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The term “resveratrol” is found in title, abstract or MESH word in 5425 or 3650 publications following searching on ISI Web of Science or PubMed, respectively. The substantially higher number of hits found in ISI Web of Science was due to abstracts or papers with focus on identification of sources of Resv. All the publications relevant for this systematic review were present in both data bases and the refinement of the search using PubMed is indicated in Figure 1. To identify the cancer preventive potential of Resv, in total 1191 papers were identified (Figure 1A), but by excluding non English papers, reviews and papers analyzing acute or in vitro effects only, 41 articles were found to test Resv in animal model systems, whereas two studies focused on the effect of Resv in human subjects. The effect of Resv on coronary heart diseases was investigated in 118 papers (Figure 1B); whereas only 26 papers show data from non acute animal experiments and one paper was identified investigating effect in humans. Focusing on the effect of Resv on obesity and related diseases such as diabetes, 218 articles were identified. but only 19 animal studies and no human studies focused on non-acute effects of Resv. Neuroprotection by Resv was in focus of 163 papers. but 40 papers concerned animal studies, including both acute exposure and sub- and chronic studies. Lastly, 559 papers focused on resveratrol and inflammation.and of these 31 papers included sub chronic and chronic studies, whereas no human studies focusing on inflammation have been published.
Flow chart of systematic literature search.
The literature search was performed to identify all relevant articles focusing on resveratrol and chemoprevention (A), effect of resveratrol on cardio vascular disease (B), effect of resveratrol obesity and diabetes (C), neuroprotective effect of resveratrol (D) and the anti-inflammatory effect of resveratrol (E). In all five groups, articles with non-english language, review articles and articles showing data from in vitro experiments only are excluded. For chemopreventive effect (A), cardio vascular disease (B), obesity and diabetes (C), also non-chronic animal studies were excluded.
A major challenge for scientists investigating Resv is to prove that it has the health promoting effects, which have been suggested based on the in vitro and animal studies available. Clinical trials with Resv in human subjects focusing on the health promoting effect of Resv are lacking. Therefore, these studies have the highest priority in recommendations from the scientific working group. Two clinical trials have been recently published analyzing the effect on biomarkers of intermediary metabolism: 2.5 g Resv/day for 29 days was found to significantly reduce the plasma level of insulin-like growth factor-1 and insulin-like growth factor binding protein-3 indicating a possible cancer preventive effect. whereas daily doses of 0.5 and 1.0 g Resv/day for 29 days caused a reduction of cell proliferation in colon cancer tissue.
Most of the available clinical studies with Resv in humans focus on bioavailability, pharmacokinetics and metabolism of Resv. These studies showed that Resv was rapidly absorbed after oral intake; a maximal plasma concentration of Resv obtained after 30 to 60 minutes. Further, the level of Resv in the blood stream was low, likely caused by rapid metabolism to glucuronide and sulphate conjugates. In addition to the studies described above, levels of Resv after ingestion of Resv-containing items such as wine or grape juice have been investigated. However, the specific effect of Resv is difficult to estimate when given as part of food matrices.
Two clinical studies were described by Elliott et al., where the effect of Resv on type 2 diabetic patients was tested at 2.5 or 5.0 g/day for 28 days. The levels of fasting and postprandial plasma glucose and postprandial serum insulin were statistically significantly decreased with 5.0 g/day, but the experimental details were not given. The tissue distribution of Resv and its metabolites was estimated in a study where twenty colon cancer patients received 0.5 g or 1.0 g Resv daily for eight days before surgical resection. The level of Resv was found in colon tissue at a level sufficient to elicit anticarcinogenic effects observed in in vitro tests. A recent experiment showed that single doses of 250 and 500 mg Resv significantly increased cerebral blood flow but the cognitive performance was unaltered.
Several clinical trials of oral Resv as a pure compound or using Resv-rich products (grapes and grape juice) are under way. In total, 24 clinical studies are listed at the homepage having Resv as the major experimental subject or as part of a clinical trial. Therefore, it is our recommendation that clinical trials should focus on biomarkers of cancers, diabetes and metabolic syndromes as well as neurological diseases. Based on the limited number of human studies, the working group has concluded that there is not at the moment enough available and scientifically valid data on the effect of Resv to conclusively state whether it could be a disease preventive substance in humans or could be used for human life extension It is therefore vital to perform such studies.
Based on animal studies, Resv is generally well tolerated, and only very few short-term or acute exposure experiments in humans have been performed. When eight healthy subjects were exposed to 2000 mg Resv twice/day for eight days, six of eight subjects had mild episodic diarrhea/loose stool, typically in the beginning of the eight days treatment period, and one of the subjects developed a temporary rash and headache. In a double-blinded, randomized, placebo-controlled study, up to 975 mg/day were given to healthy volunteers, where two adult subjects (male and female) in each group were subjected to 25, 50, 100 or 150 mg, six times/day, for two days in total. Adverse effects were mild in severity and similar between all groups. Repeated administration of Resv was well-tolerated but produced relatively low plasma concentrations of Resv, despite the high doses and short dosing interval used. Exposure of up to 270 mg Resv to 19 volunteers for one week did not cause any discomfort.
