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Biomedical subjects

H J Duff

Publications and source records attributed to H J Duff.

At least 73 records · Page 4Linked to original sources
PubMed1991

Drug response at electropharmacologic study in patients with ventricular tachyarrhythmias: the importance of ventricular refractoriness.

The clinical and electrophysiologic predictors of successful antiarrhythmic drug therapy for patients with inducible ventricular tachycardia were evaluated in 59 consecutive patients undergoing serial electropharmacologic trials. Structural heart disease was less frequently present in patients for whom effective therapy was found (p less than 0.05). The presence of coronary artery disease and a history of prior myocardial infarction were significantly more frequently present in patients for whom antiarrhythmic drug therapy could not be found (p less than 0.05). The corrected QT interval and ventricular effective refractory period measured at a pacing cycle length of 400 ms were significantly shorter in responders compared with nonresponders (QT interval 428 +/- 52 versus 460 +/- 59 ms; ventricular effective refractory period 237 +/- 28 versus 254 +/- 24 ms; (p less than 0.05). In addition, the interelectrogram coupling interval of the ventricular extrastimulus initiating ventricular tachycardia was significantly shorter in responders compared with nonresponders (223 +/- 37 versus 251 +/- 33 ms; p = 0.003). Logistic regression analysis identified a short ventricular interelectrogram coupling interval (p less than 0.01) and absence of prior myocardial infarction (p less than 0.05) as the only independent predictors of antiarrhythmic drug suppression of the induction of ventricular tachycardia. Greater drug-induced increments in the ventricular effective and functional refractory periods were observed in responders than in nonresponders as was the shortest ventricular interelectrogram coupling interval. Thus, baseline electrophysiologic measurements identify patients with inducible ventricular tachycardia who are likely to respond to antiarrhythmic drug therapy. Furthermore, these patients demonstrate greater drug-induced electrophysiologic changes.

Anti-Arrhythmia Agents↗
PubMed1991

Drug therapy for ventricular tachyarrhythmias: how many electropharmacologic trials are appropriate?

To determine how many electropharmacologic drug trials should be performed to select therapy for patients with ventricular tachyarrhythmias, the outcome of 150 consecutive patients with inducible ventricular tachyarrhythmias undergoing serial electropharmacologic testing was examined. The probability of identifying predicted effective therapy (inductive of fewer than five ventricular responses with three ventricular extrastimuli at three pacing cycle lengths) and the probability of that therapy preventing sustained ventricular tachyarrhythmia recurrences were determined as a function of the number of preceding trials. The probability ( +/- SE) of identifying predicted effective therapy by the first trial (0.23 +/- 0.03) was significantly higher than that of the second (0.09 +/- 0.04), third (0.08 +/- 0.04) and fourth (0.05 +/- 0.04) trials (p = 0.001). No patient had predicted effective therapy identified by subsequent trials. The 2 year actuarial probability of freedom from sustained ventricular tachyarrhythmias on predicted effective therapy was higher for the first (0.79 +/- 0.08), second (0.73 +/- 0.13) and third (0.86 +/- 0.13) trials than for the fourth (0.33 +/- 0.27) trial (p = 0.02). Thus, the probability of selecting therapy with long-term efficacy was highest for the first trial (0.18), intermediate for the second (0.07) and third (0.07) trials and lowest for the fourth (0.02) and subsequent (0.00) trials. Accordingly, the electropharmacologic approach to therapy selection should be abandoned after three unsuccessful trials.

Actuarial Analysis↗
PubMed1991

Reduction in defibrillator shocks with an implantable device combining antitachycardia pacing and shock therapy.

