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Biomedical subjects

D M Roden

Publications and source records attributed to D M Roden.

At least 145 records · Page 8Linked to original sources
PubMed1988

Tocainide plus quinidine for treatment of ventricular arrhythmias.

Tocainide and quinidine were administered both as single agents and in combination to 14 patients with chronic ventricular arrhythmias. Therapy with tocainide was limited by the occurrence of dose-related adverse reactions in 8 patients, but could be titrated to a dose that was well-tolerated in 13 of 14 and effective in 2 of 13. The addition of quinidine gluconate to the tolerated dose of tocainide increased the number of patients with arrhythmia suppression from 2 to 6. After tocainide washout, quinidine alone suppressed arrhythmias in only 3 patients. Analysis of electrocardiogram intervals showed that the drugs had additive effects on the coupling interval of the sinus beat to the predominant ectopic beat, but exerted antagonistic effects on the corrected QT interval. These findings suggest that the combination may be clinically useful, exerting pharmacologic effects unlike either agent alone.

Aged↗
PubMed1988

The development and testing of intravenous dosing regimens: application to flecainide for the suppression of ventricular arrhythmias.

A two-part pharmacokinetic approach was used to prospectively develop and test intravenous flecainide infusion regimens for the acute therapy for ventricular arrhythmias. Initially, each of nine known responders to oral flecainide was given a rapid flecainide infusion to characterize pharmacokinetic parameters and determine the minimum effective concentration for each patient. These data were used to calculate individually appropriate three-stage flecainide infusions of predetermined durations in eight patients. The three-stage infusions (0.15 +/- 0.02 mg flecainide acetate/kg/min for 5 minutes, 0.046 +/- 0.004 mg/kg/min for 60 minutes, and 0.31 +/- 0.05 mg/kg/hr for 5 to 47 hours; mean +/- SE) resulted in 95% +/- 0.1% suppression of ventricular ectopic depolarizations. Based on these results, six additional patients received a uniform infusion regimen (0.1 mg/kg/min for 5 minutes, 0.025 mg/kg/min for 2 hours, and 0.25 mg/kg/hr for 46 hours). Supplemental doses of 0.25 mg/kg were given (four doses per patient). With this protocol, ventricular ectopic depolarizations were 82.6% +/- 8.5% suppressed. Measured plasma flecainide concentrations were not significantly different from those predicted by pharmacokinetic models. A prompt and sustained antiarrhythmic effect was obtained with an intravenous regimen of flecainide determined by a prospective pharmacokinetic approach. However, the dosages developed in this study may have to be modified for patients with impaired cardiac or renal function.

Adult↗
PubMed1988

Plasma concentrations of quinidine, its major metabolites, and dihydroquinidine in patients with torsades de pointes.

We examined the hypothesis that excess accumulation of major quinidine metabolites or the commercial impurity dihydroquinidine contributes to the development of polymorphic ventricular tachycardia (torsades de pointes, [TdP]) in patients taking quinidine. Total and free plasma concentrations of these compounds were measured by reverse-phase HPLC with fluorescence detection and equilibrium dialysis in 19 patients with TdP and 38 control patients tolerating quinidine therapy without toxicity. No significant differences were found between the two groups of patients. Ratios of metabolite or dihydroquinidine to quinidine varied up to tenfold among patients but were similarly distributed in the TdP and control groups. Only the metabolite 3-hydroxyquinidine was present at free plasma concentrations that exceeded free concentrations of quinidine. We conclude that although quinidine metabolism is highly variable, there does not appear to be any correlation between the plasma concentrations of quinidine, its metabolites or dihydroquinidine, and the subsequent development of TdP.

Humans↗
PubMed1988

Electrophysiologic and hemodynamic effects of chronic oral therapy with the alpha 2-agonists clonidine and tiamenidine in hypertensive volunteers.

Clonidine can produce symptomatic sinus bradycardia or atrioventricular (AV) block in some patients. Electrophysiologic studies have been performed after intravenous clonidine in patients showing such side effects; these have demonstrated variable depression of sinus and AV nodal function. We have evaluated the electrophysiologic and hemodynamic effects of chronic oral treatment with either clonidine (0.2 to 0.5 mg every 12 hours; n = 7) or another centrally active alpha 2-agonist, tiamenidine (0.5 to 1.5 mg every 12 hours; n = 7), in otherwise healthy hypertensive human volunteers. At dosages that modestly lowered diastolic blood pressure, both agents significantly slowed sinus rate and increased the atrial pacing rate producing AV nodal Wenckebach. Clonidine also significantly increased corrected sinus node recovery time and lowered cardiac output while similar (but statistically insignificant) trends were seen with tiamenidine. We conclude that chronic oral treatment with these alpha 2-agonists depresses sinus and AV nodal function in virtually all subjects, including those without manifest conduction system disease.

