抗丙型肝炎药Faldaprevir

慢性丙型肝炎(简称丙肝)由丙肝病毒(HCV)引起,并可能进一步发展为肝硬化和肝细胞癌,在我国的发病率为3.2％,目前尚无特效药,其临床治疗仍需依赖于聚乙二醇化干扰素(pegIFN)和利巴韦林的联用疗法,但该疗法仅对40％ ～ 50％ HCV基因型1感染者和30％ ～ 40％合并感染HIV的HCV感染者有效,且副作用较多,常见的有流感样症状、疲劳、抑郁和贫血等.     

丙型肝炎病毒NS5A抑制剂——达卡他韦

达卡他韦(Daklinza)是由美国百时美-施贵宝公司(BMS)研制的口服丙型肝炎病毒(HCV)NS5A抑制剂。继2014年欧盟批准其与联合其他抗病毒药用于基因型1-4慢性丙型肝炎成人患者的治疗后,2015年7月美国FDA批准其与索非布韦[sofosbuvir]联合用于慢性HCV基因型3感染的治疗。达卡他韦是第一个无需同时给予干扰素或利巴韦林即可有效治疗基因型3 HCV感染的药物,为该类患者提供了一个新选择,包括那些不能耐受利巴韦林患者。笔者就达卡他韦的基本信息、作用机制、药代动力学、药物相互作用、临床试验及应用等研发动态作一概述,以期能为医院临床用药及药物研究开发提供参考。     

抗丙型肝炎病毒新药波普瑞韦和替拉瑞韦

波普瑞韦（boceprevir,BOC）和替拉瑞韦（telaprevir,TVR）均为丙型肝炎病毒NS3/4A丝氨酸蛋白酶抑制剂,用于治疗基因1型慢性丙型病毒性肝炎（chronic hepatitis C,CHC）。与现行的CHC的标准治疗方案比较,BOC或TVR联合聚乙二醇干扰素α和利巴韦林的三联疗法可大大提高初治病人的持久病毒应答率,且对既往聚乙二醇干扰素α联合利巴韦林治疗无效的病人也有较好的疗效。BOC和TVR的三联疗法比现行的标准治疗方案有更好的疗效和安全性。可以说,BOC和TVR的临床应用,使基因1型CHC的治疗进入新纪元。     

抗丙型肝炎药 Boceprevir

全球丙型肝炎病毒（HCV）感染者约有1．7亿之多，若不及时治疗，可发展为慢性肝炎，并可导致肝硬化、肝衰竭或肝细胞癌。HCV为一种包膜正链RNA病毒，一旦进人适宜的宿主细胞，其基因组便作为模板，翻译一个含3000个氨基酸的多聚蛋白，此蛋白经宿主和被命名为NS3的病毒编码的蛋白酶水解成熟。NS3与可增强酶活性的一种必需辅助因子——NS4A蛋白形成异二聚体复合物，作用于多聚蛋白的非结构部分。此外，NS3还可直接破坏宿主细胞，抑制其对于扰素的应答。     

治疗丙型肝炎新药博赛匹韦、特拉匹韦的研究进展

慢性丙型肝炎病毒（HCV）感染是一个全球性的健康问题,标准抗HCV治疗为聚乙二醇干扰素＋利巴韦林的联合方案,该治疗方案只能使42%～54%基因1型感染者得到持续病毒学应答（SVR）[1].15%～30%的丙型肝炎患者将会发展肝硬化,从而导致患者进行肝移植,甚至死亡[2].标准抗HCV方案除了疗效有限以外,不良反应发生率较高.本院的一项研究显示,联合方案的治疗期间,流感样症状发生率71.4%,白细胞减少发生率80%,甲状腺功能异常发生率14.3%,神经精神症状发生率20%[3].特拉匹韦（telaprevir）和博赛匹韦（boceprevir）于2011年先后在美国和欧洲批准上市,打开了抗HCV治疗的新篇章[4].本文对特拉匹韦和博赛匹韦的作用机制、药动学特性、联合治疗丙型肝炎的临床研究、安全性、耐药等作一综述.     

丙型肝炎病毒NS3丝氨酸蛋白酶抑制剂研究进展

综述了近年来丙型肝炎病毒NS3丝氨酸蛋白酶抑制剂的研究概况,从结构上分为肽醛类、硼酸类、α-酮酸类、肽酸类、四氢吡咯-5,5-反式-内酰胺非肽类和α-酮酰胺等.并探讨了各类药物的构效关系.     

