Gastrointestinal damage induced by celecoxib and rofecoxib in rats.
Five experimental models were developed in different groups of Wistar rats (N = 15) to study selective COX-2-inhibitor NSAIDs such as celecoxib and rofecoxib, as follows: (1) dose-dependent oral Celecoxib and Rofecoxib for 5 days, and 24 hr after oral indomethacin; (2) Same as 1 but subcutaneously; (3) gastric ulcer induced by glacial acetic acid; (4) duodenal ulcer induced by cysteamine; and (5) stress by immobilization and immersion in water at 15 degrees C for 6 hr. Celecoxib and Rofecoxib, either orally or subcutaneously, did not produce necrotic lesions in healthy gastrointestinal mucosa (0%), showing normal histology. In contrast, previously indomethacin-induced lesions were aggravated (90%, P < 0.001). Total necrosis in the small intestine as well as increased ulcers and perforation of gastric and duodenal ulcers induced by acetic acid and cysteamine were observed. There was also aggravation of the necrotic gastric area in stress (60-90%, P < 0.05). Celecoxib and rofecoxib showed neutrophilia (5000/mm3) similar to that with indomethacin. In contrast, there was no leukocyte infiltration in the gastric múcosa; thus, we can consider it a selective COX-2 NSAID. In conclusion, celecoxib and rofecoxib at doses causing COX-2 but not COX-1 inhibition did not produce toxic lesions in healthy gastrointestinal mucosa, yielding a broad therapeutic margin. In contrast, when administered in altered gastrointestinal mucosa, they aggravated and complicated gastric ulcers as well as necrosis in the small intestine, consequently restricting their clinical use.
Laudanno
O M
OM
Gastroenterología Experimental Cátedras de Patología Médica III e Histología y Embriología, Facultad de Ciencias Médicas, Rosario, Argentina.
Cesolari
J A
JA
Esnarriaga
J
J
Rista
L
L
Piombo
G
G
Maglione
C
C
Aramberry
L
L
Sambrano
J
J
Godoy
A
A
Rocaspana
A
A
D000818:Animals; D000068579:Celecoxib; D016861:Cyclooxygenase Inhibitors / Q000633:toxicity*; D004064:Digestive System / Q000187:drug effects* / Q000473:pathology*; D005260:Female; D007783:Lactones / Q000633:toxicity*; D008297:Male; D011720:Pyrazoles; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000633:toxicity*; D013450:Sulfones
D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; C116926:rofecoxib; D000068579:Celecoxib