他汀类药物:目前产品安全性信息

英国MHRA宣布:广泛检索欧洲的临床试验不良反应资料表明,所有他汀类药物(HMG-CoA还原酶抑制药:辛伐他汀、阿托伐他汀、普伐他汀、氟伐他汀及洛伐他汀),效益大于风险。但他汀类药物仍有下列ADR:睡眠障碍、记忆丧     

某院干部药房2005年～2007年调节血脂药物应用情况分析

对2005年~2007年中消耗的调血脂药物用药金额、用药频度及日均费用的变化进行统计分析。结果目前临床调脂主要还是依赖抑制HMG-CoA还原酶,辛伐他汀居用药金额第一位。辛伐他汀、阿托伐他汀、血脂康居用药频度占前3位。说明某院干部药房调节血脂药物应用基本合理。     

阿托伐他汀的应用与研究概况

阿托伐他汀是羟甲基戊二酸单酰辅酶A（HMG-CoA）还原酶抑制剂,此药通过竞争性抑制内源性胆固醇合成限速HMG-CoA还原酶,阻断细胞内甲羟戊酸代谢途径,使细胞内胆固醇合成减少[1-2]。此药除具有降低血清总胆固醇（TC）、升高高密度脂蛋白胆固醇（HDL-ch）作用外,还发现它具有抗炎、抗氧化、改善血管内皮功能、抑制血小板激活、降低血液黏度、     

新型高效降脂药物罗伐他汀

目的:介绍一种新型的3羟基-3甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂罗伐他汀.方法:通过查阅文献,从结构特征与优势、抑酶活性及肝细胞选择性、药效学、药动学、临床研究、安全性6个方面的内容对该药进行综合性评述.结果:该药不仅具有强力的HMG-CoA还原酶抑制活性,而且这种作用还呈肝细胞选择性.其药效学、药动学性质优异,安全性高.结论:罗伐他汀是一个颇具发展潜力的新一代他汀类降脂药物.     

答疑解惑Q＆A

Q他汀类药物有何不良反应？ 他汀类药物即羟甲基戌二酰辅酶A还原酶抑制剂（HMG-CoA-RI）通过抑制体内胆固醇合成限速酶（HMG-CoA）还原酶的活性而阻断或减少体内胆固醇合成,刺激低密度脂蛋白（LDL）受体增加,有效地清除体内LDL-C。该药疗效显著,不良反应小,耐受性好。近年来新品种不断涌现,洛伐他汀、普伐他汀、辛伐他汀、氟伐他汀、阿托伐他汀、西立伐他汀先后用于临床。对调节血脂、预防和治疗冠心病具有划时代的作用。     

标准剂量瑞舒伐他汀与阿托伐他汀治疗不稳定型心绞痛的疗效分析

目的:分析标准剂量瑞舒伐他汀与阿托伐他汀治疗不稳定型心绞痛的疗效.方法:采用随机数字表法将商丘市民权县李堂卫生院2014年1月~2015年2月119例不稳定型心绞痛患者进行分组,对照组59例给予阿托伐他汀口服,观察组60例给予瑞舒伐他汀口服,对比两组临床疗效及血脂指标.结果:观察组治疗后总有效率93.33%高于对照组的79.66%,P<0.05;观察组治疗后TC、TG、LDL-C、HDL-C指标改善幅度均优于对照组,其中,TC、LDL-C指标与对照组比较,P<0.05.结论:瑞舒伐他汀能够通过抑制HMG-CoA还原酶,加快LDL的吸收及分解,抑制VLDL的合成,降低血脂水平,改善心肌缺血及临床症状,治疗不稳定型心绞痛效果优于阿托伐他汀,值得临床推广.     

阿托伐他汀致相关性肌病的回顾性分析

目的 探讨阿托伐他汀致相关性肌病的特点、影响因素、临床转归情况,促进临床合理用药。方法 检索中国知网全文数据库和万方数据库,统计分析他汀相关性肌病的药物不良反应（adverse drug reaction,ADR）,并统计患者的年龄、性别、服用日剂量、发生ADR时服药时间、合并用药、基础疾病以及ADR临床表现、肌酸激酶（creatine kinase,CK）的变化、转归情况。结果 检索到38篇阿托伐他汀导致肌病发生的相关病例报告,共计41例。男性的发生率（60.98%）明显高于女性;>70岁老人（68.29%）是肌病发生的高危人群;初次服药或既往服用阿托伐他汀正常患者在服用阿托伐他汀过程中新增合并用药的前2个月内是肌病发生的危险期;肌病始发症状多见乏力、肌痛,偶见血尿/褐色尿/棕红色尿,恶心/食欲不振、抽搐、皮肤黄染,少见发热、心慌、局部肿胀。结论 阿托伐他汀致相关性肌病发生严重时可导致致死性事件;加强用药教育,避免自行添加药物,注意肌病发生的症状,用药后1~2个月密切监护肝肾功能及CK的变化,一旦出现肌病症状或CK升高,及时就医,避免致死性事件的发生。     

