美国制药企业药物研发情况分析

美国制药企业药物研发数据主要来源是药品生产者协会、国家科学基金和企业自身。1975～1990年，美国制药企业用于药物创新和药物改造的研发投入构成比相对稳定，即约80%的研发资金用于创新药物的开发研究；不同阶段的资金分配比例相对稳定，但临床研究投入稳中有升；美国企业在国内外的药物研发总投入均呈明显增长，新药（包括化学药物和生物药物）的申请也不断增加。     

美国仿制药上市后药物警戒活动分析研究和对我国集采药品的启示

目的 ：通过研究美国仿制药品上市后药物警戒活动的特殊性,为我国集中带量采购药品中占比较大的仿制药相关药物警戒活动和不良反应监测的开展提供参考。方法 ：通过文献检索,分析研究美国在开展仿制药药物警戒活动、不良反应监测等方面的特殊性。结果和结论 ：仿制药和原研药在注册流程等方面存在差异,这些差异给药物警戒活动带来了独特的挑战。临床上,仿制药的安全性、质量及治疗等效性等问题都会受到关注。美国食品药品监督管理局（FDA）对仿制药开展的药物警戒活动包括不良反应被动监测、主动监测、项目研究和公众教育等,通过多种途径保障仿制药的用药安全,并增强患者和医务人员对仿制药的信心。我国应充分关注集采中选药品中仿制药不良反应监测的特殊性,开展合适的药物警戒活动。     

硝基咪唑类抗菌药物致肝损害患者的文献分析

目的:分析硝基咪唑类抗菌药物所致肝损害的特点、危险因素和致病机制,为临床安全用药提供参考。方法:利用国内外医药数据库平台,检索与下载硝基咪唑类致肝损害的病例报告,分析硝基咪唑类抗菌药物致肝损害的危险因素及其致病机制。结果:共检索到硝基咪唑类抗菌药物致肝损害病例报告51例,其中甲硝唑为32例,奥硝唑为17例,替硝唑为2例,塞克硝唑尚未见报道;中青年、女性患者和大剂量用药、疗程过长、联合使用肝毒性药物及饮酒等是致肝损害的危险因素;肝损害机制主要涉及药物或代谢产物对肝脏的直接毒性和免疫介导的过敏反应;5例因服用大剂量的甲硝唑致肝衰竭病死。结论:慎重选择用药人群,严格按照药品说明书用药,加强临床用药监测和严格硝基咪唑类药物的监管是预防硝基咪唑类肝损害的重要措施。     

FOLFOX方案和FOLFIRI方案致肝毒性的安全信号挖掘

目的 挖掘FOLFOX方案和FOLFIRI方案致肝毒性的安全信号，为临床合理治疗方案的选择、药品不良反应（ADR）的防治提供参考。方法 利用报告比值比法和比例报告比值法对美国FDA药品不良事件报告系统中2004年1月1日至2022年6月30日FOLFOX方案和FOLFIRI方案相关药品不良事件（ADE）报告进行分析，挖掘其致肝毒性的潜在安全信号。结果 分别检索到FOLFOX方案和FOLFIRI方案相关ADE报告3 454、1 359份，涉及男、女性患者比例分别为1.50∶1、1.67∶1；上报数排名前5位的国家均为美国、日本、法国、意大利、英国，其报告总和分别占各自报告总数的58.48%和53.79%。有超过90%的患者合并用药不超过5种，FOLFOX方案和FOLFIRI方案联合抗血管生成药物或表皮生长因子受体抑制剂的患者比例分别为45.45%和86.82%。FOLFOX方案致肝毒性相关ADE报告有443份，ADR信号共22个，包括肝窦阻塞综合征、结节状再生增生、药物诱导的肝损伤、血胆红素升高等；FOLFIRI方案肝毒性相关ADE报告有128份，ADR信号共9个，包括血胆红素升高、肝毒...     

