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Biomedical subjects

D M Roden

Publications and source records attributed to D M Roden.

At least 91 records · Page 5Linked to original sources
PubMed1994

Quinidine-enhanced beta-blockade during treatment with propafenone in extensive metabolizer human subjects.

Propafenone, a sodium channel blocking antiarrhythmic drug with beta-blocking properties, is metabolized to non-beta-blocking metabolites in part by cytochrome P4502D6. Subtherapeutic doses of quinidine inhibit P4502D6 and increase plasma propafenone in extensive metabolizer subjects, in whom the active enzyme is present. In this study we tested the hypothesis that quinidine would enhance beta-blockade in extensive metabolizers receiving propafenone. Seven extensive and two poor metabolizers received propafenone (225 mg orally every 8 hours) plus quinidine sulfate (60 mg orally every 8 hours) or propafenone plus placebo for 7 days in a randomized, double-blind, crossover fashion. In extensive metabolizers, the coadministration of quinidine significantly increased the extent of propafenone-induced beta-blockade, assessed by a decrease in exercise heart rate and by sensitivity to isoproterenol. We conclude that low-dose quinidine enhances propafenone-induced beta-blockade in extensive metabolizers. Thus the polymorphic patterns of drug metabolism can result in clinically significant drug interactions on a genetic basis.

Adrenergic beta-Antagonists↗
PubMed1994

Effects of procainamide and lidocaine on defibrillation energy requirements in patients receiving implantable cardioverter defibrillator devices.

INTRODUCTION: In acute canine studies, lidocaine, but not procainamide, increases defibrillation energy requirements. We evaluated the effects of lidocaine or procainamide on defibrillation energy requirements in 27 patients undergoing intraoperative testing for implantable cardioverter defibrillator device placement. METHODS AND RESULTS: Patients were tested off antiarrhythmic drugs and again following either lidocaine (200 to 250 mg loading and 3 mg/min maintenance infusions) or procainamide (1 gm loading and 3 to 4 mg/min maintenance infusions). The defibrillation testing protocol consisted of initial testing at 15 J, followed by higher or lower energies to determine the lowest energy producing three consecutive successful defibrillations. Overall, the mean defibrillation energy increased from 14 +/- 5 J to 18 +/- 7 J during lidocaine (plasma concentration 5.1 +/- 1.6 micrograms/mL; P < 0.02) but were similar at baseline (12 +/- 5 J) and during procainamide infusion (13 +/- 6 J) (plasma concentration: procainamide 10.7 +/- 7.2 micrograms/mL; N-acetyl procainamide 1.0 +/- 0.4 micrograms/mL). A positive linear correlation was found between lidocaine plasma concentration and percent change in defibrillation energy (lidocaine: r = 0.61; P = 0.01). Procainamide raised the defibrillation energy in three patients, two with supratherapeutic plasma concentrations. The increase in defibrillation energy equaled or exceeded 25 J in four patients after lidocaine and in one patient after procainamide. CONCLUSION: The data suggest that at high plasma concentrations, lidocaine and procainamide adversely affect defibrillation energy requirements consistent with an adverse, concentration-dependent effect of sodium channel blockade on defibrillation energy requirements in patients.

Aged↗
PubMed1994

Effect of hypercapnic acidemia on anisotropic propagation in the canine ventricle.

BACKGROUND: Impulse propagation in the ventricle depends on both sodium channel availability and cell-to-cell coupling through gap junctions. Sodium channel block has been shown to depress conduction velocity (theta) more longitudinal (LONG) to than transverse (TRANS) to fiber orientation. Because exposure to CO2 produces intracellular acidosis and decreased gap junction conductance in vitro, we tested the hypothesis that increased PCO2 would result in preferential depression of transverse conduction in vivo. METHODS AND RESULTS: In anesthetized dogs, when atrial pH was reduced to 6.70 +/- 0.04 by increasing the fraction of inhaled CO2 to 40%, theta TRANS fell from 0.23 +/- 0.04 to 0.19 +/- 0.02 m/s (-16 +/- 8%, P < .03), while theta LONG was unchanged (-3 +/- 7%, P = NS). In contrast, with the same degree of acidemia produced by HCl infusion, only theta LONG fell (-8 +/- 7%), coincident with a rise in serum K+. CONCLUSIONS: The observed effect of CO2 on propagation in the intact heart is consistent with its previously described in vitro actions to uncouple cell-to-cell communication and may provide a model to study the role of cell-to-cell coupling in normal and abnormal propagation.