Implantable defibrillators reduce the risk of sudden death in patients with malignant ventricular arrhythmias, but significant restriction in quality of life can occur as a result of frequent device activation. To determine if a device that provides both antitachycardia pacing and shock therapy can safely reduce the frequency of shocks after implantation, 46 consecutive patients undergoing initial implantation of a defibrillator were studied. In all patients, the implanted device provided antitachycardia pacing and shock therapy. Detected tachycardia characteristics and the results of therapy were stored in the device's memory. There were 42 men and 4 women, aged 26 to 71 years (mean 58.7 +/- 13.5). Left ventricular ejection fraction ranged from 13% to 67% (mean 32.2 +/- 13.4%) and 31 patients had experienced one or more episodes of cardiac arrest. Induced arrhythmias included sustained monomorphic ventricular tachycardia in 38 patients, nonsustained polymorphic ventricular tachycardia in 2 and ventricular fibrillation in 4. Over a total follow-up period of 255 patient-months (range 1 to 13, mean 6.1), 25 patients experienced spontaneous arrhythmic events. In 22 patients, 909 episodes of tachycardia were treated by antitachycardia pacing, which was successful on 840 occasions (92.4%). Acceleration of ventricular tachycardia by pacing therapy was estimated to have occurred 39 times. Syncope occurred once during pacing-induced acceleration of ventricular tachycardia. Forty-four episodes of tachycardia in seven patients were treated directly by shocks because of short tachycardia cycle length; 88% of all detected tachycardias were treated without the need for shocks. Four patients died from cardiorespiratory failure and one patient died suddenly without any detected tachyarrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗
PubMed1991

Antiarrhythmic activity of amiloride: mechanisms.

We have previously shown that amiloride suppresses the induction of sustained ventricular tachycardia both in dogs late following myocardial infarction and in patients. In those studies the only electrophysiologic correlate of amiloride's antiarrhythmic activity observed was prolongation of ventricular effective refractory period at the zone bordering the infarct. The purpose of this study was to assess the pharmacologic effects of amiloride associated with antiarrhythmic efficacy. However, amiloride has multiple pharmacologic effects, including inhibition of the slow inward calcium current (ICa), inhibition of the sodium-calcium and sodium-hydronium ion exchangers, acidification of intracellular pH resulting in partial inhibition of the inwardly rectifying potassium current (IK1), and increase in serum potassium and magnesium. The approach used in this study was to use selective pharmacologic probes to produce the known components of amiloride's pharmacologic effects. The selective agents consisted of verapamil (partial blockade of ICa), 3',4'-dichlorobenzamil (partial inhibition of the Na-Ca exchanger), 5-(N-ethyl-N-isopropyl) amiloride (partial inhibition of the Na-H exchanger), the combination of these congeners, KCl infusions to increase serum potassium, MgSO4 infusions to increase serum magnesium, the combination of KCl and MgSO4 infusions, barium (partial block of IK1), ryanodine (partial blockade of sarcoplasmic reticulum calcium release), and placebo. In this study only barium produced antiarrhythmic and electrophysiologic effects similar to those of amiloride. However, amiloride prolongs border zone refractoriness selectively, whereas barium prolongs refractoriness diffusely throughout the myocardium. Blockade of ICa by verapamil, increases in serum magnesium and potassium alone or in combination, and partial blockade of sarcoplasmic reticulum by ryanodine were not antiarrhythmic in this model. Monotherapies that produced partial blockade of the Na-Ca and Na-H exchangers separately did not produce antiarrhythmic activity. However, the combination of these amiloride congeners reproduced the antiarrhythmic activity of amiloride but did not prolong border zone refractoriness. From these studies we conclude that the antiarrhythmic activity of amiloride relates to (a) selective blockade of IK1 in the border zone and/or (b) combined inhibition of sodium-calcium and sodium-hydronium ion exchangers.

Amiloride↗
PubMed1991

Upregulation of the rat cardiac sodium channel by in vivo treatment with a class I antiarrhythmic drug.

