抗侵袭性真菌感染单克隆抗体研究进展

近20多年来,随着免疫缺陷患者的增多,侵袭性真菌感染发病率呈持续上升趋势,死亡率高居不下。现用的抗真菌药物主要有氮唑类、多烯类、棘白菌素类等,存在品种少、真菌耐药性增加和毒副作用大等问题,迫切需要研制新型抗真菌药物。单克隆抗体具有精准靶向的抗真菌作用,兼有调节机体免疫反应的功能,是治疗真菌感染的一种可行且具有独特优势的药物。从作用靶点分类,可以分为靶向真菌表面多糖、毒力因子、蛋白和跨界抗真菌单克隆抗体。从抗体来源分类又可以分为天然抗体和重组抗体。其作用机制包括直接抗真菌作用,即对毒素中和或对真菌的直接抑制作用;以及免疫增强作用,主要是补体的活化以驱动吞噬细胞清除或破坏致病真菌、中性粒细胞调理吞噬作用的激活以及诱导巨噬细胞调理吞噬。本文从药效学等方面总结了目前抗真菌感染单克隆抗体的研究进展,以及存在的问题。此外,针对抗真菌单克隆抗体的新型制备方法与传统制备方法进行了对比,并探讨了未来的发展方向。     

他汀类药物治疗真菌感染研究进展CSCD

近年来,由于广谱抗生素、免疫抑制剂等广泛应用以及肿瘤放化疗、艾滋病等免疫功能低下患者增多,深部真菌感染发生率逐年上升,据统计,全球每年约有150万例致命真菌感染,远高于疟疾、乳腺癌或前列腺癌[1-2]。在我国,白念珠菌(Candida albicans)是引起深部真菌感染最主要的条件致病菌,经抗真菌药物治疗后,死亡率仍高达40%至50%[3]。目前常用的抗真菌药物主要有三类:抑制甾醇合成(氮唑类和烯丙胺类),影响细胞壁(两性霉素和棘白菌素类)和抑制DNA合成(氟胞嘧啶)[4]。     

侵袭性真菌感染治疗新进展

随着免疫受损人群的增多,近年来侵袭性真菌感染的发生率逐渐升高,由此导致的致病率也逐年上升.如何及时诊断并有效的治疗侵袭性真菌感染已成为临床上面临的挑战之一.该文就侵袭性真菌感染的流行病学、病因学及现有的治疗策略等方面进行综述.     

侵袭性真菌感染的流行病学和诊断研究进展

伴随着侵袭性真菌感染(Invasive fungal infection,IFI)的迅猛增长,逐渐认识到对许多真菌诊断的重要性,本文就侵袭性真菌感染的流行概况、危险因素以及传统和新近发展的诊断方法作一综述。     

艾滋病合并侵袭性真菌感染35例临床分析

目的 分析艾滋病(AIDS)合并侵袭性真菌感染的发生情况及临床特点,为其诊治提供参考。方法 回顾性分析85例AIDS患者的临床资料,总结侵袭性真菌感染的发病情况及临床特点。结果 85例AIDS患者继发侵袭性真菌感染35例,感染率为41．2％,感染部位以消化道为主,占44．4％,致病菌以白念珠菌(白假丝酵母)为主,占57．4％,侵袭性真菌感染病例主要发生于CD4~+T淋巴细胞计数＜100个/μl的患者,占71．8％。35例患者中27例治愈,8例死亡。结论 侵袭性真菌感染是AIDS患者主要的机会性感染之一,其发生与CD4~+T淋巴细胞计数密切相关,临床上以消化道真菌感染多见,侵袭性真菌感染的病死率高。     

糖皮质激素与侵袭性真菌感染

糖皮质激素(激素)是诱发真菌感染、特别是机会性真菌感染重要的因素,可通过抑制免疫反应的多个环节而影响真菌感染的发生与进程.内源性激素相关的疾病如Chushing综合征的患者,以及医源性皮质激素使用的患者均可成为真菌感染的易患人群.正确理解糖皮质激素免疫抑制作用和真菌感染发生的相互关系,可以提高对相关真菌感染的认识并针对性开展防治策略,改善激素应用条件下发生真菌感染的预后.     

