WINNING THE MEDICAL COMMUNITY OVER TO ANTIOXIDANTS

WINNING THE MEDICAL COMMUNITY OVER TO ANTIOXIDANTS

By Peter Huck

There is atruism that if it sounds too good to be true, then it probably is. One might be tempted tobelieve this adage applies to antioxidants. After all, antioxidants are claimed to be ableto reduce the risk of literally more than 80 diseases, as well as play a role in thetreatment of many of these diseases even after they have developed.

Further, antioxidants have generated excitement among the Baby Boomergeneration for being able to turn the clock back on the aging process. But incredibly,research has indicated the veracity of these claims about antioxidants. As the research onantioxidants continues to progress, the medical community has taken note, and probablymore than any other category of products in the dietary supplement industry, antioxidantshold the potential to be a scientifically validated preventative and therapeutic optionaccepted and utilized by doctors and pharmacists.

As a writer for a dietary supplement industry trade magazine, I am often preaching tothe choir. However, as many negative and unbalanced media reports (not to mention theFDA's antagonism toward the industry) show, not everyone has been won over to the side ofdietary supplements. This is also the case with the largely conservative, often skeptical,evidence-based medical community. Still, scientists, doctors and pharmacists very well maydetermine the future of dietary supplements more than any other group. Not only do themajority of Americans rely on their physician for making important healthcare decisions,but journalists and government regulators in large part take their cue from what thescientific and medical communities are saying. If a majority of scientists, doctors andpharmacists embrace the safety and efficacy of a category of supplements such asantioxidants, this consensus of experts will have the effect of shifting antioxidants fromthe realm of "alternative" to that of "mainstream." This in turntranslates to wider consumer acceptance and bigger sales at every level of the industry.The question, then, is: what is the attitude of the mainstream medical community towardantioxidants?

A Review of the Literature: A Definition and Identification

Before trying to discern the medical profession's view of antioxidants, it is good toreview what exactly are antioxidants. A potentially confusing aspect of the term"antioxidant" is that it is applied to nearly a dozen different kinds ofnutrients, botanicals and other supplements. As a result, literally hundreds of productsare marketed as antioxidants or as having antioxidant properties. But what these productsare all purported to have in common is the ability to significantly delay or preventoxidation in the human body.

Oxidation is caused by free radicals--damaged molecules missing a free electron--thatcrash into stable molecules in an attempt to pick up their missing electron. When aninitial free radical takes an electron from another molecule, the second molecule is thenitself left unbalanced--setting off a chain reaction that can repeat a million or moretimes daily. This continual creation of free radicals can seriously damage proteins andcell membranes, compromise cells' natural defenses, disrupt cells' genetic DNA, andpresumably make the human body more susceptible to cardiovascular disease, cancer andnumerous other diseases and afflictions. It is also believed that free radicals arepartially responsible for the aging process, as the cumulative effect of years ofcontinual free radical reactions causes cells to become inefficient, damaged, mutated oreven to die.

Free radical formation is impossible to completely negate, because it is largely causedby normal body functions of food and oxygen metabolism. In fact, oxidation is an essentialphysiological process that provides energy for vital cell processes and activities. Freeradicals also are formed as a result of lipid (such as fats, oils and steroids)peroxidation. Finally, external factors such as excessive exercise, emotional stress, sunexposure, cigarette smoke, air pollutants, heavy metals and food additives can increasefree radical formation.

Although oxidation is a basic physiological process, antioxidants are thought to beable to intervene to keep the process from running haywire by donating electrons to quenchfree radicals before they damage other molecules in cells. The beneficial activities ofantioxidants include trapping free radicals and lipid peroxides, delaying the onset oflipid peroxidation, inhibiting production of free radicals, and inhibiting the damagingeffects of certain enzymes that can degrade connective tissues.

