopherol vs mixed tocopherols), baseline status, and adherence. Vitamin E is not a single nutrient but is actu- ally a family of phenolic compounds composed of 8 types of vitamin E isomers: 4 tocopherols (α, β, δ, and γ) and 4 tocotri- enols (α, β, δ, and γ). α-tocopherol is the active form through- out the body in the blood and tissues, while γ-tocopherol is the most common form in the diet.65 For example, γ-tocopherol is now thought to possess greater anti-inflammatory properties over α-tocopherol.65 Given the potential adverse effects asso- ciated with high vitamin E doses (400 IU/d), particularly for men, vitamin E supplementation for cancer prevention or management is not recommended.
Vitamin C
Vitamin C is among the vitamins most often used or considered by oncology patients to gain the benefits associated with anti- oxidants. Unfortunately, the evidence is contradictory, making the decision about use difficult. In vitro studies have shown that high-dose vitamin C reduces cell proliferation of various cancers, including prostate, pancreatic, hepatocellular, and colon cancer, as well as mesothelioma and neuroblastoma.124 Animal studies have produced similar positive results against pancreatic cancer, liver cancer, prostate cancer, sarcoma, mesothelioma, and ovarian cancer.125
Early human trials in the 1970s, however, yielded conflict- ing results.126-128 In an early study of terminal cancer patients, those treated with intravenous (IV) ascorbic acid had a longer
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mean survival time (300 days) than matched controls.126,127 Attempts to replicate these results using high doses of oral vita- min C have failed to find any differences in symptoms, sur- vival, or performance status.128-130 More recent publications are largely case reports or those that focus on the possibility of vitamin C ameliorating cancer treatment–related side effects and improving quality of life.131-135
Perhaps the issue that has generated the most interest about vitamin C is whether or not it interferes with conventional can- cer therapies. An often-cited study found that vitamin C given before several antineoplastic agents attenuated their efficacy against leukemia and lymphoma cell lines.124 The same trial also demonstrated an antagonistic effect of vitamin C in mice treated with doxorubicin. Another animal study suggests that combining vitamin C with bortezomib interferes with the drug’s ability.135 However, a systematic review of 19 randomized con- trolled trials did not report any decrease in chemotherapy effi- cacy from antioxidant supplementation, of which vitamin C was 1 example.131 Evidence is extremely limited regarding the efficacy of using vitamin C supplements, although 2 small trials in patients with pancreatic cancer have found high-dose vitamin C infusion in combination with gemcitabine to be well tolerated and to have a favorable effect on disease progression.132,133 Trials of high-dose IV vitamin C have produced varied results thus far and are ongoing.125
A large (n = 4877) prospective cohort of Chinese women with breast cancer were asked about their use of vitamins and followed for 4 years on average.20 Mortality was reduced by 44% and the risk of recurrence, by 38%, in women who took vitamin C for >3 months. This positive benefit was seen whether the women took the supplement during chemotherapy or not, suggesting that vitamin C did not have an antagonistic effect.
It is evident that there is little consensus of the role and safety of vitamin C during cancer therapy, and subsequently there are no definitive guidelines to direct patient use. Clinicians should consider cancer type and treatment plan in helping patients make informed decisions about the use of vita- min C.
ω-3 Fatty Acids
ω-3 fatty acid supplementation, particularly with eicosapen- taenoic acid (EPA) and docosahexaenoic acid, has been actively explored, as preclinical and intervention trials have demon- strated antitumor and anticachectic benefits. Upregulation in nuclear factor κB activity is associated with promoting cancer cachexia in animal models, resulting in enhanced proteolysis and apoptosis in the myotubes and leading to protein degrada- tion via activation of the ubiquitin proteasome pathway.136 Laboratory studies reveal that EPA may prevent protein break- down by inhibiting nuclear factor κB buildup in the cell nucleus.136 The results of trials investigating the use of ω-3 fatty acid supplements for these reasons in cancer populations
are mixed.137-143 Recently, several investigators have examined whether such supplements may be beneficial for patients diag- nosed with non–small cell lung cancer; improvements in body weight, lean tissue mass, functional status, and survival were demonstrated with supplementation of ≈2 g/d of EPA.140,142 A lean body is important for maintaining functional status and quality of life, but sarcopenia has been identified as a predictor of chemotherapy toxicity.144,145 While the results are promising, further validation of the findings is needed from the completion of large randomized controlled trials, as these studies are small. Compliance with supplementation has been reported as a key aspect that should be addressed in future studies.
Glutamine
Glutamine is an amino acid that is thought to become a “condi- tionally essential” amino acid during increased times of stress, due to its importance in maintaining redox balance and its role in stimulating immune function as well as serving as a fuel for the enterocytes. Glutamine supplementation has been explored in various studies to investigate whether supplementation may provide benefits for treatment-related side effects.
Mucositis, a common nutrition-impact symptom associated with chemotherapy and radiation, reportedly is experienced by >90% of head/neck cancer patients.146 Symptoms including severe oropharyngeal pain and mucosal ulceration profoundly limit the ability to consume food and liquids. Quality of life is also adversely affected and may result in dose reduction and delays in treatment.145 Good oral hygiene, opiate analgesics, nutrition support therapy providing adequate protein intake, and other strategies are employed to help limit the extent and severity.146-148 Complementary strategies, such as the use of oral glutamine supplements (30 g/d divided in 3 doses), can reportedly reduce the severity, time to onset, and duration of mucositis in head/neck cancer patients and lessen weight loss.147,148
Wang et al investigated whether oral glutamine supple- mentation could reduce peripheral neuropathy induced by chemotherapy in patients being treated for colon or rectal cancer.149 The glutamine group consumed 15 g twice per day for 7 consecutive days, every 2 weeks, beginning on the day of oxaliplatin infusion. There were no differences between the glutamine group and the placebo group in terms of response to chemotherapy or survival, but ability to complete activities of daily living was greater in the glutamine group, which also experienced less of a need to decrease its oxalipla- tin doses (7.1% vs 27.3%). Additionally, among patients undergoing chemotherapy for colorectal cancers, when com- pared with nonusers, patients using glutamine supplements (18 g/d starting 5 days before chemotherapy and continuing for 15 days) reported less diarrhea and gut mucositis.150 Conversely, no benefits were reported with use of glutamine supplements to reduce radiation enteritis in patients undergo- ing pelvic radiation for cancer.151
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In summary, oral glutamine supplementation appears bene- ficial for reducing mucositis related to radiotherapy for head/ neck cancers and may be beneficial for reducing gut mucositis and diarrhea, although further studies are needed given the conflicting results reported thus far.
Botanical and Other Supplements
Worldwide, plants have been used for healing since ancient times.57 Only recently has the interest in using botanicals for medicine risen in the United States, while in Asia, South America, and Africa, the use of local plants is a primary com- ponent of medical treatment. In fact, the alkaloid-based che- motherapeutic agents used to treat certain cancers are derived from plants.152
Consumers, including cancer patients, are drawn to botani- cal supplements, also known as herbal remedies, because they are natural and thus considered safe. Botanical supplements are often used to improve health, stimulate immune function, relieve treatment-related side effects, and improve quality of life.153 Of concern is that patients often fail to share such usage with their medical providers, which can be problematic given the number of drug-herb interactions that can occur.152 While the evidence is limited regarding whether benefits can be obtained with the use of botanical supplements, some data are available.
Astragalus
Astragalus is an herb derived from the astragalus root, which is commonly used in Chinese medicine, primarily to boost the immune system. In vitro studies reflect the immune properties of astragalus, including enhancement of the antitumor activity of interleukin 2 and potentiation of the activity of macrophages and natural killer cells.153 While there is not a wealth of evi- dence, several investigators have evaluated the use of astraga- lus or astragalus-containing herbal supplements regarding benefits for patients with cancer.153-156 For patients with advanced non–small cell lung cancer, a meta-analysis found increased effectiveness of chemotherapy, as evidenced by improved tumor response, decreased risk of death, and improved Karnofsky performance status with use of astragalus supplements.154 Furthermore, prolonged survival was associ- ated with use of Chinese herbal medicine, which often included astragalus, in patients with acute myeloid leukemia receiving standard treatment.156 Last, in patients with colorectal cancer receiving oxaliplatin, astragalus was associated with reduced neutropenia.157 Other benefits in this study included a reduc- tion in cancer-related fatigue and chemotherapy-induced nau- sea and vomiting.
Although study results show promising outcomes, these studies are small and, in general, poorly designed. Additionally, although astragalus supplementation appears quite safe when used appropriately, larger well-designed trials are needed before findings can be applied to clinical practice.152
Melatonin
Melatonin is a pleiotropic hormone secreted primarily by the pineal gland but also by the gastrointestinal tract, perhaps in response to the presence of food.158 While the exact mecha- nism of action is unknown, it is thought to regulate the circa- dian rhythm and help facilitate sleep. Melatonin is available as an over-the-counter supplement and often used to treat a vari- ety of disorders, but it is most commonly used to help relieve jet lag, insomnia, frequency of migraine headaches, and pain and anxiety related to surgery.158 With aging, melatonin levels decrease, and some research suggests that low levels of mela- tonin may increase cancer risks.158
Melatonin is often used by cancer survivors to improve tol- erance to treatment, survival time, and quality of life. In phar- macologic doses, melatonin may provide anticarcinogenic benefits through antioxidant, antimitotic, antiproliferative, anti-inflammatory, and immunomodulatory properties; the enhanced cytotoxic action of some chemotherapeutic agents has also been demonstrated.159-161 Investigators have reported that individuals working the night shift for many years (20–30 years) had a greater risk for breast and colon cancer, potentially due to lower levels of melatonin.160
In a systematic review and meta-analysis by Seely et al, reduced mortality was found with the use of melatonin alone by cancer patients with solid tumors or when used in combina- tion with chemotherapy (RR, 0.63; 95% CI, 0.53–0.74; P < .001; RR, 0.60; 95 CI, 0.54–0.67, respectively).162 Moreover, supplementation with melatonin significantly decreased treat- ment-related side effects, including asthenia (RR, 0.44; 95% CI, 0.39–0.50), alopecia (RR, 0.86; 95% CI, 0.75–0.97), nau- sea and vomiting (RR, 0.84; 95% CI, 0.72–0.97), leucopenia (RR, 0.65; 95% CI, 0.43–0.97), thrombocytopenia (RR, 0.21; 95% CI, 0.15–0.30), and hypotension (RR, 0.21; 95% CI, 0.10–0.47). High doses of melatonin (20 mg/d orally), in addition to radiotherapy for treatment of glioblastomas, appear to improve survival in a small study, when compared with radiation alone.163 Conversely, in another study, melatonin supplementation (20 mg/d) did not improve appetite, weight, or quality of life in patients with cachexia and advanced cancer.164
Supplementation with doses ranging from 20 to 40 mg/d appeared to be well tolerated, with only headache, dizziness, sleepiness, and drowsiness reported as common side effects.165 Caution is recommended, however, when using melatonin, as moderate potential drug-nutrient interactions exist between melatonin and anticoagulants, antiplatelet, antidiabetic, anti- hypertensive, anticonvulsants, and immunosuppressive medications.165
Although melatonin can be obtained from dietary sources, such as wheat grass and rye grass, the question is whether these sources can raise serum levels sufficiently. Therefore, melato- nin supplementation appears necessary to obtain the reported benefits associated with its use.
