异烟肼与吡嗪酰胺联合抗结核治疗对肝功能的影响

目的了解异烟肼与吡嗪酰胺联合抗结核治疗对肝功能的影响。方法将81例因结核病化学治疗导致的药物性肝炎分为异烟肼(H)、利福平(R)、吡嗪酰胺(Z)联合化疗组与HR化疗组,分析比较两组的临床特点。结果HRZ联合化疗组暴发型肝炎的发生率为31%(16/51),死亡率为22%(11/51);HR化疗组暴发型肝炎的发生率及死亡率较低,分别为20%(6/30)、17%(5/30),但两组比较差异无统计学意义(P>0.05)。肝功能指标比较,HRZ联合化疗组肝功能损害程度明显大于HR化疗组:血清白蛋白(ALB)及凝血酶原活动度(PTA)两组比较差异有显著性(P<0.05)。结论异烟肼与吡嗪酰胺均有明显的肝脏毒性,联合用药可增加肝功能损害,一旦引起暴发型肝炎病死率极高,值得临床重视。     

异烟肼与吡嗪酰胺联合抗结核治疗对肝功能的影响

目的了解异烟肼与吡嗪酰胺联合抗结核治疗对肝功能的影响.方法将81例因结核病化学治疗导致的药物性肝炎分为异烟肼(H)、利福平(R)、吡嗪酰胺(Z)联合化疗组与HR化疗组,分析比较两组的临床特点.结果 HRZ联合化疗组暴发型肝炎的发生率为31%(16/51),死亡率为22%(11/51);HR化疗组暴发型肝炎的发生率及死亡率较低,分别为20%(6/30)、17%(5/30),但两组比较差异无统计学意义(P>0.05).肝功能指标比较,HRZ联合化疗组肝功能损害程度明显大于HR化疗组:血清白蛋白(ALB)及凝血酶原活动度(PTA)两组比较差异有显著性(P<0.05).结论异烟肼与吡嗪酰胺均有明显的肝脏毒性,联合用药可增加肝功能损害,一旦引起暴发型肝炎病死率极高,值得临床重视.     

高效液相色谱法测定血清中异烟肼、吡嗪酰胺及利福平浓度

目的验证反相高效液相色谱法测定结核病人血清中异烟肼、吡嗪酰胺及利福平的浓度的可行性。方法采用SymmetryC18色谱柱为分析柱,光电二极管阵列检测器(DAD)检测,EMPOWER中文色谱工作站处理数据,异烟肼、吡嗪酰胺以峰高外标法定量,利福平以峰面积外标法定量。结果INH在浓度0.5～30μg/ml的范围内线形良好,PZA在1～50μg/ml的范围内线形良好;RFP在0.5～25μg/ml的范围内线形良好。结论反相高效液相色谱法测定异烟肼、吡嗪酰胺及利福平血药浓度,方法简便、快速、灵敏、准确,重复性好。     

异烟肼致药物性肝损伤的研究

目的 调查研究抗结核药物异烟肼日剂量与药物性肝损伤(DILI)发生率的关系.方法 采用回顾性研究方法,收集采用HRZE方案(异烟肼、利福平、吡嗪酰胺、乙胺丁醇)治疗的结核病例1 509份,按照患者性别比、年龄、体重和异烟肼日剂量等情况进行统计分析.结果 所统计的1 509例患者中,年龄"21~30岁"组药物性肝损伤发生率最高(28例,10.00%),年龄"≥71岁"和"≤10岁"2组患者药物性肝损伤发生率较低[分别是3(3.95%)和0].在相同的体重范围内,异烟肼日剂量每增加0.1 g,患者DILI发生率会不同程度的升高,但仅有日剂量不大于0.5 g 的各组之间DILI发生率差异有统计学意义(P<0.05),DILI发生率升高7.48%~15.48%(P<0.05).结论 随着异烟肼日剂量增加,患者药物性肝损伤发生率逐渐升高,但日剂量>0.5 g组仍需收集更多病加以分析研究.建议临床医师严格按照说明书用药,以提高用药安全性和合理性,减少药物性肝损伤的发生.     

