ARRHYTHMOGENIC ACTIONS OF ANTIHISTAMINES

抗组胺药的致心律失常作用

• 批准号: 2460130
• 负责人: Raymond Leon Woosley
• 金额: $ 28.74万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2460130
• 关键词: action potentials; alpha adrenergic agent; antihistamines; cats; chlorpheniramine; cyproheptadine; diphenylhydramine; dosage; drug interactions; electrocardiography; heart cell; heart pharmacology; heart rhythm; human subject; pharmacokinetics; phenothiazines; potassium channel; voltage /patch clamp

Only in recent years has it become accepted that antihistamines have the potential to adversely effect cardiac rhythm. The ability of terfenadine and astemizole to prolong cardiac repolarization and induce the syndrome of torsades de pointes, demonstrated the need for careful evaluation of the cardiovascular actions of other antihistamines. The Food and Drug Administration now requires complete evaluation of the cardiac actions and arrhythmogenic potential of newly developed antihistamines. However, the older antihistamines still in widespread clinical use, such as diphenhydramine, also require testing. In this application, we propose to systematically evaluate in vitro the arrhythmogenic potential of selected first generation antihistamines (cyproheptadine, hydroxyzine, promethazine, chlorpheniramine, phenindamine and clemastine) alone and combined with drugs likely to interact. We will also seek confirmation of the clinical relevance of results obtained in in vitro models which indicate that drugs or combinations should have effects on myocardial repolarization in man. We will apply a three-stage approach in this work. Antihistamines will be examined for their ability to block potassium channels in feline cardiac myocytes using the whole cell patch technique. Those found to block potassium channels will be evaluated in isolated perfused feline hearts (Langendorff) and cardiac muscle (microelectrode recordings) for their effects on repolarization. Those agent found to prolong repolarization at concentrations likely to occur in clinical use or after overdose will be selected for evaluation in man. In the first year, diphenhydramine will be studied clinically because of our recent finding that it prolongs cardiac repolarization in vitro. The effects of diphenhydramine on the surface electrocardiogram (PR, QRS, and QT intervals) will be evaluated in healthy normal volunteers at doses used clinically. When appropriate, the effects of concomitant drugs, e.g. decongestants (alpha agonists) and specific inhibitors of cytochrome P450, will be evaluated for their potential to produce clinically relevant drug interactions in vitro and in man. Clinical protocols will make comparisons at steady state for all treatments and utilize a placebo controlled randomized crossover design. These studies should provide information that will lead to the safer use of antihistamines by detection of their ancillary actions on cardiac ion channels and human cardiac repolarization. This information will enable physicians to identify patients at risk for adverse response to these actions. Also, the appropriate treatment of patients with intentional or accidental overdose of antihistamines can be determined.

直到近年来，抗组胺药才被接受 对心律的不利影响。 Terfenadine的能力 和astemizole延长心脏复极化并诱导综合征 扭转扭转的指示表明需要仔细评估 其他抗组胺药的心血管作用。 食物和药物 现在，管理需要对心脏行动进行完整评估 新开发的抗组胺药的心律失常潜力。 但是， 较旧的抗组胺药仍在广泛的临床用途中，例如 苯胺胺，也需要测试。 在此应用程序中，我们建议 系统地评估选定的心律失常潜力 第一代抗组胺药（Cyproheptadine，羟嗪， 异丙嗪，氯苯胺，苯丙胺和clemastine）单独使用 结合可能相互作用的药物。 我们还将寻求确认 在体外模型中获得的结果的临床相关性 表明药物或组合应对心肌产生影响 人类的复极化。 我们将在这项工作中采用三阶段方法。 抗组胺药将是 检查了它们在猫心脏中阻断钾通道的能力 使用整个细胞斑块技术的心肌细胞。 那些被发现阻止的 钾通道将在孤立的灌注猫心脏中进行评估 （Langendorff）和心肌（微电极记录） 对复极化的影响。 那些发现在 可能发生在临床用途或过量后可能发生的浓度 选择进行评估。 在第一年，苯海拉明将 由于我们最近的发现延长了临床研究 体外心脏复极化。 苯胺胺对 将评估表面心电图（PR，QRS和QT间隔） 健康的正常志愿者在临床上使用的剂量使用。 适当的时候， 伴随药物的影响，例如充足的人（α激动剂）和 将评估细胞色素P450的特定抑制剂 在体外和IN中产生与临床相关的药物相互作用的潜力 男人。 临床方案将使所有人的稳定状态进行比较 处理并利用安慰剂控制的随机跨界设计。 这些研究应提供将导致更安全使用的信息 通过发现其对心脏离子的辅助作用的抗组胺药 通道和人类心脏复极。 此信息将启用 医生确定对这些反应不良反应风险的患者 动作。 此外，适当治疗有意或 可以确定意外过量的抗组胺药。