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H J Duff

Publications and source records attributed to H J Duff.

At least 127 records · Page 7Linked to original sources
PubMed1984

Pharmacology, electrophysiology, and pharmacokinetics of mexiletine.

Mexiletine is a class I antiarrhythmic agent that is active after both oral and intravenous administration and similar in structure and activity to lidocaine. It decreases phase O maximal rate of depolarization (Vmax) by fast sodium channel blockade. The marked rate dependence of Vmax depression may explain mexiletine's lack of effect on normal conduction and its efficacy against ventricular tachyarrhythmias. Mexiletine significantly decreases the relative refractory period in His-Purkinje fibers without changing the sinus rate or atrioventricular and His-Purkinje conduction times. Action potential duration is usually shortened. Mexiletine may aggravate preexisting impairment of impulse generation and conduction. Uptake and distribution of mexiletine are rapid, systemic bioavailability is about 90%, and tissue distribution is extensive. Mexiletine is primarily metabolized in the liver; 10% to 15% is excreted unchanged in the urine. Elimination half-life is 9 to 11 hours after intravenous or oral administration. Microsomal enzyme induction shortens mexiletine's elimination half-life, whereas hepatic disease and acute myocardial infarction prolong it. Renal disease has little effect, although hemodialysis increases mexiletine clearance. Plasma concentrations from 0.75 to 2.0 mg/L are usually associated with a desirable therapeutic response.

Absorption↗
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

Electrophysiological effects of high-dose propranolol in dogs: evidence in vivo for effects not mediated by the beta adrenoceptor.

Closed-chest dogs anesthetized with morphine and chloralose were studied to determine if direct or nonspecific cardiac electro-physiological effects of propranolol occur at clinically relevant plasma concentrations and to differentiate the nonspecific effects from those due to beta adrenoceptor blockade. In 19 dogs, ventricular monophasic action potential durations (MAP), ventricular effective refractory periods (VERP) and His bundle electrograms (A-H and H-V intervals) were measured at base line and during sequential infusions of isoproterenol, dl-propranolol and dl-propranolol plus an isoproterenol infusion designed to overcome beta blockade. A mean plasma propranolol level of 979 +/- 344 ng/ml produced a significant (P less than .05) prolongation of A-H (95 +/- 20-115 +/- 13 msec), MAP (179 +/- 26-194 +/- 14 msec) and VERP (159 +/- 12-177 +/- 13 msec). Infusion of the beta agonist, isoproterenol, returned A-H and MAP to values not significantly different from base line, whereas VERP remained prolonged at 174 +/- 11 msec (P less than .05). No significant changes occurred in a control group of 14 dogs infused with saline. In eight additional dogs, infusions of d- and dl-propranolol, given on separate days, were used to produce equal beta blockade determined by individual isoproterenol sensitivity tests. A-H, H-V, MAP and ventricular strength-interval curves (VRP) and diastolic thresholds (DT) were measured and treatment vs. base-line changes (delta) with d- and dl-propranolol were compared.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
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↗
PubMed1981

Recurrent ventricular tachycardia in the absence of overt heart disease: clinical characteristics and response to drug therapy.

Eight patients, seven of them women, have been followed up for a mean of 8.1 years (range, three to 18) with the uncommon syndrome of recurrent frequent episodes of ventricular tachycardia in the absence of overt cardiac abnormality. The mean age at diagnosis was 25 years (range, 12 to 44). Serious symptoms were common: five patients had syncope, cardiac arrest, and/or cerebrovascular accidents. Multiple measures to characterize this population, including study of symptoms, response to exercise, degree of prematurity of ventricular ectopic depolarizations, and response to antiarrhythmic drugs, showed little uniformity. An individualized approach to therapy, taking into account age and symptoms as well as frequency of arrhythmia, was used. Excellent control of arrhythmia was eventually achieved in four patients, but only after multiple drug trials (mean 5.3, range two to eight trials per patient) had been ineffective. Prognosis in this syndrome is generally good, but serious complications occur frequently enough that vigorous therapy is justified in selected patients.

Adolescent↗
PubMed1980

Detection of entrapped intracardiac air with intraoperative echocardiography.

Embolization of entrapped intracardiac air represents a significant risk to the patient undergoing open heart surgery. To date, there have been no menas available to ensure that the heart is free of air prior to restoration of the circulation. To assess whether M mode echocardiography can accurately detect intracardiac air, we studied 10 dogs during cardiopulmonary bypass. Randomly, air was or was not injected into the left ventricular cavity of the fibrillating heart. Intracardiac air could be recognized by the presence of a stippled granular pattern, or a loss of the discrete linear echoes or decreased far field echoes, or any combination of these three. In all, 131 random observations were made. When 1.0 cc of air was injected, sensitivity and specificity were both 100 percent, but when 0.2 cc was injected, sensitivity and specificity decreased to 86 and 58 percent, respectively. thus, M mode echocardiography appears to provide a sensitive and specific tool for detecting intracardiac air.