异烟肼、吡嗪酰胺和利福平致肝脏损害

加拿大药物不良反应监测中心(CADRMP)已经收到大量与抗结核药利福平(rifampicin)、异烟肼(isoniazid)和吡嗪酰胺(pyrazinamide)有关的肝脏损害报告,截止2001年5月18日,收到420份与上述3种抗结核药有关的肝脏损害报告(见表)。CADRMP提示医务人员,对接受抗结核药治疗     

番茄红素对异烟肼和利福平致大鼠肝损伤的保护作用

目的观察番茄红素对异烟肼(INH)和利福平(RFP)合用致大鼠肝损伤的保护作用并探讨其作用机制。方法给予异烟肼和利福平(各75mg.kg-1)用药4wk制备肝损伤动物模型,分别给予低、中、高剂量番茄红素(10、20、30mg.kg-1),4wk后测定大鼠血清中AST和ALT含量、肝脏指数,以及肝组织匀浆中的MDA、GSH的含量和SOD的活性,并作肝组织病理学检测。结果番茄红素能降低肝脏指数(P<0.05)、降低大鼠血清AST和ALT的含量、降低大鼠肝匀浆中的MDA、增加肝匀浆中GSH、升高SOD(P<0.05或P<0.01),减轻肝组织变性、坏死程度,缓解肝组织的病理改变。结论番茄红素对INH和RFP合用所致的大鼠肝损伤具有保护作用,其作用机制可能与番茄红素的抗脂质过氧化作用有关。     

异烟肼和利福平联用致小鼠肝损伤实验模型的建立

目的:为异烟肼和利福平联用致小鼠肝损伤实验模型的建立提供参考。方法:取32只小鼠,随机均分为对照组(生理盐水)和模型组(异烟肼+利福平,各75mg.kg.d-1),每日定时空腹灌胃给予药物1次,灌胃体积为20mL.kg.d-1,于第7、14天分批处死小鼠,摘眼球取血测定其血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)活性,取肝组织观察其病理学变化和肝匀浆中丙二醛(MDA)含量、超氧化物歧化酶(SOD)活性变化。结果:与对照组比较,模型组小鼠第7、14天的ALT、AST活性均明显增强,第14天的MDA含量明显增加、SOD活性明显降低;与第7天比较,模型组第14天小鼠AST显著增加(P<0.05或P<0.01)。病理学观察显示,模型组第7天小鼠肝细胞索排列较紊乱,肝细胞体积增大,有少量的肝细胞坏死和炎细胞浸润;第14天小鼠肝细胞索排列紊乱,肝细胞发生坏死较严重,并伴有明显的炎细胞浸润;对照组小鼠未见明显肝细胞损伤。结论:本方法可成功建立小鼠肝损伤实验模型。     

大蒜油对利福平和异烟肼联合所致大鼠肝损伤的保护作用

目的探讨大蒜油对利福平(rifampicin,RIF)和异烟肼(isoniazid,INH)所致大鼠肝损伤的保护作用。方法将60只雄性Wistar大鼠随机分为5组:大蒜油低、中、高剂量处理组、RIF+INH模型组和正常对照组,每组12只。大蒜油低、中、高处理组分别给予相应浓度的大蒜油20、40和80 mg/kg,正常对照组给予等体积的玉米油;2 h后RIF+INH模型组和大蒜油各处理组均给予RIF(75 mg/kg)+INH(75 mg/kg),正常对照组给予等体积的5%淀粉溶液,所有处理每天1次,连续灌胃28 d。观察大鼠体重变化,28 d后测定大鼠血清中丙氨酸转氨酶(alanine transaminases,ALT)、天冬氨酸转氨酶(aspartate transaminases,AST)、总胆红素(total bilirubin,TB)含量、肝重及肝脏系数,同时对肝脏进行病理组织学检查。结果与正常对照组比较,RIF+INH模型组体重无统计学意义,肝重和肝脏系数明显增大(P<0.01),血清中ALT、AST及TB的含量明显升高(P<0.01);与RIF+INH模型组比较,大蒜油低、中和高剂量处理组大鼠体重差异无统计学意义,肝重分别减小3.79%、3.84%和7.73%(P<0.05),脏系数分别减小0.32%、3.25%和3.57%(P<0.05),血清中ALT、AST及TB的含量明显降低(P<0.01或P<0.05)。肝脏病理结果显示,模型组有不同程度细胞浊肿、气球样变,大蒜油处理组没有明显的病理结构改变。结论大蒜油可对利福平和异烟肼联合诱导的肝损伤有保护作用。     