Increasingly aware of these beneficial attributes, there are signs that the medicalcommunity is taking a greater role in trying to define and identify antioxidants. Forexample, the prestigious Institute of Medicine (IOM), founded by the National Academy ofSciences in 1970, published a 1998 report on antioxidants titled "Dietary ReferenceIntakes: Proposed Definition and Plan for Review of Dietary Antioxidants and RelatedCompounds." This report is a first step in the direction of potentially forming acomprehensive set of Dietary Reference Intakes (DRIs) for selected antioxidant nutrientsand food components. In the report, the authors, consisting of a panel of scientists,doctors and other experts, acknowledge that there has been intense interest among thepublic and the media as to the possibility that antioxidants may protect against chronicdisease. To address this interest, the report attempts to provide a definition of dietaryantioxidants, as well as identify the nutrients and food component that will be evaluatedto potentially establish DRIs for these substances.

The proposed definition is based on three criteria: 1) the substance is found in humandiets; 2) the content of the substance has been measured in foods commonly consumed; and3) the substance decreases the adverse effects of the types of free radicals known asreactive oxygen (ROS) and nitrogen species (RNS) in humans. As such, a dietary antioxidantis defined in the IOM's report as a substance in foods that significantly decreases theadverse effects of ROS, RNS, or both on normal physiological function in humans. Thereport determines that beta carotene and other selected carotenoids, vitamin C, vitamin Eand selenium should be evaluated to find if adequate data is available. The review alsostates that the review of antioxidant substances may include other related compounds notaddressed by the panel such as flavonoids, polyphenols, phytoestrogens and lipoic acid.The significance of an IOM panel possibly deciding that there should be DRIs for thesesubstances as antioxidants would be that a mainstream medical organization will defineantioxidant function as beneficial to human health.

Antioxidant compounds such as the ones mentioned above are present in essentialnutrients found in fruits and vegetables. Vitamin E is fat-soluble and is mostsignificantly found in the lipids of cell membranes and in circulating low-densitylipoproteins. It is able to become localized in cell membrane, and as free radicals areformed by oxidation, vitamin E quenches them before they damage cellular structures.Vitamin E, of which d-alpha tocopherol is the most prominent natural alternative, isparticularly effective at protecting tissues that contain higher levels of polyunsaturatedfatty acids. A derivative of vitamin E is tocotrienols, which differ as a result of thepresence of three double binds in the carbon side chain of the tocotrienol molecule. Thishydrocarbon tail is thought to give tocotrienols greater mobility and access within cellmembranes and lipoproteins (and subsequently greater antioxidant activity) thantocopherols.

Vitamin C prevents oxidation of water-soluble molecules and is therefore thought to bea particularly effective antioxidant in the liquid areas of the body, including the bloodplasma, lung fluid, eye fluids and in between cells. Beside neutralizing free radicals,Beta carotene prevents free radical formation by quenching singlet oxygen, a highlyreactive form of oxygen that creates free radicals by transferring excessive energy tostable molecules. Beside these three nutrients, essential trace minerals, particularlyselenium, have been shown to possess antioxidant-like properties.

Many plant sources beside fruits and vegetables are rich in flavonoids, which have beenshown to possess antioxidant activity. The two most well-known sources for flavonoids aregrape seed extract and pine bark extract. Both extracts contain a class of flavonoidscalled proanthocyanidins (also termed procyanidins) that have been shown to be extremelyeffective antioxidants. The seeds of grapes are not the only portion of the fruitindicated to have antioxidant activity. Resveratrol, a phenolic constituent found in theskin of grapes, is a substance that is one of a group of compounds called phytoalexinsproduced in plants during times of environmental stress. Green tea, which also containspolyphenols, is also touted as an antioxidant. For example, a Japanese "matcha"tea by Maitake Products Inc. contains four primary polyphenols: epicatechin, epicatechingallate, epicallocatechin and epicallocatechin gallate.

Another substance indicated to have antioxidant potential is alpha lipoic acid. Some ofthis vitamin-like substance is converted by the body to dihydrolipoic acid, which quenchesfree radicals in both lipid and aqueous domains. It has also been suggested that alphalipoic acid can replenish and/or recycle other antioxidants such as vitamins C and E.Coenzyme Q10 (CoQ10) is also a vitamin-like substance and has been found to be a potentantioxidant that is being utilized by some cardiologists in the treatment of heartfailure. In simple terms, CoQ10 increases the energy output of a heart, making itstronger. Produced within the body itself, glutathione--a sulfur containing tripeptideformed in the body from amino acids--helps neutralize free radicals in cells. Levels ofglutathione in the body can be increased through supplementation with selenium, N-acetylcysteine and alpha lipoic acid.

