RESUMEN
The rate of drug release from a polymeric matrix system was influenced by the physical and chemical properties of the monolithic films. The model drugs, salicylic acid and chlorpheniramine maleate, and two poly(methyl methacrylate) copolymers of different permeabilities (Eudragit RL and Eudragit RS), with and without additional adjuvants, were used to form monolithic matrix films for controlled drug release. Adjuvants, including polyethylene glycols (PEG 400 and PEG 8000) and poly(vinylpyrrolidones) (PVP-K15 and PVP-K90), were incorporated into films of Eudragit RL PM and Eudragit RS PM. The moisture permeation constant, glass transition temperature (Tg), tensile strength, and drug release profiles were determined for each acrylic resin slab to correlate the physicochemical and physicomechanical film properties to observed drug release. Faster rates of drug diffusion were observed with the addition of PEG 400 to the films, because of its plasticizing effect and the resultant increased moisture permeability of the matrix. An exception existed with the Eudragit RL PM film containing salicylic acid where drug-polymer interactions inhibited drug diffusion. The small changes in moisture permeability, Tg, and tensile strength observed with incorporation of the PVPs had an insignificant influence on the dissolution results for salicylic acid from Eudragit RS PM films. Increases in the tensile strength and Tg after addition of PVP to the Eudragit RS PM matrix support the observed decreased rate of diffusion for chlorpheniramine maleate. The pores formed by migration of the hydrophilic adjuvants from the films altered the diffusion kinetics of the matrix, compared with that of the nonporous polymer, when only the antihistamine was present.
Asunto(s)
Adyuvantes Farmacéuticos/química , Clorfeniramina/química , Salicilatos/química , Resinas Acrílicas/química , Adyuvantes Farmacéuticos/farmacología , Fenómenos Químicos , Química Farmacéutica , Química Física , Preparaciones de Acción Retardada , Polietilenglicoles/química , Polietilenglicoles/farmacología , Povidona/química , Povidona/farmacología , Ácido SalicílicoRESUMEN
We investigated the effect of phorbol 12-myristate 13-acetate (PMA), a protein kinase C (PKC) activator on insulin receptors and insulin action in freshly isolated and primary cultures of rat hepatocytes. PMA (1 x 10(-7) M) did not alter insulin receptor numbers or affinity either acutely or chronically but within 60 minute inactivated insulin stimulated tyrosine kinase of the insulin receptor. PKC activation inhibited insulin (1 x 10(-7) M) stimulation of glycogen and lipid synthesis with a decrease or no change in basal glycogenesis and lipogenesis respectively. However, PKC activation did not alter insulin stimulated or basal amino acid transport even though PKC activation inhibited insulin stimulation of the insulin receptor tyrosine kinase. Thus, within one tissue, PKC activation has differential effect on insulin action depending on which pathway is examined. Furthermore, insulin stimulation of the insulin receptor tyrosine kinase may not be a necessary step for all insulin signaling pathways.
Asunto(s)
Insulina/farmacología , Hígado/efectos de los fármacos , Proteína Quinasa C/fisiología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Receptor de Insulina/efectos de los fármacos , Acetato de Tetradecanoilforbol/farmacología , Animales , Células Cultivadas , Diabetes Mellitus Tipo 2/fisiopatología , Insulina/fisiología , Resistencia a la Insulina , Hígado/metabolismo , Masculino , Modelos Biológicos , Ratas , Receptor de Insulina/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
An investigation was conducted to evaluate the factors influencing the release of salicylic acid and chlorpheniramine maleate from polymethacrylate amino-ester copolymer films (Eudragits RL PM and RS PM). Differential scanning calorimetry was performed on the films to study the solubility of drug in the polymer and to determine the effect of added drug on the thermal properties of the film. Incorporation of drug into the polymers decreased the glass transition temperature of the polymers. Dissolution of drug from monolithic slabs was followed as a function of temperature, drug concentration in the films, and ionic strength of the release media. In addition, adsorption studies were conducted with each drug:polymer combination to help explain release results and further characterize the drug:polymer interactions that occurred. The rate of drug release increased with increasing temperature. Adsorption of salicylic acid by the polymers was believed to influence the drug release profiles observed for different drug loadings and ionic strengths. Eudragit RL was found to adsorb salicylic acid to a greater extent than the Eudragit RS. Chlorpheniramine maleate was not found to be adsorbed by either polymer.
Asunto(s)
Preparaciones Farmacéuticas/química , Acrilatos , Adsorción , Química Farmacéutica , Clorfeniramina/química , Membranas Artificiales , Polímeros , Ácidos Polimetacrílicos , Resinas de Plantas , Salicilatos/química , Ácido Salicílico , TemperaturaRESUMEN
The ontogeny of the structural and functional characteristics of insulin receptors is determined by examining insulin binding, subunit structure, autophosphorylation, and tyrosine-specific protein kinase activity in partially purified solubilized liver receptors from fetal (approximately 21 days postconception), neonatal (1- and 7-day-old), and adult rats. Specific 125I-labeled insulin binding to these receptor preparations in the presence of different insulin concentrations was higher in fetal and neonatal rats compared with that in the adult rats. The electrophoretic mobilities of the alpha- and beta-subunits on sodium dodecyl sulfate-polyacrylamide gel electrophoresis autoradiography were similar at different stages of development. Insulin-stimulated autophosphorylation of insulin receptors was similar in the different groups. With fixed amounts of protein, the tyrosine-specific protein kinase activity in the presence of different insulin concentrations (1 X 10(-8) to 1 X 10(-6) M) was significantly higher in the fetal and neonatal rats than in adult rats. However, when expressed as a function of insulin-binding activity, the insulin-stimulated tyrosine-specific protein kinase activity in fetal and neonatal rats appears to be similar to that in adult rats because of decreased insulin binding in the latter group. These results demonstrate the structural and functional similarities of hepatic insulin receptors in fetal, neonatal, and adult rats. The relative differences in insulin-mediated biological functions in fetal and adult rat livers as reported previously are due to alterations in a step(s) distal to activation of insulin-receptor kinase.
Asunto(s)
Animales Recién Nacidos/metabolismo , Feto/metabolismo , Hígado/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Receptor de Insulina/metabolismo , Animales , Unión Competitiva , Electroforesis en Gel de Poliacrilamida , Activación Enzimática/efectos de los fármacos , Técnicas de Inmunoadsorción , Insulina/metabolismo , Insulina/farmacología , Hígado/embriología , Hígado/crecimiento & desarrollo , Peso Molecular , Fosforilación , Ratas , Ratas EndogámicasRESUMEN
We have developed a method to isolate insulin-responsive human hepatocytes from an intraoperative liver biopsy to study insulin action and resistance in man. Hepatocytes from obese patients with noninsulin-dependent diabetes were resistant to maximal insulin concentration, and those from obese controls to submaximal insulin concentration in comparison to nonobese controls. Insulin binding per cell number was similar in all groups. However, insulin binding per surface area was decreased in the two obese groups because their hepatocytes were larger. In addition, the pool of detergent-extractable receptor was further decreased in diabetics. Insulin receptors in all groups were unaltered as determined by affinity-labeling methods. However, insulin-stimulated insulin receptor kinase activity was decreased in diabetics. Thus, in obesity, decreased surface binding could explain resistance to submaximal insulin concentrations. In diabetes, diminished insulin-stimulated protein kinase activity and decreased intracellular pool of receptors could provide an explanation for postinsulin-binding defect(s) of insulin action in human liver.