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Quinidine
Selected AbstractsBLOCK OF Na+ AND K+ CURRENTS IN RAT VENTRICULAR MYOCYTES BY QUINACAINOL AND QUINIDINECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2005Michael K Pugsley SUMMARY 1.,The electrophysiological actions of quinacainol were investigated on sodium (INa), transient outward (ito) and sustained-outward plateau (iKsus) potassium currents in rat isolated cardiac myocytes using the whole-cell patch-clamp technique and compared with quinidine. 2.,Quinacainol blocked sodium currents in a concentration-dependent manner and with a potency similar to that of quinidine (mean (±SEM) EC50 50 ± 12 vs 95 ± 25 µmol/L for quinidine and quinacainol, respectively). However, quinacainol had a considerably prolonged onset and recovery from block compared with quinidine. 3.,Neither quinacainol nor quinidine significantly changed the steady state voltage dependence of activation of sodium currents. Quinidine produced a hyperpolarizing shift in the voltage dependence for sodium current inactivation, but no such shift was observed with quinacainol at doses that produced a substantial current block. 4.,Although quinacainol did not effectively block voltage-dependent potassium currents, even at concentrations as high as 1.5 mmol/L, quinidine, at a half-maximal sodium channel-blocking concentration, reduced peak ito current amplitude, increased the rate of inactivation of ito and blocked iKsus. 5.,These results indicate that quinacainol, a quinidine analogue, blocks sodium currents in cardiac myocytes with little effect on ito or iKsus potassium currents, which suggests that quinacainol may be exerting class 1c anti-arrhythmic actions. [source] Amiodarone Attenuates Fluoride-induced Hyperkalemia in VitroACADEMIC EMERGENCY MEDICINE, Issue 2 2003Mark Su MD Abstract Poisoning by hydrofluoric acid or fluoride salts results in hypocalcemia, hypomagnesemia, and hyperkalemia with subsequent cardiac dysrhythmias. In previous studies, quinidine attenuated fluoride-induced hyperkalemia in vitro, and enhanced survival in animals. Like quinidine, amiodarone is a potassium channel blocker, although amiodarone is more familiar to clinicians due to its recent inclusion in advanced cardiac life support (ACLS) protocols. Objectives: This in-vitro study of human erythrocytes was designed to determine whether amiodarone could attenuate fluoride-induced hyperkalemia. Methods: Six healthy volunteers each donated 60 mL of blood on three occasions. Each specimen was divided into 12 tubes, incubated at 37°C, and oxygenated with room air. An aqueous sodium fluoride (F,) solution was added to tubes 1,9. Incremental amounts of quinidine were added to tubes 1,4 (Q1,Q4) to attain calculated concentrations of 0.73 ,g/mL, 1.45 ,g/mL, 2.9 ,g/mL, and 5.8 ,g/mL, respectively. Incremental amounts of amiodarone were added to tubes 5,8 (A1,A4) to attain calculated concentrations of 0.38 ,g/mL, 0.75 ,g/mL, 1.5 ,g/mL, and 3.0 ,g/mL, respectively. Tubes 9,12 were controls for each of F,, amiodarone, quinidine alone, and no additive, respectively. Extracellular potassium concentration ([K+]) was followed, and an objective endpoint was defined as the rise in potassium concentration at 6 hours. Results: Fluoride produced a significant change in [K+] by 6 hours in all samples. Quinidine produced a J-shaped curve in its ability to attenuate the rise in [K+], with only one concentration, Q3, demonstrating significance versus tube 9 (control). Amiodarone also demonstrated a J-shaped dose,response effect, with statistical significance at A1, A2, and A3 versus tube 9 (control). There was no significant difference among the effective concentrations (Q3, A1, A2, and A3) of both drugs. Conclusions: In this in-vitro model using human blood, amiodarone and quinidine both attenuated F, -induced hyperkalemia. Further study is indicated to determine whether amiodarone enhances survival in F, -poisoned animals. [source] A Common SCN5A Variant Alters the Responsiveness of Human Sodium Channels to Class I Antiarrhythmic AgentsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2007MOSSAAB SHURAIH M.D. Background: The potential pathophysiological role of common SCN5A polymorphisms in cardiac arrhythmias has been increasingly recognized. However, little is known about the impact of those polymorphisms on the pharmocological response of hNav1.5 to various antiarrhythmic agents. Methods and Results: The known SCN5A polymorphism, S524Y, was studied in comparison with the wild type (WT) define the SCN5A-Q1077del variant. The ion channel gating kinetics and pharmacology were evaluated using whole-cell patch-clamp methods in HEK-293 cells. Consistent with a previous report, the basal ion channel gating kinetics of S524Y were indistinguishable from the WT. Quinidine (20 ,M) caused similar extent of tonic block reduction of sodium currents at ,120 mV in WT and S524Y. Surprisingly, quinidine (20 ,M) exerted a more use-dependent block by a 10 Hz pulse train in S524Y than in WT at 22°C (Ki: WT, 51.3 ,M; S524Y, 20.3 ,M). S524Y significantly delayed recovery from the use-dependent block, compared with the WT (,= 88.6 ± 7.9 s vs 41.9 ± 6.6 s, P < 0.005). Under more physiological conditions using a 2 Hz pulse train at 37°C, S524Y similarly enhanced the use-dependent block by quinidine. In addition, S524Y enhanced the use-dependent block by flecainide (12.5 ,M), but not by mexiletine (100 ,M). Conclusion: A common SCN5A polymorphism, S524Y, can enhance a use-dependent block by class Ia and Ic antiarrhythmic agents. Our findings may have clinical implications in pharmacological management of cardiac arrhythmias since this common SCN5A polymorphism might be a contributing factor to the variable antiarrhythmic response. [source] Extracellular Acidosis Modulates Drug Block of Kv4.3 Currents by Flecainide and QuinidineJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2003Suresh Singarayar M.D. Introduction: As a molecular model of the effect of ischemia on drug block of the transient outward potassium current, the effect of acidosis on the blocking properties of flecainide and quinidine on Kv4.3 currents was studied. Methods and Results: Kv4.3 channels were stably expressed in Chinese hamster