This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A recent case control study demonstrated that selective serotonin reuptake inhibitors (SSRI) use was associated with a significant decrease in the odds ration for first myocardial infarction among smokers; the mechanism responsible for this protective effect is unknown. We have recently described a new class of activated platelets, referred to as COAT-platelets, which require serotonin for their synthesis. Selective serotonin reuptake inhibitor use decreases platelet serotonin levels as well as an individuals ability to produce COAT-platelets. We suspect that COAT-platelets may be the link between SSRI use and reduced odds of myocardial infarction in the above study. Since SSRI doses have been previously selected for easing depression, we propose a dose ranging study to determine the minimally effective dose of paroxetine that can cause a significant reduction of COAT-platelet production in both normal volunteers and patients with cardiovascular disease. This antiplatelet dose response data is fundamental for future studies of paroxetine in the reduction of COAT-platelets and the effect on coronary artery disease. Twenty five (25) people will take part in this study, 5 normal volunteers and 20 patients with known coronary artery disease, which will be an open label dose escalation study. There will be a screening visit and then three (3) stages to this study which will take a total of about 16 weeks to complete. The three stages are: 1) a baseline run in phase of three weeks duration; 2) three weeks each of oral Paxil-CR dose escalation (12.5 mg every other day, 12.5 mg daily, and 25 mg daily) and 3) three weeks of dose reduction and discontinuation of Paxil-CR. COAT-platelets and platelet serotonin will be determined at each weekly clinic visit. Baseline laboratory data will be collected at the beginning and end of the study period. A diet survey, to estimate the intake of foods known to increase serotonin production, will be conducted at the screening visit and at the last visit on each dose during the dose escalation stage.
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