A simulation study of three sequential methods for the comparison of two treatment groups when the response criterion is censored

Three recent sequential methods, group sequential analysis (GSA), the sequential probability ratio test (SPRT) and the triangular test (TT) are well suited to randomized clinical trials with a censored response criterion, as they do not require matched pairs of patients. We undertook a simulation study to investigate their statistical properties and to compare these three methods with the fixed-sample design. Our results suggest that the three methods have the expected statistical properties for size and power; they allow an important reduction of the average number of events before stopping, except with GSA when there is no treatment difference; the triangular test (closed design) appears the optimal design, as the variance of the number of events is smaller than with the sequential probability ratio test (open design) and analysis after every twenty new events does not alter the statistical properties of these sequential methods and enhances their usefulness.     

复方18甲基炔诺酮透皮控释传递系统的LNG人体药物动力学与药效学评价

复方18甲基炔诺酮/雌二醇透皮控释传递系统(LNG/E_2 TCDS)能同时恒速释放低剂量的LNG和E_2,在1周内维持一个平稳而有效的LNG血药浓度。药动学与药效学研究证明,该系统释放的LNG能达到血清LNG目标水平,产生有效的排卵抑制(6/6)。LNG/E_2 TCDS可望发展成为一种安全、有效、非侵入性的新型生育调节避孕制剂。     

Conversion of Ouabain-Induced Ventricular Tachycardia in Dogs with Epicardial Lidocaine: Pharmacodynamics and Functional Effects

Epicardial antiarrhythmic drug administration was studied as a therapeutic approach for experimental ventricular tachycardia (VT) in an open-chest dog model. Lidocaine-polyurethane matrices (28%, w/w) were formulated as a model system. Matrices were placed on the left ventricular epicardium in each of 23 anesthetized open-chest dogs with ouabain-induced VT, to evaluate effectiveness in restoring sinus rhythm. Conversion occurred in all animals treated with matrices containing 300 mg or more of lidocaine after 1.5 to 7.0 min. The matrix lidocaine content correlated linearly with the time required for conversion to sinus rhythm (r = 0.75, P = 0.0002); irrespective of matrix size the myocardial/plasma lidocaine ratio was 20.1 ± 4.2 (mean ± SD) at the time of conversion. In a separate series of five dogs without ventricular tachycardia, systolic wall thickening measured with sonomicrometers after 5 min of controlled-release lidocaine administration (500- to 1000-mg matrix lidocaine content, 7.48 ± 3.49-mg/kg dose) was only minimally diminished (–14.1%) and this effect was observed only at the site of matrix placement on the anterior-apical epicardium. In contrast, intracoronary injection of 0.3 or 1.0 mg/kg of lidocaine-HCl resulted in complete elimination of wall thickening or replacement by systolic thinning. Thus epicardial administration of lidocaine from polyurethane matrices was an effective means of treating ouabain-induced ventricular tachycardia. Regional myocardial function in the vicinity of the matrices was modified to a very limited degree, supporting the view that the matrices can be used safely, without serious risk to ventricular contractile performance.     

A phase I/II study of continuous infusion suramin in patients with hormone-refractory prostate cancer : toxicity and response

