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  • Letter to the editors of Harvard Health Letter

    January 30, 2011: by Bill Sardi

    Re: Resveratrol not ready for humans yet.

    While it is true that supplemental resveratrol lacks human studies regarding heart health, it appears modern medicine is dragging its feet here.  Human studies should have ensued by now.   A review at the NIH Clinical Trials website reveals none appear to be even in the planning stages.

    The big problem is that the primary end point is cardiac death and there is no ethical way to rapidly test a high-risk group against plain placebo.  Almost every adult with heart disease is taking vitamins or medications that may interfere with the results, particularly because resveratrol influences cytochrome P450 liver enzymes and may require dosage adjustment of cardiac drugs in use.(1) Also results are years away and thousands of subjects would have to be tested for a period of up to 5-years to obtain conclusive coronary artery disease mortality data.

    It may be easier for modern medicine to retrospectively analyze mortality data among resveratrol pills users like aspirin was first studied than to launch a prospective study.  To do that, cardiologists would have to start identifying patients already taking resveratrol pills.  But unlike aspirin which generally is provided in two standard doses (81 mg and 325 mg), resveratrol pills come in a wide dosage range (20-1000 mg), making analysis difficult.

    The advice from the Harvard Health Letter, that consumers are “better off enjoying a glass of red wine with your dinner than dutifully choking down several tasteless resveratrol pills a day,” needs to be re-thought.

    Roger Corder, researcher at the William Harvey Research Institutes in London and author of the WINE DIET, says it is the polyphenols in dark, aged red wine, about 60 mg per 5-oz glass, which provides the heart healthy benefits.(2)

    There is little question that 3-5 glasses of dark red wine, providing ~60 mg of total polyphenols per 5-oz glass (180-300 mg total polyphenols), providing just 3-5 mg of resveratrol, exhibits a U-shaped risk curve for coronary artery disease mortality.(3) That much red wine however would cost $3-5 a day for even the most economical dark, aged red wine.  Further, that amount of red wine approaches inebriation.

    For comparison, we find the Cochrane group concludes statin drugs are of little value for healthy adults(4) and an analysis by John Abramson MD (author, OVERDOSED AMERICA) shows there is no significant reduction in mortality from statin drug use in individuals at low risk for a sudden mortal heart attack.(5)

    Another primary prevention strategy is aspirin therapy.  However, about half of the people incurring a sudden mortal heart attack were taking aspirin on the day of their demise.  A report in the American Journal of Medicine(6) indicates an 81 mg baby aspirin is insufficient to reduce clots in coronary arteries and a 325 mg aspirin tablet induces sometimes-mortal bleeding gastric ulcers and brain hemorrhages.

    So we largely have disproven technologies being promoted by modern medicine against an unproven one in resveratrol pills.  This is why there is great interest in resveratrol pills, particularly because there is no alcohol as in wine.

    A safe and effective dosage range of resveratrol –175-350 mg human equivalent dose 160-lb subject–(7) has been demonstrated to pre-condition the heart in animals that would turn a mortal heart attack into a non-mortal event.  Resveratrol upregulates protective nitric oxide, adenosine and heme oxygenase prior to a heart attack.  Resveratrol also inhibits clotting, reduces cholesterol plaque and markers of inflammation (C-reactive protein, COX-2), so it theoretically offers broader biological action than statin drugs or aspirin tablets.

    So, in essence, healthy adults are being led towards two preventive measures, aspirin and statins, which have failed scientific scrutiny and have produced a false sense of protection.  These facts should further accelerate the impetus to put resveratrol to a fair trial as lives are needlessly being lost.

    Bill Sardi, managing partner
    Resveratrol Partners LLC
    Las Vegas, NV


    Harvard Health Letter, Nov. 2010

    Resveratrol for a longer life — if you’re a yeast

    The cardiovascular promise of this red wine compound has not been confirmed in humans.

    Oh, the hype one molecule can generate. That has been the fate of resveratrol, a substance found in red wine that some research suggests accounts for the cardiovascular benefits of red wine.

    Experiments in the early 2000s showed that resveratrol extended the life spans of yeast and other relatively simple organisms. Since then, media reports have extolled its virtues with headlines like “Fountain of youth in the bottom of a wine bottle” and “Want to slow down aging? Pop some red wine pills.” Supplement makers have scurried to peddle resveratrol pills and red wine extracts, saying they will prevent heart disease and cancer, conquer obesity, and extend life. Americans have responded, buying millions of dollars worth of such supplements each year.

