DOSE RANGING STUDY OF EFFECT OF PAROXETINE ON COAT-PLATELET PROD IN VOL AMP; PTS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。最近的一项病例对照研究表明，选择性5-羟色胺再摄取抑制剂（SSRI）的使用与吸烟者首次心肌梗死的比值比显著降低相关;这种保护作用的机制尚不清楚。我们最近描述了一类新的活化血小板，称为COAT-血小板，其合成需要血清素。选择性5-羟色胺再摄取抑制剂的使用降低血小板5-羟色胺水平以及个体产生COAT-血小板的能力。我们怀疑，在上述研究中，COAT-血小板可能是SSRI使用和心肌梗死几率降低之间的联系。由于SSRI剂量以前已被选定为缓解抑郁症，我们提出了一个剂量范围研究，以确定帕罗西汀的最低有效剂量，可以导致显着减少在正常志愿者和心血管疾病患者的COAT-血小板生成。这些抗血小板剂量反应数据是帕罗西汀减少COAT血小板和对冠状动脉疾病影响的未来研究的基础。二十五（25）人将参加本研究，其中5名正常志愿者和20名已知患有冠状动脉疾病的患者，这将是一项开放标签剂量递增研究。本研究将进行一次筛选访视，然后进行三（3）个阶段，共需约16周完成。这三个阶段是：1）三周持续时间的基线运行阶段; 2）三周的口服Paxil-CR剂量递增（每隔一天12.5mg、每天12.5mg和每天25 mg）和3）三周的剂量减少和Paxil-CR的停止。将在每次每周门诊访视时测定COAT-血小板和血小板5-羟色胺。将在研究期开始和结束时收集基线实验室数据。将在筛选访视和剂量递增阶段各剂量组末次访视时进行饮食调查，以估计已知可增加5-羟色胺产生的食物摄入量。

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.