异烟肼/利福平致肝损伤的生物标志物研究进展

异烟肼(INH)和利福平(RFP)是临床抗结核一线药物,也是我国急性药物性肝损伤(DILI)的重要病因。INH和RFP单独使用均会引起DILI,二者联用会使肝损伤的发生率及严重程度显著增加。目前临床上对INH、RFP致肝损伤的检测指标主要有血清转氨酶、总胆红素等,存在灵敏度和特异性不高、早期预测性差等缺点。近年来多项研究试图通过多种方法发现更为理想的生物标志物,提高对INH、RFP致DILI检测与诊断的特异性与灵敏性。本文从代谢组学、蛋白质组学、转录组学、基因组学等方面就INH、RFP致DILI的新型潜在生物标志物予以综述。     

洛伐他汀对脓毒症大鼠肺损伤的保护作用及对脂联素表达的影响

目的：观察洛伐他汀对脓毒症大鼠肺损伤的保护作用及对脂联素表达的影响。方法健康雄性清洁级Wistar大鼠54只,体质量250～300 g,采用数字表法随机分为三组：假手术组（Sham组）、脓毒症组（CLP组）、洛伐他汀处理组（LOV组）。 Sham组及LOV组术前1周腹腔注射洛伐他汀4 mg／kg,CLP组则注射等体积的溶剂0．5％缩甲基纤维素钠（CMC）。各组术后4 h、12 h和24 h取支气管肺泡灌洗液（BALF）测定TNF-α及IL-6水平;取肺组织观察组织病理学改变及检测髓过氧化物酶（MPO）及丙二醛当量（MDA）含量;另取血标本检测血清脂联素水平。结果 Sham组4 h、12 h和24 h TNF-α含量分别是（1．80±0.13）pg／mL、（2．04±0．15）pg／mL和（1．93±0．19）pg／mL;IL-6含量分别是（20．56±0．23）pg／mL、（18．35±0．15）pg／mL和（21．23±0．20）pg／mL;MPO含量分别是（2．82±0．14）U／g组织、（2．88±0．07）U／g组织和（2.76±0．18）U／g组织;MDA含量分别是（3．32±0．12）nmol／mg、（3．09±0．11）nmol／mg和（3．21±0．08）nmol／mg;脂联素浓度分别是（2．68±0．14）μg／mL、（2．80±0．07）μg／mL和（2．86±0．18）μg／mL。与Sham组相比：（1）CLP组及LOV组肺损伤形态学改变明显,CLP组BALF中TNF-α含量[4 h、12 h和24 h分别是（4.23±0．18） pg／mL、（5．62±0．24）pg／mL和（5．14±0．10）pg／mL,t＝28．41、30．98、36．62]及IL-6含量[4 h、12 h和24 h分别是（39．12±0．17）pg／mL、（47．25±0．21）pg／mL和（44．69±0．27）pg／mL,t＝158．90、273．40、127．28]增高,肺组织匀浆中MPO水平[4 h、12 h和24 h分别是（4．85±0．13） U／g组织、（6．17±0.08） U／g组织和（7．84±0．10）U／g组织,t＝26．39、79．40、60．43]及MDA水平[4 h、12 h和24 h分别是（6．24±0．06）nmol／mg、（7．56±0.15）nmol／mg和（8．43±0．10）nmol／mg,t＝53．31?     