ovary cells. Whole-cell, voltage clamp techniques were used to measure the effect of flecainide and quinidine on Kv4.3 currents in solutions of pH 7.4 and 6.0. Extracellular acidosis attenuated flecainide block of Kv4.3 currents, with the IC50 for flecainide (based on current-time integrals) increasing from7.8 ± 1.1 ,Mat pH 7.4 to125.1 ± 1.1 ,Mat pH 6.0. Similar effects were observed for quinidine (IC50 5.2 ± 1.1 ,Mat pH 7.4 and22.1 ± 1.3 ,Mat pH 6.0). Following block by either drug, Kv4.3 channels showed a hyperpolarizing shift in the voltage sensitivity of inactivation and a slowing in the time to recover from inactivation/block that was unaffected by acidosis. In contrast, acidosis attenuated the effects on the time course of inactivation and the degree of tonic- and frequency-dependent block for both drugs. Conclusion: Extracellular acidosis significantly decreases the potency of blockade of Kv4.3 by both flecainide and quinidine. This change in potency may be due to allosteric changes in the channel, changes in the proportion of uncharged drug, and/or changes in the kinetics of drug binding or unbinding. These findings are in contrast to the effects of extracellular acidosis on block of the fast sodium channel by these agents and provide a molecular mechanism for divergent modulation of drug block potentially leading to ischemia-associated proarrhythmia.(J Cardiovasc Electrophysiol, Vol. 14, pp. 641-650, June 2003) [source] Biowaiver monographs for immediate release solid oral dosage forms: Quinidine sulfate,,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2009S. Grube Abstract Literature data are reviewed relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing quinidine sulfate. Quinidine sulfate's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. The available data are not fully conclusive, but do suggest that quinidine sulfate is highly soluble and moderately to highly permeable and would likely be assigned to BCS Class I (or at worst BCS III). In view of the inconclusiveness of the data and, more important, quinidine's narrow therapeutic window and critical indication, a biowaiver based approval of quinidine containing dosage forms cannot be recommended for either new multisource drug products or for major postapproval changes (variations) to existing drug products. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2238,2251, 2009 [source] Atrial, SA Nodal, and AV Nodal Electrophysiology in Standing Horses: Normal Findings and Electrophysiologic Effects of Quinidine and DiltiazemJOURNAL OF VETERINARY INTERNAL MEDICINE, Issue 1 2007Colin C. Schwarzwald Background: Although atrial arrhythmias are clinically important in horses, atrial electrophysiology has been incompletely studied. Hypotheses: Standard electrophysiologic methods can be used to study drug effects in horses. Specifically, the effects of diltiazem on atrioventricular (AV) nodal conduction are rate-dependent and allow control of ventricular response rate during rapid atrial pacing in horses undergoing quinidine treatment. Animals: Fourteen healthy horses. Methods: Arterial blood pressure, surface electrocardiogram, and right atrial electrogram were recorded during sinus rhythm and during programmed electrical stimulation at baseline, after administration of quinidine gluconate (10 mg/kg IV over 30 minutes, n = 7; and 12 mg/kg IV over 5 minutes followed by 5 mg/kg/h constant rate infusion for the remaining duration of the study, n = 7), and after coadministration of diltiazem (0.125 mg/kg IV over 2 minutes repeated every 12 minutes to effect). Results: Quinidine significantly prolonged the atrial effective refractory period, shortened the functional refractory period (FRP) of the AV node, and increased the ventricular response rate during atrial pacing. Diltiazem increased the FRP, controlled ventricular rate in a rate-dependent manner, caused dose-dependent suppression of the sinoatrial node and produced a significant, but well tolerated decrease in blood pressure. Effective doses of diltiazem ranged from 0.125 to 1.125 mg/kg. Conclusions and Clinical Importance: Standard electrophysiologic techniques allow characterization of drug effects in standing horses. Diltiazem is effective for ventricular rate control in this pacing model of supraventricular tachycardia. The use of diltiazem for rate control in horses with atrial fibrillation merits further investigation. [source] Arrhythmic Storm Responsive to Quinidine in a Patient with Brugada Syndrome and Vasovagal SyncopePACING AND CLINICAL ELECTROPHYSIOLOGY, Issue 8 2005MANLIO F. MÁRQUEZ A 37-year-old man with Brugada syndrome (BrS) and arrhythmic storm is described. One month after implantation of a cardioverter-defibrillator he presented with recurrent appropriate shocks for spontaneous ventricular fibrillation (VF). Because of this arrhythmic storm, quinidine therapy was initiated with total suppression of all spontaneous arrhythmias. He had remained free of arrhythmias for 22 months since quinidine initiation. Two episodes of VF occurred after the patient stopped taking the medication. The patient resumed quinidine and has been free of VF for the last 3 months. This response to quinidine in a patient with symptomatic BrS supports its role in the prophylaxis of arrhythmic events in BrS. [source] Dextromethorphan and Quinidine Combination for Heroin DetoxificationTHE AMERICAN JOURNAL ON ADDICTIONS, Issue 3 2008Evaristo Akerele MD Dextromethorphan (DM) is a low-affinity, non-competitive NMDA receptor antagonist that has shown promise in preclinical and preliminary clinical studies for the reduction of opioid withdrawal symptoms, but when used at higher doses, it is associated with deleterious side effects attributed to its metabolite, dextrorphan. A clinical trial was therefore conducted to test the withdrawal-suppressant effect of a combination of dextromethorphan with quinidine (DM/Q). Quinidine inhibits the metabolism of dextromethorphan, reducing dextrorphan levels. Opioid-dependent patients were admitted to an inpatient unit, stabilized for three days on morphine (25 mg, sc, every six hours), and randomly assigned on day 2 to DM/Q (30 mg/30 mg, twice a day) (n = 22) or matching placebo (n = 9) prior to the discontinuation