Dietary Supplements

Dietary SupplementsT H I R D E D I T I O N

Pamela Mason

BSc, MSc, PhD, MRPharmSPharmacist and Registered Nutritionist Writer and ConsultantGrosmont, Monmouthshire, UK

London Chicago

Published by the Pharmaceutical PressAn imprint of RPS Publishing

1 Lambeth High Street, London SE1 7JN, UK100 South Atkinson Road, Suite 200, Grayslake, IL 600307820, USA

c Pharmaceutical Press 2007

is a trade mark of RPS Publishing

RPS Publishing is the publishing organisation of the RoyalPharmaceutical Society of Great Britain

First edition published by Blackwell Science Ltd 1995Reprinted 1998Second edition 2001Third edition 2007

Typeset by Techbooks, New Delhi, IndiaPrinted in Great Britain by Cromwell Press, Trowbridge, Wiltshire

ISBN 978 0 85369 653 7

All rights reserved. No part of this publication may be reproduced,stored in a retrieval system, or transmitted in any form or by anymeans, without the prior written permission of the copyright holder.The publisher makes no representation, express or implied, with

regard to the accuracy of the information contained in this book andcannot accept any legal responsibility or liability for any errors oromissions that may be made.The right of Pamela Mason to be identified as the author of this

work has been asserted by her in accordance with the Copyright,Designs and Patents Act, 1988

A catalogue record for this book is available from the British Library

Contents

Preface viiAbout the author viiiIntroduction ixHow to use this book xviiiAbbreviations xxii

Aloe vera 1Alpha-lipoic acid 4Antioxidants 8Bee pollen 19Betaine 21Biotin 23Boron 25Branched-chain amino acids 28Brewers yeast 31Bromelain 33Calcium 36Carnitine 47Carotenoids 51Chitosan 61Chlorella 63Choline 65Chondroitin 68Chromium 71Coenzyme Q 76Conjugated linoleic acid 81Copper 85Creatine 89Dehydroepiandrosterone 94

Evening primrose oil 99Fish oils 103Flavonoids 118Flaxseed oil 124Fluoride 127Folic acid 129Gamma-oryzanol 139Garlic 141Ginkgo biloba 146Ginseng 152Glucosamine 159Grape seed extract 166Green-lipped mussel 169Green tea extract 171Guarana 176Iodine 177Iron 180Isoflavones 184Kelp 195Lecithin 196Magnesium 199Manganese 206Melatonin 208

v

vi Contents

Methylsulfonylmethane 215Molybdenum 217N-acetyl cysteine 219Niacin 223Nickel 227Octacosanol 229Pangamic acid 235Pantothenic acid 236Para-amino benzoic acid 239Phosphatidylserine 240Phytosterols 243Potassium 248Probiotics and prebiotics 251Psyllium 263Pycnogenol 268Quercetin 272Resveratrol 276Riboflavin 279Royal jelly 283S-adenosyl methionine 285Selenium 288Shark cartilage 294Silicon 296Spirulina 298

Superoxide dismutase 300Thiamine 301Tin 307Vanadium 309Vitamin A 312Vitamin B6 318Vitamin B12 324Vitamin C 330Vitamin D 339Vitamin E 346Vitamin K 355Zinc 359

Appendix 1Guidance on safe upper levels ofvitamins and minerals 366

Appendix 2Drug and supplementinteractions 367

Appendix 3Additional resources 370

Index 373

Preface

SINCE THE SECOND EDITON of this book waspublished five years ago, the UK and worldwidemarket for food supplements has continued togrow. Vitamins and minerals in multiple-ingredient products and as single ingredients remain very popular. Indeed, multivitamins andminerals have the largest share of the market inmost countries.

However, since the last edition, there hasbeen an enormous growth in interest in othersupplements, such as carotenoids, glucosamine,isoflavones, omega-3 fatty acids and probiotics,substances that were hardly known to thegeneral public until very recently. Technologicaladvances are increasingly making it possibleto include such ingredients in both dietarysupplements and foods, hence the blurring ofboundaries between supplements, functionalfoods and the nutraceutical ingredients that gointo them. As the range of substances identifiedin foods, and knowledge of their potentialbenefits in disease, continues to grow, it is likelythatmanymore such substances will be includedin food supplements in the future.

The amount of information about food sup-plements has grown exponentially during thelast few years, most of it appearing on theInternet and fully accessible to the public. Addedto which is the huge variety of food supplementson the shelves of pharmacies, health food shops,supermarkets and on the Internet. Finding anevidence-based path through the maze of infor-mation and products is an enormous challengefor the health professional, and it is veryconfusing for the potential buyer who wants toknow what really works.

Few health professionals, including pharma-cists, nurses, doctors or dieticians, have anin-depth knowledge of dietary supplements, yetthe public expects them to be able to answer

questions on these products. Although there isan abundance of spurious information, thereis, alongside this, a growing evidence base fordietary supplements. A large number of peer-reviewed, high-quality trials, systematic reviewsand meta-analyses have been published sincethe second edition of this book, offering healthprofessionals a better evidence base from whichto offer information to the public.

There are still, of course, many uncertainties,and the inevitable more research needed willcontinue to apply to many dietary supplementsfor some time to come. However, this shouldnot prevent health professionals from givingevidence-based information where it exists andbeing honest enough to say research has not yetprovided the answers where appropriate.

So, what has changed in the third edition ofDietary Supplements? The answer to this liesmainly in the depth of information providedin the monographs, which has arisen entirelybecause of the growth in the research base.Ten new monographs have also been added.Another significant change is the inclusion ofmaximum safe upper levels for vitamins andminerals, which have been published in theUK since the second edition. The regulatoryframework for dietary supplements has alsochanged in the UK, in that the European UnionFood Supplements Directive has now come intoforce. Although this has meant limited change tothe book, the labelling and marketing of supple-ments is likely to change in the near future.

The easy-to-use encyclopaedic format con-tinues to be retained and it is my intentionthat this book is primarily a reference source,which I hope will continue to be useful to manycolleagues around the world.

Pamela MasonJanuary 2007

vii

About the author

PAMELA MASON is a pharmacist and registerednutritionist working as a writer and consultantbased in Grosmont, Monmouthshire. She quali-fied as a pharmacist at Manchester Universityand worked as a community pharmacist forseveral years before studying at Kings CollegeLondon, where she completed an MSc and PhDin nutrition. Her interest in food supplementsbegan as a result of her studies in nutrition

and her experience in community pharmacy,where she was often asked questions aboutthese products. She is the author of threeother books, several open learning programmesand over 300 articles. She teaches nutrition topharmacists at both undergraduate and post-graduate level and gives conference presenta-tions about supplements both in the UK andabroad.

viii

Introduction

There is now considerable interest in dietarysupplements, and increasing numbers of peopleare using them. In the National Diet and Nutri-tion Survey of British adults aged 1964 years,40%were taking supplements.1 In the UK, salesof dietary supplements in 2005 were approx-imately 326 million in bricks and mortarshops (excluding health food shops).2 Sales ofsome of the different types of supplements (2005figures) are shown in Table 1.

Table 1 Sales of different types of supplementsin the UK (2005)

Type of supplement Sales( million)

Fish oils 116Multivitamins 72Single vitamins 35Evening primrose oil and other

GLA products13

Garlic 7Other 83Total 326

GLA = gamma-linolenic acid.

Individuals buy supplements for many differentreasons, which may include the following:

As an insurance policy, to supplement whatan individual may consider to be a poor diet(e.g. no time or inclination to eat regularmeals).

To improve overall health and fitness. To prolong vitality and delay the onset of

age-associated problems.

As a tonic or pick-me-up when feeling run-down or after illness.

For symptoms of stress. Recommended by an alternative health prac-

titioner or health professional. Pregnancy. Slimming. Smoking. To improve performance and body-building

in sports and athletics. To prevent or treat various signs and symp-

toms (e.g. colds, cardiovascular disease, can-cer, poor sight, skin problems, arthritis,premenstrual syndrome, etc.).

While there is a great deal of information aboutthese substances increasingly so on the Internet not all of it is reliable. Indeed, there areprobably few areas associated with health carewhere such confusion exists. This confusionextends to health professionals as well as thegeneral public. Because dietary supplements arenot considered to be drugs, pharmacists areoften unfamiliar with them and, because theyare not foods (in the sense of being part ofa normal diet), dieticians are understandablywary of recommending them. Doctors typicallyreceive little nutritional education and may nothave the knowledge or the time to give informedadvice.

In addition, supplements are a topic aboutwhich there is a great deal of disagreementeven between nutrition experts. Some say theyare largely unnecessary because a balanced dietprovides all the required vitamins and minerals,others say that supplements make a worthwhilecontribution to a healthy diet, while increas-ingly, some experts say that optimal health

ix

x Introduction

cannot easily be achieved in some areas withoutthem.

Given the growth in sales of dietary supple-ments, it is appropriate to ask what evidencethere is that they work. Are there rigoroustrials to show that these products work? Un-til the early 1990s, there were relatively fewwell-conducted trials involving vitamins andminerals, and fewer still on substances such asgarlic, fish oils, ginseng, and so on. Evidencewas largely limited to anecdotal reports andsingle case studies. The argument often usedto be made that controlled trials could notbe conducted with supplements, because theyoften contain a range of natural ingredientswhose effects are difficult to separate. However,such arguments are often misguided, and anincreasing body of evidence is now emergingfrom double-blind randomised controlled trials,and also from systematic reviews and meta-analyses. Some of these suggest that some sup-plements (e.g. folic acid, fish oils) are effectivein some groups of the population in certaincircumstances. However, for other supplements(e.g. royal jelly), there is little evidence ofbenefit.

What are dietary supplements?

DefinitionVarious definitions for dietary supplements existworldwide. In the UK, the definition developedby the Proprietary Association of Great Britain(PAGB), British Herbal Manufacturers Associ-ation (BHMA) and the Health Food Manufac-turers Association (HFMA) is that they are:

foods in unit dosage form, e.g. tablets, capsulesand elixirs, taken to supplement the diet. Most areproducts containing nutrients normally present infoods which are used by the body to develop cells,bone, muscle etc, to replace co-enzymes depleted byinfection and illness, and generally to maintain goodhealth.

