索非布韦（Sofosbuvir）

2013年12月6日美国食品药品监督管理局（FDA）批准由GileadSciences公司研发的索非布韦（sofosbuvir）在美国上市,商品名为Sovaldi。该药为片剂,是一种每日一次的口服核苷类似物抑制剂,用于慢性丙型肝炎病毒（HcV）感染的治疗。     

索非布韦合成路线图解

<正>索非布韦(sofosbuvir),化学名为(S)-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-二氧代-3,4-二氢嘧啶-1(2H)-基)-4-氟-3-羟基-4-甲基四氢呋喃-2-基)甲氧基)磷酰化苯氧基)氨基)丙酸异丙酯。它是一种新型HCV抑制剂,作用靶点为HCV NS5B聚合酶,通过干扰病毒遗传物质RNA     

索非布韦的合成工艺改进

目的对索非布韦进行合成工艺改进以提高其收率。方法以(2'R)-N-苯甲酰基-2'-脱氧-2'-氟-2'-甲基胞苷-3',5'-二苯甲酸酯(6)为起始原料,于弱酸条件下选择性脱去氮上的保护基,碱性条件下脱去氧上的苯甲酰基,制得关键中间体(2'R)-2'-脱氧-2'-氟-2'-甲基脲苷(8);以L-丙氨酸异丙酯盐酸盐、二氯磷酸苯酯和五氟苯酚为原料合成稳定的磷酰胺试剂(5);磷酰胺试剂选择性对中间体8的5'位羟基进行亲核取代反应得终产物索非布韦。结果与讨论通过1H-NM R、13C-NM R、M S、IR及mp对索非布韦进行了结构确证,HPLC检测质量分数达99.6%,以原料6计算,总收率为14.97%。     

索非布韦致不良反应文献分析

目的:分析索非布韦致不良反应(adverse drug reactions, ADR)的特点和规律,为临床合理用药提供参考。方法:检索2013年12月—2021年7月中国知网(CNKI)、万方数据库、维普网、PubMed、Web of Science数据库中关于索非布韦致ADR的个案报道,提取文献资料,进行统计分析。结果:共检索到个案报道10篇,共计12例患者。其中男8例(66.7%)、女4例(33.3%),年龄分布以51～60岁年龄段较多(4例,33.3%),多发生在用药1个月后(7例,58.3%),合并基础疾病者8例,累及的器官及系统主要有泌尿系统(6例,50%)、皮肤及附件(3例,25%)。结论:临床医师和药师应加强对索非布韦的认识和用药监测,尤其应加强肾功能监测,减少不良反应的发生。     

HPLC法测定索非布韦片的有关物质

目的：建立索非布韦片有关物质的HPLC法。方法：采用Waters Symmetry C₁₈(5μm,4.6×150mm)色谱柱,流动相为0.01 mol.L_-1磷酸二氢钠溶液(用磷酸调节pH值至3.0)-乙腈(75:25),流动相B为乙腈,梯度洗脱。流速为1.0 mL.min_-1,检测波长为210nm,柱温30℃,进样量20μL,对有关物质进行定量分析。结果：在该色谱条件下,索非布韦与各杂质均能有效分离,杂质A(中间体)、杂质B(起始原料)、杂质C(降解产物)的定量限分别为1.012、2.005、2.010ng,且在各自的线性范围内线性关系良好(r＞0.999,n=7),杂质加样回收率(n=9)在96.11%～102.20%之间,重复性、精密度、稳定性等符合规定。对3 批索非布韦片进行有关物质测定,结果总杂质量在0.108%～0.129%范围内。结论：方法学验证结果表明,本法可作为索非布韦片有关物质的测定。     

