İlker Kanzık | Gazi University (original) (raw)
Papers by İlker Kanzık
Arzneimittelforschung, 2011
Sultamicillin (CAS 76497-13-7) is a prodrug combination of ampicillin (CAS 69-53-4) and sulbactam... more Sultamicillin (CAS 76497-13-7) is a prodrug combination of ampicillin (CAS 69-53-4) and sulbactam (CAS 68373-14-8), with the antibiotic ampicillin and the beta-lactamase inhibitor sulbactam chemically linked as double ester. The present study was performed to investigate the relative bioavailability and to assess the bioequivalence of two different sultamicillin suspensions (Devasid 250 mg/5 ml as test preparation and 375 mg/7.5 ml of the originator product as reference preparation). Twenty-four healthy male volunteers received equal doses of the sultamicillin preparations according to an open, randomised, single-dose, two-period cross-over design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 8 h post-dose, and ampicillin and sulbactam plasma concentrations were determined with a validated LC-MS/MS method. Maximum plasma concentrations (C(max)) of 11,267.4 ng/ml (ampicillin, test), 10,864.4 ng/ml (ampicillin, reference), 6,360.6 ng/ml (sulbactam, test and 6,410.7 ng/ml (sulbactam, reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity) of 17,512.9 ng x h/ml (ampicillin, test), 18,388.0 ng x h/ml (ampicillin, reference), 10,971.7 ng ng x h/ml (sulbactam, test) and 11,181.2 ng x h/ml (sulbactam, reference) were calculated. The median t(max) was 0.69 h (ampicillin, test), 0.85 h (ampicillin, reference), 0.72 h (sulbactam, Devasid) and 0.83 h (sulbactam, reference). Plasma elimination half-lives (t(1/2)) of 1.04 h (ampicillin, test), 1.03 h (ampicillin, reference), 1.26 h (sulbactam, Devasid) and 1.00 h (sulbactam, reference) were determined. Both primary target parameters AUC(0-infinity) and C(max) of ampicillin and sulbactam were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 84.58%-117.80% (AUC(0-infinity), ampicillin), 92.37%-119.93% (C(max), ampicillin), 85.81%-120.50% (AUC(0-infinity), sulbactam) and 88.41%-117.57% (C(max), sulbactam). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and C(max) the 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.
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Arzneimittelforschung, 2011
The aim of the present study was to compare the bioavailability of amoxicillin (CAS 26787-78-0) f... more The aim of the present study was to compare the bioavailability of amoxicillin (CAS 26787-78-0) from two different amoxicillin tablets (Demoksil 1 g tablet as test preparation and 1 g tablet of the originator product as reference preparation). The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 4-7 days. Blood samples for pharmacokinetic profiling were taken up to 10 h post-dose, and amoxicillin plasma concentrations were determined with a validated LC-MS/ MS method. Maximum plasma concentrations (C(max)) of 13,296.4 ng/ml (test) and 12,797.7 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 39,556.7 ng x h/ml (test) and 38,599.1 ng x h/ml (reference) were calculated. The median t(max) was 1.62 h (test) and 1.54 h (reference). Plasma elimination half-lives (t(1/2)) of 1.64 h (test) and 1.65 h (reference) were determined. Both primary target parameters, AUC(0-infinity) and C(max) were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 96.76%-108.46% (AUC(0-infinity)) and 97.80%-111.98% (C(max)). Bioequivalence between test and reference preparation was demonstrated since for both parameters, AUC and C(max) the 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.
