The effects of some nonsteroidal anti-inflammatory drugs on experimental induced gastric ulcers in rats.

Celecoxib is a frequently used nonsteroidal anti-inflammatory drug (NSAID) in the treatment of rheumatoid arthritis and osteoarthritis. It selectively inhibits cyclooxygenase II (COX-2) enzyme which is responsible for the production of proinflammatory prostanoids. It has been proposed that since it does not significantly inhibit COX-1, an isoenzyme responsible for the production of cytoprotective prostanoids, celecoxib has fewer side effects in the stomach. Dipyrone which is a drug with potent analgesic activity has no significant inhibitory effect on COX. In this study, the effects of celecoxib and dipyrone on experimentally induced gastric ulcers in rats were compared with respect to different parameters. In the first experiment, in an attempt to identify the best dose for both drugs, a histamine-induced gastric ulcer model was used and each drug was administered at 5, 25 and 100 mg/kg doses, and ulcer index, acidity and mucus secretion were measured in the stomach. The best dose was determined to be 5 mg/kg for both drugs. Celecoxib was found to delay ulcer healing when compared to dipyrone especially when ulcer index was used as measure. In the second experiment, ulcer index, acidity, mucus secretion, and the levels of myeloperoxidase (MPO), lipid peroxide (MDA), non-protein sulfhydryl groups (NP-SH), and prostaglandin E2 (PGE2) were investigated in the stomach of rats with gastric ulcers induced by histamine, stress and diethyldithiocarbamate (DDC). While celecoxib increased the ulcer index in stress-induced ulcer, dipyrone decreased the index in DDC-induced ulcer. Celecoxib also caused a significant increase of gastric mucus secretion in histamine-induced ulcer model. Gastric lipid peroxidation was significantly increased by dipyrone in the control group without gastric ulcer induction, whereas it was significantly increased by celecoxib in the histamine-induced and stress-induced ulcer groups. Dipyrone promoted a decrease in gastric NP-SH levels in the control group with stress-induced ulcer. With respect to gastric MPO activity, dipyrone caused a decrease in the histamine-induced ulcer group but it caused an increase in the stress-induced and DDC-induced ulcer groups. Gastric PGE2 levels in the control group without gastric ulcer induction were not affected by celecoxib while they were increased by dipyrone. In conclusion, celecoxib prompted the formation of experimentally induced gastric ulcers more than did dipyrone. The study was supported by Osmangazi University Research Funds.

The effects of verapamil on stress- and histamine-induced gastric lesions in rats.

The influence of verapamil on stress-induced and histamine-induced gastric ulcers was investigated in rats. The influence of verapamil was also examined on various biochemical parameters that affect the development of these ulcer models. The animals were pretreated with intraperitoneal verapamil (1, 5, 25 mg/kg) by injection 1 h before the induction of experimental ulceration. The gastric lesions were induced by cold-restraint stress or intraperitoneal injection of histamine (300 mg/kg). The gastroprotective effects of verapamil were evaluated by determining the ulcer index, gastric mucus content, free and total acidity, lipid peroxidation and non-protein sulfhydryl content. Verapamil pretreatment at a dose of 25 mg/kg significantly reduced stress-induced ulcers. Verapamil enhanced mucus secretion, reduced total acidity and lipid peroxidation and decreased non-protein sulfhydryl content in a dose-dependent fashion. On the other hand, pretreatment with verapamil at any dose had no significant effect on histamine-induced ulcers. L-Arginine (L-A) (100 mg/kg) or L-nitroarginine (L-NNA) (100 mg/kg) were also injected i.p. to the animals 1 h before stress to test the role of nitric oxide (NO) in the mechanism of the gastroprotective activity of verapamil (25 mg/kg). The results suggested that verapamil stimulates gastric NO production, but the overproduction of NO worsens gastric ulcers. The effects of verapamil on experimentally induced ulcers may be related to its ability to induce biochemical alterations in the parameters measured in gastric tissue.

The effects of fusidic acid on the inflammatory response in rats.