抗丙型肝炎病毒药索非布韦的临床研究进展

目的:综述抗丙型肝炎病毒(HCV)药索非布韦的临床研究进展。方法:以"Sofosbuvir""索非布韦""索氟布韦""丙型肝炎"和"NS5B聚合酶抑制剂"等为关键词,组合检索2010年1月至2015年2月Pub Med、万方、维普、中国知网等数据库,对索非布韦的临床药理(作用机制、药动学、药物相互作用、耐药性)、适用特殊人群、临床试验及安全性评价等内容进行综述。结果:共检索到相关文献76条,其中有效文献20条。作用机制方面,索非布韦通过与HCV的RNA核苷酸竞争HCV特异性NS5B聚合酶活化位点而发挥抗病毒作用,给药剂量为400 mg/d时对病毒的抑制作用最佳。临床应用方面,索非布韦适用于HCV初治患者和既往干扰素治疗失败的患者,不同HCV基因型感染可采用不同的给药方案;索非布韦对HCV感染合并肝硬化、肝脏移植和人类免疫缺陷病毒感染患者也有效,且给药时无需调整剂量。此外,索非布韦的耐药性较好、药物相互作用少、不良事件发生率较低。结论:索非布韦用于慢性HCV感染治疗,具有病毒学应答率高、适用人群广、不良反应发生率低、给药方式简单等特点,相信在未来会拥有良好的应用前景。     

新型抗丙型肝炎病毒药索非布韦的研究进展

目的评价新型抗丙型肝炎病毒(hepatitis C virus,HCV)药索非布韦的药理作用、安全药理学、药代动力学、药物相互作用、临床研究、不良反应、耐药性。方法查阅相关文献26篇,对索非布韦基础与临床的研究进展进行了归纳与总结。结果与结论索非布韦(sofosbuvir)是经美国食品药品管理局(FDA)批准的首个NS5B HCV聚合酶抑制剂,对所有HCV基因型均有效,本药安全性及耐受性良好,与其它药物间相互作用少,具有优良的药代动力学特性和强大的抗病毒能力,其强大的治疗效果给丙型肝炎患者带来了新希望。     

FDA批准抗丙型肝炎新药索非布韦（sofosbuvir）上市

全球丙型肝炎病毒（HCV）的感染率高,且缺少有效的治疗药物。2013年12月6日,美国食品药物监督管理局（FDA）批准新分子实体药物索非布韦（sofosbuvir）片剂上市,商品名Sovaldi,用于慢性丙型肝炎的治疗。索非布韦是一种HCV聚合酶抑制剂,作用于病毒RNA复制的核苷酸类似物NS5B聚合酶位点,能中止病毒复制,是以NS5B聚合酶为靶点的唯一上市品种。本品与聚乙二醇干扰素/利巴韦林或单独与利巴韦林联用,与标准治疗方案相比治愈率更高且缩短给药时间,有广阔的应用前景。     

顶空毛细管气相色谱法测定索非布韦原料药中有机溶剂残留量

目的建立索非布韦原料药中4种残留溶剂的顶空气相色谱测定方法。方法 HP-INNOWAX毛细管气相色谱柱(30.0 m×0.32 mm×0.5μm);进样口温度:200℃;进样量0.1 mL;分流比1∶1;柱温:40℃,保持3 min,10℃·min~(-1)升温至80℃,再以40℃·min~(-1)升温至200℃,保持4 min;检测器为FID,温度:250℃;载气:N2,恒流:2 mL·min~(-1);N,N-二甲基乙酰胺为溶剂。结果各残留溶剂均可以达到基线分离。测得二氯甲烷、四氢呋喃、甲醇、乙醇与峰面积线性关系良好,准确度均> 95%,RSD均<2.5%。结论该方法操作简便,重现性好,结果准确可靠,可以用于索非布韦中残留溶剂的测定。     

Sofosbuvir and ledipasvir for HIV/HCV co-infected patients

Introduction: Hepatitis C virus (HCV) is a chronic infection that disproportionately impacts people living with HIV. In the past, HCV therapy was less effective in individuals with HIV co-infection. However, the advent of direct-acting antivirals has revolutionized HCV treatment with high rates of success in patients both with and without HIV.

Areas covered: In this paper, we review the evidence supporting the use of ledipasvir and sofosbuvir (LDV/SOF) for the treatment of HCV in patients with HIV co-infection. Articles searchable on MEDLINE/PubMed were reviewed to provide context for use of LDV/SOF in individuals with HCV and HIV co-infection.