Class I antiarrhythmic drugs inhibit the sodium channel by binding to a drug receptor associated with the channel. In this report we show that in vivo administration of the class I antiarrhythmic drug mexiletine to rats induces sodium channel upregulation in isolated cardiac myocytes. The number of sodium channels was assessed with a radioligand assay using the sodium channel-specific toxin [3H]batrachotoxinin benzoate ([3H]BTXB). The administration of mexiletine to rats induced a dose-dependent increase in [3H]BTXB total specific binding (Bmax) on isolated cardiac myocytes. Sodium channel numbers were 15 +/- 5, 29 +/- 9, and 54 +/- 4 fmol/10(5) cells after 3 d treatment with 0, 50 mg/kg per d, and 150 mg/kg per d mexiletine (P less than 0.001, analysis of variance). Sodium channel number increased monoexponentially to a steady-state value within 3 d with a half-time of increase of 1.0 d. After cessation of treatment with mexiletine the number of sodium channels returned to normal within 12 d. Finally, treatment with mexiletine altered only sodium channel number; the Kd for [3H]BTXB and the IC50 for mexiletine were not different for myocytes prepared from control and mexiletine-treated rats.

Animals↗
PubMed1991

Clinical pharmacokinetics of propafenone.

Propafenone is a class 1C antiarrhythmic agent which is administered as a racemate of S(+)- and R(-)-enantiomers. It is well absorbed and is predominantly bound to alpha 1-acid glycoprotein in the plasma. The enantiomers display stereoselective disposition characteristics, the R-enantiomer being cleared more quickly. The hepatic metabolism of propafenone is polymorphic and genetically determined: about 10% of Caucasians have a reduced capacity to hydroxylate the drug. This polymorphic metabolism accounts for the marked interindividual variability in the relationships between dose and concentration, and between concentration and pharmacodynamic effects. During long term administration, the metabolism is saturable in patients with the 'extensive metaboliser' phenotype, leading to accumulation of the parent compound. Propafenone blocks fast inward sodium channels in a frequency-dependent manner, and also has moderate beta-blocking effects. Both the enantiomers and the 5-OH metabolite have a potency to block sodium channels comparable with that of the parent compound. The S-enantiomer is a more potent beta-antagonist than the R-enantiomer. Propafenone typically slows conduction markedly but only modestly prolongs refractoriness. These cardiac effects are determined by the extent of its myocardial accumulation. The drug should be used with caution in patients with serious structural heart disease, as it may cause or aggravate life-threatening arrhythmias. Significant interactions occur when propafenone is coadministered with other drugs. It increases the plasma concentrations of digoxin, warfarin, metoprolol and propranolol as well as enhancing their respective pharmacodynamic effects. Doses of these drugs should therefore be decreased if they are coadministered with propafenone.

Animals↗
PubMed1991

Class I anti-arrhythmic drugs: structure and function at the cardiac sodium channel.

The major electrophysiologic effect of Class I anti-arrhythmic drugs is blockade of the cardiac sodium channel thereby reducing the initial depolarization of the action potential and slowing impulse propagation. Despite the widespread use of these drugs, our understanding of their mechanism of action is incomplete. Models based on electrophysiologic studies predict that a receptor for Class I drugs is associated with the sodium channel, and that occupancy of this receptor causes sodium channel blockade. Recent radioligand studies with [3H]batrachotoxin A benzoate have identified a binding site for Class I drugs associated with rat cardiac myocyte sodium channels which may be the predicted receptor. Binding of drugs to this site is saturable, reversible, stereospecific, and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. Drugs appear to bind preferentially to a closed state of the channel, thereby preventing channel opening and subsequent sodium influx.

Animals↗
PubMed1991

Mexiletine/quinidine combination therapy: electrophysiologic correlates of anti-arrhythmic efficacy.

