Fexinidazole——一种新的口服nitroimidazole的候选药物进入临床治疗昏睡病的发展。
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Torreele E,布尔Trunz B, Tweats D, Kaiser M,布朗R, Mazue G,布雷,Pecoul B
Fexinidazole——一种新的口服nitroimidazole的候选药物进入临床治疗昏睡病的发展。
公共科学图书馆Negl太说。2010年12月21日,4 (12):e923。doi: 10.1371 / journal.pntd.0000923。
- PubMed ID
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21200426 (在PubMed]
- 文摘
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背景:非洲人类锥虫病(帽子),也被称为昏睡病,是一种致命的寄生虫病由锥虫引起的。目前的治疗方案的帽子是稀缺的,有毒的,不再有效,或非常难以管理,特别是先进的致命疾病的阶段(阶段2、慢性帽子)。新一代安全、有效和易于使用的迫切需要治疗。这里显示fexinidazole, 2-substituted 5-nitroimidazole重新发现的被忽视疾病药物项目(DNDi)经过广泛综采工作超过700新的和现有nitroheterocycles,可能是一个短期安全有效的口服治疗治疗急性和慢性的帽子,可以实现在初级卫生保健水平。完成临床前开发和满足监管要求开始人体试验之前,寄生虫属性和药代动力学、代谢和毒理学fexinidazole的评估。方法和结果:标准体外和体内寄生虫活动进行了分析评估药物疗效的实验模型的帽子。同时,全方位的临床前药理学和安全性研究,根据国际监管方针发起人类研究之前,已经进行了。Fexinidazole适度活跃在体外对非洲锥虫(IC(5)(0)对实验室和近期临床分离菌株介于0.16和0.93之间microg /毫升)和口服Fexinidazole剂量100毫克/公斤/天4天或5天200毫克/公斤/天分别治愈小鼠急性和慢性感染,后者是一个先进的模型和致命疾病的阶段当寄生虫传播到大脑。在实验室动物,fexinidazole口服后吸收,容易分布在整个身体,包括大脑。小鼠口服fexinidazole的绝对生物利用度为41%,30%的老鼠,狗的10%。 Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC(0)(-)(2)(4) of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. CONCLUSIONS: The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.
beplay体育安全吗DrugBank数据引用了这篇文章
- 药物
- 药物酶
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药物 酶 类 生物 药理作用 行动 Fexinidazole 细胞色素P450 1 a2 蛋白质 人类 未知的底物抑制剂诱导物细节 Fexinidazole 细胞色素P450 2 b6 蛋白质 人类 未知的底物抑制剂诱导物细节 Fexinidazole 细胞色素P450 2 c19 蛋白质 人类 未知的底物抑制剂细节 Fexinidazole 细胞色素P450 2 d6 蛋白质 人类 未知的底物抑制剂细节 Fexinidazole 细胞色素P450 3 a4 蛋白质 人类 未知的底物抑制剂细节 Fexinidazole 细胞色素P450 3 a5 蛋白质 人类 未知的底物抑制剂细节 - 药物反应
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反应 细节
