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Ketoconazole in the treatment of experimental murine paracoccidioidomycosis
Abstract:
In a murine model of chronic disseminated paracoccidioidomycosis (strain 18; intravenous route), Ketoconazole (200 mg/kg in 0.2% agar) was given daily by gavage in three different schedules. Continuous treatment from an early stage of infection (day 3) up to week 20 was the most effective protocol, leading to remission of histopathological lesions and of both humoral and cellular anti-P. brasiliensis immune response, and clearance of the fungus in lungs; only 1 treated animal at week 20 showed pulmonary granulomas, although less extensive than control mice. Continuous treatment from early stage up to week 8, followed by a 16 week-period of drug discontinuity, caused remission of lesions in all but 3 treated mice which showed active pulmonary paracoccidioidomycosis similar to controls (14.2% of unresponsiveness to treatment). The continuous Ketoconazole protocol since a late stage of infection (week 4) up to week 20 produced a slower remission of lesions and immune response when compared with the first drug schedule. In this model of paracoccidioidomycosis, Ketoconazole showed no detectable side-effects and was a very effective drug especially in a prolonged administration protocol from an early stage of infection.
Insights
Prolonged Ketoconazole treatment effectively manages chronic disseminated paracoccidioidomycosis in mice. Early, continuous administration cleared fungal infections and immune responses with no observed side-effects.
Area of Science:
- Mycology
- Immunology
- Pharmacology
Background:
- Paracoccidioidomycosis is a systemic fungal infection prevalent in Latin America.
- Chronic disseminated forms require effective and safe treatment strategies.
Purpose of the Study:
- To evaluate the efficacy of Ketoconazole in a murine model of chronic disseminated paracoccidioidomycosis.
- To compare different treatment schedules for Ketoconazole administration.
Main Methods:
- A murine model infected with Paracoccidioidomycosis brasiliensis (strain 18) was used.
- Ketoconazole (200 mg/kg) was administered daily via gavage in three distinct schedules.
- Histopathological lesions, immune responses, and fungal load were assessed.
Main Results:
- Continuous Ketoconazole treatment from day 3 to week 20 was the most effective, leading to lesion remission and fungal clearance.
- Early treatment followed by a drug-free period showed reduced efficacy, with some mice exhibiting active infection.
- Late-stage continuous treatment resulted in slower remission compared to early-stage treatment.
Conclusions:
- Ketoconazole is a highly effective antifungal agent for paracoccidioidomycosis in this murine model.
- Prolonged, continuous administration initiated early in the infection course yields the best outcomes.
- Ketoconazole demonstrated a favorable safety profile with no detectable side-effects in this study.