Animals↗
PubMedDate not supplied

A randomized clinical trial of the noninvasive and invasive approaches to drug therapy for ventricular tachycardia: long-term follow-up of the Calgary trial.

Individualized antiarrhythmic drug therapy for patients with ventricular tachyarrhythmias may be selected by the noninvasive approach (suppression of spontaneous ventricular premature beats) or the invasive approach (suppression of ventricular tachyarrhythmias induced at an electrophysiologic study). There is controversy over which approach is superior. From a screened population of 124 patients with symptomatic ventricular tachycardia or ventricular fibrillation, 57 patients with both frequent ventricular premature beats and inducible ventricular tachycardia at baseline were randomized to have chronic therapy selected by either the noninvasive or invasive approach. These patients have now been followed up for a minimum event-free period of 6.5 years. By intention-to-treat, therapy selected by the invasive approach prevented subsequent ventricular tachyarrhythmias better than that selected by the noninvasive approach (6-year probabilities of freedom from symptomatic sustained ventricular tachyarrhythmia recurrence; noninvasive approach, 0.45 +/- 0.10; invasive approach, 0.73 +/- 0.09; p=.02). This advantage of the invasive approach was also evident for the outcome of any ventricular tachyarrhythmia recurrence and for efficacy analyses involving only those patients with a drug-efficacy prediction. We hypothesize that the difference between these results and those of the ESVEM trial are caused, in part, by differences in the characteristics of the enrolled patients and differences in criteria used to define a predicted-effective therapy.

Actuarial Analysis↗
PubMedDate not supplied

Electrophysiology of O-demethyl encainide in a canine model of sustained ventricular tachycardia.

The antiarrhythmic agent encainide produces marked suppression of ventricular arrhythmias in most patients. However, in some with sustained ventricular tachycardia, worsening of clinical arrhythmias can occur. Since the effects of this agent are mediated by its O-demethyl metabolite in most patients, we have evaluated the effects of O-demethyl encainide in dogs susceptible to the induction of ventricular tachycardia. Nonsedated animals were studied 3-5 days after 90-min left anterior descending coronary artery occlusions. Electrophysiologic evaluations were carried out at baseline, and then during a series of infusions of O-demethyl encainide that achieved low (58 +/- 5 ng/ml) (mean +/- SE), moderate (190 +/- 16 ng/ml), and high (758 +/- 98 ng/ml) plasma concentrations compared with the range seen in patients (50-300 ng/ml). Ventricular tachycardia induction was unaffected by the drug. Effective refractory period was prolonged in a dose-related fashion at both normal and infarcted epicardial sites. However, local electrogram duration was prolonged only in the infarcted zone. We conclude that O-demethyl encainide exerted no consistent effect on susceptibility to induction of ventricular tachycardia in this study. This agent appears to alter infarcted zone conduction disproportionately.

Anilides↗
PubMedDate not supplied

The antiarrhythmic activity of meobentine sulfate in man.

Meobentine (sulfate) has antifibrillatory and antiarrhythmic activity in canine models. The antiarrhythmic, pharmacokinetic, and adrenergic neuronal blocking effects of meobentine were assessed in 15 patients with chronic, high-frequency ventricular ectopic depolarizations (VEDs). Eleven of the 15 patients had recurrent nonsustained ventricular tachycardia. The patients were given a series of gradually increasing single doses of meobentine; six received oral meobentine and nine had infusions. The antiarrhythmic efficacy of meobentine was assessed by a comparison of arrhythmia frequency during placebo given on days just prior to meobentine. Oral therapy with meobentine at dosages above 20 mg/kg caused diarrhea, and well-tolerated dosages achieved peak concentrations of 0.69 micrograms/ml (range 0.5-1.0 micrograms/ml). Antiarrhythmic activity was seen in only one patient with oral meobentine. In contrast, intravenous infusions (6.75-34.2 mg/kg) achieved concentrations ranging from 1.3-9.8 micrograms/ml. There was a linear relationship between pseudo-steady-state plasma concentrations and dosage, r = 0.82, p less than 0.01. Antiarrhythmic activity was seen in four of nine patients who received intravenous meobentine over a range of concentrations from 2.5-4.5 micrograms/ml. Four patients developed evidence of adrenergic neuronal blockage (loss of the venous reflex response); two at dosages of 16.2 mg/kg, one at 24.3 mg/kg, and one at 34.2 mg/kg. In one individual (24.3 mg/kg), the adrenergic neuronal blockade was associated with an acute episode of shortness of breath, orthopnea, and cough. With intravenous meobentine, there was a linear relationship between dosage and AUC, and the elimination half-life ranged from 11-27 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