抗丙型肝炎病毒新药——聚乙二醇干扰素

聚乙二醇干扰素是一个以－CH2CH2O－为基础结构的大分子聚乙二醇对蛋白质进行修饰后的新型抗丙型肝炎病毒(HCV)的药物。与普通干扰素相比，它在吸收、分布、代谢、排泄等方面具有优良的药动学特性。聚乙二醇干扰素单药或联合利巴韦林治疗慢性丙型肝炎，治疗和随访结束时的病毒应答率和持续病毒应答率显著高于普通干扰素组，具有良好的临床疗效。聚乙二醇干扰素的安全性、耐受性与不良反应与普通干扰素类似，本身性质十分稳定，它与利巴韦林联合是治疗丙肝的最佳选择。     

聚乙二醇干扰素

聚乙二醇(PEG)具有溶解性良好、毒性很小和无抗原性的特性。PEG修饰蛋白质使分子量增加，在体内半衰期延长，可以减少用药次数，提高治疗效果。本文对PEG的结构、性状、对干扰素修饰的方法、修饰后的药代动力学和临床效果进行综述。PEG修饰重组人干扰素αZa和PEG修饰重组人干扰素αZb在体内药代动力学均有明显改善，半衰期明显延长。两种PEG干扰素均已进行临床试验。每周注射1次治疗丙型肝炎，效果明显较普通干扰素为好。其安全性与普通干扰素基本相似。     

聚乙二醇干扰素

聚乙二醇(PEG)具有溶解性良好、毒性很小和无抗原性的特性.PEG修饰蛋白质使分子量增加,在体内半衰期延长,可以减少用药次数,提高治疗效果.本文对PEG的结构、性状、对干扰素修饰的方法、修饰后的药代动力学和临床效果进行综述.PEG修饰重组人干扰素α2a和PEG修饰重组人干扰素α2b在体内药代动力学均有明显改善,半衰期明显延长.两种PEG干扰素均已进行临床试验.每周注射1次治疗丙型肝炎,效果明显较普通干扰素为好.其安全性与普通干扰素基本相似.     

聚乙二醇干扰素、利巴韦林联合治疗慢性丙型肝炎的临床效果观察

目的探讨聚乙二醇干扰素、利巴韦林联合治疗慢性丙型肝炎的临床效果。方法50例慢性丙型肝炎患者,采用随机数字表法分为普通干扰素+利巴韦林组及聚乙二醇干扰素+利巴韦林组,各25例。普通干扰素+利巴韦林组采取普通干扰素、利巴韦林联合治疗,聚乙二醇干扰素+利巴韦林组采取聚乙二醇干扰素、利巴韦林联合治疗。比较两组患者的治疗效果;治疗前后病毒丙型肝炎病毒核糖核酸(HCV-RNA)载量和生存质量评分;症状改善时间、病毒HCV-RNA转阴时间;不良反应发生情况。结果聚乙二醇干扰素+利巴韦林组总有效率100.00%高于普通干扰素+利巴韦林组的80.00%,差异具有统计学意义(P<0.05)。治疗后,两组患者的病毒HCV-RNA载量和生存质量评分均较本组治疗改善,且聚乙二醇干扰素+利巴韦林组程度改善优于普通干扰素+利巴韦林组,差异均具有统计学意义(P<0.05)。聚乙二醇干扰素+利巴韦林组症状改善时间、病毒HCV-RNA转阴时间分别为(12.16±1.07)、(33.48±1.21)周,均短于普通干扰素+利巴韦林组的(17.21±1.26)、(46.79±1.25)周,差异均具有统计学意义(P<0.05)。聚乙二醇干扰素+利巴韦林组不良反应发生率24.00%低于普通干扰素+利巴韦林组52.00%,差异具有统计学意义(χ^2=4.160,P<0.05)。结论聚乙二醇干扰素+利巴韦林治疗慢性丙型肝炎的效果确切,可有效改善症状,且无严重不良反应,安全性高,可改善患者的生存质量。     

