Public health impact of isoniazid-resistant Mycobacterium tuberculosis strains with a mutation at amino-acid position 315 of katG: a decade of experience in The Netherlands

A previous limited study demonstrated that Mycobacterium tuberculosis isolates with a mutation at amino-acid position 315 of katG (Delta315) exhibited high-level resistance to isoniazid and were more frequently resistant to streptomycin. In the present study, isoniazid-resistant M. tuberculosis isolates from 8,332 patients in The Netherlands (1993-2002) were screened for the Delta315 mutation. Isoniazid resistance was found in 592 (7%) isolates, of which 323 (55%) carried Delta315. IS6110 restriction fragment length polymorphism analysis showed that Delta315 isolates occurred in clusters, suggesting recent transmission, at the same frequency as isoniazid-susceptible isolates. In contrast, other isoniazid-resistant isolates clustered significantly less frequently. Delta315 isolates were high-level isoniazid-resistant, streptomycin-resistant and multidrug-resistant significantly more often, and may have a greater impact on public health, than other isoniazid-resistant isolates.     

Clearing the clouds: Case‐report and review of the literature

In peritoneal dialysis (PD), a cloudy dialysate is an alarming finding. Bacterial peritonitis is the most common cause, however, atypical infections and non‐infectious causes must be considered. A 46‐year‐old man presented with asthenia, paraesthesia, foamy urine and hypertension. Laboratory testing revealed severe azotaemia, anaemia, hyperkalaemia and nephrotic‐range proteinuria. Haemodialysis was started through a central venous catheter. Later, due to patient preference, a Tenckhoff catheter was inserted. Conversion to PD occurred 3 weeks later, during hospitalization for a presumed central line infection. A month later, the patient was hospitalized for neutropenic fever. He was diagnosed an acute parvovirus infection and was discharged under isoniazid for latent tuberculosis. Four months later, the patient presented with fever and a cloudy effluent. Peritoneal fluid (PF) cytology was suggestive of infectious peritonitis, but the symptoms persisted despite antibiotic therapy. Bacterial and mycological cultures were negative. No neoplastic cells were detected. Mycobacterium tuberculosis eventually grew in PF cultures, despite previous negative molecular tests. Directed therapy was then initiated with excellent response. Thus, facing a cloudy effluent, one must consider multiple aetiologies. Diagnosis of peritoneal tuberculosis is hampered by the lack of highly sensitive and specific exams. Here, diagnosis was only possible due to positive mycobacterial cultures.     

中药抗药源性肝损伤评价模型及作用机制研究进展

肝脏是药物在机体内代谢的主要场所。药源性肝损伤（drug-induced liver injury,DILI）是药物过量或不当使用导致的机体不良反应之一。非甾体类抗炎药、抗菌药等均可能引起DILI。DILI发生机制主要与细胞色素P450酶、线粒体功能障碍、药物代谢反应、氧化应激、炎症反应等密切相关。中药可通过抑制氧化应激、炎症反应、减少细胞凋亡与影响细胞色素P450酶系统等发挥治疗肝损伤作用。通过对DILI发生机制、动物模型建立方法及中药干预机制等方面进行总结归纳,为DILI动物模型的合理选择及中药防治机制研究提供参考。     

水飞蓟宾胶囊对异烟肼和利福平肝损害小鼠的保护作用

目的：观察水飞蓟宾胶囊(SC)对异烟肼(INH)与利相干(RFP)合用致肝损伤小鼠的保护作用。方法：测定肝损伤小鼠在给予SC后肝指数、血清谷丙转氨酶(ALT)的活性，肝匀浆中谷胱甘肽(GSH)及丙二醛(MDA)的含量，肝微粒体中细胞色素P450含量及其亚型2E1的活性。结果：SC可对抗INH和RFP合用引起的肝指数、血清ALT水平、肝匀浆中的MDS含量及P450、4502E1活性的升高，增加GSH含量；病理学检查SC能明显减轻肝细胞的变性和坏死。结论：SC对INH和RFP肝毒性的保护作用与其稳定肝细胞膜、抑制脂质过氧化反应、清除自由基、抑制药物代谢酶有关。     

On the 99mTc‐labeling of isoniazid with different 99mTc cores

Recent advances in the chemistry of radiolabeling with ^99mTc such as use of the ^99mTc tricarbonyl and ^99mTc–HYNIC cores have revived interest in ^99mTc‐labeling of small biomolecules and further investigation as potential radiopharmaceuticals. Isoniazid, a drug commonly used for treatment of tuberculosis, has been chosen for the present study. Three distinct strategies were utilized to radiolabel isoniazid with ^99mTc. In the direct labeling protocol, the hydrazino amide functional group of isoniazid was used for ^99mTc‐labeling in the HYNIC sense using tricine and EDDA as co‐ligands. The other strategies of ^99mTc‐labeling involved the derivatization of isoniazid to its N, N‐diacetic acid derivative, which in turn was either used as a tridentate ligand for labeling with the [^99mTc(CO)₃(H₂O)₃]⁺ synthon or directly labeled by the conventional route wherein ^99mTc is in the +3 oxidation state. The complexes prepared in >95% yields were characterized by paper chromatography, thin layer chromatography and HPLC. Comparison of the three approaches showed that maximum specific activity and stability was obtained in the ^99mTc–isoniazid derivative synthesized via the tricarbonyl method. However, in vitro cell‐binding studies indicated that none of the ^99mTc–isoniazid complexes prepared had any appreciable uptake in Mycobacterium tuberculosis. Copyright © 2005 John Wiley & Sons, Ltd.     

