PNEUMOCYSTIS CARINII THERAPY BY IRON CHELATION

铁螯合疗法治疗卡氏肺囊虫

• 批准号: 2672617
• 负责人: ALLEN B CLARKSON JR
• 金额: $ 36.59万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-01 至 2000-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2672617
• 关键词: Pneumocystis carinii; Pneumocystis pneumonia; chelation therapy; deferoxamine; disease /disorder model; dosage forms; human tissue; laboratory rat; malaria; pharmacokinetics; postmortem; starch

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.

描述：（改编自申请人摘要）。 去铁胺（DFO）， 目前用于治疗铁过载和铝中毒铁螯合剂， 在卡氏肺孢子虫肺炎（PCP）大鼠模型中具有治疗作用。 完全消除滋养体的生命周期阶段是实现在 血浆浓度低于人体报告浓度的大鼠模型 给予常规临床剂量。 DFO还具有重要的 作为一种抗炎剂的优势， 减轻与PCP相关的病理学，并消除 病原体 这可以允许减少（或消除）使用 类固醇治疗这种疾病。 以下研究旨在 为使用DFO治疗PCP提供临床前支持。 提出了DFO在大鼠中的药代动力学研究，目的是 将这些结果与人血浆的文献值联合收割机结合 药代动力学，从而帮助指导初始DFO剂量的选择 用于临床试验 改进这一指导将是 通过收集关于人肺：血浆DFO比率的数据来实现;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的治疗方案没有反应。 提出实验来检验目前的工作假设，即DFO 通过创造缺铁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设计 临床方案，以达到最大的效果，用最少的药物，他们将 指导今后寻找对五氯苯酚具有更大活性的铁螯合剂。 DFO与羟乙基淀粉加合物活性的确认 将有助于确定对卡氏肺孢子虫的作用机制。 这 加合物，其性质可能有利于处理五氯苯酚， 将在胃肠外给药和气雾剂给药时进行评价。