我院结核病患者利福平和异烟肼血药浓度监测结果分析

目的:提高临床对抗结核药血药浓度监测工作的重视程度。方法:回顾性分析我院2005年8月～2008年12月结核病患者利福平和异烟肼的血药浓度监测结果。结果:共收集并测定241例利福平和53例异烟肼患者服药后2h的血药浓度。利福平血药浓度低于正常浓度范围者占10.4%,高于正常浓度范围者占31.9%;异烟肼血药浓度低于正常浓度范围者占71.7%,高于正常浓度范围者占15.1%。结论:抗结核药血药浓度监测结果是临床调整用药剂量的重要依据,对结核病患者合理用药具有重要意义。     

一线抗结核药致肝损害分析

目前我国在临床上对于结核病采用的是直接观察下的短程督导化疗方案,一般采用异烟肼、利福平、吡嗪酰胺、乙胺丁醇(链霉素)抗结核化疗方案,但异烟肼、利福平、吡嗪酰胺等一线抗结核药均有肝损害的不良反应,联合用药会加剧肝脏的毒性及不良反应,从而会导致化疗中断,同时也会提高结核杆茵耐药的风险,有时甚至会引起患者肝囊竭致使其死亡,因此,一线抗结核药的肝损害越来越引起临床的重视.     

274例结核病患者抗结核药物血药浓度分析及其药物安全性探究

目的：监测结核病患者抗结核药物的血药浓度并对结果及其安全性进行分析。方法：回顾性分析274例结核病患者使用一线抗结核药物治疗后的血药浓度监测结果以及用药前后相关指标变化情况。结果：使用异烟肼、利福平、吡嗪酰胺、乙胺丁醇和左氧氟沙星的患者分别有54.45%、46.38%、47.96%、61.50%和22.22%血药浓度达到治疗窗;异烟肼的血药浓度对ALT有显著影响（P <0.05）,乙胺丁醇的血药浓度对尿酸水平有显著影响（P <0.05）。异烟肼与利福平联用血药浓度对ALT、AST、肌酐、尿素氮和尿酸均无显著影响。结论：抗结核一线治疗药物的血药浓度达标率普遍较低,大部分抗结核药物的血药浓度达到治疗窗并未使不良反应显著增加。但应关注异烟肼和乙胺丁醇对ALT和尿酸水平的影响。     

儿童结核患者抗结核药物血药浓度影响因素及其安全性分析

目的 监测儿童结核患者抗结核药物的血药浓度,探讨血药浓度影响因素,并评价其安全性,指导临床合理用药。方法 回顾性分析浙江省中西医结合医院40例儿童结核患者接受异烟肼、利福平、吡嗪酰胺、乙胺丁醇治疗后的血药浓度监测结果、不良反应以及药物使用前后各生化指标变化情况。结果 儿童结核患者中异烟肼、利福平、吡嗪酰胺、乙胺丁醇的血药浓度达标率分别为48.15%、34.88%、73.81%、18.52%。其中,日剂量与异烟肼(P=0.0250)和利福平(P=0.0212)浓度呈正相关;年龄也是影响异烟肼(P=0.0430)和利福平(P=0.0057)浓度的因素之一,血清白蛋白(P=0.0475)和性别(P=0.0087)分别与利福平和吡嗪酰胺血药浓度相关。药物不良反应主要表现为肝功能异常(5/40,12.50%)和皮疹(4/40,10%),抗结核药物治疗前后谷草转氨酶(aspartate aminotransferase,AST)、谷丙转氨酶(alanine aminotransferase,ALT)、尿酸水平有所升高。结论 异烟肼、利福平、乙胺丁醇在儿童结核患者中的血药浓度达标率较低,患儿抗结核治疗可能与AST、ALT、尿酸升高相关。在抗结核治疗期间进行血药浓度和肝肾功能监测有助于提高药物治疗安全性和实施个体化治疗。     

抗结核药物致大鼠肝脏损害的病理研究

目的 研究常用抗结核药物及不同抗结核药物组合对肝脏损害的程度及光、电镜下病理表现,分析抗结核药物对肝细胞超微结构的影响.方法 健康成年SD大鼠152只,体重250～300 g,雌雄各半,随机分为8组.对照组:生理盐水;H(INH)组:异烟肼;R(RFP)组:利福平;Z(PZA)组:吡嗪酰胺;HR组:异烟肼 利福平;HZ组:异烟肼 吡嗪酰胺;RZ组:利福平 吡嗪酰胺;HRZ组:异烟肼 利福平 吡嗪酰胺.大鼠用药的常规剂量:每公斤体重人的常用剂量乘以5.5倍.标本制备:根据各组的不同要求,每天对大鼠进行1次灌胃,10 d后断头取血,分离肝脏,一部分以20%甲醛固定并制备病理切片,另一部分戊二醛固定后做电镜检查.结果 肝组织病理实验组与对照组比较,R组差异显著(P＜0.05);HR组、HZ组、HRZ组、RZ组、Z组差异极显著(P＜0.01);将HRZ组、HR组、HZ组、R组、RZ组比较,HRZ组差异显著(P＜0.05);HR组、Z组、RZ组、HZ组组间差异无显著性(P＞0.05).结论 异烟肼、利福平、吡嗪酰胺均可引起大鼠肝脏的损害,多种药物联用比单药应用损害更明显;随着药物应用种类的增多,肝脏损害逐渐加重;Z组可能比其他单用药组肝脏毒性更大.     