    Here is what’s actually known about resveratrol, and why you should avoid this trendy supplement for now.

    A knockout in the laboratory

    Several species of plants make resveratrol to fight off bacteria, fungi, and other microbial attackers, or to withstand drought or lack of nutrients. Resveratrol has been found in red and purple grapes, blueberries, cranberries, mulberries, lingonberries, peanuts, and pistachios. It is also abundant in the roots of Japanese knotweed, an Asian plant that has become a hard-to-eradicate invader in the United States.

    In 1992, two Cornell University plant scientists suggested that resveratrol might be responsible for the cardiovascular benefits of red wine. Since then, hundreds of reports have indicated that resveratrol may protect against cancer, cardiovascular disease, vascular dementia, and Alzheimer’s disease, and may extend the life span.

    Exactly how resveratrol could do all this is still a mystery. One possibility is that resveratrol turns on genes that make sirtuins, ancient proteins found in virtually all species. Activating sirtuins and the genes that code for them kicks off a response that fights disease and prolongs life. Other research suggests that resveratrol may

    • act as an antioxidant, working against the buildup of cell-damaging free radicals and preventing the oxidation of LDL (bad) cholesterol
    • ease inflammation, which could help protect arteries
    • prevent platelets from sticking together, which could prevent heart attack and stroke
    • provoke cancer cells to die spontaneously, a process known as apoptosis.

    A harsher reality

    With a list like that, it’s hard not to run out and buy a bottle of resveratrol. Here are several reasons to stay put:

    Lab ≠ humans. Virtually all of the positive studies on resveratrol have come from cultures of cells or laboratory experiments with yeast, roundworms, fruit flies, the short-lived turquoise killifish, or mice. The few human studies have looked at specific intermediate markers, such as levels of antioxidants, heart rate variability, blood flow to the brain, and amounts of cancer proteins. None have measured long-term health or survival.

    Unknown side effects. Resveratrol acts on many different tissues in the body. It is chemically related to estrogen — in some situations boosting the activity of estrogen, in others blocking it. Until more is known about resveratrol and estrogen, women with cancer of the breast, ovary, uterus, or other estrogen-sensitive tissue should stay away from resveratrol, along with women trying to become pregnant or those taking an oral contraceptive. By making platelets less “sticky,” resveratrol could increase the risk of bleeding in people who take warfarin (Coumadin), clopidogrel (Plavix), aspirin, ibuprofen, or other nonsteroidal anti-inflammatory drugs. Resveratrol, like grapefruit, inhibits a key enzyme called cytochrome P-450 3A4, so high doses could increase side effects from certain statins and other medications. Finally, a clinical trial of an experimental resveratrol-like anti-cancer drug was stopped early when the trial’s safety panel observed a higher-than-expected number of cases of kidney damage.

    Buyer beware. Dietary supplements such as resveratrol aren’t covered by the same strict FDA rules that govern prescription and over-the-counter drugs, so you can’t be sure what you are getting. A review by ConsumerLab, an independent organization, also found a huge difference in price from brand to brand. One cost just 20 cents per 100 milligrams of resveratrol, while another cost $45 per 100 milligrams.

    Unanswered questions

    Resveratrol sounds like a wonder pill. But there are important questions still to be answered:

    • Does resveratrol really protect against heart disease, cancer, and other chronic diseases or extend a healthy lifespan in humans?
    • How much resveratrol is needed to achieve these goals? Studies use the amount in 300 glasses of red wine.
    • What harmful side effects does resveratrol have, and how does it interact with foods and medications?
    • Does pure resveratrol work, or does its action depend on other plant compounds?

    Until we have answers to these questions, you are better off enjoying a glass of red wine with your dinner than dutifully choking down several tasteless resveratrol pills a day.

    Date Last Reviewed: 11/1/2010
    Date Last Modified: 11/1/2010


    References:

    1. Cancer Prevention Research (Phila). 2010 Sep;3(9):1168-75.

    Resveratrol modulates drug- and carcinogen-metabolizing enzymes in a healthy volunteer study.

    Chow HH, Garland LL, Hsu CH, Vining DR, Chew WM, Miller JA, Perloff M, Crowell JA, Alberts DS.