Administration, Oral↗
PubMed1988

Antiarrhythmic activity, electrocardiographic effects and pharmacokinetics of the encainide metabolites O-desmethyl encainide and 3-methoxy-O-desmethyl encainide in man.

Although encainide is an effective antiarrhythmic agent, plasma concentrations and pharmacologic effects are not well correlated. One explanation is the generation of active metabolites: while in most patients (extensive metabolizers; EMs) concentrations of the metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3MODE) are higher than those of encainide, a small subset (poor metabolizers; PMs) lack the ability to extensively biotransform encainide. Considerable data from studies in vitro and animal studies, as well as indirect evidence in patients, indicate that ODE and 3MODE produce the effects seen during long-term encainide therapy in EMs. We now report the initial direct evaluation of the pharmacologic actions of these metabolites of encainide in man. Nine patients with ventricular arrhythmias, seven of the EM phenotype and two of the PM phenotype, were studied. Chronic high-frequency ventricular arrhythmias were suppressed by encainide therapy in seven of nine; monitoring arrhythmia frequency during withdrawal of encainide allowed definition of plasma concentrations of encainide and metabolites associated with arrhythmia suppression. Intravenous infusions of both ODE and 3MODE suppressed chronic ventricular arrhythmias, while infusions of placebo had no effect. ODE clearance was a function of metabolizer phenotype, with higher clearance (mean 914 ml/min; range 554 to 1,314) in EMs than in PMs (434, 298 ml/min); moreover, 3MODE was detected during ODE infusions in all seven EMs but in neither PM. 3MODE clearance was more uniform (mean 289 ml/min in EMs [range 180-410] vs 300 and 78 ml/min in the two PMs) and ODE was not detected in any subject during 3MODE infusion. Encainide itself was not detected after any infusion of ODE or 3MODE. During withdrawal of encainide therapy, ODE plasma concentration at the time of arrhythmia recurrence was 55 +/- 40 ng/ml (mean +/- SD), while ODE by infusion was effective at a concentration of 37 +/- 15 ng/ml. Similarly, plasma concentration of 3MODE at the time of arrhythmia recurrence after withdrawal of chronic encainide was 116 +/- 35 ng/ml and that during 3MODE infusion was 105 +/- 50 ng/ml. While both compounds prolonged QRS duration, ODE was the more potent, increasing QRS by 9.2 +/- 1.6% per 100 ng/ml vs 1.2 +/- 0.5% per 100 ng/ml for 3MODE. On the other hand, 3MODE prolonged the corrected JT interval by 1.9 +/- 0.6% per 100 ng/ml, while ODE shortened it by 2.7 +/- 1.9% per 100 ng/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1988

Quinidine delays IK activation in guinea pig ventricular myocytes.

A major action of the antiarrhythmic agent quinidine is prolongation of cardiac repolarization. In these experiments, the time-dependent effects of quinidine on the delayed rectifier potassium current, IK, a current contributing to cardiac repolarization, were investigated in acutely disaggregated guinea pig ventricular myocytes using the whole-cell recording configuration of the patch-clamp method. The effect of quinidine on IK was dependent on the duration of depolarization. After long (2,000 msec) pulses, IK was reduced by 30 +/- 27% (SD; n = 8, paired) by 10 microM quinidine; in contrast, after short (100 msec) pulses, the drug decreased IK 65 +/- 35% (p less than 0.05). This effect was found both in paired experiments as well as when quinidine-pretreated cells were compared to non-pretreated cells. Quinidine significantly delayed IK activation (9 +/- 20 msec at baseline vs. 44 +/- 25 msec in drug, p less than 0.05), but did not alter the subsequent time course of activation (time constant 659 +/- 118 msec). These findings are consistent with the hypothesis that quinidine promotes occupancy of a channel state from which opening does not occur.

Animals↗
PubMed1988

Clinical pharmacokinetics of encainide.