In addition to vitamins and minerals, this defi-nition also covers ingredients such as garlic, fishoils, evening primrose oil and ginseng, whichcan be taken to supplement dietary intake orfor their suggested health benefits.

For the purposes of the European Union (EU)Directive on food supplements the term foodsupplements means:

foodstuffs the purpose of which is to supplementthe normal diet and which are concentrated sourcesof nutrients or other substances with a nutritionalor physiological effect, alone or in combination,marketed in dose form, namely forms such ascapsules, pastilles, tablets, pills and other similarforms, sachets of powder, ampoules of liquids, dropdispensing bottles, and other similar forms of liquidsand powders designed to be taken in measured smallunit quantities.

In the USA, the Dietary Supplement HealthEducation Act (DSHEA) 1994 defines a dietarysupplement as:

a product (other than tobacco) that is intended tosupplement the diet which bears or contains one ormore of the following dietary ingredients: a vitamin,a mineral, a herb or other botanical, an amino acid,a dietary substance for use by man to supplementthe diet by increasing the total daily intake, ora concentrate, metabolite, constituent, extract orcombinations of these ingredients. It is intended foringestion in pill, capsule, tablet or liquid form, is notrepresented for use as a conventional food or as thesole item of a meal or diet and is labelled as a dietarysupplement.

This definition, like that in the UK, also expandsthe meaning of dietary supplements beyondessential nutrients, to include such substancesas ginseng, garlic, psyllium, other plant ingredi-ents, enzymes, fish oils and mixtures of these.The EU definition does not currently includesubstances apart from vitamins and minerals,but other substances may be included in thefuture.

One of the key points in these definitions isthat dietary supplements are products consumedin unit quantities in addition to normal food in-take. This differentiates supplements from otherfoods, such as fortified foods and functionalfoods, to which nutrients are added. However,a major difference in the US definition is theexplicit inclusion of herbs or other botanicalsin the list of dietary ingredients.

In the UK, herbal products are currentlymarketed under a variety of arrangements either as fully licensed medicines, under the

Introduction xi

Traditional Herbal Medicines Product (THMP)Directive, medicines exempt from licensingunder section 12 of the 1968 Medicines Act, oras cosmetics or foods, so they do not fall entirelyin the food supplements category.

Enteral feeds (e.g. Complan and Ensure)and slimming aids are also classified as dietarysupplements by nutritionists and dieticians, butfor the purposes of this book, these productswill be ignored.

Classification

Dietary supplements fall into several categoriesin relation to ingredients. These are:

1 Vitamins and minerals Multivitamins and minerals. These

normally contain around 100% of theRecommended Daily Allowance (RDA)for vitamins, with varying amounts ofminerals and trace elements.

Single vitamins and minerals. These maycontain very large amounts, and whenlevels exceed ten times the RDA, they areoften termed megadoses.

Combinations of vitamins and minerals.These may be marketed for specific popu-lation groups, e.g. athletes, children,pregnant women, slimmers, teenagers,vegetarians, etc.

Combinations of vitamins and mineralswith other substances, such as eveningprimrose oil and ginseng.

2 Unofficial vitamins and minerals, for whicha requirement and a deficiency disorder inhumans has not, so far, been recognised, e.g.boron, choline, inositol, silicon.

3 Natural oils containing fatty acids for whichthere is some evidence of beneficial effects,e.g. evening primrose oil and fish oils.

4 Natural substances containing herbal in-gredients with recognised pharmacologicalactions but whose composition and effectshave not been fully defined, e.g. echinacea,garlic, ginkgo biloba and ginseng.

5 Natural substances whose composition andeffects are not well defined but which aremarketed for their health giving properties,e.g. chlorella, royal jelly and spirulina.

6 Enzymes with known physiological effects,but of doubtful efficacy when taken bymouth, e.g. superoxide dismutase.

7 Amino acids or amino acid derivatives, e.g.N-acetyl cysteine, S-adenosyl methionine.

Uses of supplements

There are two main approaches to the use ofsupplements. They can be used to: treat or prevent nutritional deficiency; and to reduce the risk of non-deficiency disease and

promote optimal health.

When vitamins were first discovered during theearly years of the 20th century, their only indi-cation was for the prevention and treatment ofdeficiency disease such as scurvy, beri-beri, pel-lagra, etc. This led to the development of dietarystandards such as RDAs and, more recently, tothe Dietary Reference Values (DRVs).3 Thesevalues were based on amounts of nutrientsrequired to prevent deficiency, and even thoughsubject to various limitations, they are still thebest measure of dietary adequacy.

After the Second World War, it was thoughtthat nutritional deficiencies had largely disap-peared and scientific interest in vitamins andminerals waned. However, with the increase invarious chronic diseases such as cardiovasculardisease and cancer, vitamins became an area ofgrowing interest again, and it was suggested thatsupplements might help to reduce the risk ofsuch disease. At the start of the 21st century,there is growing concern among the public toimprove quality of life and supplements areincreasingly used to promote so-called optimumhealth.

Despite the idea that nutritional deficiencyhad disappeared, recent UK national diet andnutrition surveys have shown that there isno room for complacency. Although averagedietary intakes may appear adequate, somegroups of the surveyed populations are clearlyat risk of marginal deficiencies.

The National Diet and Nutrition Survey inpre-school children4 showed that 8% of the sur-veyed youngsters aged 11/2 to 41/2 were anaemic,a further 12% were mildly iron-deficient and15% had a poor intake of zinc. Vitamin A

xii Introduction

deficiency was present in 8%, vitamin B2 defi-ciency in 23% and vitamin C deficiency in 3%.

A similar nutritional survey of older children5

again showed average nutrient intakes werelargely fine, but anaemia was present in 1.5% ofboys and 5% of girls, with respective totals of13% and 27% having low serum ferritin anindication of iron deficiency. In addition, zincwas found to be low in the diets of 10% of boysand 20% of girls. Also of concern were calciumintakes, which were below the Lower ReferenceNutrient Intake (LRNI) in 6% of boys and 12%of girls. For magnesium, the respective figureswere 12% and 27% and for vitamin A, 10%and 11%. Furthermore, some of the surveyedyoungsters also appeared to have poor statusfor vitamin B12, vitamin C, vitamin D, folate,riboflavin and thiamine.

The National Diet and Nutrition Survey ofpeople aged 65 years and over6 showed thatthere were nutritional problems in someindividuals. Up to 38% of the survey populationwas deficient in vitamin D, up to 38% weredeficient in vitamin C, up to 18% in folate, upto 15% in vitamin B12 and up to 30% in iron.Of the free-living individuals, 11% of men and9% of women were anaemic.

The most recent National Diet and Nu-trition Survey involving British adults aged1964 years1 found that mean intakes of allnutrients in men are 100% of the RNI. Forwomen, mean intakes of iron, magnesium andcopper were below the RNI. However, meanintakes fail to show the proportion of peoplethat do not achieve the RNI. For example,for women, mean magnesium intake was 85%of the RNI, but 74% in this survey failed toachieve the RNI. Mean intakes also fail to showthat intakes in some age groups are particularlypoor. For example, iron intake inwomen overallwas 82% of the RNI while in 1924-year-oldwomen it was 60% of the RNI. Overall, 91%of women failed to achieve the RNI for ironwhile 41% of women aged 19 to 34 had intakesof iron below the LRNI. For magnesium andcopper, intake overall in women is 85% and86% of the RNI, respectively, but for womenaged 1924 years it was 76% of the RNI forboth minerals. Indeed, men and women aged1924 had significantly poorer intakes of all

vitamins and minerals than those aged 5064,with mineral and trace element intakes in thewomen aged 1924 years a particular cause forconcern.

Although good diet is the most appropriateroute to achieving improved nutrition in thesepopulation groups, there is no evidence tosuggest that risk of deficiency is a thing of thepast.

Various groups of the population could beat risk of nutrient deficiency and could benefitfrom supplementation. These include: People in a particular demographic category,

e.g. infants and children, adolescents, womenduring pregnancy and lactation and through-out the reproductive period, the elderly andethnic minorities.

People whose nutritional status may be com-promised by lifestyle (enforced or voluntary),e.g. smokers, alcoholics, drug addicts, slim-mers, strict vegetarians (i.e. vegans), foodfaddists, individuals on low incomes andathletes.

People whose nutritional status may becompromised by surgery and/or disease, e.g.malabsorption syndromes, hepato-biliarydisorders, severe burns and wounds andinborn errors of metabolism.

People whose nutritional status may be com-promised by long-term drug administration(e.g. anticonvulsants may increase the re-quirement for vitamin D).

Increasingly, people are taking supplements forreasons other than prevention of deficiency andat amounts higher than the RDA. Moreover,evidence is increasing that, at least for somenutrients (e.g. folic acid, vitamin D), there maybe benefits in achieving higher intakes than theRDA.

However, while there is agreement about thebeneficial effects of nutrients in the preventionof deficiency disease and the amounts requiredto achieve such effects, there is controversyabout amounts required for reduction in risk ofchronic disease and so-called optimum health.Some would argue that higher amounts arerequired and that basing requirements for nu-trients only on the prevention of deficiencydisease is inadequate. But what other end points

Introduction xiii

should be used is open to debate; longevity,increased resistance to cancer and coronaryheart disease, improved athletic performance,etc. Higher levels of intake cannot always easilybe obtained from diet alone, and supplemen-tation is required. However, excessive intakeof some nutrients can lead to toxicity, and itis with this in mind that several committeesworldwide have established safe upper limits forsupplement intake.

Legal status

The UKIn the UK, the majority of dietary supplementsare classified legally as foods, and sold underfood law. There are just a few exceptions (e.g.Abidec, Pregaday, Epogam, Efamast, Maxepaand some generic vitamin and mineral prepa-rations), which are licensed medicines. Unlikemedicines, most supplements are not, therefore,subject to the controls of the Medicines Act(1968). Because supplements classed as foods donot require product licences, they do not haveto go through such rigorous clinical trials, andare therefore much cheaper to put on the marketthan medicines.

