The scid mouse as an experimental model for the evaluation of anti-Pneumocystis carinii therapy.
The usefulness of scid mice bearing endogenous Pneumocystis carinii infection as a model for experimental chemotherapy was examined using standard compounds known to be effective against P. carinii. Trimethoprim/sulphamethoxazole was able to reduce pulmonary P. carinii cysts in a dose-dependent manner within the dose range studied (10/50 to 100/500 TMP/SMX mg/kg/d, bd, po, 5 days per week for 30 treatments). However, alterations in associated symptoms of infection (reduced body weight, increased lung weight, increased blood leucocytes and erythrocytes), was apparently not linearly dose-dependent. Blood and lung lavage fluid levels of sulphamethoxazole one hour post administration of trimethoprim/sulphamethoxazole was dose-dependent, but not linear with dose, and was apparently correlated to cyst reduction; trimethoprim was below the limit of detection at this time. Treatment of mice with 100/500 mg/kg/day trimethoprim/sulphamethoxazole required 2 weeks (bd for 10 days of treatment) before changes in indices of infection became significant. Pentamidine (20 mg/kg, sc, three times per week for 3 weeks) was nearly as effective as high-dose trimethoprim/sulphamethoxazole in reducing cysts, whereas lower doses were ineffective. Despite being unable to reduce pulmonary P. carinii infection, even low doses of pentamidine (6 or 2 mg/kg, sc, three times per week for 3 weeks) were able to reduce lung weights and blood leucocyte levels. This model of pulmonary P. carinii infections is amenable to chemotherapeutic intervention in an apparently dose-dependent fashion, and can be used to evaluate the capacity of compounds to eradicate P. carinii and resolve signs of infection.
Pharmaceutical Research, Ciba-Geigy Limited, Basel, Switzerland.
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Kunz
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Junker
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Blaser
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Joos
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Meyer
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Zak
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O'Reilly
D000818:Animals; D000890:Anti-Infective Agents / Q000627:therapeutic use*; D000935:Antifungal Agents / Q000627:therapeutic use; D001772:Blood Cell Count; D001826:Body Fluids / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D008168:Lung / Q000382:microbiology; D051379:Mice; D016513:Mice, SCID / Q000382:microbiology*; D009929:Organ Size / Q000187:drug effects; D010419:Pentamidine / Q000627:therapeutic use; D011020:Pneumonia, Pneumocystis / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000493:pharmacokinetics / Q000627:therapeutic use
D000890:Anti-Infective Agents; D000935:Antifungal Agents; D010419:Pentamidine; D015662:Trimethoprim, Sulfamethoxazole Drug Combination