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R E Kates

Publications and source records attributed to R E Kates.

At least 37 records · Page 2Linked to original sources
PubMed1986

Relation of blood level and metabolites to the antiarrhythmic effectiveness of encainide.

Encainide is a potent new antiarrhythmic agent with 2 major active metabolites and 2 distinct phenotypes for metabolism, extensive (approximately 92%) and nonextensive (8%). Encainide is an active compound with close correlation of plasma levels with antiarrhythmic effectiveness and electrocardiographic changes in nonextensive metabolizers. Its metabolites, O-demethyl-encainide and 3-methoxy-O-demethyl-encainide, are active against experimental and clinical arrhythmias. They have longer half-lives than and equal or greater potency than the parent compound. All 3 compounds contribute to the antiarrhythmic profile in extensive metabolizers. There is no readily apparent relation between encainide and its metabolites, blood levels and efficacy because of the complexity of the 3 active compounds and individual variation in pharmacokinetic and arrhythmia responsiveness. Encainide has been given for up to 2 years in 140 patients with sustained ventricular tachycardia or ventricular fibrillation. The survival curves are similar to historical control data from patients reported by Graboys and Swerdlow. The survival curves for long-term administration in patients with frequent ventricular premature complexes (greater than 30/min) are comparable to data from Califf. While these data must be viewed cautiously, it seems fair to conclude that encainide is as effective as any combination of drugs for preventing sudden death in patients with life-threatening ventricular arrhythmias.

Anilides↗
PubMed1986

Effects of encainide and its metabolites on energy requirements for defibrillation.

Encainide, a class IC antiarrhythmic agent, has been associated with proarrhythmic responses of ventricular tachycardia and fibrillation requiring defibrillation in patients. We examined the short-term effects of intravenous encainide and its two major metabolites, O-demethyl-encainide (ODE) and 3-methoxy-ODE (MODE), on the energy requirements for successful defibrillation in 25 pentobarbital-anesthetized, open-chest dogs. Truncated exponential (60% tilt) defibrillation shocks were administered through right atrial spring and left ventricular epicardial patch electrodes identical to those used in man with the automatic implantable defibrillator. At baseline multiple shocks of varying energy were applied to construct curves of percent successful defibrillation as a function of energy (DF curves) for each animal. Encainide, ODE, or MODE was then infused in loading and maintenance doses to achieve QRS widening of 20% to 50%. Saline was administered to animals serving as controls. Determination of the DF curve was repeated, after which the infusion was discontinued. After 1 hr washout period, an additional DF curve was constructed. The data were analyzed by logistic regression, and the energies required for 50% successful defibrillation (E50) were compared. No significant differences existed between the four groups in body or heart weight, extent of QRS widening, or baseline E50 values. After administration of encainide and ODE, the E50 increased by 129 +/- 43% (p less than .001) and 76 +/- 34% (p less than .005), respectively. Return of E50 toward baseline was observed after the washout periods in both groups (p less than .025), demonstrating the reversibility of the drugs' effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Anilides↗
PubMed1986

Qualitative and quantitative comparison of the cardiac effects of encainide and its three major metabolites in the dog.

We have evaluated the electrophysiologic effect of encainide and its three major metabolites, O-demethyl encainide, 3-methoxy-O-demethyl encainide and N-demethyl encainide in an anesthetized dog model. Our results support previous reports that O-demethyl encainide and 3-methoxy-O-demethyl encainide are both more potent than encainide in the depression of conduction. We also have shown that N-demethyl encainide is of about equal potency to encainide. Whereas the major differences between these compounds is primarily one of potency, there are some qualitative differences. Although O-demethyl encainide did not change the ventricular or atrial effective refractory periods significantly, 3-methoxy-O-demethyl encainide and N-demethyl encainide prolonged both. Encainide increased the atrial effective refractory period but did not produce significant changes in the ventricular refractory period. These data support previous suggestions of an important role for these metabolites as modulators of the clinical efficacy of encainide.