Expert opinion: This treatment is highly effective in achieving HCV cure or sustained virologic response, however further studies need to done to address efficacy of treatment in people with uncontrolled HIV, concerns regarding drug-interactions with antiretroviral therapy, and potential for shorter duration treatment.     

治疗慢性丙型肝炎新药Sofosbuvir

鉴于丙型肝炎病毒（HCV）感染全球高发趋势,目前治疗方案因禁忌、严重不良反应等导致其使用的局限性,因此需要一种更有效、安全、简便、不适宜干扰素治疗的治疗药物.Sofosbuvir是具有这些特性的直接抗病毒药物,为HCV NS5 B聚合酶的尿苷核苷酸类似物抑制药,可有效对抗多种基因型HCV感染,具有良好的安全性和耐受性.本文综述Sofosbuvir的作用机制、药动学、不良反应、药物相互作用及临床试验.     

Sofosbuvir (Sovaldi) for the treatment of hepatitis C

Hepatitis C (HCV) remains an important cause of chronic liver disease worldwide. Historically, treatment included pegylated-interferon and ribavirin with low efficacy and numerous side effects contributing to poor adherence and impairment of patients’ well-being. The next step in developing better treatment regimens for HCV led to the development of the first-generation direct acting antivirals (DAAs). Although these DAAs improved efficacy, they also added substantial side effects. The next generation of DAAs include Simeprevir and Sofosbuvir (SOF) which not only further enhanced the efficacy of the regimens but also improve their safety profile. This review summarizes the current clinical experience with SOF. SOF, an HCV-specific uridine nucleotide analog which inhibits the NS5B polymerase, is now available in the USA, Canada and Europe. Clinical trials of SOF-containing regimens have shown that these regimens are safe, efficacious, and well-tolerated in all genotypes. Additionally, SOF is associated with improved patient reported outcomes.     

索磷布韦片在中国健康受试者中的药代动力学和安全性研究

目的：研究中国人群中索磷布韦及其代谢产物GS-331007和GS-566500的主要药代动力学特征和安全性。方法：本试验共入组12例健康受试者,分为四个周期;前三周期为单次给药（低剂量400 mg空腹组、高剂量800 mg空腹组和低剂量400 mg高脂餐组）药代动力学试验;第四周期为多次给药（低剂量400 mg空腹组）药代动力学试验。采用HPLC-MS/MS测定给药前后不同时间点人血浆中索磷布韦及其代谢产物GS-331007和GS-566500的浓度。结果：索磷布韦及其代谢产物GS-566500的暴露与剂量有成比例增加趋势。在多次给药试验中,未观察到明显蓄积现象。与空腹相比,餐后状态下索磷布韦的Cmax变化不大,AUC增加约30%;GS-331007的Cmax和AUC分别减少约30%和10%;GS-566500的Cmax和AUC分别增加约15%和25%。饮食对索磷布韦、GS-331007和GS-56650的Tmax无显著影响。未发生严重不良事件和导致退出的不良事件,所有受试者耐受性良好。结论：在中国健康受试者中,开展的索磷布韦片药代动力学研究结果表明,其药动学特征和安全性与国外研究数据无明显差异,安全性和耐受性良好。     

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.     

Sofosbuvir,a nucleotide polymerase inhibitor,for the treatment of chronic hepatitis C virus infection

Neural cell transplantation is an emerging therapy that may provide an effective treatment for neurodegenerative disorders. The most extensive work with neural transplants has been carried out for Parkinson’s and Huntington’s diseases. However, intensive efforts are also being made for the treatment of other neurological indications, such as spinal cord repair, stroke, epilepsy, multiple sclerosis (MS), Alzheimer’s disease and amyotrophic lateral sclerosis (ALS or Lou Gehrig’s disease), to name just a few. The major barrier for the successful application of cells as therapeutics is achieving long-term survival and function. The CNS has proven to be ideal for transplantation, in part because immune rejection is attenuated in the CNS compared to peripheral locations. However, some form of immunosuppression is desirable for optimal allograft survival and required for xenograft survival. This review will focus on the challenges of restoring function to something as intricate as the CNS and on the limitations imposed by this complexity on any cellular therapeutic.