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Despite promising findings, a few significant limitations should be noted regarding the use of melatonin. Many of the studies have been conducted by the same investigators.159,163 Moreover, most studies were small, and none were blinded. Thus, before melatonin supplementation is widely recom- mended for cancer survivors, large prospective, double- blinded, placebo-controlled trials are needed to valid reported findings.
Milk Thistle
Milk thistle is commonly used as a botanical remedy for hepa- titis, cirrhosis, liver disease, cancer prevention, and mushroom poisoning.166 The active ingredient, silymarin, is associated with suppression of hepatic inflammation by providing anti- oxidant and anti-inflammatory benefits.166 Minimal safety issues have been reported with the use of milk thistle; there- fore, it is generally considered to be safe.166 Theoretically, milk thistle may have an adverse impact on cytotoxic drugs that act to generate free radicals; however, there are no trials to support or negate these concerns.166
While milk thistle may be considered safe, the evidence supporting the claims related to its benefits are supported by only a few very small trials. In 1 trial of 50 pediatric patients undergoing treatment for acute lymphoblastic leukemia with chemotherapy-induced hepatotoxicity, participants receiving silymarin had a significant lowering of liver enzymes when compared with a placebo.167 In a randomized controlled trial, the administration of oral silymarin (420 mg/d) significantly reduced the severity of radiotherapy-induced mucositis and delayed its occurrence.168 In another study, women undergoing radiation therapy for breast cancer who used a silymarin-based cream (Leviaderm) showed lower incidence and intensity of acute skin reactions.169
Last, a randomized controlled trial with 37 men following radical prostatectomy demonstrated an improved quality-of-life score, decreased low-density lipoproteins and total cholesterol, and increased serum selenium levels after a 6-month daily com- bination administration of silymarin and selenium.170
In conclusion, very little data exist related to the use of milk supplements; therefore, whether supplementation may provide any benefits for cancer survivors is unknown, although supple- mentation appears safe.
Turmeric
Turmeric is a bright yellow spice derived from the rhizomes of the Curcuma longa plant, a member of the ginger family (Zingiberaceae), which requires a warmer climate to grow. The medicinal effects of turmeric are derived from the yellow pig- ments found in turmeric, collectively known as curcumin; 3 major curcuminoids have been identified as the active compo- nents in turmeric: diferuloylmethane (82%), demethoxycur- cumin (15%), and bisdemethoxycurcumin (3%).171 Curcumin is commonly employed in Chinese and Ayurveda medicine for
its antioxidant and anti-inflammatory benefits and is often pre- scribed for the treatment of gastrointestinal and abdominal complaints.171
The anticarcinogenic biologic activity of curcumin is linked to its function as an antioxidant, anti-inflammatory agent with an ability to modulate cell proliferation, signaling pathways, transcription factors, and tumor angiogenesis.171,172 In a phase II study, curcumin supplementation downregulated nuclear factor κB activity in patients with pancreatic activity.172 The ability to alter gene transcription and induce apoptosis advo- cates for a potential utility in cancer chemoprevention and chemotherapy.172
Thus far, most of the clinical evidence available regarding the use of turmeric/curcumin supplements and possible bene- fits has been derived from phase I and II studies evaluating the feasibility and tolerance to supplementation. Preliminary evi- dence suggests that turmeric supplementation may stabilize disease in patients with advanced colorectal cancer in doses of 3.6 g/d when taken for 4 months despite low widespread tissue distribution.173 A recent phase II trial that enrolled 29 men receiving 3 cycles of docetaxel/prednisone and curcumin (6 g/d for 7 consecutive days plus chemotherapy) for castration- resistant prostate cancer found the following: in the 26 partici- pants who completed the study, 17 had lower prostate-specific antigen; 4 had normalization of levels; and 4 had progression of the cancer. No increase in toxicity-related symptoms over expected complaints was noted.174
Rao et al investigated whether swishing an oral solution with 400 mg of turmeric in 80 mL of water 6 times per day could be effective for radiation mucositis among participants with head/neck cancers. They found that the turmeric-supplemented solution delayed the onset of oral mucositis and reduced reports of it being intolerable by 49%, when compared with participants using a povidone-iodine solution.175
Recommended doses range from 1 to 3 g/d, with supple- ments available as powdered capsules and as fluid extracts or tinctures.176 Oral supplementation of turmeric or curcumin appears safe, although bioavailability is reportedly low, with doses >4 g/d needed to increase serum levels.176 Turmeric is also rapidly metabolized following absorption; thus, the extent to which turmeric reaches targeted tissues is not clear.176 Last, curcumin is known to interfere with cytochrome P450 enzyme systems, thereby potentially leading to reduction in chemo- therapy.176,177 Potential drug-nutrient interactions may also occur with turmeric supplementation, as moderate interactions with antiplatelet drugs leading to decreased platelet aggrega- tion have been reported.176,177 Caution with drugs prescribed for diabetes have been recommended, as turmeric may reduce glucose and hemoglobin A1C levels.178
In summary, while turmeric supplementation has been shown to convey some benefits in small phase I/II studies and although supplementation appears safe, the evidence thus far is insufficient to recommend its use. However, many clinical tri- als are currently underway to investigate the effectiveness
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associated with supplementation; as such, future studies will provide better direction for its use.
Resveratrol
Resveratrol is a polyphenolic compound found in a variety of foods, with the highest levels generally found in peanuts, grapes, and red wine.179 Recently, resveratrol has been widely marketed with much hype that it can be used to cure anything from Alzheimer’s disease to cancer, despite the scarcity of evi- dence supporting such claims. Preclinical studies reflect a potential chemopreventive role for resveratrol, as it promotes apoptosis, regulates cell cycling, and inhibits cyclooxygenase and prostaglandin synthesis while acting as an antioxidant, thereby preventing DNA damage that can lead to tumor formation.179,180
Potential moderate drug-nutrient interactions have been reported between resveratrol and anticoagulation and antiplate- let drugs, thereby increasing the risk for bleeding.181 Additionally, women with estrogen-sensitive cancers, including breast, uter- ine, and ovarian cancers, should avoid resveratrol supplements until more is known about resveratrol’s potential estrogenic properties.181 While resveratrol is fairly well absorbed, it is rap- idly metabolized, thereby limiting its systemic distribution.181
Ginger
Ginger is a spice commonly used as a flavor agent in Indian and Middle Eastern foods. Gingerol and shogaol components have been identified as the active ingredient in ginger, which may provide benefits related to its antispasmodic and anti- inflammatory benefits.182 Ginger is often used by cancer patients to prevent the nausea that is commonly associated with treatment.183-188
Ginger is thought to provide antinausea benefits by binding to 5-HT
3 receptor sites and acting as a receptor antagonist in the
gastrointestinal tract to inhibit the binding of certain neurotrans- mitters associated with promoting nausea.182 Because of the anti-inflammatory properties, ginger can reduce damage to tis- sues by ROS by upregulating certain detoxification enzyme systems.182 As exhibited in Table 3, most of the studies reflect that ginger supplementation in doses ranging from 1 to 1.5 g/d may be effective for reducing the incidence of chemotherapy- induced acute nausea.183-186 In the largest study to date, Ryan et al found in a randomized placebo-controlled clinical trial that ginger supplementation in doses >1.5 g/d were not effective in reducing acute nausea related to chemotherapy and that doses of 0.5 and 1.0 g/d significantly reduced the incidence of reported acute nausea (P = .013 and .003, respectively).185 In this study, patients were enrolled if they had experienced 1 prior episode of nausea after receiving chemotherapy with the antiemetic dexamethasone and a 5-HT
3 receptor antagonist (Zofran, Kytril,
etc). Patients were excluded from the study if they were receiv- ing concurrent radiation. Supplementation was prescribed as a 6-day course starting 3 days prior to their scheduled chemo- therapy infusion. Study participants were instructed to take 250 mg of ginger, 3 times a day. In contrast, Zick et al reported that study participants randomized to aprepitant and ginger (1 or 2 g/d) following their chemotherapy infusion, vs aprepitant and placebo, were more likely to have acute severe nausea than par- ticipants taking only aprepitant.186 There also was no difference between the groups regarding the prevalence of delayed nausea.
Before widespread use of ginger supplements can be rec- ommended for chemotherapy-induced nausea and vomiting, further studies enrolling larger sample sizes are needed to eval- uate whether ginger can be useful as an antiemetic during che- motherapy. Future studies should also examine which type of chemotherapeutic regimens may benefit from the use of ginger supplementation, since some chemotherapy agents are more emetogenic than others. Researchers in Italy are currently enrolling patients receiving highly emetogenic regimens for a prospective placebo-controlled randomized trial comparing
Table 3. Select Studies Regarding the Use of Ginger for Combating Nausea and Vomiting.182-186
Study Sample Intervention Outcome
Manusirivithaya et al182 N = 48 participants with gynecologic cancers
1 g/d × 5 d with chemotherapy or placebo + metoclopramide for first cycle → crossover
No ↓ in acute nausea with antiemetics but helped with delayed (equal to metoclopramide)
Fahimi et al183 N = 36 participants with various cancer
1 g (250 mg, 4×/d) or placebo + standard antiemetics → crossover
No benefit; only 2 cycles
Panahi et al184 N = 100 participants with advanced breast cancer
1.5 g/d (500 mg 3×/d) + standard antiemetic or antiemetic regimen (granisetron + dexamethasone)
↓ CINV 6-24 h past chemotherapy (P = .04); not blinded
Ryan et al185 N = 576 participants with various cancers
Placebo, 0.5, 1, or 1.5 g/d All doses ↓ acute nausea (P = .03) but not delayed; >1.5 g/d, not effective
Zick et al186 N = 162 participants with various cancers
1 g (250 mg × 4/d) or 2 g/d + 5-HT 3
or aprepitant for delayed CINV No benefits; delayed CINV worse with 2
g + aprepitant
CINV, chemotherapy-induced nausea and vomiting.
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ginger supplementation with the new antiemetics regarding the efficacy for acute and delayed nausea and vomiting.188
Caution is recommended when using ginger supplements while taking prescription medications, such as anticoagulant and antiplatelet drugs, as moderate herbal-medication interac- tions exist; major interactions may occur with nifedipine.187 Ginger is thought to be safe except during lactation.
