抗结核药物所致QTc间期延长临床监测和管理专家共识

贝达喹啉、德拉马尼、氯法齐明及氟喹诺酮类药物(如左氧氟沙星、莫西沙星)对于提高耐多药和广泛耐药结核病的治疗成功率至关重要。然而,这些药物可能导致心电图的QTc间期延长,若不及时发现和处理,严重者可危及患者生命。因此,临床医师需要采取积极措施进行预防、监测和妥善处理。本共识旨在解决抗结核药物引发的QTc间期延长的临床监测和管理问题。依托公开发表的研究数据,以及参与专家的应用经验,经过深入的讨论,形成了关于抗结核药物导致的QTc间期延长的临床监测和管理的专业建议。希望本共识能够指导医生及时和规范地预防、发现、处理抗结核治疗过程中可能出现的QTc间期延长的不良反应。

Medical plant extracts and natural compounds with a hepatoprotective effect against damage caused by antitubercular drugs: A review

Drug-induced liver injury encompasses a spectrum of diseases ranging from mild biochemical abnormalities to acute liver failure; example of this scenery is hepatotoxicity caused by the first-line antituberculous drugs isoniazid, rifampin and pyrazinamide, which are basic for treatment of drug-sensible and drug-resistant tuberculosis. In the search for pharmacological alternatives to prevent liver damage, antitubercular drugs have been the subject of numerous studies and published reviews, a great majority of them carried out by Asian countries. At the same time, hepatoprotectors from plant source are now emerging as a possible alternative to counteract the toxic effects of these therapeutic agents. The present review aims to highlight the most recent studies on the subject, based information published in scientific databases such as Scopus and Pub Med.

结核病综合治疗研究进展

结核病是由结核分枝杆菌复合群感染引起的慢性传染性疾病,尽管卡介苗和有效抗结核药物的成功问世使其有了有效的预防和治疗手段,但随着人口的不断流动、人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染、特殊疾病免疫抑制药物应用以及耐药结核病的不断出现等原因,特别是自2019年底出现的新型冠状病毒感染及流行,使结核病疫情控制至少倒退5~8年,彻底治愈结核病仍然挑战重重。而彻底治愈结核病患者仍然是阻断结核分枝杆菌传播、消除疾病传染的关键举措。在抗结核化疗的基础上,辅以外科手术治疗、介入治疗、免疫治疗、营养治疗、中医药治疗、心理治疗及康复治疗等综合治疗手段,有利于提高患者治愈率、降低不良反应等。临床医生需要综合评估患者的具体病情,有针对地选择个性化的综合治疗方案,从而获得最优的治疗效果。作者对近年来结核病综合治疗研究进展进行综述。

酪氨酸激酶抑制剂调控宿主抗结核作用的研究进展

尽管现有的抗结核治疗方案在药物敏感结核病患者的治疗中取得了显著成效,但是药物毒性及耐药菌株的问题日益突出。因此,研究者们开始寻找新的药物和治疗策略,以期更好地治疗结核病。宿主导向治疗(host-directed therapy,HDT)可利用小分子化合物调节宿主的免疫反应,进而保护组织并清除病原体。HDT的主要目的是增强宿主的抗结核免疫功能,同时缩短传统抗生素治疗的时间,提高治疗效果,被视为治疗结核病的一种有前景的方法。酪氨酸激酶(protein tyrosine kinase,PTK)主要参与激活细胞信号转导,从而调节细胞生长、增殖、死亡等一系列生理生化过程。酪氨酸激酶抑制剂(tyrosine kinase inhibitor,TKI)是一种新型抗癌药物,在多种恶性肿瘤中可靶向过表达细胞通路,也可通过诱导自噬并激活其他信号通路发挥抗肿瘤活性。研究发现,TKI也可以在巨噬细胞中调节信号转导过程,降低胞内结核分枝杆菌的载量,具有巨大的治疗潜力。因此,TKI可作为HDT的潜在候选药物,应用于临床辅助治疗结核病。笔者将从PTK及信号转导入手,针对潜在的HDT治疗结核病的靶向药物研究进行综述,旨在为HDT疗法更好地应用于现有药物及研发新药,从而辅助治疗结核病提供参考。