聚乙二醇修饰干扰素α2b的稳定性研究

目的研究聚乙二醇修饰干扰素α 2b的稳定性。方法以抗病毒活性为指标 ,考察单修饰干扰素α 2b、多修饰干扰素α 2b和干扰素α 2b的稳定性 (4℃、2 5℃、37℃ )、抗胰蛋白酶水解能力和 37℃人血清稳定性。结果在4℃、2 5℃和 37℃条件下 ,稳定性依次为多修饰干扰素α 2b >单修饰干扰素α 2b >干扰素α 2b。抗胰蛋白酶水解试验表明 :干扰素α 2b在 30min时抗病毒活性迅速降到原来的 7.1% ,单修饰干扰素α 2b剩余 5 0 % ,多修饰干扰素α 2b仍保留 71%。体外稳定性试验表明 ,在 37℃人血清放置 10h ,干扰素α 2b只保留 35 % ,单修饰干扰素α 2b保留 71% ,而多修饰干扰素α 2b仍保留 95 %的抗病毒活性。结论聚乙二醇修饰可以增加干扰素α 2b的稳定性 ,抗胰蛋白酶水解能力和 37℃人血清稳定性。除了抗胰蛋白酶水解能力 ,修饰度的增加能够明显增强这种作用     

聚乙二醇干扰素治疗慢性乙型肝炎的不良反应分析

目的:研究聚乙二醇干扰素治疗慢性乙型肝炎的不良反应。方法:随机选取我院2010年2月～2012年2月住院采用聚乙二醇干扰素治疗的慢性乙型肝炎患者225例,给予患者皮下注射聚乙二醇干扰素180μg,并采用阶梯式加量法逐渐增加聚乙二醇的用量。结果:注射聚乙二醇干扰素后产生的各项不良反应中体温升高、头痛在0～18岁的发生率高于18岁以上;而乏力、眼胀在0～18岁的发生率低于18岁以上。且随着每周阶梯式增加聚乙二醇干扰素的用量,不良反应的发生率则逐渐减少。各组数据比较均具有统计学差异(P<0.05)。结论:采用聚乙二醇干扰素治疗慢性乙型肝炎虽有不良反应发生,但均在可控制可治疗范围内,故在慢性乙型肝炎的治疗中应用聚乙二醇干扰素是安全有效的。     

治疗慢性丙型肝炎的药物研究进展

慢性丙型肝炎是一种慢性传染性疾病,目前的治疗药物和方法不多,其中聚乙二醇干扰素联合利巴韦林是治疗慢性丙肝的标准疗法。聚乙二醇干扰素比普通干扰素具有更长的半衰期,具有更好的疗效和耐受性。国内市场上已有的聚乙二醇干扰素有派罗欣和佩乐能两种,但一些副作用限制了其使用,因此,迫切需要开发新的药物,目前有以下治疗慢性丙型肝炎的新的药物正在开发研究中。     

聚乙二醇干扰素α-2a治疗HBeAg阳性慢性乙型肝炎疗效分析

目的观察聚乙二醇干扰素α-2a治疗HBeAg阳性慢性乙型肝炎的临床疗效及安全性。方法共收集我院68例HBeAg阳性慢性乙型肝炎患者,随机分为A、B两组各34例分别给予聚乙二醇干扰素α-2a和普通干扰素α-2a治疗,于治疗24周和48周时,检测两组HBV血清学标志物及血清ALT变化,并记录不良反应。结果治疗24周、48周时,A组血清HBeAg阴转率、ALT复常率均明显高于B组,差异有统计学意义(P<0.05)。结论聚乙二醇干扰素α-2a治疗慢性乙型肝炎疗效优于普通干扰素,且用药简单、方便,从而改善患者的依从性,以确保其疗效。     

新方法活化聚乙二醇修饰细胞因子类药物

文章提供一种活化聚乙二醇的新方法。其主要步骤是先把聚乙二醇两端的两个羟基转化为羧基,然后在活化两个羧基的同时,用含有氨基的试剂将其中的一个活化端封闭,从而造成单端活化的状态,使之适合对蛋白质等物质进行修饰反应。使用该方法活化的分子质量为10ku的聚乙二醇修饰了重组人白细胞介素2,分子质量为12ku的聚乙二醇修饰了重组人干扰素α2b,取得了较好的修饰效果。     

聚乙二醇干扰素治疗慢性丙型肝炎有效性的Meta分析

目的：系统评价聚乙二醇干扰素基于中国人群治疗慢性丙型肝炎的有效性。方法：检索数据库2004~2014年公开发表的聚乙二醇干扰素治疗慢性丙型肝炎的国内临床试验，以患者持续病毒学应答（SVR）获得率作为临床结果指标进行Meta分析。结果：观察组与对照组SVR获得率有显著差异，其中聚乙二醇干扰素α-2a组SVR获得率有显著差异，聚乙二醇干扰素α-2b组SVR获得率无显著差异。结论：聚乙二醇干扰素可以显著提高中国慢性丙型肝炎患者SVR获得率。其中聚乙二醇干扰素α-2a更具有效性，但聚乙二醇干扰素α-2b安全性更高。     

