RESUMEN
Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death.
Asunto(s)
Adamantano/análogos & derivados , Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Compuestos Heterocíclicos/administración & dosificación , Compuestos Heterocíclicos/uso terapéutico , Malaria/tratamiento farmacológico , Peróxidos/administración & dosificación , Peróxidos/uso terapéutico , Adamantano/administración & dosificación , Adamantano/química , Adamantano/farmacocinética , Adamantano/uso terapéutico , Animales , Antimaláricos/química , Antimaláricos/farmacocinética , Artemisininas/química , Artemisininas/farmacología , Artemisininas/uso terapéutico , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacocinética , Hierro/metabolismo , Malaria/parasitología , Masculino , Ratones , Peróxidos/química , Peróxidos/farmacocinética , Plasmodium berghei/fisiología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Resultado del TratamientoRESUMEN
In this paper we report the purification and study of the immunogenic properties of the Mycobacterium leprae 18-kDa protein antigen produced and secreted by the yeast Saccharomyces cerevisiae, using an expression system we recently described [Biotech. Lett. 16 (1994) 1241-1246]. The 18-kDa protein was purified from the yeast culture media by precipitation, ion exchange chromatography (MonoQ) and exclusion size chromatography (Sephacryl S-100). The biological properties of the recombinant protein, previously irradiated with gamma rays, were assayed by immunization of mice. Humoral and cellular responses, monitored by antibody production and delayed-type hypersensitivity, respectively, were obtained. Furthermore, gamma-irradiation of the recombinant protein prior to the administration was shown to significantly potentiate the T-cell response. The data suggest that this irradiated recombinant antigen could be used in a more sensitive standardized skin test to monitor M. leprae infection