治疗慢性丙型肝炎新药——聚乙二醇干扰素α-2b

目的:介绍治疗慢性丙型肝炎新药聚乙二醇干扰素α-2b的有效性和安全性.方法:检索国外有关文献,进行文献综述.结果:表明聚乙二醇干扰素α-2b是目前治疗慢性丙型肝炎最有效的药物之一,与利巴韦林合用可明显提高疗效.该药最常见的不良反应为流感样综合征和血液学毒性反应.结论:聚乙二醇干扰素α-2b值得临床推广应用,但须注意其不良反应.     

聚乙二醇干扰素α2b质控方法探讨

目的：采用分子量为30KD的聚乙二醇（PEG）对干扰素α2b进行N端定点修饰获得聚乙二醇干扰素α2b（PEG—IFNα2b）．并建立PEG—IFNα2b的质控方法。方法：采用Wish细胞-VSV病毒系统,以细胞病变抑制法（CPE）测定PEG—IFNα2b的生物学活性,Lowry法测定蛋白含量,SDS-聚丙烯酰胺凝胶电泳法测定相对分子质量,高效液相凝胶过滤色谱法测定纯度,胰蛋白酶消化法测定肽图,紫外分光光度法测定紫外吸收光谱,地高辛（DIG）标记的核酸探针法测定外源性DNA残留量,ELISA法测定宿主茵菌体蛋白残留量。结果：聚乙二醇干扰素α2b的比活性为1．39×10^7IU·mg^-1蛋白,蛋白含量为420μg·ml,相对分子质量约为65000道尔顿,纯度超过99．0％,紫外最大吸收峰约在278nm波长处,外源性DNA残留量小于100pg／剂量,宿主菌菌体蛋白残留量为0．01027％。结论：该质控方法可用于聚乙二醇干扰素α2b的检定。     

苦参素联合聚乙二醇α-2b干扰素治疗慢性乙型肝炎临床观察

目的：观察苦参素联合聚乙二醇α-2b干扰素治疗慢性乙型肝炎的临床疗效及安全性。方法对入选的120例患者按照不同治疗方法分为三组，每组40例，分别给予聚乙二醇α-2b干扰素（A组）、苦参素（B组）和聚乙二醇α-2b 干扰素联合苦参素（C 组）治疗，观察治疗后12、24周各组疗效及不良反应。结果12周、24周时C 组完全反应率均高于 A 组和 B 组，差异有统计学意义。而 A 组与 B 组相比，12周及24周的完全反应率无明显差异。结论慢性乙型肝炎治疗后患者完全反应率的提高及安全性良好现象，可能与应用苦参素联合聚乙二醇α-2b干扰素治疗有关，值得进一步临床研究。     

聚乙二醇干扰素α-2a注射液致严重自身免疫性溶血性贫血一例的药学实践

通过对1例聚乙二醇干扰素α-2a注射液致严重自身免疫性溶血性贫血不良反应的病例分析,提高对合理用药重要性的认识。临床药师根据Naranjo和WHO因果关系评价系统2种不良反应评价方法对此进行评估,及时停用聚乙二醇干扰素α-2a注射液,采用一线治疗药物糖皮质激素进行治疗。患者经过静脉滴注注射用甲泼尼龙琥珀酸钠80 mg/d,10 d后,贫血症状改善,网织红细胞计数降低,好转出院。治疗过程中,临床药师通过查阅国内外文献及指南,结合患者具体病情,在治疗药物选择和用药监护中发挥相应作用,为今后合理使用聚乙二醇干扰素α-2a注射液提供参考。     

欧盟批准聚乙二醇干扰素α-2b与利巴韦林联用治疗丙型肝炎病毒感染

欧委会于2007-11—15批准聚乙二醇干扰素α-2b（PegIntron或Rebetol，由Schering—Plough Corp生产）注射液与利巴韦林（ribavirin）片剂联用，治疗对干扰素-α＋利巴韦林联合治疗未获得持续应答的成年慢性丙型肝炎病毒（HCV）感染患者。     

