Comparative effects of the two angiotensin converting enzyme inhibitors perindopril and ramipril on brain dopamine content in rats

The existence of brain rennin-angiotensin system [RAS] is well established and it may affect cognitive function and movement disorders. It has been suggested that manipulation of brain angiotensin could be a new therapeutic tool to modulate brain dopamine level, abnormalities of which are implicated in a wide range of conditions including extrapyramidal movement disorders, depression, appetite control, schizophrenia and arousal. In this work, we studied the changes in behavior and brain dopamine content under the effect of two lipophilic ACEIs, perindopril and ramipril, used orally daily for one week in normal rats. Other rat groups were then given single subcutaneous reserpine injection [5 mg/kg] to study the effect of pre-treatment with the ACEIs on the reserpine-induced akinesia, neurobehavioral changes and depleted brain dopamine. In normal rats, although perindopril increased dopamine content in the three brain regions examined, ramipril had no effect on striarum but there were no significant differences between the two ACEIs in their effects on frontal cortex and midbrain. Neither perindopril nor ramipril caused neurobehavioral effects. Both drugs reduced the reserpine-induced akinesia and behavioral changes and antagonized the reserpine-induced brain dopamine depletion. We concluded that chronic ACEIs therapy can influence dopamine level and this is a class effect depending on tissue penetration and crossing BBB

Concomitant administration of the selective cox-2 inhibitor, nimesulide, and vitamin E, comared to indomethacin in experimental animals

This study was designed to assess the safety and efficacy of the selective COX-2 inhibitor, nimesulide, in comparison with the non-selective COX inhibitor, indomethacin. The potentiation of the anti-inflammatory activity of nimesulide by concomitant administration of the anti-oxidant. vitamin E, was also investi- gated. The anti-inflammatory effect was tested in 24 rats by the cot- ton pellet granulomatous test. Animals were arranged into four equal groups. The first group received no drugs and served as control. The other three groups were treated with indomethacin [2 nig/kg b.w.], nimesulide [4 nig/kg b.w.] and nimesulide in combination with vitamin E [each in a dose of 4 mg/kg b.w.], respectively. All drugs were given orally once daily for two weeks. The extent of inhibition of granulomatous formation by the test drugs was taken as a measure of antiinflamniatory activity. it was found that nimesulide alone possessed a significantly less anti-inflammatory activity compared to that of indometha cin. However, concomitant administration of vitamin E with nimesulide produced a significant increase in the anti-inflammatory activity of nimesulide so that it became more than that of indomethacin alone. The analgesic effect of the test drugs was evaluated in mice. Acetic acid was injected i.p. in a dose of 0.5 ml of 1% concentration to induce abdominal constrictions [Writhing test]. Forty mice were divided into four equal groups. The first [control] group was treated with 0.5 ml saline; the second with indomethacin [2 ing/kg b.w.]; the third with nimesulide [4 mg/ kg b.w.] and the fourth with nimesulide plus vitamin E [4 mg/ leg b.w. each]. Each drug was given as a single intramuscular injection half an hour before conducting the Writhing test The average number of abdominal constrictions per minute [Writhing Response: WR] was calculated between the 10th and 14th minutes after acetic acid injection. Reduction of this WR was taken as a measure of analgesic activity of the tested drugs. Indomethacin induced a significant analgesic effect while nimesulide induced a iess analgesic activity. Simultaneous vitamin E administration did not add to the analgesic activity of nimesulide. To study the potential gastric toxicity, tests were performed using ten times the therapeutic doses of indomethacin [20 mg/ kg b.w.] and nimesuiide [40 mg/kg b.w.] in normal fasting albino rats, each given as a single oral dose. Nimesulide administration was not associated wish gastric uiceration while indomethacin produced high incidence of gastric uiceration. In conclusion, from the present data, it couid be recommended that the selective COX-2 inhibitor, nimesulide, is a safer but less effective analgesic anti-inflammatory agent, compared with indomethacin. However, combined with vitamin E, the anti-inflammatory efficacy of nimesulide is increased. Thus, this combination could provide the double benefit of good anti-inflammatory activity beside inducing no appreciable gastric adverse effects, if any at all, when compared with the traditional NSAID, indomethacin

Effect of rofecoxib [a new selective cox-II inhibitor] on plasma insulin level and pancreatic free hydroxyl radicals in diabetic rats

This study is designed to demonstrate the effect of a newly introduced selective COX-2 inhibitor, Rofecoxib, on streptozoto-cin-induced diabetes and whether it possesses an anti-oxidant effect or not. The effects of this drug were compared to those of the relatively selective COX-I inhibitor, indomethacin. The animals were divided into four groups, twenty rats each. The first group served as normal control; the second group received streptozotocin alone [45 ing/kg, i.p.] while the remaining two groups were given the same dose of streptozotocin after being treated orally for ten days with either 2.5 nig/kg/day of "Rofecoxib" [in the third group] or 1 mg/kg/day of indomethacin [in the fourth group]. Statistical analysis of the results revealed that animals treated with streptozotocin [STZ] alone exhibited significant plasma insulin reduction [both basal and half an hour after glucose load] while those treated with Rofecoxib showed insignificant reduction in plasma insulin level following STZ, in comparison to the control group. Histopathological changes revealed dial in the STZ group, there was depletion of insulin secretory granules while in the Rofecoxib group, they appear more or less normal. In the STZ group, there was a significant rise in the pancreatic malondialdehyde [MDA] level while in the Rofecoxib group there was insignificant elevation following streptozotocin, in comparison to control group. Treatment of animals with indomethacin [the 4 group] failed to protect them against the destructive effects of streptozotocin. It is concluded that, in contrast to indomethacin, Rofecoxib has beneficial effects in insulin dependent diabetes mellitus [IDDM] both by its modulatory effects on insulin secretion and its antioxidant properties