Renal metabolism of homologous serum interferon

The metabolic behaviour of homologous native and desialylated serum and urinary interferons has been investigated by using an isolated and perfused rabbit kidney, the performance of which is comparable to that in vivo. Serum native and urinary interferons disappear from the plasma perfusate with a fractional turnover rate of 1.8 and 2% and half-lives of 37 and 35 min, respectively. Serum desialylated interferon disappears much more rapidly in keeping with the finding that the glomerular sieve poses less steric hindrance and electrophysical repulsion to the passage of less anionic proteins.These results confirm and extend our previous findings, which indicated that the kidneys have a predominant catabolic role and can explain to some extent the rapid disappearance of interferon from plasma.     

Pulmonary catabolism of interferons: alveolar absorption of 125I-labeled human interferon alpha is accompanied by partial loss of biological activity

The catabolism of interferon was examined in isolated rabbit lungs which were ventilated and perfused with homologous blood. Natural human interferon-alpha (HuIFN-alpha) from lymphoblastoid Namalwa cells or recombinant DNA-derived HuIFN-alpha 2 were labeled with 125I, mixed with an excess of the respective cold interferons and added to the perfusion blood. Protein-bound and acid-soluble radioactivity, as well as antiviral activity, were measured at regular time intervals. During the first 3 h of perfusion, only very small fractions of the interferons disappeared from the perfusate, irrespective of whether lungs were inserted in the perfusion system. This indicated that catabolism of interferons in the pulmonary circulation was negligible. On the other hand, when the interferons were instilled into the bronchial-alveolar tree, absorption of antiviral activity differed from that of acid-precipitable protein-associated radioactivity. While most of the radioactivity was transferred into the perfusate, only 2% of antiviral activity of natural HuIFN-alpha and 30% of that of HuIFN-alpha 2 were recovered in the perfusate. In both cases acid-soluble radioactivity in the system reached about 10%. Since radioiodide, instilled in the bronchial-alveolar tree, was transported rapidly into the perfusate, this type of analysis did not help in locating the site(s) of degradation. Alveolar macrophages did not catabolize or inactivate interferons in vitro.     

Potentiation of interferon action by mixtures of recombinant DNA-derived human interferons

Natural and essentially pure recombinant DNA-derived HuIFN-alpha and HuIFN-gamma were examined for their relative abilities to potentiate interferon action. Potentiation of human interferon's antiviral and antiproliferative activities were studied. The essentially pure recombinant DNA-derived human interferons were found to be as effective in their potentiating interactions as their natural counterparts. The results demonstrate that it is the human interferons themselves which interact to potentiate human interferon's varied activities.     

治疗性单克隆抗体类制品质量控制标准的思考

治疗性单克隆抗体制品在肿瘤、自身免疫、器官移植和感染性疾病的治疗中均取得了显著疗效,其品种和市场份额逐年显著提高。随着新的治疗性单克隆抗体制品的研发和上市,不同产品的质量控制研究,特别是新技术在质量控制中的应用被提到新的高度。由于治疗性单克隆抗体制品结构和生产的复杂性,使得质量控制的复杂程度也相应提高。本文结合治疗性单克隆抗体质量控制的工作经验和国际上的最新进展,对治疗性单克隆抗体质量控制项目设定、标准和方法进展进行论述。     

干扰素-α及长效干扰素抗肝炎病毒作用机制的研究进展

干扰素-α是治疗慢性病毒性肝炎的主要药物之一,可通过影响肝细胞Jak-STAT信号通路,促进2′-5′-OAS、PKR和MxA等蛋白的生成发挥抗肝炎病毒作用。干扰素-α还可通过影响MAPK通路、IRS-1/PI3K-p70S6激酶通路等信号转导通路发挥作用。为延长其半衰期、增强疗效,目前已开发出多种长效干扰素,如聚乙二醇干扰素、人血清白蛋白融合干扰素、干扰素脂质体等,并有逐渐取代普通干扰素的趋势。开发出长效、高效的干扰素也越来越成为干扰素及病毒性肝炎治疗的重要发展方向。     

Potentiating effect of murine interferon-gamma-containing lymphokine preparations on the antiviral and antiproliferative effects of murine interferon-alpha/beta: identification of the potentiation factor as murine interferon-gamma itself

