ACTIVITIES OF ANTIFOLATE, ANTIVIRAL, AND OTHER DRUGS IN AN IMMUNOSUPPRESSED RAT MODEL OF PNEUMOCYSTIS-CARINII PNEUMONIA
ACTIVITIES OF ANTIFOLATE, ANTIVIRAL, AND OTHER DRUGS IN AN IMMUNOSUPPRESSED RAT MODEL OF PNEUMOCYSTIS-CARINII PNEUMONIA
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DOI：
10.1128/aac.36.9.1935
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发表时间：
1992-09-01
影响因子：
4.9
通讯作者：
ALLEGRA, C
中科院分区：
文献类型：
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作者：
WALZER, PD;FOY, J;ALLEGRA, C
在肺孢子虫病的实验模型中比较了抗叶酸剂、抗病毒药和其他药物的疗效。磺胺甲恶唑（SMX）以大于或等于60 mg/kg/天的剂量单独给药在治疗和预防方面非常有效。低剂量（小于或等于15 mg/kg/天）SMX在治疗中显示出有限的、剂量相关的抗卡氏肺孢子虫活性，但在预防中更有效。二氢叶酸还原酶（DHFR）抑制剂甲氧苄氨嘧啶（TMP）、乙胺嘧啶和曲美曲沙单独给药时几乎没有抗卡氏肺吸虫活性，也没有增强SMX的疗效; DHFR抑制剂的作用与剂量或血清浓度无关。这些数据表明，大鼠模型是一个很好的系统，用于研究抗卡氏肺吸虫活性的磺胺类药物，但在研究DHFR抑制剂的价值有限。抗病毒药物叠氮胸苷、双脱氧肌苷、肌苷pranobex（异丙肌苷）、金刚烷胺和阿昔洛韦对卡氏肺孢子虫几乎没有或没有活性;然而，叠氮胸苷并不影响SMX或TMP-SMX的疗效。这些结果支持了抗病毒药物与抗叶酸药物一起用于人类免疫缺陷病毒感染患者的临床实践，并表明抗病毒药物对肺孢子虫病发生的有益作用主要是由于它们对病毒或宿主免疫反应的影响。与抗病毒药物相反，9-去氮肌苷，一种具有抗原动物特性的核苷类似物，表现出显著的抗卡氏肺孢子虫活性，这与剂量和给药途径有关。这些数据提出了抗卡氏肺孢子虫活性是嘌呤核苷的一般性质的可能性，并表明对这类化合物的进一步探索可能导致临床上有用的药物。
The efficacy of antifolate, antiviral, and other drugs was compared in an experimental model of pneumocystosis. Sulfamethoxazole (SMX) administered alone in doses of greater-than-or-equal-to 60 mg/kg/day was highly effective in treatment and prophylaxis. Low (less-than-or-equal-to 15 mg/kg/day) doses of SMX showed limited, dose-related anti-Pneumocystis carinii activity in therapy but were more effective in prophylaxis. The dihydrofolate reductase (DHFR) inhibitors trimethoprim (TMP), pyrimethamine, and trimetrexate exhibited little anti-P. carinii activity when administered alone and did not enhance the efficacy of SMX; the effects of the DHFR inhibitors could not be related to the dose or the concentration in serum. These data suggested that the rat model is an excellent system for studying the anti-P. carinii activity of sulfonamides but is of limited value in studying DHFR inhibitors. The antiviral drugs azidothymidine, dideoxyinosine, inosine pranobex (Isoprinosine), amantadine, and acyclovir displayed little or no activity against P. carinii; however, azidothymidine did not impair the efficacy of SMX or TMP-SMX. These results supported the clinical practice of giving antiviral agents together with antifolate drugs to patients infected with human immunodeficiency virus and suggested that the beneficial effects of antiviral agents on the occurrence of pneumocystosis are due mainly to their effects on the virus or the host immune response. In contrast to the antiviral drugs, 9-deazainosine, a nucleoside analog with antiprotozoal properties, demonstrated marked activity against P. carinii which was related to dose and route of administration. These data raised the possibility that anti-P. carinii activity is a general property of purine nucleosides and suggested that further exploration of this class of compounds might lead to clinically useful agents.