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Arzneimittelforschung, 2011
Meloxicam (CAS 71125-38-7), a non-steroidal anti-inflammatory drug (NSAID), is used for the treat... more Meloxicam (CAS 71125-38-7), a non-steroidal anti-inflammatory drug (NSAID), is used for the treatment of osteoarthritis and rheumatic arthritis. In the present study, two different oral meloxicam formulations (Melcam 15 mg tablets as test preparation and tablets of a reference preparation) were investigated in 24 healthy male subjects in order to prove bioequivalence between both preparations. A single 15 mg oral dose was administered according to an open, randomised, two-period cross-over design in the fasted state. Blood samples for the determination of meloxicam plasma concentrations were collected at pre-defined time points up to 96 h following drug administration. A wash-out period of 7-8 days separated both treatment periods. Meloxicam plasma concentrations were determined by means of a validated HPLC method with UV-detection. Maximum plasma concentrations (C(max)) of 1,146.9 ng/ml (test) and 1,064.8 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity) of 34,499.0 ng x h/ml (test) and 33,784.3 ng x h/ml (reference) were determined. The results showed nearly identical rate and extent of drug absorption. Also further pharmacokinetic parameters were well comparable. Thus, t(max) showed values of 5.00 h for both test and reference. The plasma elimination half-life (t1/2) was 18.29 h (test) und 18.94 h (reference). Both primary target parameters C(max). and AUC(0-infinity, were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 99.46%-105.24% (AUC0-infinity)) and 103.37%-112.46% (C(max)). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and C(max) the 90% confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.
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General Pharmacology: The Vascular System, 1998
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Pharmacology & toxicology, 1999
We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precur... more We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precursor (L-arginine) and nitric oxide donor (sodium nitroprusside) on digoxin-induced arrhythmias both in guinea-pig isolated hearts and in anaesthetised animals. Sodium nitroprusside (0.1 mumol kg-1 min.-1 for 70 min.) caused a marked inhibition in mortality and arrhythmia score but L-NAME (10 mg kg-1) and L-arginine (30 mg kg-1 intravenous bolus followed by 10 mg kg-1 min.-1 for 60 min.) treatments were ineffective in anaesthetised guinea-pigs. None of the drugs markedly affected the time of onset of first arrhythmias or ventricular fibrillation incidence. In isolated heart experiments, nitric oxide generated by either L-arginine (1 mM) or sodium nitroprusside (1 mM) significantly reduced the arrhythmia score whereas L-NAME (1 mM) had no effect. Ventricular fibrillation incidence was totally abolished by sodium nitroprusside and none of the hearts treated with L-arginine had an irreversibl...
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Life Sciences, 2000
Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprussid... more Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprusside (SNP) on isolated rat anococcygeus muscle were investigated. Administration of 0.1-1.0 mM ONOO- or 0.01-100.0 microM SNP produced concentration-dependent relaxations on the phenylephrine (2 microM)-precontracted muscle. Time courses of these relaxations to ONOO- and SNP were not similar and decomposed ONOO- caused a biphasic response composed of an initial contraction followed by a relaxation. NT (0.01-0.1 mM) either incubated for 20 min prior to precontraction or given during precontraction plateau did not attenuate precontraction or ONOO(-)-induced relaxations. Results of the present study demonstrate that ONOO- relaxes rat anococcygeus muscle specifically while its stable metabolite NT has no effect.
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Journal of Ethnopharmacology, 1994
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British journal of clinical pharmacology, 1997
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European Journal of Pharmacology, 1999
The simultaneous production of nitric oxide (NO) and superoxide leads to the formation of a poten... more 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.
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We have investigated the role of tyrosine kinase in the antiarrhythmic effects of peroxynitrite p... more We have investigated the role of tyrosine kinase in the antiarrhythmic effects of peroxynitrite preconditioning in rat isolated heart by using a tyrosine phosphatase inhibitor, sodium orthovanadate, and tyrosine kinase inhibitors, genistein and tyrphostin. Rat hearts were preconditioned by peroxynitrite administration at 1 microM for 3 min, which was followed by 10-min washout and 30 min of ischemia. None of the hearts had ventricular fibrillation in the peroxynitrite preconditioning group (from 64%, n=11, to 0%, n=11). Neither sodium orthovanadate (10 microM) nor genistein (50 microM) or tyrphostin (100 microM) alone showed any effects on arrhythmias. Peroxynitrite preserved its beneficial effects on arrhythmias (to 0% ventricular fibrillation, n=7) during sodium orthovanadate infusion (for 23 min) prior to 30 min of an ischemic period. On the other hand, genistein or tyrphostin treatment significantly reversed the protective effects of the peroxynitrite preconditioning (to 71% ventricular fibrillation, n=14, genistein and, to 75% ventricular fibrillation, n=8, tyrphostin). These results suggest that the tyrosine kinase pathway plays a significant role in peroxynitrite-induced preconditioning in rat isolated heart.
