title: NSAID-induced enteropathy: are the currently available selective COX-2 inhibitors all the same?
abstract: Nonsteroidal anti-inflammatory drugs (NSAIDs) can induce intestinal mucosal damage, but the underlying mechanisms remain poorly understood. The present study investigated the effects of celecoxib, etoricoxib, indomethacin, and diclofenac on small bowel integrity in rats. Male rats were treated orally with test drugs for 14 days. Animals were processed for assessment of blood hemoglobin levels and hepatic mitochondrial functions, microscopic evaluation of small intestinal damage, Western blot analysis of cyclooxygenase-1 and -2 (COX-1, COX-2) expression, and assay of malondialdehyde (MDA), myeloperoxidase (MPO), and prostaglandin E2 (PGE2) levels in small intestine. Indomethacin and diclofenac decreased blood hemoglobin levels, whereas etoricoxib and celecoxib were without effects. Celecoxib caused a lower degree of intestinal damage in comparison with the other test drugs. Indomethacin and diclofenac, but not etoricoxib or celecoxib, reduced intestinal PGE2 levels. Test drugs did not modify intestinal COX-1 expression, although they enhanced COX-2, with the exception of celecoxib, which downregulated COX-2. Indomethacin, diclofenac, and etoricoxib altered mitochondrial respiratory parameters, although celecoxib was without effects. Indomethacin or diclofenac increased MDA and MPO levels in both jejunum and ileum. In the jejunum, etoricoxib or celecoxib did not modify such parameters, whereas in the ileum, etoricoxib, but not celecoxib, increased both MDA and MPO levels. These findings suggest that nonselective NSAIDs and etoricoxib can induce enteropathy through a topic action, whereas celecoxib lacks relevant detrimental actions. The selectivity profile of COX-1/COX-2 inhibition by test drugs and the related effects on prostaglandin production do not appear to play a major role in the pathogenesis of enteropathy.
authors.affiliation: Department of Clinical and Experimental Medicine (M.F., L.A., R.C., C.P., G.G., M.T., C.B.), Department of Pharmacy (L.T., A.Mar., V.C.), Department of Translational Research and New Technologies in Medicine and Surgery (A.Mat., G.N.), University of Pisa, Pisa, Italy; Clinical Pharmacology and Digestive Pathophysiology Unit, Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy (C.S.).
authors.forename: Matteo
authors.initials: M
authors.lastname: Fornai
authors.forename: Luca
authors.initials: L
authors.lastname: Antonioli
authors.forename: Rocchina
authors.initials: R
authors.lastname: Colucci
authors.forename: Carolina
authors.initials: C
authors.lastname: Pellegrini
authors.forename: Giulio
authors.initials: G
authors.lastname: Giustarini
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.forename: Antuela
authors.initials: A
authors.lastname: Matarangasi
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Natale
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Marco
authors.initials: M
authors.lastname: Tuccori
authors.forename: Carmelo
authors.initials: C
authors.lastname: Scarpignato
authors.forename: Corrado
authors.initials: C
authors.lastname: Blandizzi
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000633:toxicity*; D052246:Cyclooxygenase 2 Inhibitors / Q000737:chemistry / Q000633:toxicity*; D007410:Intestinal Diseases / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology; D007413:Intestinal Mucosa / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors