RESUMEN
Two randomized, double-blind, placebo-controlled trials, in which levamisole (2.5 mg/kg) was given alone or co-administered with ivermectin (200 microg/kg) or albendazole (400 mg), were conducted. In Trial 1, safety and drug-drug interaction were explored in 42 healthy male volunteers. During Trial 2, the safety of the same treatment regimens and their efficacy against the adult worms and microfilariae of Onchocerca volvulus were investigated in 66 infected subjects of both sexes. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. The pharmacokinetic parameters for levamisole alone and the combinations were determined in Trial 1 and then compared with historical data for ivermectin and albendazole, given as single agents, to determine if drug-drug interaction had occurred. The level of efficacy against the adult worms was determined by the examination of histology sections of nodules excised 6 months posttreatment and from the changes seen in the levels of microfilaridermia within a year of treatment. Microfilaricidal efficacy was estimated from the reductions in the levels of microfilaridermia between day 0 (1 day pre-treatment) and day 30. Although the regimens were generally well tolerated, there were unexpected adverse effects in both healthy volunteers and infected subjects. Clinically significant drug-drug interactions resulted in an increase in the bio-availability of ivermectin but a reduction in that of albendazole when these drugs were co-administered with levamisole. Levamisole given alone or with albendazole had little effect on O. volvulus. The combination of levamisole with ivermectin was neither macrofilaricidal nor more effective against the microfilariae and the adult worms than ivermectin alone. The pathogenesis of the adverse events and the drug-drug interactions are discussed.
Asunto(s)
Albendazol/efectos adversos , Antinematodos/efectos adversos , Ivermectina/efectos adversos , Levamisol/efectos adversos , Oncocercosis/tratamiento farmacológico , Adolescente , Adulto , Albendazol/farmacocinética , Albendazol/uso terapéutico , Animales , Anticestodos/efectos adversos , Anticestodos/farmacocinética , Anticestodos/uso terapéutico , Antinematodos/farmacocinética , Antinematodos/uso terapéutico , Método Doble Ciego , Interacciones Farmacológicas , Quimioterapia Combinada , Femenino , Humanos , Ivermectina/farmacocinética , Ivermectina/uso terapéutico , Levamisol/farmacocinética , Levamisol/uso terapéutico , Masculino , Microfilarias/efectos de los fármacos , Persona de Mediana Edad , Onchocerca volvulus/efectos de los fármacos , Resultado del TratamientoRESUMEN
If ivermectin-based programmes for the control of human onchocerciasis are to be successful, the drug must remain effective for as long as necessary. In an open, case-control study, an attempt was made to determine if the persistent, significant, Onchocerca volvulus microfilaridermias seen in some individuals who had received at least nine treatments with ivermectin were the result of the development of drug resistance in the parasite. Twenty-one of these 'sub-optimal' responders (cases) were matched, by age, weight, number of treatments, locality and skin microfilarial counts, with seven amicrofilaridermic responders and 14 ivermectin-naive subjects. The number of treatments taken, any potential drug interactions and significant underlying disease were determined from detailed clinical and laboratory studies. Each subject was treated with ivermectin during the study, so that plasma concentrations of the drug could be determined for 72 h from the time of dosage. The microfilarial and adult-worm responses to this treatment were assessed from skin microfilarial counts (obtained before the treatment and at days 8, 90 and 365 post-treatment), day-90 embryogrammes, and the results of fly-feeding experiments. Parasite-sensitivity criteria for various time-points were derived from earlier data on skin microfilaridermias and the effects of ivermectin on the adult worms. The results indicate that the significant microfilaridermias that persist despite multiple treatments with ivermectin are mainly attributable to the non-response of the adult female worms and not to inadequate drug exposure or other factors. The possibility that some adult female worms have developed resistance to ivermectin cannot be excluded. These results justify the routine monitoring of treatment efficacy in any ivermectin-based programme of disease control.
Asunto(s)
Filaricidas/uso terapéutico , Ivermectina/uso terapéutico , Onchocerca volvulus/aislamiento & purificación , Oncocercosis/tratamiento farmacológico , Adolescente , Adulto , Anciano , Animales , Área Bajo la Curva , Estudios de Casos y Controles , Esquema de Medicación , Resistencia a Medicamentos , Femenino , Filaricidas/efectos adversos , Ghana , Humanos , Ivermectina/efectos adversos , Masculino , Persona de Mediana Edad , Onchocerca volvulus/efectos de los fármacos , Oncocercosis/parasitología , Piel/parasitología , Resultado del TratamientoRESUMEN
A randomized, double-blind, placebo-controlled trial was conducted, to determine whether the co-administration of ivermectin with albendazole is safe and more effective against Onchocerca volvulus than ivermectin alone, and whether a significant pharmacokinetic interaction occurs. Forty-two male onchocerciasis patients received ivermectin (200 mug/kg) alone, albendazole (400 mg) alone or the combination. Safety was determined from the results of detailed clinical and laboratory examinations before treatment, during hospitalization and on day 30. Microfilaricidal efficacy was estimated from the reductions in skin counts between day 0 (pretreatment) and day 30. To determine efficacy against the adult worms, two independent observers examined histology slides prepared from nodules excised on day 180; changes in the skin counts of skin microfilariae between days 30 and 365 provided additional indicators of the level of adulticidal activity. Pharmacokinetic parameters for ivermectin and albendazole sulphoxide were defined over 72 h post-treatment. The co-administration of ivermectin with albendazole did not produce more severe adverse effects than ivermectin alone. Both nodule examiners found that the combination was not macrofilaricidal and that it was not clearly superior to ivermectin alone in the effects on reproductive activity; this was supported by the similar efficacy of the two regimens in the suppression of skin microfilariae. There was no significant pharmacokinetic interaction. Although the co-administration of ivermectin with albendazole appears safe, it offers no advantage over ivermectin alone in the control of onchocerciasis. The combination does not require an alteration in the dosage of either component.