The brains of Alzheimer's disease victims are peppered with neuritic plaques-microscopic, spherical structures containing, among other things, deposits of β amyloid peptide, dead and dying neurons and evidence of inflammation. The inflammation is most likely a response to some kind of primary insult, but many researchers suspect that the brain's inflammatory defenses may further amplify the injury. Bolstering the theory that inflammation may play an important role in Alzheimer's disease are findings that nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the risk of developing the disease. One problem with using NSAIDs as a therapy or preventative for Alzheimer's is that they also are anticoagulants and irritate the gastrointestinal tract, side effects which are potentially dangerous, especially at the high dosages and extended periods that would be needed for Alzheimer's therapy. The beneficial effects of NSAIDs arise from the inactivation of an enzyme called COX-2, whereas the side effects result from inactivation of its chemical sibling COX-1. Several drugs that selectively inhibit COX-2 are already in clinical trials, but a new group of compounds developed by researchers at Vanderbilt University School of Medicine and Searle/Monsanto may be even better. The most potent of these new compounds, called o-(acetoxyphenyl)hept-2-ynyl sulfide, or APHS, was 60 times as reactive against COX-2 and 100 times as selective for the enzyme's inhibition, compared to aspirin. What's more, APHS is the first such drug to inactivate COX-2 in an irreversible manner, as aspirin does. Further studies in cell cultures and animals are needed before APHS can be considered for human trials. The findings will be published this week in Science.—June Kinoshita
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- Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Seibert K, Marnett LJ. Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science. 1998 May 22;280(5367):1268-70. PubMed.