OK David and Richard, I'll bite at a commentary on modafinil and obesity. I must start out by stating that I am neither long or short, CEPH, though I know several researchers and principals at the company. I do think that CEPH is currently a good buy if one gets beyond the "snake oil" commentaries of the past. One of my hobbies (read passion) is understanding the mechanisms of type 2 diabetes, obesity and the molecular mechanisms involved in the control of food intake and satiety.
First of all, after a brief reading of the modafinil published literature, I denote that this compound has alpha 1 adrenergic receptor-like activity. It's effects on several but not all endpoints are blocked by either prazosin or by phenoxybenzamine, or both. Nonetheless, its mechanism and site of action are unknown. It has been shown to increase glucose utilization in several CNS sites, indicated increased metabolic activity at those sites. IT has been shown to increase glutamate release, and either increase or decrease GABA release, depending on the site of action. It has been presumed that these are indirect effects of the drug. It has also been shown to decrease glutamate induced toxicity in neuronal cells in culture. Mechanisms related to both 5HT2 and 5HT3 have been suggested. Finally, the compound has been shown to increase neuronal c-fos activation in the suprachiasmatic nucleus (the CNS circadian clock) of the hypothalamus, and amphetamine does not. The vigilance-promoting effects are not believed to be due to an alteration in peripheral blood hormone levels.
Now for the commentary on any potential relation of modafinil and a palliative for obesity. The Nicolaidis paper that you refer to is not an in depth study for a couple of reasons, and it does have some complications. Perhaps that explains why it was published in Brain Research Bulletin. First of all, there was an apparent effect in a feeding study, though a food deprivation study should have been performed. There apparently was no effect on water intake yet there was on food intake, which is a bit complicated. Typically, on a rat pellet chow diet, water intake parallels food since it makes it more palatable. (Have you ever eaten several granola bars without any concomitant fluid consumption?) One should test the effects of the compound on food intake both acutely and chronically in food deprived animals as well as in genetic animal models of obesity. The U-shaped dose response curve is complicated in terms of efficacy and mechanisms. The apparent lack of compensation on food intake in the 24 hour study is deficient in that the study should have been carried out to at least a week. Moreover, usually there is a rebound in feeding when any potential diet drug is taken chronically.
As a final note, the initial post indicated that a patient lost 20 lbs on this drug. This is anecdotal data that is not supported by controlled studies done in sleep centers in the early to mid 90's. I suspect that if the eating effects are real, then there would have been activation of the hypothalamic paraventricular nucleus or lateral hypothalamic area in the multiple preclinical studies reported in the literature.
Postscript: There remain at least 10 or so receptor mechanisms that are currently being pursued for the anti-obesity indication, and all of these have solid preclinical data to support the mechanism.
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