POLYAMINE METABOLISM AND AIDS ASSOCIATED PNEUMONIA

艾滋病相关性卡氏肺孢子虫肺炎的治疗 在最常见的机会性感染中，通常只基于 两种药物疗法；扑热息痛和甲氧苄啶与甲氧苄啶的组合 磺胺甲恶唑。 在临床试验中已经取得了相当大的成功，使用了一种抗 多胺试剂，DL-α-二氟甲基鸟氨酸(DFMP，依氟鸟氨酸)， 对难治性或不耐受的艾滋病患者进行PCP治疗 标准治疗方案--日益普遍的现象。而当 将DFMO添加到治疗PCP的药物清单中是受欢迎的，其疗效 如果要将反多胺治疗作为第一线，则需要改进 五氯苯酚的治疗。这种改进的合理方法是通过 寄生虫多胺代谢及其相互作用的研究 用抗多胺药治疗寄生虫。尽管如此，还是有 卡氏肺孢子虫多胺代谢未见报道 致力于改善五氯苯酚的抗多胺治疗。 DFMO是一种高度特异的鸟氨酸脱羧酶(ODC)抑制剂， 多胺生物合成的关键酶(小分子 所有细胞中的多种基本功能)。尽管它的目标是 特定的酶，没有直接证据表明DFMO的效果 抗五氯苯酚的方法是通过抑制该酶。因为这种酶存在于 寄主对DFMO既是必需的又是敏感的，没有 对寄生虫选择性活性的解释。 这项建议的重点是确认DFMO的行动模式 针对五氯苯酚并确定其选择性作用的依据。 将通过基础研究寻求抗多胺治疗的改进 对寄生虫多胺代谢的影响及对其影响的研究 各种多胺的给药和给药时间 生物合成抑制剂对宿主的影响。 DFMO的生化作用将通过绕过推定的 外源性腐胺抑制代谢。选择的基础是 药物对寄生虫的作用将通过确定 寄生虫靶向酶药物敏感性、寄生虫回收率 抑制后酶活性、DFMO对寄生虫的穿透和 药物在宿主体内的分布。基本的生化调查将是 为提高抗多胺的治疗活性而设计的方法 五氯苯酚。PCP的大鼠模型将被用作寄生虫的来源 以及这种疾病的模型。

Treatment for AIDs associated Pneumocystis carinti pneumonia (PCP), one of the most common opportunistic infections, is routinely based on only two drug therapies; pentamidine and a combination of trimethoprim with sulfamethoxazole. Considerable success has been met in clinical trials using an anti- polyamine agent, DL-alpha-difluoromethylornithine (DFMP, eflornithine), to treat PCP in those AIDS patients refractory or intolerant to the standard treatment protocols - increasingly common phenomena. While the addition of DFMO to the list of drugs for PCP is welcome, the efficacy needs improvement if anti-polyamine therapy is to be a first line treatment for PCP. The rational approach to such improvement is through investigations of parasite polyamine metabolism and of the interaction of the parasite with antipolyamine agents. Despite this, there has been no exploration of polyamine metabolism in Pneumocystis carinii nor any work directed at improving antipolyamine therapy for PCP. DFMO is a highly specific inhibitor of ornithine decarboxylase (ODC), key enzyme for the biosynthesis of polyamines (small molecules having multiple essential functions in all cells). Although it is targeted to a specific enzyme, there is no direct evidence that the effect of DFMO against PCP is by inhibition of the enzyme. Since the enzyme exists in the host and is both essential and sensitive to DFMO, there is no explanation for the selective activity against the parasite. This proposal is focused on confirming the mode of action of DFMO against PCP and determining the basis for its selective action. Improvements of antipolyamine therapy will be sought via basic studies of the polyamine metabolism of the parasite and studies of the effect of administration and the timing of administration of various polyamine biosynthesis inhibitors to the host. the biochemical action of DFMO will be tested by bypassing the putative metabolic block with exogenous putrescine. The basis for the selective action of the drug against the parasite will be addressed by determining the parasite target enzyme drug sensitivity, recovery rate of parasite enzyme activity after inhibition, DFMO penetration of the parasite and drug distribution in the host. Basic biochemical investigation will be made to devise means of improving anti--polyamine activity for treatment of PCP. The rat model of PCP will be utilized for a source of parasites and a model of the disease.