An Analysis of the Accounting Costs Associated with 20-Month DR TB Regimens in Maputo City, Mozambique

Introduction: Socioeconomic and demographic conditions in a country can influence tuberculosis incidence and mortality, with nearly 95% of tuberculosis-related deaths occurring in poorer countries. Mozambique is among the 30 countries with the highest TB burden. Objective: The study aimed to estimate the average direct medical cost of treating drug-resistant tuberculosis in 19 health centers in Maputo City, Mozambique. Methods: A retrospective analysis of direct medical costs was conducted on patients aged 18 and older who completed 20-month drug-resistant tuberculosis treatment regimens in Maputo City in 2019. Results: This analysis covered 140 patients who completed a 20-month treatment regimen, with 64.3% (78) being male and 35.7% (62) female. Approximately 50% of the participants were aged between 29 and 47. The average direct medical cost of DRTB treatment was $4789.43, reaching up to $6568.00, with a standard deviation of $753.26, including clinical interventions and treatment. Conclusion: The direct medical costs for a basic treatment package for a patient with drug-resistant TB in Mozambique equal 36 minimum wages. Developing alternative and innovative funding mechanisms and identifying ways to mitigate costs through the use of generic medicines would be beneficial.

泌尿系结核误诊临床分析

目的探讨泌尿系结核(UTB)误诊原因,提高临床医师对该疾病的认识。方法对2023年2—7月收治的UTB 5例临床资料进行回顾性分析。结果本组中临床表现尿频尿急4例,血尿3例,腰痛3例,发热2例;尿常规异常4例,尿抗酸杆菌涂片阳性1例,24 h尿沉渣GeneXpert MTB/RIF阳性4例,尿分枝杆菌培养阳性4例,血结核感染T细胞斑点试验阳性5例。影像学表现有肾积水、输尿管扩张及尿路钙化4例,膀胱占位1例,肾自截1例。活动性肺结核3例,陈旧性肺结核2例。5例延误诊治时间2~6年。误诊为泌尿系感染合并肾结石2例,泌尿系感染合并膀胱恶性肿瘤1例,肾结石1例,前列腺增生1例;4例确诊后予抗结核治疗,1例未治疗,随访中2例死亡。结论UTB由于临床表现缺乏特异性、早期诊断困难以及临床医师认识不足,容易误诊导致严重后果。对于复杂性尿路感染患者常规抗感染效果不佳,尤其是有胸部影像学异常时,需高度警惕UTB可能。

Evaluation of antihepatotoxic potential of Solanum xanthocarpum fruit extract against antitubercular drugs induced hepatopathy in experimental rodents

Objective:To assess the hepatoprotective effect of Solanum xanthocarpum(S. xanthocarpum) fruit extract against antitubercular drug-induced liver toxicity in experimental animals.Methods:Ethanolic(50%) fruit extract ofS. xanthocarpum(100, 200 and 400 mg/kg bw) was administered daily for 35 days in experimental animals. Liver toxicity was induced by combination of three antitubercular drugs [isoniazid(I) 7.5 mg/kg, rifampicin(R) 10 mg/kg and pyrazinamide(P) 35 mg/kg] given orally as suspension for 35 days in rats. The hepatoprotective activity was assessed using various biochemical parameters like aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatise(ALP), total bilirubin(TBL), albumin(ALB), total protein(TP), lactate dehydroginase(LDH), and serum cholesterol(CHL). Meanwhile,in vivoantioxidant activities as lipid peroxidation(LPO), reduced glutathione(GSH), superoxide dismutase(SOD) and catalase(CAT) were measured in rat liver homogenate. The biochemical observations were supplemented by histopathological examination.Results:The results demonstrated that treatment withS.xanthocarpumsignificantly(P<0.05-P<0.001) and dose-dependently prevented drug induced increase in serum levels of hepatic enzymes. Furthermore,S. xanthocarpumsignificantly(up toP<0.001) reduced the LPO in the liver tissue and restored activities of defence antioxidant enzymes GSH, SOD and CAT towards normal levels. Histopathology of the liver tissue showed that S. xanthocarpumattenuated the hepatocellular necrosis and led to reduction in inflammatory cells infiltration.Conclusions:The results of this study strongly indicate the protective effect of S. xanthocarpumagainst liver injury which may be attributed to its hepatoprotective activity, and thereby scientifically support its traditional use.