The Proof in the Research

The key to capturing the interest and awareness of doctors and pharmacists can besummed up with one word--research. And more research and then more research. In fact,antioxidants and the theory of free radical oxidation already has been the subject of avery impressive number of studies. A recent search of the National Library of Medicine'sonline version of Medline using the keyword "antioxidant" showed 28,391citations of studies related to the topic of antioxidants. Other indications of thescientific interest in free radicals and antioxidants is the existence of the scientificjournal Free Radical Research, and the establishment of scientific organizationssuch as the Oxygen Society and the International Society for Free Radical Research, whichare dedicated to the knowledge and understanding of biooxidation, free radicals andantioxidants. The number of researchers, many of whom who are at renowned researchuniversities, currently investigating the role of free radicals and antioxidant functionshows that the study of antioxidants is not a passing scientific fad. It also means thatextensive and serious research on the role of antioxidants will continue indefinitely.

Researchers, as well as doctors and pharmacists, commonly state that much of theresearch on antioxidants is important and compelling. "The research is substantialand exciting," said Michael Janson, M.D., author of The Vitamin Revolution inHealthcare and president of the American College for Advancement in Medicine (ACAM)."Nonetheless, as with all research, it is preliminary in the sense that we know thereis going to be more that enhances, modifies, contradicts what has come before. There willbe some inevitable contradiction as there is an increasing number of studies. But theoverwhelming weight of the evidence on antioxidants is positive."

However, many in the scientific and medical communities note that the quantity ofresearch does not necessarily express the quality or significance of that body ofresearch. For example, the research on antioxidants is often characterized as preliminaryand sometimes as mixed or even negative. Even when the scientific evidence is positive,many doctors and pharmacists distinguish between in vitro (tested in a test tube)vs. in vivo (tested in live organisms). In regard to in vivo human studies,definitive research on the benefits of antioxidants is scarce. "It certainly has tobe said that in terms of human studies, the research is preliminary," said VarroTyler, dean and distinguished professor emeritus at Purdue University and author of TheHonest Herbal and Herbs of Choice. "But I think the results have beensignificant to date, so I think it is a very fruitful line of endeavor to continue."

Although many doctors and pharmacists may find many in vitro studies to bepromising, this kind of research alone rarely is enough to convince them that they shouldrecommend antioxidants to their patients and customers. "The only way to be impressedis to see what happens in long-term health outcomes," said Richard Herrier, Pharm.D.,assistant professor at the College of Pharmacy at the University of Arizona. "Thoseare the types of studies being conducted with vitamin E. I read the results of somestudies and say to myself that is really great in the test tube, but I want to see it in apatient and see how the human body handles it. For example, in the case of vitamin C, somuch of it in mega-doses is not used by the body and is just excreted away. This raisesthe question of how much vitamin C exactly is enough. We need more vitamin E-like studies,and I think you are going to find that this is going to happen."

The vitamin-E type studies that Herrier hopes to see are ones that indicate the effectsof a given antioxidant on a person's health outcome (i.e., how the person's health statuschanges). Health outcomes would include, for example, a change in the incidence of heartattacks or cancers in the tested population. Epidemiological studies with enormouspopulations of test subjects have also indicated positive outcomes of vitamin Esupplementation in reducing heart disease risk. In a study published in The New EnglandJournal of Medicine, 39,910 U.S. males aged 40 to 75 who were free of diagnosedcoronary heart disease, diabetes and hypercholesterolemia completed detailed dietaryquestionnaires that assessed their usual intake of vitamin C, beta carotene and vitamin E,in addition to other nutrients. The researchers concluded that the results providedevidence of an association between high intake of vitamin E and a lower risk of coronaryheart disease in men.