糖尿病对抗结核药物血药浓度影响的研究

目的 研究肺结核合并糖尿病对吡嗪酰胺、左氧氟沙星、对氨基水杨酸钠异烟肼、利福喷丁的血药峰浓度的影响,为糖尿病合并肺结核用药提供理论依据.方法 随机选取糖尿病合并肺结核的患者为观察组,单纯肺结核为对照组,服用抗结核药物7d后,用高效液相色谱法(HPLC)测定患者抗结核药 物(吡嗪酰胺、左氧氟沙星、对氨基水杨酸钠异...     

茵陈蒿汤加味治疗抗结核药致肝损害观察

现行治疗肺结核的短程化疗方案中主要有异烟肼、利福平、吡嗪酰胺,上述三药对肝脏功能的损害发生率高达43.5%.笔者自2000年以来在不中断原抗结核方案的基础上,应用茵陈蒿汤加味治疗抗结核药所致肝损害21例,取得了较好的效果,现将结果报告如下:     

异福酰胺胶囊及片剂增加异烟肼和吡嗪酰胺的溶出度检查

建议异福酰胺胶囊及片剂的溶出度检查方法中增加对异烟肼和吡嗪酰胺的考察,并建立了UV法测定该胶囊及片剂中的利福平、HPLC法分别测定该胶囊及片剂中的异烟肼和吡嗪酰胺.结果表明,利福平、异烟肼和吡嗪酰胺分别在16～40 μg/ml、12.2～30.8 μg/ml和38.7～117 μg/ml浓度范围内,线性关系良好.三组分的方法回收率为99.4%～100.4%,RSD均小于0.55%.     

抗结核药物致大鼠肾脏损害电镜研究

目的观察透射电镜下不同抗结核药物对SD大鼠肾脏超微结构的改变。方法健康成年SD大鼠(清洁级)152只,体重250～300g,雌雄各半,随机分为8组。对照组:0.9%氯化钠溶液;H(INH)组:异烟肼;R(RFP)组:利福平;Z(PZA)组:吡嗪酰胺;HR组:异烟肼+利福平组;HZ组:异烟肼+吡嗪酰胺组;RZ组:利福平+吡嗪酰胺组;HRZ组:异烟肼+利福平+吡嗪酰胺组。大鼠用药的常规剂量:每公斤体重人的常用剂量乘以5.5倍。标本制备:根据各组的不同要求,每天对大鼠进行一次灌胃,10d后断头取血,分离肾脏,戊二醛固定后做电镜检查。结果肾小球细胞部分线粒体溶解、髓样变,粗面内质网脱颗粒,滑面内质网池扩张;肾近曲小管上皮细胞核固缩,细胞器减少。异烟肼、利福平、吡嗪酰胺均可引起大鼠肾脏的损害,多种药物联用比单药应用损害更明显(P<0.01)。结论电镜诊断对抗结核药物所致大鼠肾脏损害有重要价值。     

护肝药对抗结核药物性肝损害患者的预防作用评价

目的:评价护肝药对抗结核药物性肝损害(ATDH)患者的预防作用。方法:选取2014年9月—2015年10月接受异烟肼、利福平、吡嗪酰胺和乙胺丁醇抗结核药物治疗的结核患者300例,随访3月,并检测其实验室肝功能各指标。结果:其中287例患者占95.67%的结核患者预防性使用护肝药物,预防性护肝药物主要有益肝灵、水飞蓟宾、甘草酸制剂、双环醇、葡醛内酯和还原性谷胱甘肽等;预防性使用护肝药的患者肝损害发生率为3.83%(11/287),与文献报道的抗结核药物性肝损害的发生率为3%~10%,经比较两者之间的差异无统计学意义(χ~2=0.419,P>0.05)。结论:护肝药物对抗结核药物性肝损害的预防意义不大,应根据患者基础情况确定是否需要预防性使用护肝药。     

