抗肿瘤药物肝损伤研究进展

本文对抗肿瘤药物肝损伤的危险因素、诊断标准和临床分型、特异性易感基因检测的研究现状进行归纳,同时结合自身研究成果,总结抗肿瘤药肝损伤的防治措施,提出建设抗肿瘤药物肝损伤分子检测与临床评价技术平台,将对预测药物肝损伤的发生、指导临床化疗药物使用和新型药物开发具有重要的意义。     

综合分析药物性肝损伤4076例

目的分析引起药物性肝损伤的原因、临床分型和预后。方法检索药物性肝损伤的相关文献并进行统计分析。结果本组资料显示药物性肝损伤以中年人居多,〉60岁者占20.4%,病死率约3.1%;引起肝损伤的前三位药物分别为中草药、抗结核药及抗生素,损伤类型以肝细胞损伤型居多,占54.2%;我国南北方未见明显地域差异。结论必须对患者加强引导,要遵照医嘱用药;对医务人员加强培训,注意鉴别诊断,及时报告,妥善处置。     

溺水引发吸入性肺炎病人使用抗感染药物致药物性肝损伤的药学监护1例分析

目的 探讨1例溺水引发吸入性肺炎病人使用抗感染药物致药物性肝损伤治疗实践.方法 临床药师参与呼吸科重症监护室(ICU)抗感染药物治疗,对抗菌药物的选择、药物相互作用和不良反应监测等方面提出合理的建议.结果 临床药师采用计算推算法(法国归因系统)评定该例肝损伤病人的可疑药物不良反应的等级,对可疑药物提供血药浓度监测(TDM),为诊断药物性肝损伤提供依据.结论 药学监护可以减少药物不良反应的发生,提高药物治疗的安全性和有效性.     

医疗机构药物性肝损伤监测路径探讨

目的 分析药物性肝损伤的发生特点和高风险因素,探讨医疗机构DILI 监测路径的建立。方法 对山东省药品不良反应监测中心数据库中2013年-2018年7月31日年5 066例和山东第一医科大学第二附属医院2016-2017年可疑DILI患者的181份的相关影响因素进行统计分析。结果 患者年龄以40-59岁患者居多;涉及药品中抗感染类药物占比最大;患者的体重、潜伏期、药品种类和原患疾病是发生严重DILI的影响因素。结论 根据药物性肝损伤发生特点和影响因素,探讨建立医疗机构药物性肝损伤的监测路径,有利于降低药物性肝损伤发生的风险。     

利奈唑胺与卡泊芬净药物合用致肝损害分析(1例)

通过对1例住院患者用药前后临床表现的分析,阐述其发生药源性损害的原因。患者肝功能快速恶化与用药有较肯定的相关性,从临床表现的综合分析看,利奈唑胺与卡泊芬净的使用是患者肝损害快速加重的关键原因,然而,其药物说明书却没有这方面的提示。由于该二药都是上市不久的药物,新药的临床试验大多是相对"健康"的患者,涉及糖尿病患者与重症患者的情况很少,所以其在不同患者中的安全性值得重视。建议卡泊芬净与利奈唑胺尽可能避免联合使用,卡泊芬净与利奈唑胺应禁止与二甲双胍同时用药,必要时采取极慎重的态度。     

144例药物性肝损伤住院患者的回顾性分析

摘 要 目的：了解长海医院住院患者中药物性肝损伤（DILI）病例的流行病学特点,及保肝药临床使用情况。方法：收集该院2016年全年确诊为DILI的病历资料,回顾性分析DILI与年龄、性别及药物的相关性,以及患者保肝药联合用药方案及保肝药的使用情况。结果：共收集到144例DILI患者,其中女性多于男性,45～65岁年龄段的患者构成比最高。导致DILI的药物有14类,中草药和中成药占54%,西药占46%。保肝药不合理使用较为明显,尤其是保肝药联合给药方案。结论：针对DILI的治疗,应在指南及循证医学证据的指导下,结合患者病情,制订个体化治疗方案,合理使用保肝药。     

抗结核治疗致药物性肝损伤的危险因素分析

目的分析抗结核治疗致药物性肝损伤的危险因素。方法回顾性分析南京市胸科医院2013年诊断为结核病的451例病例,并对可能影响抗结核治疗致药物性肝损伤的危险因素进行多因素Logistic分析。结果年龄(≤45岁)和脂肪肝为危险因素。结论对青壮年(≤45岁)人群、脂肪肝患者,应采取勤监测、早发现、早治疗的措施,以减少抗结核治疗药物性肝损伤的不良反应,改善患者临床症状,减轻患者负担。     

