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Tilo Grosser, MD Research Assistant Professor of Member, Institute for Translational Medicine and Therapeutics Contact Information:
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MECHANISM BASED RESISTANCE TO ASPIRIN
Low dose aspirin reduces the incidence of secondary myocardial infarction and stroke by roughly 25% and both traditional nonsteroidal anti-inflammatory drugs (NSAIDs) and selective inhibitors of COX-2 are efficacious in the treatment of pain and inflammation. Despite debate about divergent outcomes in clinical trials of selective inhibitors COX-2, little attention has been paid to potential sources of variability in drug response amongst and between individual patients. The term ‘aspirin resistance’ has been variably used for three observations: Treatment failure in patients on low dose aspirin who have clinical thrombotic events, failed inhibition of platelet function and biochemical evidence of failed inhibition of COX activity. ‘Treatment failure’ occurs with all drugs and may be linked to pharmacological or genetic sources of non-responsiveness. It may reflect drug interactions, noncompliance, pharmacokinetic or pharmacogenetic differences but may also infer the variable importance of other pathways of platelet activation than thromboxane. Given the wide use of aspirin for cardioprotection, there is great interest in the discovery of reproducible sources of non-responsiveness, and in the development specific tests which would allow the identification of individuals who would more likely benefit from other prophylaxes than low dose aspirin (e.g. clopidogrel). However, at present the prevalence of functionally and biochemically defined aspirin non-responsiveness in the general population is unknown and only limited information exists in patient populations. We are studying factors that contribute to the variability in the response to aspirin using well characterized in vivo and ex vivo indices of COX inhibition, whole blood assays of COX isozyme activity, platelet thromboxane (Tx) B2, platelet aggregation assays and urinary eicosanoid metabolite excretion.
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THE MECHANISM OF ACTION OF ACETAMINOPHEN
Acetaminophen has antipyretic and moderate analgesic properties, but largely lacks anti-inflammatory activity. While its mechanism of action is not entirely understood, it is probably both an isoform nonspecific and partial cyclooxygenase (COX) inhibitor in humans at doses commonly taken for mild pain and pyrexia, such as 1000 mg. Although no inhibition of platelet aggregation is observed at this dosage, platelet thromboxane formation by COX is depressed by roughly 40%. Epidemiological studies suggest that at higher doses, 2000 mg and above, acetaminophen exhibits a gastrointestinal adverse effect profile indistinguishable from traditional, nonspecific NSAIDs. Thus, it is possible that maximal COX inhibition is achieved at higher doses. While the structural interaction of acetaminophen with COX is unknown, it may inactivate the enzyme by a molecular mechanism different from other NSAIDs. Thus, acetaminophen, which is a good reducing agent, might act to reduce COX from its active, oxidized form. We are studying the mechanism of action of acetaminophen in vivo using a sensitive, mass spectrometric lipidomics approach to quantitate biomarkers of COX inhibition.
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