RESUMEN
Cerebral spinal fluid (CSF) shunts are the main treatment for hydrocephalus. They divert excess CSF from the ventricular system to the abdominal, pleural, or intravascular space where it is absorbed. The shunt valve regulates flow based on intracranial pressure (ICP) to maintain a physiologically stable and safe ICP. Shunt malfunction is difficult to detect, life-threatening and common. The present study demonstrates that snap-though buckling (STB) shells can be transformed into pressure-relief valves that act in the normal physiological range of ICP. Three different shell designs in this preliminary experiment were found to have opening and closing pressures that fall within the physiologically normal range of ICP of 6 to 25â¯cm H2O. Furthermore, these STB shells demonstrate a valve actuation that is visible by ultrasound and have an implantable form-factor that is similar to currently available shunt valves. The unique characteristics of STB shell valves have potential clinical applications for shunt monitoring using ultrasound imaging and can be fabricated from antibiotic-impregnated materials to mitigate shunt infection. These characteristics make STB valves attractive for future use in cerebral shunt systems.
Asunto(s)
Derivaciones del Líquido Cefalorraquídeo/instrumentación , Presión Intracraneal , Derivaciones del Líquido Cefalorraquídeo/efectos adversos , Diseño de Equipo , Estudios de Factibilidad , Ensayo de Materiales , Fenómenos Mecánicos , Permeabilidad , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/prevención & control , UltrasonografíaRESUMEN
The novel phosphotyrosine (pTyr) mimetic 4'-carboxymethyloxy-3'-phosphonophenylalanine (Cpp) has been designed and incorporated into a series of nonpeptide inhibitors of the SH2 domain of pp60(c-Src) (Src) tyrosine kinase. A 2.2 A X-ray crystal structure of 1a bound to a mutant form of Lck SH2 domain provides insight regarding the structure-activity relationships and supports the design concept of this new pTyr mimetic.
Asunto(s)
Benzamidas/química , Benzamidas/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Organofosfonatos/química , Organofosfonatos/farmacología , Fosfotirosina/química , Proteínas Proto-Oncogénicas pp60(c-src)/antagonistas & inhibidores , Dominios Homologos src/efectos de los fármacos , Animales , Sitios de Unión , Resorción Ósea , Cristalografía por Rayos X , Dentina/efectos de los fármacos , Diseño de Fármacos , Inhibidores Enzimáticos/metabolismo , Espectroscopía de Resonancia Magnética , Imitación Molecular , Mutación , Osteoclastos/efectos de los fármacos , Osteoclastos/metabolismo , Proteínas Proto-Oncogénicas pp60(c-src)/química , Proteínas Proto-Oncogénicas pp60(c-src)/genética , Conejos , Relación Estructura-ActividadRESUMEN
The structure-based design and synthesis of a novel class of 2,4-disubstituted thiazoles as Src SH2 inhibitors is described. Initial results are presented, including the X-ray and NMR analysis of one thiazole inhibitor bound to Lck and Src SH2.