药物的肝脏损害

目的：药物诱发肝毒性的新认识。方法：复习近几年献。结果：肝脏是药物代谢的主要器官，美国近期有50％急性肝衰是由药物引起的，上市后药物的停用主要原因也是药物的肝损害，为改善这一状况应对药物肝毒性有一较好的了解。结论：应了解药物诱发肝毒性的病理，药物引起的肝不良反应，以及新药的审批过程。     

细菌脂多糖对氯丙嗪肝毒性作用的影响

目的 确定吩噻嗪类抗精神病药氯丙嗪（CPZ）的肝毒性的特征与表现，并通过低剂量脂多糖（LPS）诱导炎症对此种肝毒物肝毒性的影响来研究短期炎症与药物肝毒性之间的关系，以枯否氏细胞（KC）特异性抑制剂氯化钆（GdCl3）为工具药，研究肝脏炎症介质在CPZ的肝毒性以及在LPS对药物肝毒性的调节效应中所发挥的作用，探讨其施加影响所发生机制、过程、环节及途径。     

抗逆转录病毒药物的肝毒性

肝毒性是与应用抗逆转录病毒药物（ART）相关的不良反应,在治疗HIV感染时可增加患者的发病率和病死率,影响HIV感染的治疗.可能的机制包括直接的药物毒性、丙型肝炎病毒和（或）乙型肝炎病毒同时感染中的免疫重建、与肝相关的过敏性反应和线粒体毒性,还可能涉及其他致病途径.高活性抗逆转录病毒药物治疗（HAART）与转氨酶水平的升高相关.在HAART中每个单独的药物在肝毒性的发展中所起的作用难以确定.仍不清楚大多数ART肝毒性的发病率.     

抗结核药物肝损伤研究进展

抗结核药物是造成药物肝损伤（ Drug－induced liver injury,DILI）的重要原因之一,本文从发病机制、危险因素、诊断和防治等方面综述了近期抗结核药物肝毒性的研究进展,旨在为抗结核药物的临床合理应用提供参考。     

肝毒性生物标志物研究进展

药物肝毒性是医药界关注的重要问题。及时准确地评价药物的肝毒性,寻找特异性强、灵敏度高的肝毒性生物标志物对新药研发及保证临床用药安全具有重要意义。针对传统的肝毒性生物标志物（包括谷氨酸氨基转移酶、天冬氨酸氨基转移酶、谷氨酸脱氢酶等）,以及新发现的生物标志物（血清F蛋白、嘌呤核苷磷酸酶、激肽原对氧磷酶）进行综述,为药物肝毒性的研究及防治提供参考。     

静脉细胞毒药物配置中的防护

美国医疗机构药师协会(ASHP)在其临床实践指南--关于处理细胞毒药物的报告中,将细胞毒药物重新定义为危险药品,并认为危险药品是指能产生职业暴露危险或危害的药品.细胞毒药物除肿瘤化疗药品外还包括一些杀细胞剂,如具有遗传毒性、致癌性、致畸或生育损害作用,在低剂量下就可产生严重的器官或其他方面毒性的药品.     

Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

The advances in the drug development that allowed the replacement of many potentially hepatotoxic agents by safer alternatives have been out-weighed by the vast expansion of the total number of agents now available for use. Now, rare adverse reactions to several commonly prescribed medications contribute to the total burden of drug-induced liver injury. Studies involving well-characterised patients with diclofenac-induced hepatotoxicity indicate that multiple steps are involved in the development of liver injury. Individual susceptibility to idiosyncratic hepatotoxicity is determined by the interaction of metabolic and immunological factors. Immunomodulatory and anti-inflammatory cytokines, such as IL-10, may have a protective role in reducing drug-induced liver injury. Understanding the mechanisms of idiosyncratic hepatotoxicity may increase our ability to identify susceptible individuals and hence, prevent serious adverse reactions.     

Regulatory causality evaluation methods applied in kava hepatotoxicity: Are they appropriate?

