The general goal of this project is to improve existing drug therapy against P. carinii pneumonia (PCP) and provide valuable information for the prevention of the disease. Although the single most common cause of death in AIDS patients is PCP, the etiology of PCP is not well understood. The mode of transmission of P. carinii has not been well established. Horizontal and vertical transmission have been suggested. In order to prevent the congenital transmission of the disease, the hypothesis of vertical transmission of P. carinii should be tested. When cell mediated immunity is suppressed PCP appears. Since alcohol suppresses the immune system, one expects alcohol to increase the susceptibility to PCP infection. Thus, it is important to determine the effects of alcohol consumption on the appearance of PCP. Currently, trimethroprim/sulfamethoxazole (TMP/SMZ) or pentamidine (PTM) are in general use for prophylaxis of PCP. TMP/SMZ and PTM produce a high rate of adverse reactions. To reduce the adverse reactions with PTM, aerosolized PTM has been adopted. However, when using aerosolized PTM, P. carinii may be manifested in organs other than the lung. Liposomal PTM has been suggested to target drug-lung delivery but therapeutic index has not been tested. PTM interferes with the phosphorylation and synthesis of nucleic acids. Thus, PTM may antagonize the anti-HIV activity of anti-AIDS nucleosides azidothymidine (AZT) and dideoxyinosine (ddI) since they need to be phosphorylated to inhibit HIV replication. This possible interaction needs to be studied. This project will investigate the pharmacokinetic interactions of AZT and ddI with PTM and a new promising PTM analog (DIMP) as well as the diffusion of P. carinii during aerosolized PTM and the therapeutic index of liposomal PTM in the rat as animal model. The effects of chronic alcohol consumption on the appearance of PCP and the hypothesis of vertical transmission of P. carinii will also be studied in the rat model.
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