    Arizona Cancer Center, The University of Arizona, Tucson, AZ 85724, USA. schow@azcc.arizona.edu

    Abstract

    Resveratrol has been shown to exhibit cancer-preventive activities in preclinical studies. We conducted a clinical study to determine the effect of pharmacologic doses of resveratrol on drug- and carcinogen-metabolizing enzymes. Forty-two healthy volunteers underwent baseline assessment of cytochrome P450 (CYP) and phase II detoxification enzymes. CYP1A2, CYP2D6, CYP2C9, and CYP3A4 enzyme activities were measured by the metabolism of caffeine, dextromethorphan, losartan, and buspirone, respectively. Blood lymphocyte glutathione S-transferase (GST) activity and GST-pi level and serum total and direct bilirubin, a surrogate for UDP-glucuronosyl transferase (UGT) 1A1 activity, were measured to assess phase II enzymes. After the baseline evaluation, study participants took 1 g of resveratrol once daily for 4 weeks. Enzyme assessment was repeated upon intervention completion. Resveratrol intervention was found to inhibit the phenotypic indices of CYP3A4, CYP2D6, and CYP2C9 and to induce the phenotypic index of 1A2. Overall, GST and UGT1A1 activities were minimally affected by the intervention, although an induction of GST-pi level and UGT1A1 activity was observed in individuals with low baseline enzyme level/activity. We conclude that resveratrol can modulate enzyme systems involved in carcinogen activation and detoxification, which may be one mechanism by which resveratrol inhibits carcinogenesis. However, pharmacologic doses of resveratrol could potentially lead to increased adverse drug reactions or altered drug efficacy due to inhibition or induction of certain CYPs. Further clinical development of resveratrol for cancer prevention should consider evaluation of lower doses of resveratrol to minimize adverse metabolic drug interactions.

    PMID: 20716633
     
    2. Clin Sci (Lond). 2002 Aug;103 Suppl 48:72S-75S.

    Comparison of red wine extract and polyphenol constituents on endothelin-1 synthesis by cultured endothelial cells.

    Khan NQ, Lees DM, Douthwaite JA, Carrier MJ, Corder R.

    William Harvey Research Institute, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, U.K.

    Abstract

    Regular consumption of red wine reduces mortality from coronary heart disease. This observation has been attributed to the anti-thrombotic effects of ethanol and to the antioxidant properties of polyphenolic compounds present in red wine. Here we show that an extract of red wine polyphenols causes a concentration-dependent inhibition of endothelin-1 synthesis in cultured bovine aortic endothelial cells. This action was associated with modifications in phosphotyrosine staining, indicating that the active components of red wine cause specific modifications of tyrosine kinase signalling. Thus inhibition of endothelin-1 synthesis by red wine may reduce the development of atherosclerosis, and hence decrease coronary heart disease.

    PMID: 12193058
     
    3. Annals N Y Academy Science 2002 May;957:16-20.

    Alcohol, type of alcohol, and all-cause and coronary heart disease mortality.

    Grønbaek M.

    Centre for Alcohol Research, National Institute of Public Health, Danish Epidemiology Science Centre, Copenhagen, Denmark. MG@si-folkesundhed.dk

    Abstract

    Many studies from a variety of countries have shown a U- or J-shaped relation between alcohol intake and mortality from all causes. It is now quite well documented from epidemiologic as well as clinical and experimental studies that the descending leg of the curve results from a decreased risk of cardiovascular disease among those with light-to-moderate alcohol consumption. The findings that wine drinkers are at a decreased risk of mortality from cardiovascular disease compared to non-wine drinkers suggest that substances present in wine are responsible for a beneficial effect on the outcome, in addition to that from a light intake of ethanol. Several potential confounding factors still remain to be excluded, however.

    PMID: 12074958
     
    4. Cochrane Reviews January 19, 2011

    Statins for the primary prevention of cardiovascular disease

    Taylor F, Ward K, Moore THM, Burke M, Davey Smith G, Casas J-P, Ebrahim S. Statins for the primary prevention of cardiovascular disease. Cochrane Database of Systematic Reviews 2011, Issue 1. Art. No.: CD004816. DOI: 10.1002/14651858.CD004816.pub4

    http://www2.cochrane.org/reviews/en/ab004816.html

    Authors’ conclusions

    Although reductions in all-cause mortality, composite endpoints and revascularisations were found with no excess of adverse events, there was evidence of selective reporting of outcomes, failure to report adverse events and inclusion of people with cardiovascular disease. Only limited evidence showed that primary prevention with statins may be cost effective and improve patient quality of life. Caution should be taken in prescribing statins for primary prevention among people at low cardiovascular risk.
     