In another study that also was published in The New England Journal of Medicine(interestingly, a medical journal with a propensity for running editorials and lettersthat question the efficacy and safety of dietary supplements), 34,486 postmenopausal womenwith no cardiovascular disease also completed a questionnaire that assessed intakes ofvitamins A, E and C from foods and supplements. During approximately seven years offollow-up, 242 of the women died of coronary heart disease. The researchers reported,"vitamin E consumption appeared to be inversely associated with the risk of deathfrom coronary heart disease. This association was particularly striking in the subgroup of21,809 women who did not consume vitamin supplements."

It is on the basis of studies such as these, appearing in preeminent medical journals,that doctors and pharmacists form their collective opinion about antioxidant supplements.And time and again, scientists, doctors and pharmacists in interviews specifically citeepidemiological studies on vitamin E as significantly perking their interest in the valueof the nutrient in preventing heart disease. In other words, there is precedent thatmembers of the mainstream medical community can be convinced of the benefits of a certainantioxidant, but only if strong evidence is present.

"I think antioxidants will eventually become another option that doctors intraditional medicine will recommend when appropriate," said Jim Clark, Ph.D.,research director at Henkel Nutrition and Health Groups, which supplies such antioxidantingredients as Pycnogenol pine bark extract, Betatene natural beta carotene with mixedcarotenoids, Covitol natural-source vitamin E and Lipoec alpha lipoic acid. "However,the integration will be subtle. And because of the conservative nature of traditionalmedicine, only antioxidants that have been studied for many, many years will be included.For example, surveys have shown that about half of all doctors take vitamin E."

While epidemiological studies of large populations have suggested the role of anantioxidant nutrient such as vitamin E, many health professionals view the epidemiologicalresults with caution. "I feel that observational epidemiology can be very persuasiveif the studies are well designed and large enough, and I am not sure that we have todemand that a randomized clinical trial be performed before we suggest anintervention," said Dr. Regina Ziegler, a nutritional epidemiologist at the NationalCancer Institute. "But on the other hand, depending on the degree to which anintervention or supplementation diverges from normal dietary patterns, you have to beconcerned about potential risks and benefits. Research that fruits and vegetables areprotective in a dietary study of a large population are fine, but once people want toextract beta carotene or vitamin C and put them in a pill, they should be sure that thoseare the only important components and that other necessary things are not getting leftbehind. Also, it is important to make sure that the chemical form is correct, and that thedosage is not too much, etc. We shouldn't rule out the research, but we should be veryprudent in terms of taking compounds in supplements and saying that they will do the samethings that are shown in studies of dietary patterns."

One way to determine whether these nutrients in supplemental form offer similarbenefits as they do when ingested as part of diet is to conduct clinical human studiesthat specifically use supplements as the therapeutic intervention. Further, whileepidemiological studies definitely catch the interest of the medical community,controlled, randomized human studies close the deal in winning doctors' and pharmacists'acceptance.

Continuing with the example of vitamin E, Andreas Papas, Ph.D., senior technicalassociate at Eastman Chemical Co., which supplies Nutriene brand tocotrienols, said thatvitamin E is well on its way to being fully scientifically validated for its antioxidantfunction. Papas explained that in order to meet the burden of proof that will convince thescientific community and the FDA to approve claims for an antioxidant substance, thefollowing steps of gathering evidence is required: 1) a good working hypothesis that abenefit is likely, with a mechanism of actions that makes good biological sense; 2)evidence from basic medical laboratory research that supports at least part of thehypothesis; 3) evidence from animal studies and small human studies that some responsesrelated to the benefit do actually occur; 4) epidemiological studies showing a strongassociation between the compound and the actual health benefit; and, 5) evidence fromrandomized, double-blind, placebo-controlled clinical trials.

"For vitamin E, evidence is available for all steps except the evidence for thelast and important step is not complete," said Papas. "If ongoing major clinicaltrials are positive, it will achieve the burden of proof required for FDA approval."

A few results from clinical trials have already been published on vitamin E, and otherlong-term clinical trials, as Papas indicated, are underway. In one completed clinicalstudy--the Cambridge Heart Antioxidant Study (CHAOS), published in the March 23, 1996issue of The Lancet, vitamin E supplementation of 400 or 800 IUs per day decreasedthe risk of non-fatal heart attack in a double-blind, placebo-controlled trial of 2,002patients with coronary disease who were treated with vitamin E or placebo and followed fora median of 510 days.