Antitubercular therapy in patients with cirrhosis:Challenges and options

Tuberculosis(TB)has been a human disease for centuries.Its frequency is increased manyfold in patients with liver cirrhosis.The gold standard of TB management is a 6-mo course of isoniazid,rifampicin,pyrazinamide and ethambutol.Although good results are seen with this treatment in general,the management of patients with underlying cirrhosis is a challenge.The underlying depressed immune response results in alterations in many diagnostic tests.The tests used for latent TB have many flaws in this group of patients.Three of four first-line antitubercular drugs are hepatotoxic and baseline liver function is often disrupted in patients with underlying cirrhosis.Frequency of hepatotoxicity is increased in patients with liver cirrhosis,frequently leading to severe liver failure.There are no established guidelines for the treatment of TB in relation to the severity of liver disease.There is no consensus on the frequency of liver function tests required or the cutoff used to define hepatotoxicity.No specific treatment exists for prevention or treatment of hepatotoxicity,making monitoring even more important.A high risk of multidrug-resistant TB is another major worry due to prolonged and interrupted treatment.

Antitubercular activity of the semi-polar extractives of Uvaria rufa

Objective:To investigate the inhibitory activity of the chloroform extract,petroleum ether and chloroform sub-extracts,lead-acetate treated chloroform extract,fractions and secondary metabolites of Uvaria rufa（U.rufa） against Mycobacterium tuberculosis（M.tuberculosis） H37Rv. Methods:The antituberculosis susceptibility assay was earried out using the colorimetric Microplate Alamar blue assay（MABA）.In addition,the cytotoxicity of the most active fraction was evaluated using the VERO cell toxicity assay.Results:The in vitro inhibitory activity against M.tuberculosis H37Rv increased as purification progressed to fractionation（MIC up to 23μg/mL）. The chloroform extract and its sub-extracts showed moderate toxicity while the most active fraction from chloroform sub-extract exhibited no cytotoxicity against VERO cells.Meanwhile, the lead acetate-treated crude chloroform extract and its fractions showed complete inhibitions （100%） with MIC values up to 8μg/mL.Phylochemical screening of the most active fraction showed,in general,the presence of terpenoids,steroids and phenolic compounds.Evaluation of the antimycobacterial activity of known secondary metabolites isolated showed no promising inhibitory activity against the test organism.Conclusions:The present results demonstrate the potential of U.rufa as a phytomedicinal source of compounds that may exhibit promising antituberculosis activity.In addition,elimination of polar pigments revealed enhanced inhibition against M.tuberculosis H37Rv.While several compounds known for this plant did not show antimycobacterial activity,the obtained results are considered sufficient reason for further study to isolate the metabolites from U.rufa responsible for the antitubercular activity.

Systematic Review of New Trends in Antitubercular Synthesis and Analysis

Many researches are undertaken to develop antibiotics to treat resistant tuberculosis. This review discusses new trends in research undertaken on new antituberculars reported to date, with a particular attention on their synthesis and analysis.