Acid-Base Equilibrium↗
PubMed1994

K+ currents and K+ channel mRNA in cultured atrial cardiac myocytes (AT-1 cells).

Atrial tumor myocytes derived from transgenic mice (AT-1 cells) maintain a well-differentiated cardiac biochemical and histological phenotype. In addition, they beat spontaneously in culture and exhibit long action potentials whose repolarization resembles that observed in native mammalian myocytes. In this study, we identified the major depolarization-activated outward currents in AT-1 cells; also, the presence of mRNAs that encode outwardly conducting ion channels was determined by cloning from an AT-1 cDNA library or by Northern hybridization. Among K+ channel isoforms, Kv2.1, minK, and Kv1.4 were readily detected in tumors and at 1 day in culture. Their abundance remained relatively stable (twofold or less change) after 14 days. The major outward current in AT-1 cells is a delayed rectifier that displays prominent inward rectification, activates rapidly (eg, 182 +/- 27 milliseconds [mean +/- SEM] at + 20 mV, n = 12), exhibits biexponential deactivation kinetics, and is extremely sensitive to the methanesulfonanilide dofetilide (IC50, 12 nmol/L). These characteristics identify this current as IKr, a delayed rectifier observed only in cardiac cells. IKr in AT-1 cells displayed slow inactivation: dofetilide-sensitive deactivating tails were greater after 1-second than after 5-second pulses. When IKr was blocked by > or = 0.5 mumol/L dofetilide, time-independent current was usually recorded (50 of 65 experiments); rapidly inactivating (6 of 65) or slowly inactivating (9 of 65) outward currents were occasionally observed. We conclude that AT-1 cells express mRNAs encoding cardiac K+ channels and display a cardiac electrophysiological phenotype.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Block of IKs, the slow component of the delayed rectifier K+ current, by the diuretic agent indapamide in guinea pig myocytes.

There is a high incidence of diuretic use among patients who develop exaggerated QT prolongation and polymorphic ventricular tachycardia (torsade de pointes) during treatment with action potential-prolonging agents. Diuretic-induced hypokalemia is thought to be the usual mechanism, but a direct effect of diuretic drugs on repolarizing currents is an additional possibility. Therefore, in this study, we examined the effects of the diuretic agents chlorthalidone and indapamide on the cardiac delayed rectifier current. In guinea pig ventricular myocytes, this current is made up of two components: IKr, a rapidly activating, inwardly rectifying current blocked by most action potential-prolonging antiarrhythmics, and IKs, a slowly activating component. In this preparation, indapamide blocked outward current in a time-, voltage- and concentration-dependent fashion, whereas chlorthalidone (1 mmol/L) was without effect. The following features of the effect of indapamide strongly suggest selective block of IKs: (1) Indapamide block was significantly greater with 5000-millisecond activating pulses (-43 +/- 5% at +50 mV [100 mumol/L indapamide]) than with 225-millisecond ones (-20 +/- 5%; n = 5, P < .01), and the signature of the indapamide-sensitive current was a slowly activating delayed rectifier current. (2) The voltage dependence of indapamide block (EC50, 101 mumol/L at +50 mV and 196 mumol/L at +10 mV) was consistent with preferential block of IKs relative to IKr. (3) In the presence of indapamide, an envelope-of-tails test for IKr was satisfied. The drug-insensitive current had rectifying properties similar to those described for IKr in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1993

Pharmacokinetics of amiodarone: implications for drug therapy.

Amiodarone is a complex molecule with multiple pharmacologic properties and a complex electrophysiologic profile. Its disposition kinetics and relation between plasma drug concentration and efficacy can be analyzed using principles identical to those applicable to other antiarrhythmic drugs. However, the drug's affinity for lipophilic tissues, its extremely slow elimination rate, and the likelihood that some of its effects may not be mediated by the usual antiarrhythmic mechanisms confounds traditional pharmacokinetic analysis. Further data that deal with the fundamental mechanisms of action of the drug, in addition to the nature of the relation between dose and uptake into cellular and subcellular fractions and its pharmacologic effects, will be of value in understanding how the drug exerts salutary actions in cardiac arrhythmias.

Amiodarone↗
PubMed1993

Current status of class III antiarrhythmic drug therapy.