If human studies in a controlled clinical setting, especially those that evaluatehealth outcomes, are the key to acceptance by the medical community, why don't researchersand companies in the industry simply conduct more of these types of studies? One largereason is that these types of studies are expensive and often take a long time to conduct.Alex Sevanian, Ph.D., a professor at the University of Southern California who hasconducted research on antioxidants, highlighted the formidable challenges of doingresearch that investigates health outcomes. "If researchers are looking for eventssuch as heart attacks and strokes, they have to take a relatively large population andlook for these coronary heart events. These types of studies take many, many years,because people live a long time."

Sevanian noted, however, that there is another research route, where rather thanwaiting for health outcome events, researchers look at specific indicators of futurehealth events. "There are more refined techniques that can now monitor progress of,for example, atherosclerosis in people, which is a surrogate to predicting events,"he said. "For instance, this type of study can monitor the thickening of vessel wallsand quickly see if that thickening does or does not occur with the intake of anantioxidant. It does not mean that the event will occur, but statistically, there is astrong correlation. These types of studies can be done over two- or three-year periods ifthe researchers get enough measurements to determine some rate of progression to see ifthat would then change with intervention."

However, subtle but sometimes important differences between these two kinds of humanstudies do exist. Garry Handelman, Ph.D., associate professor and scientist at the JeanMayer Human Nutrition Research Center on Aging at Tufts Unversity, explained,"Suppose in a study you looked at how rapidly people made an antibody in response toa tetanus shot and you intervened by making some change in their diet so they made theantibody more quickly than a second group of people who did not have a change in theirdiet. You still have to prove that the people in the first group had more actualresistance to the tetanus. Just because they make the antibody more rapidly does nottranslate into the fact that they had more resistance. That is to say that an improvedresult in a laboratory test is not the same thing as improved health income."

Similarly, research has shown that certain antioxidant substances increase theresistance of a person's lipoprotein against peroxidation. However, this result has notproven in itself that the person has a reduced heart disease or heart attack risk.Handelman explained that there are literally tens of thousands of tests that can be doneon human beings, but in every case it is still necessary to prove that an improved resultin the test corresponds to an improved health outcome.

These important distinctions between in vivo and in vitro, betweenepidemiological and clinical research, and between controlled human studies that look forhealth outcomes vs. those that do not helps explain in part why some or many in themainstream medical community view the body of research on antioxidants as preliminary eventhough Medline contains aproximately 30,000 articles related to free radical oxidationand/or antioxidants. Nevertheless, research on antioxidants is continuing and expanding atan exciting pace, and there is little dispute, even from the most conservative in themedical community, that research exists that at least suggests the potential preventativeor therapeutic role of antioxidants. In other words, one would be hard-pressed to find ascientist, doctor or pharmacist who would say that research on antioxidants is a waste oftime and money. It should also be remembered that human studies that test for healthoutcomes take years to compete, and that this type of research that the medical professionwants to see for antioxidants is right now in the process of being conducted.

"The antioxidant research completed to date has been very compelling," saidHenkel's Clark. "Scientists have made great strides in understanding how antioxidantsinteract within the body and with each other. Each new study brings us closer tounderstanding how antioxidants can promote good health."

Is the Medical Community Ready to Accept Antioxidants?

To gain an understanding of the opinions of the mainstream medical community, the mostobvious place to turn is the American Medical Association (AMA), which defines itself asthe very "voice of the American medical profession." The flagship journal of theAMA is JAMA: The Journal of the American Medical Association, and while thejournal's editorials carry a disclaimer that they represent the authors of the journal andnot those of the AMA, the content of JAMA nonetheless gives clear insight into thepositions, stances and trends of the medical profession. Further, alongside the The NewEngland Journal of Medicine and the British Medical Journal, JAMA isamong the premier medical journals in the English-speaking world. Considering all of this,it is not too great of an overstatement to say that it was a monumental event that JAMAand the AMA's nine specialty Archives journals coordinated theme issues lastNovember to provide a forum to present scientific research about alternative therapies tothe medical community and the public.