Anilides↗
PubMed1986

Myocardial uptake kinetics and pharmacodynamics of propafenone in the isolated perfused rabbit heart.

The myocardial disposition of propafenone was studied in an isolated perfused rabbit heart. Six hearts were perfused with a modified Krebs-Henseleit buffer containing propafenone 110 +/- 5 ng/ml. Pharmacokinetic parameters were determined by fitting the coronary sinus effluent propafenone concentration-time data to a one-compartment pharmacokinetic model. The mean half-life of myocardial uptake (T1/2d) was 22.3 +/- 5.9 min and the average time to approach steady-state tissue levels was 112 +/- 29 min. Propafenone accumulated extensively in myocardium and at equilibrium the average (+/- S.D.) myocardial concentration was 114 +/- 21 times that of the perfusate. The electrophysiological effect was measured as percentage of change of the baseline QRS duration. The half-life of onset of effect (T1/2e) and the effect at steady state were determined by fitting the effect-time data to a monoexponential function. The T 1/2e averaged 26.0 +/- 9.4 min and did not differ significantly from T 1/2d. The relationship between myocardial propafenone concentration and effect was linear but there was interexperimental variability in the slopes of the lines of this concentration-effect relationship. The interexperimental differences in steady-state effect could not be accounted for by differences in myocardial concentration.

Animals↗
PubMed1986

The importance of pharmacokinetics and pharmacodynamics in the clinical evaluation of antiarrhythmic drugs.

Many pharmacokinetic and pharmacodynamic factors affect clinical evaluation of antiarrhythmic agents. The route of administration and the duration of treatment are variables that influence the study outcome. Due to metabolic differences and pharmacodynamic factors, different results may be obtained depending on whether drugs are administered orally or intravenously. Moreover the achievement of steady state blood level does not insure the achievement of adequate myocardial drug level nor does it indicate that a steady state effect has been achieved. There may be significant delay in the accumulation of antiarrhythmic drugs in the myocardium. Only when the metabolic profile and pharmacodynamic characteristics of a drug are understood can the most efficient testing protocol be designed for a particular antiarrhythmic agent.

Administration, Oral↗
PubMed1985

Binding of antiarrhythmic drugs to purified human alpha 1-acid glycoprotein.

The binding of lidocaine, verapamil, propafenone and propranolol to isolated, purified human alpha 1-acid glycoprotein was studied using equilibrium dialysis. Lidocaine and verapamil bound to a single class of binding sites which was characterized by high affinity (kd1 for lidocaine was 5.79 x 10(-6)M-1 and for verapamil 3.43 X 10(-6)M-1) and low capacity (n = 0.40 for lidocaine and 0.62 for verapamil). The binding of propafenone revealed two classes of binding sites, both with high affinity (kd1 was 7.62 X 10(-6)M-1 and kd2 was 6.00 X 10(-8)M-1) and low capacity (n1 = 0.79 and n2 = 0.20). Propranolol bound to at least two classes of binding sites (kd1 was 2.56 X 10(-6)M-1; n1 = 0.58). Complete characterization of the binding parameters of the second site was not possible due to failure to achieve saturation.

Anti-Arrhythmia Agents↗
PubMed1985

Chronic lorcainide therapy for symptomatic premature ventricular complexes: efficacy, pharmacokinetics and evidence for norlorcainide antiarrhythmic effect.