This article reviews the data which support the use of selected drug combinations to enhance anti-arrhythmic activity. Specifically, we have focused on the mexiletine-quinidine interaction and the relation between anti-arrhythmic efficacy and electrophysiologic effects. In an initial clinical study, we found that combination therapy with mexiletine-quinidine produced enhanced efficacy in suppressing spontaneous ventricular tachycardia with fewer side-effects than high dose monotherapy. This enhanced efficacy has been confirmed in other laboratories. Combination therapy also enhanced suppression of inducible ventricular tachycardia in patients and in animal models. Animal models were used to assess the relation between electrophysiologic effects and anti-arrhythmic efficacy. In the animal studies, combination therapy produced selective prolongation of refractoriness and conduction in the infarct and peri-infarct zones without significant changes in the normal zone. Subsequent studies focused on the relative contribution of sodium channel and potassium channel blocking properties of these drugs to the enhanced activity seen with the combination. Studies using the selective sodium channel blocker tetrodotoxin confirmed that sodium channel blockade was necessary for this interaction. To assess the contribution of prolongation of action potential duration by quinidine to the combined effect we compared the anti-arrhythmic and electrophysiologic effects of the stereoisomers quinidine and quinine given alone and in combination with mexiletine. These experimental data confirm that the property of prolongation of action potential duration by quinidine is essential to the interaction. When comparing quinidine and quinine it is apparent that prolongation of refractoriness in the peri-infarct zone is essential for anti-arrhythmic activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effect of short-term prostacyclin administration on restenosis after percutaneous transluminal coronary angioplasty.

The effect of short-term prostacyclin (PGI2) administration on the incidence of restenosis after coronary angioplasty was studied in a prospective single-blind randomized trial of 286 patients. Of the 270 patients in whom dilation was successful, 134 received prostacyclin and 136 received placebo. Intracoronary prostacyclin was administered before and after dilation and then intravenously for 48 h. The control group received intracoronary placebo infusions before and after dilation. All patients received aspirin and dipyridamole before and after angioplasty, at least until follow-up angiography. Follow-up angiograms were obtained in 93% of patients in whom angioplasty was successful. Restenosis of one or more lesions was present in 34 patients (27%) who were given prostacyclin compared with 40 patients (32%) in the control group (p = NS). Acute vessel closure and ventricular tachyarrhythmias were more common in the control group than in the patients who received prostacyclin (acute vessel closure occurred in 14 [10.3%] of 136 versus 4 [3.0%] of 134, respectively, p less than 0.01; ventricular tachyarrhythmias occurred in 5 [3.4%] of 147 versus 0 of 139 respectively, p less than 0.05). Short-term administration of prostacyclin did not significantly lower the risk of restenosis after coronary angioplasty.

Aged↗
PubMed1990

Role of quinidine in the mexiletine-quinidine interaction: electrophysiologic correlates of enhanced antiarrhythmic efficacy.

Quinidine has multiple electrophysiologic effects, including prolongation of ventricular conduction time, repolarization, and refractoriness. The purpose of this study was to address the relative contributions of these electrophysiologic effects to the enhanced anti-arrhythmic activity observed when quinidine is combined with mexiletine. We compared antiarrhythmic and electrophysiologic effects observed when quinidine or its stereoisomer quinine were combined with mexiletine. Quinine and quinidine both prolong conduction time; however, these agents have divergent effects on ventricular repolarization time and refractoriness. The modest prolongation of conduction time observed with quinine and mexiletine-quinine in the absence of change of ventricular refractoriness was not associated with antiarrhythmic efficacy. The antiarrhythmic efficacy of mexiletine-quinidine exceeds that of mexiletine-quinine, suggesting that the ability of quinidine to prolong refractoriness and repolarization contributes to the antiarrhythmic efficacy of mexiletine-quinidine. Although, both the mexiletine-quinidine combination and quinidine monotherapy prolonged refractoriness to a similar extent, the mexiletine-quinidine combination produced greater antiarrhythmic efficacy and prolonged interventricular conduction within the periinfarct zone to an extent greater than did quinidine alone. We concluded that the role of quinidine in producing enhanced antiarrhythmic activity when combined with mexiletine includes both prolongation of refractoriness and conduction time in the periinfarct zone.

Action Potentials↗
PubMed1990

Quinidine/quinine: stereospecific electrophysiologic and antiarrhythmic effects in a canine model of ventricular tachycardia.

