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Year : 2004  |  Volume : 36  |  Issue : 4  |  Page : 256
 

Selective cyclooxygenase-2 inhibitors in inflammatory bowel disease


Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh -160 014, India

Correspondence Address:
Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh -160 014, India
skpu@yahoo.com



How to cite this article:
Kulkarni S K, Singh V P. Selective cyclooxygenase-2 inhibitors in inflammatory bowel disease. Indian J Pharmacol 2004;36:256


How to cite this URL:
Kulkarni S K, Singh V P. Selective cyclooxygenase-2 inhibitors in inflammatory bowel disease. Indian J Pharmacol [serial online] 2004 [cited 2020 Feb 29];36:256. Available from: http://www.ijp-online.com/text.asp?2004/36/4/256/11159


Sir,
The gastric (ulcer-producing) adverse relationship of conventional non-steroidal antiinflammatory drugs (NSAIDs) is now well recognized.[1] NSAIDs non-specifically inhibit the cyclooxygenase enzymes (COX-1 and COX-2) leading to loss of gastric mucosal integrity and at the same time producing the desired antiinflammatory effect.[2] It has been proposed that selective COX-2 inhibitors (coxibs) are non-toxic to the gastrointestinal tract by sparing COX-1 while retaining the potential antiinflammatory effect.[3] It was on this background that the NSAIDs, particularly the selective COX-2 inhibitors were indicated in inflammatory bowel disease (IBD). However, recent reports indicate conflicting clinical observations (exacerbation or amelioration) of IBD with the use of coxibs, the new COX-2 inhibitors.[4],[5],[6],[7]
Long-term administration of COX-2 inhibitors to knockout mice (genetically COX-2 deficient) led to development of significant intestinal pathology suggesting that COX-2 products are involved in the maintenance of bowel integrity.[8] The mechanism(s) underlying the intestinal damage and aggravation by coxibs have been poorly explored. COX-2 expression was reported to be increased in the colonic mucosa in both experimental colitis[9] and colitis of IBD,[10] suggesting its protective role in healing. It could thus be speculated that the suppression of elevated COX-2 levels by coxibs leads to further deterioration of active IBD. First-degree relatives of patients with Crohn's disease experienced increase in small bowel permeability with use of coxibs.[11] A genetic component may also be involved in IBD.
However, it remains uncertain whether the coxibs-mediated increase is linked to the depletion of cytoprotective prostaglandins derived via this isoform[12] or whether it is due to the mucosal exposure of luminal antigens that trigger local inflammatory reaction.[4] Recently, a new role of COX-2 in the maintenance of oral tolerance has been suggested. The tolerance of the intestinal immune system is assumed to be disrupted in IBD, thus causing enhanced reactivity of mucosal flora.[13],[14]
Further, the induction of COX-2 enzyme in apical and lamina propria mononuclear cells of the intestine in IBD patients suggests a function for COX-2 in repairing damaged tissue.[10] Moreover, coxibs do not provoke injury on previously normal intestine.[5] Thus, it is theoretically possible that active IBD might be even more specifically worsened by coxibs.
Though the clinical evidence is still preliminary these observations raise concern regarding the use of coxibs in preexisting IBD. However, the chemopreventive activity of coxibs against colorectal carcinomas arising from ulcerative colitis[15] might further justify the potential application of selective COX-2 inhibitors in IBD.
Thus, at the moment, the use of coxibs in patients with inflammatory bowel disease should be viewed with the same caution as with the use of conventional NSAIDs. 

  References Top

1.Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998; 38: 97-120.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Crybe B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal antiinflammatory drugs. Am J Med 1998;104:413-21.  Back to cited text no. 2    
3.Masferrer Jl, Zweifel BS, Manning PT, Hauser SD, Leahy KM, Smith WG, et al. Selective inhibition of Schachna. Med J Aust 1999;171:175-6.  Back to cited text no. 3    
4.Bonner F. Exacerbation of inflammatory bowel disease associated with use of celecoxib. Am J Gastroenterol 2001; 91:1306-8.  Back to cited text no. 4    
5.Gornet JM, Hassani Z, Modiglian R, Lemann M. Exacerbation of Crohn's colitis with severe colonic hemorrhage in a patient on rofecoxib. Am J Gastroenterol 2002;97:3209-10.  Back to cited text no. 5  [PUBMED]  [FULLTEXT]
6.Reinisch W, Miehsler W, Dejaco C, Harrer M, Waldhoer T, Lichenberger C, et al. An open-label trial of the selective cyclooxygenase-2 inhibitor, rofecoxib, in inflammatory bowel disease-associated peripheral arthritis and arthralgia. Aliment Pharmacol Ther 2003; 17: 1371-80.  Back to cited text no. 6    
7.Mahadevan U, Loftus, EV Jr, Tremaine WJ, Sandborn WJ. Safety of selective cyclooxygenase-2 inhibitors in inflammatory bowel disease. Am J Gastroenterol 2002; 97:910-4.  Back to cited text no. 7    
8.Sigthorsson G, Simpson RJ, Walley M, Anthony A, Foster R, Hotz-Behoftsitz C, et al. COX-1 and COX-2, intestinal integrity, and pathogenesis of nonsteroidal antiinflammatory drug enteropathy in mice. Gastroenterology 2002; 122: 1913-23.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Wallace JL. Nonsteroidal antiinflammatory drugs and gastroenteropathy: The second hundred years. Gastroenterology 1997; 112: 1000-16.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Singer II, Kawka DW, Schloemann S, Tessner T, Riehl T, Stenson WF. Cyclooxygenase 2 is induced in colonic epithelial cells in inflammatory bowel disease. Gastroenterology 1998; 115: 297-306.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Hilsden RJ, Meddings JB, Sutherland LR. Intestinal permeability changes in response to acetylsalicylic acid in relatives of patients with Crohn's disease. Gastroenterology 1996;110:1395-403.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Roberts PJ, Morgan K, Miller R, Hunter JO, Middleton SJ. Neuronal COX-2 expression in human myenteric plexus in active inflammatory bowel disease. Gut 2001;48: 468-72.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Newberry RD, Stenson WF, Lorenz RG. Cyclooxygenase 2-dependent arachidonic acid metabolites are essential modulators of the intestinal immune response to dietary antigen. Nat Med 1999; 5: 900-6.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Duchmann R, Kaiser DW, Hermann E, Mayet W, Ewe K, Meyer zum Buschenfelde KH. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD). Clin Exp Immunol 1995; 102: 448-55.  Back to cited text no. 14    
15.Fitzgerald GA, Patrono C. The coxibs, selective inhibitors of cyclooxygenase-2. N Engl J Med 2001; 345: 433-42.  Back to cited text no. 15  [PUBMED]  [FULLTEXT]
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