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目的探索注射用乌司他丁在中国健康成年受试者中单日多次给药的安全性、耐受性。方法采用随机、平行、双盲、安慰剂对照的1天多次给药研究设计,将24例健康受试者随机分为A、B、C 3个剂量组,每组8例,其中每组2名健康受试者作安慰剂对照,3个剂量组的安慰剂受试者合并为安慰剂组(n=6)。A组每次给药60万U,B组每次给药90万U,C组每次给药120万U,3组均1天4次,每两次给药间隔为3 h。首剂给药匀速缓慢推注30 min,其后的3次给药按每0.5 h滴注50万U的速度匀速静脉滴注。观察各剂量组的受试者在给药前后的生命体征变化、心电图检查结果、实验室各检查项目指标的变化以及异常值和不良事件。结果 24例受试者均完成试验。给药后实验室检查异常值中,仅C组和安慰剂组的5例纤维蛋白原降低为异常有临床意义,其他检查结果均为正常或异常无临床意义。试验中,未见严重不良反应。其中,A组和B组未发生任何不良事件。C组出现2例次与药物可能相关的轻度腹泻(2/6)、3例次与药物可能无关的纤维蛋白原偏低(3/6)和1例次与药物可能无关的脐周腹痛(1/6)。所有不良事件均为Ⅰ级,并且均在未采取任何措施的情况下自行缓解。结论注射用乌司他丁1天多次给药,在每天4次,每次60万U到120万U的给药范围内,安全性较好,受试者均可耐受。因此,建议后续临床使用剂量最高可达到每次120万U,每天4次。
Objective To investigate the safety and tolerability of ulinastatin for injection in healthy adult subjects in China. Methods A randomized, parallel, double-blind and placebo-controlled one-day multi-dose study design was used. 24 healthy subjects were randomly divided into three groups: A, B and C, Two healthy subjects were given placebo, and placebo subjects in the three doses were pooled into placebo (n = 6). A group of 600,000 U per administration, B group administered 900,000 U each time, C group administered 1.2 million U each time, the three groups were 4 times a day, every two doses interval of 3 h. The first dose of slow and uniform bolus injection 30 min, followed by three doses of 0.5 million per 0.5 h infusion rate of uniform intravenous infusion. Changes of vital signs, electrocardiogram (ECG) test results, indexes of laboratory items and abnormal values and adverse events in each dose group were observed before and after administration. Results 24 subjects completed the test. Among the abnormalities in laboratory tests after administration, only 5 cases of fibrinogen in group C and placebo were reduced to abnormal clinical significance, the other test results were normal or abnormal without clinical significance. In the test, no serious adverse reaction was found. Among them, A and B groups did not have any adverse events. There were 2 cases of mild diarrhea in group C (2/6), 3 cases of low fibrinogen (3/6), which could be unrelated to the drug, and 1 case of umbilical abdominal pain (1/6). All adverse events were grade I, and were relieved without any action. Conclusions Ulinastatin for injection is administered multiple times a day for four times a day, 600,000 U to 1.2 million U per dose. It is safe and can be tolerated in all subjects. Therefore, the recommended follow-up clinical use of up to 1.2 million doses of U, 4 times a day.