RESUMEN
In this project, the ability of dual growth factor-preloaded, silk-reinforced, composite hyaluronic acid-based hydrogels to elicit advantageous histologic responses when secured to ischemic myocardium was evaluated in vivo. Reinforced hydrogels containing both Vascular Endothelial Growth Factor (VEGF) and Platelet-derived Growth Factor (PDGF) were prepared by crosslinking chemically modified hyaluronic acid and heparin with poly(ethylene glycol)-diacrylate around a reinforcing silk mesh. Composite patches were sutured to the ventricular surface of ischemic myocardium in Sprague-Dawley rats, and the resulting angiogenic response was followed for 28 days. The gross appearance of treated hearts showed significantly reduced ischemic area and fibrous deposition compared to untreated control hearts. Histologic evaluation showed growth factor delivery to restore myofiber orientation to pre-surgical levels and to significantly increase elicited microvessel density and maturity by day 28 in infarcted myocardial tissue (p < 0.05). In addition, growth factor delivery reduced cell apoptosis and decreased the density of elicited mast cells and both CD68+ and anti-inflammatory CD163+ macrophages. These findings suggest that HA-based, dual growth factor-loaded hydrogels can successfully induce a series of beneficial responses in ischemic myocardium, and offer the potential for therapeutic improvement of ischemic myocardial remodeling.
Asunto(s)
Glicosaminoglicanos/metabolismo , Corazón/efectos de los fármacos , Hidrogeles/metabolismo , Miocardio/patología , Factor A de Crecimiento Endotelial Vascular/metabolismo , Animales , Ácido Hialurónico/farmacología , Isquemia/patología , Neovascularización Fisiológica/efectos de los fármacos , Ratas Sprague-Dawley , Factor A de Crecimiento Endotelial Vascular/farmacologíaRESUMEN
Incorporation of pyridines and diazines into the biphenyl region of quinolone carboxylic acid derived M(1) positive allosteric modulators was investigated as a means of lowering plasma protein binding to enhance CNS exposure.
Asunto(s)
Proteínas Sanguíneas/química , Piridinas/química , Receptor Muscarínico M1/antagonistas & inhibidores , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Regulación Alostérica , Animales , Proteínas Sanguíneas/metabolismo , Humanos , Unión Proteica , Piridinas/síntesis química , Piridinas/farmacología , Ratas , Receptor Muscarínico M1/metabolismo , Relación Estructura-ActividadRESUMEN
Replacement of a phenyl ring with N-linked heterocycles in a series of quinolone carboxylic acid M1 positive allosteric modulators was investigated. In particular, a pyrazole derivative exhibited improvements in potency, free fraction, and CNS exposure.
Asunto(s)
Ácidos Carboxílicos/síntesis química , Compuestos Heterocíclicos/síntesis química , Pirazoles/síntesis química , Quinolinas/síntesis química , Regulación Alostérica , Animales , Células CHO , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Línea Celular , Cricetinae , Cricetulus , Compuestos Heterocíclicos/química , Compuestos Heterocíclicos/farmacología , Humanos , Estructura Molecular , Pirazoles/química , Pirazoles/farmacología , Quinolinas/química , Quinolinas/farmacología , Ratas , Relación Estructura-ActividadRESUMEN
There are few reports of radiation associated colorectal-genitourinary tract (CRGU) fistulae causing Fournier's gangrene (FG). We describe a case of FG in a patient with possibly two CRGU fistulae in the context of previous high-dose brachytherapy and external beam radiation therapy for prostate cancer. Unfortunately, CRGU fistulae are not well classified as significant risk factors for the development of FG. Our case demonstrates the rationale for maintaining a broad differential in patients presenting with recurrent urinary tract symptoms or necrotising soft tissue infections to include undiagnosed fistulae.
Asunto(s)
Braquiterapia/efectos adversos , Enfermedades del Colon/complicaciones , Gangrena de Fournier/etiología , Enfermedades de los Genitales Masculinos/complicaciones , Fístula Intestinal/complicaciones , Fístula Urinaria/complicaciones , Enfermedades del Colon/diagnóstico , Diagnóstico Diferencial , Fístula/diagnóstico , Fístula/etiología , Gangrena de Fournier/diagnóstico , Enfermedades de los Genitales Masculinos/diagnóstico , Humanos , Fístula Intestinal/diagnóstico , Masculino , Persona de Mediana Edad , Neoplasias de la Próstata/radioterapia , Tomografía Computarizada por Rayos X , Fístula Urinaria/diagnósticoRESUMEN
One approach to ameliorate the cognitive decline in Alzheimer's disease (AD) has been to restore neuronal signaling from the basal forebrain cholinergic system via the activation of the M(1) muscarinic receptor. A number of nonselective M(1) muscarinic agonists have previously shown positive effects on cognitive behaviors in AD patients, but were limited due to cholinergic adverse events thought to be mediated by the activation of the M(2) to M(5) subtypes. One strategy to confer selectivity for M(1) is the identification of positive allosteric modulators, which would target an allosteric site on the M(1) receptor rather than the highly conserved orthosteric acetylcholine binding site. Quinoline carboxylic acids have been previously identified as highly selective M(1) positive allosteric modulators with good pharmacokinetic and in vivo properties. Herein is described the optimization of a novel quinolizidinone carboxylic acid scaffold with 4-cyanopiperidines being a key discovery in terms of enhanced activity. In particular, modulator 4i gave high plasma free fractions, enhanced central nervous system (CNS) exposure, was efficacious in a rodent in vivo model of cognition, and afforded good physicochemical properties suitable for further preclinical evaluation.