Carmen La Casa

Effects of dosmalfate, a new cytoprotective agent, on acute and chronic trinitrobenzene sulphonic acid-induced colitis in rats

Activated neutrophils and proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) are clearly involved in the pathogenesis of bowel disease. Increased expression of epidermal growth factor-receptor (EGF receptor) has been reported for the colon mucosa surrounding areas of ulceration, suggesting a pivotal role in mucosal defence and repair. In this study, we examined the effects of dosmalfate, a new flavonoid derivative compound (diosmin heptakis) with antioxidant and cytoprotective properties, on acute and chronic experimental trinitrobenzene sulphonic acid (TNBS)-induced colitis in rats. The inflammation response was assessed by neutrophil infiltration as evaluated by histology and myeloperoxidase activity. Mucosal TNF-alpha production and histological analysis of the lesions was also carried out. In addition, we studied the expression of the EGF receptor inmunohistochemically during the healing of TNBS-induced chronic colitis. A 2-day treatment with 400 or 800 mg/kg of dosmalfate ameliorated the colon damage score and the incidence of adhesions. It also significantly (P<0.05) decreased myeloperoxidase activity and colonic mucosal production of TNF-alpha. Chronic treatment (14 days) with 800 mg/kg/day of dosmalfate also had significant protective effects on TNBS-induced colitis which were reflected by significant attenuation (P<0.05) of the damage score while the inflammatory indicators were not improved. The chronic beneficial effect of dosmalfate was apparently related to the enhancement of EGF receptor expression. These findings confirm the protective effects of dosmalfate in acute and chronic experimental colitis.

Effects of food intake and oxidative stress on intestinal lesions caused by meloxicam and piroxicam in rats.

Large intestinal ulcers, bleeding and perforation are occasionally due to non-steroidal anti-inflammatory drugs (NSAID). In addition to suppression of prostaglandins synthesis, a number of factors have been implicated, including enterohepatic recirculation, food intake and vascular injury with oxygen free-radical generation. The present study aimed to determine the effect of food intake and the role of oxidative stress in the pathogenesis of intestinal injury induced by oral administration of meloxicam (preferential cyclooxygenase-2 inhibitor) vs. piroxicam (preferential cyclooxygenase-1 inhibitor). Therefore, the activity of oxidative stress-related enzymes such as myeloperoxidase, xanthine oxidase and superoxide dismutase, as well as levels of lipid peroxides and glutathione homeostasis were studied in an experimental model using re-fed rats. The animals treated with piroxicam (10-20 mg/kg) had a dose-dependent increase in the severity of intestinal lesions, but only the highest dose of meloxicam (15 mg/kg) caused macroscopic damage. The severity of piroxicam and meloxicam-induced damage was correlated with a significant increase of xantine oxidase activity and a decrease of superoxide dismutase activity and glutathione levels (P<0.05 and P<0.001 vs. control). In contrast, there was no significant neutrophil infiltration of the intestine after dosing. Our results support the hypothesis that oxygen free radicals, probably derived via the action of xantine oxidase, the decrease in superoxide dismutase activity, and depletion of mucosal glutathione contribute to the pathogenesis of meloxicam and piroxicam-induced intestinal ulceration in re-fed rats.

The role of Gastric Mucosal Sulphydryls in the Ulcer‐protecting Effects of Cisapride

The present study was designed to examine the role of endogenous sulphydryls (SHs) in the gastro‐protection induced by cisapride (CIS) (10, 25 and 50 mg kg−1 i.p.), a potent benzamide stimulating gastrointestinal motility in mucosal injury induced by 50% v/v ethanol. Results were compared with those of 5−hydroxytryptamine (5−HT) (10 mg kg−1).

Effects of celecoxib on acid-challenged gastric mucosa of rats: comparison with metamizol and piroxicam.

Selective COX-2 inhibitors have been shown to produce fewer gastrointestinal adverse reactionsthan classical NSAIDs. Nevertheless, these new agents may worsen and delay the healing of ex-perimentallyinduced gastric ulcers in animals. In this study, we compared the effects of a selectiveCOX-2 inhibitor (celecoxib), a preferential COX-1 inhibitor (piroxicam), and a nonnarcotic anal-gesic(metamizol) on normal gastric mucosa of rats and, on the other hand, in a setting of preexistingacute gastric lesions induced by 0.6 N hydrochloric acid. Under normal conditions, only piroxicamproduced appreciable gastric lesions. However, after acid challenge the three assayed drugs inducedsignificant macroscopic and microscopic damage. Myeloperoxidase activity as an index of neutrophilinfiltration was elevated with celecoxib and piroxicam on normal gastric mucosa. On inflamed mu-cosa,celecoxib augmented enzymatic activity at the lower dose, which was parallelled by an increasein the interleukin 1β level. Acid instillaton produced a significant rise in PGE2 content at 7 hr. Drugtreatment after acid challenge decreased prostaglandin values in all cases, although to a lesser extentthan after single drug dose administration. COX-2 mRNA expression was visible 1 hr after acidapplication, whereas COX-2 protein could only be detected at 7 hr. Piroxicam increased both ex-pressionlevels. All NSAIDs enhanced transforming growth factor α and epidermal growth factorreceptor immunoreactivity around the acid-induced lesions. It is concluded that selective COX-2inhibitors, like conventional NSAIDs, impair the healing of gastric damage, and therefore specialattention should be paid in patients with gastric pathologies.