Continually in the Nov. 11 JAMA theme issue, contributors commented on themeteoric rise of the public's interest in alternative medical therapies, which werefunctionally defined as interventions neither taught widely in medical schools norgenerally available in U.S. hospitals (i.e. herbal medicine, dietary supplements,homeopathy, energy healing, acupuncture, chiropractic, etc.). Although acknowledging thepopularity of alternative medicine, numerous contributors stated that the scientificresearch conducted on alternative medical practices has been woefully inadequate.

In an editorial, Phil Fontanarosa, M.D., and JAMA editor George Lundberg, M.D.,summarized the opinions of many contributors to the JAMA theme issue. "Despitethe increasing use of alternative medicine in the United States and throughout the world,most alternative therapies have not been evaluated using rigorously conducted scientifictests on efficacy based on accepted rules of evidence," the two doctors wrote."The lack of properly designed and conducted randomized trials is a majorconcern." Later in the editorial, Fontanarosa and Lundberg again railed, "thelack of convincing and compelling evidence on efficacy, safety and outcomes isunacceptable and troubling."

At the same time, the AMA and the editors of JAMA concede, albeit begrudgingly,that dietary supplements have taken a significant role in the health care choices ofmillions of Americans. In another JAMA editorial, Wayne Jonas, M.D., concluded,"Alternative medicine is here to stay. It is no longer an option to ignore it ortreat it as something outside the normal processes of science and medicine. The challengeis to move forward carefully, using both reason and wisdom, as we attempt to separate thepearls from the mud." This may not constitute an endorsement of dietary supplementsand other alternative practices, but it's a start in the right direction.

Keeping in mind the medical community's skepticism toward the amount of conductedresearch and the efficacy of supplement products, it is not difficult to see that thecategory of natural antioxidants faces an uphill struggle in gaining unequivocalacceptance among the majority of doctors and pharmacists. At the same time, however, thecombination of patient interest and increasing research has led the medical community tobecome more aware of antioxidant supplementation.

"Doctors certainly are becoming more aware, primarily because their patients areasking them more questions about antioxidants and supplements in general," said VarroTyler. "But to date, many doctors have not learned about these options in theirmedical school curriculums, so they are just beginning to find out about them. I would saythat there is a small group of doctors that are knowledgeable and have made an effort tounderstand supplements. Then there is a much larger group that is just in the learningstage and generally very interested but not necessarily well-informed."

Many of those in the minority group of doctors who are knowledgeable about dietarysupplements are likely members of the American College for Advancement in Medicine (ACAM).Founded in 1973, ACAM is a non-profit medical society dedicated to educating physicians onthe latest findings and emerging procedures in complementary/alternative medicine, withspecial emphasis on preventive/nutritional medicine. As a listing on the ACAM website atwww.acam.org shows, physicians who are members of ACAM can be found in or near virtuallyevery community in the United States. "The number of doctors who take antioxidantsand are recommending them is increasing," said Janson, ACAM's president. "Forexample, if you look at ACAM, doctor membership has doubled twice in the last 10 years.This increasing interest in dietary supplements by doctors is primarily a result ofpatients demanding to know more about them. Doctors are also forced to look at theoverwhelming medical evidence in support of antioxidants."

Janson argued that there are tangible indications that the medical profession as awhole is moving toward recognizing the utility of supplements. One sign is the increasingfrequency of medical conferences on topics such as antioxidants, nutrition and preventivemedicine. Also, Janson noted the recent publication by Physicians' Desk Reference of PDRfor Herbal Medicine, which he characterized as a "revolutionary" occurance.This text is designed specifically for doctors as a review of available information onindications, pharmacological effects, proper dosage, precautions, adverse reactions,symptoms of overdose, along with exhaustive citations from the scientific literature onherbs and botanicals.

Doctors are not the only health care professionals who are being forced to learn moreabout dietary supplements as a result of public demand. In many cases, pharmacists ratherthan doctors are being quizzed by the public on supplement options such as antioxidants.One reason for this is that pharmacies across the country are devoting more and more shelfspace to dietary supplements, and customers therefore assume that pharmacists have athorough knowledge of these products. Unfortunately, this is often not the case.