Chronic premature ventricular complexes (PVCs) have been effectively suppressed by oral lorcainide as reported in previous short-term studies. The plasma level-effect relation of lorcainide may be affected by the possible cardioactivity of norlorcainide, a metabolite that accumulates after repeated oral doses. This study evaluated the long-term efficacy of lorcainide in suppressing chronic symptomatic PVCs, and examined the relation of arrhythmia suppression to plasma concentrations of lorcainide and norlorcainide. Fourteen patients were treated with lorcainide, 200 to 400 mg/day, 12 of whom achieved nearly complete suppression of arrhythmias after treatment for 1 year. Chronic lorcainide treatment was well tolerated; no patient discontinued treatment because of adverse effects. Lorcainide and norlorcainide plasma concentrations remained stable after the first week of therapy. Antiarrhythmic activity persisted throughout the year. Upon drug withdrawal, the mean lorcainide washout half-life was 14.3 +/- 3.7 hours and the mean norlorcainide washout half-life was 31.9 +/- 8.9 hours. The return of arrhythmias occurred well after the lorcainide plasma concentration had decreased to subtherapeutic levels, suggesting an antiarrhythmic effect of norlorcainide. Thus, long-term lorcainide therapy is effective in treating chronic symptomatic PVCs and is well tolerated by most patients. The metabolite norlorcainide appears to have antiarrhythmic activity independent of lorcainide.

Benzeneacetamides↗
PubMed1985

Metabolite cumulation during chronic propafenone dosing in arrhythmia.

The cumulation of propafenone and two of its metabolites, 5-hydroxypropafenone (5-OHP) and N-depropylpropafenone (NDPP), was examined in patients with frequent ventricular ectopy. After 2 weeks of propafenone therapy (300 mg twice a day), propafenone was discontinued and blood samples were drawn for 24 hours. The mean (+/- SD) steady-state concentrations of propafenone, 5-OHP, and NDPP were 1010 +/- 411, 174 +/- 113, and 179 +/- 93 ng/ml. The concentration ratios of 5-OHP/propafenone and NDPP/propafenone were 0.177 +/- 0.049 and 0.227 +/- 0.203. Plasma concentrations of 5-OHP and NDPP did not decay in a log-linear manner during the sampling period and thus estimates of their disappearance t1/2s were not possible. At 24 hours after propafenone dosing, concentrations of 5-OHP and NDPP were 63% +/- 37% and 50% +/- 21% of their mean steady-state levels. Our data indicate that these propafenone metabolites cumulate in the plasma during chronic oral propafenone therapy, and that their clinical role needs to be elucidated.

Adult↗
PubMed1984

Pharmacodynamics of the initiation of antiarrhythmic therapy with lorcainide.

Lorcainide is an antiarrhythmic drug with unusual pharmacokinetics and an active metabolite, norlorcainide, which complicate oral drug loading. In order to characterize the accumulation of lorcainide and norlorcainide and to define the onset of antiarrhythmic action during lorcainide loading, 9 patients with frequent ventricular ectopic beats were studied. During lorcainide loading with 100 mg orally twice daily, frequent ambulatory electrocardiographic recordings were monitored and blood samples for drug concentrations were determined. There was a 10-fold range of intersubject variation in plasma concentrations. Despite a half-life of only 8.9 +/- 2.3 hours, lorcainide did not reach steady state until after 4.5 days of therapy. Norlorcainide had a half-life of 26.5 +/- 7.2 hours and was estimated to come to steady state after 7 to 10 days. There was considerable intersubject variation in time of onset of antiarrhythmic response (2 to more than 4.5 days) and a 4- to 5-fold range of intersubject variation in threshold therapeutic plasma concentration (lorcainide 40 to 200 ng/ml, norlorcainide 80 to 300 ng/ml). These observations suggest that lorcainide should be started at low doses and the dose should not be increased more frequently than once a week.

Administration, Oral↗
PubMed1984

High-performance liquid chromatographic isolation and fast atom bombardment mass spectrometric identification of Di-N-desethylamiodarone, a new metabolite of amiodarone in the dog.

Amiodarone is an antiarrhythmic drug which has received considerable attention in recent years. It has been suggested that the unusual pharmacodynamic characteristics of this drug may be due in part to the influence of active metabolites. Using fast atom bombardment (FAB) mass spectrometry we have identified a new metabolite of amiodarone, the di-N-desethyl analog (DDEA). This metabolite was present in the blood of dogs treated with the parent drug, and showed a greater affinity for myocardium than did the parent drug. The unique features of FAB mass spectrometry over electron impact mass spectrometry was an essential element in facilitating the identification of this new metabolite. Whether or not this metabolite has pharmacologic activity or is responsible for some of the side effects occurring during amiodarone administration is not known.

