RESUMEN
A novel series of terphenyl methyl sulfones and sulfonamides have been shown to be highly potent and selective cyclooxygenase-2 (COX-2) inhibitors. The sulfonamide analogs 17 and 21 were found to be much more potent COX-2 inhibitors and orally active anti-inflammatory agents than the corresponding methyl sulfone analogs 16 and 20, respectively, albeit with some decrease in COX-2 selectivity. Structure-activity relationship studies have determined that incorporation of two fluorine atoms in the central phenyl group, as in 20 and 21, is extremely advantageous for both in vitro COX-2 potency and selectivity as well as in vivo activity. Several noticeable examples in the 1,2-diaryl-4,5-difluorobenzenesulfonamide series are 21a-c,k,l,n (COX-2, IC50 = 0.002-0.004 microM), in which all have in vitro COX-1/COX-2 selectivity > 1000. In addition, sulfonamides 21a,b,d,g,j,m,n,q were shown to have greatly enhanced oral activity with more than 90% inhibition of prostaglandin E2 production in the air pouch model of inflammation. Furthermore, sulfonamide 21b was found to be very active in the rat adjuvant-induced arthritis model (ED50 = 0.05 mg/kg) and carrageenan-induced hyperalgesia assay (ED50 = 38.7 mg/kg) with no indication of gastrointestinal toxicity in rats at doses as high as 200 mg/kg.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Inhibidores de la Ciclooxigenasa/farmacología , Isoenzimas/efectos de los fármacos , Prostaglandina-Endoperóxido Sintasas/efectos de los fármacos , Compuestos de Terfenilo/farmacología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/química , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Experimental/tratamiento farmacológico , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Inhibidores de la Ciclooxigenasa/química , Inhibidores de la Ciclooxigenasa/uso terapéutico , Espectroscopía de Resonancia Magnética , Espectrometría de Masas , Ratas , Compuestos de Terfenilo/administración & dosificación , Compuestos de Terfenilo/química , Compuestos de Terfenilo/uso terapéuticoRESUMEN
Dystocial calves were tested for their ability to absorb colostral immunoglobulins and establish a competent passive immunity. Twenty dystocial and 20 eutocial calves were fed 1 liter of colostrum 4 h after birth and an additional liter 12 h later. Their absorption of the immunoglobulins A, G, and M, as indicated by serum concentrations, was equivalent at 16 and 24 h postpartum. Cortisol concentrations in serum at birth were high in both eutocial and dystocial calves and were correlated negatively with environmental temperatures prior to parturition. The dystocial calves had a lower cortisol concentration in serum at birth. The differences in cortisol concentrations between dystocial and eutocial calves and between experimental blocks influenced by environmental temperature could not be related to immunoglobulin absorption.