中国健康受试者单次负荷注射盐酸尼非卡兰的药效学和安全性研究

Pharmacodynamics and safety of single intravenous loading dose of nifekalant hydrochloride in healthy Chinese volunteers

目的评价中国健康志愿者单次静脉注射低、中、高3个负荷剂量的盐酸尼非卡兰的安全性及QT间期等药效学指标的变化。方法用随机双盲、安慰剂对照、剂量爬坡临床试验。低、中、高(0.15,0.30和0.50 mg·kg^(-1))3个剂量试验组,每组纳入14例受试者,每组中各有12名受试者给予试验药物,各组另外2名受试者给予安慰剂。根据体重计算给药量,药物溶于0.9%NaCl,配制为含2 mg·mL^(-1)盐酸尼非卡兰的液体,注射泵5 min匀速注射给药。评价4组受试者给药前后QT间期、PR间期、QRS间期、RR间期、QTc间期指标的变化。结果低、中、高剂量试验组和安慰剂组受试者用药后血压无明显变化,低剂量试验组心率较基线无明显变化,中、高剂量试验组心率较基线略有下降,部分时间点心率的平均值低于60次/分,均在给药后24 h回复至基线水平。低、中、高剂量试验组受试者均于给药结束即刻出现QT间期延长,静注结束后3 min达到峰值,分别为(450.33±22.25),(476.33±59.30)和(524.31±55.80)ms, QTc间期的变化趋势同QT间期。安慰剂组的QT间期、QTc间期均无明显变化。低、中、高剂量试验组及安慰剂组各时间点PR间期、QRS间期无明显变化。低、中、高剂量试验组受试者RR间期在负荷给药结束即刻至静注结束3 min出现延长,在静脉注射结束3 min至4 h稳定;RR间期在静脉结束后4~6 h较基线明显下降,6~10 h逐渐恢复至基线,10~12 h较基线下降。安慰剂组RR间期的变化趋势同试验组。低、中、高剂量试验组和安慰剂组受试者用药后均无不适主诉。本研究无严重不良事件。结论在0.15~0.50 mg·kg^(-1)剂量内,受试者单次静脉给予负荷剂量盐酸尼非卡兰的安全性好,盐酸尼非卡兰抗心律失常的药效学指标QT间期延长具有剂量依赖性。

Objective To evaluate the safety and the changes of pharmacodynamic parameters such as QT interval after single intravenous loading dose of nifekalant hydrochloride at low, medium and high doses in healthy Chinese volunteers. Methods A randomized, double-blind, placebo-controlled, dose-climbing clinical trial was conducted. Fourteen subjects were enrolled in treatment-L,-M and-H groups(0.15,0.30 and 0.50 mg·kg^(-1)), with 12 subjects receiving the experimental drug and 2 subjects receiving placebo in each group. The dosage was calculated according to body weight, and the drug was dissolved in 0.9% sodium chloride. The liquid containing 2 mg·mL^(-1) nifekalant hydrochloride was prepared and the injection pump was used to inject the drug at a constant speed for 5 minutes. The changes of QT interval,PR interval,QRS interval,RR interval and QTC interval were evaluated. Results There was no significant change in blood pressure in placebo group and treatment-L,-M and-H groups. Heart rate in treatment-L group did not change significantly from baseline,while which in treatment-M,-H groups decreased slightly from baseline. The mean heart rate at some time points was less than 60 beats per min and returned to the baseline at 24 hours after administration. In treatment-L,-M and-H groups,QT interval prolonged immediately after administration,and the peak values reached 3 min after intravenous injection which were( 450. 33 ± 22. 25),( 476. 33 ± 59. 30) and( 524. 31 ± 55. 80) ms,respectively. The change trend of QTcinterval was the same as QT interval. There were no significant changes in QT interval and QT c interval in placebo group. There were no significant changes in PR and QRS interval in placebo group and treatment-L,-M and-H groups at each time point. The RR interval of subjects in treatment-L,-M and-H groups was prolonged from the end of intravenous administration immediately to 3 min,and was stable from 3 min to 4 h after intravenous administration. The RR interval decreased significantly from baseline at 4 h to 6 h after the end of intravenous administration,gradually recovered to baseline at 6 h to 10 h,and decreased from baseline at 10 h to 12 h. The change trend of RR interval in placebo group was the same as that in treatment-L,-M and-H groups. The placebo group and treatment-L,-M and-H groups had no complaints of discomfort after treatment. There were no serious adverse events in this study. Conclusion In the dose range of 0. 15-0. 50 mg·kg^(-1),the safety of single intravenous loading dose of nifekalant hydrochloride is good,and the QT interval prolongation,a pharmacodynamics index of antiarrhythmia,is dose-dependent.