Amiodarone↗
PubMed1984

Propafenone disposition kinetics in cardiac arrhythmia.

Propafenone disposition kinetics were studied after intravenous and oral doses in patients with ventricular arrhythmias. Plasma concentration-time data were fit to a two-compartment model for all but one patient, whose data required fitting to a three-compartment model. The model-independent calculated values of clearance, steady-state volume of distribution, and terminal t1/2 were 11.2 +/- 4.8 ml/min/kg, 3.6 +/- 2.1 l/kg, and 5.0 +/- 3.6 hr. After 5 days on oral propafenone, elimination t1/2 was 6.2 +/- 3.3 hr. The longer t1/2s and the estimates of steady-state bioavailability above 100% suggests that clearance decreases during chronic oral dosing. Considerable intersubject variability was noted in all disposition parameters.

Adult↗
PubMed1984

Metabolites of cardiac antiarrhythmic drugs: their clinical role.

Most antiarrhythmic drugs are extensively metabolized, and the accumulation of the metabolites of several of these drugs has been documented. In some cases, the steady-state plasma concentrations of metabolites are considerably greater than is the concentration of the parent drug. Several of these metabolites have been evaluated in animal models for antiarrhythmic activity and their potencies have been defined relative to the activity of their parent compound. Evaluations of activity are generally conducted in animal arrhythmia models, and very few metabolites of antiarrhythmic drugs have been evaluated directly in patients. However, from knowledge of antiarrhythmic activity in animals and the degree to which a metabolite accumulates in the plasma of patients, one can make qualitative judgments about its therapeutic role. Such judgments, however, need to be recognized as tenuous. Quantitative judgments require further information regarding the relationship between the parent drug and metabolite when present simultaneously in the myocardium. One must consider whether the effects of the parent drug and metabolite are additive, synergistic, or even antagonistic. The latter case is most possible with drug-metabolite pairs where the metabolite accumulates substantially, but does not have significant antiarrhythmic potency. Other considerations include noncardiac effects of the metabolites. As in the case of the mono-desethyl metabolite of lidocaine, the significance of its accumulation relates more to central nervous system side effects than to direct cardiac actions. The role of active metabolites also much be considered in regard to differences in the disposition kinetics between the parent drug and metabolite. The most obvious situation where this is important is in designing clinical drug evaluation protocols. As illustrated by the metabolites of encainide and lorcainide, the time course of accumulation and disappearance of the metabolites may be much longer than that of the parent drug. Clinical evaluations at steady state must take into account the time required to achieve steady-state concentrations of the metabolites as well. Similarly, after discontinuation of drug administration, the time required before washout is complete may be totally dependent on the kinetics of the metabolite, and not the parent drug. Variability in metabolic activity also needs to be considered. It has been shown with procainamide and encainide that genetic factors can influence the rate of production of active metabolites and consequently influence the clinical efficacy of these drugs. Another consideration that deserves attention is the question of drug interactions.(ABSTRACT TRUNCATED AT 400 WORDS)

Amiodarone↗
PubMed1983

Clinical efficacy and electrophysiology of oral propafenone for ventricular tachycardia.

