Pharma’s Cutting Edge

It was hard to miss last week’s News Release  and related press regarding the recent mouse study of resveratrol in Nature (sub. req.).  In a nutshell, resveratrol appeared able to prevent many of the deleterious effects of over-eating/obesity and extended the lives of obese mice.  The study’s senior author (David Sinclair, from Harvard) is co-founder of Sirtris Pharmaceuticals, a start-up that hopes to profit from the research.  The WSJ did a nice piece on resveratrol and related research just before the study’s announcement (sub req).

Why am I writing on the topic?  First of all, I don’t think any line of research today interests me more.  For as long as I’ve been in the biz, I’ve thought that the holy grail of obesity research is a therapeutic that ameliorates the effects of fat accumulation on cardiovascular risk.  The resveratrol researchers appear to share my belief.  But besides that I wanted to echo some of the cautious remarks being made in response to it.  It’s not that I think the research is invalid; it’s that I think it’s too early to risk taking high doses of resveratrol until more is known about it from human studies, which are recently underway in cancer patients and diabetics.

Some expert commentary made in response to the publication mentions having to drink hundreds of bottles of red wine daily to get the same levels of resveratrol given to the mice.  These comments are clearly intended as some sort of pseudo-warning to those who would consider boosting their intake of wine.  They’re not going to deter anyone with half a brain who is interested in applying this research directly to look for a way to do so.  The way, of course, is to take supplements.  Dr. Sincair himself proudly admits to doing so for several years, implying that it’s okay for others to do so.  It’s not.

As much as I’d like to believe that resveratrol or its cogeners will be life-extending to people, I’ve learned not to let my hopes serve as a substitute for evidence.  It’s one thing to consider using a supplement that has been extensively tested in people (think vitamin C, E, etc); it’s quite another to consider taking a supplement like resveratrol, for which clinical experience is scant.  The risk of harm is high and the risk of benefit is speculative at best. 

There’s no more reason to think resveratrol is safe to experiment with than there is reason to think that a synthetic new molecular entity in Phase 1 clinical trials is safe to experiment with.  Indeed, because resveratrol is not synthetic and not regulated by FDA it faces unregulated hurdles to its use prior to clinical testing.  That means no requirements for toxicology studies conducted under Good Laboratory Practices (GLP) and no required standards for drug-substance or drug-product quality under Good Manufacturing Practices (GMP).  There are also no standards for commercially available resveratrol supplements that may be used to compare the quality of the supplements from lot to lot or between manufacturers.  None of the manufacturers’ websites I visited disclosed the methods they used to isolate resveratrol nor data on intra- or inter-lot variability of resveratrol quantity (by HPLC or another reliable method).  None of the supplements I saw were certified by the USP or another third-party quality assurance laboratory.  Couple this lack of product-quality data with the reportedly markedly low systemic oral bioavailability when resveratrol is used alone (NB for this reason resveratrol supplements often include other natural compounds, such as quercetin, intended to, but not proven to, increase its systemic bioavailabilty in humans) and the lack of information on drug-food and drug-drug interactions, and you have a perfect storm–a medical disaster waiting to happen.

In other words, buyer beware and buyer, please be careful.  If you are going to experiment with resveratrol despite my admonitions, find a manufacturer of some repute and have yourself checked out by a doctor soon after starting.  I wish I could advise you well on the appropriate starting dose.  I’ll do the best I can.  In the Nature study, the mice had the observed benefits while eating a diet containing resveratrol at a dose of 0.04% (wt/wt).  This was reportedly roughly equivalent to 24 mg/kg/day.  Assuming that this dose really was non-toxic, and assuming the supplement you choose provides systemic bioavailability similar to what was provided by the dietary resveratrol, and further assuming that interspecies toxic effects scale on a mg/kg basis, you can use a scaling factor of 0.08 to find the human equivalent dose that will provide a safe starting dose.  In other words multiply 24 by 0.08, and that gives you the human equivalent dose in mg/kg.  So, a dose of 2 mg/kg/day might be considered a maximally recommended starting dose, given the myriad assumptions.  I’d suggest adding additional safety margins if the chosen supplement contains high levels of other substances intended to decrease the metabolism of resveratrol.