Fatma Sultan Kilic

Synthesis of some thiazolyl-pyrazoline derivatives and preliminary investigation of their hypotensive activity

Some 1-(4-arylthiazol-2-yl)-3,5-diaryl-2-pyrazoline derivatives were synthesized by reacting 1-thiocarbamoyl-3,5-diaryl-2-pyrazoline derivatives with phenacetylbromide in ethanol. The structural elucidation of the compounds were performed by IR, 1H-NMR and Mass spectral data and elemental analyses. The hypotensive activities of 13 compounds were evaluated by using the tail-cuff method. All examined compounds showed appreciable hypotensive activities. Clonidine was used as reference substance in the pharmacological evaluation.

Synthesis and analgesic activity of some triazoles and triazolothiadiazines

The synthesis of some triazoles and triazolothiadiazines starting from (5,6,7,8-tetrahydronaphthalen-2-yl)oxyacetic acid is described. The chemical structure of the compounds were elucidated by analytical, IR, 1H NMR and mass spectral studies. Some of the newly synthesized compounds were tested for analgesic activity and compounds 5b, 5c, and 5d exhibited promising analgesic activity.

Synthesis of some triazolyl-antipyrine derivatives and investigation of analgesic activity.

The synthesis of some triazolyl-antipyrine derivatives starting from 4-chloroacetamidoantipyrine and 3-(aryloxyalkyl)-4-ethyl/phenyl-5-mercapto-1,2,4-triazoles is described. The chemical structures of the compounds were elucidated by IR, 1H-NMR and mass spectral studies. These compounds were tested for analgesic activity.

Synthesis and anticonvulsant activity of some ω-(1H-1-imidazolyl)-N-phenylalkanoic acid amide derivatives

In this study, 15 omega-(1H-imidazol-1-yl)-N-phenylacetamide, propionamide and butyramide derivatives having methoxyl, methyl, nitro and chloro in ortho position of N-phenyl ring or without any substituent have been realized by two-step synthesis. Their anticonvulsant activity was determined against seizures induced by maximal electroshock (MES). The most active compound in the series was 2-(1H-imidazol-1-yl)-N-(o-chlorophenyl)acetamide.

Effects of verapamil and nifedipine on different parameters in lipopolysaccharide-induced septic shock

Septic shock has a high mortality rate due to the hypotension and circulatory disorder that occurs during its pathogenesis. Recently, humoral factors such as cytokines and nitric oxide became important in the complex pathophysiology of septic shock because there is a close relationship between the determined levels of these humoral factors and the responses to the therapy and survival periods. Verapamil and nifedipine are calcium channel blockers commonly used in the pharmacotherapy of cardiovascular disorders. In the present study these drugs were investigated in the rat septic shock model. In vivo hemodynamic parameters were recorded using a data acquisition system in endotoxin-induced septic shock in rats. The animals were followed for 5 h and blood pressure, rectal temperature, and ECG were recorded. Blood samples were collected at 1 h and 5 h time points after the injection of endotoxin, and serological samples were stored at −25°C. Subsequently, tumor necrosis factor-α, interleukin-10 (enzyme-linked immunosorbent assay), and nitrite (Griess reagent) were determined in these serological samples. Significant correlations were observed between these humoral factors and the disordered hemodynamic factors. A reversal of changes was observed in the levels of serum cytokines, nitrite levels, and hemodynamic parameters with verapamil and nifedipine preadministration (P < 0.05). Additionally, superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) were determined in livers obtained from these animals at the end of the experiments, and these results were compared to hemodynamic parameters and cytokines. Nifedipine and verapamil increased the levels of MDA and SOD but did not change catalase activity.