The disposition kinetics of the new antiarrhythmic agent encainide are a function of the genetic polymorphism which also controls debrisoquin 4-hydroxylation. In the majority of subjects (extensive metabolisers) encainide undergoes extensive first-pass hepatic biotransformation to the active metabolites O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (MODE). The plasma concentrations of these metabolites are higher than those of encainide, and pharmacological effects correlate better with plasma metabolite concentrations than they do with those of encainide itself. In poor metabolisers, who make up to 7% of the population, a first-pass effect is absent, encainide clearance is lower, and plasma encainide concentrations are higher than those in extensive metabolisers. In poor metabolisers, plasma concentrations of active metabolites are low or undetectable, and the effects of encainide therapy can be closely correlated with plasma concentrations of the parent drug. Despite the marked differences in encainide disposition between extensive and poor metabolisers, the dosages which produce pharmacological effects (QRS prolongation and arrhythmia suppression) are similar in both groups. Encainide biotransformation is impaired in hepatic disease, but no major dosage changes are required. On the other hand, excretion of encainide and its metabolites is impaired in individuals with renal disease, and starting dosages should be decreased. The time required to achieve steady-state concentrations of metabolites (in extensive metabolisers) and of encainide itself (in poor metabolisers) is similar (3 to 5 days); therefore, the dosage should be increased no more often than every 3 to 5 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1988

Potent electrophysiologic effects of the major metabolites of propafenone in canine Purkinje fibers.

Marked interindividual variability has been reported in the plasma concentrations of the antiarrhythmic agent propafenone required for arrhythmia suppression. One possible explanation is the variable generation of active metabolites: it is known that the major metabolite 5-hydroxypropafenone and the more recently described metabolite N-depropylpropafenone can accumulate in plasma to concentrations similar to those of propafenone, and 5-hydroxypropafenone has proven active in animal models. We therefore compared the effects of these metabolites to those of propafenone on action potential characteristics of canine Purkinje fibers at a wide range of cycle lengths. After base-line measurements, propafenone or 5-hydroxypropafenone was superfused at successive concentrations of 0.1, 0.3 and 1.0 microM for 30 min each and measurements were repeated. Both drugs depressed maximum phase zero upstroke slope of the action potential (Vmax); 5-hydroxypropafenone was similar to propafenone in potency with both causing significant effects at very low concentrations (0.1 microM). Vmax depression was cycle length-dependent and the time constants for onset of and recovery from use-dependent Vmax depression were similar. The compounds also shortened action potential duration at 50% but not 90% repolarization. N-depropylpropafenone produced electrophysiologic effects that were similar to those of propafenone and 5-hydroxypropafenone but was less active. We conclude that these metabolites are sufficiently potent that they may explain at least in part the unpredictable concentration-response relationship seen with propafenone.

Action Potentials↗
PubMed1987

Pharmacologic causes of arrhythmogenic actions of antiarrhythmic drugs.

All currently known antiarrhythmic agents can induce or worsen arrhythmias. Inappropriate dosage selection, mistakenly based on pharmacokinetic data from "normal" subjects, may result in adverse reactions when an antiarrhythmic drug is given to patients. Unexpected variations in drug clearance can increase plasma concentration of antiarrhythmic agents and aggravate arrhythmias. Changes in the rate of drug metabolism by the liver, e.g., due to cessation of alcohol or drugs that induce hepatic metabolism, can reduce drug clearance, making a previously well-tolerated dose toxic. Another possible explanation for adverse drug reactions is nonlinear protein binding. Recently, genetic determinants of drug metabolism have been identified as explanations of interindividual variations in drug responsiveness. Finally, the interactions of antiarrhythmic agents may also lead to aggravation of arrhythmias. A better understanding of the pharmacology of antiarrhythmic agents can reduce, if not prevent, the occurrence of potentially lethal proarrhythmic events.

Anti-Arrhythmia Agents↗
PubMed1987

Effects of low potassium or magnesium concentrations on isolated cardiac tissue.

Low potassium and magnesium concentrations not only cause cardiac arrhythmias, but also interfere with the efficacy or enhance the toxicity of drugs commonly used to treat patients with heart disease. Arrhythmias may develop in hypokalemia due to enhanced normal automaticity, abnormal automaticity, or slowed conduction; moreover, hypokalemia is associated with enhanced digitalis toxicity, quinidine-related Torsades de pointes, and interference with the antiarrhythmic activity of quinidine. Hypomagnesemia, especially in the presence of other electrolyte abnormalities, also affects automaticity and is associated with decreased efficacy of digitalis and with quinidine-related Torsades de pointes. Therefore, treatment that controls hypertension without causing electrolyte abnormalities is preferable for patients who are at risk of arrhythmias, or who are receiving drugs such as digitalis or quinidine.

