LIDOFLAZINE IN PATIENTS WITH HCM REFACTORY TO STANDARD MEDICAL THERAPY

利多黄嗪治疗对标准药物治疗无效的 HCM 患者

• 批准号: 3966712
• 负责人: C M TRACY
• 金额: --
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 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/3966712
• 关键词: antiarrhythmic agent; benzofurans; beta adrenergic agent; calcium channel blockers; drug screening /evaluation; exercise; heart circulation; heart pharmacology; human subject; human therapy evaluation; hypertrophic myocardiopathy

Many patients with hypertrophic cardiomyopathy have severe symptoms in spite of medical therapy with beta adrenergic blocking agents and/or calcium channel blocking agents. Recently we have been investigating the use of amiodarone, a benzofuran derivative with potent hemodynamic and antiarrhythmic properties in this same subgroup of patients and have noted an improvement in cardiac symptoms and an increase in exercise capacity. However, there remains a subgroup of patients who are intolerant of amiodarone or who do not improve on amiodarone and continue to have marked symptomatology. In response to a compelling clinical need in this subgroup of refractory patients, we felt it appropriate to explore other potential pharmacologic modalities. We have hypothesized that the functional and structural abnormalities in HCM are related to a primary membrane disorder leading to increased cytosolic calcium levels as a result of altered calcium fluxes involving both the myocardium and the vascular smooth muscle of the small intramural coronary arteries. Lidoflazine has been shown to be a potent calcium entry blocker, and has a cellular protective effect against calcium overload in vascular smooth muscle and cardiac muscle during ischemia, preventing ischemic contraction and myonecrosis. These properties of the drug afford an ideal mechanism for testing the above hypotheses, as well as offering a potentially important therapeutic alternative. The study will consist of 3 phases. The first phase to assess the clinical efficacy of the drug; the second to characterize the hemodynamic/metabolic correlates of the drug that may determine its efficacy; and the third to compare in a double blind fashion lidoflazine versus standard therapy. We have enrolled thus far 3 patients in phase I, two of whom have had symptomatic and exercise improvements.

许多肥厚型心肌病患者的症状严重。 尽管使用β-肾上腺素能阻滞剂和/或 钙通道阻滞剂。最近我们一直在调查 使用胺碘酮，一种苯并呋喃衍生物，具有强大的血流动力学和 在同一组患者中的抗心律失常特性，并注意到 心脏症状的改善和运动能力的增加。 然而，仍有一部分患者不能耐受 胺碘酮或对胺碘酮没有改善并继续显著 症状学。为了满足这一亚组中迫切的临床需求 对于难治性患者，我们认为应该探索其他潜力 药理模式。我们假设了功能性的和 肥厚性巨噬细胞的结构异常与原发的膜功能紊乱有关 导致细胞内钙水平升高的结果是改变 涉及心肌和血管平滑肌的钙离子流量 冠状动脉壁内的细小动脉。利多氟嗪已经被证明可以 是一种有效的钙离子进入阻滞剂，并具有细胞保护作用 抗血管平滑肌和心肌钙超载 在缺血期间，防止缺血性收缩和心肌坏死。这些 药物的性质为检验上述情况提供了一个理想的机制 假说，以及提供了一种潜在的重要治疗方法 另类选择。这项研究将分为三个阶段。第一阶段到 评估药物的临床疗效；第二，确定 药物的血流动力学/代谢相关性可能决定其 疗效比较：利多拉嗪双盲对照试验 而不是标准疗法。到目前为止，我们已经招募了3名I期患者， 其中两人的症状和运动有所改善。