Design, Synthesis and Biological Evaluation of Novel Antitubercular Agents by Combining Pyrazoline and Benzoxazole Pharmacophores

Various recent reports on Tuberculosis have alarmed an increase in the patient class and subsequent death rates across the globe. Over and above the spread of more dangerous and fatal forms of tuberculosis like MDR-TB i.e. multiple-drug resistance tuberculosis, XDR-TB i.e. extensively-drug resistance tuberculosis & TDR-TB i.e. total-drug resistance tuberculosis has forwarded an urgent need to discover novel antitubercular agents. The current work is aimed at combining two previously well-known pharmacophores (pyrazoline and benzoxazole nucleus) in order to design and synthesize a series of novel benzoxazole-based pyrazoline derivatives. The synthesized target compounds were structurally confirmed by LCMS, 1H-NMR and 13C-NMR analysis. The target compounds were In vitro evaluated against M. tuberculosis H37Rv strain, multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) strains. The In vitro screening results depicted that majority of the target compounds displayed potent activity with MIC in a range of ~0.8 to 6.25 μg/mL. Many compounds were found to be more potent than isoniazid against MDR-TB with MIC value 3.12 μg/mL and XDR-TB with MIC value 12.5 μg/mL. Cytotoxicity assay of these active compounds on VERO cell lines also displayed good selectivity index.

Synthesis of New Mannich Products Bearing Quinoline Nucleous Using Reusable Ionic Liquid and Antitubercular Evaluation

A series of Mannich products bearing quinoline nucleus was synthesized, characterized, and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv. The results showed that compounds 4b, and 4d found most active with percentage inhibition of 95, and 96, respectively, at minimum inhibitory concentration (MIC) of >6.25 μg/mL, among the synthesized compounds. Whereas, compounds 4a, 4c, 4e, and 4f exhibited considerable antitubercular activity with percentage inhibition of 71, 79, 55, and 68, respectively, at MIC of >6.25 μg/mL. The structures of synthesized compounds were elucidated by various spectroscopic tools like IR, 1H NMR, 13C NMR, mass and elemental analysis.

Synthesis and Evaluation of 2-Amino-4H-Pyran-3-Carbonitrile Derivatives as Antitubercular Agents

A series of 2-amino-4H-pyran-3-carbonitrile derivatives were designed and synthesized. Their antitubercular activities were evaluated against autoluminescent M. tuberculosis H37Ra and standard strain M. tuberculosis H37Rv. No obvious antitubercular activities could be observed (MIC > 10 ug/mL). The results are in sharp contrast with the previously reported data.

选择适宜治疗方案正确评估抗结核治疗疗效提高利福平敏感结核病治疗质量

规范利福平敏感结核病的治疗,提高治疗质量,无论是对耐药结核病防治,还是控制结核病流行都至关重要。首先,重视病原学检查,结合结核病患者病情选择适宜辅助检查,按照结核病病变类型使用对应治疗方案;第二,首选一线抗结核药品,无胃肠道吸收功能障碍患者,全疗程口服用药;第三,使用标准抗结核治疗方案,即强化期使用H-R-Z-E治疗方案,足量用药,利福平敏感结核病抗结核治疗推荐使用抗结核固定剂量复合制剂(FDC);第四,病原学检查是判断抗结核治疗疗效的金标准,客观评价患者治疗疗效,完成抗结核治疗疗程,符合治疗成功条件的患者可以停止抗结核治疗。

肩关节结核临床误诊分析

目的 探讨肩关节结核的临床特点及误诊原因。方法 回顾性分析2019年1月—2021年1月收治误诊的肩关节结核4例的临床资料。结果 4例因肩关节疼痛3个月~1年就诊,左肩2例,右肩2例;其中1例有肺结核病史,误诊为肩关节炎;1例误诊为肩关节滑囊炎伴细菌感染;1例误诊为肩关节色素沉着绒毛结节性滑膜炎;1例误诊为肩袖损伤行手术治疗,术后切口不愈合。误诊时间3个月~1年。4例均在关节镜下行病灶清理+闭式冲洗引流术,术后病理检查结果均证实为肩关节结核,正规服用抗结核药物,4例随访12个月肩关节功能评价量表评分80~95分。结论 肩关节结核诊断困难,漏误诊率高,临床医生应提高警惕,特别是对有结核病史的患者,应及早行病理检查以明确诊断,从而减少误诊。