艾滋病患者侵袭性真菌感染的治疗

艾滋病患者由于严重免疫缺陷而易于并发各种机会感染和肿瘤。高效抗反转录病毒联合治疗(HAART)的出现明显改善了艾滋病患者的预后,提高了患者生存质量,随着HAART在临床的广泛使用,艾滋病患者出现各种机会感染包括侵袭性真菌感染的概率大大降低。然而,由于我国艾滋病患者明确诊断时大多处于疾病晚期,机体免疫功能极低;部分患者尽管接受了HAART,但是由于依从性、病毒耐药性等原因导致患者未能出现良好的应答反应,患者的免疫功能仍未能得到     

正确认识,合理对待——浅谈侵袭性真菌感染

随着侵袭性真菌感染(invasive fungal infec-tion,IFl)的日益多见和危害频繁,国内外广为重视。在2007年3月15日至17日的我国第二届深部真菌感染会议上,各科医生对此颇多讨论。现归纳欧洲癌症研究和治疗组织/侵袭性真菌感染协作组(EORTC/FICG)和美国国家变态反应和感染病研究所真菌研究组(NIAlDMSG)有关专家制定IFI临床研究的诊断标准(Clin lnfect Dis,2003,34:7-12)以及2005年中华内科杂志(2005,44:554)根据中国侵袭性真菌感染工作组制定的对血液病和恶性肿瘤患者的诊断标准与治疗原则。他山之石可以攻玉,我们希望在实践中能制定…     

米卡芬净治疗重症侵袭性真菌感染40例的临床分析

目的评价米卡芬净治疗重症侵袭性真菌感染患者的疗效和安全性。方法采用回顾性分析2007年12月~2009年6月大连医科大学附属二院ICU病房40例侵袭性真菌感染患者应用米卡芬净治疗的临床资料。结果40例患者中,痊愈10例(25%),显效18例(45%),总有效率为70%,真菌清除率为60.8%,不良反应少,所有患者均耐受治疗。结论米卡芬净治疗重症侵袭性真菌感染安全、有效。     

6种抗真菌药物对皮肤癣菌体外抗真菌活性评价

目的评价6种抗真菌药物对皮肤癣菌体外抗真菌活性。方法采用CLSI推荐的M-38P方案对分离自足癣和体、股癣的皮肤癣菌进行联苯苄唑、硝酸舍他康唑、硝酸异康唑、盐酸布替萘芬、阿莫洛芬、利拉萘酯6种抗真菌药物敏感性测定。结果联苯苄唑MIC范围为0．03—4mg／L,MIC50为1mg／L,MIC90为2mg／L。硝酸舍他康唑分别为0．06—16mg／L、0．5mg／L和2mg／L。硝酸异康唑分别为0．03～2mg／L、0．25mg／L和0．5mg／L。盐酸布替萘芬分别为0．0025～0．04mg／L、0．01mg／L和0．02mg／L。阿莫罗芬分别为0．01～〉0．08mg／L、0．02mg／L和0．04mg／L。利拉萘酯分别为0．004—0．625mg／L、0．039mg／L和0．312mg／L。结论6种抗真菌药物对皮肤癣菌均有强的抗菌活性,由强到弱依次为布替萘芬、阿莫罗芬、利拉萘酯和咪唑类药物。     

抗真菌药物增效剂的研究进展

近年来,真菌耐药发生率呈逐年上升趋势,真菌对氟康唑等氮唑类药物的耐药性最为严重,成为临床抗真菌治疗失败的原因之一.对于耐药真菌的治疗,往往采用加大剂量或联合用药的方法.此外,文献报道了一些植物提取物、小分子化合物能显著增强抗真菌药物对耐药真菌的敏感性,两个药物的协同作用有望成为治疗耐药真菌的新策略.该文结合近几年的研究报道,简要综述了抗真菌药物增效剂的研究进展.     

北京朝阳医院深部真菌感染的临床分析和药敏试验

目的对院内临床深部真菌感染的标本进行分离鉴定和药敏试验,为临床感染性疾病提供病原学诊断和合理使用抗真菌药物的依据。方法采用念珠菌显色培养基进行鉴定。对真菌(丝状菌)用棉蓝染色直接镜检和培养相结合的方法进行鉴定。采用纸片扩散法进行药敏试验。结果450株真菌标本中,念珠菌396株,占88.0%;真菌(丝状菌)54株,占12.0%。分离菌株对药物的敏感性分别为氟康唑90.15%,两性霉素B97.98%,伊曲康唑91.67%,氟胞嘧啶89.1%。结论院内真菌感染以念珠菌最为多见,特别是白念珠菌和热带念珠菌。     

作用于细胞壁的抗真菌药物研究进展

与人类细胞相比,细胞壁为真菌的特有结构,因此作用于细胞壁的抗真菌药物相较于其他类型抗真菌药物而言具有高效、低毒的特点,是迄今为止安全性最高的一类抗真菌药物。本文对作用于细胞壁的抗真菌药物进行综述,根据作用机制及靶点的不同分别介绍葡聚糖合成酶抑制剂、几丁质合成酶抑制剂及糖基磷脂酰肌(glycosylphosphatidylinositol,GPI)锚定蛋白抑制剂,对其进行总结和归纳,为相关药物的研发及将来的临床应用前景提供参考。     

