RESUMO
Two poly(DL-lactide-co-glycolide) microsphere formulations (A, 10% wt/wt, and B, 23% wt/wt, 1-10 microns) were evaluated for intracellular delivery of rifabutin using the J774 murine and Mono Mac 6 (MM6) human monocytic cell lines. Within 7 days, formulation A released 100% in both cell lines and B released 53 and 67% in the J774 and MM6, respectively. Intracellular release of rifabutin with both formulations caused significant reduction of intracellularly replicating Mycobacterium avium (MAC). In MAC-infected beige mice, formulation B (50 mg, intraperitoneal days 0 and 7) completely eliminated infection by 21 days (p < 0.001), similar to a rifabutin daily oral regimen.
Assuntos
Antibióticos Antituberculose/administração & dosagem , Antibióticos Antituberculose/farmacologia , Macrófagos/microbiologia , Infecção por Mycobacterium avium-intracellulare/tratamento farmacológico , Rifabutina/administração & dosagem , Rifabutina/farmacologia , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Contagem de Colônia Microbiana , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Microesferas , Monócitos/microbiologia , Infecção por Mycobacterium avium-intracellulare/microbiologia , Mycobacterium phlei/efeitos dos fármacos , Fagocitose/efeitos dos fármacos , Teste Bactericida do SoroRESUMO
Biodegradable microspheres made with poly-[D,L-lactide-co-glycolide] represent an evolving technology for drug delivery into the central nervous system. Even though these microspheres have been shown to be engulfed by astrocytes in vitro, the purpose of the present study was to track the fate of biodegradable microspheres in vivo. This was accomplished using microspheres containing the fluorescent dye coumarin-6 followed 1 day, 1 week and 1 month after intracerebral injections of this material were made into the rat brain. Using dual color immunohistochemistry and antisera against glial fibrillary acidic protein for astrocytes versus phosphotyrosine for microglia, results demonstrate that phagocytosis of small coumarin-containing microspheres <7.5 microm in diameter was primarily by microglia in vivo during the first week post-injection. In contrast, only a small minority of these microspheres appeared to be engulfed by astrocytes.
Assuntos
Encéfalo/metabolismo , Ácido Láctico/administração & dosagem , Ácido Láctico/farmacocinética , Ácido Poliglicólico/administração & dosagem , Ácido Poliglicólico/farmacocinética , Polímeros/administração & dosagem , Polímeros/farmacocinética , Animais , Astrócitos/metabolismo , Materiais Biocompatíveis/administração & dosagem , Materiais Biocompatíveis/farmacocinética , Injeções Intraventriculares , Masculino , Microesferas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico , Ratos , Ratos Sprague-DawleyRESUMO
Controlled release rifampin-loaded microspheres were evaluated for the first time in nonhuman primates. Animals received either 2.0 g of a large formulation (10-150 microm, 23 wt% rifampin) injected subcutaneously at Day 0 (118-139 mg rifampin/kg), 4.0 g of a small formulation (1-10 microm, 5.8 wt% rifampin) administered intravenously in 2.0 g doses on Day 0 and 7 (62.7-72.5 mg rifampin/kg), or a combination of small and large microspheres (169-210 mg rifampin/kg). Extended rifampin release was observed up to 48 days. Average rifampin concentrations remaining in the liver, lung, and spleen at 30 days were 14.03, 4.09, and 1.98 microg/g tissue, respectively.