酪氨酸激酶抑制剂引起的肝损伤机制研究进展

酪氨酸激酶抑制剂(tyrosine kinase inhibitors,TKIs)为一类靶向抑癌基因相关受体酪氨酸激酶的小分子化合物,通过阻断下游的信号通路发挥抗癌作用。TKIs广泛用于癌症的治疗,对于部分肿瘤显示出较传统化疗药物更好的疗效。然而,TKIs引起的药物性肝损伤是其在临床应用中面临的难题之一。笔者通过查阅国内外相关文献,对TKIs的分类、临床应用及其引起肝损伤的机制等进行综述,以期为阐明TKIs肝损伤的机制和寻找有效的防治手段提供一定的参考。     

抗菌药物致肝损伤的研究进展

近年来,药物引起的肝损伤报道逐年增加。其中,抗菌药物是引起药物性肝损伤的最常见药物之一。抗菌药物临床应用非常广泛,如果应用不当会增加肝损伤的发生率和严重程度。本文按照抗菌药物的分类,从研究现状、流行病学、发病机制、病例报道等方面,综述了近期各类抗菌药物所致肝损伤的研究进展,旨在为抗菌药物的合理应用提供参考。     

补骨脂致药物性肝损伤一例

补骨脂为豆科植物补骨脂Psoralea corylifolia的干燥成熟果实,是一味常见的补虚药,按照炮制方法可分为生补骨脂和盐补骨脂。生补骨脂长于温补脾肾而止泻,外用治白瘢风;盐补骨脂温肾助阳、纳气、止泻之功较强,多用于阳痿遗精、遗尿、尿频等[1]。补骨脂的保健作用值得认可,但在应用过程中的用药安全问题值得关注。现将我院发现的1例补骨脂致药物性肝损伤报道如下。     

Lipopolysaccharide exposure augments isoniazide‐induced liver injury

Isoniazide (INH) is a classic antituberculosis drug associated with clinical idiosyncratic drug‐induced liver injury. It has been hypothesized that the interaction between a drug and modest inflammation results in a decreased threshold for drug toxicity. In this study, we tested the hypothesis that INH causes liver injury in rats when coadministered with lipopolysaccharide (LPS). Neither INH nor LPS alone caused liver injury. The coadministration of INH and LPS was associated with increases in serum and histopathological markers of liver injury. Tumour necrosis factor‐α expression was significantly increased in the coadministered group. The downregulation of the bile acid transporter, bile salt export pump, and multidrug resistance protein 2 at both mRNA and protein levels was observed. Furthermore, the level of Farnesoid X receptor, which regulates the bile salt export pump and multidrug resistance protein 2, were clearly decreased. These results indicate that the coadministration of nontoxic doses of LPS and INH causes liver injury; the disruption of biliary excretion is considered the primary inflammation‐related characteristic of INH‐induced hepatotoxicity. Copyright © 2014 John Wiley & Sons, Ltd.     

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。     

T‐helper cell‐mediated factors in drug‐induced liver injury

Drug‐induced liver injury (DILI) leads to a large burden on the healthcare system due to its potential morbidity and mortality. The key for predicting and preventing DILI is to understand the underlying mechanisms. Hepatic inflammation is one of the most common features of DILI. The inflammation can be attributed to the innate immune response. The adaptive immune system is also affected by the innate immune response resulting in liver damage. T‐helper cells are important regulators of acquired immunity. T‐helper cell‐mediated immune responses play pivotal roles in the pathogenesis of a variety of liver disorders. This review summarizes recent advances in the T‐helper cell‐mediated factors in DILI and potential mechanisms, which may lead to a better understanding of DILI. Copyright © 2015 John Wiley & Sons, Ltd.     

