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1.
Br J Pharmacol ; 153(5): 983-91, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18157165

RESUMO

BACKGROUND AND PURPOSE: Leukotriene B(4) (LTB(4)), formed by the sequential actions of the 5-lipoxygenase (5-LO) and leukotriene A(4) hydrolase (LTA(4)H), is a pro-inflammatory mediator implicated in the pathogenesis of inflammatory bowel disease. However, inhibitors of 5-LO have not proved to be consistent in their therapeutic efficacy in colitis. Another approach to inhibiting LTB(4) synthesis is through the use of inhibitors of LTA(4)H, such as the novel, potent and selective compound, JNJ 26993135. EXPERIMENTAL APPROACH: The effect of oral administration of JNJ 26993135 has been evaluated in a rat model of colitis provoked by colonic instillation of trinitrobenzenesulphonic acid (TNBS). The extent and severity of the macroscopic inflammatory response, the colonic levels of myeloperoxidase (MPO) and LTB(4) and of the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured. KEY RESULTS: Oral administration of JNJ 26993135 (5, 15 and 30 mg kg(-1), twice a day) dose-dependently reduced both the extent and intensity of the colonic inflammatory damage observed 3 days after TNBS challenge. JNJ 26993135 also dose-dependently reduced the elevated colonic levels of LTB(4), as well as the inflammatory biomarkers, MPO, IL-6 and TNF-alpha. This dosing regimen was supported by the pharmacokinetic profile of JNJ 26993135, along with the demonstration of the inhibition of ex vivo production of LTB(4) in whole blood following oral administration. CONCLUSIONS AND IMPLICATIONS: These results with JNJ 26993135 in the rat TNBS model support the role of LTB(4) in colitis and the potential value of targeting LTA(4)H for the treatment of inflammatory bowel diseases.


Assuntos
Benzotiazóis/farmacologia , Colite/tratamento farmacológico , Inibidores Enzimáticos/farmacologia , Epóxido Hidrolases/antagonistas & inibidores , Inflamação/tratamento farmacológico , Piperidinas/farmacologia , Administração Oral , Animais , Benzotiazóis/administração & dosagem , Benzotiazóis/farmacocinética , Colite/induzido quimicamente , Colite/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Sistemas de Liberação de Medicamentos , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/farmacocinética , Inflamação/etiologia , Interleucina-6/metabolismo , Masculino , Peroxidase/efeitos dos fármacos , Peroxidase/metabolismo , Piperidinas/administração & dosagem , Piperidinas/farmacocinética , Ratos , Ratos Wistar , Índice de Gravidade de Doença , Ácido Trinitrobenzenossulfônico , Fator de Necrose Tumoral alfa/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
2.
Gut ; 52(9): 1379-81, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12912874

RESUMO

Recent experimental studies may undermine our understanding of the gastrointestinal side effects of non-steroidal anti-inflammatory drugs and cast a shadow on the original concept that underpins the development of the recent addition to the clinical anti-inflammatory armamentarium, the COX-2 selective inhibitors. But is this just a passing cloud or a total eclipse of the COX theory?


Assuntos
Anti-Inflamatórios não Esteroides/efeitos adversos , Inibidores de Ciclo-Oxigenase/uso terapêutico , Gastroenteropatias/induzido quimicamente , Ciclo-Oxigenase 2 , Inibidores de Ciclo-Oxigenase 2 , Humanos , Isoenzimas/uso terapêutico , Proteínas de Membrana , Prostaglandina-Endoperóxido Sintases/uso terapêutico
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