of morphine on day 4. Withdrawal symptoms, measured with the Modified Himmelsbach Opioid Withdrawal Scale (MHOWS), increased significantly on days 4 and 5 (Z = 3.70, p = .0002), and by day 6, 90% of the sample (28/31) had dropped out of the study. There were no differences between treatment groups on either outcome measure. The combination of dextromethorphan and quinidine appears ineffective as a primary treatment for opioid withdrawal. Future studies should examine dextromethorphan as an adjunct to other anti-withdrawal medications and focus more on the relationship between dextrorphan levels and withdrawal suppression. [source] Quinidine for Pharmacological Cardioversion of Atrial Fibrillation: A Retrospective Analysis in 501 Consecutive PatientsANNALS OF NONINVASIVE ELECTROCARDIOLOGY, Issue 2 2009Bernhard Schwaab M.D. Background: Although quinidine has been used to terminate atrial fibrillation (AFib) for a long time, it has been recently classified to be used as a third-line-drug for cardioversion. However, these recommendations are based on a few small studies, and there are no data available of a larger modern patient population undergoing pharmacological cardioversion of AFib. Therefore, we evaluated the safety of quinidine for cardioversion of paroxysmal AFib in patients after cardiac surgery and coronary intervention. Methods: In 501 consecutive patients (66 ± 9 years, 32% women), 200,400 mg of quinidine were administered every 6 hours until cardioversion or for a maximum of 48 hours. Patients were included with QT interval ,450 ms, ejection fraction (EF) ,35%, and plasma potassium >4.3 mEq/L. Exclusion criteria were: unstable angina, myocardial infarction <3 months, and advanced congestive heart failure. Patients received verapamil, beta-blockers, or digitalis to slow down ventricular rate <100 bpm. Results: Quinidine therapy did not have to be stopped due to adverse drug reactions (ADR), and no significant QTc interval prolongation (Bazett and Fridericia correction) and no life-threatening ventricular arrhythmia occurred. Mean quinidine dose was 617 ± 520 mg and 92% of the patients received verapamil or beta-blocker to decrease ventricular rate. Cardioversion was successful in 84% of patients. All ADRs were minor and transient. Multivariate analysis revealed female gender (OR 2.62, CI 1.61,4.26, P < 0.001) and EF 45,54% (OR 1.97, CI 1.15,3.36, P = 0.013) as independent risk factors for ADRs. Conclusions: Quinidine for pharmacological cardioversion of AFib is safe and well tolerated in this subset of patients. [source] The in vitro Inhibitory Potential of Trade Herbal Products on Human CYP2D6-Mediated Metabolism and the Influence of EthanolBASIC AND CLINICAL PHARMACOLOGY & TOXICOLOGY, Issue 5 2007Bent H. Hellum Herbal components were extracted from commercially available products in a way that ensured the same composition of constituents in the extract as in the original trade products. c-DNA baculovirus expressed CYP2D6 was used with dextromethorphan as substrate. Quinidine was included as a positive control inhibitor. A validated high performance liquid chromatography methodology was used to quantify the formation of dextrorphan (product of dextromethorphan O-demethylation). Ethanol showed a biphasic effect on CYP2D6 metabolism, increasing initially the CYP2D6 activity with 175% of control up to a concentration of 1.1%, where after ethanol linearly inhibited the CYP2D6 activity. All the investigated herbs inhibited CYP2D6 activity to some extent, but only St. John's wort, common sage and common valerian were considered possible candidates for in vivo clinically significant effects. They showed IC50 values of 0.07 ± 7 × 10,3 mg/ml, 0.8 ± 0.05 mg/ml and 1.6 ± 0.2 mg/ml, respectively. St. John's wort inhibited CYP2D6-mediated metabolism in an uncompetitive manner, while common valerian and common sage in a non-competitive manner demonstrated interherb differences in inhibition patterns and differences when compared to the more homogenous competitive inhibitor quinidine. Common valerian was the only herb that showed a mechanistic inhibition of CYP2D6 activity and attention should be paid to a possible toxicity of this herb. [source] Improved RP-HPLC determination of quinine in plasma and whole blood stored on filter paperBIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 9 2000J.A. Kolawole Abstract Analysis of quinine in plasma and whole blood samples dried on filter paper is described. Sample preparation involves liquid extraction of plasma and whole blood from the filter paper and subsequent solid-phase extraction using C8 Bond Elut cartridges. A reverse-phase liquid chromatography system with UV detection and fluorescence detection was used. The analytical characteristics of the method are reported, with a quantification limit of 0.1 µg mL,1 and within an assay coefficient of variation of 5.6,8.4% in plasma and 6.5,12% in whole blood. Representative chromatograms are shown as a function of time for samples from human subjects after ingestion of a single 400-mg dose of quinine sulphate. Quinidine, dihydroquinine and metabolites are well separated from quinine with a resolution of above 1 (Rs>1). Copyright © 2000 John Wiley & Sons, Ltd. [source] BLOCK OF Na+ AND K+ CURRENTS IN RAT VENTRICULAR MYOCYTES BY QUINACAINOL AND QUINIDINECLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 1-2 2005Michael K Pugsley SUMMARY 1.,The electrophysiological actions of quinacainol were investigated on sodium (INa), transient outward (ito) and sustained-outward plateau (iKsus) potassium currents in rat isolated cardiac myocytes using the whole-cell patch-clamp technique and compared with quinidine. 2.,Quinacainol blocked sodium currents in a concentration-dependent manner and with a potency similar to that of quinidine (mean (±SEM) EC50 50 ± 12 vs 95 ± 25 µmol/L for quinidine and quinacainol, respectively). However, quinacainol had a considerably prolonged onset and recovery from block compared with quinidine. 3.,Neither quinacainol nor quinidine significantly changed the steady state voltage dependence of activation of sodium currents. Quinidine produced a hyperpolarizing shift in the voltage dependence for sodium current inactivation, but no such shift was observed with quinacainol at doses that produced a substantial current block. 