甲巯咪唑致肝损伤的特点、机制及防治研究进展

目的:为甲巯咪唑的临床合理应用提供参考。方法:以"甲巯咪唑,肝功能损伤"和"Methimazole,Hepatotoxicity"为关键词,分别检索中国期刊全文数据库和PubMed数据库,就检索到的甲巯咪唑致肝损伤病例进行简要回顾,并从发生率、临床表现、作用机制、危险因素、防治措施等方面进行综述和分析。结果与结论:甲巯咪唑致肝损伤以胆汁淤积型为主,其次为肝细胞损伤型和混合型;临床表现主要为消化道症状,其次为血清氨基转移酶升高或胆汁淤积性黄疸;其机制可能与甲巯咪唑及其代谢产物破坏肝细胞并激活自身免疫系统有关;甲巯咪唑致肝损伤的发生似有剂量相关性趋势,有肝病史会增加发生风险。故使用甲巯咪唑时应有用药指征,定期监测肝功能,避免联合用药,并注意剂量和疗程等。一旦发生肝损伤应及时减量或停药,并采取相应治疗措施。     

阿托伐他汀和辛伐他汀在调脂与抗动脉粥样硬化及卒中防治方面的应用进展

他汀类药物为HMG-CoA还原酶的抑制剂,不仅能有效降低低密度脂蛋白胆固醇(LDL-C),还有抗炎、抗平滑肌增殖作用,能有效逆转动脉粥样硬化,是卒中防治的一线药物,临床上应用最多的是阿托伐他汀及辛伐他汀。目前的临床研究表明,与辛伐他汀相比较,阿托伐他汀的生物利用度更高,其调脂、抗动脉粥样硬化作用更强,并仅有阿托伐他汀对缺血性脑卒中有二级预防作用。     

北京市71家基层医疗机构2010-2012年HMG-CoA还原酶抑制剂应用情况分析

目的：调查北京市71家基层医疗机构2010-2012年羟甲基戊二酸单酰辅酶A（HMG-CoA）还原酶抑制剂的应用情况。方法：对北京市71家基层医疗机构在2010-2012年HMG-CoA还原酶抑制剂的应用情况进行统计,包括药品名称、生产厂家、医院归属地和级别。结果：各种HMG-CoA还原酶抑制剂的用量和用药金额均呈逐年上升的趋势。阿托伐他汀和辛伐他汀占据垄断地位,两者的用药金额占HMG-CoA还原酶抑制剂总用药金额的约90%份额。一级医院HMG-CoA还原酶抑制剂的院均用药量和用药金额均明显低于二级医院,郊区医院明显高于市区医院。结论：北京市基层医疗机构使用的HMG-CoA还原酶抑制剂以阿托伐他汀和辛伐他汀为主,外资企业所产药品的用药金额高于内资企业。     

Farnesoid X receptor contributes to oleanolic acid-induced cholestatic liver injury in mice

Farnesoid X receptor (FXR) is a nuclear receptor involved in the metabolism of bile acid. However, the molecular signaling of FXR in bile acid homeostasis in cholestatic drug-induced liver injury remains unclear. Oleanolic acid (OA), a natural triterpenoid, has been reported to produce evident cholestatic liver injury in mice after a long-term use. The present study aimed to investigate the role of FXR in OA-induced cholestatic liver injury in mice using C57BL/6J (WT) mice and FXR knockout (FXR^−/−) mice. The results showed that a significant alleviation in OA-induced cholestatic liver injury was observed in FXR^−/− mice as evidenced by decreases in serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase as well as reduced hepatocyte necrosis. UPLC-MS analysis of bile acids revealed that the contents of bile acids decreased significantly in liver and serum, while increased in the bile in FXR^−/− mice compared with in WT mice. In addition, the mRNA expressions of hepatic transporter Bsep, bile acid synthesis enzymes Bacs and Baat, and bile acids detoxifying enzymes Cyp3a11, Cyp2b10, Ephx1, Ugt1a1, and Ugt2b5 were increased in liver tissues of FXR^−/− mice treated with OA. Furthermore, the expression of membrane protein BSEP was significantly higher in livers of FXR^−/− mice compared with WT mice treated with OA. These results demonstrate that knockout of FXR may alleviate OA-induced cholestatic liver injury in mice by decreasing accumulation of bile acids both in the liver and serum, increasing the export of bile acids via the bile, and by upregulation of bile acids detoxification enzymes.     

