Efficacy of MK-991 (L-743,872), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii
Efficacy of MK-991 (L-743,872), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii
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DOI：
10.1128/aac.42.8.1985
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发表时间：
1998-08-01
影响因子：
4.9
通讯作者：
Schmatz, D
中科院分区：
文献类型：
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作者：
Powles, MA;Liberator, P;Schmatz, D
除了在动物模型中对念珠菌、烟曲霉和组织胞浆菌有很强的疗效外，临床候选的肺炎粘附素MK-991(以前的L-743,872)在免疫低下的动物模型中对卡氏肺孢子虫也非常有效。MK-991的效力大约是原始天然产品铅的14倍，即肺炎粘附素B-0。MK-991对大鼠肺孢子虫模型包囊清除的90%有效剂量(ED_1)为0.011 mg/kg体重，连续给药4天，每天2次。在小鼠模型中，在相同的实验参数下，ED_1为0.02 mg/kg，MK-991对大鼠急性感染的包囊清除量为2.2 mg/kg(b.i.d)。连续4天)，在免疫低下的小鼠中，每天口服2.25 mg/kg的MK-991可以完全防止卡氏肺孢子虫的发育，就像之前报道的其他肺炎粘附素和棘球绦虫一样，MK-991选择性地阻止卡氏肺孢子虫包囊的发展。当用作预防措施时，动物的肺部都没有出现这两个阶段的生物体，对急性感染的反应是，包囊被迅速消除，而滋养体形式仍然存在。尽管MK-991作为一种口服制剂在小鼠模型中有很好的疗效，但这种药物的低口服吸收可能会限制MK-991的使用，使其只能用于非肠道治疗。
In addition to its potent efficacy in animal models against Candida sp,, Aspergillus fumigatus, and Histoplasma capsulatum, the clinical candidate pneumocandin MK-991 (formerly L-743,872) was also extremely potent against Pneumocystis carinii In models of immune-compromised animals. MK-991 was approximately 14 times more potent than the original natural product lead, pneumocandin B-0. The 90% effective dose (ED,,) of MK-991 for cyst clearance in the rat model for pneumocystis was 0.011 mg/kg of body weight when delivered parenterally for 4 days twice a day (b.i.d.). In a mouse model, under the same experimental parameters, the ED,, was 0.02 mg/kg, MK-991 was also effective orally, with an ED,, for cyst clearance of 2.2 mg/kg against acute infection in rats (b.i.d. for 4 days), Complete prevention of P, carinii development was achieved in immunocompromised mice at a daily oral dose of 2.25 mg/kg, As reported previously for other pneumocandins and echinocandins, MK-991 selectively prevented the development of P. carinii cysts. When used as a prophylactic agent, neither stage of the organism appeared in the lungs of animals, In response to an acute infection, cysts were eliminated rapidly, while trophozoite forms persisted. Despite good efficacy as an oral agent in murine models, the low oral absorption of this class may limit the use of MK-991 to parenteral therapy.