İclal Çakıcı

Hypoglycaemic effect of Momordica charantia extracts in normoglycaemic or cyproheptadine-induced hyperglycaemic mice

The hypoglycaemic effect of orally administered extracts of Momordica charantia L. fruits was examined in normoglycaemic or cyproheptadine-induced hyperglycaemic mice. The aqueous extract reduced the fasting glucose levels of hyperglycaemic or normoglycaemic mice. However, the ethanol extract did not affect the fasting or nonfasting glucose levels significantly in both groups of mice. There was no significant difference between the glucose-loaded and glucose-loaded plus aqueous extract given group. On the other hand, oral glucose-loading of the cyproheptadine-induced hyperglycaemic animals reduced the fasting glucose levels significantly. These results showed that aqueous extract of M. charantia fruits has a hypoglycaemic activity without improving the tolerance to glucose in cyproheptadine-induced diabetic mice.

Participation of the components of L-arginine/nitric oxide/ cGMP cascade by chemically-induced abdominal constriction in the mouse

The purpose of this study was to investigate the role of the L-arginine/nitric oxide (NO)/cGMP pathway in p-benzoquinone-induced writhing model in mouse. L-arginine, a NO precursor, displayed antinociceptive effects at the doses of 0.125-1.0 mg/kg. When the doses of L-arginine were increased gradually to 10-100 mg/kg, a dose-dependent triphasic pattern of nociception-antinociception-nociception was obtained. The NO synthase (NOS) inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) (18.7515 mg/kg), possessed antinociceptive activity. Methylene blue (MB), a guanylyl cyclase and/or NOS inhibitor, (5-160 mg/kg) also produced a dose-dependent triphasic response. When L-arginine (50 mg/ kg) was combined with L-NAME (75 mg/kg). L-arginine-induced antinociception did not change significantly. Cotreatment of L-arginine with 5 mg/kg MB significantly decreased MB-induced antinociception and reversed the nociception induced by 40 mg/kg MB to antinociception. It is concluded that the components of L-arginine/nitric oxide/cGMP cascade may participate in nociceptive processes both peripherally and centrally by a direct effect on nociceptors or by the involvement of other related pathways of nociceptive processes induced by NO.

Flow Injection Analysis for Monitoring Antioxidant Effects on Luminol Chemiluminescence of Reactive Oxygen Species

Abstract Knowledge of the antioxidant capacity of specific chemicals is essential to understanding the susceptibility to oxidative stress. Various assays have been developed for measuring the scavenging capacity of molecules. In the present study we used a continuous flow system for monitoring chemiluminescence (CL) reactions initiated by superoxide ( ) (derived from xanthine–xanthine oxidase reaction), hydrogen peroxide (H2O2), hypochlorite anion (−OCl) (derived from NaOCl), hydroxyl (·OH) (generated from O2–FeSO4-buffer), or peroxynitrite (ONOO−) (freshly synthesized). By adapting the flow injection analysis (FIA) method, inhibition of luminol-CL responses of these reactive oxygen species (ROS) by ascorbic acid (well-characterized, chain-breaking antioxidant) and other antioxidants were also investigated. Data showed that to monitor the antioxidant sensitivity of CL responses initiated by ROS is possible by using FIA method.

The beneficial effects of peroxynitrite on ischaemia–reperfusion arrhythmias in rat isolated hearts