"Natural products were probably covered in courses under pharmacognasy, whichmostly has been eliminated from pharmacy school programs in the last 20 or 30 years,"said Robert Anderson, Pharm.D., professor of pharmacy practice at Mercer University inAtlanta. "There is still information on vitamins, but a lot of the herbal medicationshad pretty much gone out of favor in pharmacy school curricula in the late 1960s and early70s. But there is a trend now where it is coming back, and so I think the knowledge baseof the pharmacist is getting adequate. But the difficult thing is trying to assess allthis new information that is coming in almost every day, and I think there is a need formore Continuing Education (C.E.) programs in this area."

According to Herrier of the College of Pharmacy at the University of Arizona, manypharmacists realize the need to bone up on their knowledge of herbs and other supplementoptions. "In terms of C.E. opportunities, topics such as herbal medicines have beenreally high on the request list, and whenever there is a session on one of these topics,it is extremely well attended and there are a wealth of questions from the audience aboutspecific issues. At the last one I attended, the speaker in fact talked about therespective merits of the individual antioxidants."

Comparing the various substances that have been termed antioxidants appears to beimportant to pharmacists. Much of this is due to pharmacists', like doctors', emphasis onscientifically validated research. For example, Rex Force, Pharm.D., assistant professorof family medicine and pharmacy practice at Idaho St. University, is careful todifferentiate one supplement that has been indicated as an antioxidant from another."I don't have any problem recommending that people take a supplemental dose ofvitamin E. Certainly, for people with cardiovascular disease, it is reasonable for them totake a vitamin E supplement," he explained. "They do not have to be inmegadoses--400 or so IUs is appropriate."

Force continued with an evaluation of some other antioxidants. "I don't recommendvitamin A or beta carotene to anyone. Vitamin A/beta carotene has not been shown inprospective studies where it is administered to patients to make a difference. And, infact, in some studies beta carotene has been shown to be harmful. As far as otherantioxidants go, there is really no strong data for vitamin C, particularly with cancerand cardiovascular disease. There are epidemiological studies that suggest diets rich invitamin C reduces risk for these diseases, but when supplements are used in the studies itdoesn't seem to make a difference. I am going to be very conservative about people puttingthings in their body when we don't know what the long-term adverse or beneficial effectsmay be. So I am very evidence-based--show me what types of studies have been done and whatwe really know."

Ziegler of the National Cancer Institute does not find the evidence in support of anyantioxidants to be substantial enough to warrant their role at this time against cancers,which is her area of expertise. "I don't think there is any persuasive evidence atthe present time that oxidative damage plays a critical role in the genesis of cancers. Ialso don't feel that there is strong evidence that vitamins E, C and beta carotene protectagainst cancer by working as antioxidants. I am not saying that they do not, and these areimportant hypotheses that need further exploration. But they have not been proved ordisproved. I am not trying to knock the hypotheses, but I am concerned about making theleap to giving scientific advice to the public on the basis of limited evidence."

However, there can be a range of divergent opinions and interpretations amongscientists and doctors of what constitutes "limited" evidence. Some scientistsbelieve that research to date has shown the validity of antioxidants for the preventionand/or treatment of cancer. "Antioxidants have demonstrated positive results in theprevention or alleviation of many chronic and degenerative diseases such as cancer,"said Debasis Bagchi, Ph.D., director of research and development at InterHealthNutraceuticals and adjunct associate professor at Creighton Universitry. "Recentstudies at the University of Nebraska in Omaha have found that ActiVin, a proanthocyandingrape seed extract, does more than simply neutralize harmful free radicals. It actuallyworks at the genetic level, increasing the activity of tumor suppressor genes anddecreasing the activity of tumor promotion genes."

Differences in awareness of what research is available may also factor into varyingopinions about antioxidants. It likely does not come as a surprise that many doctors andpharmacists are out of the loop when it comes to the wealth of research data that isavailable on some antioxidants. For example, grape seed extract is widely viewed by themedical community as an antioxidant more on the scientific fringe than, say, essentialvitamins. For this reason, grape seed extract is often regarded as new and not welltested. But Paulo Morazzoni, Ph.D., scientific director at Indena S.p.A., supplier ofLeucoSelect Phytosome--derived from grape seed extract--relates a very different story inwhich extensive research of every type has been conducted on grape seed extract. Ininstances such as this one, it may not necessarily be that the research has yet to havebeen done, but rather that American doctors and pharmacists are not aware of the researchthat it is out there on an antioxidant substance.

