Mg Of Quinidine Research Articles

Quinidine for Pharmacological Cardioversion of Atrial Fibrillation: A Retrospective Analysis in 501 Consecutive Patients

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. 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 < or =450 ms, ejection fraction (EF) > or =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. 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. Quinidine for pharmacological cardioversion of AFib is safe and well tolerated in this subset of patients.

Effects of Ketoconazole and Quinidine on Pharmacokinetics of Pactimibe and Its Plasma Metabolite, R-125528, in Humans

Pactimibe sulfate is a novel acyl coenzyme A:cholesterol acyltransferase inhibitor developed for the treatment of hypercholesterolemia and atherosclerotic diseases. Pactimibe has two equally dominant clearance pathways forming R-125528 by CYP3A4 and M-1 by CYP2D6 in vitro. R-125528 is a plasma metabolite and is cleared solely by CYP2D6 despite its acidity. To evaluate contributions of the cytochrome P450 enzymes on the pharmacokinetics of pactimibe and R-125528 in humans, drug-drug interaction studies using ketoconazole and quinidine were conducted. Eighteen healthy male subjects were given a single dose of pactimibe sulfate without and with 400 mg of ketoconazole (q.d.). With the concomitant treatment, the area under the plasma concentration-time curve (AUC(0-inf)) of pactimibe modestly increased 1.7-fold and AUC(0-tz) of R-125528 decreased by 55%. In addition, 17 healthy male subjects were given a single dose of pactimibe sulfate without and with 600 mg of quinidine (b.i.d.). With the concomitant treatment, the AUC(0-inf) for pactimibe modestly increased 1.7-fold. On the other hand, the AUC(0-tz) of R-125528 was markedly elevated 5.0-fold, although the AUC(0-inf) could not be adequately defined because the terminal elimination phase of R-125528 was not obtained in the study period up to 72 h. As the f(m CYP3A4) and f(m CYP2D6) values of pactimibe estimated from in vitro studies were 0.40 and 0.33, respectively, AUC increase ratios of pactimibe were estimated to be 1.7 with ketoconazole and 1.5 with quinidine. These values were well in accordance with the values observed in this study. Moreover, the f(m CYP2D6) of R-125528 estimated to be almost 1 would well explain the accumulation of R-125528 observed with the quinidine treatment.

The Efficacy of Intravenous Amiodarone for the Conversion of Chronic Atrial Fibrillation

Chronic atrial fibrillation (CAF) is a serious condition with significant morbidity and mortality. The mainstay of drug therapy for the conversion of atrial fibrillation to sinus rhythm continues to be quinidine. The value and safety of intravenously (i.v.) administered amiodarone therapy vs quinidine sulfate therapy was compared in a cohort of patients with CAF of more than 3 weeks' duration. To evaluate the efficacy of i.v. administered amiodarone and oral quinidine sulfate containing 300 mg of quinidine in the conversion of CAF and to assess the effect of oral amiodarone in the conversion of CAF in the patients in whom CAF did not convert with IV amiodarone. Thirty-two patients with CAF of more than 3 weeks' duration were randomized to either i.v. amiodarone treatment or oral digoxin/quinidine treatment in a randomized unblinded single crossover study. The converters continued either oral amiodarone therapy or quinidine extended-action tablet (Quinidex) therapy. Seventeen patients were randomized to the quinidine group and 15 patients to the amiodarone group. Nonconverters from the quinidine group crossed over to the amiodarone group. Amiodarone and quinidine were equally effective at 24 hours in converting CAF (eight [47%] of 17 patients in the quinidine group vs 12 [44%] of 27 patients in the amiodarone group; P, not significant). At 2 and 9 months of oral therapy, amiodarone was superior to quinidine in maintaining sinus rhythm. Only two of eight patients in the quinidine group tolerated the medication. All patients in the amiodarone group tolerated the medication. One additional patient converted to sinus rhythm at 2 months (13 [48%] of 27), and five more patients converted at 9 months (18 [67%] of 27). Amiodarone therapy and digoxin/quinidine therapy were equally effective at 48 hours in controlling ventricular response at rest. During the first 48 hours of treatment, i.v. amiodarone and oral quinidine were equally effective in converting CAF to sinus rhythm. At 2 and 9 months of therapy, treatment with oral amiodarone was superior to that of quinidine in restoring sinus rhythm. Long-term treatment with oral amiodarone is better tolerated than with quinidine.

