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Treatment of histoplasmosis with MK-991 (L-743,872)
J R Graybill1, L K Najvar, E M Montalbo
1The University of Texas Health Science Center at San Antonio, 78284, USA. GRAYBILL@UTHSCSA.EDU
Abstract:
BALB/c nu/+ immunocompetent and athymic (nu/nu) mice were infected intravenously with yeast cells of Histoplasma capsulatum. Mice were either given water (controls) intraperitoneally (i.p.) or given MK-991 i.p. once daily or twice daily. Protection was measured as prolonged survival or reduction in tissue counts. MK-991 was protective in immunocompetent mice, prolonging survival and reducing counts in spleen and livers at a dose as low as 0.05 mg/kg of body weight/day. MK-991 was modestly effective in athymic mice at a higher dose, 5 mg/kg/day. These studies suggest that MK-991 may be appropriate for clinical development in histoplasmosis.
Insights
MK-991 demonstrated significant protection against Histoplasma capsulatum infection in immunocompetent mice, showing efficacy in athymic mice at higher doses. This suggests MK-991
Area of Science:
- Medical Mycology
- Infectious Diseases
- Pharmacology
Background:
- Histoplasma capsulatum causes histoplasmosis, a serious fungal infection.
- Effective treatments are crucial, especially for immunocompromised individuals.
Purpose of the Study:
- To evaluate the efficacy of MK-991 against Histoplasma capsulatum infection.
- To assess MK-991's protective effects in different mouse models.
Main Methods:
- BALB/c immunocompetent and athymic mice were infected with Histoplasma capsulatum.
- Mice received either water (control) or MK-991 intraperitoneally (i.p.) once or twice daily.
- Protection was assessed by survival rates and reduction in fungal tissue counts.
Main Results:
- MK-991 significantly prolonged survival and reduced fungal burden in spleen and liver of immunocompetent mice at 0.05 mg/kg/day.
- MK-991 showed modest efficacy in athymic mice at a higher dose of 5 mg/kg/day.
Conclusions:
- MK-991 exhibits protective activity against Histoplasma capsulatum.
- The drug shows potential for clinical development in treating histoplasmosis.