聚乙二醇干扰素α-2a联合利巴韦林治疗丙型肝炎肝硬化的疗效观察

目的对应用聚乙二醇干扰素α-2a与利巴韦林联合对患有丙型肝炎肝硬化的患者实施治疗的临床效果进行研究。方法抽取86例患有丙型肝炎肝硬化的患者,随机分为对照组和治疗组,平均每组43例。采用利巴韦林对对照组患者实施治疗;采用聚乙二醇干扰素α-2a与利巴韦林联合对治疗组患者实施治疗。结果治疗组患者丙型肝炎肝硬化病情治疗效果明显优于对照组;丙肝肝硬化控制时间和实际临床用药时间明显短于对照组。结论应用聚乙二醇干扰素α-2a与利巴韦林联合对患有丙型肝炎肝硬化的患者实施治疗的临床效果非常明显。     

探讨聚乙二醇干扰素α-2a与胸腺肽α1对于慢性乙型肝炎患者产生的影响

目的研究聚乙二醇干扰素α-2a与胸腺肽α_1对于慢性乙型肝炎患者产生的影响。方法选取我院2012年6月至2015年8月收治的HBeAg阳性的慢性乙型肝炎患者100例为研究对象,根据患者不同的临床治疗的方式,将患者分成两组,对照组采用聚乙二醇干扰α-2a进行治疗,观察组采用聚乙二醇干扰素α-2a联合胸腺肽α_1进行治疗,对比治疗效果。结果相对于对照组,观察组的HBeAg血清转换率、HBsAg清除、ALT复常率以及HBV-DNA阴转率要高。结论聚乙二醇干扰素α-2a与胸腺肽α_1治疗慢性乙型肝炎的效果显著,在临床上值得广泛推广。     

护理沟通技巧对聚乙二醇聚α-2a抗病毒治疗乙型肝炎患者临床疗效的相关性

目的:评价护理沟通技巧护理对聚乙二醇聚乙二醇干扰素α-2aα-2a抗病毒治疗乙型肝炎(CHB)患者临床疗效的相关性。方法:选取2013年3月—2015年3月间收治的乙型肝炎患者93例作为研究对象,按照随机数字表法将其分为观察组患者(n=47)与对照组患者(n=46);对照组患者均给予聚乙二醇聚乙二醇干扰素α-2aα-2a和常规护理治疗,观察组患者均给予聚乙二醇聚乙二醇干扰素α-2aα-2a治疗并采用护理沟通技巧护理治疗,比较两组患者服药前后治疗依从性、HBV-DNA阴转率及治疗前后HBe Ag定量值。结果:观察组患者治疗依从性与HBV-DNA阴转率分别为91.49%和74.47%,高于对照组为76.09%和54.35%(P<0.05);两组患者治疗前HBe Ag定量与对照组比较其差异无统计学意义(P>0.05);治疗后观察组患者HBe Ag定量低于对照组(P<0.05),提示观察组患者病情得到更大幅度缓解。结论:聚乙二醇聚乙二醇干扰素α-2aα-2a对乙型肝炎患者抗病毒治疗过程中,采用护理沟通技巧护理有利于提高患者治疗依从性和临床疗效。     

聚乙二醇化干扰素α-2a治疗HBeAg阴性的慢性乙肝药物经济学分析

目的：探讨聚乙二醇化干扰素α-2a治疗HBeAg阴性的慢性乙型肝炎的临床效果和经济效果。方法：运用成本-效果分析法对48例HBeAg阴性的慢性乙型肝炎患者分别用聚乙二醇化干扰素α-2a和干扰素两种方案治疗的结果进行比较。结果：聚乙二醇化干扰素组疗效对比干扰素组有显著差异，且成本-效果比较低。结论聚乙二醇化干扰素α-2α作为一种新型抗病毒药物，治疗HBeAg阴性的慢性乙型肝炎具有较好的成本-效果比，有着良好的发展前景。     