Pharmacokinetics of Dextromethorphan and Metabolites in Humans

Dextromethorphan is primarily metabolized to dextrorphan by cytochrome P450 2D6 (CYP2D6), a genetically polymorphic enzyme in humans. Dextrorphan is an active metabolite that produces phencyclidine-like behavioral effects in animals and exhibits anticonvulsant and neuroprotective properties in a variety of experimental models. In these studies, we examined the effects of CYP2D6 phenotype and quinidine inhibition on the pharmacokinetics of dextromethorphan and its metabolites in humans. After a single oral dose of dextromethorphan HBr (30 mg), the major metabolites in the plasma of extensive metabolizers (N = 5) were conjugated dextrorphan and conjugated 3-hydroxymorphinan. Free dextrorphan concentrations were about 100-fold less than the conjugated dextrorphan, and dextromethorphan was not detectable. Pretreatment of these subjects with 100 mg of quinidine, a selective inhibitor of CYP2D6, significantly suppressed the formation of dextrorphan and elevated the concentrations of dextromethorphan (t1/2, 16.4 hours). In poor metabolizers (N = 4) given the same dose, dextromethorphan was the major component in the plasma with a t1/2 of 29.5 hours. Present at concentrations 5- to 10-fold less were conjugated dextrorphan and the other two metabolites. Urinary recovery studies indicated that the inhibition by quinidine was reversible and that the elimination of dextromethorphan primarily depends on CYP2D6 activity rather than renal elimination. These data demonstrated that the CYP2D6 phenotype and the concurrent administration of quinidine significantly affect the disposition of dextromethorphan and the formation of the active metabolite dextrorphan and are important factors to be considered in studies of the pharmacologic and behavioral effects of dextromethorphan.

Treatment of atrial fibrillation in horses by intravenous administration of quinidine

Summary Intravenous administration of quinidine gluconate converted atrial fibrillation (af) to sinus rhythm in 9 of 12 horses. Twelve horses that were diagnosed by ecg to have af were administered up to 11 mg of quinidine gluconate/kg of body weight in 1.0 -to 1.5-mg/kg bolus injections every 10 to 15 minutes. The total dose of quinidine administered iv ranged from 1.8 to 5.8 g. Increased ventricular rate, apprehension, and mild depression were observed during treatment. Other signs of toxicosis were not observed. One horse was successfully treated with iv administered quinidine gluconate on 3 occasions. Intravenous administration of quinidine is a safe and effective alternative for treatment of af in some horses.

Low dose quinidine-mexiletine combination therapy versus quinidine monotherapy for treatment of ventricular arrhythmias

Low dose quinidine-mexiletine combination therapy was compared with quinidine monotherapy in 15 patients with frequent ventricular premature complexes and nonsustained ventricular tachycardia in a dose escalation crossover study. Oral combination therapy was initiated with quinidine gluconate (165 mg) plus mexiletine (150 mg) every 8 h. If ventricular premature complexes were not suppressed ≥80% and nonsustained ventricular tachycardia ≥90%, the dose was increased to a maximum of 330 mg of quinidine plus 200 mg of mexiletine. Quinidine monotherapy was initiated with 330 mg and escalated to a maximum of 660 mg every 8 h if criteria for effectiveness were not met.Combination quinidine-mexiletine therapy suppressed 80% of ventricular premature complexes in 13 of 14 patients and suppressed 100% of episodes of ventricular tachycardia in 6 of 8 patients (mean quinidine dose 200 ±70 mg; mean mexiletine dose 146 ± 24 mg every 8 h). The mean effective trough quinidine and mexiletine concentration was 1.0 ± 0.7 and 0.9 ± 0.4 μg/ml, respectively. Monotherapy was less effective; that is, ≥80% suppression of ventricular premature complexes was observed in 5 of 15 patients and 100% suppression of ventricular tachycardia in 2 of 9 patients. The mean quinidine monotherapy dose was 462 ± 155 mg every 8 h; the mean quinidine concentration was 1.8 ± 0.8 μg/ml.Adverse systemic effects occurred in 3 patients on quinidine-mexiletine therapy and in 11 on quinidine monotherapy. Neither treatment prolonged PR or QRS intervals, but monotherapy prolonged the QTc interval (p < 0.05); both treatments prolonged the coupling interval (p < 0.05). Low dose quinidine-mexiletine is more effective and better tolerated than are standard doses of quinidine.