The two major electrophysiologic effects of quinidine are prolongation of refractoriness and prolongation of conduction time. To determine which of these effects contributes to its antiarrhythmic effect, we compared the electrophysiologic effects of quinidine and its stereoisomer quinine (which was expected to prolong conduction time but not refractoriness) in 24 dogs with inducible sustained ventricular tachyarrhythmia late after ischemic injury. Conscious but sedated animals were randomly assigned to receive infusions of saline, quinidine, or quinine. Serum concentrations of quinidine and quinine were 18 +/- 9 and 23 +/- 8 microM, respectively. Both drugs prolonged conduction times to a similar extent, but quinidine prolonged local repolarization times and refractoriness much more than quinine. Sustained ventricular tachyarrhythmia was consistently inducible during placebo (saline) studies. Antiarrhythmic efficacy was observed with quinidine (3 of 12) but not quinine (0 of 15) or saline (0 of 13) (p less than 0.05, Chi-square test). Quinidine also significantly prolonged monomorphic ventricular tachycardia (VT) cycle length (157 +/- 33 ms on quinidine vs. 129 +/- 26 ms at baseline, p less than 0.001) whereas quinine had no significant effect. Thus, prolonging refractoriness is important in preventing the induction of ventricular tachyarrhythmias and in prolonging VT cycle length.

Animals↗
PubMed1990

Monophasic versus biphasic cardiac stimulation: mechanism of decreased energy requirements.

The purpose of the present study was to examine the effects of monophasic and biphasic stimulation under conditions of full and incomplete repolarization in an in vivo dog model and in an in vitro rabbit ventricular single cell model. Strength-interval curves were constructed with monophasic cathodal stimulation and biphasic subthreshold anodal followed by cathodal stimulation in dogs prior to and late after left anterior descending coronary artery occlusion. At the monophasic absolute refractory period plus 10 msec, less cathodal current was required for biphasic compared to monophasic stimulation (P = 0.04). Moreover, the biphasic absolute ventricular refractory period (116 +/- 8 msec) was significantly shorter than the monophasic absolute ventricular refractory period (136 +/- 15 msec) (P less than 0.02). At coupling intervals greater than 30 msec after the monophasic absolute ventricular refractory period, there was no distinction between monophasic and biphasic stimuli. Similarly enhanced excitability was observed with biphasic stimuli in infarcted hearts. Voltage clamp measurements mimicking conditions of the in vivo studies demonstrated that when repolarization is incomplete, a hyperpolarizing prepulse reactivates additional sodium current resulting in enhanced excitability. In conclusion, biphasic stimulation consisting of a hyperpolarizing anodal prepulse followed by a cathodal pulse decreases the current required for excitation compared to cathodal monophasic stimulation in a critical zone near the ventricular absolute refractory period.

Animals↗
PubMed1990

Melperone: electrophysiologic and antiarrhythmic activity in humans.

Previous studies in animals and in humans have shown that melperone, a neuroleptic butyrophenone, has class III electrophysiologic activity. However, its antiarrhythmic activity has not been assessed in humans. Accordingly, the electrophysiologic and antiarrhythmic effects of melperone were assessed in 23 patients with symptomatic ventricular tachyarrhythmias. Seventeen patients had electrophysiologic testing while receiving melperone. At oral daily dosages greater than or equal to 240 mg, melperone produced significant prolongations of QT intervals (385 +/- 11 vs. 355 +/- 22 ms, p less than 0.05), ventricular effective refractory periods (263 +/- 18 vs. 243 +/- 28 ms, p less than 0.05; 260 +/- 18 vs. 235 +/- 27 ms, p less than 0.01; and 243 +/- 23 vs. 222 +/- 28 ms, p less than 0.01; at 600-, 500-, and 400-ms pacing cycle lengths, respectively) and ventricular tachycardia (VT) cycle lengths (286 +/- 46 vs. 239 +/- 70 ms, p less than 0.05). Inducible VT was suppressed entirely in one patient. In three other patients, inducible sustained VT became nonsustained. No significant negative inotropic effects were observed. The majority of patients (70%) experienced some adverse effect, the commonest of which was neurologic. In conclusion, melperone had significant class III electrophysiologic and antiarrhythmic activity in humans. Its clinical use may be limited by the high incidence of adverse effects.

Adult↗
PubMed1989

Importance of effective, early and sustained reperfusion during acute myocardial infarction.

