A multicentre, double-blind randomized crossover comparative study on the efficacy and safety of dofetilide vs sotalol in patients with inducible sustained ventricular tachycardia and ischaemic heart disease.

BACKGROUND: Antiarrhythmic drugs are still used for the treatment of ventricular tachyarrhythmias, in combination with implantable cardioverter-defibrillators or without them. AIM OF THE STUDY: In a double-blind randomized crossover design, the short- and long-term efficacy and safety of oral dofetilide or oral sotalol were compared in 135 patients with ischaemic heart disease and inducible sustained ventricular tachycardia. METHODS: The inducibility of ventricular tachycardia was determined by programmed electrophysiological stimulation at baseline. Patients were then blindly randomized to receive either oral dofetilide 500 microg twice daily or oral sotalol 160 mg twice daily, for 3 to 5 days. Suppression of inducible ventricular tachycardia on the drug was then assessed by programmed electrophysiological stimulation. After a wash-out period of at least 2.5 days, the patients received the alternative treatment for 3 to 5 days. Suppression of inducible ventricular tachycardia on the alternate drug was again determined by programmed electrophysiological stimulation. Selection of long-term treatment was allocated blindly according to programmed electrophysiological stimulation results. RESULTS: During the acute phase, 128 patients received both dofetilide and sotalol. Sixty-seven patients were responders to either drug. Forty-six patients (35.9%) were responders to dofetilide compared with 43 (33.6%) to sotalol (P=ns). Only 23 patients responded to both dofetilide and sotalol. Adverse events, deemed to be treatment related, were seen in 2.3% of patients receiving dofetilide and 8.6% of patients receiving sotalol (P=0.016). Three patients on dofetilide had torsade de pointes. Two patients receiving sotalol died during the acute phase (one was arrhythmic death, and the other was due to heart failure). During the long-term phase, two of 42 patients (4.8%) receiving dofetilide and three of 27 patients (11.1%) receiving sotalol withdrew from treatment due to lack of efficacy. Overall, during the long-term phase, 23.8% of the patients receiving dofetilide and 37.0% of the patients receiving sotalol, withdrew from treatment with a similar pattern of withdrawals for the two drugs. CONCLUSION: Dofetilide was as efficacious as sotalol in preventing the induction of sustained ventricular tachycardia. There was no concordance in the response rate in two-thirds of the patients. Dofetilide was significantly better tolerated during the acute phase than sotalol. Both dofetilide and sotalol were well tolerated during the long term with no statistically significant difference in the adverse events.     

The effects of beta-adrenoreceptor blockers on blood pressure responses to central angiotensin II

Experiments were carried out in rats to study the effects of beta-adrenoreceptor blockade on the central angiotensin blood pressure responses. Immediately following acute administration of sotalol, l-propranolol and d-propranolol into the brain ventricles (i.c.v.), the beta-adrenoreceptor antagonists and d-propranolol produced transient increases of resting blood pressure, but they reduced the blood pressure increases following intraventricular injection of angiotensin II. Chronic oral beta-adrenoreceptor blockade with dl-propranolol racemate reduced heart rate in Wistar Kyoto rats and in spontaneously hypertensive rats. Mean arterial blood pressure decreased in spontaneously hypertensive rats but not in Wistar Kyoto rats. The blood pressure increases following intraventricular angiotensin II infusions were greater in spontaneously hypertensive than in Wistar Kyoto rats. Chronic oral propranolol treatment reduced the angiotensin II-induced blood pressure increases in Wistar Kyoto but not in spontaneously hypertensive rats.It is concluded that beta-adrenoreceptor blockers inhibit the blood pressure effects of brain angiotensin, but this appears not to be solely due to specific blockade of brain beta-adrenoreceptors.     

小剂量索他洛尔和美托洛尔治疗肥厚型心肌病伴恶性室性心律失常的疗效观察

目的观察小剂量索他洛尔和美托洛尔(倍他乐克)联合治疗肥厚型心肌病伴恶性室性心律失常的疗效。方法对36例肥厚型心肌病伴恶性心律失常的患者,给予索他洛尔和美托洛尔口服治疗,并对心率、QT间期最大值、QT间期最小值和QT间期离散度进行治疗前后的测量。结果治疗后,总有效率为75%,心率由基础的(84.5±5.4)次/min降至(66.5±8.3)次/min(P<0.01),QT间期最大值由治疗前的(411±34)ms延长到治疗后的(415±41)ms(P>0.05),QT间期最小值由治疗前(313±32)ms延长至(353±42)ms(P<0.01),QT间期离散度由治疗前(95±31)ms缩小至(63±20)ms(P<0.01)。无心功能恶化,不良反应轻微。结论本方法疗效确切、方便、安全,无明显致心律失常作用,值得临床推广应用。     

低剂量索他洛尔治疗老年房颤的疗效及安全性评价

目的探讨低剂量索他洛尔（80～160mg/d）对老年房颤的疗效及安全性。方法选择60例年龄大于65岁的房颤患者随机接受索他洛尔（施太可）或可达龙治疗。施太可的剂量每天80mg开始,未达到疗效者每周增加40mg/d,直至达到疗效或剂量增加到160mg/d。可达龙组剂量每天200mg/d。未达疗效者每周增加100mg/d,直至达到疗效或剂量增加到400mg/d。疗效及不良反应采用临床及动态心电图结果评定。结果①施太可组及可达龙组治疗老年房颤的总有效率分别为63.3%与62.1%(P＞0.05);②治疗第一周后施太可组的有效率为26.7%较可达龙组一周后的有效率10.3%明显较高（P＞0.05）;③施太可组房颤的有效率与平均心率下降呈显著的负相关(r=-0.85,P＜0.001)与QTc延长无显著的正相关（r=0.74,P＜0.001）;④施太可组有2例（6.7%）出现轻度副作用,包括无力、头晕、耳鸣,均能耐受,无1例出现尖端扭转型室速。结论低剂量索他洛尔（80～160mg/d）治疗国人老年房颤的疗效确切,副作用少,无明显的致心率失常作用。     