Isoniazid preventive therapy-related adverse events among Malawian adults on antiretroviral therapy: A cohort study

Adverse events may be a cause of observed poor completion of isoniazid preventive therapy (IPT) among people living with HIV in high tuberculosis burden areas. Data on IPT-related adverse events (AE) from sub-Saharan Africa are scarce. We report IPT-related AEs, associated clinical characteristics, and IPT discontinuations in adults who were stable on antiretroviral therapy (ART) when they initiated IPT. Cohort study nested within a randomized, controlled, clinical trial of cotrimoxazole and chloroquine prophylaxis in Malawians aged ≥ 18 years and virologically suppressed on ART. Eight hundred sixty-nine patients were followed for a median of 6 months after IPT initiation. IPT relatedness of AEs was determined retrospectively with the World Health Organization case-causality tool. Frailty survival regression modeling identified factors associated with time to first probably IPT-related AE. The overall IPT-related AE incidence rate was 1.1/person year of observation. IPT relatedness was mostly uncertain and few AEs were severe. Most common were liver and hematological toxicities. Higher age increased risk of a probably IPT-related AE (aHR = 1.02; 95% CI 1.00–1.06; P = .06) and higher weight reduced this risk (aHR = 0.98; 95% CI 0.96–1.00; P = .03). Of 869 patients, 114 (13%) discontinued IPT and 94/114 (82%) discontinuations occurred at the time of a possibly or probably IPT-related AE. We observed a high incidence of mostly mild IPT-related AEs among individuals who were stable on ART. More than 1 in 8 persons discontinued IPT. These findings inform strategies to improve implementation of IPT in adults on ART, including close monitoring of groups at higher risk of IPT-related AEs.     

异烟肼人体血药浓度测定及药代动力学研究

目的建立测定人血浆中异烟肼质量浓度的反相高效液相色谱法并研究异烟肼的药代动力学。方法采用YWG-C18色谱柱(200mm×4.6 mm,5μm),以0.02 mol/L磷酸二氢钾-甲醇(61∶39)为流动相,检测波长为340 nm,进样量20μL。结果异烟肼的血浆质量浓度在0.2～12.0 mg/L范围内与峰面积线性关系良好(r=0.999 6);日内、日间精密度RSD均小于4.0%;平均回收率为97.67%,RSD=2.31%(n=9)。结论反相高效液相色谱法适用于异烟肼药代动力学研究和临床血药浓度监测。     

乙胺吡嗪利福异烟片(Ⅱ)治疗肺结核致不良反应/事件106例分析

目的:探讨肺结核患者应用乙胺吡嗪利福异烟片(Ⅱ)致不良反应/事件(ADR/ADE)的一般规律及特点,为临床合理用药及安全性评价提供参考。方法:采用回顾性研究方法,对2011年1月-2013年10月间接受乙胺吡嗪利福异烟片(Ⅱ)治疗的386例肺结核患者中发生ADR/ADE的相关情况进行统计和分析。结果:386例患者出现ADR/ADE共106例,发生率为27.46%。ADR/ADE发生时间最多见于用药2周内(92.45);其中,胃肠系统损害构成比为38.71%,皮肤及其附件损害构成比为29.57%,肝胆系统损害构成比为19.35%,居前3位;经停药、调整用法用量或对症治疗后105例(99.06%)好转或痊愈。结论:临床应掌握乙胺吡嗪利福异烟片(Ⅱ)所致ADR/ADE的特点,加强监测,并及时发现和正确处理,从而可提高肺结核患者的用药依从性和治愈率。     

LC／ESI—MS测定小鼠血浆中异烟肼及其代谢物

目的:建立测定小鼠血浆中异烟肼及其代谢物乙酰肼、肼的液相色谱-电喷雾质谱联用(LC/ESI—MS)法。方法:血浆样品经甲醇沉淀蛋白后,用衍生化试剂3-甲氧基苯甲醛 MBA 进行柱前衍生化,衍生化产物以甲醇-5 mmol·L~(-1)醋酸铵(pH5.0)缓冲溶液(60:40)为流动相,采用 Agilent Zorbax XDB—C_8柱(5 μm,4.6 mm×150 mm)分离,通过 ESI~ -MS 以选择离子监测(SIM)模式进行检测,用于定量分析的离子分别为 m/z 256.1(异烟肼衍生物),m/z 193.2(乙酰肼衍生物),m/z 151.1(肼衍生物)。结果:异烟肼、乙酰肼、肼的线性范围分别为1～64,0.05～3.2,0.025～1.6μg·mL~(-1);定量下限分别为1,0.05,0.025μg·mL~(-1);方法的平均回收率分别为98.9%,98.0%,97.2%;平均 RSD 值分别为2.7%,2.4%,3.1%。结论:本法简便、准确,适用于小鼠血浆中异烟肼、乙酰肼和肼血药浓度的测定。     

骨载异烟肼缓释微球的制备及其在动物模型中的释放研究

目的：观察探讨骨载异烟肼聚乳酸微球的设计和制备方法及其在动物模型中的释放效果。方法：选择24只雄性新西兰大白兔作为实验动物模型,采用复乳法制备缓释微球,对微球进行形态学观察、粒径分布观察、体内释药和体外释药观察。结果：平均微球粒径（10.59±0.3）μm,平均包封率（44.9±0.9）%,平均载药率（13.0±0.6）%。在24h、72h、1w、3w微球组滑膜药物浓度明显高于口服组和原药组,P＜0.05。与口服组和原药组对比,微球组0～24h药物波动差值明显更低,P＜0.05。结论：本研究制备的骨载异烟肼缓释微球具有良好的缓释性,能够在抗结核治疗中置入骨结核病灶对术后病灶发挥持久的疗效。