Overview of anti-tuberculosis (TB) drugs and their resistance mechanisms

One-third of the world's population is infected with Mycobacterium (M.) tuberculosis. Tuberculosis continues to be the most common infectious cause of death and still has a serious impact, medically, socially and financially. Multidrug-resistant tuberculosis (MDR-TB), caused by tubercle bacilli that are resistant to at least isoniazid and rifampin, is among the most worrisome elements of the pandemic of antibiotic resistance because TB patients for whom treatment has failed have a high risk of death. Drugs used to treat tuberculosis are classified into first-line and second-line agents. First-line essential anti-tuberculosis agents are the most effective, and are a necessary component of any short-course therapeutic regimen. The drugs in this category are isoniazid, rifampin, ethambutol, pyrazinamide and streptomycin. Second-line anti-tuberculosis drugs are clinically much less effective than first-line agents and elicit severe reactions much more frequently. These drugs include para-aminosalicylic acid (PAS), ethionamide, cycloserine, amikacin and capreomycin. New drugs, which are yet to be assigned to the above categories, include rifapentine, levofloxacin, gatifloxacin and moxifloxacin. Recently there has been much development in the molecular pharmacology of anti-tuberculosis drugs. This review summarizes information for isoniazid, rifampicin, ethambutol, pyrazinamide, and fluoroquinolones, and describes their resistance mechanisms.     

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.     

The decline of high drug resistance rate of pulmonary Mycobacterium tuberculosis isolates from a southern Taiwan medical centre, 1996-2000

To investigate the anti-tuberculosis drug resistance pattern of pulmonary tuberculosis isolates in southern Taiwan, we performed a hospital-based surveillance at a southern Taiwan medical centre from 1996 to 2000. The combined drug resistance rates to at least one of four first-line agents (isoniazid, rifampicin, ethambutol, streptomycin) was 52.4%, and to both isoniazid and rifampicin was 11.4%, indicating high resistance rates compared with those reported in the World Health Organization (WHO)/International Union Against Tuberculosis and Lung Disease (IUATLD) global project and in northern Taiwan. The resistance rates to two second-line drugs, cycloserine, and kanamycin, were 75.7 and 23.7%, respectively. A significant decreasing trend in resistance rates to all tested drugs except streptomycin was observed during the 5-year period. The resistance rates in 1996 and 2000 were 43.1 and 16.4% for isoniazid, 23.4 and 9.5% for rifampicin, 23.4 and 12.1% for ethambutol, 92.7 and 50.9% for pyrazinamide. The combined drug resistance rate may not be the most accurate tool as it includes previously treated cases that may inflate the resistance rate and cases without a history of treatment. However, the observation of trends in the susceptibility of pulmonary tuberculosis with the increasing percentages of tuberculosis patients receiving the complete treatment course and the decreasing percentages of cases lost to follow-up in Kaohsiung after the institution of new governmental regulations for case management in 1997, suggest that such intervention programs are useful.     

Mechanistic explanation to the catalysis by pyrazinamide and ethambutol of reaction between rifampicin and isoniazid in anti-TB FDCs

Rifampicin and isoniazid are known to interact with each other in solid formulation environment to yield isonicotinyl hydrazone (HYD). In earlier studies, this reaction was indicated to be catalyzed by pyrazinamide and ethambutol hydrochloride, the two other co-drugs present in oral anti-tuberculosis fixed-dose combination (FDC) formulations. Accordingly, the present study was carried out to understand the catalytic role of pyrazinamide and ethambutol hydrochloride on the reaction between rifampicin and isoniazid. For the purpose, organic bases and amides similar in structure to pyrazinamide and ethambutol hydrochloride were combined individually with rifampicin and isoniazid. The compounds employed were pyrazine, piperdine, pyrollidine, pyridine, triethylamine, diisopropylethylamine, picolinamide, benzamide, ethylenediamine, ethanolamine, diethanolamine, and triethanolamine. An additional study was also carried out in the presence of free base of ethambutol. The mixtures were exposed to accelerated stability test condition of 40 °C/75% RH for 15 d. The nature of the products formed and the changes in relative concentrations of the drugs and products were followed by HPLC. The drugs showed different extent of degradation, yielding HYD, and in some cases degradation products of rifampicin. The results confirmed the catalytic role of pyrazinamide and ethambutol hydrochloride. The catalysis is postulated to involve intra-molecular proton transfer during transhydrazone formation process, entailing a tetrahedral mechanism.     

