Novel pentamidine analogs in the treatment of experimental Pneumocystis carinii pneumonia.
Novel pentamidine analogs in the treatment of experimental Pneumocystis carinii pneumonia.
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新型喷他脒类似物治疗实验性卡氏肺孢子虫肺炎。
DOI：
10.1128/aac.34.6.1026
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发表时间：
1990
影响因子：
4.9
通讯作者：
Tidwell,RR
中科院分区：
文献类型：
--
作者：
Jones,SK;Hall,JE;Allen,MA;Morrison,SD;Ohemeng,KA;Reddy,VV;Geratz,JD;Tidwell,RR
我们最近已经证明，用咪唑啉部分取代五烷胺的酰胺基，可以产生一种对大鼠卡氏肺孢子虫肺炎有效的分子，而且毒性明显低于五烷双胺。为此，对10个新的咪唑啉取代化合物进行了抗大鼠卡氏肺孢子虫肺炎作用的评价。虽然在大鼠模型中观察到几种新化合物在治疗疾病方面比五烷双胺有优势，但只有一种化合物作为潜在的新临床药物脱颖而出。静脉滴注治疗2周。剂量为1 mg/kg/d的1，3-二(4-咪唑基-2-甲氧基苯氧基)丙烷(DIMP)可产生抗P。卡氏肺炎的效果相当于静脉注射。剂量为每天10毫克/公斤的扑热息痛。尽管戊双胺和其中一种受试药物1，3-二(4-咪唑啉苯氧基)丙烷口服给药时对卡氏肺孢子虫肺炎没有显示出任何活性，但DIMP显示出很强的抗P。每天灌胃剂量为40毫克/公斤和25毫克/公斤时，卡氏肺孢子虫肺炎的活性。当每隔一天灌胃剂量为25 mg/kg时，DIMP保持了显著的活性。在任何剂量水平或任何一种给药途径下，该药物均未观察到毒性。然而，药物的低溶解度阻碍了在更高的静脉注射下进行测试。剂量。我们的结论是，DIMP有可能成为治疗卡氏肺孢子虫肺炎的一种更安全、更有效的替代药物。
We have recently demonstrated that substitution of imidazoline moieties for the amidine groups of pentamidine produces a molecule that is effective against rat Pneumocystis carinii pneumonia and that is apparently less toxic than pentamidine. For this reason, 10 novel imidazoline substituted compounds were evaluated for their effect against rat P. carinii pneumonia. While several of the new compounds were observed to have advantages over pentamidine in the treatment of disease in the rat model, only one compound stood out as a potential new clinical agent. Treatment for 2 weeks with intravenous (i.v.) doses of 1,3-di(4-imidazolino-2-methoxyphenoxy)propane (DIMP) at 1 mg/kg per day produced an anti-P. carinii pneumonia effect equivalent to i.v. doses of pentamidine at 10 mg/kg per day. Although pentamidine and one of the test drugs, 1,3-di(4-imidazolinophenoxy)propane, showed no activity against P. carinii pneumonia when administered per os, DIMP exhibited potent anti-P. carinii pneumonia activity when given by daily gavage doses of 40 and 25 mg/kg. DIMP retained significant activity when given every other day by a gavage dose of 25 mg/kg. No toxicity was observed with the drug at any of the dose levels or by either of the routes of administration. However, the low solubility of the drug prevented testing at higher i.v. doses. Our conclusion is that DIMP has the potential of providing a safer and more effective alternative to pentamidine for the treatment of P. carinii pneumonia.