BSEP inhibition – In vitro screens to assess cholestatic potential of drugs

Bile salt export pump (BSEP, ABC11) is a membrane protein that is localized in the cholesterol-rich canalicular membrane of hepatocytes. Its function is to eliminate unconjugated and conjugated bile acids/salts from hepatocyte into the bile. In humans there is no compensatory mechanism for the loss of this transporter. Mutations of BSEP result in a genetic disease, called progressive familial intrahepatic cholestasis type 2 (PFIC2), that is characterized with decreased biliary bile salt secretion, leading to decreased bile flow and accumulation of bile salts inside the hepatocyte, inflicting damage. BSEP inhibitor drugs produce similar bile salt retention that may lead to severe cholestasis and liver damage. Drug-induced liver injury is a relevant clinical issue, in severe cases ending in liver transplantation.Therefore, measurement of BSEP inhibition by candidate drugs has high importance in drug discovery and development. Although several methods are suitable to detect BSEP-drug interactions, due to interspecies differences in bile acid composition, differences in hepatobiliary transporter modulation, they have limitations. This review summarizes appropriate in vitro methods that could be able to predict BSEP-drug candidate interactions in humans before the start of clinical phases.     

Drug-induced liver disease.

The large number of chemical agents administered for therapeutic or diagnostic purposes can produce various types of hepatic injury by several mechanism. Acute injury may be cytotoxic, cholestatic or mixed. Cytotoxic injury may consist of necrosis or steatosis. Cholestatic injury may be cholangiolitic (hepatocanalicular) or bland (canalicular). Chronic hepatic lesions caused by medicinal agents include chronic active hepatitis, steatosis, cirrhosis, fibrosis, hepatoportal sclerosis (non-cirrhotic portal hypertension), hepatic vein thrombosis, peliosis hepatis, adenoma, carcinoma, and angiosarcoma. There is a useful relationship between the type of hepatic injury and the chemical setting in which the drugs are employed. Some agents produce the liver damage because they are intrinsic (true, predictable) hepatotoxins. Other (non-predictable "hepatotoxins"), produce hepatic injury only in the rare and unusually susceptible individual (idiosyncratic injury). Hepatotoxic agents can be recognised by their dose-dependent and experimental reproducibility, properties which are not shared by agents which produce hepatic injury only in idiosyncratic hosts. Intrinsic hepatotoxins may be categorised as direct or indirect. Direct hepatotoxins injure the hepatocyte by direct physiochemical alteration and as a consequence produce metabolic defects. Indirect hepatotoxins selectively block metabolic pathways and, by producing a precise biochemical lesion, lead to structural changes. They may lead to hepatic steatosis or necrosis (cytotoxic indirect hepatotoxins) or block bile flow (cholestatic indirect hepatotoxins). Direct hepatotoxins are rarely encountered as drugs. Overdoses of some drugs and antineoplastic agents appear to be indirect cytotoxic hepatotoxins, and the C-17 alkylated anabolic and contraceptive steroids are indirect, cholestatic hepatotoxins. Idiosyncracy of the host is the mechanism for most types of drug-induced hepatic injury. It may reflect allergy to the drug or a metabolic aberration of the host permitting the production of hepatotoxic metabolites.     

Pharmacogenetics of hepatocellular transporters

One of the main functions of the liver is the production of bile and the biliary secretion of endogenous and exogenous substances, including drugs and drug metabolites. Bile formation is a complex sequence of cellular events, which involves uptake of bile constituents and xenobiotics on the basolateral (sinusoidal) plasma membrane of hepatocytes and secretion of cholephilic compounds across the apical (canalicular) membrane. These uptake and efflux processes are maintained by distinct transport systems expressed at the two polar surface domains of liver cells. Any functional disturbance of these canalicular transport systems can lead to cholestatic liver disease, which is associated with intracellular accumulation of toxic bile constituents and consecutive cholestatic liver cell damage. Interaction of drugs with hepatobiliary transport systems is increasingly recognized as cause of acquired cholestatic syndromes. Thereby, genetically determined alterations of hepatobiliary transporter functions are important risk factors for an individual's susceptibility to develop cholestasis. Especially, mutations in canalicular transporter genes can cause certain forms of hereditary cholestatic liver disease, including progressive familial intrahepatic cholestasis or intrahepatic cholestasis of pregnancy. In addition, systematic genetic screenings have discovered numerous single nucleotide polymorphisms in hepatobiliary transporter genes that lead to amino acid exchanges in the encoded proteins. However, the functional consequences and the clinical relevance of most of these polymorphisms remain to be defined. This overview summarizes the physiological function of human hepatobiliary transport systems and discusses the impact of their genetic variations for the pathophysiology of cholestatic syndromes and the pharmacogenetics of drug-induced cholestasis.     