丙型肝炎病毒非结构5A蛋白(NS5A)抑制剂研究进展

非结构5A蛋白(NS5A)是治疗丙型肝炎病毒感染的新靶标。尽管NS5A蛋白不具备酶催化活性,但它对病毒RNA复制起着重要作用。NS5A蛋白的小分子抑制剂显示出很强的体外抑制病毒生长的活性,并且初步的临床评价也证实了NS5A抑制剂能很好的抑制体内丙型肝炎病毒的生长。因此,研发高效的NS5A小分子抑制剂为治疗丙型肝炎提供了新的策略。本文综述了NS5A抑制剂的结构类型、构效关系、生物活性和作用机制等方面的研究进展。     

难治性丙型肝炎的治疗进展

难治性丙型肝炎因其标准治疗方案的病毒学应答率低,30％～60％的患者治疗后无持续病毒学应答,且病程反复极易导致肝硬化、肝癌等终末期肝病的发生.本文综述难治性丙型肝炎的治疗进展,包括优化治疗方案及新药的应用.     

初级医疗服务治疗丙型肝炎结果分析

社区卫生服务模式是公众健康管理的重要方式,对于慢性疾病的治疗和管理具有重要意义[1]。丙型肝炎(HCV)是一重要的慢性传染性疾病,社区卫生服务的目标在于监测HCV感染,制定HCV安全有效的治疗策略,达到良好控制和改善预后[2]。HCV感染引起的肝硬化和肝细胞癌逐渐增多[3]。持续性病毒学应答可以遏止肝脏病变的进展,逆转纤维化,降低肝细胞癌危险。但是,HCV感染的治疗是复杂的。聚乙二醇化干扰素和利巴韦林因有严重的副作用需要多学科的强化管理[4]。     

上市新药

丙型肝炎治疗药telaprevir1商品名Incivek2开发与上市厂商本品由美国Verterx制药公司开发,于2011年5月在美国首次上市,同年10月分别在英国、加拿大、瑞典、法国以及德国上市。3适应证本品是一种丙型肝炎病毒（HCV）NS3／4A蛋白酶抑制剂,与聚乙二醇α干扰素和利巴韦林联用治疗慢性丙型肝炎成年患者（年满18周岁）,包括既往未经治疗,或既往干扰索和利巴韦林治疗失败的患者。     

Protease inhibitor therapy for hepatitis C virus-infection

Introduction: The hepatitis C virus (HCV) has affected an estimated of 80 million individuals worldwide and is a strain on public health. Around 25–30% of patients in Europe and the US who are infected with HIV are coinfected with HCV. Prior to 2013, treatment modalities containing an NS3/4A protease inhibitor in combination with pegylated interferon and ribavirin improved sustained virological response (SVR) rates. However, rates of severe side effects were high. Nowadays, oral direct-acting antiviral (DAA) combination therapy offers excellent treatment efficacy, safety and tolerability.

Areas covered: This review focuses on the current literature and clinical evidence and their impact regarding NS3/4A protease inhibitors. The pitfalls encountered in treating HIV- and HBV-coinfected patients are also discussed.

Expert opinion: In the era of DAA treatment, third-generation pan-genotypic NS3/4A protease inhibitors (mainly glecaprevir and voxilaprevir) show high antiviral activity and a genetic resistance barrier with cure rates of over 95% when combined with an NS5A inhibitor, irrespective of baseline resistance associated variants (RASs) being present. These new key components of DAA combination therapy are impressive options to eradicate HCV in the so-called difficult-to-treat population (e.g. compensated cirrhosis, end-stage renal disease and patients who failed previous DAA treatment).     

Targeting the non-structural proteins of hepatitis C virus: beyond hepatitis C virus protease and polymerase

Background: Chronic hepatitis C virus (HCV) infection is a main cause of cirrhosis of the liver and hepatocellular carcinoma. The standard of care is a combination of pegylated interferon with ribavirin, a regimen that has undesirable side effects and is frequently ineffective. Compounds targeting HCV protease and polymerase are in late-stage clinical trials and have been extensively reviewed elsewhere. Objective: To review and evaluate the progress towards finding novel HCV antivirals targeting HCV proteins beyond the already precedented NS3 protease and NS5B polymerase. Methods: Searches of CAplus and Medline databases were combined with information from key conferences. This review focuses on NS2/3 serine protease, NS3 helicase activity and the non-structural proteins 4A, 4B and 5A. Conclusions: Use of the replicon model of HCV replication and biochemical assays of specific targets has allowed screening of vast libraries of compounds, but resulted in clinical candidates from only NS4A and NS5A. The field is hindered by a lack of good chemical matter that inhibits the remaining enzymes from HCV, and a lack of understanding of the functions of non-structural proteins 4A, 4B and 5A in the replication of HCV.     