Sixteen patients with ventricular tachycardia (VT) or nonfatal cardiac arrest were treated with propafenone (P), 900 mg/day. Electrophysiologic studies were performed before and during therapy with P. All patients had inducible sustained VT at the baseline study. During P therapy, VT was not inducible in 1 patient, was unsustained in 1 and was harder to induce in 2 patients. P increased the cycle length of VT from 307 +/- 67 to 382 +/- 107 ms. Five patients began outpatient therapy with P, including 2 in whom VT was slowed to less than 125 beats/min. Two are arrhythmia-free during follow-up of 2 and 8 months. P significantly increased intraatrial conduction time (from 44 +/- 12 to 72 +/- 22 ms), AH interval (from 115 +/- 36 to 152 +/- 45 ms), HV interval (from 55 +/- 18 to 92 +/- 42 ms), QRS duration (from 140 +/- 36 to 180 +/- 48 ms) and QT interval (from 402 +/- 30 to 459 +/- 60 ms). P increased atrial (from 247 +/- 36 to 288 +/- 38 ms) and ventricular (from 249 +/- 20 to 277 +/- 32 ms) effective refractory periods, Sinus cycle length did not change, but the corrected sinus node recovery time increased (from 162 +/- 85 to 821 +/- 1,607 ms). P aggravated arrhythmias in 4 patients. The plasma P concentration, measured either at the time of electrophysiologic studies of when therapy was discontinued, was 753 +/- 428 ng/ml. P suppressed ventricular ectopic beats in 33% and increased them in 1 patient. P has antiarrhythmic activity against VT similar to that of other antiarrhythmic drugs and has potential for serious adverse effects in some patients.

Administration, Oral↗
PubMed1983

Plasma level monitoring of antiarrhythmic drugs.

It is widely accepted that the effects (both cardiac and extracardiac) of antiarrhythmic drugs are modulated by their concentration at some unidentified active site, and that the drug concentrations in the systemic circulation and at these active sites are in equilibrium. Thus, antiarrhythmic drug effects can be related directly to systemic plasma concentrations, and an optimal plasma concentration can be identified at which satisfactory arrhythmia suppression can be achieved in the absence of intolerable adverse effects. This optimal concentration is influenced by several factors that give rise to significant interpatient variability. These factors include serum protein binding, active metabolites, intrinsic responsiveness and myocardial accumulation. Although plasma concentration guidelines have been suggested for most antiarrhythmic drugs, they are generally not statistically derived and, with the exception of procainamide, are extrapolated from small patient samples. They generally represent the experience of an investigator or group of investigators treating a small homogeneous patient population. Interpretation of plasma concentrations of antiarrhythmic drugs also requires consideration of pharmacokinetic factors. Plasma drug levels are only useful when dosing history and timing of the blood sample, relative to drug administration, are considered. Despite several limitations, plasma concentration monitoring of antiarrhythmic drugs can be helpful if evaluated with an understanding of the pharmacokinetic properties of the drug being measured, the clinical status of the patient and an appreciation of the factors that may influence the relation between the measured level and resultant clinical response.

Anti-Arrhythmia Agents↗
PubMed1983

Possible contribution of encainide metabolites to the long-term antiarrhythmic efficacy of encainide.

To establish long-term efficacy and the relation between drug plasma concentration and antiarrhythmic response, 12 patients with encainide-responsive frequent complex ventricular ectopic activity underwent 1 year of therapy with encainide. Twenty-four hour ambulatory electrocardiograms were obtained at baseline and every 2 months. Drug withdrawal with concomitant plasma sampling and electrocardiographic monitoring was performed at 6 and 12 months. Average group premature ventricular contraction (PVC) suppression during the year was 97 to 99%, with nearly total suppression of pairs and salvos. The most common adverse effects were transient visual disturbances and dizziness or lightheadedness. During a dose interval (6 to 12 hours) the concentration of encainide metabolites exceeded that of encainide by several-fold. The median time of arrhythmia return after drug withdrawal was 12 to 14 hours. At the time of arrhythmia return encainide was generally no longer detectable but the average concentration of O-demethylencainide and 3 methoxy-O-demethylencainide was 72 +/- 49 and 172 +/- 74 ng/ml, respectively. It is concluded that encainide therapy is extremely effective for continuous long-term suppression of complex ventricular arrhythmias and its metabolites contribute significantly to its antiarrhythmic action during chronic oral therapy.

Adult↗