高效液相色谱法测定复方利福平片中利福平、异烟肼及吡嗪酰胺的含量

用HPLC法测定复方利福平片中利福平、异烟肼及吡嗪酰胺的含量。方法 :采用SpherisorbCN(2 50mm× 4 6mm ,5μm)色谱柱 ,流动相采用 0 0 1mol/L庚烷磺酸钠溶液 (pH2 2 )—乙腈 (44∶56,v/v) ,流速为 2 0ml/min,检测波长为 2 54nm。结果 :利福平在 71 76～ 1 66 40 μg/ml、异烟肼在 47 64～ 1 1 1 1 6μg/ml、吡嗪酰胺在 1 37 76～ 32 1 44μg/ml范围内线性良好 ,r分别为 0 9999、 0 9991、 0 9999(n =9) ,平均回收率分别为 :99 57%、 99 51 %、 1 0 0 1 0 % ,RSD分别为 :0 71 %、 0 51 %、0 62 % (n =7)。结论 :本法简便、准确、灵敏度高     

高产液相色谱法测定复方利福平片中利福平、异烟肝及吡嗪酰胺的含量

用HPLC法测定复方利福平片中利福平、异烟肼及吡嗪酰胺的含量.方法采用Spherisorb CN(250mm×4.6mm,5μm)色谱柱,流动相采用0.01mol/L庚烷磺酸钠溶液(pH2.2)-乙腈(4456,v/v),流速为2.0ml/min,检测波长为254nm.结果利福平在71.76～166.40μg/ml、异烟肼在47.64～111.16μg/ml、吡嗪酰胺在137.76～321.44μg/ml范围内线性良好,r分别为0.9999、0.9991、0.9999(n=9),平均回收率分别为99.57%、99.51%、100.10%,RSD分别为0.71%、0.51%、0.62%(n=7).结论本法简便、准确、灵敏度高.     

The effect of pyrazinamide and rifampicin on isoniazid metabolism in rats

Hepatotoxicity is the main concern during tuberculosis chemotherapy with the first-line drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR). Since these hepatotoxic events have been associated with INH metabolites, the study aimed to measure the area under curve (AUC) parameter for INH and its metabolites acetylisoniazid (AcINH), hydrazine (Hz) and acetylhydrazine (AcHz), when groups of rats were pre-treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg + RMP 100 mg; INH 100 mg + PYR 350 mg; INH 100 mg + PYR 350 mg + RMP 100 mg. It was found that co-administration of RMP, PYR and RMP + PYR caused a significant decrease in the AUC for INH. Co-administration of PYR was the only treatment that caused a significant increase in the AUC for Hz and a decrease in the AUC for its acetylated product AcHz. The AUC for AcINH was not significantly altered in any experimental group. In conclusion, the increased metabolism of INH in all the drug combinations and the significantly higher production of Hz in the group INH + PYR might be linked with exacerbated hepatotoxic effects of these drug associations.     

The effect of rifampicin and pyrazinamide on isoniazid pharmacokinetics in rats

Tuberculosis chemotherapy involves combination of the drugs isoniazid (INH), rifampicin (RMP) and pyrazinamide (PYR) for a 6-month period. The present work investigated the influence of RMP and PYR on the pharmacokinetic parameters of INH when groups of rats were pre-treated for 21 days with INH alone or in combination with RMP and/or PYR, in the following amounts per kg body weight: INH 100 mg; INH 100 mg+RMP 100 mg; INH 100 mg+PYR 350 mg; INH 100 mg+PYR 350 mg+RMP 100 mg. It was found that the co-administration of PYR caused an increase in the INH distribution volume (V(d)/F), half-life of elimination (t(1/2beta)) and clearance (Cl(T)/F), and a decrease in the area under curve 0 to 24 h (AUC). Co-administration of RMP caused an increase in the Cl(T)/F and a decrease in the AUC. The combination INH+PYR+RMP caused an increase in the Cl(T)/F and a decrease in the AUC. These significant pharmacokinetic interactions between the tuberculostatic drugs might be related to differences in the therapeutic and toxic effects.     