聚乙二醇干扰素α-2a与利巴韦林联合方案治疗慢性丙型肝炎的疗效分析

目的观察聚乙二醇干扰素α-2a与利巴韦林联合方案治疗慢性丙型肝炎的疗效。方法选择2008年10月至2011年2月就治于我科的慢性丙型肝炎患者144例为研究对象,随机进行分组,实验组(聚乙二醇干扰素α-2a与利巴韦林联合方案治疗组)73例,对照组(单纯聚乙二醇干扰素α-2a组)71例,观察治疗效果。结果实验组持续应答率为53.4%,明显比对照组高,经χ2检验,P<0.05,差异明显;并发症发生率为12.3%,与对照组比较差异不明显,经χ2检验,P>0.05。结论聚乙二醇干扰素α-2a与利巴韦林联合方案治疗慢性丙型肝炎的疗效优于单纯应用聚乙二醇干扰素α-2a的患者,同时两药合用并未增加药物不良反应的发生率,是目前治疗慢性丙型肝炎的最佳方案。     

Emerging PEGylated drugs

PEGylation is a pharmaceutical technology that involves the covalent attachment of polyethylene glycol (PEG) to a drug to improve its pharmacokinetic, pharmacodynamic, and immunological profiles, and thus, enhance its therapeutic effect. Currently, PEGylation is used to modify proteins, peptides, oligonucleotides, antibody fragments, and small organic molecules. Research groups are striving to improve the consistencies of PEGylated drugs and to PEGylate commercialized proteins and small organic molecules. Furthermore, the PEGylations of novel medications, like oligonucleotides and antibody fragments, are being pursued to improve their bioavailabilities. This active research in the PEGylation field and the continued growth of the biopharmaceutical market predicts that PEGylated drugs have a bright future.     

药物聚乙二醇化的研究进展

聚乙二醇化是化学分子变构中重要的技术之一,是药物研究和开发的里程碑。本文介绍了聚乙二醇修饰药物的优化条件以及优化后药物在体内药动学和药效学等性质的改变,举例说明聚乙二醇化技术在蛋白多肽及纳米脂质体等方面的研究应用,并展望聚乙二醇修饰技术在国内外医药领域的应用前景。     

PEG-modified biopharmaceuticals

PEGylation is a process in which one or more units of chemically activated polyethylene glycol reacts with a biomolecule, usually a protein, peptide, small molecule or oligonucleotide, creating a putative new molecular entity possessing physicochemical and physiological characteristics that are distinct from its predecessor molecules. In recent years, PEGylation has been used not only as a drug delivery technology but used also as a drug modification technology to transform existing biopharmaceuticals clinically more efficacious than before their PEGylation. PEGylation bestows several useful properties upon the native molecule, resulting in improved pharmacokinetic and pharmacodynamic properties, which in turn enable the native molecule to achieve maximum clinical potency. In addition, PEGylation results in sustained clinical response with minimal dose and less frequency of dosing, leading to improved quality of life via increased patient compliance and reduced cost. During the course of development of various pegylated protein therapeutics, several new insights have been gained. This review article focuses on the approaches, strategies and the utilization of modern PEGylation concepts in the design and development of well-characterized pegylated protein therapeutics.     

PEGylation of proteins and liposomes: a powerful and flexible strategy to improve the drug delivery

PEGylation is one of the most successful strategies to improve the delivery of therapeutic molecules such as proteins, macromolecular carriers, small drugs, oligonucleotides, and other biomolecules. PEGylation increase the size and molecular weight of conjugated biomolecules and improves their pharmacokinetics and pharmacodinamics by increasing water solubility, protecting from enzymatic degradation, reducing renal clearance and limiting immunogenic and antigenic reactions. PEGylated molecules show increased half-life, decreased plasma clearance, and different biodistribution, in comparison with non-PEGylated counterparts. These features appear to be very useful for therapeutic proteins, since the high stability and very low immunogenicity of PEGylated proteins result in sustained clinical response with minimal dose and less frequent administration. PEGylation of liposomes improves not only the stability and circulation time, but also the 'passive' targeting ability on tumoral tissues, through a process known as the enhanced permeation retention effect, able to improve the therapeutic effects and reduce the toxicity of encapsulated drug. The molecular weight, shape, reactivity, specificity, and type of bond of PEG moiety are crucial in determining the effect on PEGylated molecules and, at present, researchers have the chance to select among tens of PEG derivatives and PEG conjugation technologies, in order to design the best PEGylation strategy for each particular application. The aim of the present review will be to elucidate the principles of PEGylation chemistry and to describe the already marketed PEGylated proteins and liposomes by focusing our attention to some enlightening examples of how this technology could dramatically influence the clinical application of therapeutic biomolecules.     