Comparative study of four antifungal drugs in an experimental model of murine cryptococcosis

A comparative study among amphotericin B, 5-fluorocytosine, itraconazole and fluconazole in the treatment of experimental cryptococcosis in mice, was carried out.Seventy male Balb C mice were inoculated intraperitoneally with 10⁷ cells of Cryptococcus neoformans var. neoformans. They were divided in 7 groups of 10 animals each one: 1) treated with fluconazole by gavage at a daily dose of 16 mg/kg; 2) treated with itraconazole by gavage at a daily dose of 16 mg/kg; 3) treated with 5-fluorocytosine by gavage at a daily dose of 300 mg/kg; 4) treated with amphotericin B intraperitoneally at a dose of 6 mg/kg every other day; 5) control animals receiving polietilenglicol 200 by gavage; 6) control animals receiving distilled water by gavage and 7) control animals receiving sterile distilled water by intraperitoneal route. All the treatments started 5 days after the challenge inoculation and they were given for 2 weeks.The following parameters were taken into account: survival time, macroscopic aspect of the organ after the complete autopsy, microscopic investigation of yeasts in brain, lungs, spleen and liver, histopathology studies of these organs, the colony forming units per gram and massive seeding of brain and lungs.The survival index of the different groups was the most efficient method to measure the antifungal compounds activity. Amphotericin B increased significantly the animals survival and modified the histopathologic response in the studied organs. The colony forming units and the massive seeding in brain and lung showed that this antifungal agent is unable of producing the biological cure of this experimental model.The remaining drugs assayed did not promote important modifications in the histopathologic picture as well as in the tissues cultures. However, the three drugs increased the animals survival. In this aspect, fluconazole proved to be slightly superior.     

Synthesis and anticonvulsant activity of new N-mannich bases derived from benzhydryl- and isopropyl-pyrrolidine-2,5-dione

Synthesis and anticonvulsant properties of 26 new N-Mannich bases of 3-benzhydryl-(5–17) and 3-isopropyl-pyrrolidine-2,5-diones (18–30) have been described. Initial anticonvulsant screening for these compounds was evaluated in mice after intraperitoneal administration in the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The acute neurological toxicity was determined by applying the rotorod test. The in vivo results in mice showed that the majority of 3-benzhydryl-pyrrolidine-2,5-dione derivatives revealed effectiveness, while 3-isopropyl-pyrrolidine-2,5-dione derivatives were practically devoid of activity. The quantitative evaluation in both tests revealed that the most active were N-[{4-(3-chlorophenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (9) with ED_{5 0} value?=42.71?mg/kg (MES), ED_{5 0} value?>150?mg/kg (scPTZ), and N-[{4-(3-trifluoromethylphenyl)-piperazin-1-yl}-methyl]-3-benzhydryl-pyrrolidine-2,5-dione (13) with ED_{5 0} value?=101.46?mg/kg (MES) and ED_{5 0} value?=72.59?mg/kg (scPTZ). These molecules showed higher potency and lower neurotoxicity than the reference antiepileptic drugs (ethosuximide and valproic acid). To explain the probable mechanism of action of selected active derivatives (9 and 13), their influence on Na_v1.2 and l-type calcium channel was evaluated in vitro.     

Role of racemization in optically active drugs development

U.S. Food and Drug Administration issues certain guidelines for marketing of optically active drugs as some enantiomers racemize into human body, leading to the generation of other antipodes, which may be toxic or ballast to the human beings. Moreover, racemization reduces the administrated dosage concentration as optically active enantiomer converted into its inactive counter part. Therefore, the study of racemization of such type of drugs is an important and urgent need of today. This article describes in vitro and in vivo racemization of optically active drugs. The racemization process of various optically active drugs has been discussed considering the effect of different variables i.e. pH, temperature, concentration of the drug, ionic concentration, etc. Attempts have also been made to discuss the mechanisms of racemization. Besides, efforts have been made to suggest the safe dosages of such type of drugs too.     

基于新靶点的抗真菌药物研究进展

侵袭性真菌感染的发病率正逐年上升。现有抗真菌药物由于抗菌谱有限、副作用大等原因,致使临床应用受限。因此,基于新靶点的抗真菌药物成为治疗真菌感染的迫切需要。近年来,抗真菌药物研究取得较大进展。其中,抑制真菌细胞壁合成的药物（如E1210和D11?2040）、抑制蛋白激酶或蛋白磷酸酶信号通路的药物（如KP?372?1、17?AAG、Mycograb）、靶向真菌毒力因子的单克隆抗体（如C7、213 Bi?18B7、188 Re?18B7）、激活宿主免疫系统的疫苗[如PEV7和β?（ Man）3?Fba?TT]等,正引起人们的关注。