Dietary supplements are not controlled byquite the same strict conditions of dosage,labelling, purity criteria and levels of ingredientsas medicines. The retail supply of those vitaminsthat have product licences (i.e. medicines) aresubject to limitations which depend on theirstrength and maximum daily dose, as shown inTable 2.

Dietary supplements containing levels of vi-tamins in excess of those in prescription-onlymedicines are available to the public. However,in recognition of the fact that consumers areincreasingly using high-dose products, the FoodStandards Agency (FSA) Expert Group on Vi-tamins and Minerals (EVM) has published safelevels of intake for vitamins and minerals.6 (SeeAppendix 3.)

Claims that can be made for supplementsare currently regulated by food law, but willalso be regulated at European level, possiblyfrom 2007 (see below). Advertising of dietarysupplements is regulated by various advertisingcodes for both the broadcast media (TV and

Table 2 Limitations on the sale or supply oflicensed medicines containing certain vitamins

Vitamin Legal status

Vitamin A Up to 2250g (7500 units) GSLOver 2250g (7500 units) POM

Vitamin D Up to 10g (400 units) GSLOver 10g (400 units) P

Cyanocobalamin Up to 10g GSLOver 10g P

Folic acid Up to 200g GSL200500g POver 500g POM

GSL = subject to control under the Medicines (General Sales List) Order,1977.

POM = subject to control under the Medicines (Prescriptions Only)Order, 1977.

P = Pharmacy only products.

radio advertising standards codes) and the non-broadcast media. These codes are policed bythe Advertising Standards Authority (ASA), anindependent body set up by the advertisingindustry.

EuropeAcross the countries of the European Union(EU), the diversity of regulation for food supple-ments has been wide, with several approachesto regulating vitamin and mineral supplementssuch that one product of the same strength (e.g.vitaminC 1000mg) can be a food in one countrybut a medicine in another.

However, the regulatory environment inEurope is changing rapidly. The European Com-mission has adopted Directive 2002/46/EC,which lays down specific rules for vitaminsand minerals used as ingredients for foodsupplements (see http://europa.eu.int). All foodsupplements containing vitamins or mineralsas well as other ingredients should conformto the specific rules for vitamins and mineralslaid down in the Directive. The Directive wasimplemented in the UK in August 2005.

The Directive includes a positive list ofvitamins and minerals permitted in food supple-ments (Annex 1), and a second list identifying

xiv Introduction

the chemical substances that can be used intheir manufacture (Annex 2). Only vitamins andminerals in the forms listed may be used inthemanufacture of food supplements. However,until 31 December 2009, Member States mayallow the use of vitamins and minerals not listedin Annex 1 or in forms not listed in Annex 2provided that: the substance was an ingredient in a food

supplement marketed in the EC before 12July 2002;

the European Food Safety Authority (EFSA)has not given an unfavourable opinion inrespect of the use of the substance, or itsuse in that form, in the manufacture offood supplements, on the basis of a dossiersupporting use of the substance that had to besubmitted to the Commission by theMemberState not later than 12 July 2005.

Dossiers have been submitted for around 300substances (see http://europa.eu.int). These areprincipally salts of minerals and trace elements,such as salts of boron, calcium, chromium,cobalt, copper, iron, magnesium, manganese,molybdenum, potassium, selenium, vanadiumand zinc. However, some vitamin ingredientsalso appear on the list of submitted dossiers.

Specific rules concerning nutrients, otherthan vitamins and minerals, or other substanceswith a nutritional or physiological effect usedas ingredients of food supplements (e.g. fattyacids, amino acids, fibre, and herbal ingredients)will be laid down at a later stage. A proposalon the advisability of establishing specific ruleson other nutritional substances is expected bymid-2007.

The Directive will also establish maximumpermitted levels of vitamins and minerals forfood supplements. These will take into accountupper safe levels of vitamins and mineralsestablished by scientific risk assessment basedon generally accepted scientific data, intakeof vitamins and minerals from other dietarysources and the varying degrees of sensitivityof different consumer groups. Figures for upperlevels of vitamins and minerals unlikely to haveadverse effects have been published by officialgroups such as the EU Scientific Committeeon Food (SCF), the UK Expert Vitamin and

Mineral Group and the US National Academyof Sciences (see Appendix 3).

The Directive also pays attention to adver-tising, presentation, purity criteria and labellingof content and dosage. Labels on dietary supple-ments express their nutrient content in terms ofRDAs. EU RDAs are based on the requirementsof men and are said to apply to averageadults. They take no account of differencesin nutritional requirements according to age,sex and other factors, and are therefore simpleapproximations used for labels only.

Labelling should not imply that a variedand adequate diet cannot provide sufficientquantities of nutrients. In addition, medicinalclaims relating to the prevention, treatmentor cure of disease in the labelling, advertis-ing or promotion of food supplements areprohibited.

Health claims will be regulated by the pro-posed Health and Nutrition Claims Regulation,which is expected to be adopted before the endof 2006 and be applied six months later, by themiddle of 2007. Health claims such as calciumis good for your bones may be used on a labelso long as they are proven to apply to thefood supplement in question. Within 3 years ofthe Regulation entering force, the Commissionis to draw up a list of well-established healthclaims to be used on labels, and Member Stateswill be asked to submit a list of claims alreadyapproved at national level. New health claimssubmitted for the list after this period or anydisease risk reduction claims such as calciumhelps reduce the risk of osteoporosis or Xreduces cholesterol, will have to be assessedby the European Food Safety Agency (EFSA)and be approved by the Commission. In theUK, the work of the Joint Health Claims Ini-tiative (see http://www.jhci.org.uk) has helpedto inform health claims regulation at Europeanlevel.

This EC Regulation will also apply totrademarks. Within 15 years of the Regulationentering into force, existing brand namessuggesting health benefits (such as promises ofweight loss) that do not meet the requirementsof the Regulation must be phased out andremoved from the market. However, certaingeneric descriptors such as digestives may

Introduction xv

apply for derogation from this rule (seehttp://ec.europa.eu/comm./food/labellingnutri-tion/claims/index en.htm).

The USAIn the USA, the Food and Drug Administration(FDA) regulates dietary supplements accordingto the Dietary Supplement Health and Edu-cation Act (DSHEA) 1994. Under this law,supplements are regulated in a similar mannerto food products, while prohibiting their regu-lation as medicines or food additives. This Actincludes a framework for safety, guidelines forthird-party literature provided at the point ofsale, guidance on good manufacturing practice(GMP) and labelling standards. Under DSHEA,manufacturers are responsible for marketingsafe and properly labelled products, but theFDA bears the burden of proving that a productis unsafe or improperly labelled. However, theFDA has insufficient resources for doing this,and there is concern that not all supplementsare marketed according to best standards ofpractice.

DSHEA regulates the labelling of supple-ments and the claims that can be made. Thisincludes permissible statements describing thelink between a nutrient and a deficiency orbetween a nutrient and its effect on the bodysstructure or function, or its effect on well-being. Examples include promotes relaxationor builds strong bones. But to make theseclaims, the supplement label must also carrythe disclaimer: This statement has not beenvalidated by the Food andDrug Administration.This product is not intended to diagnose, treat,cure or prevent any disease.

Under the US Nutrition Labelling and Ed-ucation Act of 1990, a number of specifichealth claims are also permitted. These describethe link between a specific nutrient and thereduction in risk of a particular disease orcondition and they are based on significantscientific agreement. Claims applicable to di-etary supplements include those in relation tocalcium and osteoporosis, folic acid and neuraltube defects, soluble fibre (from oat bran andpsyllium seed) and coronary heart disease andsoya and coronary heart disease.

InternationalGlobal standards for vitamin and mineral sup-plements have also been developed and adoptedat an international level by the Codex Alimen-tarius Commission. The Codex AlimentariusCommission or Codex was created by two UNorganisations (the Food and Agricultural Orga-nization and the World Health Organization)and its main purpose is to protect consumerhealth and ensure fair practice in internationaltrade in food through the development of foodstandards, codes of practice, guidelines andother recommendations.

The Codex guidelines on vitamin andmineralsupplements are voluntary and apply to sup-plements that contain vitamins and/or mineralsthat are regulated as foods. The guidelinesaddress the composition of vitamin and mineralsupplements, including the safety, purity andbioavailability of the sources of vitamins andminerals. They do not specify upper limits forvitamins and minerals in supplements, but pro-vide criteria for establishing maximum amountsof vitamins and minerals per daily portion ofsupplement consumed, as recommended by themanufacturer. The criteria specify that maxi-mum amounts should be established by scien-tific risk assessment based on generally acceptedscientific data and taking into consideration, asappropriate, the varying degrees of sensitivity ofdifferent population groups. The guidelines alsoaddress the packaging and labelling of vitaminand mineral supplements.

Law enforcement

In the UK, enforcement of food law, includinghealth claims, is the responsibility of the localauthorities trading standards officers. The localauthority associations are in turn coordinatedby LACORS (Local Authorities Co-ordinatorsof Regulatory Services). LACORS (formerly LA-COTS) is responsible for improving the qualityof trading standards and food enforcement bypromoting coordination, consistency and goodregulation.

Other EU countries have various arrange-ments for enforcing the law, while in the USA itis the responsibility of the FDA.

xvi Introduction

Patient/client counselling

The following questions may be used by healthprofessionals before making any recommenda-tions about supplement use:

1 Who is the supplement for? The individ-ual buying the product may not be theconsumer; requirements for vitamins andminerals vary according to age and sex.

2 Why do you think you need a supplement?The individual may have misconceptionsabout the need for and benefits of supple-ments that should be addressed.

3 What are your symptoms (if any) and howlong have you had them? The individualcould have a serious underlying disorderthat should be referred for appropriatediagnosis and treatment.

4 What do you eat? A simple dietary assess-ment should be undertaken to give some in-dication as to whether vitamin and mineraldeficiency is likely.

