PNEUMOCYSTIS CARINII THERAPY BY IRON CHELATION

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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.