Histopathological and hormonal study of subacute toxicity of celecoxib on thyroid gland in rats

Celecoxib, a selective cyclo-oxygenase 2 inhibitor, was developed as a potential treatment for rheumatoid arthritis and osteoarthritis. It has good bioavailability and distribution and excellent safety profile in preclinical models. Although the effects of several NSAlDs on thyroid function tests have been investigated, a little was reported in literature about the toxic effect of celecoxib on thyroid functions. This study is one of fewer studies that investigated the subacute toxicity of celecoxib on thyroid function tests as well as on the morphology of thyroid gland in male rats. In this study, the doses of 10, 50 and 75 mg/kg/day of celecoxib were given to male rats orally for 28 days. At the end of the study, serum total triiodothyronine [T[3]], total thyroxine [T[4]] and thyroid stimulating hormone [TSH] levels of rats were analyzed by enzyme immunoassay [EIA] test kits. Thyroid glands of male rats were examined histopathologically. While there was no change in serum T[3] and T[4] of celecoxib-treated rats, there were a significant decrease in serum TSH levels of rats treated with 50, 75 mg/kg/day celecoxib for 28 days compared with those of control rats. In histopathological examinations, celecoxib-related changes were found in thyroid glands of celecoxib-treated rats [50 and 75 mg/kg for 28 days] showing lymphocytic infiltration, distorted acini, degenerated, exhausted colloid and interstitial hemorrhage. These changes in thyroid hormones and histopathology were dose-dependent

Comparative gastrointestinal toxicity of selective cyclooxygenase (COX-2) inhibitors.

Cyclooxygenase (COX-2) inhibitors were developed with the hope that they will cause fewer gastrointestinal adverse effects. Ability of selective as well as nonselective COX inhibitors to alter ischemia-reperfusion induced damage of gastric mucosa and hapten-induced colitis in rats has been compared. Celecoxib (10, 20 and 40 mg/kg(-l)) was significantly more potent at aggravating ischemia-reperfusion injury as compared to nimesulide. Similarly, celecoxib was found to maximally potentiate TNBS-induced colitis, followed by nimesulide and indomethacin. Celecoxib at its highest dose produced maximum deep histological injury. This paradoxic ulcer and colitis aggravating effect of selective COX-2 inhibitors may be explained by suppression of protective prostaglandins generated as a consequence of COX-2 induction in inflammatory states.

Daño gastrointestinal inducido por celecoxib y rofecoxib, en ratas / Gastrointestinal damage induced by celecoxib and rofecoxib in rats

En diferentes grupos de ratas Wistar (n=15), se estudiaron AINEs inhibidores selectivos de la COX-2, como delecoxib y refecoxib, en cinco modelos experimentales: 1) Celecoxib y rofecoxib por vía oral y dosis dependiente durante 5 días y 24 hs. Después de indometacina oral. 2) Similar a 1, pero subcutáneo. 3) Ulcera gástrica inducida por ácido acético glacial. 4) Ulcera duodenal por cisteamina. 5) Estrés por inmovilización e inmersión en agua a 15 grados Celsius durante 6 horas. Celecoxib y rofecoxib por vía oral o SC en mucosa gastrointestinal sana no provaron lesiones necróticas en una superficie del 0 grados Celsius, presentanto histología normal; en cambio, agravaron y complicaron lesiones inducidas en forma previa por indometacina en más del 90 por ciento (p<0,001), con necrosis masiva del intestino delgado, así como ampliaron y causaron perforaciones en las úlceras gástricas y duodenales inducidas por ácido acético y cisteamina. Se produjo asimismo agravación de la zona necrótica gástrica por estrés en un 60-90 por ciento (p<0,05). Celecoxib y rofecoxib condujeron a una neutrofilia de 5000/mm3, similar a la inducida por la indometacina; en cambio, no produjeron infiltración leucocitaria en mucosa gástrica (MPO), siendo un marcador de AINE selectivo COX-2. Se concluyó que celecoxib y rofecoxib, administrados en dosis dependiente como inhibidores de COX-2 y no COX-1, no provocaron en mucosa gastrointestinal sana ninguna lesión por toxicidad, observándose un amplio margen terapéutico. En cambio, suministrados en mucosa gastrointestinal dañada agravaron y complicaron las lesiones ulcerosas gástricas y necróticas intestinales, limitando su uso en clínica.

Celecoxib vs indometacina y lesiones gastricas agudas en ratas / Celecobix vs indomethacin and acute gastric lesions in rats

En diferentes grupos de ratas Wistar (n = 15 en c/grupo), se estudiaron las dosis ulcerogénicas AINES COX-1 como Indometacina vs Celecoxib (inhibidor selectivo COX-2), en la producción de úlceras antrales gástricas y necrosis de la mucosa del intestino delgado y colon. Se encontró que Celecoxib, dado en forma oral o subcutánea cada 12 hs durante 5 días, no provocó lesiones en mucosa gastrointestinal, en cambio, dado el Celecoxib después de la Indometacina, agravé las úlceras antrales gástricas y dio necrosis masiva tanto del intestino delgado y del colon y óbito de todas las ratas. Se concluyó que Celecoxib no provocó lesiones gastrointestinales en mucosa sana; en contraste, se amplificaron las lesiones preexistentes gastrointestinales inducidas por Indometacina.