4.,Although quinacainol did not effectively block voltage-dependent potassium currents, even at concentrations as high as 1.5 mmol/L, quinidine, at a half-maximal sodium channel-blocking concentration, reduced peak ito current amplitude, increased the rate of inactivation of ito and blocked iKsus. 5.,These results indicate that quinacainol, a quinidine analogue, blocks sodium currents in cardiac myocytes with little effect on ito or iKsus potassium currents, which suggests that quinacainol may be exerting class 1c anti-arrhythmic actions. [source] Regional variations in action potential alternans in isolated murine Scn5a+/, hearts during dynamic pacingACTA PHYSIOLOGICA, Issue 2 2010G. D. K. Matthews Abstract Aim:, Clinical observations suggest that alternans in action potential (AP) characteristics presages breakdown of normal ordered cardiac electrical activity culminating in ventricular arrhythmogenesis. We compared such temporal nonuniformities in monophasic action potential (MAP) waveforms in left (LV) and right ventricular (RV) epicardia and endocardia of Langendorff-perfused murine wild-type (WT), and Scn5a+/, hearts modelling Brugada syndrome (BrS) for the first time. Methods:, A dynamic pacing protocol imposed successively incremented steady pacing rates between 5.5 and 33 Hz. A signal analysis algorithm detected sequences of >10 beats showing alternans. Results were compared before and following the introduction of flecainide (10 ,m) and quinidine (5 ,m) known to exert pro- and anti-arrhythmic effects in BrS. Results:, Sustained and transient amplitude and duration alternans were both frequently followed by ventricular ectopic beats and ventricular tachycardia or fibrillation. Diastolic intervals (DIs) that coincided with onsets of transient (tr) or sustained (ss) alternans in MAP duration (DI*) and amplitude (DI,) were determined. Kruskal,Wallis tests followed by Bonferroni-corrected Mann,Whitney U -tests were applied to these DI results sorted by recording site, pharmacological conditions or experimental populations. WT hearts showed no significant heterogeneities in any DI. Untreated Scn5a+/, hearts showed earlier onsets of transient but not sustained duration alternans in LV endocardium compared with RV endocardium or LV epicardium. Flecainide administration caused earlier onsets of both transient and sustained duration alternans selectively in the RV epicardium in the Scn5a+/, hearts. Conclusion:, These findings in a genetic model thus implicate RV epicardial changes in the arrhythmogenicity produced by flecainide challenge in previously asymptomatic clinical BrS. [source] A Comparative Pharmacokinetic Study in Healthy Volunteers of the Effect of Carbamazepine and Oxcarbazepine on Cyp3a4EPILEPSIA, Issue 3 2007Astrid-Helene Andreasen Summary:,Purpose: Carbamazepine (CBZ) and oxcarbazepine (OXCZ) are well-known inducers of drug metabolism via CYP3A4. Indirect interaction studies and clinical experience suggest that CBZ has a stronger potential in this regard than OXCZ. However this has never been subject to a direct comparative study. We performed a study in healthy volunteers to investigate the relative inductive effect of CBZ and OXCZ on CYP3A4 activity using the metabolism of quinidine as a biomarker reaction. Methods: Ten healthy, male volunteers participated in an open, randomized crossover study consisting of two periods separated by a 4-week wash-out period. The subjects received 1200 mg oral OXCZ daily for 17 days and 800 mg oral CBZ for 17 days. A single 200 mg oral dose of quinidine was administered at baseline and following administration of CBZ and OXCZ. Outcome parameters were the formation clearance of 3-hydroxyquinidine dose and the ratio of the AUCs of 3-hydroxyquinidine to quinidine. Results: Formation clearance of 3-hydroxyquinidine was increased by means of 89% (CI: 36,164; p = 0.0022) and 181% (CI: 120,260, p < 0.0001) after treatment with OXCZ and CBZ, respectively, compared to baseline. The relative inductive effect of CBZ was 46% higher than for OXCZ. AUC ratio increased by means of 161% (CI: 139,187, p < 0.0001) (OXCZ) and 222% (CI: 192,257, p < 0.0001) (CBZ). Quinidine Cmax decreased by means of 29% (CI: 16,40, p = 0.0018) (OXCZ) and 33% (CI: 18,45, p = 0.0020) (CBZ). T½ decreased by means of 12% (CI: 6,17, p < 0.0014) (OXCZ) and 32% (CI: 25,38, p < 0.0001) (CBZ). tmax was not changed in either period. Conclusion: We confirm a clinically significant inductive effect of both OXCZ and CBZ. The inductive effect of CBZ was about 46% higher than that of OXCZ, a difference that may be of clinical relevance. [source] Inhibitory Effect of Lamotrigine on A-type Potassium Current in Hippocampal Neuron,Derived H19-7 CellsEPILEPSIA, Issue 7 2004Chin-Wei Huang Summary:,Purpose: We investigated the effects of lamotrigine (LTG) on the rapidly inactivating A-type K+ current (IA) in embryonal hippocampal neurons. Methods: The whole-cell configuration of the patch-clamp technique was applied to investigate the ion currents in cultured hippocampal neuron,derived H19-7 cells in the presence of LTG. Effects of various related compounds on IA in H19-7 cells were compared. Results: LTG (30 ,M,3 mM) caused a reversible reduction in the amplitude of IA. The median inhibitory concentration (IC50) value required for the inhibition of IA by LTG was 160 ,M. 4-Aminopyridine (1 mM), quinidine (30 ,M), and capsaicin (30 ,M) were effective in suppressing the amplitude of IA, whereas tetraethylammonium chloride (1 mM) and gabapentin (100 ,M) had no effect on it. The time course for the inactivation of IA was changed to the biexponential process during cell exposure to LTG (100 ,M). LTG (300 ,M) could shift the steady-state inactivation of IA to a more negative membrane potential by approximately ,10 mV, although it had no effect on the slope of the inactivation curve. Moreover, LTG (100 ,M) produced a significant prolongation in the recovery of IA inactivation. Therefore in addition to the inhibition of voltage-dependent Na+ channels, LTG could interact with the A-type K+ channels to suppress the amplitude of IA. The blockade of IA by LTG does not simply reduce current magnitude, but alters