RESUMEN
Irritable bowel syndrome (IBS) is a pathopysiolocal condition characterized by abnormal bowel habits that are frequently accompanied by abdominal pain. Current therapy based on reducing high-amplitude GI contractions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. We have previously found potent antinociceptive agents acting through muscarinic receptors. In the present work, new 1,2,5-thiadiazole-based structures with muscarinic activity have been evaluated both for activity as analgesics in the mouse withing assay and for activity in normalizing spontaneous cluster contractions in ferret jejunum as a model of IBS in humans. (5R,6R)-exo-6-[4-[(4,4,4-Trifluorobutyl)thio]-1,2,5-thiadiazol+ ++-3-yl] -1-azabicyclo[3.2.1]octane (35, LY316108/NNC11-2192) was found to offer an exceptional profile combining analgesic potency in mouse writhing (ED50 = 0.1 mg/kg) along with potency for normalization of GI motility (ED50 = 0.17 mg/kg). This combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.
Asunto(s)
Analgésicos no Narcóticos/uso terapéutico , Enfermedades Funcionales del Colon/tratamiento farmacológico , Diseño de Fármacos , Agonistas Muscarínicos/uso terapéutico , Analgésicos no Narcóticos/síntesis química , Analgésicos no Narcóticos/química , Animales , Hurones , Motilidad Gastrointestinal/efectos de los fármacos , Masculino , Ratones , Agonistas Muscarínicos/síntesis química , Agonistas Muscarínicos/química , Nociceptores/efectos de los fármacos , Oxotremorina/análogos & derivados , Oxotremorina/metabolismoRESUMEN
A 54-year-old female patient admitted with a diagnosis of tetanus had her sedation reversed with an infusion of flumazenil. Flumazenil appears to be of use in reversal of sedation in patients with accumulation of benzodiazepine after prolonged administration.
Asunto(s)
Benzodiazepinas/antagonistas & inhibidores , Flumazenil/farmacología , Tétanos/complicaciones , Femenino , Flumazenil/administración & dosificación , Escala de Coma de Glasgow , Humanos , Infusiones Intravenosas , Persona de Mediana EdadRESUMEN
A 54-year-old female patient admitted with a diagnosis of tetanus had her sedation reversed with an infusion of flumazenil. Flumazenil appears to be of use in reversal of sedation in patients with accumulation of benzodiazepine after prolonged administration.