This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Resveratrol (3,5,4-trihydroxy-trans-stilbene) is a compound found in grapes, mulberries, peanuts and Cassia quinquangulata plants which may help to protect against potential pathogens [Jang et al., 1997]. It has been reported to have antioxidant properties, and as a constituent of red wine it has been implicated as one possible explanation for the French paradox, i.e. the finding that the incidence of coronary heart disease is relatively low in southern France despite the high dietary intake of saturated fats. Resveratrol has also been reported to possess a variety of anti-inflammatory, anti-platelet, and both pro- and anti-estrogenic effects. These may indicate that resveratrol could be used as a cancer chemopreventive. The objectives of this study are to characterize potential adverse effects in humans associated with a single oral dose of resveratrol, and to measure levels of resveratrol and its metabolites in plasma, urine, and feces at different timepoints after the dose has been taken. We want to understand the relationship between the size of the dose and the levels of resveratrol and its metabolites in the body over time. Special emphasis will be placed on the identification and characterization of resveratrol metabolites using chromatographic techniques coupled with mass-spectrometry. This study, to be conducted at the University of Michigan and the University of Leciester in the United Kingdom, will be a two-site, phase I dose-escalation clinical trial of a single dose of oral resveratrol. Participants will be healthy persons aged 18 to 80 who are willing to comply with the protocol requirements. The doses we will be using are 1.0, 2.5, 5 and 7.5 grams. Participants will be enrolled on a first come first serve basis to each dose level in cohorts of 10 participants per level. If there are no unacceptable adverse events within one week after the last patient at each level has taken their dose, then participants will be added at the next dose level. Should any two participants in a level experience an unacceptable drug-related adverse event (defined as Grade 2 or higher according the Common Toxicity Criteria), recruitment at that level will cease and the level below it will be increased to a studywide total of 16 participants. This lower dose will be defined as the maximum tolerable dose and the study would then be concluded. If there are two or more further adverse events in the further six participants at this dose level (whether there have been six participants or fewer) then the dose will be reduced again (to the previous dose) and a further six participants recruited at this level (and repeated until there have been sixteen participants at one specific dosing level). If there are no adverse events experienced by the participants, there will have been a total of 40 participants and the study will be concluded. From available data it is unlikely that the study will reach the maximum tolerated dose of resveratrol in healthy participants, however if the maximum tolerated dose (MTD) is achieved the study will be thus concluded.
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