Difficult Establishment of a Chronic Nonsteroidal Anti-inflammatory Drugs Induced Gastric Inflammation Rat Model due to Gastric Adaptation and Small Bowel Damage / 대한소화기학회지

BACKGROUND/AIMS: The prevalence of peptic ulcer disease has not decreased mainly due to an increase in the use of NSAIDs. This study was conducted in order to determine whether a chronic NSAID-induced gastric inflammation model could be established by repeated administration of NSAID. METHODS: Indomethacin (10 mg/kg) was administered once per week for six weeks in 8- and 26-week rats and animals were sacrificed every week after administration. Gross ulcer index, histologic damage index, myeloperoxidase (MPO) activity, and mucus (glucosamine) levels were measured. Small bowel damage was also evaluated. RESULTS: Gross gastric damage index showed a peak level at three weeks and then decreased slowly in the 26-week indomethacin group. Gastric mucosal glucosamine level increased in both the 8-week (p=0.038) and 26-week groups (p=0.007). In addition, gastric mucosal MPO level decreased in the 8-week group (p=0.018) but did not show a decrease in the 26-week group. Small bowel damage began to occur at three weeks during the schedule and eight of 36 rats (22.2%) died due to perforation or peritonitis of the small bowel in the 8- and 26-week indomethacin groups, respectively. CONCLUSIONS: Due to gastric adaptation and small bowel damage, repeated administration of NSAID to experimental animals may not be an adequate method for establishment of the chronic gastric inflammation model.

Difficult Establishment of a Chronic Nonsteroidal Anti-inflammatory Drugs Induced Gastric Inflammation Rat Model due to Gastric Adaptation and Small Bowel Damage / 대한소화기학회지

BACKGROUND/AIMS: The prevalence of peptic ulcer disease has not decreased mainly due to an increase in the use of NSAIDs. This study was conducted in order to determine whether a chronic NSAID-induced gastric inflammation model could be established by repeated administration of NSAID. METHODS: Indomethacin (10 mg/kg) was administered once per week for six weeks in 8- and 26-week rats and animals were sacrificed every week after administration. Gross ulcer index, histologic damage index, myeloperoxidase (MPO) activity, and mucus (glucosamine) levels were measured. Small bowel damage was also evaluated. RESULTS: Gross gastric damage index showed a peak level at three weeks and then decreased slowly in the 26-week indomethacin group. Gastric mucosal glucosamine level increased in both the 8-week (p=0.038) and 26-week groups (p=0.007). In addition, gastric mucosal MPO level decreased in the 8-week group (p=0.018) but did not show a decrease in the 26-week group. Small bowel damage began to occur at three weeks during the schedule and eight of 36 rats (22.2%) died due to perforation or peritonitis of the small bowel in the 8- and 26-week indomethacin groups, respectively. CONCLUSIONS: Due to gastric adaptation and small bowel damage, repeated administration of NSAID to experimental animals may not be an adequate method for establishment of the chronic gastric inflammation model.

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.

Partial suppressive effect of melatonin on indomethacin-induced renal injury in rat.

Intramuscular injection of a single high dose of indomethacin (20 mg/kg) in fasted rats produced renal injury. The results showed increases in the level of lipid peroxidation and cholesterol, and activity of acid phosphatase and alkaline phosphatase in the kidney. Also, the renal contents of both reduced glutathione and activity of total adenosine triphosphatase were decreased by the toxicant. In serum, indomethacin increased activity of lactate dehydrogenase and acid phosphatase, and levels of creatinine and inorganic phosphorus. Paradoxically, administration of melatonin (0.75 mg/rat/day) alone for 7 days decreased significantly the activity of lipid peroxidation and acid phosphatase, and increased, but not significantly, the level of reduced glutathione in the kidney. Also, serum level of creatinine tended to decrease, but not significantly. Pretreatment with melatonin prevented the increase by subsequently administered indomethacin in the renal activity of lipid peroxidation and acid phosphatase. However, this pretreatment regimen partially suppressed the adverse changes in the remaining analyzed cytotoxic parameters induced by indomethacin in both serum and kidney. These results indicate that oral administration of melatonin at a low dose level exerted moderate antioxidant action, thereby it protected against some of the renal detrimental effects produced by indomethacin.

