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1.
J Pharmacol Exp Ther ; 331(2): 504-12, 2009 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-19648470

RESUMEN

Gastroesophageal reflux disease (GERD) affects >10% of the Western population. Conventionally, GERD is treated by reducing gastric acid secretion, which is effective in most patients but inadequate in a significant minority. We describe a new therapeutic approach for GERD, based on inhibition of transient lower esophageal sphincter relaxation (TLESR) with a proposed peripherally acting GABA(B) receptor agonist, (R)-(3-amino-2-fluoropropyl)phosphinic acid (AZD3355). AZD3355 potently stimulated recombinant human GABA(B) receptors and inhibited TLESR in dogs, with a biphasic dose-response curve. In mice, AZD3355 produced considerably less central side effects than the prototypical GABA(B) receptor agonist baclofen but evoked hypothermia at very high doses (blocked by a GABA(B) receptor antagonist and absent in GABA(B)-/- mice). AZD3355 and baclofen differed markedly in their distribution in rat brain; AZD3355, but not baclofen, was concentrated in circumventricular organs as a result of active uptake (shown by avid intracellular sequestration) and related to binding of AZD3355 to native GABA transporters in rat cerebrocortical membranes. AZD3355 was also shown to be transported by all four recombinant human GABA transporters. AR-H061719 [(R/S)-(3-amino-2-fluoropropyl)phosphinic acid], (the racemate of AZD3355) inhibited the response of ferret mechanoreceptors to gastric distension, further supporting its peripheral site of action on TLESR. In summary, AZD3355 probably inhibits TLESR through stimulation of peripheral GABA(B) receptors and may offer a potential new approach to treatment of GERD.


Asunto(s)
Esfínter Esofágico Inferior/efectos de los fármacos , Agonistas del GABA/farmacología , Agonistas de Receptores GABA-B , Nervios Periféricos/efectos de los fármacos , Ácidos Fosfínicos/farmacología , Propilaminas/farmacología , Animales , Autorradiografía , Baclofeno/farmacología , Unión Competitiva/efectos de los fármacos , Calcio/metabolismo , Perros , Relación Dosis-Respuesta a Droga , Esfínter Esofágico Inferior/inervación , Femenino , Hurones/metabolismo , Proteínas Transportadoras de GABA en la Membrana Plasmática/metabolismo , Humanos , Hipotermia/inducido químicamente , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Ratones , Relajación Muscular/efectos de los fármacos , Unión Proteica , Isoformas de Proteínas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de GABA-B/metabolismo , Nervio Vago/efectos de los fármacos , Nervio Vago/fisiología
2.
J Pharm Biomed Anal ; 54(4): 826-9, 2011 Mar 25.
Artículo en Inglés | MEDLINE | ID: mdl-21131157

RESUMEN

The option, for practical and ethical reasons, to replace animal plasma with human plasma for calibration standards was successfully applied to 73 analytical methods developed in our laboratory during the last years. The animals used for obtaining blank plasma could then be reduced with a number corresponding to about 25% of mice or 5% of rats in ordinary one-month toxicology studies. This is of important public concern and also in accordance with the 3R-strategy. The methods were successfully validated for determination of drug concentrations in plasma from rat, dog, mouse, rabbit and cynomolgus monkey. Reproducibility of study samples from dosed animals was established, showing a mean accuracy of 100.8% with a CV of 7.2% (n=1339). The purpose of this paper is to present a scientific basis for the alternative approach to adopt human plasma matrix for calibration standards, which will reduce animal use, without compromising the quality of appropriately validated assays. Additional advantages are cheaper and simplified plasma maintenance and the possibility to validate methods for several species in the same analytical batch.


Asunto(s)
Alternativas a las Pruebas en Animales , Evaluación Preclínica de Medicamentos/métodos , Drogas en Investigación/análisis , Preparaciones Farmacéuticas/sangre , Animales , Calibración , Cromatografía Líquida de Alta Presión , Evaluación Preclínica de Medicamentos/economía , Estabilidad de Medicamentos , Humanos , Reproducibilidad de los Resultados , Espectrometría de Masa por Ionización de Electrospray , Espectrometría de Masas en Tándem , Pruebas de Toxicidad/economía , Pruebas de Toxicidad/métodos
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