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Biomedical subjects

D M Roden

Publications and source records attributed to D M Roden.

At least 181 records · Page 10Linked to original sources
PubMed1984

Clinical pharmacology of propafenone: pharmacokinetics, metabolism and concentration-response relations.

Propafenone is a promising new antiarrhythmic agent marketed in Europe for the past 7 years. The drug is remarkable for great interindividual variability in its pharmacokinetic and pharmacodynamic properties. Propafenone undergoes extensive presystemic clearance that appears to be saturable, with bioavailability increasing as dosage increases. The drug is highly protein bound. Elimination half-life is 5 to 8 hours in most patients, although a range of 2 to 32 hours has been reported. Propafenone slows intracardiac conduction in a concentration-dependent manner. It is a weak beta-adrenergic blocker, but this property is of uncertain clinical significance. The major metabolic pathway for propafenone begins with aromatic ring hydroxylation, a pathway that may be determined by genetic factors.

Anti-Arrhythmia Agents↗
PubMed1984

Differential effects of O-demethyl encainide on induced and spontaneous arrhythmias in the conscious dog.

Encainide is highly effective in suppressing most nonsustained ventricular arrhythmias, but there is evidence that the drug is less effective and may worsen some arrhythmias, particularly in patients with sustained ventricular tachycardia. In most patients it is likely that the major antiarrhythmic effects of encainide are mediated through a potent metabolite, O-demethyl encainide. The effects of infusions of saline solution or O-demethyl encainide on spontaneous ventricular ectopic activity and ventricular fibrillation (VF) threshold were compared in 25 dogs with a mottled myocardial infarct produced by transient coronary occlusion. Plasma levels of the metabolite above 100 ng/ml suppressed (greater than 92%) the spontaneous ventricular ectopic activity that occurred 48 hours after MI, whereas saline solution had no effect. In 15 dogs treated with O-demethyl encainide, the VF threshold decreased an average of 23%, from a baseline level of 23 +/- 8 mA to 18 +/- 9 mA (p less than 0.05). There was a concentration-dependent fall in VF threshold with plasma concentrations of O-demethyl encainide above 150 ng/ml. In 2 dogs with very high plasma concentrations of the metabolite (greater than 1,000 ng/ml), VF was induced by right ventricular pacing alone (S1S1 300 ms). No change in VF threshold was observed in the 8 dogs treated with saline solution, and in each of these dogs VF could be terminated by the countershock protocol. However, in 7 of the 17 dogs treated with O-demethyl encainide, VF could not be terminated by the countershock protocol.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1984

Flecainide dose-response relations in stable ventricular arrhythmias.

Flecainide acetate was evaluated in a placebo-controlled, dose-ranging study performed in patients with stable, high-frequency ventricular arrhythmias. Three centers studied 35 patients in a 3-stage protocol. After a placebo baseline, increasing oral dosages from 100 to 300 mg twice daily were evaluated. Placebo was then reinstituted and after arrhythmia had recurred, the patients were discharged on the effective dosage to return to the clinic for evaluation 7 and 14 days later. Thirty of 35 patients had more than 80% suppression (mean 96%) of ventricular premature complexes (VPCs) and more than 95% reduction in complex VPCs. Arrhythmia suppression was seen at dosages of 100 to 200 mg twice daily in 73% of the patients. Twenty-three percent of patients required 500 to 600 mg/day. Mild side effects were seen in 46% of patients. These resolved or became tolerable at lower dosages in most patients. Effective therapy continued for 2 years in 24 of 29 patients, without any evidence of chronic toxicity. Pharmacokinetic studies indicate that many patients require 5 to 7 days of constant dosing before reaching steady state. Flecainide acetate is an effective antiarrhythmic with a narrow range of effective dosages.

Adult↗
PubMed1984

Antiarrhythmic therapy: clinical pharmacology update.

Currently available antiarrhythmic agents are limited by side effects and the potential for increasing arrhythmias. In addition, drug interactions, altered disposition of drug as a result of changes in protein binding or concomitant disease processes, active metabolites, and poorly defined therapeutic ranges with great interpatient variability are some of the factors which complicate therapy. An awareness of the possible contribution of these factors in the use of antiarrhythmics is invaluable in both the choice of agent and the establishment of an optimum benefit-to-risk ratio for the patient.