Studies in animal models, as well as clinical experience with amiodarone and sotalol, suggest that action potential prolongation may be a useful antiarrhythmic mode of action. A number of agents that produce this class III effect are currently under development. The single greatest liability for further development of this group of drugs is the occasional, and apparently unpredictable, development of exaggerated QT prolongation and polymorphic ventricular tachycardia (torsades de pointes). Available data suggest that QT interval prolongation is not a good indicator of whether or not a class III antiarrhythmic will suppress a target arrhythmia; however, exaggerated QT prolongation is a predictor of torsades de pointes. Further studies to delineate the mechanism underlying the development of torsades de pointes might lead to safer and more effective antiarrhythmic drugs.

Animals↗
PubMed1993

Usefulness of sotalol for life-threatening ventricular arrhythmias.

Two trial designs have been used in evaluating sotalol in patients with sustained tachyarrhythmias: open-label dose escalation and randomized comparison with reference agents. At least 7 open-label studies (n = 16-65) have been reported from single centers in patients in whom trials of numerous other antiarrhythmic agents were unsuccessful. At the doses used, usually 320-640 mg/day, plasma concentrations were in the range associated with both beta blockade and class III antiarrhythmic activity (2-3 micrograms/mL). These concentrations produced electrophysiologic changes that were consistent across studies: 10-16% increase in right ventricular effective refractory period (ERP), 4-8% increase in corrected QT interval (QTc), and 17-30% increase in sinus cycle length (corresponding to a 15-23% decrease in heart rate). In these open-label trials, sotalol suppressed inducible ventricular tachyarrhythmias in 20-72% of patients; the higher degrees of efficacy were reported when induction protocols were confined to double extrastimuli. Side effects leading to discontinuation of sotalol in patients with sustained ventricular tachycardia or fibrillation include fatigue (4.0%), marked bradycardia (3.0%), torsades de pointes (3.0%), and heart failure or pulmonary edema (1.0%). A multicenter randomized trial compared intravenous sotalol with intravenous procainamide in a double-blind prospective fashion. Sotalol suppressed ventricular tachyarrhythmias inducible with triple extrastimuli in 15 (30%) of 50 patients, whereas procainamide was effective in 10 (20%) of 50. In this and other series, responsiveness to sotalol was prospectively identified by a particularly fast tachycardia at baseline (e.g., cycle length of < 270 msec), but not by the extent of changes in global indices of repolarization (QTc, ERP).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Torsade de pointes.

The polymorphic ventricular tachycardia torsade de pointes can occur in the congenital long QT syndromes or as a consequence of therapy with QT-prolonging drugs. The latter can include not only antiarrhythmic drugs such as quinidine, but also a number of drugs which are not usually considered to have major cardiovascular effects: these include nonsedating antihistamines, such as terfenadine; antibiotics such as erythromycin; and neuroleptics such as thioridazine. The electrocardiographic hallmark of both the congenital and acquired forms of the long QT syndrome is marked QT(U) lability, particularly as a function of heart rate. The underlying mechanism is thought to be triggered activity arising as a consequence of early afterdepolarizations. An understanding of the basic mechanism has led to an understanding of the effective forms of therapy, which include maneuvers to include the heart rate (pacing, isoproterenol) as well as maneuvers which may not necessarily alter the QT interval but may prevent the arrhythmia (magnesium, beta blockers). Intensive study of the clinical features and basic mechanisms underlying torsade de pointes has led to the definition of a new mechanism for cardiac arrhythmias; understanding such mechanisms may ultimately lead to the development of safer antiarrhythmic therapy.

Adrenergic beta-Antagonists↗
PubMed1993

Immediate- versus controlled-release disopyramide: importance of saturable binding.