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Journal of Ethnopharmacology, 2000
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European Journal of Pharmacology, 2003
We have investigated the role of tyrosine kinase in the antiarrhythmic effects of peroxynitrite p... more We have investigated the role of tyrosine kinase in the antiarrhythmic effects of peroxynitrite preconditioning in rat isolated heart by using a tyrosine phosphatase inhibitor, sodium orthovanadate, and tyrosine kinase inhibitors, genistein and tyrphostin. Rat hearts were preconditioned by peroxynitrite administration at 1 microM for 3 min, which was followed by 10-min washout and 30 min of ischemia. None of the hearts had ventricular fibrillation in the peroxynitrite preconditioning group (from 64%, n=11, to 0%, n=11). Neither sodium orthovanadate (10 microM) nor genistein (50 microM) or tyrphostin (100 microM) alone showed any effects on arrhythmias. Peroxynitrite preserved its beneficial effects on arrhythmias (to 0% ventricular fibrillation, n=7) during sodium orthovanadate infusion (for 23 min) prior to 30 min of an ischemic period. On the other hand, genistein or tyrphostin treatment significantly reversed the protective effects of the peroxynitrite preconditioning (to 71% ventricular fibrillation, n=14, genistein and, to 75% ventricular fibrillation, n=8, tyrphostin). These results suggest that the tyrosine kinase pathway plays a significant role in peroxynitrite-induced preconditioning in rat isolated heart.
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European Journal of Pharmacology, 1998
Complex and incompletely understood mechanisms underline the vascular responses to hypoxia. Recen... more Complex and incompletely understood mechanisms underline the vascular responses to hypoxia. Recent studies showed that the tyrosine kinase pathway is involved in vasoconstriction of vascular smooth muscle. Therefore, the aim of this study was to determine the tyrosine kinase pathway for the hypoxic contraction in large-diameter sheep pulmonary artery rings in vitro by studying the effects of selective inhibitors of tyrosine kinase and of a protein tyrosine kinase inhibitor. Lowering the pO2 from 96 to 5 mm Hg caused a contraction in arteries precontracted with 5-hydroxytryptamine (5-HT) but not under resting force. Preincubation of arteries with the tyrosine kinase inhibitors, genistein and tyrphostin, abolished the hypoxic contraction without affecting 5-HT contractions. Inhibition of tyrosine phosphatase activity by sodium orthovanadate increased the hypoxic vasoconstriction in 5-HT-precontracted arteries. These results suggest that the tyrosine kinase pathway is involved in hypoxic pulmonary vasoconstriction in sheep isolated pulmonary artery rings.
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European Journal of Pharmacology, 1999
The simultaneous production of nitric oxide (NO) and superoxide leads to the formation of a poten... more 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.
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Analytical Letters, 2003
... DOI: 10.1081/AL-120018797 Meltem Sarıahmetoğlu a * , R. Alan Wheatley b , İclal Çakıcı a , İl... more ... DOI: 10.1081/AL-120018797 Meltem Sarıahmetoğlu a * , R. Alan Wheatley b , İclal Çakıcı a , İlker Kanzık a & Alan Townshend b pages 749-765. Available online: 02 Feb 2007. ...