4药联用抗结核方案所致多器官功能障碍综合征

1例75岁男性肺结核患者,口服利福平0.6 g,1次/d;异烟肼0.3 g,1次/d;吡嗪酰胺0.3 g,3次/d;左氧氟沙星0.2 g,2次/d。用药11 d后,患者出现红色斑丘疹,体温最高38℃。用药14 d,因症状加重,自行停药。随后,患者出现皮肤、巩膜黄染,呕吐,水肿,遂入院。实验室检查:丙氨酸转氨酶(ALT)652 U/L,天冬氨酸转氨酶(AST)5066 U/L,碱性磷酸酶(ALP)66 U/L,直接胆红素(DBil)30.9μmol/L,总胆红素(TBil)53.5μmol/L,肌酐(SCr)150.0μmol/L,尿素氮(BUN)13.9 mmol/L,血小板(PLT)65×109/L。入院诊断:继发性肺结核;药物性肝损害;Ⅰ型呼吸衰竭;肾功能不全;心房颤动;多器官功能障碍综合征。停用所有抗结核药物,给予胺碘酮、苯海拉明、葡萄糖酸钙、可的松、腺苷蛋氨酸等对症、支持治疗。入院2周后,患者明显好转。实验室检查ALT 36 U/L,AST 29 U/L,DBil 27.6μmol/L,TBil 45.5μmol/L,PLT 93×109/L,SCr 51.5μmol/L,BUN10.1 mmol/L。重新给予抗结核治疗:乙胺丁醇0.75g,1次/d。1周后,加用吡嗪酰胺0.1 g,3次/d。2周后,加用异烟肼0.3 g,1次/d。入院1个月后,患者病情稳定,出院。     

还原型谷胱甘肽对抗结核治疗致ALT异常的作用及其机制探讨

目的:探讨还原型谷胱甘肽对抗结核药物致谷氨酸氨基转移酶(ALT)异常的预防作用及其机制。方法:178例结核病患者随机分为治疗组(n=93)和对照组(n=85),在抗结核治疗最初2个月,治疗组采用抗结核病方案+还原型谷胱甘肽1.2g加入0.9%氯化钠注射液250mL中,静脉滴注,qd;对照组采用抗结核方案+葡醛内酯片0.2g,口服,tid。所有病例治疗前及治疗最初2个月每2周查肝肾功能、血常规及过氧化脂质(LPO)各1次。结果:治疗组和对照组患者2个月内ALT异常发生率分别为10.8%和27.1%,2组比较有显著性差异(P<0.05)。肝损害发生后患者的LPO水平有所提高,与治疗前及无肝损害者相比,差异有统计学意义(P<0.05),对照组血清LPO水平明显高于治疗组(P<0.05)。结论:抗结核药物所致肝损害与体内的LPO过氧化有关,应用还原型谷胱甘肽能减少体内LPO产生,显著降低肝损害的发生率。     

Comparative bioavailability of rifampicin, isoniazid and pyrazinamide from a four drug fixed dose combination with separate formulations at the same dose levels

Fixed dose combination (FDC) formulations became popular in the treatment of tuberculosis (TB) because of the better patient compliance, reduced risk of monotherapy and emergence of drug resistance in contrast to treatment with separate formulations of two to four first-line drugs. However, its successful implementation in national programs is limited by probable bioinequivalency of rifampicin if present in FDC form. In this regard, World Health Organization (WHO) and International Union Against Tuberculosis and Lung Disease (IUATLD) recommend FDCs only of proven bioavailability. Hence, bioequivalence study of four drug FDC tablet was conducted using 22 healthy male volunteers according to WHO recommended protocol to determine bioavailability of rifampicin, isoniazid and pyrazinamide compared to standard separate combination at the same dose level. The study was designed as two period, two treatment crossover experiment with a washout period of 1 week. Bioequivalence of rifampicin was estimated by plasma and urinary method for both rifampicin and its active metabolite, des-acetyl rifampicin whereas isoniazid and pyrazinamide were estimated from plasma. Mean concentration time profiles and all the pharmacokinetic parameters of rifampicin, isoniazid and pyrazinamide from FDC tablet were comparable to individual formulations and passed the bioequivalence test with power of the test above 95%. Further, bioequivalence of both rifampicin and isoniazid shows that in vitro interaction of rifampicin and isoniazid is clinically insignificant. Thus, it was concluded that FDC formulation is bioequivalent for rifampicin, isoniazid and pyrazinamide and ensures the successful treatment of TB without compromising therapeutic efficacy of any of these components of anti-TB therapy.     

武冈市158株结核杆菌耐药性分析

目的：了解武冈市结核病患者结核杆菌的耐药状况,为结核病的防治提供实验依据。方法：连续收集我院2009年2月～2010年3月肺结核患者的结核杆菌158株,采用WHO/IUATLD推荐的比例法,对异烟肼、利福平、链霉素和乙胺丁醇4种抗结核药物进行药敏试验。结果：158株结核分枝杆菌中,91例对4种抗结核药物全部敏感,占57.59%;67例耐药,耐药率为42.41%,以耐链霉素为最高,占34.18%。结论：武冈市结核病患者结核杆菌耐药严重,必须进一步加强对耐药结核杆菌的监控。