Ginseng
Ginseng is a botanical supplement that has been widely mar- keted to increase energy and stimulate the immune system. There are many species, with American and Asian species from the Panax genus typically used in available supplements. Ginsenosides are the active ingredient identified with the poten- tial benefits gained from ginseng’s anti-inflammatory and corti- sol-modulating effects. Improvements in immune function through activation of monocytes, natural killer cells, interleukin 2, and B-lymphocytes have been reported.189 Additionally, human studies conducted with Asian and American ginseng have found a reduction in cancer-related fatigue.189,190 As reflected in Table 4, a pilot study noted a trend for less cancer- related fatigue with doses of 2000 mg/d for 8 weeks among participants with stage I–IV cancers receiving chemotherapy or radiation or having recently completed treatment, as compared with placebo.190 In their follow-up study, Barton et al recon- firmed their initial findings of a reduction in fatigue in the gin- seng-supplemented group compared with placebo (P = .003).191
To gain any apparent benefits of using ginseng supple- ments, 2000 mg daily is the typical dose recommended.191,192 Ginseng is likely safe; however, potential drug-herbal interac- tions exist between ginseng and warfarin, diabetic medica- tions, and immunosuppressants.192
Potential Adverse Effects of Using Dietary Supplements
The Dietary Supplement Health and Education Act was estab- lished to define and regulate the sales of dietary supplements in the United States with oversight by the Food and Drug Administration (FDA).193 While supplement manufacturers are required to ensure that their products are safe for consumers,
they are not required to receive FDA approval nor submit evi- dence on safety before marketing them.194 In contrast, pharma- ceutical companies must provide safety data prior to selling their products. The FDA does monitor for any safety issues once products are available in the marketplace, and it can issue safety warnings or stipulate their removal when safety con- cerns arise. However, despite FDA warnings and recommenda- tions to avoid some products, these products are often still widely available on the shelf or online.
Aloe vera, arrowroot juice, black cohosh, chaparral, com- frey, germander, green tea extract, kava, and pennyroyal, to name a few, are herbs that can reportedly cause hepatotoxicity and should be avoided.195,196 Additionally, essiac, or Flor Essence, has long been marketed to oncology patients for immune support during antineoplastic treatments due to pur- ported benefits, such as antioxidant, anti-inflammatory, and immunostimulatory benefits associated with its use.197 Essiac is a combination of burdock root, sheep sorrel root, slippery elm bark, and rhubarb root. Despite the lack of evidence to support its use, essiac continues to be popular with oncology patients. Amygdalin (Laetrile) is another common dietary sup- plement used by cancer patients. Amygdalin is a cyanogenic glycoside found in plants, nuts, and the pits of fruits (particu- larly apricots).198 Since the 1960s, amygdalin has been avail- able in a purified form known as laetrile.198 In a trial completed by the National Cancer Institute in the 1970s, no benefits were found for amygdalin, but several study participants had cya- nide toxicity or elevated serum levels close to cyanide poison- ing.199 Moreover, a systematic review did not find any clinical efficacy for using amygdalin to prevent or treat cancer.200 While the FDA removed amygdalin from the marketplace, it can be readily obtained online. In addition to being marketed as laetrile, it can also be purchased as vitamin 17.
Challenges
Botanical supplements present unique challenges given that many botanicals are derived from the whole plant, parts of the plant, or plant extracts, which may provide concentrated doses.201 The presence of contaminates in products is also a challenge, since many may contain pesticides, natural toxins, and heavy metals. The active constituents may vary on the
Table 4. Studies Investigating the Benefits of Ginseng.
Study Sample Intervention Outcome
Barton et al190 N = 290; cancer survivors (breast, colon, and lung)
Placebo vs various doses (750, 1000, or 2000 mg/d)
↓ Fatigue by 40% with ginseng vs 17% with placebo; quality of life > with ginseng
Barton et al191 N = 364 (multicenter); stage I-III cancers with 49% on treatment
Placebo vs 2000 mg/d; Multidimensional Fatigue Symptom Inventory to assess fatigue
Significant difference: 20 ± 27 (ginseng) vs 10.3 ± 26.1 (placebo; P = .003); best results: on treatment and used supplement for 8 wk
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basis of growing and harvesting practices, geography, and manufacture processing, resulting in differences in properties and safety among products.152 Additionally, the lack of stan- dardization required among products may result in significant variations among available products. Safety is a concern given that many products have not been adequately studied for poten- tial herb-drug interactions.
The conflicting results reported by investigators examining whether supplements may provide any advantages for disease risk reduction, including cancers, are likely due to a number of reasons. Many of the studies completed thus far have been affected by limitations in methodology, including small sample sizes, variations in doses used, different species used, and lack of diversity in terms of sex, ethnicity, health status, and age.
Implications for Practice
Dietary supplements are a billion-dollar business, and the use of such supplements by cancer survivors is common, with many patients failing to report their use to their healthcare practitio- ners.5 Given that supplements are widely available and thus eas- ily accessible, a multitude of concerns exist, particularly since data are lacking regarding not only effectiveness and quality control but also safety—especially in terms of possible drug/ herb-nutrient interactions. Information regarding the risk and benefits is available from a number of sources, as outlined in Table 5. With >55,000 dietary supplements available in the mar- ketplace, it is impossible for clinicians to keep up with all the new options that are continually available.202,203 However, infor- mation is available from a number of third-party organizations,
such as ConsumerLab.com, NSF International, and U.S. Pharmacopeial, which test various dietary supplements on a continuous basis to examine products for quality, strength, and presence of contaminants (microbes, heavy metals, pesticides, etc). Data regarding their clinical findings can be obtained online at their websites, although some may require a subscription to access testing results.
Information about supplement use should be elicited with a nonjudgmental approach in a supportive environment. Patient involvement in making treatment-related decisions is essential for promoting satisfaction with medical care, reducing anxiety, and improving quality of life.
Future Directions
Double-blinded PRCTs are the gold standard for practicing evidence-based medicine and, many times, report findings dif- ferent from those of observational trials. Hence, PRCTs should be the methodology used moving forward to better understand the role of dietary supplements in cancer prevention and treat- ment. Such trials should be designed to enroll a diverse popula- tion of individuals who are at high risk for developing a nutrient deficiency or currently have a deficiency, since many trials thus far have enrolled primarily healthy non-Hispanic women and men or highly educated participants, such as nurses or physi- cians. Studies need to be designed that control for confounding factors, such as body weight, physical activity habits, overall diet, prior supplement use, medication use, and presence of genetic polymorphisms known to affect outcomes. Studies also need to be long-term, which allows for ongoing evaluation of continued exposure given that many of the trials completed thus far have found either benefits or adverse effects related to sup- plement use after many years of supplementation.
Conclusion and Summary
In an effort to obtain any possible benefits for risk reduction, many cancer survivors frequently use a variety of dietary sup- plements. Examining the relationship between various dietary supplements and cancer outcomes is complicated, as outcomes are likely influenced by many factors, including overall life- style habits and health status, type of cancer and treatment, type and doses of supplement and formulation used, and con- sistency in actually ingesting the supplement, as well as many other covariates previously described. Most studies have not demonstrated any benefits for healthy people related to the use of various dietary supplements. Whether supplements such as MVMs/botanicals will convey any benefits to cancer survivors is unclear. Cancer patients should be encouraged to obtain micronutrients and phytonutrients associated with a reduced risk for cancer by consuming a prudent diet rich in fruits, veg- etables, legumes, nuts, and seeds, and avoiding processed and fast foods. Living a healthy lifestyle has been associated more with a reduced risk for developing cancer and other chronic
Table 5. Recommended Resources.
Resource Web Address
Natural Medicines Comprehensive Database (subscription-based service)
http://naturaldatabase. therapeuticresearch.com/ home.aspx
Consumer Lab (subscription-based service)
consumerlab.com
Memorial Sloan Kettering Cancer Center
https://www.mskcc.org/ cancer-care/treatments/ symptom-management/ integrative-medicine/herbs
National Center for Complementary and Integrative Health
https://nccih.nih.gov/
Linus Pauling Institute, Oregon State University
http://lpi.oregonstate.edu/mic
USDA National Agricultural Library
https://fnic.nal.usda.gov/ dietary-supplements/ herbal-information
USDA, United States Department of Agriculture.
622 Nutrition in Clinical Practice 32(5)
diseases than using dietary supplements. National cancer orga- nizations support the use of taking a standard MVM supple- ment that does not exceed 100% of the recommended daily allowance when dietary nutrient intake is severely inadequate or nutrition deficiencies are exhibited.6,25 Given the extent of research reflecting that vitamin D supplementation may be needed to promote serum levels >20 ng/mL for skeletal health, vitamin D levels should be periodically assessed to determine if supplementation is necessary. Practice guidelines recom- mend that a trained professional who can provide guidance regarding supplement use should be consulted.25 A variety of online resources are available that provide reliable and accu- rate information to assist practitioners in providing advice (see Table 5).
Acknowledgment
The author thanks Michelle Bratton, RD, CSO, for her editorial assistance.
Statement of Authorship
M. J. Marian contributed to conception/design of the research and to acquisition, analysis, or interpretation of the work; drafted and critically revised the manuscript; agrees to be fully accountable for ensuring the integrity and accuracy of the work; and read and approved the final manuscript.
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Liver Injury From Herbal and Dietary Supplements Victor J. Navarro,1 Ikhlas Khan,2 Einar Bj€ornsson,3 Leonard B. Seeff,1 Jose Serrano,4 and Jay H. Hoofnagle4
Herbal and dietary supplements (HDS) are used increasingly both in the United States and worldwide, and HDS-induced liver injury in the United States has increased proportionally. Current challenges in the diagnosis and management of HDS-induced liver injury were the focus of a 2-day research symposium sponsored by the American Association for the Study of Liver Disease and the National Institutes of Health. HDS-induced liver injury now accounts for 20% of cases of hepatotoxicity in the United States based on research data. The major implicated agents include anabolic steroids, green tea extract, and multi-ingredient nutritional supplements. Anabolic steroids marketed as bodybuilding supplements typical- ly induce a prolonged cholestatic but ultimately self-limiting liver injury that has a distinctive serum biochemical as well as histological phenotype. Green tea extract and many other products, in contrast, tend to cause an acute hepatitis-like injury. Currently, however, the majority of cases of HDS-associated liver injury are due to multi-ingredient nutritional supple- ments, and the component responsible for the toxicity is usually unknown or can only be suspected. HDS-induced liver injury presents many clinical and research challenges in diagnosis, identification of the responsible constituents, treatment, and prevention. Also important are improvements in regulatory oversight of nonprescription products to guarantee their constituents and ensure purity and safety. The confident identification of injurious ingredients within HDS will require strategic alignments among clinicians, chemists, and toxicologists. The ultimate goal should be to prohibit or more closely regulate potentially injurious ingredients and thus promote public safety. (HEPATOLOGY 2017;65:363-373).
Herbal and dietary supplements (HDS) areused commonly around the world, either inplace of or to supplement conventional (Western) medical therapies. There is little dispute that some HDS have been responsible for causing liver injury. Indeed, the issue of HDS-related hepatotoxicity is a growing concern particularly with the evidence in both the United States and Europe that the use of these products appears to be increasing.(1-4)
The authors have chosen to use the phrase “herbal and dietary supplements”, or HDS, to refer to any sup- plement that might be implicated in causing liver inju- ry. These products would include herbal or botanical
supplements; products such as vitamins, minerals, ami- no acids, and proteins that are used to supplement the diet; as well as performance-enhancing supplements that may contain chemically synthesized and illicit ana- bolic steroids. Because of the special problems surrounding liver
injury from HDS, a clinical research workshop to con- sider the issues was organized, sponsored jointly by the National Institutes of Health (NIH) and the American Association for the Study of Liver Disease. The sym- posium focused mainly on liver injury from HDS in the United States, although speakers from around the world were invited to put the problem into perspective.
