Pneumocystis carinii pneumonitis (PCP) is fatal in the immunocompromised host. It occurs in 75% of AIDS patients and with the most effective treatment the fatality rate is 25%. Furthermore, adverse reactions occur in over 40% of patients to drugs in current use. The objective of the proposed study is to identify effective and safe drugs for PCP. The corticosteroid-treated rat model will be used for in vivo studies to determine the therapeutic and prophylactic efficacies of a series of hydroxynephthoquinone compounds, one of which we have already found to have anti-P. carinii activity in preliminary studies. The relative efficacies of menoctone, parvaquone, lawsone, danthron, alkannin, lapinone, lapachone and buparvaquone will be determined by experiments in which each compound is administered to a group of P. carinii immunosuppressed rats for 6 to 8 weeks, after which the extent of pulmonary infection will be compared to untreated controls. Therapeutic effects will be determined by administration of the drugs at varying dose levels to animals with well established PCP. Histology of pulmonary parenchyma will determine the extent of PCP. Potential synergistic combinations of hydroxynaphthoquinones will be tested with a pyridine, clopidol and the quinolone, decoquinate. All drugs will be compared to the 3-hydroxy-1, 4-naphthoquinone (St. Jude #1) we have found to have anti-P. carinii activity. P. carinii """"""""cidal"""""""" and """"""""static"""""""" effects will be determined. The inhibition of P. carinii by a hydroxynaphthoquinone compound suggests the site of action to be on mitochondrial respiration, as occurs with other protozoa. We propose to isolate P. carinii mitochondria from intracystic sporozoites. P. carinii cysts will be separated from host cells and other microbes by centrifugation methods to isolate mitochondria. Rat hepatocyte mitochondria will serve as controls and 02 uptake will be measured by the method Frye and Williams. Drugs will be applied and the inhibition expressed as an EC 50 (concentration required to cause 50% inhibition of respiration). Correlations will be made between in vitro and in vivo activity of each drug. Thus, an in vitro system to screen drugs for anti-P carinii activity might be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI020673-09
Application #
3130479
Study Section
Special Emphasis Panel (ARR (V1))
Project Start
1983-04-01
Project End
1992-06-30
Budget Start
1991-07-01
Budget End
1992-06-30
Support Year
9
Fiscal Year
1991
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; Vargas, S L (1996) Search for extrapulmonary Pneumocystis carinii in an animal model. J Parasitol 82:357-9
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
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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