Since 1998 liver injury has been assumed in some patients after the use of kava (Piper methysticum G. Forster) as an anxyolytic herbal extract, but the regulatory causality evaluation of these cases was a matter of international and scientific debate. This review critically analyzes the regulatory issues of causality assessments of patients with primarily suspected kava hepatotoxicity and suggests recommendations for minimizing regulatory risks when assessing causality in these and other related cases. The various regulatory causality approaches were based on liver unspecific assessments such as ad hoc evaluations, the WHO scale using the definitions of the WHO Collaborating Centre for International Drug Monitoring, and the Naranjo scale. Due to their liver unspecificity, however, these causality approaches are not suitable for assessing cases of primarily assumed liver related adverse reactions by drugs and herbs including kava. Major problems emerged trough the combination of regulatory inappropriate causality assessment methods with the poor data quality as presented by the regulatory agency when reassessment was done and the resulting data were heavily criticized worldwide within the scientific community. Conversely, causality of cases with primarily assumed kava hepatotoxicity is best assessed by structured, quantitative and liver specific causality algorithms such as the scale of the CIOMS (Council for International Organizations of Medical Sciences) or the main-test as its update. Future strategies should therefore focus on the implementation of structured, quantitative and liver specific causality assessment methods as regulatory standards to improve regulatory causality assessments for liver injury by drugs and herbs including kava.     

抗结核药物肝毒性研究现状及其存在的问题

肝损害是抗结核药物治疗中最常见的毒副作用之一。其发生机制尚不完全清楚,大多数抗结核药物的肝毒性是剂量依赖性的,部分与药物的超敏反应有关。老年、女性、营养不良、嗜酒、慢乙酰化表型、携带乙肝病毒或既往有肝病以及严重结核病是公认的危险因素。抗结核药物致肝损害的治疗目前尚无统一规范,以非特异性保肝、对症治疗为主,但加强监控与管理可预防严重肝损伤的发生。     

Review article: drug hepatotoxicity

Background Drug toxicity is the leading cause of acute liver failure in the United States. Further understanding of hepatotoxicity is becoming increasingly important as more drugs come to market. Aims (i) To provide an update on recent advances in our understanding of hepatotoxicity of select commonly used drug classes. (ii) To assess the safety of these medications in patients with pre‐existing liver disease and in the post‐liver transplant setting. (iii) To review relevant advances in toxicogenomics which contribute to the current understanding of hepatotoxic drugs. Methods A Medline search was performed to identify relevant literature using search terms including ‘drug toxicity, hepatotoxicity, statins, thiazolidinediones, antibiotics, antiretroviral drugs and toxicogenomics’. Results Amoxicillin‐clavulanic acid is one of the most frequently implicated causes of drug‐induced liver injury worldwide. Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. Newer thiazolidinediones are not associated with the degree of liver toxicity observed with troglitazone. Careful monitoring for liver toxicity is warranted in patients who are taking antiretrovirals, especially patients who are co‐infected with hepatitis B and C. Genetic polymorphisms among enzymes involved in drug metabolism and HLA types may account for some of the differences in individual susceptibility to drug hepatotoxicity. Conclusions Drug‐induced hepatotoxicity will remain a problem that carries both clinical and regulatory significance as long as new drugs continue to enter the market. Future results from ongoing multicentre collaborative efforts may help contribute to our current understanding of hepatotoxicity associated with drugs.     

Herbal hepatotoxicity by Greater Celandine (Chelidonium majus): causality assessment of 22 spontaneous reports

Toxic liver injury due to the herb Greater Celandine (GC) (Chelidonium majus L.) has been assumed in patients originating from various European countries and created concern. Based on regulatory and liver unspecific ad hoc causality assessments in 22 spontaneous cases of Germany, causality levels for GC were considered probable in 16 and possible in 6 cases. We now analyzed the data of these 22 cases regarding their causality levels employing the liver specific, standardized, structured and quantitative assessment method of the updated scale of CIOMS (Council for International Organizations of Medical Sciences). Causality for GC was found highly probable (n = 2), probable (n = 6), possible (n = 10), unlikely (n = 1), and excluded (n = 3). Thus, causality could be upgraded in 2 cases to a highly probable causality level, but had to be down graded to excluded, unlikely, or possible causality levels in 3, 1, or 9 cases, respectively. GC hepatotoxicity shows a hepatocellular pattern of liver injury with female gender predominance. On average, age of the patients was 56.4 years, treatment 36.4 days, and latency period until first symptoms and jaundice 29.8 and 35.6 days, respectively. This analysis therefore provides further evidence for the existence of GC hepatotoxicity as a distinct form of herb induced liver injury, but due to poor data quality the causal association between GC use and liver injury is less strong than hitherto assumed. We propose replacement of the regulatory organ unspecific by a liver specific causality assessment method in cases of herb induced liver injury as well as stricter pharmacovigilance strategies towards improvements of data quality. Toxicological studies are now warranted to elucidate the mechanism(s) of human GC hepatotoxicity that represents a European issue.     

