TY - JOUR
T1 - Lack of effects of acemetacin on signalling pathways for leukocyte adherence may explain its gastrointestinal safety
AU - Chávez-Piña, A. E.
AU - Vong, L.
AU - McKnight, W.
AU - Dicay, M.
AU - Zanardo, R. C.O.
AU - Ortiz, M. I.
AU - Castañeda-Hernández, G.
AU - Wallace, J. L.
PY - 2008/11
Y1 - 2008/11
N2 - Background and purpose: Acemetacin is a non-steroidal anti-inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin. Experimental approach: The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B 4 and thromboxane B 2, on leukocyte-endothelial adherence in post-capillary mesenteric venules, and on gastric expression of tumour necrosis factor-α (TNF-α) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX-2 and NOS. Key results: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF-α. Pretreatment with L-nitro-arginine methyl ester or lumiracoxib increased the severity of indomethacin-induced gastric damage, but this was not the case with acemetacin. Conclusions and implications: The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte-endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene-B 4 synthesis and TNF-α expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption.
AB - Background and purpose: Acemetacin is a non-steroidal anti-inflammatory drug which is rapidly bioconverted to indomethacin, but produces significantly less gastric damage than indomethacin. This study was performed to investigate several possible mechanisms that could account for the gastrointestinal tolerability of acemetacin. Experimental approach: The gastric and intestinal damaging effects of acemetacin and indomethacin were examined in the rat. Effects of the drugs on blood levels of leukotriene B 4 and thromboxane B 2, on leukocyte-endothelial adherence in post-capillary mesenteric venules, and on gastric expression of tumour necrosis factor-α (TNF-α) were determined. The two drugs were also compared for gastric toxicity in rats pretreated with inhibitors of COX-2 and NOS. Key results: Acemetacin induced significantly less gastric and intestinal damage than indomethacin, despite markedly suppressing COX activity. Indomethacin, but not acemetacin, significantly increased leukocyte adherence within mesenteric venules, and gastric expression of TNF-α. Pretreatment with L-nitro-arginine methyl ester or lumiracoxib increased the severity of indomethacin-induced gastric damage, but this was not the case with acemetacin. Conclusions and implications: The increased gastric and intestinal tolerability of acemetacin may be related to the lack of induction of leukocyte-endothelial adherence. This may be attributable to the reduced ability of acemetacin to elevate leukotriene-B 4 synthesis and TNF-α expression, compared to indomethacin, despite the fact that acemetacin is rapidly bioconverted to indomethacin after its absorption.
KW - COX
KW - Gastrointestinal
KW - Leukocyte adherence
KW - NSAID
KW - Nitric oxide
UR - http://www.scopus.com/inward/record.url?scp=57349089418&partnerID=8YFLogxK
U2 - 10.1038/bjp.2008.316
DO - 10.1038/bjp.2008.316
M3 - Artículo
SN - 0007-1188
VL - 155
SP - 857
EP - 864
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
IS - 6
ER -