5 Is your diet restricted in any way? Slimming,vegetarianism or religious conviction couldincrease the risk of nutritional deficiency.

6 Do you take any prescription or over-the-counter medicines? This information canbe used to assess possible drugnutrientinteractions.

7 Do you take other supplements? If so, whichones? This information can be used to assesspotential overdosage of supplements whichcould be toxic.

8 Do you suffer from any chronic illness, e.g.diabetes, epilepsy, Crohns disease? Nutri-ent requirements in patients with chronicdisease may be greater than in healthyindividuals.

9 Are you pregnant or breast-feeding? Nutri-ent requirements may be increased.

10 Do you take part in sports or other regularphysical activity?

11 Do you smoke? Requirements for somevitamins (e.g. vitamin C) may be increased.

12 How much alcohol do you drink? Excessivealcohol consumption may lead to deficiencyof the B vitamins.

Guidelines for supplement use

The following guidelines may be useful inmaking recommendations: Compare labels with dietary standards (usu-

ally RDAs). In the absence of an indication for a specific

nutrient, a balanced multivitamin/mineralproduct is normally preferable to one thatcontains one or two specific nutrients.

Use a product that provides approximately100% of the RDA for as wide a range ofvitamins and minerals as possible.

Avoid preparations containing unrecognisednutrients or nutrients in minute amounts; thisincreases the cost, but not the value.

Avoid preparations that claim to be natural,organic or high potency; this increases thecost and, in the case of high-potency prod-ucts, the risk of toxicity.

Distinguish between credible claims and un-substantiated claims.

If there is uncertainty about product quality,check with the companies concerned. Askabout quality assurance. For example, isthe final product analysed to guarantee thecontents in the bottle match the label declara-tions? Are tests for disintegration, dissolutionor other tests for bioavailability conducted?

Role of the health professional

When asked about supplements, health pro-fessionals should emphasise the importanceof consuming a diet based on healthy eatingguidelines. This is a diet rich in starchy, fibrouscarbohydrates, including fruit and vegetables,and low in fat, sugar and salt. Dietary supple-ments do not convert a poor diet into a goodone.

Health professionals should be aware ofdietary standards and good food sources fornutrients. They should be able to assess anindividuals risk of nutrient deficiency and needfor further referral, by asking questions to detectcultural, physical, environmental and socialconditions which may predispose to inadequateintakes.

There is a need to be aware of the potentialfor adverse effects with supplements. Thus,

Introduction xvii

when a client or patient presents with anysymptoms, questions should be asked aboutthe use of dietary supplements. Individuals willnot always volunteer this information withoutprompting because they believe that supple-ments are natural and therefore safe.

Health professionals should make theirclients aware of the existence of badly wordedclaims and adverts and of the dangers ofsupplement misuse.

Pharmacists have a particular responsibility,simply because they sell these products. Whensupplying any supplement with perceived healthbenefits, pharmacists must be careful to avoidgiving their professional authority to a productthat may lack any health or therapeutic benefitand has risks associated with its use. In accor-dance with the Code of Ethics of the RoyalPharmaceutical Society of Great Britain, thismay involve not stocking or selling the product.Pharmacists must not give the impression thatany dietary supplement is efficacious when thereis no evidence for such efficacy.

However, providing a product is not harmfulfor a particular individual, the freedom to useit should be respected. What is important is

that consumers are able to make informed andintelligent choices about the products they buy.

References

1 Henderson L, Irving K, Gregory J (Office for Na-tional Statistics), with Bates CJ, Prentice A, ParksJ (Medical Resource Council, Human NutritionResearch), and Swan G, Farron M (Food StandardsAgency) The National Diet and Nutrition Survey:adults aged 19 to 64 years. Volume 3. Vitaminand mineral intake and urinary analysis. London:HMSO, 2003.

2 Figures from Information Resources Inc. (IRI) pro-vided by the Proprietary Association of Great Britain(PAGB).

3 Department of Health. Dietary Reference Valuesfor Food Energy and Nutrients for the UnitedKingdom. Report on Health and Social Subjects No41. London: HMSO, 1991.

4 The National Diet and Nutrition Survey: childrenaged 11/2 to 4

1/2 years. London: HMSO, 1995.5 The National Diet and Nutrition Survey: young

people aged 4 to 18 years. London: HMSO, 2000.6 The National Diet and Nutrition Survey. People

aged 65 years and over. Report of the diet andnutrition survey. London: HMSO, 1998.

7 European Commission. Scientific Committee onFood (SCF). Tolerable Upper Intake Levelsfor Vitamins and Minerals. http://ec.europa.eu/comm./food/fs/sc/scf/out80 en.htm (accessed 12November 2006).

How to use this book

This book covers 82 commonly available di-etary supplements, including vitamins, minerals,trace elements and other substances, such asgarlic, ginseng and fish oils. For ease of refer-ence, they are arranged in alphabetical orderand give information, where appropriate, underthe following standard headings.

Description

States the type of substance; e.g. a vitamin,mineral, fatty acid, amino acid, enzyme, plantextract, etc.

Nomenclature

Lists names and alternative names in currentusage.

Units

Includes alternative units and conversionfactors.

Constituents

Lists active ingredients in supplements that arenot pure vitamins or minerals (e.g. eveningprimrose oil contains gamma-linolenic acid).

Human requirements

Lists for different ages and sex (where estab-lished):

UK Dietary Reference Values and safe upperlevels;

US Recommended Dietary Allowances(RDAs) and Tolerable Upper Intake Levels(ULs);

World Health Organization (WHO) Refer-ence Nutrient Intakes;

European Union Recommended Dietary Al-lowances (RDAs).

Definitions

The UKDietary reference values (DRVs) were estab-lished in 1991 to replace recommended dailyamounts (RDAs).

EAR: Estimated Average Requirement. Anassessment of the average requirement forenergy or protein for a vitamin or mineral.About half the population will need morethan the EAR, and half less.

LRNI: Lower Reference Nutrient Intake.The amount of protein, vitamin or mineralconsidered to be sufficient for the few peoplein a group who have low needs. Most peoplewill need more than the LRNI and if peopleconsistently consume less they may be at riskof deficiency of that nutrient.

RNI: Reference Nutrient Intake. The amountof protein, vitamin or mineral sufficient foralmost every individual. This level of intakeis much higher than many people need.

Safe Intake: A term used to indicate intakeor range of intakes of a nutrient for whichthere is not enough information to estimateRNI, EAR or LRNI. It is considered to beadequate for almost everyones needs but notlarge enough to cause undesirable effects.

DRV: Dietary Reference Value. A term usedto cover LRNI, EAR, RNI and safe intake.

xviii

How to use this book xix

The USAThe US Institute of Medicine and the Food andNutrition Board have established a set of refer-ence values to replace the previous RDAs. TheDietary Reference Intakes encompass EARs,RDAs, AI (adequate intakes) and TolerableUpper Intake Levels (UIs). RDAs and AIs areset at levels that should decrease the risk ofdeveloping a nutritional deficiency disease. RDA: Recommended Dietary Allowance.

The average amount of energy or a nutrientrecommended to cover the needs of groupsof healthy people.

Safe Intake and Adequate Daily DietaryIntakes: These are given for some vitaminsand minerals where there is less informationon which to base allowances, and figures areprovided in the form of ranges.

Tolerable Upper Intake Levels: Defined bythe Food and Nutrition Board of the USNational Academy of Sciences as the highesttotal level of a nutrient (diet plus supple-ments) which could be consumed safely ona daily basis, that is unlikely to cause adversehealth effects to almost all individuals in thegeneral population. As intakes rise above theUL, the risk of adverse effects increases. TheUL describes long-term intakes, so an isolateddose above the UL need not necessarily causeadverse effects. The UL defines safety limitsand is not a recommended intake for mostpeople most of the time.

EuropeRDA: Recommended Dietary Allowance. Pro-vides sufficient for most individuals. The EURDA is used on dietary supplement labels.

The following points should be noted inrelation to dietary standards: Dietary standards are intended to assess

the diets of populations, not of individuals.Thus, both the RDA and the UK ReferenceNutrient Intake (RNI) are set at two stan-dard deviations above the average populationrequirement and are intended to cover theneeds of 95% of the population. So, if anindividual is typically consuming the RDAor the RNI for a particular nutrient, it canbe assumed that his or her diet provides

adequate amounts (or more than adequateamounts) of that nutrient to prevent defi-ciency. If intake is regularly below the RNI,it cannot necessarily be assumed that thediet is inadequate, because the person mayhave a lower requirement for that nutrient.However, if an individual is consistentlyconsuming less than the Lower ReferenceNutrient Intake (LRNI) for a nutrient, itcan be assumed that the diet is deficient inthat nutrient. Nevertheless, individuals differin the amounts of nutrients they need andthe quantities they absorb and utilise, andalthough the dietary standards are the bestfigures currently available, they were neverintended to assess the adequacy of individualdiets.

Dietary standards are estimates, which areassessed from a variety of epidemiological,biochemical and nutritional data, including: The intake of a nutrient required to pre-

vent or cure clinical signs of deficiency. The intake of a nutrient required to main-

tain balance (i.e. intake output = zero). The intake of a nutrient required to main-

tain a given blood level, tissue concentra-tion or degree of enzyme saturation.

The intake of a nutrient in the diet of ahealthy population.

Dietary standards apply only to healthypeople but not to those with disease whosenutrient needs may be very different. Re-quirements may be increased in patientswith disorders of the gastrointestinal tract,liver and kidney, and in those with inbornerrors of metabolism, cancer, severe infec-tions, wounds, burns and following surgery.Drug administration may also alter nutrientrequirements.

Dietary intake

States amounts of nutrients provided by theaverage adult diet in the UK.1

Action

Describes the role of the substance in main-taining physiological function and identifiespharmacological actions where appropriate.

xx How to use this book

Dietary sources

Lists significant food sources based on averageportion sizes. In addition, a food may bedescribed as an excellent or good source of anutrient. This does not describe any food asexcellent or good overall. It defines only theamount of the nutrient (per portion or serving)in relation to the Reference Nutrient Intake(RNI) of the nutrient for the average adult male.

