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.

Detrimental Effect of Fungal 60-kDa Heat Shock Protein on Experimental Paracoccidioides brasiliensis Infection

“…The differences between our results and those of Soares et al [37] may be due to the different infection routes and protocols for the administration of recombinant PbHsp60. While Soares et al [37] used intranasal infection, we performed intravenous infection, which mimics a disseminated form of the disease and advantageously constitutes a model for preclinical therapeutic trials [38]. Furthermore, we administrated rPbHsp60 in a therapy regimen, whereas Soares et al [37] adopted a prophylactic regimen.…”

Utilização de peptídeo sintético (P10) associado ao tratamento com drogas antifúngicas no controle da paracoccidioidomicose experimental

“…animais infectados e tratados com sulfametoxazol associado à imunização com P10. Foram analizados 100 campos microscópicos para cada grupo, encontrando-se os seguintes resultados: Grupo A: granulomas com leveduras (24%) e áreas não-inflamadas (27%); Grupo B: granulomas com leveduras (15%) e áreas não-inflamadas (46%); Grupo C: granulomas com leveduras (32%) e áreas não-inflamadas (26%); Grupo D: granulomas com leveduras (12%) e áreas não-inflamadas (55% (MARTINEZ et al, 1999;PASKO et al, 1990;PELLEGRINO et al, 2003;RESTREPO et al, 1973;RESTREPO et al, 1983a;VILLA et al, 2000 (UEDA et al, 1987). Hoyos et al (1984) também usaram um modelo murino de PCM pulmonar crônica disseminada e trataram seus animais com cetoconazol (100 mg kg -1 em 0.3% agar), administrando-o duas vezes por dia (gavage), durante 1 ou 2 meses.…”

Monofosforil lipídeo A e diidrolipoil desidrogenase de <i>Paracoccidioides brasiliensis</i> têm efeito terapêutico na paracoccidiodomicose experimental

“…The differences between our results and those of Soares et al [37] may be due to the different infection routes and protocols for the administration of recombinant PbHsp60. While Soares et al [37] used intranasal infection, we performed intravenous infection, which mimics a disseminated form of the disease and advantageously constitutes a model for preclinical therapeutic trials [38].…”