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General Pharmacology: The Vascular System, 1998
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Arzneimittelforschung, 2011
Sultamicillin (CAS 76497-13-7) is a prodrug combination of ampicillin (CAS 69-53-4) and sulbactam... more Sultamicillin (CAS 76497-13-7) is a prodrug combination of ampicillin (CAS 69-53-4) and sulbactam (CAS 68373-14-8), with the antibiotic ampicillin and the beta-lactamase inhibitor sulbactam chemically linked as double ester. The present study was performed to investigate the relative bioavailability and to assess the bioequivalence of two different sultamicillin suspensions (Devasid 250 mg/5 ml as test preparation and 375 mg/7.5 ml of the originator product as reference preparation). Twenty-four healthy male volunteers received equal doses of the sultamicillin preparations according to an open, randomised, single-dose, two-period cross-over design with a wash-out phase of 7 days. Blood samples for pharmacokinetic profiling were taken up to 8 h post-dose, and ampicillin and sulbactam plasma concentrations were determined with a validated LC-MS/MS method. Maximum plasma concentrations (C(max)) of 11,267.4 ng/ml (ampicillin, test), 10,864.4 ng/ml (ampicillin, reference), 6,360.6 ng/ml (sulbactam, test and 6,410.7 ng/ml (sulbactam, reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity) of 17,512.9 ng x h/ml (ampicillin, test), 18,388.0 ng x h/ml (ampicillin, reference), 10,971.7 ng ng x h/ml (sulbactam, test) and 11,181.2 ng x h/ml (sulbactam, reference) were calculated. The median t(max) was 0.69 h (ampicillin, test), 0.85 h (ampicillin, reference), 0.72 h (sulbactam, Devasid) and 0.83 h (sulbactam, reference). Plasma elimination half-lives (t(1/2)) of 1.04 h (ampicillin, test), 1.03 h (ampicillin, reference), 1.26 h (sulbactam, Devasid) and 1.00 h (sulbactam, reference) were determined. Both primary target parameters AUC(0-infinity) and C(max) of ampicillin and sulbactam were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 84.58%-117.80% (AUC(0-infinity), ampicillin), 92.37%-119.93% (C(max), ampicillin), 85.81%-120.50% (AUC(0-infinity), sulbactam) and 88.41%-117.57% (C(max), sulbactam). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and C(max) the 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.
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Arzneimittelforschung, 2011
The aim of the present study was to compare the bioavailability of amoxicillin (CAS 26787-78-0) f... more The aim of the present study was to compare the bioavailability of amoxicillin (CAS 26787-78-0) from two different amoxicillin tablets (Demoksil 1 g tablet as test preparation and 1 g tablet of the originator product as reference preparation). The study was conducted according to an open-label, randomised two-period cross-over design with a wash-out phase of 4-7 days. Blood samples for pharmacokinetic profiling were taken up to 10 h post-dose, and amoxicillin plasma concentrations were determined with a validated LC-MS/ MS method. Maximum plasma concentrations (C(max)) of 13,296.4 ng/ml (test) and 12,797.7 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity)) of 39,556.7 ng x h/ml (test) and 38,599.1 ng x h/ml (reference) were calculated. The median t(max) was 1.62 h (test) and 1.54 h (reference). Plasma elimination half-lives (t(1/2)) of 1.64 h (test) and 1.65 h (reference) were determined. Both primary target parameters, AUC(0-infinity) and C(max) were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 96.76%-108.46% (AUC(0-infinity)) and 97.80%-111.98% (C(max)). Bioequivalence between test and reference preparation was demonstrated since for both parameters, AUC and C(max) the 90% confidence intervals of the T/R-ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.