聚乙二醇修饰小分子药物的研究进展

聚乙二醇修饰技术是目前药物化学修饰的研究热点,它能够显著提高药物分子水溶性,同时改善药物的药动学和药效学特性,增加了药物临床应用的范围和疗效,具有较好的开发应用前景;但同时也存在诸多问题,有待改进,目前在国内研究相对较少,值得进一步研究开发。本文从聚乙二醇修饰技术被修饰的小分子药物种类、连接臂类型、聚乙二醇载体以及修饰后药物药动学性质和药效学性质改变等方面进行系统综述。     

What is the future of PEGylated therapies?

The tremendous potential of biologic drugs is hampered by short half-lives in vivo, resulting in significantly lower potency than activity seen in vitro. These short-acting therapeutic agents require frequent dosing profiles that can reduce applicability to the clinic, particularly for chronic conditions. Therefore, half-life extension technologies are entering the clinic to enable improved or new biologic therapies. PEGylation is the first successful technology to improve pharmacokinetic (PK) profiles of therapeutic agents and has been applied in the clinic for over 25 years. Over 10 PEGylated therapeutics have entered the clinic since the early 1990s, and new PEGylated agents continue to expand clinical pipelines and drug patent life. PEGylation is the most established half-life extension technology in the clinic with proven safety in humans for over two decades. Still, it is one of the most evolving and emerging technologies that will be applied for the next two decades.     

Advances in PEGylation of important biotech molecules: delivery aspects

BACKGROUND: Although various injected peptide and protein therapeutics have been developed successfully over the past 25 years, several pharmacokinetic and immunological challenges are still encountered that can limit the efficacy of both novel and established biotech molecules. OBJECTIVE AND METHOD: PEGylation is a popular technique to address such properties. PEGylated drugs exhibit prolonged half-life, higher stability, water solubility, lower immunogenicity and antigenicity, as well as potential for specific cell targeting. Although PEGylated drug conjugates have been on the market for many years, the technology has steadily developed in respect of site-specific chemistry, chain length, molecular weights and purity of conjugate. These developments have occurred in parallel to improvements in physicochemical methods of characterization. CONCLUSION: This review will discuss recent achievements in PEGylation processes with an emphasis on novel PEG-drugs constructs, the unrealized potential of PEGylation for non-injected routes of delivery, and also on PEGylated versions of polymeric nanoparticles, including dendrimers and liposomes.     

Cleavable PEGylation: a strategy for overcoming the “PEG dilemma” in efficient drug delivery

To prolong the circulation time of drug, PEGylation has been widely used via the enhanced permeability and retention (EPR) effect, thereby providing new hope for better treatment. However, PEGylation also brings the "PEG dilemma", which is difficult for the cellular absorption of drugs and subsequent endosomal escape. As a result, the activity of drugs is inevitably lost after PEG modification. To achieve successful drug delivery for effective treatment, the crucial issue associated with the use of PEG-lipids, that is, “PEG dilemma” must be addressed. In this paper, we introduced the development and application of nanocarriers with cleavable PEGylation, and discussed various strategies for overcoming the PEG dilemma. Compared to the traditional ones, the vehicle systems with different environmental-sensitive PEG-lipids were discussed, which cleavage can be achieved in response to the intracellular as well as the tumor microenvironment. This smart cleavable PEGylation provides us an efficient strategy to overcome “PEG dilemma”, thereby may be a good candidate for the cancer treatment in future.     

Pegnology: a review of PEG-ylated systems

Polyethylene glycol conjugation or linking with the system is called PEGylation. Many novel drug systems are used for the delivery of drugs and bioactive substances to particular sites in a controlled or sustained manner, but various side effects or shortcomings restrict their use for the intended purpose. The shortcomings such as RES uptake, drug leakage, immunogenicity, stability, hemolytic toxicity etc. can generally be overcome by PEGylation of novel drug delivery systems such as liposomes, proteins, enzymes, drugs, nanoparticles etc. In this article the whole aspect of PEGylation starting from activation and derivatisation of poly (ethylene glycol) to the linking and designing of systems and their purification and characterization is discussed. The various properties of Pegylated systems are also discussed.