Action Potentials↗
PubMed1987

Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences.

The relationship between debrisoquine metabolic phenotype and the pharmacokinetics and pharmacodynamics of propafenone was studied in 28 patients with chronic ventricular arrhythmias (22 extensive metabolizers [EMs] and six poor metabolizers [PMs] of debrisoquine). EMs were characterized by a shorter propafenone elimination half-life (5.5 +/- 2.1 vs 17.2 +/- 8.0, p less than .001), lower average plasma concentration (Cp) (1.1 +/- 0.6 vs 2.5 +/- 0.5 ng/ml/mg daily dosage, p less than .001), and higher oral clearance (1115 +/- 1238 vs 264 +/- 48 ml/min, p less than .001). The active metabolite 5-hydroxypropafenone, assayed in 12 patients, was identified in nine of 10 EMs but in neither of the PMs. A lower incidence of central nervous system side effects was noted in EMs (14% vs 67%, p less than .01). The magnitude of QRS widening at any given propafenone Cp was greater in EMs than PMs. There was no significant difference between EMs and PMs in effective propafenone dose or frequency of antiarrhythmic response. Inhibition of debrisoquine 4-hydroxylation by propafenone was demonstrated both in vivo and in a human liver microsomal system in vitro. We conclude that propafenone is metabolized via the same cytochrome P-450 responsible for debrisoquine's 4-hydroxylation, and that its pharmacokinetics and concentration-response relationships and the incidence of central nervous system side effects are different in patients of different debrisoquine metabolic phenotype.

Adult↗
PubMed1987

Frequency- and orientation-dependent effects of mexiletine and quinidine on conduction in the intact dog heart.

Myocardial conduction depends on the magnitude of the fast inward sodium current as well as on cardiac fiber orientation, with more rapid propagation along myocardial fibers than across them. Although antiarrhythmic drugs depress the sodium current in a frequency-dependent fashion in vitro, their effects on conduction in the intact ventricle have been less well studied. We therefore evaluated the frequency- and orientation-dependent actions of mexiletine, quinidine, and their combination on epicardial conduction in 24 pentobarbital-anesthetized dogs. These interventions were chosen because the time constant of recovery from sodium-channel blockade by mexiletine in vitro is shorter than that from blockade by quinidine, and because we have previously shown that the combination of these drugs is often clinically effective when single-agent therapy fails. An electrode array that permitted measurement of conduction times in multiple orientations over short segments of epicardium without contamination by rapid Purkinje fiber propagation or by latency or virtual cathode effects at the stimulus site was developed for these studies. In all animals, the atrioventricular node was destroyed by injection of formalin to permit measurements over a wide range of cycle lengths (250 to 1500 msec). In the absence of drugs, conduction in any direction was frequency independent. In the presence of mexiletine, however, frequency-dependent increases in conduction times were found at cycle lengths of 600 msec or less; these changes were significantly greater in orientations for which baseline conduction was rapid. Quinidine, on the other hand, increased conduction times at all tested cycle lengths without significant orientation-dependent effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Frequency-dependent interactions of mexiletine and quinidine on depolarization and repolarization in canine Purkinje fibers.

The use of the antiarrhythmic agents mexiletine and quinidine in combination can be clinically beneficial when single agent therapy is ineffective in ventricular tachyarrhythmias. We therefore compared the effects of mexiletine (10 microM), quinidine (10 microM) and a series of their combinations (total concentration 10 microM) in canine cardiac Purkinje fibers driven at a wide range of stimulation frequencies. All treatments depressed Vmax in tissues driven rapidly (cycle length 300 msec), but only with greater than or equal to 5 microM quinidine was Vmax depressed at longer cycle lengths. Moreover, the time constants for development of and recovery from frequency-dependent block were different: short (200-500 msec) for mexiletine, long (3-5 sec) for quinidine and intermediate or biexponential for the combination. Although both drugs depressed Vmax (albeit with different time dependencies), action potential duration at all cycle lengths from 300 to 8000 msec was shortened by mexiletine, lengthened by quinidine and largely unaltered by combinations. Fibers treated with quinidine in low Ko and driven at slow rates developed marked action potential prolongation and abnormal automaticity in the form of early afterdepolarizations; the addition of mexiletine was sufficient to reverse this effect. In summary, mexiletine and quinidine produced different and frequency-dependent effects on depolarization and repolarization. The effects of their combinations reflected these actions, with opposing actions on repolarization at any stimulation rate but additive frequency-dependent depression of Vmax. We conclude that the clinically beneficial effects of this combination may reflect additive frequency-dependent effects on cardiac sodium channels in the face of unaltered repolarization time.