MK-5172: a second-generation protease inhibitor for the treatment of hepatitis C virus infection

Introduction: Approximately 170 million people worldwide are chronic carriers of the hepatitis C virus (HCV). Twenty-five percent of them develop liver cirrhosis and hepatocellular carcinoma during their life. Successful antiviral treatment dramatically reduces the risk of disease progression. HCV infection is treated with pegylated interferon and ribavirin; the addition of a protease inhibitor (boceprevir or telaprevir) can also be considered for patients with genotype 1.

Areas covered: This review summarizes the data about the pharmacokinetics, pharmacodynamics, efficacy and safety of MK-5172, a second-generation inhibitor of HCV NS3/4A protease.

Expert opinion: The pharmacokinetic profile allows for once-a-day administration. Combined with pegylated interferon and ribavirin, MK-5172 results in a high rate of HCV eradication (in about 90% of cases) and a better outcome than boceprevir-based triple therapy. Also in interferon-free combinations, MK-5172-associated eradication rates are very high (89 – 100%). MK-5172 has a higher barrier to resistance than first-generation protease inhibitors and is active against most variants associated with resistance to first-generation protease inhibitors. Tolerability and safety profile are good. Although data are limited, MK-5172 appears to overcome most of the drawbacks of the first-generation protease inhibitors and is thus a very promising agent to be used in combination with other antivirals to eradicate HCV infection.     

The metabolism and disposition of a potent inhibitor of hepatitis C virus NS3/4A protease

1. Compound A ((1aR,5S,8S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-8-carboxamide) is a prototype of a series of subnanomolar inhibitors of genotypes 1, 2, and 3 hepatitis C virus (HCV) NS3/4A proteases. HCV NS3/4A protease inhibitors have demonstrated high antiviral effects in patients with chronic HCV infection and are likely to form a key component of future HCV therapy.

2. Compound A showed excellent liver exposure in rats, which is essential for compounds intended to treat HCV. The compound was mainly eliminated intact in bile and showed greater than dose proportional systemic exposure in rats. Compound A demonstrated time- and temperature-dependent uptake into rat and human hepatocytes and proved to be a substrate for rat hepatic uptake transporter Oatp1b2 and for human hepatic uptake transporters OATP1B1 and OATP1B3. The liver selectivity observed for this compound is likely to be due to transporter-mediated hepatic uptake together with moderate passive permeability.

3. Metabolism was mainly CYP3A-mediated and generated a reactive epoxide on the vinylcyclopropyl sulfonamide moiety that could be quenched by glutathione. Similar metabolic profiles of Compound A were obtained in liver microsomes of rats and humans. The oral bioavailability at 5?mg/kg was low due to extensive hepatic first-pass effect but clearly the intestinal absorption was enough to deliver a high amount of the compound to the liver. The metabolism and disposition properties of Compound A are particularly attractive to support its evaluation as a drug candidate for the treatment of hepatitis C.

     

Sofosbuvir + velpatasvir + voxilaprevir for the treatment of hepatitis C infection

Introduction: Hepatitis C is a disease with a significant global impact. Over the last several years, the treatment of the disease has been revolutionized. Therapy has transformed over the last several years with the approval of second generation direct acting antivirals, and currently utilized medications for the treatment of hepatitis C are significantly more efficacious with better safety profiles than previously approved treatments. Treatment for individuals who have failed therapy on direct acting antivirals has, until recently, been complex and difficult to treat, but the approval of sofosbuvir/velpatasvir/voxilaprevir represents a new therapeutic option for these individuals.

Areas covered: Sofosbuvir/velpatasvir/voxilaprevir is a recently approved therapeutic combination for the treatment of hepatitis C. This article reviews the studies leading to the approval of the combination, and its efficacy and safety profile.