current kinetics, suggesting a state-dependent blockade. LTG might have a higher affinity to the inactivated state than to the resting state of the IA channel. Conclusions: This study suggests that in hippocampal neurons, during exposure to LTG, the LTG-mediated inhibition of these K+ channels could be one of the ionic mechanisms underlying the increased neuronal excitability. [source] Amiodarone Attenuates Fluoride-induced Hyperkalemia in VitroACADEMIC EMERGENCY MEDICINE, Issue 2 2003Mark Su MD Abstract Poisoning by hydrofluoric acid or fluoride salts results in hypocalcemia, hypomagnesemia, and hyperkalemia with subsequent cardiac dysrhythmias. In previous studies, quinidine attenuated fluoride-induced hyperkalemia in vitro, and enhanced survival in animals. Like quinidine, amiodarone is a potassium channel blocker, although amiodarone is more familiar to clinicians due to its recent inclusion in advanced cardiac life support (ACLS) protocols. Objectives: This in-vitro study of human erythrocytes was designed to determine whether amiodarone could attenuate fluoride-induced hyperkalemia. Methods: Six healthy volunteers each donated 60 mL of blood on three occasions. Each specimen was divided into 12 tubes, incubated at 37°C, and oxygenated with room air. An aqueous sodium fluoride (F,) solution was added to tubes 1,9. Incremental amounts of quinidine were added to tubes 1,4 (Q1,Q4) to attain calculated concentrations of 0.73 ,g/mL, 1.45 ,g/mL, 2.9 ,g/mL, and 5.8 ,g/mL, respectively. Incremental amounts of amiodarone were added to tubes 5,8 (A1,A4) to attain calculated concentrations of 0.38 ,g/mL, 0.75 ,g/mL, 1.5 ,g/mL, and 3.0 ,g/mL, respectively. Tubes 9,12 were controls for each of F,, amiodarone, quinidine alone, and no additive, respectively. Extracellular potassium concentration ([K+]) was followed, and an objective endpoint was defined as the rise in potassium concentration at 6 hours. Results: Fluoride produced a significant change in [K+] by 6 hours in all samples. Quinidine produced a J-shaped curve in its ability to attenuate the rise in [K+], with only one concentration, Q3, demonstrating significance versus tube 9 (control). Amiodarone also demonstrated a J-shaped dose,response effect, with statistical significance at A1, A2, and A3 versus tube 9 (control). There was no significant difference among the effective concentrations (Q3, A1, A2, and A3) of both drugs. Conclusions: In this in-vitro model using human blood, amiodarone and quinidine both attenuated F, -induced hyperkalemia. Further study is indicated to determine whether amiodarone enhances survival in F, -poisoned animals. [source] The functional properties of the human ether-à-go-go -like (HELK2) K+ channelEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2002Andrea Becchetti Abstract The voltage-dependent K+ channels belonging to the ether-à-go-go family (eag, erg, elk) are widely expressed in the mammalian CNS. Their neuronal function, however, is poorly understood. Among the elk clones, elk2 is the most abundantly expressed in the brain. We have characterized the human ELK2 channel (HELK2) expressed in mammalian cell lines. Moreover, we have detected helk2 mRNA and ELK2-like currents in freshly dissociated human astrocytoma cells. HELK2 was inhibited by Cs+ in a voltage-dependent way (Kd was 0.7 mm, at ,120 mV). It was not affected by Way 123398 (5 µm), dofetilide (10 µm), quinidine (10 µm), verapamil (20 µm), haloperidol (2 µm), astemizole (1 µm), terfenadine (1 µm) and hydroxyzine (30 µm), compounds known to inhibit the biophysically related HERG channel. The crossover of the activation and inactivation curves produced a steady state ,window' current with a peak around ,20 mV and considerably broader than it usually is in voltage-dependent channels, including HERG. Similar features were observed in the ELK2 clone from rat, in the same experimental conditions. Thus, ELK2 channels are active within a wide range of membrane potentials, both sub- and suprathreshold. Moreover, the kinetics of channel deactivation and removal of inactivation was about one order of magnitude quicker in HELK2, compared to HERG. Overall, these properties suggest that ELK2 channels are very effective at dampening the neuronal excitability, but less so at producing adaptation of action potential firing frequency. In addition, we suggest experimental ways to recognize HELK2 currents in vivo and raise the issue of the possible function of these channels in astrocytoma. [source] Simple Preparation of Dimeric Cinchona Alkaloid Derivatives on Polystyrene Supports and a Highly Enantioselective Catalytic Heterogeneous Dimerization of KetenesADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 9 2010Ravindra Abstract A convenient route for the covalent immobilization of quinidine and hydroquinidine pyridazine ethers on insoluble polystyrene supports is described, which avoids the need of chromatographic purifications at any stage. The use of the heterogeneized alkaloid derivatives in the asymmetric organocatalytic dimerization of ketenes afforded high enantioselectivity values (90,97% ee) in the course of 20 reaction cycles. [source] Non-Linear Effect of Modifier Composition on Enantioselectivity in Asymmetric Hydrogenation over Platinum MetalsADVANCED SYNTHESIS & CATALYSIS (PREVIOUSLY: JOURNAL FUER PRAKTISCHE CHEMIE), Issue 1-2 2003Wolf-Rüdiger Huck Abstract Prominent non-linear behavior was observed when mixtures of cinchona alkaloids were applied as chiral modifiers in enantioselective hydrogenations over Pt/Al2O3 and Pd/TiO2. The phenomenon is traced to differences in the strength and geometry of alkaloid adsorption on the metal surface. In ethyl pyruvate hydrogenation under close to ambient conditions the weaker adsorbing quinidine (QD) outperformed the generally preferred modifier cinchonidine (CD) and afforded the highest ee (96,98%) at 1,5,bar. In the partial hydrogenation of 4-methoxy-6-methyl-2-pyrone to the dihydro derivative 4 CD gave 73% ee to (S)- 4 and QD provided 72% ee to (R)- 4, and still the alkaloid mixture containing less than 5,mol,% CD afforded 15% ee to (S)- 4. This non-linear behavior may be advantageous in asymmetric synthesis as low purity chiral compounds can be applied as efficient modifiers