ARRHYTHMOGENIC ACTIONS OF ANTIHISTAMINES

抗组胺药的致心律失常作用

• 批准号: 2750477
• 负责人: Raymond Leon Woosley
• 金额: $ 29.27万
• 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/2750477
• 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.

只是在最近几年才被接受，抗组胺药具有 可能对心律产生不利影响。 特非那定的能力 和阿司咪唑延长心脏复极， 尖端扭转型室性心动过速，表明需要仔细评价 其他抗组胺药的心血管作用。 食品药品 给药现在需要对心脏活动进行全面评估， 新开发的抗组胺药的促肾上腺皮质激素生成潜力。 但 较老的抗组胺药仍在广泛的临床使用，如 苯海拉明，也需要测试。 在本申请中，我们建议 系统地评价体外选择的 第一代抗组胺药（赛庚啶，羟嗪， 异丙嗪、氯苯那敏、苯茚达明和氯马斯汀）， 与可能相互作用的药物结合。 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， 表明药物或组合对心肌细胞有影响， 人的复极 在这项工作中，我们将采用三个阶段的方法。 抗组胺药将 检测其阻断猫心脏钾通道的能力 使用全细胞贴片技术。 那些被发现阻止 将在离体灌注的猫心脏中评估钾通道 （Langendorff）和心肌（微电极记录）， 对复极的影响。 发现这些药物可延长复极， 在临床使用中或过量后可能发生的浓度将 选择在人的评价。在第一年，苯海拉明将 临床研究，因为我们最近发现， 体外心脏复极化。 苯海拉明对大鼠脑缺血再灌注损伤的影响 将评价体表心电图（PR、QRS和QT间期）， 健康的正常志愿者在临床上使用的剂量。 酌情为 伴随药物的作用，例如减充血剂（α激动剂）和 细胞色素P450的特异性抑制剂，将评价其 在体外和体内产生临床相关药物相互作用的可能性 伙计 临床方案将在稳态下比较所有 治疗，并利用安慰剂对照随机交叉设计。 这些研究应该提供信息，将导致更安全的使用 通过检测抗组胺药对心脏离子的辅助作用 通道和人体心脏复极。 这些信息将使 医生识别有不良反应风险的患者， 行动 此外，适当的治疗患者的故意或 可以确定抗组胺药意外过量。