The simultaneous production of nitric oxide (NO) and superoxide leads to the formation of a potent toxic metabolite peroxynitrite (ONOO(-)). However, ONOO(-) at low concentrations has been found to exert cardioprotective effects. The purpose of the present study was to investigate the effects of exogenous ONOO(-) on ischaemia-reperfusion arrhythmias. We studied the concentration-response effects of ONOO(-) (0.4, 4, 40 microM ml(-1) min(-1) for 20 min) in rat isolated hearts perfused with Krebs-Henseleit solution. The 0.4 microM concentration of ONOO(-) was selected for further experiments since it did not affect the sinus rhythm. In the hearts subjected to 10 min of ischaemia followed by 10 min of reperfusion during 0.4 microM ml(-1) min(-1) ONOO(-) infusion, the incidence of ventricular fibrillation was decreased significantly from 93% to 38% (n=8) and none of the hearts had an irreversible ventricular fibrillation. Urate, a ONOO(-) scavenger (at 1 mM, n=7), added to the perfusate 5 min prior to the coronary artery occlusion and maintained throughout the experimental period, did not significantly modify the beneficial effects of ONOO(-). Although L-N(G)-nitroarginine methylester (L-NAME) (100 microM, n=8) had no effect, superoxide dismutase (10 U ml(-1))+catalase (100 U ml(-1)) increased the number of ventricular ectopic beats from 91+/-32 to 286+/-83 (n=5) and augmented the incidence of irreversible ventricular fibrillation from 0% to 60%. There were no marked changes in the time of onset of the first arrhythmias in any group. These results suggest that ONOO(-) at a low concentration may exert beneficial effects on ischaemia-reperfusion-induced arrhythmias in rat isolated hearts.

Antinociceptive effect of some Amaryllidaceae plants in mice

The antinociceptive effects of ethanolic extracts of Pancratium maritimum L., Narcissus tazetta subspecies tazetta and Leucojum aestivum L. bulbs have been investigated in mice using the p‐benzoquinone‐induced abdominal constriction and hot‐plate tests.

Effects of cyclooxygenase and lipoxygenase inhibitors on digoxin-induced arrhythmias and haemodynamics in guinea-pigs

Effects of cyclooxygenase and lipoxygenase inhibitors of digoxin-induced arrhythmias and haemodynamics were studied in guinea-pigs. ECG, mean arterial blood pressure heart rate, pressure rate index and arrhythmias were recorded, starting 15 min before digoxin administration and continuing for 30 min afterwards. The cyclooxygenase inhibitor aspirin (50 mg kg-1) and the dual cyclooxygenase/lipoxygenase inhibitor BW 755C (0.25-10.0 mg kg-1) were found to produce a significant protection against the arrhythmias, whereas aspirin (100 mg kg-1) and CGS 8515 were found to be ineffective. SK&F 104 353, a potent and selective peptidoleukotriene receptor antagonist significantly attenuated the arrhythmias and mortality in a dose-dependent manner. It is concluded that production of both cyclooxygenase and lipoxygenase metabolites could favour the occurrence and/or the maintenance of digoxin-induced cardiac toxicity.

Effects of Peroxynitrite on the Reactivity of Diabetic Rat Aorta

Endogenous nitric oxide (NO) reacts with superoxide to form peroxynitrite, which is capable of either oxidizing or nitrating various biological substrates. We compared the vasodilatory effect of exogenous peroxynitrite with the effects of decomposed peroxynitrite or sodium nitrite in precontracted aorta isolated from streptozotocin-induced diabetic and age-matched control rats. Peroxynitrite (10 nmol/l to 300 µmol/l) produced a concentration-dependent relaxation in aortic rings with or without endothelium. Relaxation was also observed with a higher concentration of its decomposition product or sodium nitrite, although these relaxations were considerably slower and with reduced sensitivity. Endothelium-containing rings were less sensitive to the vasorelaxant effect of peroxynitrite than the endothelium-denuded rings in control (pD2 was 5.19 ± 0.06 in rings with endothelium and 5.86 ± 0.03 in rings without endothelium, p < 0.01) but not in diabetic aorta (pD2 was 5.97 ± 0.05 in rings with endothelium and 6.12 ± 0.06 in rings without endothelium, p > 0.05). The maximum relaxation to peroxynitrite also increased in diabetics, but did not change by removal of the endothelium either in diabetic or control rings. Diabetes did not alter the relaxations elicited by both decomposed peroxynitrite and sodium nitrite. Peroxynitrite-induced relaxation was not inhibited by diethylenetriaminepentaacetic acid, an inhibitor of hydroxyl radical formation. Pretreatment with peroxynitrite (1 µmol/l, 15 min) significantly suppressed the phenylephrine-induced tone and acetylcholine-stimulated endothelium-dependent relaxation, both effects were more pronounced in diabetic than in control aorta. The increased responsiveness of diabetic vessels to exogenous peroxynitrite seems to be related to depressed basal NO bioavailability and may be considered as a compensatory way against activated contractile mechanisms of diabetic vascular smooth muscle.

