Wang T, Bergstrand R H, Thompson K A, Siddoway L A, Duff H J, Woosley R L, Roden D M
Am J Cardiol. 1986 May 1;57(13):1160-5. doi: 10.1016/0002-9149(86)90692-2.
Sotalol is a nonselective beta-receptor antagonist that prolongs action potential duration and refractoriness in vitro at higher concentrations than those associated with heart rate slowing. To determine if this additional action can be expressed in humans, 17 patients with chronic stable ventricular premature complexes were studied. Each patient was hospitalized and arrhythmia frequency was quantified during a 48-hour drug-free baseline and during every third day of therapy with increasing incremental sotalol dosages. The dosages were 160, 320, 640 and 960 mg/day, administered in 1 or 2 doses. An index of action potential duration, the rate-corrected QT (QTc), was measured using serial 12-lead electrocardiograms on the third day of each dosage at presumed steady state and the degree of beta-receptor blockade was assessed by the reduction of the maximal exercise-induced heart rate. Of the 17 patients, 11 had an antiarrhythmic response (70 to 100% reduction in VPCs), at a wide range of plasma concentrations (340 to 3,440 ng/ml). The responders to sotalol included 8 patients in whom therapy with conventional beta-receptor antagonists had failed. In the group as a whole, the concentration associated with significant QTc prolongation (2,550 ng/ml) was greater than that associated with 50% reduction of the maximal slowing in heart rate (804 ng/ml). Sotalol was generally well tolerated, but in 1 nonresponder torsades de pointes developed 3 hours after the first 640-mg dose at a plasma sotalol concentration well within the concentration range measured in other patients. Sotalol's repolarization-prolonging actions are seen at higher concentrations than those associated with heart rate slowing and may contribute to its clinical effects.
索他洛尔是一种非选择性β受体拮抗剂，在体外，当浓度高于与心率减慢相关的浓度时，它可延长动作电位时程和不应期。为了确定这种额外的作用在人体中是否能够表现出来，对17例慢性稳定性室性早搏患者进行了研究。每位患者均住院治疗，在48小时无药基线期以及使用递增剂量索他洛尔治疗的每第三天，对心律失常频率进行量化。剂量分别为160、320、640和960mg/天，分1或2次给药。在每个剂量的第三天假定达到稳态时，使用连续12导联心电图测量动作电位时程指标——校正QT（QTc），并通过最大运动诱发心率的降低来评估β受体阻滞程度。17例患者中，11例有抗心律失常反应（室性早搏减少70%至100%），血浆浓度范围很广（340至3440ng/ml）。索他洛尔的反应者包括8例使用传统β受体拮抗剂治疗失败的患者。在整个组中，与显著QTc延长相关的浓度（2550ng/ml）高于与最大心率减慢50%相关的浓度（804ng/ml）。索他洛尔一般耐受性良好，但1例无反应者在首次服用640mg剂量3小时后发生尖端扭转型室速，当时血浆索他洛尔浓度完全在其他患者测量的浓度范围内。索他洛尔延长复极的作用在高于与心率减慢相关的浓度时可见，可能有助于其临床疗效。