Anti-Arrhythmia Agents↗
PubMed1984

Encainide and its metabolites. Comparative effects in man on ventricular arrhythmia and electrocardiographic intervals.

To assess the relative contributions of encainide and its putatively active metabolites, O-demethyl encainide (ODE) and 3 methoxy-O-demethyl encainide (3MODE), to the drug's pharmacologic effects, we compared intravenous infusions and sustained oral therapy in two phenotypically distinct groups of patients, extensive and poor metabolizers of encainide. Unlike poor metabolizers, extensive metabolizers had appreciable quantities of both metabolites detectable in plasma and had fourfold shorter elimination half-lives for encainide. By quantitating electrocardiogram intervals, arrhythmia frequency, and plasma concentrations, we found that, in poor metabolizers, arrhythmia suppression and ventricular complex (QRS) prolongation were correlated positively with encainide concentrations (r greater than or equal to 0.570, P less than 0.014). In these two subjects, antiarrhythmic concentrations of encainide (greater than 265 ng/ml) were at least fivefold higher than those sustained in the six extensive metabolizers during steady state oral therapy. In extensive metabolizers, encainide concentrations were uncorrelated with effects. Arrhythmia suppression and QRS prolongation in extensive metabolizers correlated best with ODE (r greater than or equal to 0.816, P less than 0.001); QTc change correlated positively with both 3MODE and ODE. Arrhythmia suppression paralleled QRS prolongation; the relationship between them appeared similar in both phenotypic groups. In most patients, extensive metabolizers, encainide effects during oral therapy are mediated by metabolites, probably ODE.

Aged↗
PubMed1984

Potential applications of free drug level monitoring in cardiovascular therapy.

Cardiovascular drugs, as a class, have low therapeutic indices, but also have great therapeutic potential. Plasma concentration information is therefore often of value when using these drugs. Unfortunately, the total plasma concentration may not reflect the concentration of pharmacologically active free drug, since a number of factors including disease states, heparin anticoagulation, non-linear binding characteristics, and in vitro artefacts can affect the protein binding of these agents. This may also explain their poor dose-response relationships and great interindividual variability in plasma concentration data. Careful studies relating bound and free drug concentration to pharmacological response may provide the clinician with a better guide to therapy, and enhance the usefulness of these drugs.

Anti-Arrhythmia Agents↗
PubMed1984

A new method for constant plasma drug concentrations: application to lidocaine.

Optimal intravenous drug therapy often requires the rapid achievement and maintenance of therapeutic plasma drug concentrations. Simple regimens (single bolus and maintenance infusion) can produce wide variations in plasma drug concentrations early in therapy, and more complex regimens require a series of precisely timed infusion rate changes to minimize such variability. A new simple method of delivering an infusion produces a delivery rate that declines exponentially, thereby providing stable plasma concentrations after a bolus dose. The method requires no specialized equipment and no intervention once started. The method has been tested both ex vivo and in normal volunteers receiving lidocaine. Stable lidocaine plasma concentrations are rapidly achieved and maintained within the therapeutic range. Further evaluation of this approach in patients is indicated.

Humans↗
PubMed1984

Influence of genetic polymorphism on the metabolism and disposition of encainide in man.

