Pneumocystis carinii pneumonitis (PCP) is a major life-threatening infection associated with the acquired immune deficiency (AID) syndrome. Only two drugs are available for treatment, pentamidine and trimethoprim-sulfamethoxazole (TMP-SMZ). The manufacture of pentamidine has been discontinued and about 1/3 of patients will not respond to TMP-SMZ. The objective of this study is to develop new drugs for the treatment of PCP.
The specific aims are to evaluate a variety of drugs in the corticosteroid treated rat model for PCP, using the experimental design of our previous studies in the development of TMP-SMZ for PCP. The animal model correlates precisely with the disease in humans and employs young Sprague-Dawley rats maintained on dexamethasone and tetracycline. Within 3 months of immunosuppression over 90% of animals develop extensive PCP. Drugs to be tested are selected because of known activity against other protozoal agents and include: allopurinol, suramin, nifurtimox, benzonidazole, melarsoprol, salicylhydroxamic acid and glycerol, a difluoromethylornithine, primaquine, quinacrine, emetine hydrochloride and ketoconazole. Initial experiments will screen drugs for efficacy by administering the test drug during the immunosuppression and determining the effect on the prevention of PCP in comparison to untreated controls. Promising drugs will then be tested for effects in the treatment of PCP once the pneumonitis is established, using 3 dose levels. When optimal doses of effective drugs are determined comparison will be made with the drugs in current use separately and in rational combinations. Efficacy will be determined from histological examination of lungs in comparison to untreated controls.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020673-06
Application #
3130477
Study Section
(SSS)
Project Start
1983-04-01
Project End
1989-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Choueiry, M A; Scurto, P L; Flynn, P M et al. (1998) Disseminated infection due to Mycobacterium fortuitum in a patient with desmoid tumor. Clin Infect Dis 26:237-8
Oz, H S; Hughes, W T (1997) Pneumocystis carinii infection alters GTP-binding proteins in the lung. J Parasitol 83:679-85
Oz, H S; Hughes, W T (1996) Effect of sex and dexamethasone dose on the experimental host for Pneumocystis carinii. Lab Anim Sci 46:109-10
Oz, H S; Hughes, W T (1996) Acute fulminating babesiosis in hamsters infected with Babesia microti. Int J Parasitol 26:667-70
Oz, H S; Hughes, W T; Vargas, S L (1996) Search for extrapulmonary Pneumocystis carinii in an animal model. J Parasitol 82:357-9
Hughes, W T; Oz, H S (1995) Successful prevention and treatment of babesiosis with atovaquone. J Infect Dis 172:1042-6
Vargas, S L; Hughes, W T; Wakefield, A E et al. (1995) Limited persistence in and subsequent elimination of Pneumocystis carinii from the lungs after P. carinii pneumonia. J Infect Dis 172:506-10
Hughes, W T (1993) Prevention of infections in patients with T cell defects. Clin Infect Dis 17 Suppl 2:S368-71
Hughes, W T (1991) Macrolide-antifol synergism in anti-Pneumocystis carinii therapeutics. J Protozool 38:160S
Hughes, W T; Killmar, J T (1991) Synergistic anti-Pneumocystis carinii effects of erythromycin and sulfisoxazole. J Acquir Immune Defic Syndr 4:532-7

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