Indecainide compared with quinidine for chronic stable ventricular arrhythmias secondary to coronary artery disease or to cardiomyopathy

Indecainide, a new type Ic antiarrhythmic agent, and quinidine sulfate were compared in a randomized double-blind parallel study. Cardiac patients with ≥30 ventricular premature complexes per hour hour received indecainide, 50 mg, or quinidine, 200 mg every 6 hours, and the doses were increased until more than 80% suppression was noted, adverse effects occurred or a maximal dose of 100 mg of indecainide or 400 mg of quinidine given every 6 hours. Efficacy was achieved in 8 of 10 taking indecainide (p < 0.05) and 7 of 9 taking quinidine (p < 0.05). At least 90% of episodes of ventricular tachycardia were suppressed in 4 of 7 patients taking indecainide and 1 of 4 taking quinidine. No adverse effects were observed in the 7 patients who responded to indecainide and the 4 who responded quinidine, resulting in short-term efficacy without adverse effects in 7 patients (70%) taking indecainide and 4 (44%) taking quinidine. The effective or maximal mean daily indecainide and quinidine doses were 190 ± 32 mg and 1,022 ± 291 mg, respectively; mean trough indecainide and quinidine concentrations were 617 ± 247 ng/ml and 3.3 ± 1.4 μg/ml, respectively. Indecainide prolonged mean PR and QRS intervals (p < 0.05), but not QT and QTc intervals. Quinidine did not change PR or QRS intervals but prolonged QTc interval (p < 0.05). During dosing, 1 patient discontinued indecainide treatment because of nausea; 3 discontinued quinidine because of gastrointestinal complaints. One patient taking indecainide had proarrhythmic effects and died suddenly. Indecainide is an effective antiarrhythmic agent that is well tolerated systemically; however, the incidence of proarrhythmic effects must be explored.

Quinidine and the identification of drugs whose elimination is impaired in subjects classified as poor metabolizers of debrisoquine.

Quinidine and its diastereoisomer quinine were tested in vitro for their effect on the 4-hydroxylation of debrisoquine, the O-deethylation of phenacetin and the 1'-hydroxylation of bufuralol, by human liver microsomal samples; quinidine was studied for its effect on debrisoquine 4-hydroxylation in vivo. Quinidine was a potent inhibitor of the 4-hydroxylation of debrisoquine and the 1'-hydroxylation of bufuralol, with IC50 values of 0.7 and 0.2 microM, being around 100 times more potent in this respect than quinine. Very much higher (1000-fold) levels of quinidine were required to inhibit the O-deethylation of phenacetin, being rather less potent in this than quinine. Eight subjects were phenotyped for their debrisoquine oxidation status and found to be extensive metabolisers (EM). They were tested again after the co-administration of 50 mg of quinidine with the debrisoquine. The concomitant administration of quinidine increased the metabolic ratios (MRs) by a mean of 26-fold. The effects of quinidine at a dose of only 50 mg, on the metabolism of a new drug in EM subjects may prove a useful method of assessing the contribution of the debrisoquine 4-hydroxylase isozyme to the elimination of the drug tested.

Quinidine-Induced Lupus Erythematosus

<h3>To the Editor.</h3> —We read with interest the article by Lavie and associates¹in the March 1984Archives. Since a review of the literature revealed only a few cases of suspected quinidine-induced lupus erythematosus,¹we believe the following case should be added to the group. We suspect that this entity may not be as rare as the literature would indicate. <h3>Report of a Case.</h3> —A 52-year-old white man was admitted to St Joseph's Hospital, Atlanta, on June 24,1979, for evaluation of fever, arthralgias, and myalgias of several months' duration. About ten days prior to admission, he began complaining of pleuritic-type chest pain. The patient's history included a myocardial infarction in 1968. Because of frequent premature ventricular contractions, he was given 200 mg of quinidine four times a day for approximately 11 months prior to this admission. Physical examination revealed no pertinent findings, except for some skin lesions

Efficacy of propafenone compared with quinidine in chronic ventricular arrhythmias