Antinociceptive effects of H1- and H2-antihistaminics in mice

1. Two methods were used to study the analgesic effects of subcutaneous injections of antihistaminics in mice: the p-benzoquinone(PBQ)-writhing test and caudal compression test. 2. Mepyramine, lupitidine (SKF 93479), and famotidine produced significant antinociceptive effects dose-dependently, during both the PBQ-writhing and caudal compression tests. 3. However, ranitidine did not reveal any antinociceptive effect. 4. Icotidine (SKF 93319) produced significant antinociception and also augmented the analgesic effect of morphine, on the caudal compression test. 5. However, mepyramine, famotidine, and lupitidine did not affect morphine-induced analgesia on the caudal compression test and displayed a nonsignificant potentiation on morphine-induced analgesia in the PBQ-writhing test.

Biological Time‐Dependent Difference in Effect of Peroxynitrite Demonstrated by the Mouse Hot Plate Pain Model

We previously demonstrated the rhythmic pattern of L‐arginine/nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) cascade in nociceptive processes. The coupled production of excess NO and superoxide leads to the formation of an unstable intermediate peroxynitrite, which is primarily responsible for NO‐mediated toxicity. In the present study, we evaluated the biological time‐dependent effects of exogenously administered peroxynitrite on nociceptive processes and peroxynitrite‐induced changes in the analgesic effect of morphine using the mouse hot‐plate pain model. Experiments were performed at four different times of day (1, 7, 13, and 19 hours after lights on, i.e., HALO) in mice of both sexes synchronized to a 12 h:12 h light‐dark cycle. Animals were injected intraperitoneally (i.p.) with saline or 10 mg/kg morphine 30 min before and 0.001 mg/kg peroxynitrite 30 sec before hot‐plate testing, respectively. The analgesic effect of morphine exhibited significant biological time‐dependent differences in the thermally‐induced algesia; whereas, administration of peroxynitrite alone exhibited either significant algesic or analgesic effect, depending on the circadian time of its injection. Concomitant administration of peroxynitrite and morphine reduced morphine‐induced analgesia at three of the four different study time points. In conclusion, peroxynitrite displayed nociceptive and antinociceptive when administered alone according to the circadian time of treatment, while it diminished analgesic activity when administered in combination with morphine at certain biological times.

Clinical study on the bioequivalence of two tablet formulations of flurbiprofen

SummaryFlurbiprofen (CAS 5104-49-4) is a member of phenylaikanoic acid derivative group of nonsteroid anti-inflammatory drugs. It exhibits anti-inflammatory, analgesic and antipyretic activities. Two different tablets containing flurbiprofen (FLU) were investipted in 24 healthy volunteers to prove the bioequivalence between both treatments after single oral dose administrations. Fluroben® 100 mg tablet and 100 mg tablet of the originator product were used as test and reference preparation respectively. The study was performed open label, randomized, two period cross-over design with 15 days wash out period. Blood samples were taken up to 24 hours for pharmacokinetic profiling. The plasma concentrations of flurbiprofen were determined with validated HPLC-UV method. Maximum plasma concentration (Cmax) of FLU 19 143.65 ng/ml and 19 164.22 ng/ml were found for test and reference formulation respectively. Areas under the plasma concentration time curve AUC0-∞ of 118 501.4 ng.h/ml and lii 339.8 ng.h/ml were calculated test and reference formulation respectively. Primary target parameters AUC0-∞ and Cmax, both of them were tested parametrically by analysis of variance (ANOVA); 90% confidence intervals were between 100.5%–111.18% for AUC0-∞ and 87.6%–115.0% for Cmax. All these values were within the acceptance range (80%–125%) for bioequivalence studies.