Karam R, Marcello S, Brooks R R, Corey A E, Moore A
Procter & Gamble Pharmaceuticals, Cincinnati, Ohio 45061, USA.
Am J Cardiol. 1998 Mar 19;81(6A):40D-46D. doi: 10.1016/s0002-9149(98)00152-0.
Azimilide, a novel class III antiarrhythmic agent, blocks both the slowly activating (IKs) and rapidly activating (IKr) components of the delayed rectifier potassium current, which distinguishes it from conventional potassium channel blockers such as sotalol and dofetilide, which block only IKr. Azimilide is being developed to prolong the time to recurrence of atrial fibrillation, atrial flutter, and paroxysmal supraventricular tachycardia in patients with and without structural heart disease. Azimilide is also being studied for its role in prevention of sudden cardiac death in high-risk patients after myocardial infarction (MI). Preclinical and clinical studies indicate that azimilide prolongs cardiac refractory period in a dose-dependent manner, as manifested by increases in action potential duration, QTc interval, and effective refractory period. Azimilide does not affect PR or QRS interval and minimally affects hemodynamic properties such as blood pressure and heart rate. Its in vivo effects appear to be rate-independent and are maintained under ischemic or hypoxic conditions, properties of potential clinical significance. Azimilide has shown excellent efficacy (>85%) in suppressing supraventricular arrhythmias in a variety of dog models. It also suppressed complex ventricular arrhythmias in infarcted dogs and, in a sudden death cardiac model, decreased mortality. Azimilide pharmacokinetics are very predictable. The drug is completely absorbed, and the extent of absorption is not affected by food. It can be administered once daily. Clinical data suggest that dose adjustments of azimilide are not required for age, gender, hepatic or renal function, or concomitant use of digoxin or warfarin. Azimilide has a good safety profile in open-label safety studies in >800 supraventricular arrhythmia patients, most with structural heart disease. The incidence of serious adverse events, including torsade de pointes, is low. The rate of patient withdrawal from long-term studies is also encouragingly low. Unlike amiodarone, azimilide has shown no evidence of pulmonary or ocular toxicity. Azimilide is expected to provide a unique new therapy for the prevention of supraventricular arrhythmias and sudden cardiac death when Phase III clinical trials are complete and safety and efficacy are confirmed.
阿齐利特是一种新型III类抗心律失常药物，可阻断延迟整流钾电流的缓慢激活成分（IKs）和快速激活成分（IKr），这使其有别于传统的钾通道阻滞剂，如索他洛尔和多非利特，后者仅阻断IKr。正在研发阿齐利特，以延长有或无结构性心脏病患者房颤、房扑和阵发性室上性心动过速复发的时间。也正在研究阿齐利特在预防心肌梗死（MI）后高危患者心源性猝死中的作用。临床前和临床研究表明，阿齐利特以剂量依赖的方式延长心脏不应期，表现为动作电位时程、QTc间期和有效不应期增加。阿齐利特不影响PR或QRS间期，对血压和心率等血流动力学特性影响极小。其体内作用似乎与心率无关，且在缺血或缺氧条件下仍能维持，这些特性具有潜在的临床意义。在多种犬类模型中，阿齐利特在抑制室上性心律失常方面显示出优异的疗效（>85%）。它还抑制梗死犬的复杂性室性心律失常，并且在心脏猝死模型中降低死亡率。阿齐利特的药代动力学非常可预测。该药物完全吸收，吸收程度不受食物影响。它可以每日给药一次。临床数据表明，年龄、性别、肝肾功能、或同时使用地高辛或华法林均无需调整阿齐利特的剂量。在超过800例室上性心律失常患者（大多数患有结构性心脏病）的开放标签安全性研究中，阿齐利特具有良好的安全性。严重不良事件的发生率，包括尖端扭转型室速，很低。长期研究中的患者退出率也低得令人鼓舞。与胺碘酮不同，阿齐利特未显示出肺部或眼部毒性的证据。当III期临床试验完成且安全性和有效性得到证实时，阿齐利特有望为预防室上性心律失常和心源性猝死提供一种独特的新疗法。
