ARRHYTHMOGENIC ACTIONS OF ANTIHISTAMINES

直到最近几年，人们才接受了抗组胺药物对 有可能对心率产生不利影响。特非那定的药效研究 和阿司咪唑延长心脏复极并诱发综合征 尖端扭矩，表明有必要仔细评估 其他抗组胺药物的心血管作用。食品与药品 政府现在要求对心脏活动进行全面评估 新开发的抗组胺药物的致心律失常潜力。然而， 较老的抗组胺药物仍在临床广泛使用，例如 苯海拉明也需要检测。在本申请中，我们建议 系统评价所选药物的体外致心律失常作用 第一代抗组胺药物(赛庚啶、羟基锌、 异丙嗪、扑尔敏、苯达明和氯马斯汀)单独和 与可能相互作用的药物相结合。我们还将寻求确认 体外模型研究结果的临床相关性 表明药物或联合用药应对心肌有影响 人类的复极化。 我们将在这项工作中采用三阶段方法。抗组胺药物将是 检查它们对猫心脏钾通道的阻断能力 使用全细胞贴片技术培养心肌细胞。被发现阻止的那些 钾通道将在离体猫心脏灌流中进行评估 和心肌(微电极记录)，用于他们的 对复极的影响。那些被发现延长复极的药剂 临床使用或过量用药后可能出现的浓度将是 选择在MAN中进行评估。在第一年，苯海拉明将 被临床研究，因为我们最近发现它延长了 体外心脏复极。苯海拉明对大鼠心脏功能的影响 体表心电图(PR、QRS和QT间期)将在 健康的正常志愿者，临床使用的剂量。在适当的情况下， 伴随药物的效果，例如减充血剂(阿尔法激动剂)和 细胞色素P450的特定抑制剂将被评估其 在体外和体内产生临床相关药物相互作用的可能性 天哪。临床方案将在稳定状态下对所有患者进行比较 治疗并采用安慰剂对照随机交叉设计。 这些研究应该提供将导致更安全使用的信息 检测抗组胺药物对心脏离子的辅助作用 通道和人类心脏复极。此信息将使 医生识别有不良反应风险的患者 行为。另外，对有故意或故意的患者进行适当的治疗 意外过量的抗组胺药物可以确定。

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.