for Pt or Pd. [source] Increased Right Ventricular Repolarization Gradients Promote Arrhythmogenesis in a Murine Model of Brugada SyndromeJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 10 2010CLAIRE A. MARTIN M.R.C.P. Repolarization Gradients in Brugada Syndrome.,,Introduction: Brugada syndrome (BrS) is associated with loss of Na+ channel function and increased risks of a ventricular tachycardia exacerbated by flecainide but reduced by quinidine. Previous studies in nongenetic models have implicated both altered conduction times and repolarization gradients in this arrhythmogenicity. We compared activation latencies and spatial differences in action potential recovery between different ventricular regions in a murine Scn5a+/, BrS model, and investigated the effect of flecainide and quinidine upon these. Methods and Results: Langendorff-perfused wild-type and Scn5a+/, hearts were subjected to regular pacing and a combination of programmed electrical stimulation techniques. Monophasic action potentials were recorded from the right (RV) and left ventricular (LV) epicardium and endocardium before and following flecainide (10 ,M) or quinidine (5 ,M) treatment, and activation latencies measured. Transmural repolarization gradients were then calculated from the difference between neighboring endocardial and epicardial action potential durations (APDs). Scn5a+/, hearts showed decreased RV epicardial APDs, accentuating RV, but not LV, transmural gradients. This correlated with increased arrhythmic tendencies compared with wild-type. Flecainide increased RV transmural gradients, while quinidine decreased them, in line with their respective pro- and antiarrhythmic effects. In contrast, Scna5+/, hearts showed slowed conduction times in both RV and LV, exacerbated not only by flecainide but also by quinidine, in contrast to their differing effects on arrhythmogenesis. Conclusion: We use a murine genetic model of BrS to systematically analyze LV and RV action potential kinetics for the first time. This establishes a key role for accentuated transmural gradients, specifically in the RV, in its arrhythmogenicity. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1153-1159) [source] A Common SCN5A Variant Alters the Responsiveness of Human Sodium Channels to Class I Antiarrhythmic AgentsJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 4 2007MOSSAAB SHURAIH M.D. Background: The potential pathophysiological role of common SCN5A polymorphisms in cardiac arrhythmias has been increasingly recognized. However, little is known about the impact of those polymorphisms on the pharmocological response of hNav1.5 to various antiarrhythmic agents. Methods and Results: The known SCN5A polymorphism, S524Y, was studied in comparison with the wild type (WT) define the SCN5A-Q1077del variant. The ion channel gating kinetics and pharmacology were evaluated using whole-cell patch-clamp methods in HEK-293 cells. Consistent with a previous report, the basal ion channel gating kinetics of S524Y were indistinguishable from the WT. Quinidine (20 ,M) caused similar extent of tonic block reduction of sodium currents at ,120 mV in WT and S524Y. Surprisingly, quinidine (20 ,M) exerted a more use-dependent block by a 10 Hz pulse train in S524Y than in WT at 22°C (Ki: WT, 51.3 ,M; S524Y, 20.3 ,M). S524Y significantly delayed recovery from the use-dependent block, compared with the WT (,= 88.6 ± 7.9 s vs 41.9 ± 6.6 s, P < 0.005). Under more physiological conditions using a 2 Hz pulse train at 37°C, S524Y similarly enhanced the use-dependent block by quinidine. In addition, S524Y enhanced the use-dependent block by flecainide (12.5 ,M), but not by mexiletine (100 ,M). Conclusion: A common SCN5A polymorphism, S524Y, can enhance a use-dependent block by class Ia and Ic antiarrhythmic agents. Our findings may have clinical implications in pharmacological management of cardiac arrhythmias since this common SCN5A polymorphism might be a contributing factor to the variable antiarrhythmic response. [source] Ionic Basis of Pharmacological Therapy in Brugada SyndromeJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 2 2007MANLIO F. MÁRQUEZ M.D. An implantable cardioverter-defibrillator is considered the only effective therapy to terminate ventricular arrhythmias in symptomatic patients with Brugada syndrome. However, it does not prevent future arrhythmic episodes. Only antiarrhythmic drug therapy can prevent them. There have been several reports of a beneficial effect of oral quinidine in both asymptomatic and symptomatic patients. Other possible beneficial oral agents could be Ito blockers. Intravenous isoproterenol has been reported to be especially useful in abolishing arrhythmic storms in emergency situations. Also, isolated case reports on the usefulness of cilostazol, sotalol, and mexiletine have been described. The present article reviews the mechanisms by which these drugs may act and their possible role in the pharmacotherapy of this disease. [source] Electrophysiological Basis and Genetics of Brugada SyndromeJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 2005AUGUSTUS O. GRANT M.B.Ch.B., Ph.D. Brugada syndrome is a primary arrhythmic syndrome arising in the structurally normal heart. Any proposed mechanism should account for the major features of the syndrome: localization of the ST segment and T-wave changes to the right precordial leads, association of conduction slowing at several levels, precipitation or aggravation of the major ECG changes by sodium channel-blocking drugs and the occurrence of ventricular fibrillation. Heterogeneity of repolarization across the ventricle wall plays a major role. Any agency that shifts the net current gradient during phase I outward would exaggerate the normal heterogeneity of repolarization and result in the ST segment and T-wave changes characteristic of the syndrome. When the outward current shift is marked, premature repolarization may occur in epicardial zone and the resulting gradient may precipitate reentry. The syndrome is inherited as an autosomal dominant. However, 75% of clinically affected individuals are males. In 20% of cases, the syndrome is associated with mutations of the cardiac sodium channel gene SCN5A. The mutations result in