AlohaDan: Just some historical background material regarding some of the complex biochemistry and physiology issues regarding obesity and their relationships to Millenium's interest. Hope that some of the scientists on board can piece together the loose ends, but it would appear that Millenium' might be targeting the hypothalmus where it has found a defective receptor.. Again, there is really little published that I am able to find regarding cyclopeptidase inhibitors in relationship to obesity, but will keep trying inasmuch as you are making an admirable and sustained effort in finding it. Jack http://www.the-scientist.com/yr1998/july/lewis_p1_980720.html The Scientist - Unraveling Leptin Pathways Identifies New Drug Targets "....New understanding of the signaling pathways that control body weight means a more targeted and rational approach to anti-obesity drug development, even as basic research continues. Says Tartaglia, "If you want a safe drug for body weight regulation, the right approach is not to manipulate in a broad sweep a neurotransmitter that regulates everything, but to deal with specific pathways that regulate body weight-- even though it might take a little longer." http://www.msu.edu/course/lbs/149h/Obesity.html Molecular Genetics of Obesity, Friedman's group at Rockefeller used genetic map-based cloning to isolate the ob-defective gene and showed that this gene did encode a protein hormone called leptin. Tartaglia's group at Millenium Pharmaceuticals isolated the gene for the ob receptor, Ob-R, and showed (along with Friedman) that a particular form of the Ob-R protein is defective, as predicted, in db/db mice. This specific form of Ob-R is primarily made in the hypothalamus in the brain, the probable site of leptin action. http://aci.mta.ca/Courses/Biochemistry/BC4511B-Lipid/Kevin/1leptin Leptin, Kevin Larade Style.(From Mt. Allison University Biochem Dept., Regulation of Body Weight and Metabolism) ".....For many years it has been suggested that the energy balance in mammals ought to be controlled by a feedback loop in which the amount of stored energy is sensed by the hypothalamus, which in turn adjusts food intake and energy expenditure to maintain a constant body weight. This hypothesis has postulated a product originating from adipose tissue, which circulates in plasma and affects the energy balance by interacting with the hypothalamus. (34)...." ".....At present, a number of large pharmaceutical companies are spending large amounts of money, in hopes of producing an anti-fat pill or injection that people (not necessarily obese people) can take to regulate their weight. Amgen recently paid Rockefeller University $20 million for patent rights to make products based on the ob gene. They have announced that they hope to begin conducting human trials as early as next year. Many experts find these plans too optimistic. Just because researchers have not noted worrisome side effects yet, critics say, does not mean that none will emerge. Leptin, they point out, is a serious drug, not the easy-to-swallow "thin pill" dieters have dreamed of for so long. To do its work, leptin would probably have to be injected daily, like insulin (41). Also, at the time of writing of this paper, only one case of obesity has been documented in humans where a mutation in the ob gene was exhibited. This was due to considerable intermarriage in a Pakistani family, leading to inheritance of a defective copy of the ob gene in offspring (64). "In simple terms, mice are not humans. Medical literature is replete with instances of drugs that cured or killed rodents yet had no effect on humans (22). Another pharmaceutical company, Millenium Pharmaceuticals is currently trying to produce an obesity "remedy" involving the leptin receptor (Ob-R)...."
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