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编号:10275077
新一代三唑抗真菌药活力康唑

     作者:吴绍熙 郭宁如

    单位:(中国医学科学院 中国协和医科大学皮肤病研究所,南京 210042)

    关键词:活力康唑;药效学;曲霉

    中国新药杂志990707 摘要 介绍新一代三唑类抗真菌药活力康唑的临床前和临床研究新进展,尤其是此药的药效学研究结果,为今后临床应用提供参考。

    VORICONAZOLE-A NEW TRIAZOLE ANTIFUNGAL DRUG

    Wu Shaoxi,Guo Ningru

    (Institute of Dermatology,Chinese Academy of Medical Sciences and

    Peking Union Medical College,Nanjing 210042)

    ABSTRACT For clinical reference,the new approaches in pre-clinical and clinical trials of voriconazole,a new triazole antifungal drug,especially results of its pharmacodynamic studies were reviewed.

    KEY WORDS Voriconazole;Itraconazole;Fluconazole;Amphotericin B

    活力康唑(voriconazole,UK109406)是一种最新型的第二代三唑类抗真菌药,是为进一步提高和改进氟康唑的抗菌谱和功效而研制的三唑类抗真菌新药[1],有报告称此药的抗真菌活性10~500倍于氟康唑,而其抗菌谱则类似伊曲康唑,对一些条件致病真菌如曲霉属、隐球菌属及念珠菌属包括对氟康唑耐药的克柔念珠菌和光滑念珠菌(MIC范围可达0.001~0.5 g/ml者)均有抗菌活性。

    活力康唑对曲霉种具杀菌作用,其MIC(最低杀菌浓度)是最低抑菌浓度的2倍[2]。在体外,活力康唑对一些地方流行性真菌如皮炎芽生菌、粗球孢子菌、巴西副球孢子菌及荚膜组织胞浆菌,甚至一些污染真菌如镰刀菌、克林塞支顶孢、扁平赛多孢、毛孢子菌种及波氏赛多孢亦具有抗菌活性[3~6],而这些对氟康唑、伊曲康唑及二性霉素B等不敏感。与这些体外实验相平行的是,在豚鼠体内实验感染中,活力康唑亦有明显疗效和防止致病真菌侵入组织的作用。当与人体感染相似的豚鼠全身感染所引起肺曲霉病时,分别用活力康唑10 mg/kg及8 mg/kg,po,bid,均获治愈,即可使组织内无菌,其效果不管动物免疫状态如何均比用伊曲康唑及4 mg/kg隔日腹腔内注射二性霉素B的效果更为明显[7]。用活力康唑10 mg/kg,po,bid,也可治愈曲霉性心内膜炎,且比相同剂量的伊曲康唑效果为好[2,6,8]

    对免疫功能正常或免疫功能障碍的动物白念珠菌引起的侵袭性念珠菌病,用活力康唑5 mg/kg,po,bid进行治疗,可获氟康唑同样效果[7];而且对氟康唑耐药的白念珠菌、克柔念珠菌和光滑念珠菌所引起的侵袭性感染,活力康唑比氟康唑的疗效更好。活力康唑2.5~20 mg/kg,po,bid对肺及颅内隐球菌病也具有氟康唑同样疗效[9]。最近有材料证明活力康唑对大鼠肺曲霉病(30 mg/(kgd))及兔侵袭性曲霉病(15 mg/(kgd))分别与二性霉素B(4,1 mg/(kgd))[10,11]进行对比研究,其疗效高,药代动力学显示其代谢更快。

    活力康唑已在300名志愿者和患者中口服及静脉注射进行临床应用药代动力学研究[6],全身应用时量效和时效关系不一定成正比。可能是由于第1次应用后即已部分饱和,而且随着用药时间和剂量增加,主要是以代谢产物排出,仅1%以原药由尿排出,口服后生物利用度达90%,其在体内分布可达到2 L/kg,故可持久广泛地分布各种组织和体液内。

    据Ⅱ期临床研究发现,活力康唑对口咽念珠菌病(OPO)及急性和慢性侵袭性曲霉病的疗效满意[8,9,11]。一组双盲、不同剂量(50 mg或200 mg,po,qd或bid)治疗艾滋病患者的口咽念珠菌病研究结果显示,200 mg,po,qd或bid,po组,活力康唑临床有效率达97%~100%,未见明显副作用,只有32例出现可能与用药有关的不良反应,其中6例因此而中止治疗,亦曾见到17例发生与剂量有关的视力障碍(3例为50 mg/d,4例为200 mg/d,10例为bid,po 20 mg/d),其中2例因此而中止治疗,一般表现为对光反应更敏感而有光刺激感,或视力模糊,均为一过性而且完全可以恢复,有的甚至在继续用药时亦可恢复。