Abbreviations: DILI, drug-induced liver injury; DILIN, Drug-Induced Liver Injury Network; FDA, Food and Drug Administration; GTE, green tea extract; HDS, herbal and dietary supplements; NIH, National Institutes of Health.
Received May 15, 2016; accepted August 2, 2016. This summary is based upon the research symposium Liver Injury From Herbal and Dietary Supplements, held May 4-5, 2015, in Bethesda, MD,
which was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health (NIH), in collaboration with the American Association for the Study of Liver Diseases with support from the Office of Dietary Supplements, Office of the Director, NIH; the National Center for Complementary and Integrative Health, NIH; the National Institute of Environmental Health Services, NIH; the US Department of Agricul- ture; and the Centers for Disease Control and Prevention, with a special contribution by The National Center for Natural Products Research, School of Pharmacy, University of Mississippi (University, MS).
CopyrightVC 2016 by the American Association for the Study of Liver Diseases View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.28813
Potential conflict of interest: Nothing to report.
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HEPATOLOGY, VOL. 65, NO. 1, 2017
A HE STUDY OF LIVER D I S E ASEST MERICAN ASSOCIATION FOR
Topics included current uses of HDS; regulation; cur- rent rates and features of liver injury attributable to HDS; mechanisms of injury; problems in identifica- tion, purity, and standardization of HDS; and future directions in diagnosis, prevention, treatment, and control of HDS-related hepatotoxicity.
HDS and Their Use in the United States As stated, we use the term “HDS” to refer to the
broad spectrum of supplements, including vitamins, minerals, dietary elements, food components, natural herbs, herbal preparations, and synthetic compounds, that are used to supplement the diet and that could induce liver injury.(4) They are generally obtained with- out prescription and taken without specific medical advice or monitoring. In contrast to conventional drugs, however, the safety and efficacy of HDS are not always well defined. In the United States, dietary supplements are
regarded as foods rather than as drugs and are assumed to be safe, unless proven otherwise. The Food and Drug Administration (FDA) regulates dietary supple- ments under the 1994 Dietary Supplement Health and Education Act.(5) The act designates that manufac- turers are required to submit notification of a new die- tary ingredient to the FDA for any ingredients introduced after October 15, 1994, providing informa- tion on safety prior to marketing the product. These premarketing requirements do not apply to dietary ingredients legally marketed before that date. Unlike the requirement for drugs, however, documentation of efficacy need not be reported. Manufacturers are pro- hibited from making medical claims for efficacy in treating diseases or conditions, such as hypertension or hyperlipidemia. They are, however, able to make
nonspecific claims of function, such as enhancing ener- gy, wellness, liver health, sexual enjoyment, or weight control. Population surveys indicate that one-third to one-
half of the adult US population take dietary supple- ments.(1,2) Users are more likely to be women, non- Hispanic whites and more financially secure than are those who do not use these products. Supplement sales in the United States have increased in recent years from $9.6 billion in 1994 to $36.7 billion in 2014.(6,7)
The most common products taken are vitamins and minerals. Reliable and readily accessible information on most
products is provided by the NIH websites maintained by the Office of Dietary Supplements (https://ods.od. nih.gov/) and the National Center for Complementary and Integrative Health (https://search.usa.gov/search?- utf85%E2%9C%93&affiliate5nccih&query5factsh- eets&commit5Search). A descriptive categorization of HDS used by the US Drug-Induced Liver Injury Network (DILIN) is shown in Table 1.
Frequency of Liver Injury from HDS: United States and Worldwide Although there are no population-based estimates
for the frequency of liver injury from HDS in the Unit- ed States, the incidence appears to be increasing. In the prospective study of drug-induced liver injury (DILI) from the NIH-funded DILIN, HDS accounted for 16% of cases overall.(8) Importantly, however, the proportion increased during the 8 years of the study from 7% in 2004-2005 to 19% by 2010- 2012. Since then, the proportion of cases of liver injury attributable to HDS in the DILIN prospective study
ARTICLE INFORMATION:
From the 1Division of Hepatology, Einstein Healthcare Network, Philadelphia, PA; 2Department of Pharmacognosy, School of Pharmacy, University of Mississippi, Jackson, MS; 3National University Hospital of Iceland and Faculty of Medicine, University of Iceland, Reykjavik, Iceland; 4Liver Disease Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO:
Victor J. Navarro, M.D. Division of Hepatology, Einstein Medical Center 5401 Old York Road, Suite 505
Philadelphia, PA 19141 E-mail: Navarrov@einstein.edu Tel: 11-215-932-9431
NAVARRO ET AL. HEPATOLOGY, January 2017
364
has remained high and is, as of 2013-2014, 20% (Fig. 1). Studies in Europe also show increases in HDS use
over the last 10 years. In the Spanish DILI registry, the proportion of cases attributed to HDS was 2% in 2006, representing a trend over a 10-year period,(9)
and increased to 13% for the period 2010-2013.(10)
Interestingly, the proportion of liver injury cases attrib- uted to HDS varies greatly in Asia, reported to be 70% in Singapore(11) and 73% in Korea(12) but 18.6% in China(13) and only 2.5% in India(14) despite similar wide scale use of alternative or traditional medicines in all four countries. Perhaps the best estimate for the incidence of
HDS-related liver injury comes from a population- based survey in Iceland where the overall incidence of DILI in 2011-2012 was estimated to be 19 cases per 100,000 persons. In that study, 16% of cases were attributed to HDS, suggesting that the incidence of HDS-related acute liver injury was 3 per 100,000 persons.(15)
HDS Commonly Associated with Liver Injury One hundred and thirty cases of HDS-related liver
injury were reported in the course of the first 8 years of enrollment into the US DILIN prospective study.(8) At least 45 were attributed to bodybuilding agents, present- ing with a phenotype suggestive of injury due to anabolic steroids. Because prescription-strength anabolic steroids used in performance-enhancing and bodybuilding sup- plements are largely synthetic derivatives of testosterone added illegally to products and without prescription, they are perhaps better designated as “agents of abuse” or hor- monal compounds rather than HDS. The remaining 85 HDS-related cases enrolled in the
DILIN study were attributed to 116 products with labels specifying their ingredients. Importantly, these implicated products rarely contained only one ingredient.(8) The majority of agents implicated were complex mixtures sold under commercial names. Among the 85 non-anabolic steroid-associated cases of liver injury, 14 (16%) were attributed to a single or multiple named herbal products (e.g., green tea, kratom, black cohosh), 7 (8%) to tradi- tional botanical mixtures (e.g., Chinese herbs, Korean herbs, Ayurvedic medications), 6 (7%) to simple vitamins or minerals or dietary supplements (e.g., niacin, multivita- mins, levocarnitine), and the remaining 58 (68%) to multi-ingredient nutritional supplements. Among these were products marketed under various companies’ labels, including “Slimquick” (n 5 6), “Herbalife” (n 5 4), “Hydroxycut” (n 5 4), “Move Free” (n 5 2) and “Airborne” (n 5 2). Assigning causality to these and oth- er named agents proved daunting because they typically contained multiple ingredients (3-20), with only rare descriptions of their concentration and source. In 24 instances, including 15 attributed to a multi-ingredient nutritional supplement, green tea was listed as a compo- nent and was believed to be the causative agent. The types of HDS implicated in the DILIN, organized by their marketed purpose for use, are displayed in Fig. 2.(16)
TABLE 1. The DILIN Categorization for HDS
Category Examples
Vitamins Vitamin C, niacin, folate Minerals and elements Iron, calcium, potassium Named botanical or herbal products GTE, ginseng, black cohosh, Chinese herbs Multi-ingredient nutritional supplements Products with mixtures of ingredients such as vitamins, minerals, amino
acids, proteins, and botanical extracts having proprietary names such as “Hydroxycut” and “Airborne”
Anabolic steroids Bodybuilding products containing anabolic steroids
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
FIG. 1. Proportion of DILIN Cases due to HDS.
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
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Thus, HDS-induced liver injury encompasses a spectrum of presentations. One entity is anabolic steroid-related jaundice, resulting from the use of illicit synthetic derivatives of androgens that presents as a highly characteristic phenotype. The second is acute liver injury that follows the use of an identifiable spe- cific, single botanical product or traditional herbal medicine, which generally proves no more difficult in assigning causality than is the case for a pharmaceutical drug; the most common single agent in this category is green tea (Camellia sinensis). The third is the occur- rence of acute liver injury associated with a multi- ingredient nutritional supplement that usually chal- lenges and often defies identification of the responsible component. A complicating factor is that the implicat- ed product may also be contaminated with a synthetic chemical or with an unknown and toxic botanical.
Green Tea Extract Hepatotoxicity Green tea is one of the most frequently consumed
beverages in the world, used daily by hundreds of mil- lions of people. Green tea extract (GTE), derived from leaves of the Camellia sinensis plant, is considered to have beneficial medicinal properties. Recently, there are claims that GTEs have weight-loss properties, enhancing fat metabolism (“fat burning”). The bases for these claims are in vitro studies using concentrated GTEs that demonstrate antioxidant activity, inhibition of lipogenesis, and increase in several metabolic path- ways.(17) Studies of green tea in humans have not
demonstrated an effect on weight loss, although small studies have suggested a trend.(18) Nevertheless, a large number of commercial products have been developed containing GTE which are advertised as weight loss agents. While prospective clinical trials have not shown clear effects on weight, they also have not shown appreciable adverse events. With this background, it came as a surprise when
GTE was first linked to rare instances of acute hepati- tis.(19) Since 2006, there have been more than 50 reports in the medical literature of clinically apparent acute liver injury with jaundice attributed to GTEs.(20,21) In 2008, the US Pharmacopeia assessed 34 reports of liver injury linked to GTE.(22) It concluded that a warning label in the quality monograph for GTE was not warranted at the time for several reasons, including a lack of additional adverse reports over time, missing epidemiological data, and a paucity of information on the quality of the preparations specifi- cally linked to liver injury. Among cases of HDS- related liver injury in the DILIN prospective trial, 97 implicated products were available for testing; 49 con- tained catechins indicative of GTE, 29 of which were from products that were not labeled as containing GTE.(23) The patients with liver injury attributed to GTE presented with a characteristic acute hepatitis- like illness occurring within 1-3 months of starting use of the product. The illness was generally self-limited, but fatal instances have been reported in up to 10% of cases, typically those who presented with acute hepato- cellular injury and jaundice. The cause of the liver injury due to GTE is not
known. High doses of the types of catechins present in GTE are hepatotoxic in mice, particularly epigallocate- chin gallate which represents 30%-50% of the dry weight of GTE.(24) In most reports of GTE hepato- toxicity, however, the human dose of epigallocatechin gallate (generally <12 mg/kg daily) did not appear to be excessive or in the range that might have direct tox- icity (estimated for humans to be 30-90 mg/kg). These findings suggest that the liver injury from GTE is an idiosyncratic reaction, typical of conventional DILI. Other popular herbal products have been linked to
cases of clinically apparent liver injury, but in many instances, there have been alternative explanations for the liver injury. One important potential contributor is contamination of the HDS product, not just with toxic elements but also with other unknown herbs or the illicit addition of actual conventional Western medica- tions (such as 5-phosphodiesterase inhibitors [sildena- fil], nonsteroidal anti-inflammatory agents, statins, and
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FIG. 2. Distribution of HDS implicated in liver injury in the DILIN.