Effect of methanolic leaf extract of Cissampelos mucronata A. Rich against indomethacin induced ulcer in rats.

Five fractions (F1-F5) isolated from the methanolic leaf extract of Cissampelos mucronata A. Rich were investigated for antiulcer activity. At the dose of 450 mg/kg, they showed varying degree of protection against ulcer induced by indomethacin; the order of protection being F1>F4>F5>F2>F3. The antiulcer potency of F1 and F2 is comparable with that of cimetidine (100 mg/kg, i.p.). Inhibition of gastric mucosal damage may partly contribute to the antiulcer activity of the fractions.

Effect of melatonin and beta-carotene on indomethacin induced gastric mucosal injury.

The study was conducted to examine the role of free radicals in Indomethacin induced gastric mucosal injury and to evaluate the gastroprotective effects of melatonin and beta-carotene. Gastric mucosal injury was produced in rats by administering indomethacin 30 mg/kg subcutaneously. Melatonin was administered in three different doses of 5, 10 and 20 mg/kg, 30 minutes prior to the administration of indomethacin. Beta-carotene was administered as a single dose of 100 mg/kg. Following parameters were calculated: ulcer index, lipid peroxidation and antioxidant defense enzymes i.e. superoxide dismutase, glutathione peroxidase and catalase. Indomethacin caused gastric mucosal injury in the form of haemorrhages, increased the lipid peroxidation and decreased the levels of the antioxidant defense enzymes. Melatonin (20 mg/kg) and beta-carotene decreased the ulcer index and lipid peroxidation, and reduced the decrease in antioxidant enzyme levels. These findings suggest the melatonin and beta-carotene show protective effect against indomethacin induced gastric injury and this effect is mediated by scavenging of oxygen derived free radicals.

Mutagenic and teratogenic effects of indomethacin and cyclosporine - A on dams and fetuses of mice

Eighty pregnant female mice were allotted among 16 groups. The animalswere given intraperitoneal injections equalized to therapeutic doses used forhuman. Indomethacin was given at 25 mg/kg and 75 mg/kg body weight andcyclosporine-A was given at 5 mg/kg, 10 mg/kg and 15 mg/kg body weight. Bothdrugs induced a significant increase in fetal resorption and a significantdecrease in fetal body weight. Also, reduction in the size of the skeleton ofembryos was observed. A 150 mg/kg dose of indomethacin was the lethal dose todams. Various chromosomal aberrations in maternal bone marrow cells, embryocells and mitotic activity were recorded, quantified and statisticallyanalyzed. Indomethacin at a dose of 75 mg/kg induced more chromosomalaberrations in both pregnant females and fetuses than the lower dose [25mg/kg]. The high dose of cyclosporine-A [15 mg/kg b. wt.] induced a higherincrease in chromosomal aberrations in bone marrow cells of female mice thanthe lower doses [5 and 10 mg/kg b. wt.], while no significant differences wereobserved between the 5 and 10 mg/kg doses. Also, cyclosporine-A [15 mg/kg]showed a highly significant increase in chromosomal aberrations in embryosthan medium [10 mg/kg] or lower doses [5 mg/kg]

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.

Gastric mucosal cellular changes induced by indomethacin (NSAID) in male albino rats.

Indomethacin (2 mg/100 g body weight), induces haemorrhagic gastric ulcers in albino rats. The incidence and severity of ulceration increased with starvation period. Indomethacin caused little or no effect on the cellular and the nuclear diameter of parietal and chief cells while reduction was observed in mucus and endocrine cells. The effect was enhanced with increased duration of starvation. Both mucous and endocrine cells decreased in their number after 72 hr of starvation. Thus prolonged starvation enhanced the gastric mucosal damage induced by indomethacin.