Mixed preparations of murine interferon-gamma (MuIFN-gamma) and murine interferon-alpha/beta (MuIFN-alpha/beta) have been shown to induce more than additive levels of antiviral protection, when compared to those induced by these interferons given separately. MuIFN-gamma preparations contain many lymphokines and several of these as well as MuIFN-gamma itself may participate in this potentiation. In the present study, natural as well as three recombinant DNA-derived MuIFN-gamma's, in combination with antibody to MuIFN-gamma have been employed to examine the precise role of MuIFN-gamma. The antiviral effect was examined with a single cycle virus yield reduction assay and the antiproliferative effect with a colony formation inhibition assay. Recombinant DNA-derived MuIFN-gamma was as effective as natural MuIFN-gamma at participating in the potentiation of both the antiviral and antiproliferative activities. Antibody to MuIFN-gamma effectively blocked the potentiation of both the antiviral and the antiproliferative activities of natural and recombinant DNA-derived MuIFN-gamma's. Since the recombinant DNA-derived preparations from E. colie can be assumed not to contain mammalian proteins other than MuIFN-gamma, the data conclusively demonstrate that the potentiation factor in MuIFN-gamma preparations is MuIFN-gamma itself.     

药物中有关物质的色谱分析研究近况

综述近年来药物中有关物质检查的色谱分析技术及其应用,比较了各种方法的优缺点,并简要介绍了对药物中有关物质进行检查、结构分析的一般流程。药物中的有关物质与药物的质量密切相关,对有关物质的检测和控制也显得愈发重要。     

Developments in the treatment of chronic hepatitis C

Hepatitis C virus is the most common chronic, blood-bourne infection, affecting 170 million people worldwide, approximately 3% of the global population. Of those infected with hepatitis C virus, 50 – 85% will develop chronic hepatitis C. Although hepatitis C is primarily a disease of the liver, a diagnosis is currently defined by the presence of the hepatitis C virus and treatment success is defined by the clearance of the virus. IFN-α is currently the mainstay of chronic hepatitis C therapy; the antiviral and anti-inflammatory components of IFN target both the infectious and the hepatic manifestations of the disease. However, even in combination with ribavirin, interferon therapy is not fully efficacious. Recently, the search for a more effective treatment has led investigators to optimise interferon therapy by developing pegylated interferons. Challenges facing our current treatment of hepatitis C virus include lack of efficacy in patients with difficult-to-treat disease, such as patients with cirrhosis or infected with hepatitis C virus genotype 1 (who represent a majority of US hepatitis C virus infections), the toxicity of combination therapy, the expense and difficulty of therapy and the poor reception of these treatments by many patients. The development of new hepatitis C antiviral agents is critical to our management of this disease. A number of approaches are under investigation, including long-acting interferons, immunomodulators, antifibrotics, specific hepatitis C virus-derived enzyme inhibitors, drugs that either block hepatitis C virus antigen production from RNA or prevent normal processing of hepatitis C virus proteins and other molecular approaches to treating hepatitis C virus, such as ribozymes and antisense oligonucleotides.     

Computer-assisted analysis demonstrates that polypeptides induced by natural and recombinant human interferon-alpha are the same and that some have related primary structures

The biological effects on diploid and trisomy 21 human fibroblasts of pure human interferon IFLrA, a single IFN-alpha species produced from cloned DNA, were compared with those of partially purified natural IFN-alpha. Twelve interferon-induced polypeptides were visualized by two-dimensional gel electrophoresis and autoradiography. Seven of these were shown to have related primary structures and are therefore products of related genes or are related through post-translational modification. Qualitative visual comparisons and computer-aided quantitation of autoradiograms revealed no differences in the patterns of polypeptide induction following treatment with the two types of IFN-alpha, and the two interferons also induced (2'-5') oligoisoadenylate synthetase equally. By these criteria, the activities of the two interferons are qualitatively and quantitatively indistinguishable. In addition, the effects of trisomy 21 on IFLrA-induced polypeptide synthesis and on antiviral response were similar to those previously demonstrated with natural IFN-alpha.     

中成药中牛黄的检测研究

目的：探讨中药质量标准研究的有关问题。方法：分析牛黄药材的应用及含牛黄中成药质量准研究的现状。结果：针对牛黄类药材及含牛黄类药材的制剂检测存在的不足建议进行有针对的质量标准研究。结论：中成药质量标准的研究是一项与时俱进的研究,应制定出能更好的控制药品质量的标准。