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Arzneimittelforschung, 2011
Meloxicam (CAS 71125-38-7), a non-steroidal anti-inflammatory drug (NSAID), is used for the treat... more Meloxicam (CAS 71125-38-7), a non-steroidal anti-inflammatory drug (NSAID), is used for the treatment of osteoarthritis and rheumatic arthritis. In the present study, two different oral meloxicam formulations (Melcam 15 mg tablets as test preparation and tablets of a reference preparation) were investigated in 24 healthy male subjects in order to prove bioequivalence between both preparations. A single 15 mg oral dose was administered according to an open, randomised, two-period cross-over design in the fasted state. Blood samples for the determination of meloxicam plasma concentrations were collected at pre-defined time points up to 96 h following drug administration. A wash-out period of 7-8 days separated both treatment periods. Meloxicam plasma concentrations were determined by means of a validated HPLC method with UV-detection. Maximum plasma concentrations (C(max)) of 1,146.9 ng/ml (test) and 1,064.8 ng/ml (reference) were achieved. Areas under the plasma concentration-time curve (AUC(0-infinity) of 34,499.0 ng x h/ml (test) and 33,784.3 ng x h/ml (reference) were determined. The results showed nearly identical rate and extent of drug absorption. Also further pharmacokinetic parameters were well comparable. Thus, t(max) showed values of 5.00 h for both test and reference. The plasma elimination half-life (t1/2) was 18.29 h (test) und 18.94 h (reference). Both primary target parameters C(max). and AUC(0-infinity, were tested parametrically by analysis of variance (ANOVA) and the 90% confidence intervals were between 99.46%-105.24% (AUC0-infinity)) and 103.37%-112.46% (C(max)). Bioequivalence between test and reference preparation was demonstrated since for both parameters AUC and C(max) the 90% confidence intervals of the T/R ratios of logarithmically transformed data were in the generally accepted range of 80%-125%.
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General Pharmacology: The Vascular System, 1998
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Pharmacology & toxicology, 1999
We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precur... more We have investigated the effects of nitric oxide synthase inhibitor (L-NAME), nitric oxide precursor (L-arginine) and nitric oxide donor (sodium nitroprusside) on digoxin-induced arrhythmias both in guinea-pig isolated hearts and in anaesthetised animals. Sodium nitroprusside (0.1 mumol kg-1 min.-1 for 70 min.) caused a marked inhibition in mortality and arrhythmia score but L-NAME (10 mg kg-1) and L-arginine (30 mg kg-1 intravenous bolus followed by 10 mg kg-1 min.-1 for 60 min.) treatments were ineffective in anaesthetised guinea-pigs. None of the drugs markedly affected the time of onset of first arrhythmias or ventricular fibrillation incidence. In isolated heart experiments, nitric oxide generated by either L-arginine (1 mM) or sodium nitroprusside (1 mM) significantly reduced the arrhythmia score whereas L-NAME (1 mM) had no effect. Ventricular fibrillation incidence was totally abolished by sodium nitroprusside and none of the hearts treated with L-arginine had an irreversibl...
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Life Sciences, 2000
Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprussid... more Effects of peroxynitrite (ONOO-), its stable product 3-nitrotyrosine (NT) and sodium nitroprusside (SNP) on isolated rat anococcygeus muscle were investigated. Administration of 0.1-1.0 mM ONOO- or 0.01-100.0 microM SNP produced concentration-dependent relaxations on the phenylephrine (2 microM)-precontracted muscle. Time courses of these relaxations to ONOO- and SNP were not similar and decomposed ONOO- caused a biphasic response composed of an initial contraction followed by a relaxation. NT (0.01-0.1 mM) either incubated for 20 min prior to precontraction or given during precontraction plateau did not attenuate precontraction or ONOO(-)-induced relaxations. Results of the present study demonstrate that ONOO- relaxes rat anococcygeus muscle specifically while its stable metabolite NT has no effect.
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Journal of Ethnopharmacology, 1994
Bookmarks Related papers MentionsView impact
British journal of clinical pharmacology, 1997
Bookmarks Related papers MentionsView impact
European Journal of Pharmacology, 1999
The simultaneous production of nitric oxide (NO) and superoxide leads to the formation of a poten... more 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.
