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.

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.

The effects of graded doses of verapamil on ethanol-induced stomach mucosal damage were studied in rats. Gastric lesions were induced in vivo by oral administration of 80% ethanol and evaluated with regard to ulcer index, gastric mucus content, free and total acidity, lipid peroxidation and nonprotein sulfhydryl groups. Orally administered ethanol markedly increased the ulcer index and lipid peroxidation. Pretreatment of rats with verapamil (1, 5, and 25 mg/kg i.p.) was carried out 1 h before the administration of ethanol. Verapamil showed a protective effect against ethanol-induced mucosal damage only at high dose (25 mg/kg). Verapamil dose dependently decreased the total acidity, lipid peroxidation, and nonprotein sulfhydryl content. Verapamil 25 mg/kg also increased significantly the gastric mucus secretion. L-arginine (100 mg/kg) or L-nitroarginine (100 mg/kg) with verapamil were also administered to the animals to determine the role of nitric oxide in the mechanism of the gastroprotective activity of verapamil (25 mg/kg). The results indicate that reduced acidity and lipid peroxidation and increased mucus secretion participate in the protective effects of verapamil against ethanol damage. On the other hand, a decrease in the nonprotein sulfhydryl content was observed with decreased gastroprotective effects of verapamil.

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Summary 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.