The metabolism of the new, highly effective antiarrhythmic agent, encainide, appears to be polymorphically distributed in a similar fashion to the genetically determined oxidative biotransformation of debrisoquine. Accordingly, the disposition of encainide and known metabolites was investigated after simultaneous acute i.v. (radiolabeled) and single and multiple oral (nonradiolabeled) dosing to two groups of normal subjects characterized as "poor" (PM) and "extensive" (EM) metabolizers of debrisoquine. Pronounced differences in both the plasma concentration/time curves and the 24-hr urinary excretion of encainide and metabolites were observed between the two phenotypes. In the EM group, the oral bioavailability of encainide was only about 25 to 30% because of extensive presystemic (first-pass) metabolism, and no accumulation occurred after multiple oral dosing with 50 mg every 8 hr for 3 days, as the elimination half-life of the drug was about 2.5 hr. The major metabolite formed was O-desmethylencainide which accounted for almost half of the identified urinary metabolites and represented about 10% of the administered dose. This metabolite was present in 5- to 10-fold higher concentrations in the plasma than unchanged drug and accumulated almost 2-fold after multiple oral dosing. 3-Methoxy-O-desmethylencainide also was present at higher concentrations than encainide and accumulated on multiple dosing similarly to O-desmethylencainide. N,O-didesmethylencainide was a minor metabolite only detectable in the urine and N-desmethylencainide was not measurable in either plasma or urine. In contrast, in the PM group, encainide plasma concentrations were 10- to 20-fold higher than in the EMs after both oral and i.v. administration and the elimination half-life was 3- to 4-fold longer.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1983

Importance of metabolites in antiarrhythmic therapy.

The presence of metabolites with pharmacologic activity can produce unanticipated drug efficacy or toxicity. This is particularly true during treatment with drugs that have narrow therapeutic-toxic ratios, such as the antiarrhythmic agents. The presence of active metabolites can often be inferred from variability in the relation between pharmacologic effect and steady-state plasma concentrations of the parent drug. Moreover, metabolites may ordinarily be unimportant but can accumulate to therapeutic (or toxic) levels in disease states such as congestive heart failure, renal failure and hepatic failure. Further characterization of the contribution of such metabolites during treatment requires direct evaluation of their pharmacology in vitro, in animal models and, if indicated, in man. Procainamide and its active metabolite N-acetylprocainamide provide the best and most complete example of this sequence of observations. Other drugs, including quinidine, disopyramide, verapamil and the investigational agents encainide and lorcainide, have active metabolites for which pharmacologic activity is less well-defined. Further studies in this area will help reduce the frequency of antiarrhythmic drug adverse effects, make successful therapy more frequent, and perhaps allow insights into structure-activity relations.

Acecainide↗
PubMed1983

Amiodarone dosing: a proposal based on its pharmacokinetics.

The available data concerning amiodarone dosing may be summarized as follows: (1) there is an empirically demonstrated improvement in lag before onset of antiarrhythmic effect if amiodarone is given initially in large "loading" doses. (2) A regimen such as that described in this article may allow more predictable and safe therapy and should be evaluated in patients, in order to develop uniform dosing guidelines. (3) Amiodarone clearance appears to decrease with time, and for this reason guidance of long-term therapy by plasma concentration determinations could potentially improve safety and efficacy. However, a close correlation between drug levels and drug toxicity and efficacy is lacking. (4) Finally, plasma concentrations, although potentially useful for monitoring long-term therapy, are likely to be unhelpful or misleading during the 4- to 6-week loading period at the beginning of treatment.

Amiodarone↗
PubMed1983

Electrophysiologic actions of high plasma concentrations of propranolol in human subjects.

The authors have previously shown that 40% of patients whose ventricular arrhythmias respond to propranolol require plasma concentrations in excess of those producing substantial beta-receptor blockade (greater than 150 ng/ml). However, the electrophysiologic actions of propranolol have only been examined in human beings after small intravenous doses achieving concentrations of less than 100 ng/ml. In this study, the electrophysiologic effects of a wider concentration range of propranolol was examined in nine patients. Using a series of loading and maintenance infusions, measurements were made at baseline, at low mean plasma propranolol concentrations (104 +/- 17 ng/ml) and at high concentrations (472 +/- 68 ng/ml). Significant (p less than 0.05) increases in AH interval and sinus cycle length were seen at low concentrations of propranolol, with no further prolongation at the high concentrations; these effects are typical of those produced by beta-blockade. However, progressive shortening of the endocardial monophasic action potential duration and QTc interval were seen over the entire concentration range tested (p less than 0.05). At high concentrations, there was significant (p less than 0.05) further shortening of both the QTc and monophasic action potential duration beyond that seen at low propranolol concentrations, along with a progressive increase in the ratio of the ventricular effective refractory period to monophasic action potential duration. No significant changes were seen in HV interval, QRS duration or ventricular effective refractory period. In summary, the concentration-response relations for atrioventricular conductivity and sinus node automaticity were flat above concentrations of 150 ng/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1983

Electrophysiologic actions of O-demethyl encainide: an active metabolite.