Thus, an excellent source provides 30% ormore of the RNI; a good source provides 1530% of the RNI.

Where no RNI has been set for a particularnutrient, excellent and good are numericallydefined.

Metabolism

Discusses absorption, transport, distributionand excretion.

Bioavailability

Includes the effects of cooking, processing,storage methods, and substances in food whichmay alter bioavailability.

Deficiency

Lists signs and symptoms of deficiency.

Uses

Discusses potential indications for use with thelevel of evidence. Evidence for use of supple-ments is obtained from several types of studies: Epidemiological studies. These are

population-based studies and early evidencefor the potential value of a nutrient usuallycomes from epidemiological research.For example, the idea that antioxidantsupplements could reduce the risk of cancercame from studies in populations that highintake of fruit and vegetables was associatedwith a low risk of cancer.

In vitro (laboratory) studies and animalstudies. Data from these studies can be usedto support evidence, but is not enough on itsown. Although both types of study allow for

good control of variables such as nutrientsand more aggressive intervention, each suf-fers from uncertainties of extrapolating anyobserved effects to human.

Observational studies. These may beprospective and retrospective and include,in decreasing order of persuasiveness, co-hort studies, case-control studies and un-controlled studies. In prospective studies,subjects are recruited and observed prior tothe occurrence of the outcome. In retrospec-tive studies, investigators review the recordsof subjects and interview subjects after theoutcome has occurred. Retrospective stud-ies are more vulnerable to recall bias andmeasurement error but less likely to sufferfrom the subject selection bias that can occurin prospective studies. In all observationalstudies, the investigator has no control of theintervention.

Intervention studies. The investigator con-trols whether subjects receive an interven-tion or not. The randomised controlled trial(RCT) is the gold standard. Interventiontrials with supplements differ from thosefor drugs. Unlike studies with drugs, thosewith foods and nutrients may have additionalconfounders secondary to the interventionitself. For example, results from interventionstudies with antioxidant supplements (e.g.vitamins A, C and E) in the prevention ofcancer are inconsistent, even though epi-demiological studies have consistently shownthat diets high in these nutrients are asso-ciated with reduced cancer risk. This couldbe because such diets contain a range ofother substances apart from those in thetested supplements and the antioxidants aremerely acting as markers for a type ofdiet that is protective. Moreover, chronicdisease, such as cancer and coronary heartdisease, develops over many years and toinvestigate the effect of a supplement ondisease risk therefore requires a prolongedstudy period (e.g. 2030 years) as well as ahuge number of subjects, and this makes suchstudies difficult and expensive to conduct.However, without such trials, evidence forefficacy of many supplements will remainsparse.

How to use this book xxi

Systematic reviews and meta-analyses. Thesemay include RCTs only or they may alsoinclude observational studies. Decisions onthe part of reviewers to include or leave outcertain types of studies can lead to differingconclusions from the analysis.

Precautions/contraindications

Lists diseases and conditions in which the sub-stance should be avoided or used with caution.

Pregnancy and breast-feeding

Comments on safety or potential toxicity duringpregnancy and lactation.

Adverse effects

Describes the risks that may accompany exces-sive intake, and signs and symptoms of toxicity.

Interactions

Lists drugs and other nutrients that may interactwith the supplement. This includes drugs thataffect vitamin and mineral status and supple-ments that influence drug metabolism.

Dose

Gives usual recommended dosage (if estab-lished).

References

1 Henderson L, Irving K, Gregory J (Office for Na-tional Statistics), with Bates CJ, Prentice A, ParksJ (Medical Resource Council, Human NutritionResearch), and Swan G, Farron M (Food StandardsAgency) The National Diet and Nutrition Survey:adults aged 19 to 64 years. Volume 3. Vitaminand mineral intake and urinary analysis. London:HMSO, 2003.

Abbreviations

ACE angiotensin-converting enzymeADP adenosine 5-diphosphateARMD age-related macular degenerationATP adenosine triphosphateBCAAs branched-chain amino acidsBMD bone mineral densityCHD coronary heart diseaseCHF congestive heart failureCNS central nervous systemCOPD chronic obstructive pulmonary

diseaseCVD cardiovascular diseaseDNA deoxyribonucleic acidDRI Dietary Reference IntakeDRV Dietary Reference ValueEAR Estimated Average Requirement

HDL high-density lipoproteinHIV human immunodeficiency virusHRT hormone replacement therapyIBS irritable bowel syndromeLDL low-density lipoproteinNSAID non-steroidal anti-inflammatory

drugPMS premenstrual syndromePUFAs polyunsaturated fatty acidsRCT randomised controlled trialRDA Recommended Daily AllowanceRNA ribonucleic acidRNI Reference Nutrient IntakeSLE systemic lupus erythematosusVLDL very-low-density lipoprotein

xxii

Aloe vera

Description

Aloe vera is the mucilaginous substance ob-tained from the central parenchymatous tissuesof the large blade-like leaves of Aloe vera.It should not be confused with aloes, whichis obtained by evaporating water from thebitter yellow juice that is drained from theleaf.

Constituents

Aloe vera contains polysaccharides, tannins,sterols, saponins, vitamins, minerals, choles-terol, gamma-linolenic acid and arachidonicacid. Unlike aloes, aloe vera does not containanthraquinone compounds and does not there-fore exert a laxative action.

Action

Used externally, aloe vera acts as a moisturiserand reduces inflammation. Internally, it mayact as an anti-inflammatory, hypoglycaemic andhyperlipidaemic agent. It also has anti-plateletactivity.

Possible uses

TopicalTopical aloe vera has been investigated for itseffects on wound healing and psoriasis, whileoral aloe vera has been investigated in patientswith diabetes mellitus and hyperlipidaemia.

A review in 1987 concluded that topicalapplication of aloe vera gel reduces acuteinflammation, promotes wound healing, re-duces pain and exerts an antipruritic effect.1 A

further review in 19992 stated that research hadcontinued to confirm these benefits.

A double-blind, placebo-controlled study of60 people with psoriasis of mean duration8.5 years found that applying aloe vera to skinlesions three times a day for 8months led tosignificant improvement in 83% of aloe verapatients but in only 6% of those who usedplacebo.3

In rabbits, aloe vera cream was found tobe better than placebo and as effective as oralpentoxifylline in improving tissue survival afterfrostbite.4

In a study of 27 patients, aloe vera gelhealed burns faster than Vaseline gauze,5 and inrats enhanced wound healing in second-degreeburns.6

However, a recent Cochrane review identi-fied a single trial of aloe vera supplementationthat suggested delayed wound healing withaloe vera, but the reviewers concluded that theresults of the trial were not easily interpretable.7

SystemicA recent systematic review of 10 studies8

showed that oral aloe vera might be useful asan adjunct for lowering blood glucose concen-trations in diabetes and for reducing blood lipidlevels in hyperlipidaemia.

There is some evidence that the anti-inflammatory actions of aloe vera might havetherapeutic potential in inflammatory boweldisease. An in vitro study found that aloevera gel had a dose-dependent inhibitory effecton the production of reactive oxygen metabo-lites and eicosanoids in human colorectalmucosa.9

A randomised controlled study in 44 pa-tients with ulcerative colitis found that aloe

1

2 Aloe vera

vera gel 100ml four times weekly produceda clinical response more often than placebo,reducing histological disease activity. The re-searchers recommended that further evaluationof aloe vera in inflammatory bowel disease isneeded.10

ConclusionA huge number of in vitro and animal studieshave examined aloe vera over the past30 years. However, there have been fewstudies in humans, and these have beenpoorly controlled.

Topical aloe vera may be helpful in psoria-sis, but whether it is useful for wound healingis unclear. There is some albeit limited evidence that oral aloe vera may be usefulfor lowering blood glucose in diabetes,reducing blood lipids in hyperlipidaemiaand it may have therapeutic potential ininflammatory bowel disease.

Precautions/contraindications

None established, although the potential hypo-glycaemic effect means that it should be usedwith caution in patients with diabetes mellitus.Preliminary research in rats has suggested thataloe vera has a hypoglycaemic effect.11

Pregnancy and breast-feeding

No problems have been reported, but therehave not been sufficient studies to guaranteethe safety of aloe vera in pregnancy and breast-feeding.

Adverse effects

None reported apart from occasional allergicreactions. However, there are no long-termstudies investigating the safety of aloe vera.

Interactions

Aloe vera has antiplatelet activity and couldtheoretically interact with drugs with anti-platelet effects. A case study in one individual

found a potential interaction between aloe veraand sevoflurane, in which the woman lost 5 L ofblood during surgery.12

Dose

Aloe vera is available in the form of creams, gels,tablets, capsules and juice. The InternationalAloe Science Council operates a voluntary ap-proval scheme that gives an official seal (IASC certified) on products containing certified rawingredients processed according to standardguidelines.

Used internally, there is no established dose.Product manufacturers suggest 1/2 to 3/4 cup ofjuice or 1 to 2 capsules three times a day. Thejuice in the product should ideally contain atleast 98% aloe vera and no aloin.

Used externally, aloe vera should be appliedliberally as needed. The product should containat least 20% aloe vera.

References

1 Heggers JP, Kucukcelebi A, Listengarten B, et al.Beneficial effects of aloe in wound healing in anexcisional wound model. J Altern Complement Med1996; 2: 271277.

2 Reynolds T. Aloe vera leaf gel: a review update. JEthnopharmacol 1999; 68: 337.

3 Syed TA, Ahmad SA, Holt AH, et al. Managementof psoriasis with aloe vera extract in a hydrophiliccream: a placebo controlled double blind study.TropMed Int Health 1996; 1: 505509.

4 MillerMB. Treatment of experimental frostbite withpentoxifylline and aloe vera cream. Arch Otolaryn-gol Head Neck Surg 1995; 121: 678680.

5 Visuthikosol V, Chowchuen B, Sukwanarat Y, et al.Effect of aloe vera gel to healing of burn wound:a clinical and histological study. J Med Assoc Thai1995; 78: 403409.

