RESUMO
In this work we present the synthesis, aqueous solubility and stability, hydrolysis by alkaline phosphatase, and in vivo fasciolicidal activity in sheep of a highly water soluble phosphate salt prodrug of triclabendazole (MFR-5). The aqueous solubility of MFR-5 at pH 7 was 88,000-fold that of triclabendazole. MFR-5 showed excellent aqueous stability (>95% after 26h) at pH 7, making it ideal for developing pharmaceutical compositions in the form of solutions that can easily be hydrolyzed by the enzyme alkaline phosphatase (t=13.6s) to liberate the precursor compound. An aqueous solution of MFR-5 administered intramuscularly to sheep at concentrations of 4, 6 and 8mg/kg presented a fasciolicidal efficiency of 96.5%, 98.4% and 99.2%, respectively. In the in vivo experiments, MFR-5 reduced 100% the excretion of eggs in all of the above concentrations.
Assuntos
Benzimidazóis/química , Organofosfatos/química , Pró-Fármacos/química , Água/química , Animais , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Benzimidazóis/uso terapêutico , Fasciola hepatica/efeitos dos fármacos , Fasciola hepatica/crescimento & desenvolvimento , Fasciolíase/tratamento farmacológico , Organofosfatos/síntese química , Organofosfatos/farmacologia , Óvulo/efeitos dos fármacos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Ovinos , Solubilidade , TriclabendazolRESUMO
This study describes the synthesis of compound (7), a highly hydrosoluble phosphonooxymethyl prodrug of compound alpha (4). Compound (7) improved the aqueous solubility of its precursor compound (4) by 50,000 times and it is stable at neutral pH. The prodrug showed faciolicidal activity when evaluated in vitro against excysted Fasciola hepatica metacercariae. The in vivo evaluation of (7) was carried out via oral, intramuscular and subcutaneous administration in sheep artificially infected with F. hepatica metacercariae. At an intramuscular dose of 4 mg/kg, the activity of (7) was similar to that of compound alpha (4) at an oral dose of 15 mg/kg.