小剂量索他洛尔与普罗帕酮治疗心律失常的疗效比较

目的比较小剂量索他洛尔与普罗帕酮治疗心律失常的疗效。方法收集心律失常患者78例,随机分为索他洛尔(S)与普罗帕酮(P)两组,S的用法为40,80,120mg/d,每2d递加,P的用量为450mg/d,治疗2周后做24h动态心电图判定疗效。结果室性早搏组40例次,S组22例,总有效率为77.3%;P组18例,总有效率为72.2%。二者之间无统计学差异(P=1.000)。室上性早搏(SV)组38例次,S组20例,总有效率为70.0%;P组18例,总有效率为66.7%。二者之间无统计学差异(P=0.731)。结论小剂量索他洛尔抑制室性早搏、室上性早搏的疗效与传统药物普罗帕酮相同。     

What Is the Minimal Pacing Rate that Prevents Torsades de Pointes? Insights from Patients with Permanent Pacemakers

In the acquired long QT syndrome, torsades de pointes (TP) is invariably preceded by pauses or bradycardia. Thus, it has been proposed that out-of-hospital initiation of drugs that prolong repolarization should be safe in patients with permanent pacemakers. However, a minimal protective pacing rate has not been identified. The authors reviewed published reports of acquired TP in patients with permanent pacing. Those providing documentation of tachycardia onset and pacemaker programming were included in the analysis. Events occurring < or = 1 month after AV nodal ablation were excluded. Eighteen cases were identified (age 74 +/- 5; 10 women). QT prolonging drugs were present in 15 patients (quinidine 5, sotalol 3, disopyramide 3, amytriptiline, chloroquine, cisapride + haloperidol, and monopride + flecainide 1 each). Hypokalemia was present in eight patients. At the time of TP, the programmed lower rate was 63 +/- 13 beats/min. However, the effective pacing rate was lower (55 +/- 11 beats/min) due to invocation of pause-promoting features (hysteresis [4 patients]; + PVARP extension on PVC [1 patient]) or ventricular oversensing (2 patients). No patient developed TP with an effective pacing rate > 70 beats/min. TP is possible in the presence of a functional permanent pacemaker. Programmed lower rates < or = 70 beats/min are not protective. At programmed lower rates > 70 beats/min, TP may occur only when facilitated by programmable pause-promoting features or oversensing. It remains to be seen if rate smoothing algorithms can prevent TP when the baseline rate is programmed < or = 70 beats/min.     

INFLUENCE OF CIMETIDINE COADMINISTRATION ON THE PHARMACOKINETICS OF SOTALOL ENANTIOMERS IN AN ANAESTHETIZED RAT MODEL: EVIDENCE SUPPORTING ACTIVE RENAL EXCRETION OF SOTALOL

Sotalol (STL) is an amphoteric, chiral β-adrenergic blocking drug useful in the treatment of both hypertension and ventricular arrhythmias. In the human and rat, STL enantiomers are predominantly cleared from the body by the kidney as intact drug. The renal clearance (Cl_r) of STL enantiomers substantially exceeds the glomerular filtration rate (GFR) in the human and rat. In this report, the hypothesis that STL enantiomers are excreted by an active renal transport system was investigated in the rat by coadministering racemic STL (10 mg kg⁻¹) with cimetidine, an inhibitor of renal tubular secretion of organic cations. To compare the effects of short-term and sustained cimetidine exposure on STL enantiomer disposition, cimetidine was administered either as a single bolus (30 mg kg⁻¹, n=7) immediately prior to the STL dose, or as a 30 mg kg⁻¹ bolus plus a 50 mg kg⁻¹ infusion over the 6 h study period (n=7). Blood and urine samples were collected over 6 h, during which time anaesthesia was maintained via intraperitoneal administration of pentobarbital. Cimetidine bolus and cimetidine infusion reduced STL enantiomer Cl_r by 43 and 59%, respectively, compared with respective saline controls. Significant stereoselectivity was observed in the cimetidine infusion group: systemic clearance, Cl_r (R>S), and AUC (S>R), although the magnitude of stereoselectivity was less than 5%. This study supports the hypothesis that STL enantiomers are predominantly cleared from the rat via a renal cationic transport mechanism, and that this system can be competitively inhibited by the presence of cimetidine.     

Comparison of the activity and plasma levels of oxprenolol,slow release oxprenolol,long acting propranolol and sotalol

Summary Observations were made in 5 healthy subjects who exercised before and 1, 3, 6, 8 and 24 h after the oral administration on separate occasions of 160 mg oxprenolol, 160 mg slow release oxprenolol, 160 mg long acting propranolol and 400 mg sotalol. Blood samples were obtained before and at 1, 2, 3, 6, 8, 10 and 24 h after drug administration and assayed for drug concentration. Although the plasma concentration of oxprenolol after S. R. oxprenolol was significantly less at 1 and 2 h and significantly greater at 24 h than after conventional oxprenolol, there was little difference between the effects of the two drugs on an exercise tachycardia. The plasma level of propranolol and the reduction in an exercise tachycardia after L. A. propranolol increased slowly to reach a peak at 6 h and then declined gradually to 24 h. The maximum plasma concentration and effect after sotalol occurred at 3 h and then declined with an elimination half-life of 12.1 h. At 24 h the percentage reduction in an exercise tachycardia was 8.3±2.5 after oxprenolol, 10.0±2.3 after S. R. oxprenolol, 18.0±3.2 after L. A. propranolol and 14.7±3.4% after sotalol.     