6 Somboonwong J, Thanamittramanee S, Jariyapong-shul A, Patumraj S. Therapeutic effects of aloe veraon cutaneous microcirculation and wound healing insecond degree burn model in rats. J Med Assoc Thai2000; 83: 417425.

7 Vermeulen H, Ubbink D, Goossens A, et al. Dress-ings and topical agents for surgical wounds healingby secondary intention. Cochrane database, issue 2,2004. London: Macmillan.

8 Vogler BK, Ernst E. Aloe vera: a systematic reviewof its clinical effectiveness. Br J Clin Pract 1999; 49:823828.

Aloe vera 3

9 Langmead L, Makins RJ, Rampton DS. Anti-inflammatory effects of aloe vera gel in humancolorectal mucosa in vitro. Aliment Pharmacol Ther2004; 19: 521527.

10 Langmead L, Feakins RM, Goldthorpe S, et al.Randomized, double-blind, placebo-controlled trialof oral aloe vera gel for active ulcerative colitis.Aliment Pharmacol Ther 2004; 19: 739747.

11 Rajasekaran S, Sivagnanam K, Ravi K, Subra-manian S. Hypoglycaemic effect of aloe veragel on streptozotocin-induced diabetes in ex-perimental rats. J Med Food 2004; 7: 6166.

12 Lee A, Chui PT, Aun CS, et al. Possible interactionbetween sevoflurane and aloe vera. Ann Pharma-cother 2004; 38: 16511654.

Alpha-lipoic acid

Description

Alpha-lipoic acid is a naturally-occurringsulphur-containing cofactor. It is synthesised inhumans.

Nomenclature

Alternative names include alpha-lipoate, thioc-tic acid, lipoic acid, 2-dithiolane-3-pentatonicacid, and 1,2-dithiolane-3-valeric acid.

Action

Alpha-lipoic acid functions as a potent anti-oxidant and as a cofactor for variousenzymes (e.g. pyruvate dehydrogenase andalpha-ketoglutarate dehydrogenase) in energy-producing metabolic reactions of the Krebscycle.

In addition, it appears to improve recyclingof other antioxidant compounds, including vita-mins C and E,1 coenzyme Q2 and glutathione.3

It may also protect against arsenic,4 cadmium,5

lead6 and mercury7 poisoning.

Dietary sources

Alpha-lipoic acid is present in foods such asspinach, meat (especially liver) and brewersyeast, but it is difficult to obtain amountsused in clinical studies (i.e. possibly therapeuticamounts) from food.

Metabolism

Alpha-lipoic acid is both fat-soluble and water-soluble, and this facilitates its diffusion intolipophilic and hydrophilic environments. It is

metabolised to dihydrolipoic acid (DHLA),which also demonstrates antioxidant proper-ties.

Possible uses

As a dietary supplement, alpha-lipoic acid isclaimed to improve glucose metabolism andinsulin sensitivity in diabetes, and to reducereplication of the human immunodeficiencyvirus (HIV). It has been investigated for possibleuse in patients with diabetes mellitus, glaucoma,HIV, hypertension and Alzheimers disease.

Diabetes mellitusAlpha-lipoic acid has long been of interest asa potential therapeutic agent in diabetes, in-cluding both the microvascular and neuropathicpathologies. This stems from alpha-lipoic acidsmetabolic role and also because diabetes resultsin chronic oxidative stress. Alpha-lipoic acidappears to increase muscle cell glucose uptakeand increase insulin sensitivity in individualswith type 2 diabetes mellitus. In vitro, alpha-lipoic acid has been found to stimulate glucoseuptake by muscle cells in a manner similar toinsulin.8

In an uncontrolled study, patients with type2 diabetes given 1000mg lipoic acid intra-venously experienced a 50% improvement ininsulin-stimulated glucose uptake.9 In a furtheruncontrolled pilot study,10 20 patients withtype 2 diabetes were given 500mg lipoic acidintravenously for 10 days. Glucose uptake in-creased by an average of 30%, but there wereno changes in either fasting blood glucose orinsulin levels.

In a study involving 10 lean and 10 obesepatients with type 2 diabetes,11 alpha-lipoic acid

4

Alpha-lipoic acid 5

improved glucose effectiveness and preventedhyperglycaemia-induced increases in serum lac-tate and pyruvate. In the lean diabetic patients,but not the obese patients, alpha-lipoic acidresulted in improved insulin sensitivity andlower fasting glucose.

In a placebo-controlled, multicentre pilotstudy,12 74 patients with type 2 diabetes wererandomised to receive alpha-lipoic acid 600mgonce, twice or three times a day, or placebo.When compared to placebo, significantly morepatients had an increase in insulin-stimulatedglucose disposal. As there was no dose effect, allthree treatment groups were combined into oneactive group and compared with placebo. Theincrease in insulin-stimulated glucose disposalwas then statistically significant, suggesting thatoral administration of alpha-lipoic acid canimprove insulin sensitivity in patients with type2 diabetes.

Diabetic neuropathyAlpha-lipoic acid has been used extensively inGermany for the treatment of diabetic neuropa-thy. An in vitro study showed that lipoic acidreduced lipid peroxidation of nerve tissue.13

A study in rats with diabetes induced bystreptozotocin showed that alpha-lipoic acidreversed the reduction in glucose uptake thatoccurs in diabetes, and that this change wasassociated with an improvement in peripheralnerve function.14

In a randomised, double-blind, placebo-controlled multicentre trial, 73 patients withnon-insulin-dependent diabetes mellitus wereassigned to receive oral alpha-lipoic acid 800mgdaily or placebo for 4months. Of the total,17 patients dropped out of the study, butthe results suggested that alpha-lipoic acidmight slightly improve cardiac autonomic neu-ropathy (assessed by measures of heart ratevariability) in non-insulin-dependent diabeticpatients.15

In a randomised, placebo-controlled studyinvolving 24 patients with type 2 diabetes,16

oral treatment with 600mg alpha-lipoic acidthree times a day for 3weeks appeared toreduce the chief symptoms of diabetic neuropa-thy. A further placebo-controlled, randomised,double-blind trial showed that oral alpha-lipoic

acid 600mg once or twice a day appeared tohave a beneficial effect on nerve conduction inpatients with both type 1 and type 2 diabetes.17

A review18 of the evidence of the effect ofalpha-lipoic acid in the treatment of diabeticneuropathy concluded that short-term treat-ment with oral or intravenous alpha-lipoic acidappears to reduce the chief symptoms of diabeticneuropathy, but this needs to be confirmed bylarger studies.

A meta-analysis of four trials of alpha-lipoicacid involving 1258 patients found a benefitof 1625% (compared with placebo) in signsand symptoms of neuropathy (e.g. ankle re-flexes, pain, burning, numbness, pin-prick andtouch-pressure sensation) after 3weeks of treat-ment. This is supported by three more recenttrials, which have also shown favourable resultswith alpha-lipoic acid in diabetic neuropathy.19

Three non-blinded trials (one in Korea andtwo in Bulgaria) tested alpha-lipoic acid in adose of 600mg daily. In the Korean study,total symptom score was significantly reducedat 8weeks, as were individual symptom scoresfor pain, burning sensation, paraesthesia andnumbness.20 In one of the Bulgarian trials, therewas a significant improvement in several aspectsof autonomic function, including postural bloodpressure change and overall cardiovascularautonomic neuropathy score.21 In the secondBulgarian study, alpha-lipoic acid was foundto be effective in peripheral and autonomicdiabetic neuropathy and also diabetic mononeu-ropathy of the cranial nerves, leading to fullrecovery of the patients.22

GlaucomaIn a study involving 75 patients with open-angleglaucoma,23 alpha-lipoic acid was administeredin a dose of either 75mg daily for 2monthsor 150mg daily for 1month. Improvementsin biochemical parameters and visual functionwere found, particularly in the group receiving150mg lipoic acid.

Human immunodeficiency virusAlpha-lipoic acid blocks activation of NF-kappaB, which is required for HIV virus transcription,and has also been noted to improve anti-oxidant status, T-helper lymphocytes, and the

6 Alpha-lipoic acid

T-helper/suppressor cell ratio in HIV-infectedT-cells.24 However, it is not known whethersupplementation would improve survival inindividuals who are HIV-positive.

MiscellaneousResults of preliminary studies suggest thatalpha-lipoic acid may lower blood pressure,25

improve the symptoms of burning mouthsyndrome26 and improve T-cell functions invitro in advanced stage cancer patients.27 Alpha-lipoic acid has also been investigated for apotential role in dementia, but there is only verylimited evidence available.28,29Alpha-lipoic acidhas been investigated for an effect in conditionssuch as cancer cachexia, liver disease, ischaemiareperfusion injury, photoageing of the skin andcataract. However, there is no convincing dataas yet from human randomised controlled trial(RCT) data.

ConclusionThere is evidence that alpha-lipoic acidmight have a role in patients with diabetesmellitus in improving glucose utilisation,insulin sensitivity and diabetic neuropathy.Very limited evidence also exists that alpha-lipoic acid may be helpful in glaucoma, de-mentia, hypertension and slow replication ofHIV and cancer cells, but evidence of benefitin all these conditions, including diabetes,is too limited to make recommendations forsupplementation.

Precautions/contraindications

Alpha-lipoic acid should be used with caution inpatients predisposed to hypoglycaemia, includ-ing patients taking antidiabetic agents.

Pregnancy and breast-feeding

No problems have been reported, but therehave not been sufficient studies to guaranteethe safety of alpha-lipoic acid in pregnancy andbreast-feeding.

Adverse effects

None reported, apart from occasional skinrashes. Studies investigating the effect of alpha-lipoic acid have suggested that it is a safesupplement at reasonable doses. However, thereare no long-term studies assessing the safety ofalpha-lipoic acid.

Interactions

DrugsOral hypoglycaemics and insulin: Theoretically,alpha-lipoic acid could enhance the effects ofthese drugs.

Dose

Alpha-lipoic acid is available in the form oftablets and capsules.