Action Potentials↗
PubMed1987

Pharmacologic evaluation of standard and controlled-release disopyramide.

Controlled-release disopyramide offers many potential advantages over the standard formulation for improved patient compliance, possible reduction of concentration-related adverse effects, and predictability of pharmacologic effect. The pharmacology of disopyramide, potential advantages and disadvantages of the use of sustained- (or controlled-)release formulations of drugs, and the preliminary finding of our use of controlled-release disopyramide are described. Controlled-release disopyramide is a promising addition to the antiarrhythmic formulary that may increase the clinical utility of disopyramide.

Anti-Arrhythmia Agents↗
PubMed1987

Comparative in vitro electrophysiology of quinidine, its major metabolites and dihydroquinidine.

Although metabolites of quinidine are active in animal models and can accumulate to plasma levels similar to those of quinidine during chronic therapy, their effects on cardiac transmembrane action potentials have not been reported. We therefore examined the effects of quinidine, its major metabolites, 3-hydroxyquinidine, quinidine-N-oxide, O-desmethylquinidine, and 2'-oxoquinidinone, and a common commercial impurity, dihydroquinidine, on action potentials from canine Purkinje fibers. Using standard microelectrode techniques, measurements at stimulation basic cycle lengths (BCLs) of 300 to 8000 msec were made at base line and repeated after a 1 hr of superfusion with a 10 microM concentration of drug or vehicle controls. Vehicle controls (n = 5) produced no change in maximum phase 0 upstoke slope of the action potential (Vmax) or action potential duration at 90% repolarization (APD90). Vmax depression when present was greatest at short BCL with statistically significant changes seen at BCL = 300 msec with all compounds tested except quinidine-N-oxide. The time constants for the onset of and recovery from frequency-dependent Vmax depression were similar to those of quinidine. In contrast, changes in APD90 were greatest at long BCL, with significant prolongation seen with all drugs at BCL = 4000 msec. In addition, the agents prolonging repolarization to the greatest extent, quinidine, dihydroquinidine, 3-hydroxyquinidine and O-desmethylquinidine, caused early afterdepolarizations at long BCL. We conclude that these metabolites and dihydroquinidine may contribute to the antiarrhythmic and/or arrhythmogenic effects of quinidine therapy.

Action Potentials↗
PubMed1986

Disposition kinetics of encainide and metabolites.

Interpretation of plasma concentration data during encainide therapy is predicated on an understanding of the role of active metabolites during treatment. In over 90% of patients, encainide is rapidly biotransformed to O-desmethyl encainide (ODE) and 3-methoxy-O-desmethyl encainide (3-MODE), which persist in plasma hours after encainide itself is undetectable. This metabolism occurs in the liver, and encainide clearance is sufficiently high that a significant first-pass effect is seen during oral therapy (bioavailability 30 +/- 7%). In these extensive metabolizers, ODE and 3-MODE appear to mediate the arrhythmia suppression and electrocardiographic changes seen during encainide therapy. In less than 10% of patients, a genetic defect prevents expression of the enzyme responsible for the rapid biotransformation of encainide. In this poor metabolizer subset, the systemic clearance of encainide is 10-fold lower than in extensive metabolizers (0.18 +/- .002 vs 1.9 +/- 0.2 liters/min), the first-pass effect is virtually absent (bioavailability 83% to 88%), plasma concentrations are higher and an antiarrhythmic effect may be seen at usual encainide doses. Minimally effective plasma concentrations appear to be 35 ng/ml (ODE), 100 ng/ml (3-MODE) and 300 ng/ml (encainide), making ODE one of the most potent sodium channel blockers yet used in man. The elimination half-life of encainide is 2.3 +/- 0.3 hours in extensive metabolizer patients. Despite this rapid elimination, encainide can be administered every 8 to 12 hours in both extensive and poor metabolizer subsets; this is because of slowly eliminated metabolites in extensive metabolizers and slower elimination of encainide itself (11.3 +/- 0.3 hours) in poor metabolizers.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