The antinociceptive effect and mechanisms of action of pregabalin in mice

BACKGROUND Pregabalin, a potent anticonvulsant agent, is used in treatment-resistant epileptic patients. It is reported that pregabalin also has analgesic effect in different pain syndromes. However, there is limited data on its antinociceptive mechanisms of action. We aimed to investigate the central and peripheral antinociceptive effects of pregabalin and the contribution of nitrergic, serotonergic, and opioidergic pathways in mice. METHODS We used tail flick, tail clip and hot plate tests to investigate the central antinociceptive effects and acetic acid-induced writhing test to assess peripheral antinociceptive effects of pregabalin (10, 30, 100mg/kg). We also combined pregabalin (100mg/kg) with, a nonspecific nitric oxide synthase inhibitor l-NAME (100mg/kg), a serotonin receptor antagonist cyproheptadine (50 μg/kg), and an opioid receptor antagonist naloxone (1mg/kg). RESULTS Pregabalin 30 mg/kg enhanced the percentage of maximal possible effect (% MPE) in tail flick test. Pregabalin 100mg/kg significantly increased % MPE in tail clip and tail flick tests and decreased the number of writhings. Pregabalin made no significant alteration in hot plate test at all doses. The combined use of pregabalin 100mg/kg with l-NAME, cyproheptadine, and naloxone showed that % MPE was reduced only in the combination of pregabalin with naloxone and solely in tail clip test while no significant difference was observed in writhing test. CONCLUSIONS We suggest that pregabalin (30 and 100mg/kg) presents central spinal but not central supraspinal antinociceptive effect and pregabalin 100mg/kg shows peripheral antinociceptive effect. The opioidergic pathway seems to mediate the central spinal antinociceptive effect of pregabalin while nitrergic and serotonergic pathways are not involved.

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 compared 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. (Chronobiology International, 18(5), 841–849, 2001)

Effects of Nabumetone and Dipyrone on Experimentally Induced Gastric Ulcers in Rats

Nabumetone and dipyrone are non-acidic, nonsteroidal anti-inflammatory drugs. Both of them are known to have weak inhibitory effects of cyclooxygenases. Gastric side effects represent the most common adverse drug effects of the widely used nonsteroidal anti-inflammatory drugs. The gastric effects of these drugs may be comparable in experimental ulcer models. In the present study, the gastric ulcerogenic activity of nabumetone and dipyrone were investigated on stress- and diethyldithiocarbamate-induced experimental ulcer models by determining the ulcer index and gastric mucus secretion in rats. It was found that diethyldithiocarbamate increased both ulcer index and mucus secretion. Nabumetone inhibited dose-dependently the increase of diethyldithiocarbamate-induced mucus secretion. Dipyrone inhibited both stress- and diethyldithiocarbamate-induced ulcer index and mucus secretion. Nabumetone inhibited stress-induced ulcer index at 25-mg/kg dose but stimulated dose-dependently mucus secretion. These effects may be attributed to their non-acidic structures and weak inhibitory effects on gastric mucosal cyclooxygenases.

Preventive Effects of Ginkgo biloba Extract on Ischemia-Reperfusion Injury in Rat Bladder

Aims: The aim of this experimental study was to evaluate the effects of Ginkgo biloba (EGb 761) on ischemia-reperfusion (I-R) injury in the rat bladder. Methods: A bladder I-R injury was induced by abdominal aorta occlusion by ischemia for 30 min, followed by 45 min reperfusion in rats. The rats were divided into four groups of 7 rats each; the control, I-R, and I-R groups were pretreated intraperitoneally with 50 or 100 mg/kg G. biloba 60 min before ischemia induction. Contractile responses to carbachol through isolated organ bath studies were recorded, histological sections were evaluated by light microscopy, and TUNEL staining was performed for the evaluation of apoptosis. Results: In the I-R group, the contractile responses of the bladder strips were lower than those of the control group (p < 0.01–0.001) and were restored by pretreatment with 100 mg/kg G. biloba (p < 0.05–0.001). Decreased polymorphonuclear leukocyte infiltration was detected in the G. biloba pretreatment groups when compared to the I-R group during histological evaluation. The ratio of TUNEL-positive nuclei was 1.84% in the I-R group, whereas it was decreased in both of the G. biloba pretreatment groups (p < 0.01, p < 0.01). Conclusion: Our data indicated that G. biloba has a preventive effect on I-R injury in rat urinary bladder.

Central components in the antinociceptive activity of dipyrone in mice

Dipyrone is classified as a nonsteroidal anti-inflammatory drug. It has analgesic, antipyretic and anti-inflammatory properties and exerts its analgesic effect via both peripheral and central action. Dipyrone at the dose of 250 and 500 mg/kg showed dose-dependent antinociceptive activity in the hot plate, tail flick tests to radiant heat and tail clip test and the writhing test induced by acetic acid in mice. The antinociceptive effects of dipyrone (500 mg/kg) were antagonized by naloxone (1, 2, 5 mg/kg) in the tail flick test to radiant heat and tail clip test and hot plate tests but not in the writhing test. Cyproheptadine (100 μg/kg) decreased the antinociceptive effect of dipyrone. There was an increase in the antinociceptive effects of dipyrone (500 mg/kg) when combined with buspiron (0.5 mg/kg) in the tail flick test to radiant heat and tail clip test. The results provide evidence for a central antinociceptive effect of dipyrone antagonized by naloxone which suggests that its activity may also involve the serotoninergic system.