The dose is not established. Studies have used300600mg daily. Dietary supplements provide50300mg daily.

References

1 Scholich H, Murphy ME, Sies H. Antioxidantactivity of dihydrolipoate against microsomal lipidperoxidation and its dependence on -tocopherol.Biochem Biophys Acta 1989; 1001: 256261.

2 Kagan V, Serbinova E, Packer L. Antioxidant effectsof ubiquinones in microsomes and mitochondria aremediated by tocopherol recycling. Biochem BiophysRes Comm 1990; 169: 851857.

3 Busse E, Zimmer G, Schopohl B, et al. Influence ofalpha-lipoic acid on intracellular glutathione in vitroand in vivo. Arzneimittelforschung 1992; 42: 829831.

4 Grunert RR. The effect of DL--lipoic acid on heavymetal intoxication in mice and dogs. Arch BiochemBiophys 1960; 86: 190194.

5 Muller L, Menzel H. Studies on the effect of lipoateand dihydrolipoate in the alteration of cadmiumtoxicity in isolated hepatocytes. Biochem BiophysActa 1990; 1052: 386391.

6 Gurer H, Ozgunes H, Oztezcan S, Ercal N. Antiox-idant role of alpha-lipoic acid in lead toxicity. FreeRadic Biol Med 1999; 27: 7581.

7 Keith RL, Setiarahardjo I, Fernando Q, et al.Utilization of renal slices to evaluate the efficacyof chelating agents for removing mercury from thekidney. Toxicology 1997; 116: 6775.

8 Estrada DE, Ewart HS, Tsakiridis T, et al. Stimu-lation of glucose uptake by the natural coenzyme

Alpha-lipoic acid 7

alpha-lipoic acid/thioctic acid: participation ofelements of the insulin signaling pathway. Diabetes1996; 45: 17981804.

9 Jacob S, Henricksen EJ, Schiemann AL, et al.Enhancement of glucose disposal in patients withtype 2 diabetes by alpha-lipoic acid. Arzneimit-telforschung 1995; 45: 872874.

10 Jacob S, Henricksen EJ, Tritschler HJ, et al. Improve-ment of insulin-stimulated glucose disposal in type 2diabetes after repeated parenteral administration ofthioctic acid. Exp Clin Endocrinol Diabetes 1996;104: 284288.

11 Konrad T, Vicini P, Kusterer K, et al. Alpha-lipoicacid treatment decreases serum lactate and pyruvateconcentrations and improves glucose effectivenessin lean and obese patients with type 2 diabetes.Diabetes Care 1999; 22: 280287.

12 Jacob S, Ruus P, Hermann R, et al. Oral adminis-tration of RAC-alpha-lipoic acid modulates insulinsensitivity in patients with type 2 diabetes mellitus:a placebo-controlled pilot trial. Free Radic Biol Med1999; 27: 309314.

13 Nickander KK, McPhee BR, Low PA, et al. Alpha-lipoic acid: antioxidant potency against lipid peroxi-dation of neural tissues in vitro and implications fordiabetic neuropathy. Free Radic Biol Med 1996; 21:631639.

14 Kishi Y, Schmeizer JD, Yao JK, et al. Alpha-lipoicacid: effect of glucose uptake, sorbitol pathway,and energy metabolism in experimental diabeticneuropathy. Diabetes 1999; 48: 20452051.

15 Ziegler D, Schatz H, Conrad F, et al. Effects oftreatment with the antioxidant alpha-lipoic acid oncardiac autonomic neuropathy in NIDDM patients.A 4-month randomized controlled multicenter trial(DEKAN Study). Deutsche Kardiale AutonomeNeu-ropathie. Diabetes Care 1997; 20: 369373.

16 Ruhnau KJ, Meissner HP, Finn JR. Effects of a3-week oral treatment with the antioxidant thiocticacid (alpha-lipoic acid) in symptomatic diabeticpolyneuropathy. Diabet Med 1999; 16: 10401043.

17 Reljanovic M, Reichel G, Rett K, et al. Treatmentof diabetic polyneuropathy with the antioxidantthioctic acid (alpha-lipoic acid): a two year multi-center randomized double-blind placebo-controlledtrial (ALADIN II). Alpha-lipoic acid in diabeticneuropathy. Free Radic Res 1999; 31: 171179.

18 Ziegler D, Reljanovic M, Mehnert H. Alpha-lipoicacid in the treatment of diabetic polyneuropathyin Germany: current evidence from clinical trials.Exp Clin Endocrinol Diabetes 1999; 107: 421430.

19 Ziegler D, Nowak H, Kempler P, et al. Treatment ofsymptomatic diabetic polyneuropathy with the anti-oxidant alpha-lipoic acid: a meta-analysis. DiabetMed 2004; 21: 114121.

20 Hahm JR, Kim BJ, Kim KW. Clinical experiencewith thioctacid (thioctic acid) in the treatment ofdistal symmetric polyneuropathy in Korean diabeticpatients. J Diabetes Complications 2004; 18: 7985.

21 Tankova T, Koev D, Dakovska L. Alpha-lipoic acidin the treatment of autonomic diabetic neuropathy(controlled, randomized, open-label study). Rom JIntern Med 2004; 42: 457464.

22 Tankova T, Cherninkova S, Koev D. Treatment fordiabetic mononeuropathy with alpha-lipoic acid. IntJ Clin Pract 2005; 59: 645650.

23 Filina AA, Davydova NG, Endrikhovskii SN, et al.Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn Oftalmol 1995; 111: 68.

24 Baur A, Harrer T, Peukert M, et al. Alpha-lipoic acidis an effective inhibitor of human immunodeficiencyvirus (HIV-1) replication. Klin Wochenschr 1991;69: 722724.

25 Vasdev S, Ford CA, Parai S, et al. Dietary alpha-lipoic acid supplementation lowers blood pressure inspontaneously hypertensive rats. J Hypertens 2000;18: 567573.

26 Zakrzewska JM, Forssell H, Glenny AM. Inter-ventions for the treatment of burning mouth syn-drome. Cochrane database, issue 1, 2005. London:Macmillan.

27 Mantovani G, Maccio A, Melis G, et al. Restorationof functional defects in peripheral blood mononu-clear cells isolated from cancer patients by thiolantioxidants alpha-lipoic acid and N-acetyl cysteine.Int J Cancer 2000; 86: 842847.

28 Savitha S, Sivarajan K, Havipriya D, et al. Efficacy oflevo carnitine and alpha-lipoic acid in amelioratingthe decline in mitochondrial enzymes during aging.Clin Nutr 2005; 24: 794800.

29 Sauer J, Tabet N, Howard R. Alpha-lipoic acidfor dementia. Cochrane database, issue 1, 2004.London: Macmillan.

Antioxidants

Description

Various antioxidant systems have evolved tooffer protection against free radicals and pre-vent damage to vital biological structures suchas lipid membranes, proteins and DNA. Anti-oxidant capacity is a concept used to describethe overall ability of tissues to inhibit processesmediated by free radicals.1 It is dependent on theconcentrations of individual antioxidants andthe activity of protective enzymes. The mostcommon and important antioxidant defencesare shown in Table 1.

The antioxidant vitamins can be dividedinto those that are water-soluble and exist inaqueous solution primarily vitamin C andthose that are fat-soluble and exist in mem-branes or lipoproteins primarily vitamin E.Lipid membranes are particularly vulnerable tooxidative breakdown by free radicals. VitaminE protects cell membranes from destructionby undergoing preferential oxidation anddestruction. Carotenoids, such as beta-carotene,which are found in most dark green, red oryellow fruits and vegetables and some quinones,such as ubiquinone (coenzyme Q) also appearto have antioxidant properties. Flavonoids andother phenols and polyphenols found in foodssuch as green tea, red wine, olive oil, grapesand many other fruits are also antioxidants.All these substances can act as free radicalscavengers and can react directly with freeradicals.

Some trace elements act as essential compo-nents of antioxidant enzymes copper, mag-nesium or zinc for superoxide dismutase andselenium for glutathione peroxidase.

Supplements that are marketed as havingantioxidant activity include:

vitamin A (usually as beta-carotene), vita-mins C and E (ACE vitamins, often withselenium)

alpha-lipoic acid (see Alpha-lipoic acid) carnitine (see Carnitine) carotenoids (see Carotenoids) coenzyme Q (see Coenzyme Q) green tea (see Green tea extract) zinc (see Zinc).

Action

Antioxidants are believed to protect againstcertain diseases by preventing the deleteriouseffects of processes mediated by free radicals incell membranes and by reducing the susceptibil-ity of tissues to oxidative stress.

Free radicalsEach orbital surrounding the nucleus of an atomis occupied by a pair of electrons. If an orbitalin the outer shell of a molecule loses an electron,the molecule becomes a free radical. As a resultof the unpaired electron, the molecule becomesunstable and, therefore, highly reactive. The freeradical may then react with any other nearbymolecule, also converting that molecule to afree radical which can then initiate anotherreaction. Some free radicals are capable ofseverely damaging cells.

Theoretically, a single free radical can ulti-mately cause an endless number of reactions.This chain reaction is terminated either by thefree radicals reaction with another free radical,resulting in the formation of a covalently boundmolecule, or by the free radicals reactionwith an antioxidant, an antioxidant enzyme, orboth. Fortunately, many enzyme systems have

8

Antioxidants 9

Table 1 Antioxidant defences

Intracellular antioxidantsEnzymes

catalaseglutathione peroxidasesuperoxide dismutase

Extracellular antioxidantsVitamin CSulphydryl groups

Membrane antioxidantsCarotenoidsUbiquinoneVitamin E

Substances essential for synthesis ofantioxidant enzymesCopperManganeseSeleniumZinc

evolved to provide protection from free radicalproduction.

Because antioxidant defences are not com-pletely efficient, increased free radical formationin the body is likely to increase damage. Theterm oxidative stress is often used to refer tothis effect. If mild oxidative stress occurs, tissuesoften respond by increasing their antioxidantdefences. However, severe oxidative stress cancause cell injury and cell death.

