CLINICAL PHARMACOLOGY OF POTASSIUM CHANNEL MODULATORS

钾通道调节剂的临床药理学

• 批准号: 3756343
• 负责人: DAN M RODEN
• 金额: --
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3756343
• 关键词: antiarrhythmic agent; antihistamines; clinical trials; combination chemotherapy; dogs; drug adverse effect; drug interactions; drug metabolism; drug screening /evaluation; glyburide; human subject; human therapy evaluation; inhibitor /antagonist; ion transport; laboratory rabbit; laboratory rat; minoxidil; pharmacogenetics; pharmacokinetics; potassium channel; quinidine; racemization; stereoisomer; tachycardia

Potassium channels play an important role in the physiology of diverse tissues, including pancreatic beta-cells, vascular smooth muscle, and the heart. Drugs which inhibit or activate potassium egress through these channels are increasingly being applied in the treatment of common human diseases such as diabetes, hypertension, and cardiac arrhythmias. The overall goal of this Project is to determine factors which account for variability in response to potassium channel modulators in humans. In vitro data indicate that the effects of inhibitors such as quinidine or glyburide can be blunted by activators such as minoxidil or pinacidil; clinical studies will assess the consequences of such combinations in modulating these compounds' antihypertensive, hypoglycemic or electrophysiologic effects. A risk with potassium channel blocking (Class III) antiarrhythmics is unpredictable and excessive QT interval prolongation and induction of the polymorphic tachycardia, torsades de pointes. The hypothesis, derived from cellular studies, that sympathetic activation will blunt the QT interval prolonging actions of Class III agents, will be tested in normal volunteers and in patients undergoing pharmacologic conversion of atrial fibrillation. Torsades de pointes is also a well-recognized complication of treatment with a number of compounds not generally thought to have electrophysiologic activity; these include the very widely-used "non-sedating" antihistamines, terfenadine and astemizole, both of which are administered as racemates. To determine if enantiomer-specific therapy is justified, the electrophysiologic effects of terfenadine's enantiomers will be assessed in models predictive of torsades de pointes, and enantiomers will be administered to humans to assess the extent of racemization in vivo. This series of studies will not only provide information to increase the safety of drugs targeting potassium channels, but also will provide insights into the basic mechanisms responsible for individual variability in their desirable and undesirable actions.

钾通道在多样化的生理学中起着重要作用 组织，包括胰腺β细胞，血管平滑肌和 心。 通过这些抑制或激活钾出口的药物 渠道越来越多地应用于人类的治疗 糖尿病，高血压和心律不齐等疾病。 这 该项目的总体目标是确定因素 响应于人类钾通道调节剂的变异性。 在 体外数据表明抑制剂，例如奎尼丁或 格列本伯被激活剂（例如米诺地尔）或皮纳基迪（Pinacidil）钝化； 临床研究将评估此类组合的后果 调节这些化合物的降血糖，降血糖或 电生理效应。 钾通道阻塞的风险 （III类）Antiarranthmics是不可预测的，QT间隔过多 多态性心动过速的延长和诱导，扭转 点。 该假设来自细胞研究，该假设是交感神经的 激活将钝化QT间隔延长III类的延长动作 代理人将在正常志愿者和正在接受的患者中进行测试 房颤的药理转换。 扭矩是 也有多个识别的治疗并发症 通常不认为化合物具有电生理活性。 这些包括非常广泛使用的“非隔离”抗组胺药， Terfenadine和Astemizole，两者均为种族。 为了确定对映异构体特异性治疗是否合理， 将评估Terfenadine映体的电生理效应 在预测扭转点的模型中，将会是 给人类管理以评估体内种族化的程度。 这一系列研究不仅将提供信息来增加 针对钾通道的药物的安全性，但也将提供 了解负责个人可变性的基本机制 在他们理想的和不良的行动中。