药物性慢性肝损害40例分析

目的提高临床对引起慢性肝病药物的认识。方法回顾性分析确诊的40例慢性药物性肝病的临床资料。结果药物诱发慢性肝炎18例，慢性肝内胆汁淤积7例，肝硬化3例，脂肪肝6例，肝脏腺瘤3例，肝静脉血栓形成2例，肝肉芽肿1例；40例中治愈35例(87．5％)，好转4例(10．0％)，死亡1例(2．5％)。常见诱导慢性肝病的药物有抗结核药、化疗药、镇静安眠抗惊厥药、非甾体类抗炎药、抗雌激素、降脂药等。结论诱导慢性肝病的药物应引起临床上的重视。     

Establishment of a mouse model for amiodarone‐induced liver injury and analyses of its hepatotoxic mechanism

Drug‐induced liver injury (DILI) is the most frequent cause of post‐marketing warnings and withdrawals. Amiodarone (AMD), an antiarrhythmic, presents a risk of liver injury in humans, and its metabolites, formed by cytochrome P450 3A4, are likely more toxic to hepatocytes than AMD is. However, it remains to be clarified whether the metabolic activation of AMD is involved in liver injury in vivo. In this study, to elucidate the underlying mechanisms of AMD‐induced liver injury, mice were administered AMD [1000 mg kg^–1, per os (p.o.)] after pretreatment with dexamethasone [DEX, 60 mg kg^–1, intraperitoneal (i.p.)], which induces P450 expression, once daily for 3 days. The plasma alanine aminotransferase (ALT) levels were significantly increased by AMD administration in the DEX‐pretreated mice, and the liver concentrations of desethylamiodarone (DEA), a major metabolite of AMD, were correlated with the changes in the plasma ALT levels. Cytochrome c release into the hepatic cytosol and triglyceride levels in the plasma were increased in DEX plus AMD‐administered mice. Furthermore, the ratio of reduced glutathione to oxidized glutathione disulfide in the liver significantly decreased in the DEX plus AMD‐administered mice. The increase of ALT levels was suppressed by treatment with gadolinium chloride (GdCl₃), which is an inhibitor of Kupffer cell function. From these results, it is suggested that AMD and/or DEA contribute to the pathogenesis of AMD‐induced liver injury by producing mitochondrial and oxidative stress and Kupffer cell activation. This study proposes the mechanisms of AMD‐induced liver injury using an in vivo mouse model. Copyright © 2015 John Wiley & Sons, Ltd.     

地塞米松对双氯芬酸钠肝损伤的保护作用

目的探讨地塞米松(dexamethasone,Dex)对双氯芬酸钠诱导的大鼠药物性肝损伤的保护作用及部分机制。方法大鼠随机分为正常对照组、模型对照组、Dex(10 mg.kg-1)给药组。Dex(10 mg.kg-1)腹腔注射,1 h后腹腔注射双氯芬酸钠100 mg.kg-1,24 h后检测ALT和AST活性、测定肝匀浆中MDA、GSH含量和GSH-Px、SOD活性,观察肝组织病理学变化,并测肝线粒体膜电位、线粒体肿胀度、NADH水平、SDH及ATPase活性。结果模型对照组血清ALT、AST升高,光镜下可见肝小叶内肝细胞片状坏死,肝匀浆MDA含量升高,GSH、GSH-Px和SOD含量降低,肝线粒体NADH含量、SDH及ATPase活性降低。Dex可明显降低ALT、AST活性(P<0.05),减轻肝脏炎症,降低肝匀浆中MDA含量(P<0.01),升高GSH含量、GSH-Px和SOD活性以及线粒体中NADH含量、SDH及ATPase活性(P<0.01)。结论 Dex对双氯芬酸钠诱导的大鼠药物性肝损伤有保护作用,作用机制可能与减轻线粒体损伤有关。     

药物性肝损伤的机制

综述产生药物性肝损伤的主要机制,从而找寻预防或减轻药物造成肝损害的方法。通过查阅近年来国内外相关文献并对其进行总结。结果显示,药物性肝损伤的机制十分复杂,主要包括代谢激活造成肝损伤,线粒体损伤,免疫损伤,遗传易感性,溶酶体损伤,胆汁淤积。通过对从以上方面进行综述,以期对药物性肝损伤的机制做进一步的了解,有助于预防或减轻药物造成的肝损害。     

硫普罗宁治疗抗结核药物所致肝损害的效果观察

目的探讨硫普罗宁治疗抗结核药物所致肝损害的效果。方法选取本院收治的抗结核药物性肝损害患者130例,随机分为两组,分别行常规治疗与硫普罗宁注射液治疗,对比两组临床效果与安全性。结果观察组患者治愈率与总有效率高于对照组,肝功能检测显示丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、总胆红素（TBiL）、谷氨酰转肽酶（γ-GT）、AST／ALT均显著优于对照组,两组患者均无严重不良反应发生。结论硫普罗宁治疗抗结核药物性肝损害效果显著,能有效改善肝功能,减轻临床症状,且安全性较好,适合临床推广。