A double-blind, randomized study was designed to evaluate the efficacy of oral propafenone and oral quinidine in suppressing premature ventricular complexes (Ms). Twenty-five men were studied for 3 weeks. Twelve were randomized to the quinidine group and 13 to the propafenone group. Small doses of the drugs were administered for 1 week (200 mg of quinidine every 6 hours or 300 mg of propafenone every 12 hours) and large doses were administered for another week (400 mg of quinidine every 6 hours or 300 mg of propafenone every 8 hours). Strict criteria were used to define responders to antiarrhythmic therapy. For more than 85% reduction in total PVCs per hour: During the low-dose week, 36 % in the quinidine group and 50 % in the propafenone group were responders (difference not significant [NS]), while during the high-dose week 33% and 64% were responders (NS). For more than 95 % reduction of ventricular couplets per hour: During the low-dose week, 45% in each group were responders, while during the high-dose week, 56% and 60% were responders (NS). For 100% abolition of ventricular tachycardia (VT) beats per 24 hours: During the low-dose week, 60% in the quinidine group and 56 % in the propafenone group were responders (NS); during the high-dose week 80% and 67% were responders (NS). There was no significant difference in the 2 groups in incidence of side effects. This study shows comparable efficacy and tolerance of propafenone and quinidine for the control of ventricular arrhythmias in ambulatory patients with diverse forms of heart diseases.

A polymeric prodrug of quinidine for controlled and programmed release

AbstractA macromolecular prodrug of quinidine was synthesized by linking the amino ester of L‐phenylalanine with quinidine to carboxymethylcellulose via an amide bond. The release of the drug results from the hydrolysis of the ester linkage which occurs only in the presence of α‐chymotrypsin at pH 8. This specificity is relative to the nature of the ester derivative whose carboxylic moiety is an aromatic amino acid residue with L‐configuration. This prodrug contains 160 mg of quinidine per g of dry powder and allows a prolonged release (5–7 h) of the drug in an intestinal medium.

In vitro Interaction of Quinidine with Kaolin and Pectin

The adsorption of quinidine onto kaolin was studied as a function of pH in aqueous solutions in which the ionic strength was adjusted to 0.1. The interaction of quinidine with pectin also was investigated in water and in phosphate buffer; the buffer pH and ionic strength were adjusted to 6.5 and 0.1, respectively. The in vitro results indicated that quinidine was adsorbed onto kaolin. At the highest concentration studied, the extent of adsorption increased from 3.64 mg of quinidine adsorbed/g of adsorbent at pH 2.4 to an average of 5.81 mg/g in the pH 5.5-7.5 range. In the presence of electrolytes, the interaction of quinidine with pectin was relatively small (3-13% bound) as compared to studies performed in water (66-90% bound). The data indicate that some quinidine may be adsorbed when this drug is administered concurrently with kaolin-pectin preparations.

Interaction of quinidine and digoxin in humans (author's transl)

After full digitalisation, 11 healthy subjects received 0.375 mg digoxin daily as maintenance dose. Under steady-state conditions and determination of serum concentration and renal clearance of digoxin, they were then given 500 or 1000 mg quinidine daily in addition to the digoxin. While serum concentration of digoxin rose significantly from 0.75 +/- 0.2 ng/ml after one week on 500 mg quinidine, and to 1.8 +/- 0.6 ng/ml after 1000 mg of quinidine, renal digoxin clearance fell from 186.2 +/- 67.4 to 125.4 +/- 61.8 ml/min after 500 mg of quinidine. Raising quinidine dosage to 1000 mg daily caused no further digoxin clearance reduction. During the total experimental period endogenous creatinine clearance remained unchanged. The results indicate that the rise in serum digoxin concentration on simultaneous quinidine administration is largely due to reduction in renal digoxin clearance. A clinical observation confirms the considerable practical importance of this interaction.

Effects of quinidine on blood flow rate and developed tension in blood-perfused canine papillary muscle.

1. The effects of quinidine on blood flow rate and developed tension were studied in isolated, blood-perfused papillary muscle preparations of the dog. Drugs were injected into the anterior septal artery. 2. Quinidine caused a dose-related increase in blood flow rate; the mean dose producing a 100% increase in blood flow rate was about 0-3 mg. 3. Quinidine in doses of 0-01-0-1 mg produced a positive inotropic response. With 0-3--1 mg of quinidine the positive inotropic response was preceded by a transient negative inotropic response. With 3 mg there was a monophasic negative inotropic response, the developed tension being reduced by about 40% of control. 4. Propranolol had no statistically significant effects on the responses of the blood flow rate and developed tension caused by quinidine. 5. These results indicate that quinidine has an action on coronary vessels in lower doses than on the myocardium, and that in low doses it has a positive inotropic action rather than the well-known negative inotrophic action exerted with higher doses.