摘要

PURPOSE:Itraconazole is a triazole antifungal drug that has recently been found to inhibit angiogenesis. Itraconazole is a relatively well-tolerated drug but shows hepatotoxicity in a small subset of patients. Itraconazole contains three chiral centers and the commercial itraconazole is composed of four cis-stereoisomers (named IT-A, IT-B, IT-C, and IT-D). We sought to determine whether the stereoisomers of itraconazole might differ in their antiangiogenic activity and hepatotoxicity.
EXPERIMENTAL DESIGN:We assessed in vitro antiangiogenic activity of itraconazole and each stereoisomer using human umbilical vein endothelial cell (HUVEC) proliferation and tube formation assays. We also determined their hepatotoxicity using primary human hepatocytes in vitro and a mouse model in vivo Mouse Matrigel plug and tumor xenograft models were used to evaluate in vivo antiangiogenic and antitumor activities of the stereoisomers.
RESULTS:Of the four stereoisomers contained in commercial itraconazole, we found that IT-A (2S,4R,2'R) and IT-C (2S,4R,2'S) were more potent for inhibition of angiogenesis than IT-B (2R,4S,2'R) and IT-D (2R,4S,2'S). Interestingly, IT-A and IT-B were more hepatotoxic than IT-C and IT-D. In mouse models, IT-C showed more potent antiangiogenic/antitumor activity with lower hepatotoxicity compared with itraconazole and IT-A.
CONCLUSIONS:These results demonstrate the segregation of influence of stereochemistry at different positions of itraconazole on its antiangiogenic activity and hepatotoxicity, with the 2 and 4 positions affecting the former and the 2' position affecting the latter. They also suggest that IT-C may be superior to the racemic mixture of itraconazole as an anticancer drug candidate due to its lower hepatotoxicity and improved antiangiogenic activity. Clin Cancer Res; 22(11); 2709-20. ©2016 AACR.

译文

目的: 伊曲康唑是最近发现的一种抑制血管生成的三唑类抗真菌药物。伊曲康唑是一种耐受性相对较好的药物,但在一小部分患者中显示出肝毒性。伊曲康唑含有三个手性中心,商业伊曲康唑由四个顺立体异构体 (命名为 IT-A 、 IT-B 、 IT-C 和 IT-D) 组成。我们试图确定伊曲康唑的立体异构体是否在抗血管生成活性和肝毒性方面有所不同。
实验设计: 我们使用人脐静脉内皮细胞 (HUVEC) 增殖和试管形成试验评估了伊曲康唑和每种立体异构体的体外抗血管生成活性。我们还使用体外原代人类肝细胞和小鼠模型确定了它们的肝毒性。小鼠 Matrigel plug 和肿瘤异种移植模型被用来评估立体异构体的体内抗血管生成和抗肿瘤活性。
结果: 在市售伊曲康唑中含有的四种立体异构体中,我们发现 IT-A (2 S,4R,2 'r) 和 IT-C (2 S,4R,2' S) 比 IT-B (2R,4S,2 'r) 和 IT-D (2R,4S,2' s) 更能抑制血管生成。有趣的是,IT-A 和 IT-B 比 IT-C 和 IT-D 更具有肝毒性。在小鼠模型中,与伊曲康唑和 IT-C 相比,IT-A 显示出更有效的抗血管生成/抗肿瘤活性,肝毒性更低。
结论: 这些结果证明了伊曲康唑不同位置的立体化学对其抗血管生成活性和肝毒性影响的分离,2 和 4 个位置影响前者,2 '位置影响后者。他们还建议,IT-C 作为抗癌候选药物可能优于伊曲康唑的消旋混合物,因为它具有较低的肝毒性和增强的抗血管生成活性。Clin Cancer Res; 22 (11); 2709-20。©2016 AACR。

Itraconazole

呼吸 三唑类抗真菌药 药物
概述  :  

伊曲康唑用于治疗浅部皮肤真菌病(花斑癣、体癣、股癣、手足癣)、甲真菌病、外阴阴道念珠菌病、真菌性角膜炎、口腔食管念珠菌病、肺曲霉病等。伊曲康唑注射液适用于治疗以下系统性真菌疾病:曲霉病、念珠菌病、隐球菌病(包括隐球菌性脑膜炎)和组织胞浆菌病。 使用方法 口服给药:①皮肤真菌病:200mg/d,餐时同服或餐后服,连服7d。②甲真菌病:采用冲击间歇疗法,200mg,bid,餐后服,连服1周,停3周,为1疗程。指甲感染治疗2~3个疗

Itraconazole   /ɪtrə'kənəzəʊl/

释    义   伊曲康唑

例    句   Systemic candidiasis requires treatment with systemic antifungal agents such as fluconazole, ketoconazole, itraconazole or amphotericin. 全身性念珠菌病需要使用全身性抗真菌药物,如氟康唑、酮康唑、伊曲康唑或两性霉素。

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