Interactions of combined bile acids on hepatocyte viability: cytoprotection or synergism

Cholestasis results from hepatocyte dysfunction due to the accumulation of bile acids in the cell, many of which are known to be cytotoxic. Recent evidence implicates competitive antagonism of key cytotoxic responses as the mechanism by which certain therapeutic bile acids might afford cytoprotection against cholestasis. In this work, we compare the relative cytotoxicity of bile acids in terms of dose- and time-dependence. To better elucidate the controversy related to the therapeutic use of ursodeoxycholate (UDCA) in cholestatic patients, we also evaluated the effects of bile acid combinations. Viability of Wistar rat hepatocytes in primary culture was measured by LDH leakage after 12 and 24 h exposure of cells to the various bile acids. All unconjugated bile acids caused a dose-dependent decrease in cell viability. The tauro- and glyco-conjugates of chenodeoxycholate (CDCA) and UDCA were all less toxic than the corresponding unconjugated form. Although relatively non-toxic, UDCA caused synergistic cell killing by lithocholate (LCA), CDCA, glyco-CDCA (GCDC) and tauro-CDCA (TCDC). Glycoursodeoxycholate decreased the toxicity of GCDC, but potentiated the toxicity of unconjugated CDCA and LCA. The tauro-conjugate of UDCA had no significant effect. These data suggest that at cholestatic concentrations, bile acid-induced cell death correlates with the degree of lipophilicity of individual bile acids. However, these results indicate that the reported improvement of biochemical parameters in cholestatic patients treated with UDCA is not due to a direct effect of UDCA on hepatocyte viability. Therefore, any therapeutic effect of UDCA must be secondary to some other process, such as altered membrane transport or nonparenchymal cell function.     

转运体和代谢酶在胆汁淤积性肝损伤中的作用机制

胆汁淤积性肝损伤是临床常见的肝脏疾病,主要由体内胆汁酸平衡失调引起,其发病机制与胆汁酸转运体、合成酶和代谢酶的表达和功能变化直接相关。核受体通过调控胆汁酸转运体及代谢酶的表达,在胆汁淤积所致的肝损伤中发挥重要作用。对肝脏转运体和代谢酶在胆汁淤积性肝损伤中的作用及核受体对转运体和代谢酶的调控机制作一综述。     

Acute hepatic injury with atorvastatin: An unusual occurrence

Atorvastatin, a commonly used and well-tolerated hypolipidemic drug, belongs to the class of statins or hydroxymethylglutaryl-coenzyme A reductase inhibitors. Use of atorvastatin may be associated with minor asymptomatic elevations in serum aminotransferases, but clinically significant hepatotoxicity is usually infrequent. Here we present a case of self-limiting clinically apparent acute hepatic injury attributable to atorvastatin occurring at recommended daily dose of 20 mg once a day. This case was postulated to be an unusual idiosyncratic reaction of the drug.KEY WORDS: Acute hepatotoxicity, aminotransferase enzymes, atorvastatin     

2010—2021年福州市长乐区医院阿托伐他汀致肝损伤不良反应相关性因素分析

目的 分析阿托伐他汀致肝损伤不良反应的发生规律及特点,并进行相关性因素分析,为其安全使用提供参考。方法 对福州市长乐区医院2010—2021年74例阿托伐他汀致肝损伤不良反应报告病例进行回顾性分析,统计分析患者的一般情况、临床症状、临床分型、严重程度和转归情况等临床资料。结果 收集到的74例阿托伐他汀致肝损伤患者,男女比例1.74∶1;患者年龄33～93岁;原患疾病主要是心脑血管疾病（93.24%）,发生时间平均为用药后（42.78±75.98）d,临床表现主要为乏力、纳差、皮肤巩膜黄染、腹部不适,53例患者无症状;临床分型中肝细胞损伤型比例最高为29例（39.19%）、混合型次之为27例（36.49%）,胆汁瘀积型最少为18例（24.32%）,RUCAM量表评分均在3分以上,14例（18.92%）≥6分;3种临床分型之间的丙氨酸氨基转移酶（ALT）、碱性磷酸酶（ALP）、γ-谷氨酰转肽酶（GGT）水平比较差异具有统计学意义（P<0.05）;严重程度分级中轻度肝损伤63例（85.13%）,中度肝损伤9例（12.17%）,重度肝损伤2例（2.70%）;停药/减量并给予保肝及对症治疗...     