"Plants such as green tea, grape seed and pine bark are all characterized by theircontent in polyphenols, particularly procyanidins," recounted Morazzoni."Numerous in vitro studies have shown that procyanidins have been indicated inthe test tube to exert a significant antioxidant effect. What makes procyanidins even moreinteresting, in my opinion, is the in vivo situation, which is mainly due to thefact that these procyanidins are contained in dietary foods. And if you considerepidemiology as the science that can provide information about the linkage between, forinstance, the intake of dietary polyphenols and incidence of certain pathologies, what wecan say now in a short summary is that there is strong evidence that the dietary intake ofcertain polyphenols such as procyanidins, because of mostly their antioxidant effect,corresponds to a lower incidence of some diseases."

"There is an additional element in that there have been controlled humanstudies," continued Morazzoni. "In Europe, going back decades, the product ofgrape seed extract has been the subject of controlled human studies and shown to improvecertain pathological situations in the vascular system. It is this kind of documentationin Europe that has allowed the registration of some grape seed products as prescriptiondrugs."

However, there is almost always a need for more scientific investigation. For example,how exactly proanthocyanidins biochemically impact the human body is not yet known. AsBagchi of InterHealth Nutraceuticals noted, grape seed extract does more than simplyquench free radicals. Sevanian of USC recently completed a pre-clinical study onproanthocyanidins and the role they play in the prevention of cardiovascular disease thatutilized Indena's LeucoSelect Phytosome. "The more investigation we do on some ofthese antioxidants, the more we realize that their role is not simply as anantioxidant--that is strictly scavenging free radicals--but that they seem to havefundamental effects on the biochemistry of cells that may be related to antioxidant-typeactivity but not of the classical nature." Sevanian said there are indications thatproanthocyanidins affect the signaling of specific cell membrane proteins that elicitsignals into cells that control the cascade of gene expression.

Papas of Eastman Chemical also explained that antioxidant substances work together inthe human body, and that it is therefore necessary to not oversimplify and/or draw toobroad of conclusions based on research conducted on individual antioxidants. "Therelative ability of antioxidants to prevent oxidation in foods or in vitro systemsis often extrapolated to their antioxidant function in human tissue," he said."Because antioxidants act as components of a complex system, comparisons based on asingle test or criterion are mostly inaccurate and not very meaningful. Antioxidantsshould be viewed as a team, where each member brings special strengths. Vitamin C, forexample is water-soluble, while vitamin E is fat-soluble. Working together, antioxidantsproduce synergies, and their combined action is stronger than the sum of their individualpotential."

The possibility that antioxidant substances function in the human body beyond simply asantioxidants and that antioxidants act in the body in a complex synergistic manner helpsshow what scientists have known for centuries: that research findings often raise morequestions than they answer. However, any scientist will tell you that this phenomenonalmost always indicates that scientific progress is being made. And this is clearly thecase in regard to antioxidant substances and their role in the human body.

A Day When Doctors and Pharmacists are Friends of the Industry

It is estimated that 100 million Americans take dietary supplements--heretofore withlittle or no endorsement from the mainstream medical community. Given this, one mightremark that the dietary supplement industry has and will continue to succeed with orwithout the support of the medical establishment. However, with success comes intensifiedoutside scrutiny from a FDA still smarting from losing the battle over the passage ofDSHEA, a media that thrives on controversial or negative stories, and a legion ofso-called "quackbusters" who unabashedly attack alternative therapies.

Since each of these potential adversaries has a tendency to defer to the judgments ofscientists, doctors and pharmacists, the support of the scientific and medical communitiesis critical to the future of the industry. Already a substantial amount of peer-reviewedpublished research on antioxidants has caught the attention of doctors and pharmacists.Rather than resting on its laurels, the dietary supplement industry should work to seethat research continues, so that the mainstream medical community is converted andintegrated medicine and healthcare can become a reality in this country.