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We have investigated the role of tyrosine kinase in the antiarrhythmic effects of peroxynitrite p... more We have investigated the role of tyrosine kinase in the antiarrhythmic effects of peroxynitrite preconditioning in rat isolated heart by using a tyrosine phosphatase inhibitor, sodium orthovanadate, and tyrosine kinase inhibitors, genistein and tyrphostin. Rat hearts were preconditioned by peroxynitrite administration at 1 microM for 3 min, which was followed by 10-min washout and 30 min of ischemia. None of the hearts had ventricular fibrillation in the peroxynitrite preconditioning group (from 64%, n=11, to 0%, n=11). Neither sodium orthovanadate (10 microM) nor genistein (50 microM) or tyrphostin (100 microM) alone showed any effects on arrhythmias. Peroxynitrite preserved its beneficial effects on arrhythmias (to 0% ventricular fibrillation, n=7) during sodium orthovanadate infusion (for 23 min) prior to 30 min of an ischemic period. On the other hand, genistein or tyrphostin treatment significantly reversed the protective effects of the peroxynitrite preconditioning (to 71% ventricular fibrillation, n=14, genistein and, to 75% ventricular fibrillation, n=8, tyrphostin). These results suggest that the tyrosine kinase pathway plays a significant role in peroxynitrite-induced preconditioning in rat isolated heart.
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Journal of Ethnopharmacology, 2000
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European Journal of Pharmacology, 2003
We have investigated the role of tyrosine kinase in the antiarrhythmic effects of peroxynitrite p... more We have investigated the role of tyrosine kinase in the antiarrhythmic effects of peroxynitrite preconditioning in rat isolated heart by using a tyrosine phosphatase inhibitor, sodium orthovanadate, and tyrosine kinase inhibitors, genistein and tyrphostin. Rat hearts were preconditioned by peroxynitrite administration at 1 microM for 3 min, which was followed by 10-min washout and 30 min of ischemia. None of the hearts had ventricular fibrillation in the peroxynitrite preconditioning group (from 64%, n=11, to 0%, n=11). Neither sodium orthovanadate (10 microM) nor genistein (50 microM) or tyrphostin (100 microM) alone showed any effects on arrhythmias. Peroxynitrite preserved its beneficial effects on arrhythmias (to 0% ventricular fibrillation, n=7) during sodium orthovanadate infusion (for 23 min) prior to 30 min of an ischemic period. On the other hand, genistein or tyrphostin treatment significantly reversed the protective effects of the peroxynitrite preconditioning (to 71% ventricular fibrillation, n=14, genistein and, to 75% ventricular fibrillation, n=8, tyrphostin). These results suggest that the tyrosine kinase pathway plays a significant role in peroxynitrite-induced preconditioning in rat isolated heart.
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European Journal of Pharmacology, 1998
Complex and incompletely understood mechanisms underline the vascular responses to hypoxia. Recen... more Complex and incompletely understood mechanisms underline the vascular responses to hypoxia. Recent studies showed that the tyrosine kinase pathway is involved in vasoconstriction of vascular smooth muscle. Therefore, the aim of this study was to determine the tyrosine kinase pathway for the hypoxic contraction in large-diameter sheep pulmonary artery rings in vitro by studying the effects of selective inhibitors of tyrosine kinase and of a protein tyrosine kinase inhibitor. Lowering the pO2 from 96 to 5 mm Hg caused a contraction in arteries precontracted with 5-hydroxytryptamine (5-HT) but not under resting force. Preincubation of arteries with the tyrosine kinase inhibitors, genistein and tyrphostin, abolished the hypoxic contraction without affecting 5-HT contractions. Inhibition of tyrosine phosphatase activity by sodium orthovanadate increased the hypoxic vasoconstriction in 5-HT-precontracted arteries. These results suggest that the tyrosine kinase pathway is involved in hypoxic pulmonary vasoconstriction in sheep isolated pulmonary artery rings.
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European Journal of Pharmacology, 1999
The simultaneous production of nitric oxide (NO) and superoxide leads to the formation of a poten... more 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.
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Analytical Letters, 2003
... DOI: 10.1081/AL-120018797 Meltem Sarıahmetoğlu a * , R. Alan Wheatley b , İclal Çakıcı a , İl... more ... DOI: 10.1081/AL-120018797 Meltem Sarıahmetoğlu a * , R. Alan Wheatley b , İclal Çakıcı a , İlker Kanzık a & Alan Townshend b pages 749-765. Available online: 02 Feb 2007. ...
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General Pharmacology: The Vascular System, 1998
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