Efecto del misoprostol en la prevención de la nefrotoxicina inducida por indometacina / The effect of the misoprostol in the prevention of the nephrotoxicity induced by indometacin

El uso de desinflamatorio no esteroides (DINE) inhibe la síntesis de prostaglandinas vasodilatadoras renales alterando el flujo plásmatico renal y la tasa de filtración glomerular, pudiendo producir falla renal aguda en pacientes nefrópatas o con factores de riesgo asociados. El misoprostol es un análogo sintético de la prostaglandina E1, que utilizado en estudios experimentales y clínicos ha demostrado propiedades nefroprotectoras, evitando así el deterrioro funcional y los cambios hemodinámicos intrarrenales nefastos por el uso de DINE como la indometacina. Lo novedoso de este tratamiento, a difencia de los estudios clínicos similares hasta el momento, radica en que todos los pacientes incluidos, no presetaban nefropatía previa ni factores de riesgo que los hiciera proclives a desarrollar nefrotoxicidad por desinflamatorios. El proposito de este estudio es demostrar si el uso de misoprostol previene las alteraciones funcionales renales producidas en pacientes sin nefropatía y sin factores de riesgo para el desarrollo de nefrotoxicidad por el uso de indometacina a corto plazo (10días). Se estudiaron 35 pacientes (17 hombres y 18 mujeres) ingresados en el Servicio de Medicina Interna del Hospital Militar "Dr. Carlos Arvelo" por artropatías dolorosas inflamatorias; en un trabajo aleatorio, prospectivo, doble ciego, comparado con placebo. Los pacientes se distribuyeron al azar en dos grupos. El grupo 1 recibió indometacina, 50 mg V.O.TID, más misoprostol, 200 Mg V.O.TID, y el grupo 2, indometacina a la misma dosis y placebo. Los parámetros paraclínicos utilizados para evaluar la función renal u nefrotoxicidad aguda fueron: tasa de filtración glomerular (depuración de creatinina sensibilizada con cimetidina) y proteinuria en 24 horas, antes y después del tratamiento. Treinta pacientes concluyeron el estudio. En el grupo 1 se observó que la depuración de cratinina promedio al final del estudio aumentó con respecto a la inicial en un 13,1 por ciento (de 107,7 a 121,8 cc/min/1,73 m. cuadrado) (p<0,001), mientras que en el grupo 2 la misma disminuyó en un 14,5 por ciento (de 112,75 a 96,4 cc/min/1,73 m. cuadrado) (P=0,001). La proteinuria no varió en ningún grupo (p>0,05). Se concluye, que el misoprostol previno en pacientes sin nefropatía previa ni factores de riesgo asociados, la disfunción renal ocacionada por la indometacina, en el tratamiento a corto plazo de artropatías inflamatorias dolorosas

Possible prostaglandin-dopamine interactions during experimental gastric ulcer formation.

The effects of dopamine (DA) agonists and antagonists were investigated on indomethacin--and restraint stress (6 hr at RT)--induced gastric ulcer formation in rats. The DA-agonists, apomorphine and bromocryptine (both at 5 mg/kg) significantly attenuated the frequency and severity of gastric mucosal lesions in both experimental models. The DA-antagonist, haloperidol (0.05 and 1.0 mg/kg) aggravated the gastric ulcerogenesis of both indomethacin and stress, the effects with the lower dose being statistically significant. Haloperidol (0.05 mg/kg) also prevented the cytoprotective effects of apomorphine on indomethacin-ulcers. The atypical DA-antagonist, sulpiride (10 and 50 mg/kg), however, showed differential dose- and model-specific effects. Whereas, the lower dose attenuated indomethacin-ulcers, the higher dose (50 mg/kg) tended to aggravate this phenomenon. The trend of results were reversed in the restraint stress model. Indomethacin (1 mg/kg) aggravated stress-ulcers, an effect which was also appreciably neutralised by apomorphine (5 mg/kg) pretreatment. These results are discussed in light of possible prostaglandin-DA interactions during such experimental gastric pathology.