Drug-induced cholestasis

Drugs may cause several overlapping syndromes of cholestasis, the pathophysiological syndrome resulting from impaired bile flow. These reactions comprise approximately 17% of all hepatic adverse drug reactions (ADRs) and they may be severe. Causes of 'pure' (bland) cholestasis include oestrogens and anabolic steroids; rarer associations are with antimicrobials and NSAIDs. 'Cholestatic hepatitis' is a common drug reaction in which liver injury and inflammation cause significant elevation of serum alanine aminotransferase (ALT) as well as cholestasis. Chlorpromazine and ketoconazole are classic examples, but it is now exemplified by amoxycillin-clavulanate and other oxy-penicillins. Chronic cholestasis results from small bile duct injury leading to the vanishing bile duct syndrome (VBDS), a disorder mimicking primary biliary cirrhosis, or from injury to larger bile ducts causing secondary sclerosing cholangitis. Whilst there is increasing evidence of a genetic predisposition to cholestatic drug reactions, there are currently no pretreatment tests to predict drug safety. Prevention of severe reactions therefore relies on early detection of liver injury and prompt drug withdrawal. Symptomatic management includes relief of pruritus and correction of fat-soluble vitamin deficiency. In small cohort studies, ursodeoxycholic acid (UDCA) arrested progressive cholestasis in two-thirds of cases, but evidence for use of corticosteroids is anecdotal. This review considers diagnosis, pathogenesis, prevention and management of drug-induced cholestasis, with particular reference to frequently- and newly-described causes.     

Clinical pharmacokinetics of atorvastatin

Hypercholesterolaemia is a risk factor for the development of atherosclerotic disease. Atorvastatin lowers plasma low-density lipoprotein (LDL) cholesterol levels by inhibition of HMG-CoA reductase. The mean dose-response relationship has been shown to be log-linear for atorvastatin, but plasma concentrations of atorvastatin acid and its metabolites do not correlate with LDL-cholesterol reduction at a given dose. The clinical dosage range for atorvastatin is 10-80 mg/day, and it is given in the acid form. Atorvastatin acid is highly soluble and permeable, and the drug is completely absorbed after oral administration. However, atorvastatin acid is subject to extensive first-pass metabolism in the gut wall as well as in the liver, as oral bioavailability is 14%. The volume of distribution of atorvastatin acid is 381L, and plasma protein binding exceeds 98%. Atorvastatin acid is extensively metabolised in both the gut and liver by oxidation, lactonisation and glucuronidation, and the metabolites are eliminated by biliary secretion and direct secretion from blood to the intestine. In vitro, atorvastatin acid is a substrate for P-glycoprotein, organic anion-transporting polypeptide (OATP) C and H+-monocarboxylic acid cotransporter. The total plasma clearance of atorvastatin acid is 625 mL/min and the half-life is about 7 hours. The renal route is of minor importance (<1%) for the elimination of atorvastatin acid. In vivo, cytochrome P450 (CYP) 3A4 is responsible for the formation of two active metabolites from the acid and the lactone forms of atorvastatin. Atorvastatin acid and its metabolites undergo glucuronidation mediated by uridinediphosphoglucuronyltransferases 1A1 and 1A3. Atorvastatin can be given either in the morning or in the evening. Food decreases the absorption rate of atorvastatin acid after oral administration, as indicated by decreased peak concentration and increased time to peak concentration. Women appear to have a slightly lower plasma exposure to atorvastatin for a given dose. Atorvastatin is subject to metabolism by CYP3A4 and cellular membrane transport by OATP C and P-glycoprotein, and drug-drug interactions with potent inhibitors of these systems, such as itraconazole, nelfinavir, ritonavir, cyclosporin, fibrates, erythromycin and grapefruit juice, have been demonstrated. An interaction with gemfibrozil seems to be mediated by inhibition of glucuronidation. A few case studies have reported rhabdomyolysis when the pharmacokinetics of atorvastatin have been affected by interacting drugs. Atorvastatin increases the bioavailability of digoxin, most probably by inhibition of P-glycoprotein, but does not affect the pharmacokinetics of ritonavir, nelfinavir or terfenadine.