RESUMEN
Abnormal protein kinase C (PKC) function contributes to many pathophysiological processes relevant for Alzheimer's disease (AD), such as amyloid precursor protein (APP) processing. Phorbol esters and other PKC activators have been demonstrated to enhance the secretion of soluble APPα (sAPPα), reduce the levels of ß-amyloid (Aß), induce synaptogenesis, and promote neuroprotection. We have previously described isophthalate derivatives as a structurally simple family of PKC activators. Here, we characterised the effects of isophthalate derivatives HMI-1a3 and HMI-1b11 on neuronal viability, neuroinflammatory response, processing of APP and dendritic spine density and morphology in in vitro. HMI-1a3 increased the viability of embryonic primary cortical neurons and decreased the production of the pro-inflammatory mediator TNFα, but not that of nitric oxide, in mouse neuron-BV2 microglia co-cultures upon LPS- and IFN-γ-induced neuroinflammation. Furthermore, both HMI-1a3 and HMI-1b11 increased the levels of sAPPα relative to total sAPP and the ratio of Aß42/Aß40 in human SH-SY5Y neuroblastoma cells. Finally, bryostatin-1, but not HMI-1a3, increased the number of mushroom spines in proportion to total spine density in mature mouse hippocampal neuron cultures. These results suggest that the PKC activator HMI-1a3 exerts neuroprotective functions in the in vitro models relevant for AD by reducing the production of TNFα and increasing the secretion of neuroprotective sAPPα.
Asunto(s)
Enfermedad de Alzheimer/enzimología , Ácidos Ftálicos/farmacología , Enfermedad de Alzheimer/metabolismo , Péptidos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Brioestatinas/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Espinas Dendríticas/efectos de los fármacos , Activadores de Enzimas/farmacología , Hipocampo/metabolismo , Humanos , Ratones , Microglía/metabolismo , Neuronas/efectos de los fármacos , Óxido Nítrico/metabolismo , Fragmentos de Péptidos/metabolismo , Ácidos Ftálicos/química , Cultivo Primario de Células , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Plasma concentrations of diftalone have been examined in normal volunteers after a single dose (500 mg) and after 500 mg doses given twice daily for one week. An increase in post dosing urinary excretion of D-glucaric acid showed a correlation with the ratio of calculated to observed areas under the plasma concentration, time curve following the final dose in the multiple dosing studies, indicating that hepatic microsomal enzymes are induced after repeated administration of the drug. Single dose studies in the presence of aluminium hydroxide and sodium bicarbonate showed that the antacids had no significant effect on the absorption of diftalone.
Asunto(s)
Inducción Enzimática/efectos de los fármacos , Piridazinas/farmacología , Adulto , Femenino , Ácido Glucárico/orina , Glucuronidasa/metabolismo , Humanos , Cinética , Masculino , Factores de Tiempo , gamma-Glutamiltransferasa/metabolismoRESUMEN
The four parameter equation, applicable to drug absorption kinetics over a limited time period, has been used to interpret plasma concentration, time results following oral dosage with three different formulations of sulphadiazine tablets, to each of five subjects. Assessment parameters for the formulations, the time for ten percent absorption, the time interval between 10-90% absorption and the plasma concentration with no disposition (relative availability) have been estimated. Intersubject variation obscured many of the differences between formulations. To blank off this variation, plasma concentrations at each time were averaged and then random variation corresponding to the error of the assay method was applied so as to generate a number of sets of data which including the mean concentrations was equal to the number of sets in the original measurements. Kinetic analysis of these sets indicated a number of significant differences between the formulations.
Asunto(s)
Absorción Intestinal , Sulfadiazina/metabolismo , Humanos , Cinética , Modelos Biológicos , Sulfadiazina/administración & dosificación , Comprimidos , Factores de TiempoRESUMEN
A method has been developed for assessing absorption parameters from plasma concentration-time results taken over a relatively short time period. In this method, the disposition function is simplified so as to reduce the number of parameters to be evaluated from the five of the two compartment disposition equation of four, and to avoid the requirement for the evaluation of a slow disposition rate constant. The measurments need not therefore be continued over a period long after absorption is complete. A suitable design for kinetic experiments using this method for interpreting the results, is described. A random noise statistical method is proposed for assessing the stability of the calculated parameters.