 Introduction: Suramin is a synthetic polysulfonated naphthylurea which has been used for the treatment of African trypanosomiasis and onchocerciasis, but since the mid-1980s has received attention as a possible antiretroviral and antineoplastic agent. Objective: This clinical trial of suramin was undertaken as a phase I/II study in patients with hormone-refractory prostate cancer, with the hypothesis that the intensity of therapy with suramin could be increased significantly if measures were undertaken to maintain the plasma concentrations of the drug under 300 μg/ml. Methods: We report the clinical results of this trial, wherein patients were treated at three different targeted plasma suramin concentrations (275, 215 and 175 μg/ml) for varying periods of time (2, 4 or 8 weeks), with delivery of the drug by continuous intravenous infusion. Results: The major toxicity observed in this trial was neurologic, consisting of a motor and sensory peripheral neuropathy that resulted in both paresis and paralysis of the limbs. Nearly all of this severe (CTEP grade III, IV) neurologic toxicity was observed in the patients treated at a plasma suramin concentration of 275 μg/ml for 4 or more weeks. A single patient treated at 215 μg/ml for 8 weeks developed moderate (CTEP grade III) proximal lower extremity weakness, and no patient treated at 175 μg/ml developed this toxicity. The second most common toxicity observed was infection of the central venous catheter. The overall response rate for all of the evaluable patients was 17% (13 of 75 patients). In addition, prostate-specific antigen (PSA)-defined responses were observed in six patients receiving therapy at 175 μg/ml, but these responses were confounded by cessation of therapy with flutamide during suramin treatment. Conclusions: In summary, although plasma suramin concentrations were maintained below 300 μg/ml, neurologic toxicity nonetheless occurred with high frequency in patients treated at 275 μg/ml for 4 or more weeks. Therapy at 215 and 175 μg/ml was in general well tolerated, but central venous catheter-related infection, as well as the inconvenience and expense of continuous infusional therapy, make this method of drug delivery impractical. Only moderate antitumor activity was observed during this trial, but it is possible that both continuation of flutamide and flutamide withdrawal during suramin therapy confounded the assessment of suramin’s activity in hormone-refractory prostate cancer. Received: 9 June 1995/Accepted: 18 March 1996     

甲磺酸帕珠沙星注射液治疗急性细菌性感染有效性和安全性的多中心临床研究

目的评价甲磺酸帕珠沙星注射液治疗急性细菌性呼吸系统、泌尿生殖系统感染的有效性、安全性。方法采用随机单盲平行对照多中心试验方法。选择急性细菌性呼吸系统、泌尿生殖系统感染患者213例，可评价病例209例，随机编人试验组或对照组。试验组101例．每日1次给予甲磺酸帕珠沙星注射液300mg，iv，gtt，bid；对照组108例，每日1次给予加替沙星注射液200mg，iv，gtt，bid。疗程7～10d。结果甲磺酸帕珠沙星组、加替沙星组有效率分别为94．06％（95／101）和90．74％（98／108）；痊愈率分别为67．33％（68／101）和70．37％（76／108）；细菌清除率分别为94．62％（88／93）和93．62％（88／94）；不良反应发生率分别为7，69％（8／104）和5．50％（6／109）。两组有效性、安全性相似（P〉0．05）。结论甲磺酸帕珠沙星注射液治疗急性细菌性呼吸系统、泌尿生殖系统感染有效、安全，与加替沙星相当。     

有效控制与控制不佳的MRI阴性的GTCS病人发作间期SPECT对照研究

目的:利用单光子发射计算机断层摄影(SPECT)半定量分析有效控制与控制不良的MRI阴性的全面性强直阵挛发作癫(GTCS)病人的局部脑血流差异,探讨脑血流灌注与其预后的关系.材料和方法:对29例有效控制的和12例控制不佳的MRI阴性的GTCS病人进行发作间期99mTc-ECD-SPECT脑血灌流显像,10例年龄匹配的健康人作对照,用感兴趣区(ROI)的不对称指数(%AI)进行半定量分析.将SPECT分析结果与病人的临床表现与EEG相比较.结果:①控制不佳组与有效控制组在丘脑和基底节区的%AI存在显著性差异(P<0.05);②控制不佳组SPECT脑显像的异常率(83.3%,10/12)明显高于有效控制组的异常率(17.2%,5/29),两组具有显著性差异(P<0.01);而两组病人的EEG异常率分别为58.3%、44.8%(7/12、13/29),无显著性差异(P>0.05).结论:控制不佳的MRI阴性的GTCS病人往往存在发作间期的低血流灌注脑区,提示癫的难治性;而控制良好的病人多无明显异常发现,可能预后较好.