In the present study the antiinflammatory activity of fusidic acid was investigated in a model of formalin-induced edema formation in rats. Fusidic acid at doses of 50 and 100 mg kg (-1) was administered p.o. to rats for ten days. It was observed that fusidic acid inhibited edema formation significantly (P< 0.05). After this period, gastric mucus secretions were evaluated by the Alcian blue dye binding method. Mucus secretion decreased significantly in the control group. Fusidic acid increased the amount of gastric mucus. Moreover, in all of the animals with paw edema, platelet count was also increased. Red blood cell count, haemoglobin concentration and haematocrit were all higher in the control group than those of the fusidic acid groups. The present observations suggest that fusidic acid suppressed the inflammatory response and stimulated the gastric mucus secretion and it prompts further experiments for delineation of the mechanism of these actions as well as clinical trials.

Morning-evening administration time differences in digoxin kinetics in healthy young subjects.

Digoxin, frequently used in the treatment of congestive heart failure, has a very narrow therapeutic index. We studied the differences in digoxin pharmacokinetics when ingested in the morning versus evening. A single digoxin (0.25 mg) dose was given orally to the same group of 10 diurnally active healthy (6 male and 4 female) volunteers in the morning at 08:00 and evening at 20:00 in separate experiments scheduled 2 weeks apart. Blood samples were collected at specific times for 48h after each timed dose; digoxin was determined by radioimmunoassay (RIA). Maximum plasma concentration Cmax; Tmax, the time to reach Cmax; area under plasma concentration curve AUC; and elimination half-time T1/2 of digoxin were determined. Tmax was statistically significantly shorter (54 min) following 08:00 dosing com pared to 20:00 dosing (96 min). Although the Cmax was higher after morning than evening dosing, it was not significantly so. No other parameter of digoxin pharmacokinetics except Tmax exhibited administration time dependency.

Studies on calcium modulatory activities of 2,6,6-trimethyl-3-acetyl-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline derivatives.

Twenty-two new 2,6,6-trimethyl-3-acetyl-4-aryl-5-oxo-1,4,5,6,7,8-hexahydroquinoline+ ++ derivatives (compounds 1-22) have been prepared. The structures of the compounds were characterised by IR, 1H-NMR, mass spectroscopy and elemental analyses. The calcium antagonistic activities of the compounds were determined by the tests performed on isolated rabbit ileum and lamb carotid artery. According to the isolated rabbit ileum activity tests the most active compounds are 10 and 12 and according to the lamb carotid activity tests the most active compounds are 6 and 10.

Synthesis, structural elucidation and pharmacological properties of some 5-acetyl-3,4-dihydro-6-methyl-4-(substituted phenyl)-2(1H) -pyrimidinones.

In this study, the synthesis of some new 5-acetyl-3,4-dihydro-6-methyl-4-(substituted phenyl)-2(1H)-pyrimidinones has been reported. The compounds were prepared by the Biginelli reaction of acetylacetone with aromatic aldehydes and urea. The structures of the compounds were characterized by UV, IR, 1H NMR, 13C NRM, mass spectra and elementary analysis. The calcium antagonistic activity of these compounds was tested in vitro on rat ileum precontracted with 4 x 10(-3) M barium chloride.

New beta-diketone and 3,5-dimethyl isoxazole derivatives of theophylline as potential bronchodilator agents.

Ten new compounds having 7-[(2,4-pentanedione-3-yl)alkyl]- and 7-[(3,5-dimethylisoxazole-4-yl)alkyl]-3,7-dihydro-1,3-dimethyl-1H- purine-2, 6-dione structures were synthesized and their bronchodilator activities investigated using the method based on inhibition of acetylcholine and histamine-induced contractions in guinea pig trachea. None of the compounds were effective on acetylcholine-induced contractions. However, the compounds 4d, 4e, 5d and 5c were potent inhibitors of the bronchospasm induced by histamine, whereas the others (4b, 4c, 5b and 5c) were weak inhibitors.