There is growing evidence that free-radicaldamage is involved in the development ofmany diseases, such as atherosclerosis, cancer,Parkinsons disease and other neurodegenera-tive disorders, inflammatory bowel disease andlung disease.

Possible uses

Epidemiological evidence suggests that lowplasma levels of antioxidant nutrients and lowdietary intakes are related to an increasedrisk of diseases such as coronary heart disease(CHD) and cancer. There is also increasingevidence that these diseases can be preventedor delayed to some extent by dietary changes,in particular by increased consumption of fruits

and vegetables. Several substances in fruit andvegetables (e.g. beta-carotene, vitamin C andvitamin E) may act to diminish oxidative dam-age in vivo and, because endogenous anti-oxidant defences are not completely effective,dietary antioxidants may be important in di-minishing the cumulative effects of oxidativedamage in the human body.

A question of particular interest is whethersupplementation of adequately nourished sub-jects with antioxidant nutrients will reduce theincidence of such diseases. The few interventiontrials of antioxidants reported so far have shownlittle evidence for the value of supplements.Some have shown harmful effects.

Cardiovascular disease

Epidemiological studiesExperimental studies suggest an inverse asso-ciation between CHD mortality and vitaminsC, E and beta-carotene, and argue strongly infavour of a protective role of antioxidants inthe development of atherosclerosis.

In a cross-cultural study of middle-agedmen representing 16 European populations,1

differences in mortality from ischaemic heartdisease were primarily attributable to plasmalevels of vitamin E. Twelve of the 16 populationshad similar blood cholesterol levels and bloodpressure but differed greatly in tocopherol levelsand heart disease death rates. For vitamin E,mean plasma levels lower than 25mol/L wereassociated with a high risk of CHD, whereasplasma levels above this value were associatedwith a higher risk of the disease. In the caseof vitamin C, mean plasma levels less than22.7mol/L were found in those regions thathad a moderate to high risk of CHD, whereasplasma levels in excess of this level tended to befound in those areas at low risk.

In a large case-control study in Scotland,2

6000 men aged 3554 were studied for apossible association between antioxidant statusand risk of angina pectoris. Highly significantcorrelations between low plasma concentrationsof beta-carotene, vitamin C, vitamin E and riskof angina were found.

The Health Professionals Study,3 a largeprospective investigation that looked at 39 910

10 Antioxidants

US male health professionals aged 4075,showed that men who took more than 100 unitsof vitamin E daily for over 2 years had a 37%reduction in risk of heart disease. The NursesHealth Study,4 in which 87 245 female nursesaged 3459 took part, showed that women whotook more than 200 units of vitamin E daily formore than 2 years had a 41% reduction in riskof CHD.

Intervention trialsThe first intervention trial published was astudy of 333 male physicians aged between 40and 84 with angina pectoris and/or coronaryrevascularisation, which showed that 50mg ofbeta-carotene on alternate days resulted in a44% reduction in major coronary events.5

However, another study6 tested aspirin,vitamin E and beta-carotene in the preventionof cardiovascular disease (CVD) and cancerin 39 876 women aged 45 and older. Amongthose randomly assigned to receive 50mg beta-carotene or a placebo every other day, therewere no statistically significant differences inincidence of CVD, cancer or overall death rateafter a median of 2 years of treatment and2 years of follow-up.

In a study of 1862 smoking men aged50 to 59 [participants in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention(ATBC) Study]7 who were followed for amedian of 5.3 years, dietary supplements ofalpha-tocopherol (50mg a day), beta-carotene(20mg a day), both, or a placebo were given.There were significantly more deaths fromCHDamong those who took beta-carotene supple-ments, and a non-significant trend towardsmore deaths in the vitamin E group. This samestudy also found that neither alpha-tocopherolnor beta-carotene had a preventive effect forlarge abdominal aortic aneurysm.8 During the6-year post-trial follow-up in the ATBC study,beta-carotene increased the post-trial risk offirst-ever non-fatal myocardial infarction, sug-gesting that these supplements should not beused in the prevention of CVD among malesmokers.9

Another large trial involving 20 536 UKadults aged 4080 with coronary disease, otherocclusive arterial disease or diabetes, randomly

allocated participants to receive antioxidantvitamin supplementation (600mg vitamin E,250mg vitamin C and 20mg beta-carotenedaily) or matching placebo over 5 years. Therewere no significant differences in all-cause mor-tality, or in deaths due to vascular or non-vascular causes. Nor were there any significantdifferences in the number of participants havingnon-fatal myocardial infarction or coronarydeath, non-fatal or fatal stroke, or coronaryor non-coronary revascularisation. For the firstoccurrence of these major vascular events,there were no material differences overall andno significant differences in cancer incidenceand hospitalisation for any other non-vasculardisease.10

A double-blind clinical trial11 found thattaking high doses of vitamin C (500mg twicea day) and E (700 units twice a day) andbeta-carotene (30 000 units twice a day) didnot reduce the risk of arteries re-clogging afterballoon coronary angioplasty. The patients tookprobucol, probucol plus three antioxidants, theantioxidants alone or placebo. All patients alsoreceived aspirin. After 6months the rates ofrepeated angioplasty were 11% in the probucolgroup, 16.2% in the combined treatment group,24.4% in the multivitamin group and 26.6% inthe placebo group.

A trial in post-menopausal women withcoronary disease found that supplementationwith vitamin E 400 units twice daily andvitamin C 500mg twice daily did not retardatherosclerosis and provided no cardiovascularbenefit.12 Results from the SU.VI.MAX trialalso suggested that a combination of antioxi-dants (120mg vitamin C, 30mg vitamin E, 6mgbeta-carotene, 100g selenium, 20mg zinc)over an average of 7.2 years had no beneficialeffects on carotid atherosclerosis and arterialstiffness13 or risk of hypertension14 in healthypatients. A further trial in 520 smoking andnon-smokingmen and post-menopausal women(all of whomhad serum cholesterol> 5mmol/L)found that supplementation with combinationvitamin E and slow-release vitamin C slowsdown atherosclerotic progression.15

More recent trials have shown some benefi-cial effect of antioxidant supplements on certainaspects of CVD. A Polish trial involving 800

Antioxidants 11

patients with acute myocardial infarction foundthat supplementation with vitamin C 1200mgdaily and vitamin E 600mg daily over 30 dayshad a positive influence on primary end points(i.e. in-hospital cardiac mortality, non-fatal newmyocardial infarction) and concluded that alarger study is warranted to generate furtherevidence for this particular regimen.16

An RCT involving 100 patients with asymp-tomatic or mildly symptomatic moderate aorticstenosis found that supplementation withvitamin E (400 units) and vitamin C (1000mg)daily had modest anti-inflammatory effect,although the clinical relevance requires furtherclarification.17 A 15-day clinical trial in patientswith early-stage untreated type 2 diabetes mel-litus or impaired glucose tolerance found thatsupplementation with N-acetyl cysteine 600mgdaily, vitamin E 300mg daily and vitamin C250mg daily reversed unfavourable oxidativechanges occurring after a moderate fat meal andmay therefore have decreased oxidative stress.18

A further trial involving 48 acute ischaemicstroke patients (evaluated within 12 h of symp-tom onset) found that compared with placeboalpha-tocopherol 800 units daily and vitamin C500mg daily over 14 days increased antioxidantcapacity, reduced lipid peroxidation productsand may have an anti-inflammatory effect.19

There is some evidence that folate statuscould have an influence on the response toantioxidant supplementation in patients at car-diovascular risk. One study found that folatedeficiency may amplify the effect of otherrisk factors such as elevated homocysteine orvariant methylene tetrahydrofolate reductase(MTHFR) genotype, as well as influencingthe ability of antioxidant supplementation toprotect against genetic damage.20 A reductionin systolic blood pressure has been observedin young healthy men supplemented with bothfolic acid (10mg daily) and antioxidants (vita-min C 100mg, vitamin E 800mg).21 However,in a further study involving patients in the imme-diate aftermath of stroke, supplementation withantioxidant vitamins (vitamin E 800 units andvitamin C 500mg daily), or B group vitamins(5mg folic acid, 5mg vitamin B2, 50mg vitaminB6, 0.4mg vitamin B12), both vitamins togetheror no supplements found that supplementation

with antioxidant vitamins with or without B-group vitamins enhances antioxidant capac-ity, mitigates oxidative damage and may havean anti-inflammatory effect immediately post-infarct in stroke.22

The effect of antioxidant supplementation inCVD has been evaluated in systematic reviewsand meta-analyses. One systematic review as-sessed whether antioxidants in food or sup-plements can offer primary prevention againstmyocardial infarction or stroke.23 Eight RCTswere included, six of which tested supplementsof beta-carotene, four tested alpha-tocopheroland two ascorbic acid. None of the RCTsshowed any benefit of antioxidant supplemen-tation on CVD. In one study there was asignificantly increased risk for fatal or non-fatalintracerebral and subarachnoid haemorrhagein participants taking alpha-tocopherol. Thereviewers concluded that from these RCTs(which had limitations) antioxidants as foodsupplements had no beneficial effects in theprimary prevention of myocardial infarctionand stroke and cannot be recommended for suchpurposes.

A meta-analysis that looked at the effect ofantioxidant vitamins on long-term cardiovascu-lar outcomes included 12 RCTs, of which sevenexamined vitamin E and eight beta-carotene.24

Over all the studies there was no statisticallysignificant difference between vitamin E andcontrol for all-cause mortality, cardiovascularmortality or cerebrovascular accident. Beta-carotene was associated with a slight statisti-cally significant increase in all-cause mortalityand cardiovascular death compared with con-trol. The authors concluded that the routine useof vitamin E cannot be recommended and thatthe use of supplements containing beta-caroteneshould be actively discouraged.

The US Agency for Healthcare Research andQuality (AHRQ) commissioned an extensivereport on the efficacy and safety of antioxidantsupplements (vitamins C, E and coenzyme Q10)for the prevention and treatment of CVD.25

From a review and analysis of the 144 clini-cal trials the authors identified, the followingconclusions were reached. Firstly, the