耐药结核病患者利奈唑胺血药浓度对血液系统毒性发生的影响

目的:分析应用利奈唑胺的耐药结核病患者的血药浓度对发生血液系统毒性的影响,并探索血液系统毒性发生的其他危险因素。方法:采用前瞻性队列研究方法,连续纳入首都医科大学附属北京胸科医院2019年1月至2021年2月应用含利奈唑胺化疗方案治疗的耐药结核病患者作为研究对象,共219例。收集研究对象的临床资料及服药后2 h的血液标本。应用高效相色谱-质谱法测定利奈唑胺的血药浓度。通过绘制受试者工作特征曲线(receiver operating characteristic curve,ROC曲线)确定血药浓度(峰浓度)对血液系统毒性的诊断价值,并确定最佳诊断临界值;采用多因素logistic回归分析研究对象发生血液系统毒性的影响因素。结果:219例研究对象中有92例(42.0%)发生了血液系统毒性反应,包括白细胞计数减少[15.5%(34/219)]、贫血[21.5%(47/219)]、血小板减少症[27.4%(60/219)]等,127例(58.0%)未发生任何相关毒性反应。发生血液系统毒性者利奈唑胺血药峰浓度为17.1(11.8,22.8)μg/ml,明显高于未发生者[14.7(10.4,18.0)μg/ml],差异有统计学意义(Z=-3.206,P=0.001)。未发生血液系统毒性者中的血清白蛋白<40 g/L者的比例为29.1%(37/127),明显低于血清白蛋白≥40 g/L者的比例[70.9%(90/127)],差异有统计学意义(χ2=7.998,P=0.005)。ROC曲线分析显示,利奈唑胺血药峰浓度对血液系统毒性有预测价值(曲线下面积为0.627),血药峰浓度为20.7μg/ml时是最佳诊断点。多因素logistic回归分析显示,血清白蛋白<40 g/L者血液系统毒性发生的风险是血清白蛋白≥40 g/L者的2.622倍(OR=2.622,95%CI:1.344~5.117);利奈唑胺血药峰浓度>20.7μg/ml者血液系统毒性发生的风险是血药峰浓度≤20.7μg/ml者的6.419倍(OR=6.419,95%CI:2.874~14.337)。结论:利奈唑胺引起的血液系统毒性发生比例高,尤其对于血清白蛋白<40 g/L和利奈唑胺血药峰浓度>20.7μg/ml的患者在应用利奈唑胺治疗时,应警惕血液系统毒性的发生。

临床医生对一线抗结核药物及治疗支持的知信行研究

目的了解临床医生对一线抗结核药物及治疗支持的知信行现状。方法随机抽取重庆各级卫生机构诊治成人肺结核的医生,调查其对一线抗结核药物及治疗支持的知信行。结果知识得分中位数16(14,18)分,知道治疗支持提供者推荐顺序的医生占19.2%。15.4%的参与者认为复方制剂效果优于单一制剂,72.1%的人认为复方制剂不便于调整用药,27.9%的医生倾向开复方制剂处方,这些情况在感染专业、三级医院医生中更为显著(P<0.05)。认为门诊医生进行健康教育效果更好的占85.6%。大多数医生选择剂型时考虑的主要因素为疗效(76.0%),没有医生选择患者要求和价格。受访医生所接诊患者的治疗支持主要由家庭成员提供(50.0%),其次是医务人员(34.6%),健康教育由门诊医生进行的占70.2%。结论重庆地区不同类型临床医生对一线抗结核药物的知信行存在较大差异,治疗支持知识不全面,感染专业及三级医院医生更偏好单一制剂。