OBJECTIVE: To examine the effects of saturable plasma binding on the pharmacokinetics of immediate-release (IR) and controlled-release (CR) disopyramide. BACKGROUND: Saturable binding causes a lack of correspondence between the pharmacokinetics of total and unbound plasma disopyramide. Levels of total drug may therefore be insensitive to important differences between formulations. METHODS: Patients receiving long-term disopyramide underwent serial blood sampling during withdrawal of equivalent doses of IR and CR disopyramide, and during accumulation of IR disopyramide. Plasma disopyramide was measured by enzyme-multiplied immunoassay technique, protein binding by ultrafiltration, and alpha 1-acid glycoprotein by radial immunodiffusion. Pharmacologic effect was assessed by use of high-speed ECGs. Values for plasma area under the concentration-time curve and elimination half-life were determined from the log-plasma concentration data; rate of plasma drug accumulation was determined by nonlinear modeling. RESULTS: Saturable plasma binding was evident in all patients. Comparison of total to unbound drug showed that peak-to-trough ratios during steady state were smaller (1.45 versus 2.39; p < 0.001), elimination half-life was longer (12.1 versus 4.5 hours; p < 0.001), and the time to achieve 50% of steady-state levels during drug accumulation was shorter (8.1 versus 4.3 hours; p < 0.05). Comparison of IR and CR disopyramide showed that unbound drug levels for CR disopyramide revealed lower peak plasma concentrations (0.75 versus 0.96 micrograms/ml) and peak-to-trough ratios (1.83 versus 2.31; p < 0.001). Trough plasma concentrations were similar. Fluctuations in ECG intervals during usual dosing were observed only with IR disopyramide. CONCLUSIONS: Because of saturable plasma binding, total plasma concentrations underestimate fluctuations in unbound disopyramide during usual dosing and are insensitive to significant differences between IR and CR formulations. CR disopyramide provides less interdose variation in free drug levels and more constant pharmacologic effects.

Aged↗
PubMed1993

Early after-depolarizations and torsade de pointes: implications for the control of cardiac arrhythmias by prolonging repolarization.

Common clinical features in drug-induced torsade de pointes include hypokalemia and cycle-length prolongation just prior to initiation of the arrhythmia. In canine Purkinje fibres, drugs known to be associated with torsade de pointes, such as quinidine, sotalol or N-acetylprocainamide, consistently produce early after-depolarizations (EADs) and triggered activity at slow drive rates; for quinidine, these abnormalities are exaggerated by low extracellular potassium. Triggered activity can be abolished in vitro in two ways. First, action-potential shortening with abolition of EADs can be accomplished by increasing stimulation rates, beta-stimulation and action-potential shortening antiarrhythmics such as lidocaine. Second, triggered activity can be suppressed, with less prominent effects on EADs, by magnesium, alpha- and/or beta-adrenergic blockade and calcium-channel blockers. The parallels between these in vitro findings and clinical torsade de pointes suggest that EADs and triggered activity play a role in the genesis of the clinical arrhythmia. Further research directed at determining the mechanisms underlying the cellular abnormalities and their propagation to the whole heart should yield information that will increase the safety of antiarrhythmic therapy.

Action Potentials↗
PubMed1993

Penetrating injuries to the neck: a safe, selective approach to management.

The most appropriate management of patients with penetrating injuries to the neck remains a controversial issue. In order to determine the safety and efficacy of a selective approach to the management of such patients, a retrospective review of our experience with penetrating injuries to the neck at Northwestern Memorial Hospital over the past 5 years since the designation as a Level I trauma center was undertaken. A total of 30 patients fulfilled entry criteria. Twelve patients underwent immediate operative exploration based upon clinical indications present at admission. Seventeen patients underwent further diagnostic evaluation, including angiography in 17 and contrast esophagography in eight. Endoscopy was used infrequently. The mortality rate was 13.3 per cent, there were two negative cervical explorations, and there were no missed injuries. The results support the application of a selective approach to the operative management of penetrating injuries to the neck.

Adolescent↗
PubMed1992

Pharmacology of the class III antiarrhythmic agent sematilide in patients with arrhythmias.

Sematilide, a close structural analog of N-acetylprocainamide, prolongs cardiac action potentials in vitro, whereas it does not depress maximum action potential upstroke slope, a "class III" action. This report outlines an evaluation of the clinical pharmacologic actions of sematilide in 14 patients with chronic high-frequency nonsustained ventricular arrhythmias. In all, 36 intravenous infusions (range 0.15 to 1.5 mg/kg over 15 minutes) were administered in a dose-ranging, placebo-controlled study design. Sematilide prolonged rate-corrected QT (QTc) in a dose- and concentration-related fashion, did not alter PR or QRS, and slowed heart rate at high concentrations (greater than or equal to 2 micrograms/ml). The relations between dose and total area under the time-concentration curve, dose and peak plasma concentration, and peak plasma concentration and increase in QTc were linear (r = 0.66 to 0.92; p less than 0.001). QTc increases of approximately equal to 25% were seen at plasma concentrations of approximately equal to 2.0 micrograms/ml. The mean elimination half-life (+/- SD) was 3.6 +/- 0.8 hours, and most of a dose (77 +/- 13%) was recovered unchanged in the urine. Plasma concentrations greater than or equal to 0.8 micrograms/ml suppressed arrhythmias (5 patients) or aggravated them (3), including 1 patient who needed cardioversion for an episode of torsades de pointes (2.7 micrograms/ml). Thus, sematilide exerts class III actions in patients. Further studies to evaluate the role of this antiarrhythmic mode of action should be conducted at doses designed to limit QTc increases.