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corticosteroids). Other implicated herbal products in the DILIN database included black cohosh (Actaea racemosa), kratom (Mitragyna speciosa), valerian (Valeriana officinalis), Eurycoma longifolia, wormwood (Artemisia herba-alba), cat’s claw (Uncaria tomentosa), Ganoderma applanatum (artist’s conk), fo-ti (Fallopia multiflora), red yeast rice (Monascus purpureus), and Garcinia cambogia. However, the role of these specific herbal products in causing the liver injury was often difficult to assign with any assurance because of the lack of documentation of their chemical presence and purity, the possibility of contamination with other herbal products, or mislabeling of the ingredients.
Acute Liver Injury From an OxyELITE Pro Weight Loss Product A dramatic outbreak of severe acute hepatitis was
reported to the Hawaii Department of Health in Sep- tember 2013 in which 7 previously health young men and women developed jaundice with marked serum aminotransferase elevations, all of whom reported tak- ing a product known as OxyELITE Pro as a weight- loss and muscle-building agent.(25) Subsequently, Hawaiian investigators reported a total of 36 cases of acute liver injury with jaundice in persons taking this supplement,(26,27) and the product was withdrawn by the manufacturer later in the year. The clinical features of the illness consisted of an acute hepatitis-like illness with initial symptoms of fatigue and anorexia together with dark urine and jaundice. Fever and rash were uncommon. Laboratory tests showed peak mean serum bilirubin values of 9.4 (range 2.6-41.6) mg/dL, mean alanine aminotransferase values of 1,740 (428-3,285) U/L, and mean alkaline phosphatase values of 141 (72-277) U/L. Liver biopsies showed an acute hepatitis suggestive of a toxic injury. One patient died, and 2 others underwent emergency liver transplantation, a fatality rate of 8%, which is typical of drug-induced acute hepatocellular injury. Other patients recovered; but many had a protracted course, and some developed autoimmune hepatitis-like features and thus received corticosteroid therapy. Additional cases have since been reported from the
continental United States, particularly in military per- sonnel, possibly due to the availability of OxyELITE Pro in military post exchanges.(28) While initial reports suggested a strong association with Asian-Pacific race,
cases from the continental United States have included all racial groups. In the DILIN database covering this same period (May to December 2013), there were 6 cases of liver injury attributed to OxyELITE Pro, 5 in women, 2 non-Hispanic whites, 1 Hispanic, and 3 Asians, most having taken the specific product for 1-5 months. All presented with a hepatocellular pattern of injury, requiring emergency liver transplantation in 2 patients.(29)
The cause of liver injury in consumers of OxyE- LITE Pro was suspected to be the addition of aegeline to the commercial product in March 2013. Chemical analyses of implicated lots of OxyELITE Pro showed the presence of aegeline but no evidence of other toxins or contaminants. Aegeline is the major alkaloid found in the fruit of the bael tree, Aegle marmelos, which has been used for centuries in Ayurvedic medicine to treat digestive complaints. Why aegeline might cause severe liver injury is uncertain, but the added product may have been synthetic and thus contain intermediates of its synthesis or racemic mixtures of the main components.
Anabolic Androgenic Steroid Jaundice Testosterone and the anabolic androgenic steroids
include many FDA-approved drugs that are used for male sex hormone replacement among other medical indications. Because anabolic steroids increase muscle growth and can improve athletic performance, they have attracted illicit use for bodybuilding and perfor- mance enhancement.(30)
Use of the 17a-alkylated androgenic steroids has long been associated with a distinctive form of liver injury marked by intense and prolonged jaundice.(31,32)
Many of these products continue to be widely available on the Internet. As shown through several case reports, injury typically presents in young or middle-aged men interested in bodybuilding or performance enhance- ment who develop jaundice and pruritus 1-6 months after starting a supplement regimen that includes an anabolic steroid.(31-33) Laboratory tests demonstrate hyperbilirubinemia typically with minimal elevations in serum enzymes. Serum aminotransferase levels may be high initially but soon fall into the range of 1-3 times the upper limit of normal, while alkaline phosphatase levels are normal or minimally elevated on presentation but slowly rise during the course of injury. Liver histol- ogy shows marked canalicular cholestasis with minimal
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inflammation and necrosis, a pattern often referred to as “bland cholestasis,” similar to that seen with estro- genic steroids. Although jaundice can be severe and prolonged,
with bilirubin levels reaching 40-50 mg/dL and jaun- dice persisting for 2-4 months, death from liver failure is uncommon. Severe cholestasis can be accompanied by renal dysfunction and need for temporary dialysis, but both the renal and liver injuries ultimately resolve.(10,31-33) Chronic liver injury, cirrhosis, and the vanishing bile duct syndrome as a result of anabolic steroid liver injury are exceedingly rare, if they occur at all. Management of anabolic steroid jaundice involves watchful waiting. Symptomatic therapies for the pruri- tus (cholestyramine, ursodiol, antihistamines) are usu- ally given but have only modest efficacy. Corticosteroids do not seem to ameliorate the liver injury or speed recovery. The mechanism of cholestasis caused by anabolic
steroids remains unknown. The pattern of canalicular jaundice with scant hepatocytic necrosis suggests selec- tive impairment of canalicular function rather than hepatocellular and cholangiocytic damage or loss. The pattern is similar to that seen in benign recurrent intra- hepatic cholestasis, caused by mutations in the ATP8B1 gene (formerly FIC1), whose dysfunction leads to impaired bilirubin and bile acid secretion, or in ATPB11 (formerly FIC2), which encodes for the bile salt canalicular transporter. Sequencing of coding exons and intron-exon junctions of these two genes in 2 patients with anabolic steroid-induced jaundice revealed no variants in the ATP8B1 gene and a nonsy- nonymous coding variant in ABCB11 of unknown sig- nificance in 1 patient.(34)
Diagnosis of HDS-Induced Liver Injury The diagnosis of DILI relies largely on a compatible
history, a drug with a known record of causing liver injury, and exclusion of other causes. There are no spe- cific diagnostic tests for DILI, and the pattern of injury can mimic virtually any acute or chronic liver disease. In many cases, the possibility of contamination or mis- identification of the botanical constituent remains a concern. The typical clinical presentation of HDS- associated liver injury is an acute hepatitis with marked elevations in serum aminotransferase levels but no or only modest increases in alkaline phosphatase values. Immunoallergic and autoimmune features are not
common. The latency to onset is usually 1-4 months and the time to resolution, typically within 1-2 months. Fatalities can occur, but the true case fatality rate is unclear, given that the frequency of supplement use in the population is unknown. Liver biopsy can rule out chronic liver injury and
provide evidence for or against a contribution of other liver diseases. The liver histology of anabolic steroid- associated liver injury is quite distinctive in showing a bland cholestasis with canalicular cholestasis and scant hepatocyte necrosis and inflammation, a pattern rarely seen with other forms of liver injury, except for estrogen-associated cholestasis. Further information on the hepatotoxicity of HDS
products and clinical examples of liver injury from these products are available on the LiverTox website (http:/www.LiverTox.nih.gov), a resource developed by the Liver Disease Research Branch of the National Institute of Diabetes and Digestive and Kidney Dis- eases in collaboration with the National Library of Medicine. A proposed diagnostic approach to liver injury due to HDS is shown in Fig. 3.
Chemical Analytical Approaches for HDS Current FDA regulations on good manufacturing
practices stipulate that manufacturers must provide full verification that “specifications are met for the identity,
� � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � �
FIG. 3. The approach to diagnosing liver injury from Herbal and Dietary Supplements.
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purity, strength, and composition of the dietary sup- plements.”(35) However, regulations do not specify which analytical methods are required for verification. The “identity” criterion states that each dietary ingredi- ent must be authenticated by a specific, scientifically valid method; but no guidance is given regarding the sensitivity, specificity, or accuracy of the method used. As discussed in this section, scientists have looked to various newer approaches to authenticate products and identify ingredients. Botanical authentication consists of macroscopic
and microscopic examination of the entire plant or plant parts as well as dried and/or processed plants. While usually reliable, these microscopic/macroscopic techniques are not always ideal, such as when trying to separate closely related genera or when the sample has been extensively processed, particularly when working with a complex multicomponent powdered sample. Thus, the authentication relies upon comparison to verified authentic material and expert opinion. In addi- tion, good manufacturing practices require that manu- facturers set specifications and test for reasonably anticipated contaminants, such as natural toxins, toxic elements, mycotoxins, pesticides, and pathogenic microorganisms. Several approaches have been pursued in the
attempt to “standardize” botanical materials. The customary pharmacognostic approaches typically entail chemical standardization based on the quanti- fication and manipulation of a selected marker com- pound(s) to assure batch-to-batch consistency of raw material extracts and finished products. The most commonly used and dependable methods for chemi- cal characterization of HDS products are modern analytical separation techniques such as high- performance liquid chromatography and gas chroma- tography, followed by a suitable detection mode such as ultraviolet or mass spectrometry. In addition to information about the quantity of selected com- pounds of interest (marker compounds), these meth- ods can provide an analytical “fingerprint” of botanical components.(36) A limiting factor to the widespread adoption of these types of quality control approaches for botanicals is expense or the lack of relevant pure marker compounds to be used as cali- brants. To address this issue, many researchers have turned to nontargeted spectroscopy-based analysis techniques in combination with chemometric analy- sis for identity testing.(37)
Genetic fingerprinting or profiling using DNA technologies is a fast-growing research field in
botanical authentication.(38) These methodologies begin with DNA extraction procedures that must be effective in yielding sufficient quantities of high- quality DNA as well as being reproducible, economi- cal, and flexible enough to be compatible with high- throughput analysis. DNA authentication is most fre- quently confounded by poor-quality plant material. DNA extracted from most commercially available, dehydrated powdered plant parts is often degraded and rarely suitable for analysis. Statistical techniques for the interpretation of phyto-
chemical fingerprinting data include hierarchical clus- ter analysis and principal component analysis. These techniques can be used to compare the total mass spec- trum, ultraviolet spectrum, or infrared spectrum of an extract of the authentic target botanical with that of an unknown material. Hierarchical cluster analysis and principal component analysis can also be used to com- pare chromatographic “fingerprints” of authentic mate- rials with those of unknown materials.(39) One of the advantages of this type of statistical approach is that it uses pattern recognition parameters to evaluate peaks/ components within the data clusters in order to see if the “test” sample correlates to the population of authenticated samples.
Toxicological Analysis for HDS Accurate identification of the chemical composition
of HDS is a key step in determining ingredients responsible for injury, but it is only the beginning; a process must be followed to determine which ingre- dient(s) has hepatotoxic potential and is responsible for injury. Conventional toxicological analysis requires in vitro and in vivo testing of a component for cellular and organ toxicity. Single compounds are well suited for this approach, as occurs in the conventional para- digm of pharmaceutical drug development. For HDS, however, the complexity of components and mixtures challenges the interrogation of a toxicological effect. That is to say, if a product induced cellular or organ toxicity, it would be incumbent upon the evaluator to determine which ingredient(s) was responsible and at what concentration. Thus, toxicological analysis of HDS must be predicated upon valid methods to tease apart the products into their component parts so that they can be interrogated, either alone or in a biological- ly relevant approach.