a loss-of-function as a result of the synthesis of a non-functional protein, altered protein trafficking, or change in gating. Agencies that reduce the sodium current may precipitate the characteristic ECG changes, for example, sodium channel blockers and membrane depolarization by hyperkalemia. Sympathetic stimulation may reverse the ECG changes and reduce arrhythmia recurrence. By its nonspecific potassium channel blocking action, quinidine may also reduce arrhythmia recurrence. We still do not know the basis for defect in the majority of patients with Brugada syndrome. [source] Extracellular Acidosis Modulates Drug Block of Kv4.3 Currents by Flecainide and QuinidineJOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, Issue 6 2003Suresh Singarayar M.D. Introduction: As a molecular model of the effect of ischemia on drug block of the transient outward potassium current, the effect of acidosis on the blocking properties of flecainide and quinidine on Kv4.3 currents was studied. Methods and Results: Kv4.3 channels were stably expressed in Chinese hamster ovary cells. Whole-cell, voltage clamp techniques were used to measure the effect of flecainide and quinidine on Kv4.3 currents in solutions of pH 7.4 and 6.0. Extracellular acidosis attenuated flecainide block of Kv4.3 currents, with the IC50 for flecainide (based on current-time integrals) increasing from7.8 ± 1.1 ,Mat pH 7.4 to125.1 ± 1.1 ,Mat pH 6.0. Similar effects were observed for quinidine (IC50 5.2 ± 1.1 ,Mat pH 7.4 and22.1 ± 1.3 ,Mat pH 6.0). Following block by either drug, Kv4.3 channels showed a hyperpolarizing shift in the voltage sensitivity of inactivation and a slowing in the time to recover from inactivation/block that was unaffected by acidosis. In contrast, acidosis attenuated the effects on the time course of inactivation and the degree of tonic- and frequency-dependent block for both drugs. Conclusion: Extracellular acidosis significantly decreases the potency of blockade of Kv4.3 by both flecainide and quinidine. This change in potency may be due to allosteric changes in the channel, changes in the proportion of uncharged drug, and/or changes in the kinetics of drug binding or unbinding. These findings are in contrast to the effects of extracellular acidosis on block of the fast sodium channel by these agents and provide a molecular mechanism for divergent modulation of drug block potentially leading to ischemia-associated proarrhythmia.(J Cardiovasc Electrophysiol, Vol. 14, pp. 641-650, June 2003) [source] Dielectric study of equimolar acetaminophen,aspirin, acetaminophen,quinidine, and benzoic acid,progesterone molecular alloys in the glass and ultraviscous states and their relevance to solubility and stabilityJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 3 2010G.P. Johari Abstract Equimolar mixtures of acetaminophen,aspirin, acetaminophen,quinidine, and benzoic acid,progesterone have been vitrified and dielectric properties of their glassy and ultraviscous alloys have been studied. For 20,K/min heating rate, their Tgs are 266, 330, and 263,K, respectively. The relaxation has an asymmetric distribution of times, and the distribution parameter increases with increase in temperature. The dielectric relaxation time varies with T according to the Vogel,Fulcher,Tammann equation, log10(,0),=,AVFT,+,[BVFT/(T,,,T0)], where AVFT, BVFT, and T0 are empirical constants. The equilibrium permittivity is highest for the aspirin,acetaminophen and lowest for the benzoic acid-progesterone alloy, indicating a substantial interpharmaceutical hydrogen bonding that makes the alloy more stable against crystallization than the pure components. The benzoic acid,progesterone alloy is thermodynamically the most nonideal. It showed cold crystallization on heating, which is attributed to its relatively greater magnitude of the JG relaxation in relation to its ,-relaxation. It is argued that the difference between the free energy of an alloy and the pure components would have an effect on the solubility. Studies of solution thermodynamics of a glassy molecular alloy may be useful for optimizing choice of components and composition to form molecular alloys and to impact drug delivery. © 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1358,1374, 2010 [source] Biowaiver monographs for immediate release solid oral dosage forms: Quinidine sulfate,,JOURNAL OF PHARMACEUTICAL SCIENCES, Issue 7 2009S. Grube Abstract Literature data are reviewed relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of new multisource and reformulated immediate release (IR) solid oral dosage forms containing quinidine sulfate. Quinidine sulfate's solubility and permeability, its therapeutic use and index, pharmacokinetics, excipient interactions and reported BE/bioavailability (BA) problems were taken into consideration. The available data are not fully conclusive, but do suggest that quinidine sulfate is highly soluble and moderately to highly permeable and would likely be assigned to BCS Class I (or at worst BCS III). In view of the inconclusiveness of the data and, more important, quinidine's narrow therapeutic window and critical indication, a biowaiver based approval of quinidine containing dosage forms cannot be recommended for either new multisource drug products or for major postapproval changes (variations) to existing drug products. © 2008 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 98:2238,2251, 2009 [source] In vitro assessment of cytochrome P450 inhibition: Strategies for increasing LC/MS-based assay throughput using a one-point IC50 method and multiplexing high-performance liquid chromatographyJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 9 2007Tong Lin Abstract A fast and robust LC/MS-based cytochrome P450 (CYP) inhibition assay, using human liver microsomes, has been fully developed and validated for the major human liver CYPs. Probe substrates were phenacetin, diclofenac, S-mephenytoin, and dextromethorphan for CYP1A2, CYP2C9, CYP2C19, and CYP2D6, respectively. Midazolam and testosterone were chosen for CYP3A4. Furafylline, sulfaphenazole, tranylcypromine, quinidine, and ketoconazole were identified as positive control inhibitors for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4, respectively. To increase the throughput of the assay, a one-point method was developed, using data from CYP inhibition assays conducted at one concentration (i.e., 10 µM), to estimate the drug concentration at which the metabolism of the CYP probe substrate was reduced by 50% (IC50). The IC50 values from the one-point assay were validated by correlating the results with IC50 values that were obtained with a traditional eight-point concentration,response curve. Good correlation was achieved with the slopes of the trendlines between 0.95 and 1.02 and with R2 between 0.77 and 1.0. Throughput was increased twofold by using a Cohesive multiplexing high-performance liquid chromatography system. The one-point IC50 estimate is useful for initial compound screening, while the full concentration,response IC50 method provides detailed CYP inhibition data for later stages of drug development. