PNEUMOCYSTIS CARINII THERAPY BY IRON CHELATION

描述：(改编自申请人摘要)。去铁胺(DFO)，以及 目前用于治疗铁超载和铝中毒的铁络合剂， 对卡氏肺孢子虫肺炎(PCP)大鼠模型有治疗作用。 完全消除滋养体生命周期阶段是在 大鼠模型的血浆浓度低于人类报告的浓度 按临床常规剂量给药。DFO还具有重要的 作为一种抗炎剂的优势，可以预期会有所帮助 减轻与PCP相关的病理变化，并消除 致病因素。这可以减少(或消除)使用 类固醇在治疗这种疾病中的作用。以下研究旨在 为使用DFO治疗PCP提供临床前支持。 目的：研究DFO在大鼠体内的药代动力学 将这些结果与人类血浆的文献价值结合起来 药物动力学，从而有助于指导DFO初始剂量的选择 用于针对PCP的临床试验。本指南的改进将是 通过收集关于人类肺的数据：血浆DFO比率；这些数据 将从脑型疟疾患者的尸检样本中获得 对包括使用DFO在内的治疗方案没有反应。 实验被用来检验当前的工作假设，即DFO 通过创造缺铁的环境来对抗卡氏肺孢子虫 抑制卡氏肺孢子虫生长。这些数据可能有助于指导一种 临床方案，以最小的药物达到最大的效果，他们将 指导未来寻找对五氯苯酚有更大活性的铁络合剂。 DFO与羟乙基淀粉加合物的活性确认 将有助于确定对抗卡氏肺孢子虫的作用机制。这 加合物，其具有可能有利于治疗PCP的性质， 将在非肠道给药和气雾剂给药时进行评估。

DESCRIPTION: (Adapted from Applicant's Abstract). Deferoxamine (DFO), an iron chelator currently used to treat iron-overload and aluminum toxicity, is therapeutic in a rat model of Pneumocystis carinii pneumonia (PCP). Complete elimination of the trophozoite life cycle stage is achieved in the rat model at plasma concentrations below those reported in humans administered a routine clinical dosage. DFO also has the important advantage of being an anti-inflammatory agent which can be expected to help alleviate the pathology associated with PCP as well as eliminate the etiological agent. This may allow a reduction (or elimination) in the use of steroids in treating this disease. The following studies are intended to provide preclinical support for the use of DFO to treat PCP. Pharmacokinetic studies of DFO in rats are proposed with the purpose being to combine these results with literature values of human plasma pharmacokinetics and thereby help guide the selection of an initial DFO dose for clinical trails against PCP. Improvement of this guidance will be achieved by collection of data on human lung: plasma DFO ratios; these data will be obtained from autopsy samples of patients with cerebral malaria who fail to respond to treatment protocols which include the use of DFO. Experiments are proposed to test the current working hypothesis that DFO operates against P. carinii by creating an iron deficient environment thus inhibiting P. carinii growth. These data may help guide the design of a clinical protocol to achieve maximal effect with minimal drug and they will guide future searches for iron chelators with greater activity against PCP. Confirmation of the activity of an adduct of DFO with hydroxyethyl starch will help determine the mechanism of action against P. carinii. This adduct, which has properties which may be advantageous for treatment of PCP, will be evaluated when administered parenterally and by aerosol.