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Liver Injury From HDS: Agenda for the Future RESEARCH ISSUES
The issues raised by HDS-related liver injury pose several important research challenges that, when addressed, would help considerably in the understand- ing, control, and prevention of this evolving problem (Table 2). The mechanisms by which HDS cause liver injury are unclear and require exploration. Identifying the chemical composition of HDS is a key step in determining the responsible ingredients, but this needs to be followed by studies of the toxic properties of the specific compounds using cell biology, cell cultures, and animal models. Prediction of toxicity from animal models is not always reliable, particularly for idiosyn- cratic liver injury, which is often immunologic but may have metabolic idiosyncrasy as well. HDS-associated liver injuries demonstrate some features of idiosyncra- sy, although marked immunoallergic and autoimmune features are uncommon. One example of a promising tool for testing HDS
and purported active constituents is high-throughput screening using in vitro assays, such as those included in the Tox21 Program. Tox21 is an initiative involving a partnership of the National Center for Advancing Translational Sciences (NIH), the National Institute of Environmental Health Sciences (NIH), the Envi- ronmental Protection Agency, and the FDA.(40) The goals of Tox21 are to identify mechanisms of compound-induced biological activity and toxicity and develop predictive models for both. The Tox21 pro- gram has screened thousands of single chemicals, as well as some mixtures. In addition to the Tox21 high- throughput screening platform, in vitro liver models for prediction of human drug metabolism and cell inju- ry are being developed. The National Toxicology Pro- gram is currently applying cell-based models to the evaluation of biological and toxic responses of botanical products and multi-ingredient herbal supplement mix- tures. Clinical research progress in HDS hepatotoxicity is also an important part of a future agenda. Most
clinical research has been limited to accrual of case reports and analysis of commonality of the course and outcome of injury from related and unrelated HDS products. A major need is a standardized method of causality assessment in cases of liver injury in which HDS products are implicated that is reliable, is repro- ducible, and can be used by both the research and clin- ical communities. The clinical instruments developed for assessing hepatotoxicity of medications do not per- form well for HDS products and have inherent short- comings that prevent their reliable use.(4) Compilation of well-described cases of HDS liver injury is also important for collection of serum, tissue, and DNA samples to allow assessment of immunologic, cell bio- logic, and genetic factors that predict or contribute to the injury. Finally, because almost 20% of prescription drug users consume HDS concurrently,(41) the concern for herb-drug interactions is one that must concern cli- nicians. This topic has been reviewed extensively elsewhere.(42)
REGULATORY ISSUES
Current regulations of dietary supplements in the United States have been criticized as being inadequate and not completely rational.(43) The FDA has special and varied challenges when dealing with supplements. For instance, the FDA does not require manufacturers to register their products with the agency, so it has lim- ited information on the number, types, and ingredients of products in the marketplace. Product labels may not provide a full disclosure of the ingredients, their con- centrations, purity, and source. There are also products that change in composition without appropriate notifi- cation of the FDA. When the Dietary Supplement Health and Education Act was first published in 1994, there were an estimated 4,000 supplements available in the United States.(43) Currently, there are more than 80,000.(44)
The FDA is also limited in its ability to monitor and identify adverse events from dietary supplements. The usual means of capturing adverse event informa- tion is through the FDA’s Adverse Event Reporting System, which has accumulated a large database of
TABLE 2. Future Challenges With Research and Regulation of HDS
1. Analysis to verify ingredients and to identify pharmaceutical adulterants and chemical/botanical contaminants. 2. Toxicological evaluation for suspected injurious ingredients and interactions with prescription drugs. 3. Standardize nomenclature and classification across countries, and causality assessment process for HDS-associated injury. 4. Enhance product monitoring and safety, as well as public awareness of the risks of injury from HDS. 5. Improve spontaneous reporting of adverse events.
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spontaneous reports of adverse events from prescrip- tion drugs and products.(45,46) The difficulty is that consumers and others may be underreporting adverse events to the FDA. The Dietary Supplement and Nonprescription Drug Consumer Protection Act was passed in 2007 and requires dietary supplements and over-the-counter drug manufacturers or distributors to report serious adverse events to the FDA. Most consumers of HDS are taking the supplement
on their own, without medical direction or monitoring. Adverse events may go undetected and, if detected, are often underreported and, even if reported, often inade- quately documented for reliable assessment of causali- ty, severity, and outcome. Even with adequate reporting or detection of
adverse events due to HDS, the FDA is limited in its ability to act on the safety concerns. The FDA employs warning letters to manufacturers and alerts to consum- ers. Regulatory actions include recalls, which are large- ly voluntary; refusal of importation of suspicious products at US borders; legal action against dietary supplement firms including product seizures; and, most aggressively, banning of the production and dis- tribution of the agent and removal of products from shelves. These more intrusive actions often occur after the fact, once clear toxic reactions have been identified. Examples of FDA actions include banning of ephed- rine alkaloids because of multiple cases of sudden death in patients taking products(47); the voluntary with- drawal of OxyELITE Pro because of multiple cases of acute liver failure with its use(25,27); and warning letters concerning products containing kava kava and black cohosh after reports of severe liver injury.(48) Despite actions affecting some products of a particular brand, other products from the same manufacturer remain available in stores and on the Internet. A major obstacle to better understanding and
improving the safety of HDS is the difficulty in deter- mining what is actually in a supplement. Although there are current good manufacturing practice regula- tions for supplements, which include some controls over the quality of products, the enigmatic term “proprietary blend” is commonly used. The disclaimer
concerning the lack of medical indication is obviated by claims about structure and function, such as benefit for general health, joint health, liver wellness, or weight control. Such claims do not require proof in prospective controlled trials yet lead the consumer to believe that the product has demonstrated efficacy. Finally, of great concern is the presence of undeclared ingredients in HDS, not infrequently with pharmaceu- tical action or toxic potential. The authors’ proposal for changes to regulation of HDS are listed in Table 3. Liver injury from HDS is a growing problem that
poses special challenges in clinical care, clinical and basic research, and regulatory oversight. A heightened awareness of the problem, stimulation of clinical and basic research, and new approaches for the monitoring and regulation of supplements to ensure their safety to the consumer are important priorities.
Conclusions Bringing together experts of varied backgrounds
through this workshop has made clear that to reduce the apparent rising burden of liver injury due to HDS, clinical, basic, and translational scientists must collabo- rate on a common agenda for the future. The most important priorities for this collaboration should be to better understand the epidemiological impact of HDS- related liver injury, for clinicians to accurately identify those products that cause injury, and for chemists and toxicologists to isolate and test the products’ ingre- dients for their toxic potential. Ultimately, the findings from the collaborations must be used to inform regula- tion, thus providing regulatory authorities with infor- mation necessary to guide the development of safer products and the removal of injurious products from the market.
Acknowledgment: The following were presenters at the May 2015 conference from which the content of this review was prepared: Joseph M. Betz, Ph.D., direc- tor, Analytical Methods and Reference Materials Program, Office of Dietary Supplements, NIH; Einar Bj€ornsson, M.D., Ph.D., The National University
TABLE 3. Proposed Changes to US Regulation for HDS
1. Differentiate regulatory requirements for foods, vitamin-containing and mineral-containing dietary supplements, and dietary supplements containing multiple ingredients that are not nutrients.
2. Require FDA registration of HDS with a complete list of ingredients on the label. Proprietary blends, if listed, should list the actual amount of each ingredient in the blend.
3. List reported adverse events on the label/consumer information factsheet. 4. Prohibit structure-function claims without proof of effectiveness.
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Hospital of Iceland; Mark Blumenthal, founder and executive director, American Botanical Council, edi- tor, HerbalGram and HerbClip; Herbert Bonkovsky, M.D., professor of Medicine and Molecular Medi- cine and Translational Science, chief of Hepatology, Wake Forest University School of Medicine; Paul Coates, Ph.D., director, Office of Dietary Supple- ments, NIH; Pieter Cohen, M.D., Cambridge Health Alliance, Harvard Medical School; Harshad Devarbhavi, M.D., D.M., head, Department of Gas- troenterology and Hepatology, St. John’s Medical College Hospital, Bangalore, India; Jamie Dunn, Center for Drug Evaluation and Research, Division of Pharmaceutical Analysis, FDA; Stephen Ferguson, National Toxicology Program, National Institute of Environmental Health Sciences, NIH; James Harnly, research leader, Food Composition and Methods Development Lab, Beltsville Human Nutrition Research Center, Agricultural Research Service, US Department of Agriculture; D. Craig Hopp, Ph.D., program director, National Center for Complementa- ry and Integrative Health, NIH; Neil Kaplowitz, M.D., Division of Gastroenterology and Liver, Uni- versity of Southern California Keck School of Medi- cine; David Kleiner, M.D., Ph.D., Laboratory of Pathology, National Cancer Institute, NIH; Ikhlas Khan, Ph.D., D.Litt. (Hon. Causa), assistant direc- tor, National Center for Natural Products Research, director, FDA Center of Excellence, research profes- sor, Department of Pharmacognosy, School of Phar- macy, University of Mississippi; Chenghai Liu, M.D., Ph.D., Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine; M. Isabel Lucena, M.D., Ph.D., professor of Pharmacology, Clinical Pharmacology Service, Biomedical Research Institute of M�alaga, Hospital Universitario Virgen de la Victoria, Malaga Universi- ty, Malaga, Spain; Victor Navarro, M.D., chair, Division of Hepatology, Einstein Healthcare Net- work; Stephen Ostroff, M.D., acting chief scientist, Center for Food Safety and Applied Nutrition, FDA; Cynthia Rider, Ph.D., DABT, National Toxi- cology Program, National Institute of Environmental Health Sciences, NIH; Nandakumara Sarma, R.Ph., Ph.D., director, Dietary Supplements, US Pharmaco- peia; Leonard Seeff, M.D., consultant in Hepatology, Einstein Healthcare Network; Andrew Stolz, M.D., associate professor of Medicine, chief Gastrointestinal Service LAC1USC General Hospital; Ethel V. Tay- lor, D.V.M., M.P.H., Health Studies Branch, National Center for Environmental Health, Centers
for Disease Control and Prevention; Lisa Van Ars- dale, senior analyst, US General Accountability Office; Larry Walker, Ph.D., director, National Cen- ter for Natural Products Research, professor of Phar- macology, School of Pharmacy, associate director for Basic Sciences, University of Mississippi Cancer Institute; Cara Welch, Ph.D., senior advisor, Office of Dietary Supplement Programs, Center for Food Safety and Applied Nutrition, FDA. The opinions expressed are those of the authors;
an opportunity for input on the content was given to presenters.
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HEPATOLOGY, Vol. 65, No. 1, 2017 NAVARRO ET AL.
373
REVIEW ARTICLE
Correspondence:
Edward D. Kim, Division of Urology, Department
of Surgery, University of Tennessee Graduate
School of Medicine, 1928 Alcoa Highway, Suite
222, Knoxville, TN 37920, USA.