Terminalia chebula (fruit) prevents liver toxicity caused by sub-chronic administration of rifampicin, isoniazid and pyrazinamide in combination

Terminalia chebula Gertn. (Combetraceae) is an important herbal drug in Ayurvedic pharmacopea. In the present study, a 95% ethanolic extract of T. chebula (fruit) (TC extract), which was chemically characterized on the basis of chebuloside II as a marker, was investigated for hepatoprotective activity against anti-tuberculosis (anti-TB) drug-induced toxicity. TC extract was found to prevent the hepatotoxicity caused by the administration of rifampicin (RIF), isoniazid (INH) and pyrazinamide (PZA) (in combination) in a sub-chronic mode (12 weeks). The hepatoprotective effect of TC extract could be attributed to its prominent anti-oxidative and membrane stabilizing activities. The changes in biochemical observations were supported by histological profile.     

HPLC法测定结核病患者血浆中异烟肼、吡嗪酰胺和利福平的质量浓度

目的：建立快速、灵敏的同时测定人血浆中异烟肼、吡嗪酰胺和利福平的质量浓度的高效液相色谱法。方法血浆样品采用甲醇沉淀蛋白法萃取,采用C18色谱柱（150mm×4．6mm,5．0μm）,用甲醇、乙腈、0.05mol·L-1KH2PO3水溶液（三乙胺调pH6.0）进行梯度洗脱,柱温40℃,进样量20μL,采用PDA紫外检测器。结果以峰面积外标法定量,异烟肼在0．20～25．6μg·mL-1范围内,与峰面积线性关系良好（r＝0．9998）,吡嗪酰胺在0．20～25．6μg·mL-1范围内,与峰面积线性关系良好（r＝0．9999）,利福平胶囊在0．40～25．6μg·mL-1范围内,与峰面积线性关系良好（r＝0．9996）,回收率为85％～115％,日内、日间精密度RSD均＜9．4％（n＝5）。结论该方法专属性强、灵敏、准确,适用于同时测定人血浆样品中异烟肼、吡嗪酰胺和利福平的质量浓度。     

骨康胶囊合并非甾体抗炎药致肝损伤2例

目的　提醒临床医生联合用药时注意药物不良反应的叠加。方法　报道2例骨康胶囊合并非甾体类抗炎药后出现肝功能损伤的病例资料,查阅文献分析该药导致肝功能损伤的关联性和发病机制。结果　2例患者停用骨康胶囊及非甾体抗炎药物并给予保肝药物治疗后,肝功能均恢复正常。通过因果关系评估表评估得分均为7分,相关性判断为“很可能”。结论　患者使用骨康胶囊合并非甾体抗炎类药物时需加强肝功能监测,关注其肝损伤的不良反应。     

Bioequivalence assessment of rifampicin,isoniazid and pyrazinamide in a fixed dose combination of rifampicin,isoniazid, pyrazinamide and ethambutol vs. separate formulations

Depending on the patient category, tuberculosis requires treatment with 3 to 5 drugs which means that patient's compliance to therapy may not be optimal. To increase patient's adherence to treatment schedules, these drugs can be given as single drug preparations or fixed dose combinations (FDCs) of 2 or more drugs in a single formulation. However, an important issue associated with a rifampicin-containing FDC is its quality. Hence, to avoid spurious formulations entering the market, the World Health Organization and the International Union Against Tuberculosis and Lung Disease have recommended FDCs only of proven bioavailability. In this study, the relative bioavailability of rifampicin, isoniazid and pyrazinamide was assessed in a group of 14 healthy male subjects using the FDC tablet containing 4 drugs versus separate formulations at the same dose levels. The study was designed as an open, crossover trial. A total of 9 blood samples were collected over a period of 24 h. The concentration of rifampicin, its main metabolite desacetyl rifampicin, isoniazid and pyrazinamide in plasma were assessed using HPLC analysis. The pharmacokinetic parameters AUC(0-24) and Cmax were subjected to parametric and non-parametric statistical tests at 90% confidence interval. In addition, time to reach peak concentration (tmax), elimination rate constant (Kel) and terminal elimination half-life (t1/2) for each drug were also calculated. It was concluded that the FDC tablet containing 4 drugs is bioequivalent to separate rifampicin, isoniazid and pyrazinamide formulations at the same dose levels.