According to Elliott et al. healthy volunteers tolerated Resv well in a seven-day exposure study, but experimental details were not provided thus making evaluation of results challenging. The same article describes very briefly a study which included daily exposure to 2.5 g or 5 g Resv for 28 days. The authors reported that “Adverse events were generally mild in nature and reversible” but no experimental details are shown, which made a closer evaluation impossible. The 20 colon cancer patients receiving 0.5 g or 1.0 g Resv daily for eight days before surgical resection tolerated it well. It is difficult to estimate the normal human consumption of Resv as the intake of red wine (verified main source of Resv) differs greatly in the population and the content of Resv varies (mean 1.9±1.7 mg/L). but the dose may be up to 4 mg/person/day.
Only a single experiment has tested Resv in a classical chronic exposure experiments, i.e. at least 24 months in rats or 18 months in mice and Resv does not in general cause any toxic effects in animal studies published except at doses above 1 g/kg bw/day. Besides acute exposure to Resv, several sub chronic experiments have indicated low toxicity. In male Sprague-Dawley rats, 20 mg Resv/kg bw/day given for 28 days did not indicate systemic toxicity. Oral doses of 300, 1000 or 3000 mg Resv/kg bw/day for 28 days only showed toxic effects in the 3000 mg treatment group (CD rats, both sexes). where nephropathy and renal toxicity were observed as well as changed clinical markers of liver metabolism. Exposure of Wistar rats to Resv (50, 150 or 500 mg/kg bw/day) for four weeks or three months to 120, 300 or 700 mg/kg bw/day did not show significant toxicological effects. An additional study of 28 days in rats is mentioned by Elliott et al., which showed “a no effect level” at 300 mg/kg bw/day but no experimental details were given and the results could not be fully evaluated. CD rats (both sexes) exposed to 0, 300, 1000 or 3000 mg Resv/kg bw/day by gavages for 28 days showed only mild liver toxicity as well as nephrotoxicity when exposed to the highest dose. In a study, where female Sprague-Dawley rats were exposed to Resv (1 g/kg diet, corresponding to about 100 mg/kg bw/day in an adult), for the entirety of their life starting at birth showed no toxicological signs such as reduced food intake, reduced body weight, or delayed sexual maturation.
In mice (C57BL/6 p53−/−) oral administration of Resv (1000, 2000, 3000, 4000 or 5000 mg/kg bw/day) showed an increased death rate caused by impaction of Resv in the gastrointestinal tract. Long term administration of Resv in drinking water (14 mg/L water) to mice for six months cause a reduced organ weight but these differences were not present in a corresponding 12 month experimen. Elliott et a cites a study of Resv exposure to rabbits: Severe toxicity was observed at high doses with the kidney as the primary target. The ‘no effect level’ was estimated at 500 mg/kg bw/day in males and 250 mg/kg bw/day in females. but no further details were given in the paper. Likewise, Elliott et al. cites a study on the effect of Resv in dogs for 28 days, which showed no toxic effects at 300 mg Resv/kg bw/day, but no details were given. Several experiments have shown that Resv does not have genotoxic activity, based on the Ames test. but experimental details are too limited to evaluate the data fully. Supporting this, there was no increase in the frequency of micronucleated immature erythrocytes observed in rats exposed to up to 200 mg Resv/kg bw/day.
Reproductive toxicity was evaluated in rats and the maternal ‘no observed adverse effect level’ (NOAEL) was estimated at 300 mg/kg bw/day and the developmental NOAEL was estimated at 300 mg/kg bw/day, but no experimental details were given. A study described by Williams et al, indicated that the NOAEL for maternal toxicity and embryo–fetal development was around 750 mg Resv/kg bw/day. Based on these observations, the paper concluded that a daily dose of 450 mg was safe for a 60 kg person, using a 10 fold safety factor which is further the basis of the self affirmed GRAS (Generally Recognized As Safe) status up to 450 mg Resv/day from several Resv producers.
Several examples of self reported side effects of Resv intake may be found on various homepages from the internet, but there is no comprehensive evaluation of these self reported side effects. Based on the available data, which mostly originate from studies of very short duration, the working group formulated the following conclusions:
Article Produced By
Department of Science, System and Models, Roskilde University, Department of Science, System and Models, Roskilde University, Department of Dermatology, University of Wisconsin, Madison, Wisconsin, United States of America, Department of Animal and Dairy Science, University of Georgia, Department of Physiology and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Department of Cancer Studies and Molecular Medicine, The Biocentre, University of Leicester, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Cardiovascular Research Center, University of Connecticut School of Medicine, Farmington, Connecticut, United States of America, INSERM U866, University of Burgundy, Department of Biochemistry, Postgraduate Programme of Biochemistry, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Signal Transduction Laboratory, Ordway Research Institute, Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Laboratory of Physiological Studies, Section on Oxidative Stress Tissue Injury, National Institutes of Health, Department of Biochemistry and Biotechnology, Annamalai University, College of Pharmacy, University of Hawaii at Hilo,15 UFR Pharmacie, University of Bordeaux, Proteomics Laboratory, Indian Institute of Toxicology Research, College of Pharmacy, Seoul National University, Clinical Institute of Medical and Chemical Laboratory Diagnostics, General Hospital of Vienna, Medical University of Vienna, Department of Animal Physiology and Biochemistry, August Cieszkowski University of Agriculture, Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Department of Biochemistry and Molecular Biology, New York Medical College,
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116821/
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