【摘要】 目的 评价在无肝损伤易感因素人群中应用水飞蓟宾保肝治疗对预防抗结核药物性肝损伤(druginduced liver injury,DILI)的临床疗效和安全性。方法 采用多中心、随机开放、对照研究的方法 进行,采用随机数字表法随机选取患者。2012年11月至2013年5月从12个研究中心随机纳入568例初治、无肝损伤易感因素的肺结核患者,其中观察组277例,对照组291例。两组均采用2H-R-E-Z(S)/4H-R方案进行抗结核治疗,观察组加用水飞蓟宾胶囊(70 mg/次,3次/d)口服,疗程8周,观察8周内两组的肝功能指标变化及肝损伤发生情况、抗结核治疗方案的中断情况、抗结核治疗疗效,并记录不良反应。计量资料采用t检验分析,计数资料采用卡方检验(或Fisher确切概率法)分析,等级资料采用Wilcoxon秩和检验分析,组间资料比较采用CMH(Cochran-MantelHaensel)检验方法,P<0.05为差异有统计学意义。结果 在治疗2、4、8周末,观察组的肝损伤发生率分别为:3.97%(11/277)、1.44%(3/277)、2.17%(6/277);对照组的肝损伤发生率分别为:4.12%(12/291)、4.12%(12/291)、2.41%(7/291),两组患者在各治疗时段的肝损伤发生率差异均无统计学意义(Hc值分别为4.801、8.386、5.024,P值均>0.05)。8周内总体DILI发生数观察组为20例(7.22%),对照组为27例(9.28%);34.30%(95/277)的观察组患者,27.49%(80/291)的对照组患者出现一过性肝功能异常或症状;3.25%(9/277)的观察组患者及6.19%(18/291)的对照组患者出现肝功能损伤及症状,并中断抗结核治疗,两组差异无统计学意义(Z=-0.649,P>0.05)。治疗4周厌食发生率观察组为2.26%(6/266),对照组为8.46%(23/272),两组比较差异有统计学意义(χ~2=10.138,P<0.05);治疗4周恶心发生率观察组为1.14%(3/264),对照组为5.90%(16/271),两组比较差异有统计学意义(χ~2=8.874,P<0.05)。治疗8周厌食发生率观察组为0.78%(2//258),对照组为3.82%(10/262)两组比较差异有统计学意义(χ~2=5.334,P<0.05);治疗8周恶心发生率观察组为0.39%(1/255),对照组为4.99%(13/261),两组比较差异有统计学意义(χ~2=10.289,P<0.05)。在治疗8周末,观察组痰结核涂片阴性率为98.30%(231/235),高于对照组的92.98%(225/242)(χ~2=-2.83,P<0.05)。结论 在无肝损伤易感因素人群中进行预防性保肝治疗的意义不大,但可能会降低抗结核药物的停药率,提高患者的依从性及抗结核治疗疗效。更多还原

【Abstract】 Objective To assess the clinical efficacy and safety of Silibinin in preventing drug-induced liver injury(DILI) in the general population(patients without high-risk factors of DILI).Methods A prospective,multi-center,randomized,open-label and controlled trial was conducted with 568 patients from 12 clinical centers undergoing primary treatment of pulmonary tuberculosis.Study subjects were recruited between November,2012 and May,2013,using random numbers to select patients randomly.The study included 277 patients in experimental group and 291 patients in control group.The patients in the two group were treated with conventional 2H-R-E-Z(S)/4H-R for tuberculosis(TB),and additional Silibinin capsules(oral administration of 70 mg per time,3 times/day for 8 weeks in experimental group.Outcomes of liver function,interruption of anti-TB treatment and therapeutic results,as well as adverse reactions were observed and analyzed.The t-test and chi square test were used to analyze the measurement and count data,respectively.The Wilcoxon signed-rank test was used to assess nonparametric data.Analysis of variance or non-parametric analysis was used to compare data within the same curative effect indexes,and the CMH(Cochran-Mantel-Haensel) method was used to test the difference between groups.P<0.05 was considered statistically significant.Results At 2,4 and 8 weeks of treatment,the incidences of liver injury in experimental group were 3.97%(11/277),1.44%(3/277) and 2.17%(6/277),respectively;the incidences in control group were 4.12%(12/291),4.12%(12/291) and 2.41%(7/291),respectively.Statistical analysis showed that there was no significant difference in the incidence between the two groups at each treatment period(Hc:4.801,8.386,5.024,respectively,P>0.05).At 8 weeks,the numbers of patients diagnosed of DILI were20(7.22%) and 27(9.28%) in experimental and control groups,respectively(P>0.05).34.30%(95/277) and27.49%(80/291) of the patients in experimental and control groups had transient abnormal liver function or symptoms,respectively;similar percentages(3.25%(9/277) and 6.19%(18/291)) of the patients in two groups had liver function injury and symptoms,and were suspended for anti-TB treatment(Z=- 0.649,P>0.05).The incidences of anorexia and nausea symptoms were lower in experimental group(anorexia 2.26%(6/266) at 4 weeks,0.78%(2/258) at 8 weeks;nausea 1.14%(3/264) at 4 weeks,0.39%(1/255) at 8 weeks) than in control group(anorexia 8.46%(23/272) at 4 weeks,3.82%(10/262) at 8 weeks;nausea 5.90%(16/271) at 4 weeks,4.99%(13/261) at 8 weeks),and the differences were significant at 4(anorexia χ~2 =10.138,nausea χ~2 =8.874,P<0.05)and 8 weeks(anorexia χ~2 =5.334,nausea χ~2 = 10.289,P<0.05).8 weeks after the treatment,98.30%(231/235) of the sputum smear culture were negative in experimental group,which was significantly higher(χ~2 =-2.83,P<0.05) than that in control group(92.98%(225/242)).Conclusion Preventive hepatoprotective therapy in the patients without high-risk factors may be meaningless,but may reduce drug discontinuation rate,improve patient’s compliance and outcomes of anti-TB treatment.更多还原