儿童抗结核药物性肝损伤状况及相关影响因素分析

目的:分析儿童抗结核药物性肝损伤(drug-induced liver injury during anti-tuberculosis treatment,ATB-DILI)状况及相关影响因素。方法:采用回顾性研究方法,收集2018年6月至2022年6月南华大学衡阳医学院附属长沙中心医院确诊为结核病且符合纳入标准的200例住院或门诊儿童患者临床资料。所有患儿均全疗程使用护肝药物,其中,发生肝损伤患儿52例,ATB-DILI发病率为26.0%。分析结核病患儿发生ATB-DILI的临床表现、严重程度、病理损害、发生时间分布及相关影响因素。结果:52例肝损伤患儿中,20例(38.5%)无明显症状仅肝功能指标异常,32例(61.5%)厌食,29例(55.8%)呕吐,3例(5.8%)黄疸,均加用护肝药及对症处理后好转;51例为1级(轻度)ATB-DILI,1例为2级(中度),无3~5级肝损伤患者;均为肝细胞损伤型患者。在开始抗结核治疗2周内有29例(55.8%)发生ATB-DILI,第3~8周有8例(15.4%),第9~12周有5例(9.6%),第13~16周有7例(13.5%),第16~24周有3例(5.7%)。多因素logistic回归分析显示,体质量指数低于18.5[OR(95%CI)=2.340(1.104~4.959)]、血清前白蛋白低于200 mg/L[OR(95%CI)=2.337(1.093~4.997)]和血红蛋白低于120 g/L[P=0.016,OR(95%CI)=2.403(1.176~4.908)]均是儿童结核病患者发生ATB-DILI的独立危险因素。结论:儿童结核病在抗结核治疗全疗程中使用护肝药物的基础上,ATB-DILI的发生率仍不低,但其临床表现、严重程度、病理损害明显降低。临床医师应重点关注治疗2周内体质量指数、血清前白蛋白和血红蛋白降低的患儿发生ATB-DILI的风险。

中西医结合治疗复治肺结核的疗效评价

目的 探究中西医结合治疗对复治肺结核病人的治疗效果及生活质量的影响。方法 选取2019年1月至2021年1月间在陕西省结核病防治院进行治疗的复治肺结核病人70例,采用随机数字表法将其分为两组,每组各35例。对照组采用西医化疗法治疗,研究组采用中医抗痨丸结合西医化疗法治疗,对两组病人的临床疗效、中医症状积分、T淋巴细胞亚群、肺功能、生活质量进行比较分析。结果 治疗后,两组中医症状积分和CD8+水平下降,CD3+、CD4+、CD4+/CD8+水平上升,且研究组中医症状积分和CD8+水平显著低于对照组,CD3+、CD4+、CD4+/CD8+水平显著高于对照组(P<0.05)。研究组显效28例、有效5例、无效2例,对照组显效19例、有效8例、无效8例,研究组疗效显著优于对照组(P<0.05)。治疗后,两组第一秒用力呼气容积/用力肺活量(FEV1/FVC)及呼气流速峰值(PEFR)参数、WHO生存质量测定量表简表(WHOQOL-BREF)各维度评分均上升,且研究组FEV1/FVC参数(83.47±9.27)%显著高于对照组(77.65±8.63)%,PEFR参数(5.62±1.12)L/s显著高于对照组(4.73±0.95)L/s,WHOQOL-BREF各维度评分显著高于对照组(P<0.05)。结论 中西医结合治疗复治肺结核病人能显著提升病人疗效,改善病人中医症状及免疫功能,提升病人肺功能、生活质量。

抗结核药物所致肝损伤及肝病患者抗结核药物治疗——大陆地区诊治建议与台湾《结核病诊治指引》相关介绍

结核病是全球性公共卫生问题,抗结核治疗过程中的不良反应以药物所致的肝损伤最为多见,危害性最大。出现肝损伤可降低抗结核治疗的有效性,导致治疗失败、复发和耐药的出现[1];而肝病患者结核病发病率和病死率均显著高于一般人群,肝病是感染结核病的独立危险因素[2-4]。2013年,台湾卫生署疾病管制局制订了第五版《结核病诊治指引》（下文简述为《台湾结核病指引》）[5],对抗结核治疗所致肝损伤提出了具体的处理意见。