E-mail: ekim@utmck.edu
Keywords:
anabolic steroid-induced hypogonadism, designer
steroids, dietary supplements, dimethazine,
mentabolan, methylstenbolone
Received: 3-May-2014
Revised: 19-Oct-2014
Accepted: 31-Oct-2014
doi: 10.1111/andr.307
Designer steroids – over-the-counter supplements and their androgenic component: review of an increasing problem
C. D. Rahnema, L. E. Crosnoe and E. D. Kim
Division of Urology, Department of Surgery, University of Tennessee Graduate School of Medicine, Knoxville, TN, USA
SUMMARY Colloquially referred to by various misleading monikers (‘pro-hormones’, ‘natural steroids’, ‘testosterone boosters’, etc.) designer
anabolic steroids have been popular now for over a decade as a way to achieve classic anabolic steroid-like results from products sold
in the legal marketplace. Recent evidence suggests that anabolic steroid use may be the most common cause of hypogonadism in
men of reproductive age. Despite recent regulatory efforts that have banned specific compounds, many anabolic-androgenic steroids
(AAS) remain available in over-the-counter dietary supplements that are legally sold in the United States. Severe side effects includ-
ing hepatotoxicity, cholestasis, renal failure, hypogonadism, gynecomastia, and infertility have been reported secondary to the use of
these products. While some of these side effects may be reversible, more aggressive use may result in more permanent end-organ
damage as has been previously described for the case of aggressive AAS users (Rahnema et al., Fertil Steril, 2014). Designer AAS
remain easily available for purchase in over-the-counter bodybuilding supplements and these products appear to be increasingly
popular, despite the known health risks associated with their use. We conducted a systematic search to identify the designer steroids
that are most commonly sold in dietary supplements as of April 2014 and review what is known regarding their potency and toxicity.
We propose that the impact of AAS use on the reproductive and hormonal health of men is underestimated in the literature owing to
previous studies’ failure to account for designer steroid use. Lastly, we make clinical recommendations to help physicians steer
patients away from potentially harmful supplements, and summarize key regulatory obstacles that have allowed potent androgens to
remain unregulated in the legal marketplace.
INTRODUCTION The modern perception of ‘ideal’ body image has arguably
fueled the development and use of dietary supplements and
‘body image drugs’ such as anabolic-androgenic steroids (AAS) –
use is widespread, no longer limited to bodybuilders or elite ath-
letes (Rahnema et al., 2014). Recent evidence suggests that illicit
AAS use may be the most common cause of severe hypogona-
dism in younger men (Coward et al., 2013). A recent meta-analy-
sis of the epidemiology of AAS use included 187 published
studies to obtain a global lifetime prevalence rate of 3.3% (Sagoe
et al., 2014). While these data confirms that AAS use is a wide-
spread and important public health concern, such studies have
historically focused exclusively on illicit androgens (mostly
injectable) obtained on the black market. Since 2002, potent syn-
thetic oral AAS have been detected in as many as 20% of legally
sold sports nutrition products (Baume et al., 2006; Geyer et al.,
2008; Rahnema et al., 2014). With global sales of dietary supple-
ments reaching tens of billions of dollars yearly (Geyer et al.,
2008), significant public consumption of these over-the-counter
AAS can be inferred (Kanayama et al., 2001).
While dietary supplement adulteration with a variety of drugs
including controlled androgens, PDE5 inhibitors, and prescrip-
tion diuretics remains an important problem (Cohen, 2012), a
number of bona fide AAS are listed openly on product labels
(Cavalcanti et al., 2013). Despite this, many patients and physi-
cians may be unaware that these products contain ‘real’ ana-
bolic steroids that often come with side effects that are unique
from their more thoroughly studied injectable pharmaceutical
counterparts. Because of designer steroids, the impact of non-
medical AAS exposure on the development of hypogonadism
150 Andrology, 2015, 3, 150–155 © 2015 American Society of Andrology and European Academy of Andrology
ISSN: 2047-2919 ANDROLOGY
and infertility, especially in men of reproductive age, is likely
underestimated by current published statistics (Kanayama et al.,
2001; Van Thuyne et al., 2006; Brennan et al., 2013; Sagoe et al.,
2014). Although there are a paucity of published data regarding
the risks of designer steroids, there is a need for increased aware-
ness among physicians regarding the nature and availability of
these over-the-counter compounds. While we have previously
reported on the complications of well-known anabolic steroids
(Rahnema et al., 2014), the purpose of this systematic review of
the literature was to introduce and provide an overview of
designer steroids, a relatively unknown segment of the anabolic
steroid market.
MATERIALS ANDMETHODS A comprehensive list of popular designer AAS was obtained
from Internet blog postings on www.prohormonedb.com and
www.totalflexblog.com. An exhaustive search of the Internet
using the three most trafficked search engines in the United
States (Google, Yahoo, and Bing) was conducted to identify In-
ternet retailers selling these designer AAS. Search criteria
included the names of each designer steroid as well as the terms
‘prohormones’, ‘designer steroids’, ‘testosterone boosters’, and
‘legal steroids’. Products met initial inclusion criteria if they were
legal for sale in the United States as of April 2014 and their
advertised ingredient label included the chemical name of a
known designer AAS.
A systematic PubMed search was then conducted from the
time periods 1950–2014 using the chemical as well as generic
names of the designer AAS identified from the Internet search.
In addition, PubMed was searched for key terms, which included
‘designer steroids’, ‘dietary supplements’, ‘AAS’, and ‘andro-
gens’. We included specific designer steroids for review if associ-
ated literature in peer-reviewed journals existed (Table 1).
RESULTS
Definition
A ‘designer steroid’ is an AAS synthesized from a known parent
steroid and chemically modified with the intent to circumvent
controlled substances laws (Van Thuyne et al., 2006; Kazlauskas,
Table 1 Currently unscheduled designer steroids
Generic name References Product label name(s) Summary
Dimethazine De Ruggieri et al. (1963) and
Matscher et al. (1962) • 2a,17a-dimethyl-5a-androstan-17b-ol-3,30-azine• 2a,17a-dimethyl-5a-androstan-17b-ol-3-one-azine •
17aa oral androgen with high potential for hepatotoxicity
• Studied in humans in Italy for its anabolic effects
• Chemically detected in dietary supplements
Methylepitiostanol Okano et al. (2009), Kurachi
et al. (1975) and Ueda
et al. (1986)
• 2a,3a-epithio-17a-methyl-5a-androstan-17b-ol • 17aa oral androgen with high potential for hepatotoxicity
• Oral version of an androgen/antiestrogen previously used for breast cancer in Japan
• Chemically detected in dietary supplements
Methoxygonadienea Edgren et al. (1966) and
Buzby et al. (1966) • 13b-ethyl-3-methoxy-gona-2,5(10)-dien-17-one • Progestin related to
levonorgesterel
• Effects of oral consumption in humans unknown
Methylclostebol Lootens et al. (2011) • 4-chloro-17a-methyl-androst-4-en-17b-ol-3-one • 17aa oral androgen with high potential for hepatotoxicity
• Oral version of the pharmaceutical androgen clostebol
• Chemically detected in dietary supplements
• Minimal data on toxicity Methylstenbolonea Geldof et al. (2014) and
Cavalcanti et al. (2013) • 2,17a-dimethyl-17b-hydroxy-5a-androst-1-en-3-one • 17aa oral androgen with
high potential for hepatotoxicity
• Oral version of the pharmaceutical androgen stenbolone
• Chemically detected in dietary supplements
Mentabolan/Trestione Campbell et al. (1963) and
Segaloff (1963) • 7a-methyl-estra-4-en-3,17-dione• 7a-methyl-19-norandrostenedione •
Closely related to MENT/Trestolone
• May convert to MENT/Trestolone
• Strong androgen aThese designer steroids are specifically listed in the WADA Prohibited List.
© 2015 American Society of Andrology and European Academy of Andrology Andrology, 2015, 3, 150–155 151
DESIGNER STEROIDS IN DIETARY SUPPLEMENTS ANDROLOGY
2010; Lootens et al., 2011). Designer steroids share a common
mechanism of action with testosterone, acting at the androgen
receptor (Diel et al., 2007; Kazlauskas, 2010). Like all androgens,
parameters by which designer steroids are characterized differ
among compounds – aromatization and 5-alpha reduction are
possible for some designer AAS, and all exhibit varying ratios of
anabolic to androgenic activity. A vast number of designer ste-
roids exist, many are novel compounds with no associated pub-
lished research. We review six compounds that are currently
sold over the counter or on the Internet and are not scheduled
as controlled substances. These compounds are dimethazine,
methylclostebol, mentabolan, methoxygonadiene, methylepi-
tiostanol, and methylstenbolone. Table 1 summarizes our
knowledge regarding these compounds and their consumption
in humans.
Currently popular designer steroids
Dimethazine
‘DMZ’ was first studied in Italy in the 1960s for its potent ana-
bolic effects employed for a variety of indications including
gynecologic malignancy, osteoporosis, fibrocystic dysplasia,
tuberculosis, and cachexia in children (Matscher et al., 1962; De
Ruggieri et al., 1963). In animal studies, dimethazine was found
to have a greater myotrophic effect than methyltestosterone,
oxymetholone (Anadrol), and testosterone propionate (Mat-
scher et al., 1962; De Ruggieri et al., 1963). Dimethazine first
appeared as a labeled ingredient in dietary supplements in
2008. In 2009 the FDA charged one supplement manufacturer
with the sale of unapproved drugs, including dimethazine,
resulting in a fine of $125 000 (Criminal Investigations, 2011).
In 2013 the FDA issued a press release warning consumers that
dimethazine and the controlled AAS methasteron (Superdol)
were detected in a vitamin B dietary supplement (Press
Announcements, n.d.). Despite these actions, dimethazine con-
tinues to appear as a labeled ingredient (2a,17a-dimethyl-5a-an-
drostan-17b-ol-3-one-azine) in dietary supplements and was
identified on the label of 17 currently sold products by our In-
ternet search method.
Methylclostebol
Clostebol (4-chloro-17b-hydroxyandrost-4-en-3-one) is the chlorinated derivative of testosterone (17b-hydroxyandrost-4- en-3-one). Clostebol is a Schedule III controlled substance used
medically in topical ophthalmologic and dermatologic treat-
ments. A 17-alpha-alkylated version of clostebol (methylcloste-
bol) was determined by chemical analysis to be present in
significant amounts in a nutritional supplement (Lootens et al.,
2011). We found methylclostebol to be a listed as an ingredient
in four currently sold ‘dietary supplements’. Common to many
designer steroids products, the labeled ingredient (4-chloro-17a- methyl-androst-4-en-17b-ol-3-one) is written in a convoluted and outdated nomenclature, and could be more succinctly
described as 4-chloro-17a-methyltestosterone (methylclostebol). As a 4-chlorinated derivative of testosterone, methylclostebol,
like clostebol, is not a substrate for aromatase or 5-alpha reduc-
tase. Thus, it can be predicted that gynecomastia and virilization
would be less common with this compound. Likely owing to its
non-virilizing side effect profile, German athletes in the 1960s
and 1970s used methylclostebol as an ergogenic, but this oral
androgen has never been studied for medical use. In vivo animal
assays found oral methylclostebol to be approximately half as
anabolic and significantly less androgenic than testosterone
(Vida, 1969).