The hepatotoxicity of Polygonum multiflorum: The emerging role of the immune-mediated liver injury

Herbal and dietary supplements(HDS)-induced liver injury has been a great concern all over the world.Polygonum multiflorum Thunb.,a well-known Chinese herbal medicine,is recently drawn increasing attention because of its hepatotoxicity.According to the clinical and experimental studies,P.multiflorum-induced liver injury(PM-DILI)is considered to be immune-mediated idiosyncratic liver injury,but the role of immune response and the underlying mechanisms are not completely elucidated.Previous studies focused on the direct toxicity of PM-DILI by using animal models with intrinsic drug-induced liver injury(DILI).However,most epidemiological and clinical evidence demonstrate that PM-DILI is immune-mediated idiosyncratic liver injury.The aim of this review is to assess current epidemiological,clinical and experimental evidence about the possible role of innate and adaptive immunity in the idiosyncratic hepatotoxicity of P.multiflorum.The potential effects of factors associated with immune tolerance,including immune checkpoint molecules and regulatory immune cells on the individual’s susceptibility to PM-DILI are also discussed.We conclude by giving our hypothesis of possible immune mechanisms of PM-DILI and providing suggestions for future studies on valuable biomarkers identification and proper immune models establishment.     

Hepatic injury and drug metabolism in patients with alpha-methyldopa-induced liver damage

Summary The clinical picture and drug metabolism in 36 consecutive patients with alpha-methyldopa — induced hepatic injury were investigated. The diagnosis was based on case history and biochemical, histological and follow-up studies after withdrawal the drug. Alpha-methyldopa-induced liver damage was found to occur in two phases, acutely within months and chronically within years after beginning treatment. Differences were also found in clinical symptoms and the results of liver tests on the patients if they were divided on the basis of the time factor. Drug metabolism was impaired in patients with alpha-methyldopa-induced liver damage, as indicated by low cytochrome P-450 level in liver biopsies and prolonged antipyrine elimination rate from plasma. Disappearance of the symptoms and normalisation of the liver tests after drug withdrawal occurred faster in patients with an acute type of hepatotoxicity than in subjects with delayed onset of the symptoms. The occurrence of hepatotoxicity in four members of a family suggests a genetic disposition to alpha-methyldopa-induced hepatic injury. The occurrence of two phases of liver damage suggests that a possible mechanism for acute hepatotoxicity might be an allergic reaction to metabolic intermediates produced during breakdown of alpha-methyldopa in the liver. For cases of delayed onset the cause might be increasing damage to microsomal liver protein due to covalent binding during long-term exposure to the drug.     

Clinical perspectives on xenobiotic-induced hepatotoxicity

Drug-induced hepatotoxicity is an important cause of liver disease with significant medical, economic, legal, and regulatory implications. Clinically, it presents a diagnostic challenge to health care professionals since drug-induced liver disease can mimic the clinicopathologic features of all other acute and chronic liver diseases. However, individual drugs tend to have a characteristic clinical signature. Early identification of hepatotoxicity by either laboratory monitoring or patients' awareness as a result of education may avert serious liver injury in delayed idiosyncratic toxicity. Most adverse hepatic reactions require metabolism of the drug to reactive metabolites and free radicals, which then either lead to direct overwhelming lethal insult, nonlethal sensitization to the lethal effects of the innate immune system, or haptenization eliciting an immunoallergic response of the adaptive immune system. Besides licensed drugs, herbal and natural supplements are recognized as causing hepatotoxicity with increasing frequency as patients turn more and more to alternative medicine.