    在一组开放、无对照的免疫缺陷患者中试用活力康唑治疗急性侵袭性曲霉病。(其中许多患者曾用二性霉素B或伊曲康唑治疗,其临床症状均未见改善)。

    活力康唑的剂量用6 mg/kg,q12h,iv,bid,5 d,继以3 mg/kg,经6~27 d,再用200 mg/d q12h,iv,bid,经4~24 d,在71例治疗患者中53例可供分析,其中74%(39/53)疗效很好(8例痊愈,17例部分进步,14例病情稳定),而另外26%(14/53)治疗失败,疗效判定是根据临床症状加真菌学和影象学检验的结果。8%的患者(6/71)出现轻至中度视力障碍,但是可不中止用药,6%(4/71)的患者曾因不良反应而中止治疗,其中1例为发生皮疹,3例是由于肝酶升高。

    在一开放、无对照研究中观察活力康唑治疗无中性粒细胞减少的慢性侵袭性曲霉病,其中许多患者曾用过二性霉素B及伊曲康唑均未收到疗效,症状无改善,改用活力康唑200 mg,po,bid,经4~24周,并根据其临床症状和实验室检验进行判断,在25例中可进行分析的13例,69%(9/13)疗效显著,31%(4/13)治疗失败,44%(11/25)有轻至中度视力障碍,但不需要停止用药,有8%(2/25)的患者因肝酶升高而中止治疗。

    总之,从以上材料可知活力康唑具有体外广谱抗真菌活性,口服或静脉注射后血和组织中浓度持续较高,具体表现在上述Ⅱ期临床研究中。因此,此药很快就可进入Ⅲ期临床研究并可与已上市的一些抗真菌药对比,研究其治疗侵袭性曲霉病和其他真菌感染症的疗效。

    参考文献

    1 Dickinson RP,Bell AS,Hitchcock CA,et al.Novel antifungal 2-aryl-1-(1H-1,2,4-triazol-1-yl)butan-2-ol derivatives with high activity against aspergillus fumigatus.Bioorgan Med Chem Lett,1996,65(12)∶2031

    2 Denning D,Favero A,Gluckman E,et al.UK-109,496,a novel,wide-spectrum triazole derivative for the treatment of fungal infections:clinical efficacy in acute invasive aspergillosis.In:Proceedings and abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy.Washington DC:Ammerican Society for Microbiology,1995.126

    3 Espinel-Ingroff A.Evaluation of the in vitro activity of the newtriazole voriconazole against opportunistic filamentous fungi.In:Proceedings and abstracts of the 36th Intersciences Conference on Antimicrobial Agents and Chemotherapy.Washington DC:American Society for Microbiology,1996.114

    4 Sutton DA,Fothergill AW,Barchiesi FJ,et al.In vitro activity of voriconazole against dimorphic fungi.In:Proceedings and abstracts of the 36th Intersciences Conference on Antimicrobial Agents and Chemotherapy.Washington DC:American Society for Microbiology,1996.114

    5 Radford SA,Johnson EM,Warnock DW.In vitro studies of activity of voriconazole[UK-109,496],a new triazole antifungal agent,against emerging and less common mould pathogens.Antimicrob Agents Chemother,1997,414∶841

    6 Patterson BE,Coates PE.UK-109,496,a novel,wide-spectrum triazole derivative for the treatment of fungal infections:pharmacokinetics in man.In:Proceedings and abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy.Washington DC:American Society for Microbiology,1995.126

    7 Hitchcock CA,Pye GW,Oliver GP,et al.A novel wide-spectrum triazole derivative for the treatment of fungal infections:antifungal activity and selectivity in vitro.In:Proceedings and abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy.Washington DC:American Society for Microbiology,1995.125

    8 Troke PF,Brammer KW,Hitchcock CA.UK-109,496,a novel,wide-spectrum triazole derivative for the treatment of fungal infections:activity in systemic candidiasis models and early clinical efficacy in oropharyngeal candidiasis.In:Proceedings and abstracts of the 35th Intersciences Conference on Antimicrobial Agents and Chemotherapy.Washington DC:American Society for Microbiology,1998.125

    9 Hitchcock CA,Andrews RJ,Lewis BGH,et al.UK-109,496,a novel,wide-spectrum triazole derivative for the treatment of fungal infections:antifungal activity in experimental infections with cryptococcus.In: Proceedings and abstracts of the 35th Intersciences Conference on Antimicrobial Agnets and chemotherapy.Washington DC:American Society for Microbiology,1995.126

    10 Murphy M.Bernard EM,Ishimaru T,et al.Activity of voriconazole[UK-109,496]against clinical isolates of aspergillus species and its effectiveness in an experimental model of invasive aspergillosis.Antimicrob Agents Chemother,1997,413∶696

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    (收稿:1998-06-15 修回:1999-04-27)
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