Mentabolan
In the 1960s 7-alpha-alkylated derivatives of nandrolone were
synthesized and shown to exhibit increased androgenic activity
(Segaloff, 1963). One such compound was 7-alpha-methyl-19-
nortestosterone (MENT). MENT, also known as Trestolone, is
currently being evaluated as an experimental male contracep-
tive in studies supported by the Population Council (Nieschlag
et al., 2013). A related compound, 7a-methyl-19-nor-andro-
stenedione (mentabolan, trestione) has recently emerged as a
designer steroid and was identified as a labeled ingredient in
two products from our systematic product search. The similarity
in name to MENT (Trestolone) is warranted as ‘trestione’ is sim-
ply the ‘dione’ version of trestolone, just as androstenedione is
to testosterone (Fig. 1). We know from early studies, that men-
tabolan along with trestolone exhibit increased androgenicity
relative to other 19-nor androgens such as nandrolone (Deca
Durabolin). Mentabolan by oral administration effectively sup-
pressed gonadotropins while increasing the weight of the ventral
prostate, seminal vesicles, and levator ani, more so than nandro-
lone albeit less so than trestolone or testosterone (Segaloff,
1963).
Methoxygonadiene
In the 1960s and 1970s organic chemist Herchel Smith and
colleagues filed a series of patents leading to the development of
some of the first synthetic oral contraceptives. One of these
early experimental compounds was methoxygonadiene (18-
methyl-19-nortestosterone) (Hughes & Smith, 1976). This com-
pound was identified by our systematic search as a labeled
ingredient in ten products with the chemical name 13b-ethyl- 3-methoxy-gona-2,5(10)-dien-17-one. Related to the levonorge-
strel family of progestins, methoxygonadiene is a potent
anabolic by injection with an anabolic : androgenic ratio of
approximately 54 : 27 vs. testosterone propionate and 90 : 625
vs. 19-nortestosterone (Edgren et al., 1966). However, no data
exist regarding the oral activity of methoxygonadiene in
humans.
Methylepitiostanol
Commonly known as ‘epistane’, this compound is the 17-
alpha-alkylated version of the known AAS epitiostanol (Fig. 1),
an androgen developed in Japan for the treatment of breast can-
cer (Konishi et al., 1988). Regarded as a steroidal antiestrogen as
well as an androgen (Konishi et al., 1988), epitiostanol inhibits
the hypothalamic-pituitary-gonadal (HPG) axis (Kurachi et al.,
1975) and thus has the potential to cause ASIH (Rahnema et al.,
2014). As a 17-alpha-alykylated androgen, there is a potential for
hepatotoxicity (Kazlauskas, 2010). Methylepithiostanol has been
chemically detected in nutritional supplements and it is sus-
pected that methlyepithiostanol may degrade into the controlled
AAS desoxymethyltestosterone (Madol) while in some product
containers (Okano et al., 2009). We identified over 30 currently
sold products listing methylepitiostanol (2a,3a-epithio-17a- methyl-5a-androstan-17b-ol) as an ingredient on their product label.
152 Andrology, 2015, 3, 150–155 © 2015 American Society of Andrology and European Academy of Andrology
C. D. Rahnema, L. E. Crosnoe and E. D. Kim ANDROLOGY
Methylstenbolone
Commonly known as ‘Ultradrol’, this compound appears to be
a popular new generation designer steroid and was recently
detected in a nutritional supplement (Cavalcanti et al., 2013).
Methylstenbolone is the 17-alpha alkylated oral version of the
controlled AAS stenbolone (Cavalcanti et al., 2013). Early animal
studies report oral methylstenbolone to be 660% as myotrophic
and 124% as androgenic as orally administered methyltestoster-
one (Nutting et al., 1966). Methylstenebolone has never been
studied for medical use, however, as an androgen with activity at
the HPG axis, it has the potential to cause ASIH and infertility.
Our Internet search identified at least 20 distinct, legally sold
products listing methylstenbolone (2,17a-dimethyl-17b-
hydroxy-5a-androst-1-en-3-one) on their product label.
DISCUSSION
Chemical tricks to evade regulation
Most designer steroids are orally formulated with varying
degrees of bioavailability. Some compounds are 17-alpha alkyl-
ated to improve the oral bioavailability of injectable pharma-
ceutical androgens, but this modification increases the toxicity
of the androgen (Kazlauskas, 2010). The designer steroid meth-
asteron (Superol) is an example of the hepatotoxicity associated
with the consumption of 17-alpha alkylated steroids. This oral
AAS, also known as methyldrostanolone, was sold over-the-
counter until 2012 and is a methylated (17-alpha alkylated) ver-
sion of the injectable steroid drostanolone (Masteron). Con-
sumption of methasteron as a dietary supplement for
bodybuilding has been reported to cause severe hepatotoxicity,
cholestasis, and acute renal failure (Shah et al., 2008; Nasr &
Ahmad, 2009; Singh et al., 2009). Chemists may employ meth-
ods to deliver potent androgens without technically selling con-
trolled substances by using pro-drugs that are unclassified
compounds in the bottle, but in vivo are metabolized to Sche-
dule III Controlled AAS (Van Thuyne et al., 2006; Lootens et al.,
2011). For example, compounds such as boldione (banned in
2010) and prostanozolol (banned in 2012) were designed as oral
pro-drugs to boldenone (Equipoise) and stanozolol (Winstrol),
respectively (Baume et al., 2006; Geyer et al., 2008; Kazlauskas,
2010).
Complications of designer steroid use
About 30% of classic AAS users develop dependence, and the
ease of availability of designer steroids could potentially contrib-
ute to a dependence disorder (Kanayama et al., 2001, 2009).
Many designer steroids or their closely related parent com-
pounds have been studied at some point for therapeutic or
research purposes. As exogenous androgens, designer steroids
have the potential to cause reversible adverse effects such as
hypertension, secondary hypogonadism, infertility, as well as
polycythemia and adverse shifts in lipoprotein subfractions. Evi-
dence exists that some designer steroid compounds may cause
more permanent adverse effects including hepatotoxicity, car-
diotoxicity, and ischemic stroke (Bagatell & Bremner, 1996; Rah-
nema et al., 2014; Shamloul et al., 2014). The 17-alpha alkylated
compounds, which are designed to increase oral bioavailability,
may be significantly hepatotoxic (Shah et al., 2008; Nasr & Ah-
mad, 2009; Singh et al., 2009). In our experience, some patients
have reported the use of dietary supplement products branded
as ‘liver protectors’, believing that these products mitigate the
hepatotoxicity of the 17-alpha alkylated compounds. These ‘liver
protectors’ typically contain N-acetylcysteine, milk thistle
extract, and other herbs, none of which have been demonstrated
to have any protective effect against oral androgen induced
hepatotoxicity.
Regulatory obstacles
Most designer AAS are analogues of compounds initially
developed in the 1960s – early generation synthetic androgens
abandoned in the pipeline for better alternatives. Permitting the
sale of over-the-counter synthetic androgens was likely not the
Figure 1 Structural similarities between known androgens and several designer steroids currently available over-the-counter.
© 2015 American Society of Andrology and European Academy of Andrology Andrology, 2015, 3, 150–155 153
DESIGNER STEROIDS IN DIETARY SUPPLEMENTS ANDROLOGY
intent of the Dietary Supplement Health and Education Act of
1994, but because these experimental compounds were dis-
carded early in development, many slipped under the regulatory
radar and were not explicitly named in the Anabolic Steroid
Control Act of 1990. As such, they remained as uncontrolled
substances (DEA rules, 2009). Sources within the sports supple-
ment industry informed us that these products are typically
manufactured and sold by smaller scale companies that often
disband or change their names when they encounter resistance
from regulatory agencies. However, the recent detection of AAS
in contaminated vitamin products (Press Announcements, n.d.)
suggests the possibility that companies selling non-sports die-
tary supplements may be affiliated with or may share some
manufacturing equipment with these designer steroid compa-
nies. Increased media coverage has improved public awareness
of AAS in dietary supplements and the FDA has directed warn-
ing letters at the manufacturers of some of these products (FDA
Warns, n.d.).
Currently, it is economically and technically difficult to classify
newer generation designer steroids as DEA Schedule III con-
trolled AAS. The World Anti-Doping Agency prohibits athletes
from using any known AAS as well as any unknown related com-
pound (World Anti-Doping Program, 2013). However, to become
a DEA Schedule III controlled substance, a designer steroid must
undergo multiple bioassays confirming biological activity at the
AR regardless of structural similarity to known androgens. The
Designer Anabolic Steroid Control act was introduced to the
United States Senate in 2012, and proposed preemptive schedul-
ing of all potential anabolic steroids and related compounds,
however, this bill was not enacted by the legislature (FDA Law
Blog, n.d.). The current regulatory system favors the designer
steroid chemist – as fast as the DEA adds substances to the con-
trolled substances list, new compounds emerge in the market-
place to replace the previous generation (Fig. 2). Adding further
to this complex regulatory issue, many products may be contam-
inated with a variety of unlabeled ingredients (Van Thuyne et al.,
2006; Lootens et al., 2011). Multiple studies have exposed ‘nutra-
ceuticals’ containing AAS not included on their product label
(Baume et al., 2006; Van Thuyne et al., 2006; Lootens et al.,
2011).
CONCLUSION Over the past decade, potent oral AAS have become more
accessible to the public than ever before. The anabolic steroid
subculture, something that had been clandestine and typically
limited to elite athletes and hardcore bodybuilders for over
30 years (Rahnema et al., 2014), is now readily available over-
the-counter. It is paramount for physicians to understand the
widespread availability of these potentially harmful substances
when evaluating patients for a variety of conditions from hypog-
onadism and infertility to acute hepatotoxicity. It should be
noted that adverse effects reported from designer steroid use do
not necessarily occur with clinical use of medical testosterone
owing to differences such as route of administration, standard-
ized dosing, and physician supervision. Most physicians are
unfamiliar with specific androgens that may be available in die-
tary supplements, and we have highlighted six of the most popu-
lar, currently available, and legally sold compounds. Further
research is needed to accurately estimate the prevalence of use
of designer steroids, but their persistent availability over-the-
counter for more than 10 years suggests the potential for signifi-
cant exposure (Kanayama et al., 2001). Patients should be
advised against the use of dietary supplements known or sus-
pected to contain designer steroids owing to reported adverse
effects, theoretical effects of exogenous synthetic androgens, and
an inability to accurately determine product contents, doses, and
purity. Determining whether specific products contain AAS is
difficult without chemical analysis (Geyer et al., 2008), especially
as there is no guarantee of label accuracy and the chemical
names listed on product labels often do not follow modern con-
ventional nomenclature. Owing to such a high prevalence of
intentional and accidental contamination of bodybuilding and
sports supplements reaching the consumer the question arises if
the legality of labeled ingredients even matters (Cohen, 2012),
prompting a broader concern with good manufacturing practice
(GMP) and the FDA regulation of dietary supplements in general.
DISCLOSURES The authors declare no conflict of interests.
AUTHOR CONTRIBUTIONS All authors contributed to writing and preparation of the
manuscript.
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