Effects of pindolol,sotalol and the optical isomers of propranolol on muscle action potentials and depolarization-secretion coupling in the rat

Muscle action potentials and miniature end-plate potential frequency were studied in different concentrations of pindolol, d-and l-propranolol and sotalol using intracellular microelectrode recording from rat phrenic nerve-diaphragm preparations, d-and l-propranolol at concentrations of 10 to 40 mg/1 and pindolol at 20 to 100 mg/1 slowed down the rate of rise, prolonged rise and half-decay times and reduced the overshoot of the muscle action potentials. Sotalol had similar effects but only at higher concentrations (100 to 200 mg/1). The drugs had no effect on the increase in the miniature end-plate potential frequency obtained with depolarization by increased extracellular potassium concentration.     

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。     

Critical appraisal of commercially available suspending vehicles for extemporaneous compounding of cardiovascular medicines: physical and chemical stability mini review

Oral liquid formulations are compounded by pharmacists to meet the needs of patients when a suitable commercially available product is not available. To minimize the errors associated with measuring multiple excipients and to enhance the shelf-life of the medicines, commercially available suspending bases are commonly used. This review aims to compare the stability and shelf life of commercially available extemporaneous formulation to traditional formulation methods. Five (5) databases were searched (Pubmed, SCOPUS, Science direct, Embase, and EBSCOhost). Twelve articles, comprising of seven cardiovascular medications (amiodarone, captopril, carvedilol, furosemide, nifedipine, sotalol, and valsartan), met the study inclusion criteria and were reviewed. Chemical stability of the drugs was comparable between the two formulation methods except for furosemide, captopril, and valsartan. The traditional compounding method provided superior stability for furosemide (90?vs. 14?days) and captopril (50?vs. 14?days), while the commercial vehicles provided superior stability for valsartan (90?vs. 14?days). Physical stability tests indicated that sedimentation does occur with both formulation methods. Microbial studies within the data were lacking and further research can be undertaken in this area. This review highlights the importance of assessing the suitability of compounding ingredients prior to preparation of the formulation.     

索他洛尔治疗室性早搏的临床观察

目的通过室性早搏患者在用索他洛尔治疗前后室性早搏及心率变异(HRV)的变化,以了解索他洛尔对室性早搏、HRV的影响.方法对75例室性早搏病人在索他洛尔治疗前后用动态心电图时域分析法对心率变异性各项指标进行了检测,并与对照组75例进行比较.结果与对照组进行比较,代表心率总变异程度的SDNN、SDANNI和SDNNI明显下降(P＜0.01),代表迷走神经功能的指标YMSSD、PNN50也有所下降(P＜0.05).治疗组用药后与用药前比较显示对室性早搏有效率70.6%,HRV的SDNNI、SDANNI、rMSSD和PNN50均有所升高(P＜0.05).结论索他洛尔不但能减少室性早搏,改善症状,而且能提高心率变异性,改善预后.     

盐酸索他洛尔生物黏附微球的体外释药及黏附性能研究

目的考察盐酸索他洛尔生物黏附微球的体外释药特性并评价其黏附性能。方法采用高效液相色谱法测定释放介质与微球中盐酸索他洛尔含量,并以滞留率为指标考察微球的黏附特性。结果盐酸索他洛尔生物黏附微球30min累积释药百分率达30％,4h释药达90％;离体法与在体法测得微球胃黏膜上的滞留率分别为87．60±2．8％与60．2％±9．8％。结论盐酸索他洛尔高效液相色谱测定方法简便、可靠,与盐酸索他洛尔普通片相比,盐酸索他洛尔生物黏附微球具有一定缓释特性,且其在离体与在体模型中黏附性能良好。     

The Time Course of New T‐Wave ECG Descriptors Following Single‐ and Double‐Dose Administration of Sotalol in Healthy Subjects

Introduction: The aim of the study was to assess the time course effect of IKr blockade on ECG biomarkers of ventricular repolarization and to evaluate the accuracy of a fully automatic approach for QT duration evaluation. Methods: Twelve‐lead digital ECG Holter was recorded in 38 healthy subjects (27 males, mean age = 27.4 ± 8.0 years) on baseline conditions (day 0) and after administration of 160 mg (day 1) and 320 mg (day 2) of d‐l sotalol. For each 24‐hour period and each subject, ECGs were extracted every 10 minutes during the 4‐hour period following drug dosage. Ventricular repolarization was characterized using three biomarker categories: conventional ECG time intervals, principal component analysis (PCA) analysis on the T wave, and fully automatic biomarkers computed from a mathematical model of the T wave. Results: QT interval was significantly prolonged starting 1 hour 20 minutes after drug dosing with 160 mg and 1 hour 10 minutes after drug dosing with 320 mg. PCA ventricular repolarization parameters sotalol‐induced changes were delayed (>3 hours). After sotalol dosing, the early phase of the T wave changed earlier than the late phase prolongation. Globally, the modeled surrogate QT paralleled manual QT changes. The duration of manual QT and automatic surrogate QT were strongly correlated (R²= 0.92, P < 0.001). The Bland and Altman plot revealed a nonstationary systematic bias (bias = 26.5 ms ± 1.96*SD = 16 ms). Conclusions: Changes in different ECG biomarkers of ventricular repolarization display different kinetics after administration of a potent potassium channel blocker. These differences need to be taken into account when designing ventricular repolarization ECG studies. Ann Noninvasive Electrocardiol 2010;15(1):26–35