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 2485,2493, 2007 [source] Dielectric relaxation and crystallization of ultraviscous melt and glassy states of aspirin, ibuprofen, progesterone, and quinidineJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 5 2007G.P. Johari Abstract Molecular relaxation in ultraviscous melt and glassy states of aspirin, ibuprofen, progesterone, and quinidine has been studied by dielectric spectroscopy. The asymmetric relaxation spectra is characterized by the Kohlrausch distribution parameter of 0.46,±,0.02 for aspirin to 0.67,±,0.02 for progesterone. The dielectric relaxation time varies with the temperature, T, according to the Vogel,Fulcher,Tammann Equation, log10(,0),=,AVFT,+,[BVFT/(T,,,T0)], where AVFT, BVFT, and T0 are empirical constants. The extrapolated ,0 at calorimetric glass-softening temperature is close to the value expected. The equilibrium permittivity, ,0, is lowest for ibuprofen which indicates an antiparallel orientation of dipoles in its liquid's hydrogen-bonded structure. A decrease in ,0 with time shows that ultraviscous aspirin, progesterone, and quinidine begin to cold-crystallize at a relatively lower temperature than ibuprofen. ,0 of the cold-crystallized phases are, 4.7 for aspirin at 290 K, 2.55 for ibuprofen at 287 K, 2.6 for progesterone at 320 K, and 3.2 for quinidine at 375 K. It is argued that hydrogen-bonding, the Kohlrausch parameter, extent of localized motions and the long-range diffusion times all determine the physical and chemical stability of an amorphous pharmaceutical during storage. © 2007 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 96: 1159,1175, 2007 [source] Influence of P-glycoprotein on the transplacental passage of cyclosporineJOURNAL OF PHARMACEUTICAL SCIENCES, Issue 10 2001P. Pávek Abstract The transfer kinetics of cyclosporine across the dually perfused rat placenta in the maternal to fetal direction and a possible involvement of P-glycoprotein were investigated. The transplacental clearance of cyclosporine in the materno,fetal direction was found to be dependent on the maternal inflow concentration of cyclosporine. Coadministration of cyclosporine with an excess of quinidine or chlorpromazine into the maternal compartment revealed 1.7- and 1.9-fold increase in cyclosporine concentration in the fetal compartment. In the experiments where quinidine was present both in the maternal and fetal compartments, cyclosporine appeared in the fetal compartment significantly faster, and its amount was three times higher when compared with controls. Conversely, quinidine or chlorpromazine did not affect the transplacental passage of L-[3H]-glucose. The interference of quinidine with the metabolism of cyclosporine in the placenta was excluded because only traces of M-1 and M-17 metabolites were found in the fetal solutions. Sodium azide, a mitochondrial respiratory inhibitor, was found to double the rate of cyclosporine, but not L-[3H]-glucose, passage across the placenta. Our findings indicate that P-glycoprotein pumps cyclosporine out of the trophoblast cells of the rat placenta in the ATP-dependent manner and restricts the passage of cyclosporine across the placental barrier. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1583,1592, 2001 [source] Influence of Extracellular K+ Concentrations on Quinidine-induced K+ Current Inhibition in Rat Ventricular MyocytesJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 1 2000MICHIKO HIROTA Hypokalaemia is one of the important risk factors for development of torsades de pointes. We recently reported that hypokalaemia increased the electrocardiographic QT interval in rats treated with quinidine, but did not alter the arrhythmogenic potency of quinidine. In this study, we have investigated the influence of extracellular potassium concentration ([K+]o) on the inhibition of several types of cardiac potassium currents by quinidine. Such types of currents include the delayed rectifier potassium current (IK), the transient outward current (Ito), and the inward rectifier potassium current (IK1), as measured in isolated rat ventricular cells using patch-clamp techniques. Concentration-dependent effects of quinidine on IK, Ito, and IK1 were evaluated under both normal ([K+]o = 5.4 mM) and hypokalaemic ([K+]o = 3.5 mM) conditions. In contrast to both IK and Ito, which were barely influenced by changes in [K+]o, IK1 was significantly inhibited by hypokalaemia. Furthermore, while quinidine suppressed both IK and Ito in a concentration-dependent manner, the inhibitory potency of quinidine on these currents was not influenced by changes in [K+]o. The respective normal and hypokalaemic IC50 values for quinidine were 11.4 and 10.0 ,M (IK), and 17.6 and 17.3 ,M (Ito). Although higher concentrations of quinidine were required to inhibit IK1, the inhibitory potency of quinidine was also found to be insensitive to changes in [K+]o. Thus, in rats, the inhibitory potency of quinidine for the K+ current-types IK, Ito and IK1 is barely influenced by changes in [K+]o. These findings are consistent with our previous report showing that the QT-prolonging potency of quinidine was not altered under hypokalaemic conditions. However, whilst hypokalaemia does not affect IK or Ito, it can inhibit IK1 and can result in QT prolongation in-vivo. [source] | ||||||||||||||||||||||||||||||||||