    5. Lancet. 2007 Jan 20;369(9557):168-9.

    Are lipid-lowering guidelines evidence-based?

    Abramson J, Wright JM.

    Harvard Medical School, Cambridge, Massachusetts, USA.

    PMID: 17240267
     
    6. Am J Med. 2006 Mar;119(3):198-202.

    Aspirin to prevent heart attack and stroke: what’s the right dose?

    Dalen JE.

    University of Arizona, Tucson 85718, USA. jamesdalen@yahoo.com

    Abstract

    Despite hundreds of clinical trials, the appropriate dose of aspirin to prevent myocardial infarction (MI) and stroke is uncertain. In the US, the doses most frequently recommended are 80, 160, or 325 mg per day. Because aspirin can cause major bleeding, the appropriate dose is the lowest dose that is effective in preventing both MI and stroke because these two diseases frequently co-exist. Five randomized clinical trials have compared aspirin with placebo or no therapy for the prevention of stroke and MI. These trials varied with regard to the dose of aspirin, the duration of treatment, and, most important, the populations selected for study varied in their baseline risk of stroke and MI. In men, 160 mg/day consistently lowered the risk of MI. In women, doses of 50 mg, 75, and 100 mg/day did not significantly decrease the risk of MI; therefore, the appropriate dose in women must exceed 100 mg/day. The appropriate dose for the primary prevention of stroke in men and women has not been established. Doses of 75 and 100 mg/day have been ineffective in men and women. The appropriate dose must be at least 160 mg/day. The lowest dose to prevent recurrent MI or death in patients with stable coronary artery disease (CAD) is 75 mg/day. In acute MI the lowest dose is 160 mg/day. In patients with a history of stroke or transient ischemic attack (TIA), 50 mg/day has been shown to be effective in men and women. In acute stroke, 160 mg/day is effective in preventing recurrent stroke or death. The risk of major bleeding with 160 mg/day is the same as with 80 mg/day: 1 to 2 cases per 1000 patient years of treatment, and the risk of fatal bleeding is the same with 80 and 160 mg/day. These studies indicate that the most appropriate dose for the primary and secondary prevention of stroke and MI is 160 mg/day.

    PMID: 16490462
     
    7. Journal Nutritional Biochemistry 2009 Jun;20(6):443-52..

    Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose.

    Dudley J, Das S, Mukherjee S, Das DK.

    Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, CT 06030-1110, USA.

    Abstract

    Recent studies have demonstrated the cardioprotective abilities of resveratrol, a polyphenolic antioxidant present in red wine. Resveratrol can also kill cancer cells at relatively higher doses by exerting a death signal. We reasoned that resveratrol might possess the ability to protect the cells at lower doses as observed during pharmacological preconditioning of the heart, while at higher doses cause cell death as found for cancer cells. To test this hypothesis, rats were randomly fed for 14 days by gavaging any of the four doses of resveratrol – 2.5, 5.0, 25 or 50 mg/kg – while vehicle-fed animals served as placebo control. After 14 days, isolated working hearts were prepared from both experimental and control animals, and the hearts were subjected to 30-min global ischemia followed by 2 h of reperfusion. The rats fed either 2.5 or 5 mg/kg dose of resveratrol for 14 days provided cardioprotection as evidenced by improved post-ischemic ventricular recovery and reduction of myocardial infarct size and cardiomyocyte apoptosis compared to control. In contrast, the hearts fed either 25 or 50 mg/kg dose of resveratrol depressed cardiac function and increased myocardial infarct size and number of apoptotic cells. The results for Western blots and RT-PCR demonstrated an increase of protein and RNA transcripts of redox proteins including thioredoxin (Trx)-1, Trx-2, glutaredoxin (Grx)-1, Grx-2, redox factor Ref-1 as well as redox-sensitive transcription factor NFkappaB, and survival factors such as phosphorylated-Akt (p-Akt), and Bcl-2 in the animals fed lower doses (2.5 and 5 mg/kg) of resveratrol, while the reverse was true for the animals fed higher doses (25 and 50 mg/kg) of resveratrol. The results thus indicate that at lower doses (2.5 or 5 mg/kg), resveratrol exerts survival signal by up-regulating anti-apoptotic and redox proteins Akt and Bcl-2, while at higher doses (>25 mg/kg), it potentiates a death signal by down-regulating redox proteins and up-regulating pro-apoptotic proteins.

    PMID: 18789672

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