Hughes W T, Jacobus D P, Canfield C, Killmar J
Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee 38105.
Antimicrob Agents Chemother. 1993 Jul;37(7):1417-9. doi: 10.1128/AAC.37.7.1417.
A newly synthesized biguanide inhibitor of dihydrofolate reductase in Plasmodium species was evaluated for its anti-Pneumocystis carinii activity. The compound N-3-(2,4,5-trichlorophenoxypropyloxy)-N'-(1-methylethyl)imidoca rbonimidic diamide hydrochloride, designated PS-15, was administered prophylactically and therapeutically to immunosuppressed rats latently infected with P. carinii. Doses of 5 and 25 mg of PS-15 per kg of body weight per day given orally during 7 weeks of dexamethasone immunosuppression prevented P. carinii infection in all (100%) 19 rats given the drug, while 6 of 9 (67%) untreated control rats developed P. carinii pneumonitis. A single weekly dose of 50 mg of PS-15 per kg also prevented the infection in all 10 rats. P. carinii pneumonitis was established after 4 weeks of immunosuppression and was then treated orally for 3 weeks with 25, 5, and 1 mg of PS-15 per kg/day. Complete resolution of the infection occurred in all (100%) 10 rats given 25 mg of PS-15, 6 of 9 (67%) rats given 5 mg of PS-15, and 6 of 8 (75%) rats given 1.0 mg of PS-15 per kg per day and in all (100%) 9 rats treated with trimethoprim-sulfamethoxazole. PS-15 was well tolerated at all doses. Because drug studies in the P. carinii rat model have been highly predictable of the effects of drugs on the disease in humans, these experiments suggest that PS-15 may have promise as a drug for the treatment of P. carinii pneumonitis in humans.
对一种新合成的疟原虫二氢叶酸还原酶双胍抑制剂的卡氏肺孢子虫活性进行了评估。化合物N-3-(2,4,5-三氯苯氧基丙氧基)-N'-(1-甲基乙基)亚氨基碳酰二胺盐酸盐，命名为PS-15，对潜伏感染卡氏肺孢子虫的免疫抑制大鼠进行了预防性和治疗性给药。在7周地塞米松免疫抑制期间，每天口服5和25mg/kg体重的PS-15可预防所有（100%）19只给药大鼠感染卡氏肺孢子虫，而9只未治疗的对照大鼠中有6只（67%）发生了卡氏肺孢子虫肺炎。每周一次50mg/kg的PS-15也可预防所有10只大鼠感染。免疫抑制4周后建立卡氏肺孢子虫肺炎，然后每天口服25、5和1mg/kg的PS-15进行3周治疗。给予25mg PS-15的所有10只大鼠（100%）、给予5mg PS-15的9只大鼠中的6只（67%）、给予1.0mg PS-15/kg/天的8只大鼠中的6只（75%）以及接受甲氧苄啶-磺胺甲恶唑治疗的所有9只大鼠（100%）感染均完全消退。所有剂量的PS-15耐受性良好。由于在卡氏肺孢子虫大鼠模型中的药物研究对药物在人类疾病中的作用具有高度预测性，这些实验表明PS-15可能有望作为治疗人类卡氏肺孢子虫肺炎的药物。