Anti-Arrhythmia Agents↗
PubMed1992

The Cardiac Arrhythmia Suppression Trial: first CAST ... then CAST-II.

The Cardiac Arrhythmia Suppression Trial (CAST) was a study designed to test the hypothesis that suppression of ventricular premature complexes after a myocardial infarction would improve survival. Preliminary results showed that suppression of ventricular premature complexes with encainide and flecainide worsened survival, and the CAST continued as the CAST-II with moricizine compared with its placebo. The protocol for the CAST-II was changed to attempt to enroll patients more likely to experience serious arrhythmias. The enrollment time was narrowed to 4 to 90 days after myocardial infarction; the qualifying ejection fraction was lowered to less than or equal to 0.40; a higher dose of moricizine could be used; early titration itself was double-blind with a placebo, and the definition of disqualifying ventricular tachycardia was changed to allow patients with more serious arrhythmias to be entered into the trial. The Cardiac Arrhythmia Suppression Trial-II was subsequently terminated prematurely because 1) patients treated with moricizine had an excessive cardiac mortality rate during the 1st 2 weeks of exposure to the drug, and 2) there appeared to be little chance of showing a long-term survival benefit from treatment with moricizine. This report outlines the rationale behind the Cardiac Arrhythmia Suppression Trial and the reasons for selection of the drugs used in the CAST and CAST-II.

Anti-Arrhythmia Agents↗
PubMed1992

Stereoselective genetically-determined interaction between chronic flecainide and quinidine in patients with arrhythmias.

1. Recent reports have indicated a role for the P450IID6 polymorphism in the stereoselective disposition of single doses of the antiarrhythmic flecainide. 2. In this study, we evaluated the effects of adding low dose quinidine, a potent inhibitor of P450IID6, to chronic flecainide therapy in patients with arrhythmias. 3. In five extensive metabolizer patients, quinidine significantly reduced the clearance of R-(-)-flecainide, from 395 +/- 121 (s.d.) to 335 +/- 88 ml min-1. This change was attributable to a decrease in metabolic clearance, was accompanied by decreased formation of the two major metabolites of flecainide and was not observed in a poor metabolizer subject. The renal clearance of R-(-)-flecainide rose significantly. 4. Quinidine did not alter the clearance of S-(+)-flecainide. 5. The pharmacologic effects of flecainide therapy (QRS widening, % arrhythmia suppression) were slightly, but not significantly, increased. 6. In extensive metabolizer patients receiving chronic flecainide, increased plasma concentrations will develop if P450IID6 is inhibited.

Arrhythmias, Cardiac↗
PubMed1992

Suppression of longitudinal versus transverse conduction by sodium channel block. Effects of sodium bolus.

BACKGROUND: Arrhythmias resulting from treatment with sodium channel-blocking antiarrhythmic drugs have been successfully treated with sodium infusion, although the mechanism underlying this effect is uncertain. METHODS AND RESULTS: In this study, we used a multielectrode array to examine the effects of O-desmethyl encainide (ODE), a potent sodium channel-blocking metabolite of encainide, on conduction in canine ventricle. ODE depressed both longitudinal and transverse conduction velocities in a plasma concentration-related fashion (r = -0.74, -0.60; p less than 0.001). At ODE concentrations less than or equal to 300 ng/ml (n = 34), conduction velocity was depressed to the same extent in the longitudinal (-21.9 +/- 8.4%, SD) and transverse orientations (-22.0 +/- 8.8%). However, at concentrations greater than 300 ng/ml (n = 17), conduction was significantly more impaired longitudinally than transversely (-44.5 +/- 11.7% versus -34.4 +/- 13.7%, p less than 0.02). In 12 animals with high concentrations (mean, 432 +/- 32 ng/ml), a 5-meq/kg bolus of sodium chloride over 1 minute immediately increased conduction velocity; this effect was significantly greater and longer lasting in the longitudinal orientation. In two animals, conduction block in the longitudinal orientation was documented at high plasma ODE and was immediately reversed by sodium bolus. CONCLUSIONS: We conclude that the major effect of sodium in animals with excess sodium channel block is improvement of longitudinal propagation; this effect may underlie the antiarrhythmic action of sodium in the analogous clinical setting.

Animals↗