索他洛尔对培养乳鼠心肌细胞自发性搏动及动作电位的影响

观察了索他洛尔对培养乳鼠心肌细胞的作用，索他洛尔３－３００μｍｏｌＬ－１引起心肌细胞簇搏动频率浓度依赖性减小，３和３０μｍｏｌＬ－１能部分对抗乌头碱的正性频率作用，３０μｍｏｌＬ－１也能部分对抗毒毛花苷Ｇ的正性频率作用，索他洛尔３和３０μｍｏｌＬ－１延长５０％和９０％动作电位时程和搏动周期长度．结果提示，索他洛尔的抗心律失常作用与抑制Ｋ＋外流有关，也可能抑制Ｎａ＋内流．     

Stereospeciflc High-Performance Liquid Chromatographic Assay of Sotalol in Plasma

A convenient high-performance liquid chromatographic (HPLC) assay was developed for determination of sotalol (STL) enantiomers in plasma. Following addition of the internal standard (IS; racemic atenolol), enantiomers of STL and IS were extracted using ethyl acetate. After evaporation of the organic layer, samples were derivatized with a solution of S-( + )-l-(l-naphthyl)ethyl isocyanate (NEIC). The resulting diastereomers were chromatographed with normal-phase HPLC with chloroform:hexane:methanol [65:33:2 (v/ v)] as the mobile phase at a flow rate of 2 ml/min. The fluorescence detection wavelength was set at 220 nm for excitation with no emission filter. The suitability of the assay for pharmacokinetic studies was determined by measuring STL enantiomers in the plasma of a healthy subject after administration of a single 160-mg oral, racemic dose of STL.     

索他洛尔对正常人和心律失常病人心率变异性的影响

分析１０例健康志愿者和２０例室性早搏病人应用索他洛尔前后的心率变异性，旨在了解索他洛尔对ＨＲＶ的影响。结果；索他洛尔增加健康志愿者和室早病人反映迷走神经活性的ＨＲＶ时域指标，且心率变异性的改变与室早抑制无相关关系，用荭前后ＨＲＶ时域指标间相关关系无明显改变。     

索他洛尔治疗室性期前收缩

目的 :观察索他洛尔治疗室性期前收缩 (室性早搏 )的疗效及不良反应。方法 :采用逐渐增加剂量的方法。索他洛尔组 30例 ,用药剂量 ( 2 2 7± 62 )mg·d- 1。胺碘酮组 31例 ,用药剂量 ( 0 .4 7± 0 .10 )g·d- 1,均连用 2wk。通过 2 4h动态心率测定观察疗效。结果 :索他洛尔组总有效率 57% ,胺碘酮组总有效率 64% ,2药均有减慢心率 ,延长QT间期作用。结论 :索他洛尔是一种安全、有效的治疗室性期前收缩的药物     

Superiority of ibutilide (a new class III agent) over DL-sotalol in converting atrial flutter and atrial fibrillation. The Ibutilide/Sotalol Comparator Study Group

OBJECTIVE: To compare the efficacy and safety of a single dose of ibutilide, a new class III antiarrhythmic drug, with that of DL-sotalol in terminating chronic atrial fibrillation or flutter in haemodynamically stable patients. DESIGN: Double blind, randomised study. SETTING: 43 European hospitals. PATIENTS: 308 patients (mean age 60 years, 70% men, 48% with heart disease) with sustained atrial fibrillation (n = 251) or atrial flutter (n = 57) (duration three hours to 45 days) were randomised to three groups to receive a 10 minute infusion of 1 mg ibutilide (n = 99), 2 mg ibutilide (n = 106), or 1.5 mg/kg DL-sotalol (n = 103). Infusion was discontinued at termination of the arrhythmia. MAIN OUTCOME MEASURE: Successful conversion of atrial fibrillation or flutter, defined as termination of arrhythmia within one hour of treatment. RESULTS: Both drugs were more effective against atrial flutter than against atrial fibrillation. Ibutilide was superior to DL-sotalol for treating atrial flutter (70% and 56% v 19%), while the high dose of ibutilide was more effective for treating atrial fibrillation than DL-sotalol (44% v 11%) and the lower dose of ibutilide (44% v 20%, p < 0.01). The mean (SD) time to arrhythmia termination was 13 (7) minutes with 2 mg ibutilide, 19 (15) minutes with 1 mg ibutilide, and 25 (17) minutes with DL-sotalol. In all patients, the duration of arrhythmia before treatment was a predictor of arrhythmia termination, although this was less obvious in the group that received 2 mg ibutilide. This dose converted almost 48% of atrial fibrillation that was present for more than 30 days. Concomitant use of digitalis or nifedipine and prolongation of the QTc interval were not predictive of arrhythmia termination. Bradycardia (6.5%) and hypotension (3.7%) were more common side effects with DL-sotalol. Of 211 patients given ibutilide, two (0.9%) who received the higher dose developed polymorphic ventricular tachycardia, one of whom required direct current cardioversion. CONCLUSION: Ibutilide (given in 1 or 2 mg doses over 10 minutes) is highly effective for rapidly terminating persistent atrial fibrillation or atrial flutter. This new class III drug, under monitored conditions, is a potential alternative to currently available cardioversion options.