Differences between the electrophysiologic actions of the antiarrhythmic agent encainide have been reported after short-term intravenous and oral administration. Only prolongation of the HV interval and QRS duration have been described immediately after short-term intravenous administration of encainide in dogs and man. However, during oral therapy or more prolonged infusions, prolongation of the AH interval and atrial and ventricular effective refractory periods have also occurred. In most patients receiving encainide therapy, metabolites (O-demethyl encainide and 3-methoxy-O-demethyl encainide) accumulate during prolonged therapy to concentrations greater than those of the parent drug. We compared the electrophysiologic action of O-demethyl encainide with that of saline in anesthetized dogs to determine if this metabolite has pharmacologic activity and whether its electrophysiologic effects could account for the disparities noted between effects of intravenous and oral encainide therapy. An initial pharmacokinetic evaluation allowed design of a series of loading and maintenance infusions that produced plasma concentrations similar to those seen during encainide therapy in man (concentration after first maintenance dose, 149 +/- 27 ng/ml [+/- SE] and after second maintenance dose, 230 +/- 45 ng/ml). Significant increases in atrial effective refractory period and ventricular refractoriness, and prolongation of AH interval and HV conduction time were observed. These effects are similar to those reported after prolonged oral encainide therapy but are substantially different from those seen after short-term infusions of encainide. These findings indicate that the difference between the electrophysiologic actions of intravenous and oral encainide may be due to pharmacologic effects of at least one encainide metabolite, O-demethyl encainide.

Action Potentials↗
PubMed1982

Selection of an antiarrhythmic drug for a sudden-death-prevention trial.

Several therapeutic approaches have sought to prevent the occurrence of sudden cardiac death. Many sudden deaths are presumed to be due to an arrhythmia, but the drugs best known for antiarrhythmic activity, the local anesthetic agents, have not been suitable prophylactic agents because of their toxicities and other undesirable pharmacologic characteristics. Several new drugs in this class have been synthesized and are currently being tested for antiarrhythmic activity in clinical trials. One of them may prove to be worthy of a large-scale clinical trial to determine whether chronic arrhythmia suppression reduces the risk of sudden death. The characteristics of the "ideal" antiarrhythmic agent are discussed, and a brief summary of the drugs currently being tested in the United States is presented. The discussion of each drug emphasizes the characteristics that might make it suitable--or unsuitable--for use in a sudden-death trial. Many agents being tested are clearly not satisfactory for such a trial. However, they may be prototypes for an ideal drug or combination of drugs that might yet be developed.

Acecainide↗
PubMed1982

Antiarrhythmic activity of the O-demethyl metabolite of encainide.

Clinical trials of the new antiarrhythmic agent encainide have demonstrated a high degree of efficacy in association with marked slowing of intracardiac conduction (prolongation of QRS). Indirect evidence has strongly suggested that at least some of these effects are mediated by the O-demethyl metabolite. The activity of a series of dosages of O-demethyl encainide, encainide and procainamide were compared against aconitine-induced ventricular arrhythmias in rats. Effective dosages were lowest for O-demethyl encainide and highest for procainamide: a 25% increase in the time to aconitine-induced ventricular tachycardia was produced by 0.02, 0.46 and 13 microM/kg of O-demethyl encainide, encainide and procainamide, respectively. QRS prolongation correlated well (r greater than 0.7, p less than .001) with enhanced survivorship for each agent tested and the cycle length of the ventricular tachycardia induced was lengthened in a dose-related fashion. Post-mortem plasma analysis showed that concentrations of the metabolite usually associated with pharmacological activity were present after encainide administration. However, encainide itself produced antiarrhythmic and electrocardiographic effects even when its metabolism was blocked. We conclude that both O-demethyl encainide and encainide exert antiarrhythmic actions in this model, but the metabolite is active at much lower dosages.

Aconitine↗