The determinants of myocardial salvage after thrombolytic therapy during acute myocardial infarction (AMI) have not been clearly defined. In 1984, a prospective randomized trial was undertaken to define the relations between delay to treatment and effectiveness of perfusion to salvage of myocardium. Patients presenting within 2 hours of symptom onset received intravenous streptokinase immediately (group 1, 20 patients) or 5 hours after symptom onset (group 2, 16 patients). Effective perfusion (less than or equal to 90% residual stenosis with rapid distal runoff) occurred in 63% of patients in both groups. Five patients, all in group 1, had recurrent AMI; 4 of the 5 had effective perfusion. There was no group difference in left ventricular ejection fraction at baseline or before discharge. However, group 1 patients with effective perfusion tended to have a greater predischarge mean ejection fraction than those in group 1 with ineffective perfusion (53 +/- 13 vs 44 +/- 16%, p less than 0.10) and had a greater mean value than those in group 2 with ineffective perfusion (53 +/- 13 vs 38 +/- 17%, p less than 0.03). The ejection fraction did not change significantly between admission and discharge in either group, but it increased significantly in group 1 patients with effective perfusion and no recurrent AMI (delta EF = +6 +/- 8%, p less than 0.04). Group 1 patients with ineffective perfusion had a significant decrease in ejection fraction (delta EF = -4 +/- 4%, p less than 0.04). In group 2 patients the ejection fraction did not change, regardless of the state of perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1989

Hemodialysis removal of propafenone.

Propafenone kinetics were studied after intravenous and oral dosing in a patient with end-stage renal disease. Hemodialysis was performed within 10 hours of dosing in order to assess its effects. After intravenous administration of 70 mg propafenone, total-body clearance was 10.5 ml/min/kg before and 10.4 ml/min/kg during hemodialysis. After a single oral dose of 300 mg, clearance was 19.4 ml/min/kg before and 18.9 ml/min/kg during hemodialysis. Bioavailability was 48%.

Administration, Oral↗
PubMed1989

Cardiac refractoriness. Age-dependence in normal subjects.

The effects of age on cardiac electrophysiologic measurements were assessed in 30 subjects between the ages of 18 and 73 years and free of structural heart disease. Occult heart disease was excluded by a normal treadmill exercise tolerance test, a rest and exercise radionuclide angiogram, and/or a cardiac catheterization. Effective and functional refractory periods of right atrium, right ventricle, and atrioventricular node were assessed. The relationship between these measurements and age was examined using linear regression. There were significant correlations between age and atrial effective and functional refractory periods, atrioventricular effective refractory period, and ventricular effective and functional refractory periods. Other electrophysiologic measures showed no such relationship with age.

Adult↗
PubMed1989

Contribution of quinidine metabolites to electrophysiologic responses in human subjects.

The quinidine metabolites 3-hydroxyquinidine, 2'-oxoquinidione, and quinidine-N-oxide and the contaminant dihydroquinidine have been shown to have electrophysiologic activity. This study investigated the time-dependent contributions of quinidine, dihydroquinidine, and the quinidine metabolites to the electrophysiologic effects of a prolonged quinidine infusion in 14 patients referred for management of symptomatic ventricular tachyarrhythmias. Electrophysiologic testing and blood sampling were done at baseline and every 5 minutes throughout a 110-minute quinidine infusion. Changes in ventricular effective refractory periods correlated significantly with serum concentrations of quinidine-N-oxide (r = 0.54; p less than 0.001), 3-hydroxyquinidine (r = 0.50; p less than 0.001), and time (r = 0.52; p less than 0.001) but did not correlate with the quinidine concentrations (r = 0.19). Multiple linear regression revealed that only 3-hydroxyquinidine and time contributed independently to changes in the ventricular effective refractory period. Quinidine concentration was the only variable that contributed independently to changes in ventricular tachycardiac cycle lengths. Time was the only variable that correlated independently with changes in QRS and QTc durations. These data indicate that active metabolites accumulate during an intravenous infusion that attains therapeutic quinidine levels and that quinidine and its metabolites may have different electrophysiologic effects.

Aged↗