RESUMO
Five AZT (azidothymidine) prodrugs conjugated with the 1-adamantane moiety via an ester bond were synthesized to improve the transport of AZT into the central nervous system (CNS). In in vitro degradation studies with rat and human plasma, it was demonstrated that the prodrugs were degraded enzymatically and converted quantitatively to their parent drug. AZT. As assessed by octanol-buffer partitioning, the prodrugs were much more lipophilic than AZT and were expected to penetrate the blood-brain barrier (BBB) readily. In in vivo studies, in which the prodrugs were administered intravenously to rat, the prodrugs in brain tissue were detected at 7-18 times higher concentrations than AZT in spite of the negligible amount of the prodrug in the cerebrospinal fluid. These results indicate that the introduction to AZT of the 1-adamantane moiety results in the enhancement of the BBB penetration. This pharmaceutical approach would be beneficial for the efficient treatment of the CNS infection by human immunodeficiency virus.
Assuntos
Adamantano/farmacologia , Encéfalo/metabolismo , Pró-Fármacos/farmacologia , Zidovudina/farmacocinética , Adamantano/farmacocinética , Animais , Barreira Hematoencefálica/fisiologia , Fenômenos Químicos , Físico-Química , Cromatografia Líquida de Alta Pressão , Portadores de Fármacos , Humanos , Hidrólise , Técnicas In Vitro , Masculino , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Ratos , Ratos Wistar , Zidovudina/administração & dosagem , Zidovudina/análogos & derivadosRESUMO
Acidolytic deprotection and cleavage conditions for an acid-labile Tyr(SO3H)-containing peptide were systematically examined with respect to acid, temperature, and scavenger. The 90% aqueous trifluoroacetic acid (TFA)-based reagent systems (90% aqueous TFA/m-cresol and 90% aqueous TFA/m-cresol/2-methylindole) at 4 degrees C were found to minimize the deterioration of Tyr(SO3Na) in the peptide. The latter deprotection/cleavage system was applied to the 9-fluorenylmethyloxycarbonyl (Fmoc)-based solid-phase synthesis of cholecystokinin (CCK)-12 on an acid-labile PAL-linked support (PAL = peptide amide linker), with Fmoc-Tyr(SO3Na)-OH as a building block.
Assuntos
Colecistocinina/síntese química , Peptídeos/síntese química , Tirosina/análogos & derivados , Sequência de Aminoácidos , Cromatografia Líquida de Alta Pressão , Cresóis , Dados de Sequência Molecular , Ácido Trifluoracético , Tirosina/químicaAssuntos
Colágeno , Tendão do Calcâneo , Animais , Bovinos , Conformação Proteica , Água , Difração de Raios XRESUMO
The present study was designed to investigate the effect of verbal information processing upon CNV, using a lexical decision task. Subjects performed a choice reaction time (RT) task under possible combinations of sense and nonsense syllables serving as warning (S1) and imperative (S2) stimuli. The results showed that CNV developed exclusively when the expectant information for motor response was given at S1. It was also found that CNV resolution time as well as RT was shorter in the near meaning condition than in the far meaning condition. These findings were discussed in relation to verbal information processing.