Expert opinion: Sofosbuvir/velpatasvir/voxilaprevir fills one of the previously unfilled niches for the treatment of hepatitis C, that of the treatment of individuals who have failed therapy with resistant virus. With the filling of this niche, there appears to be a general slowing of the development of new therapeutics. Although understandable, in the long term, there are considerable risks associated with the decreased development of new drugs to treat hepatitis C.     

Novel tripeptide inhibitors of hepatitis C virus NS3 serine protease

Available therapies for hepatitis C viral infection, a disease with a growing impact worldwide, have limited success and serious side effects. Among different possibilities to control the infection, the NS3 serine protease inhibitors constitute a promising alternative, based on a similar approach proved successful in the case of HIV antiviral agents. However, the structural particularities of this viral serine protease make the design of small molecule inhibitors a difficult task. In contrast, the peptidic and peptidomimetic approach gave better results, allowing submicromolar levels of inhibition. In this patent, Bristol-Myers Squibb presents new tripeptide inhibitors with improved potency against NS3 protease and a very good selectivity against related serine proteases. The disclosed compounds also exhibited a good inhibitory profile against different viral strain proteases, giving good hopes to the use of NS3 protease inhibitors as a cure to treat hepatitis C viral infections.     

Pharmacodynamics and pharmacokinetics of elbasvir and grazoprevir in the treatment of hepatitis C

Introduction: Approximately 130 – 150 million people have chronic hepatitis C virus (HCV) infection and upwards of 500,000 deaths annually are attributed to HCV related liver disease worldwide. Pegylated interferon and ribavirin have been the mainstay of treatment for greater than 25 years until recent advent of protease inhibitors which has led to all oral HCV treatment regimens that have changed the outlook of hepatitis C treatment.

Areas covered: This review provides summary of pharmacokinetics, pharmacodynamics, efficacy and safety of grazoprevir/elbasvir therapy for treatment of HCV infection.

Expert opinion: Grazoprevir/elbasvir provides an all-oral once daily treatment option for HCV infection with high rates of efficacy and tolerability in a pangenotypic fashion. It highly efficacious in treating patients with cirrhosis, patients who have previously failed treatment with pegylated interferon and ribavirin, and patients with HIV co-infection. Grazoprevir/elbasvir has demonstrated higher barrier to resistance even in the presence of variants associated with resistance such as Q41R, F43S, R155K, V36M, T54S, and D168. It is one of only few HCV treatment regimens evaluated for use in patients with advanced chronic kidney disease and dialysis. It is a very promising regimen for treatment of HCV infection.     

Rational drug discovery: Ellagic acid as a potent dual‐target inhibitor against hepatitis C virus genotype 3 (HCV G3) NS3 enzymes

Structure‐based virtual screening (SBVS) has served as a popular strategy for rational drug discovery. In this study, we aimed to discover novel benzopyran‐based inhibitors that targeted the NS3 enzymes (NS3/4A protease and NS3 helicase) of HCV G3 using a combination of in silico and in vitro approaches. With the aid of SBVS, six novel compounds were discovered to inhibit HCV G3 NS3/4A protease and two phytochemicals (ellagic acid and myricetin) were identified as dual‐target inhibitors that inhibited both NS3/4A protease and NS3 helicase in vitro (IC₅₀ = 40.37 ± 5.47 nm and 6.58 ± 0.99 µm , respectively). Inhibitory activities against the replication of HCV G3 replicons were further assessed in a cell‐based system with four compounds showed dose‐dependent inhibition. Compound P8 was determined to be the most potent compound from the cell‐based assay with an EC₅₀ of 19.05 µm . The dual‐target inhibitor, ellagic acid, was determined as the second most potent (EC₅₀ = 32.37 µm ) and the most selective in its inhibitory activity against the replication of HCV replicons, without severely affecting the viability of the host cells (selectivity index > 6.18).     

NS5A inhibitor,daclatasvir, for the treatment of chronic hepatitis C virus infection

Gonadal and adrenal steroidal hormones and their related neuropeptides affect seizures. Seizures, in their turn, may affect the functioning of these endocrine systems. Both these sets of effects may be clinically important and open to therapeutic manipulation. Recent advances in understanding the effects of these hormones and their metabolites on neuronal excitability have opened the way for a number of new, hormonally-based therapeutic approaches to seizure management. Some of these have reached various stages of clinical trials, while others are still in the preclinical stages of testing. Similarly, treatment of some of the hormonal consequences of seizures has recently been explored and will be discussed.