Resveratrol in human cancer chemoprevention - Choosing the 'right' dose.
From PubMed:
http://www.ncbi.nlm....2?dopt=Abstract
Abstract
There is now robust preclinical evidence to suggest that resveratrol possesses cancer chemopreventive properties. A series of clinical pilot studies has provided insights into its pharmacokinetics, and data on its human antineoplastic pharmacodynamics start to emerge. It is likely that resveratrol will be developed further in the clinic as a putative cancer chemopreventive agent. The question that remains unresolved is: What is the most suitable dose of resveratrol for effective cancer preventive intervention? Mechanistic studies in cells in vitro have almost invariably used concentrations of resveratrol in the 10(-5) to 10(-4) ?M range, which is much higher than those which can be achieved in the human biophase after consumption of doses up to 1?g. Many of the preclinical efficacy studies in rodent models of carcinogenesis have employed doses which are dramatically above those which can be ingested with the diet. New experimental paradigms need to be used to obtain information on pharmacological changes elicited by resveratrol when present at very low concentrations or when administered at dietary-relevant doses.
From the paper itself:
3.3 High dose versus dietary dose
How can we exploit the information emanating from the results of the preclinical experiments and human pilot studies outlined above to optimise the design of future chemoprevention intervention trials of resveratrol? The data presented above need to be interpreted from two different standpoints: resveratrol has been, and is being, studied on the one hand at low doses relevant to its role as a dietary constituent, and on the other hand at high doses as a synthetic bioactive agent, which just happened to be isolated from fruits originally. It is pertinent to stress that there are not many studies in the literature in which dietary-relevant doses of resveratrol have been studied.Both approaches constitute different paradigms and need to be interpreted separately. Efficacy in rodents has been reported at low 12, 15 and high doses 16-18. Nevertheless, the lack of extended dose-response relationships encompassing dietary doses in most of the models renders it impossible to ascertain which model responded only to high doses, and whether the efficacy of low-dose resveratrol in the azoxymethane- and dimethylhydrazine-induced rat colon cancer models 12, 15 was also observed at high doses. To enable the identification of optimal doses with maximal efficacy in vivo, more comprehensive analysis of a wide dose range is needed in each preclinical system. If the dose chosen for clinical intervention studies is to be based on the results of the published in vitro experiments using cultured cells, it appears that doses capable of generating tissue levels exceeding -5 pM would be required, since this is arguably the lowest concentration at which resveratrol precipitates biochemical changes consistent with anti-cancer activity. Thus far, the highest well-tolerated dose reported in clinical trials in which resveratrol was administered repeatedly is 1 g 22, 23. This regimen afforded peak plasma levels of parent compound below 5 pM; however, peak plasma concentrations of resveratrol conjugates were close to, or above, this value (Table D. Inthe mammalian organism, resveratrol undergoes avid metabolism by conjugation with sulphate and glucuronic acid, and the levels of resveratrol sulphates and glucuronides in the blood of individuals who consumed resveratrol dramatically exceed those of parent agent. Little is known about the pharmacological properties of resveratrol conjugates, although recent in vitro studies hint at the possibility that resveratrol-3-0-sulphate and resveratrol-4'-0-sulphate may contribute to some of the pharmacological properties elicited by their parent 32, 33. If the sulphate and/or glucuronide metabolites will be proven to contribute to activity, a dose of 1 g resveratrol may potentially yield efficacious plasma levels of total resveratrol species. Furthermore, the levels of resveratrol measured in human colorectal tissue after repeated oral ingestion of 1 g 25 were consistent with concentrations at which resveratrol elicits anti-carcinogenic effects in cells in vitro and those achieved in the gastrointestinal tract of Apc min mice after a dose which interfered with adenomagenesis 17 (Table D. The above consideration suggests that 1 g might be a potentially suitable dose for colorectal cancer chemopreventive activity. Nevertheless, one needs to be extremely mindful that this dose of resveratrol can modulate drug metabolising enzyme activity 24 and may thus cause untoward drug interactions, so lower doses may be necessary in certain populations.
Again, I suggest talking to a doctor when considering this information as no supplement company will state that it can help without getting into trouble with the FDA. Most resveratrol used in studies is dissolved and tends to be micronized or smaller.
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Edited by Anthony_Loera, 06 January 2012 - 10:35 PM.
