Biomedical subjects

H J Duff

Publications and source records attributed to H J Duff.

At least 91 records · Page 5Linked to original sources

PubMed1989

Concentration-response relationships of disopyramide in patients with ventricular tachycardia.

The protein binding of disopyramide is altered when concentration is increased within the therapeutic range. A wide range of free concentrations may be produced at a given total concentration. The present study assessed whether intracardiac electrophysiologic responses to disopyramide related better to free or to total concentration. Intravenous infusions of disopyramide were evaluated in 17 patients with inducible sustained ventricular tachycardia. The first maintenance infusion produced total serum concentrations of 11.7 +/- 2 mumols/L, and no significant increase occurred at higher-dose infusions. However, free concentrations during the first and second maintenance infusions were significantly different at 5.3 +/- 1 mumols/L and 6.8 +/- 1 mumols/L, respectively. Free fraction also increased significantly, from 45% +/- 8% to 50% +/- 7%. Overall change in QTc interval and ventricular tachycardia cycle length correlated with free concentration but not with total concentration. This study showed that some intracardiac measurements correlate with free concentration but that none correlate with total concentration.

Disopyramide↗

PubMed1989

Mexiletine-quinidine in isolated hearts: an interaction involving the sodium channel.

Combination therapy with mexiletine and quinidine has been shown to be more effective than either monotherapy in treating patients with ventricular tachycardia. This enhanced efficacy was associated with prolongation of ventricular refractoriness and conduction time in the infarct zone. As sodium channel activity is a determinant of both conduction time and refractoriness we formed the hypothesis that the mexiletine-quinidine interaction was due at least in part to interactions involving the sodium channel. To assess the role of sodium channel blockade in the enhanced anti-arrhythmic activity of mexiletine-quinidine combination we determined whether the electrophysiological and anti-arrhythmic effects of tetrodotoxin combined with mexiletine or quinidine mimicked the effect seen with mexiletine combined with quinidine. Eighty isolated perfused rabbit hearts were treated with mexiletine, quinidine and tetrodotoxin either alone or in combination before and after circumflex occlusion-reperfusion. Ventricular fibrillation occurred in response to single extrastimuli in all 24 hearts treated with a saline control infusion. Combinations of mexiletine and quinidine at concentrations which alone had little electrophysiological activity produced anti-arrhythmic activity greater than that seen with high concentrations of mexiletine or quinidine alone. The combination of similarly low concentrations of tetrodotoxin and quinidine also produced enhanced anti-arrhythmic efficacy and enhanced prolongation of ventricular refractoriness and conduction which mimicked the effect of mexiletine and quinidine in combination. In contrast, the combination of mexiletine and tetrodotoxin did not produce enhanced anti-arrhythmic and electrophysiological activity. Since tetrodotoxin is a highly specific sodium channel blocker, these data suggest that the enhanced antiarrhythmic activity of mexiletine-quinidine combination therapy involves, at least in part, blockade of the cardiac sodium channel.

Action Potentials↗

PubMed1989

The impact of a therapeutic drug monitoring program for phenytoin.

The current study was performed to document the cost savings and need for a therapeutic drug monitoring program for phenytoin. The methodology employed a prospective, randomized, crossover design that utilized two control and two therapeutic drug monitoring phases. The therapeutic drug monitoring program significantly decreased the average number of assays performed per patient from 2.14 to 0.61. Withdrawal of the program resulted in a significant increase in the average number of assays performed per patient (from 0.61 to 2.41), the average number of assays drawn incorrectly (from 0.39 to 1.89), and in the average number of assays used inappropriately (from 0.50 to 2.07). Withdrawal of the program was also associated with a significant increase in the average number of readmissions (from 0 to 0.19) within 3 months of discharge. Reinstitution of the program was associated with a significant decrease in the average number of readmissions (from 0.19 to 0.03) within 3 months of discharge. The cost savings from decreasing the number of assays performed was estimated to be $100.00 for the first year.

Costs and Cost Analysis↗

PubMed1989

Amiloride. Antiarrhythmic and electrophysiologic actions in patients with inducible sustained ventricular tachycardia.

This study assessed the antiarrhythmic activity of amiloride in 35 patients with inducible sustained ventricular tachycardia. Patients had failed to respond to 3.6 +/- 1.0 antiarrhythmic drugs. Ventricular tachycardia was reproducibly induced by programmed electrical stimulation in all patients at the baseline study. Amiloride was given at 10 and 20 mg/day p.o. on a twice-daily schedule that achieved serum concentrations of 21 +/- 17 and 36 +/- 18 ng/ml, respectively. The mean left ventricular ejection fraction was unchanged from 36 +/- 14% at baseline to 37 +/- 17% during amiloride treatment. Amiloride significantly increased serum potassium from 4.6 +/- 0.4 to 5.1 +/- 0.4 mM. Four patients failed amiloride therapy with spontaneous nonsustained ventricular tachycardia. The remaining 31 patients were assessed by repeat programmed stimulation. Six patients had complete antiarrhythmic response, and an additional six patients had less than 15 beats of ventricular tachycardia induced. Therefore, amiloride was an efficacious antiarrhythmic treatment in 12 of 35 (34%) patients. Amiloride concentrations were significantly higher (52 +/- 20 ng/ml) in patients that responded than in patients that did not respond (30 +/- 15 ng/ml). The only electrophysiologic measurement that changed significantly was the ventricular functional refractory period (from 269 +/- 24 to 283 +/- 25 msec, p less than 0.05). Amiloride also suppressed frequent, spontaneous ventricular premature beats in eight of 15 patients (53%). No somatic side effects occurred. Two of the five patients discharged on amiloride therapy developed asymptomatic nonsustained ventricular tachycardia, and this prompted a change in antiarrhythmic therapy. Both died suddenly of arrhythmia during substitute empiric antiarrhythmic drug therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Electropharmacology of amiodarone therapy initiation. Time courses of onset of electrophysiologic and antiarrhythmic effects.

The time courses of onset of the electrophysiologic and antiarrhythmic effects of amiodarone were determined with serial electrophysiologic studies in 34 patients with inducible ventricular tachycardia. A standardized oral loading dosage was used for all patients (1,200 mg/day for 14 days; 800 mg/day for 7 days; and 400 mg/day thereafter). Eleven patients had the studies performed at baseline and after 2, 6, 10, and 20 weeks. Subsequently, 23 patients had studies at baseline and after 2 and 10 weeks. Changes in atrial, sinus, and atrioventricular nodal properties and in conduction intervals were maximal within 2 weeks (early effects). For example, atrioventricular nodal Wenckebach cycle length increased between baseline (369 +/- 80 msec) and 2 weeks (498 +/- 78 msec) (p less than 0.001) but did not change further after 10 weeks (500 +/- 89 msec). However, ventricular Class III effects required 10 weeks to become maximal (late effects). For example, the QT interval during atrial pacing increased between baseline (355 +/- 36 msec) and 2 weeks (406 +/- 37 msec) (p less than 0.001) and increased further after 10 weeks (436 +/- 45 msec) (p less than 0.001). Antiarrhythmic effects also followed different time courses of onset. Suppression of ventricular premature beats was maximal within 2 weeks. However, suppression of ventricular tachycardia inducibility and slowing of ventricular tachycardia rate was not maximal for 10 weeks. Correlations between serum desethylamiodarone concentrations and some late effects suggest that the mechanism of the time delay to maximal ventricular Class III effects may involve desethylamiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1989

Amiodarone: biochemical evidence for binding to a receptor for class I drugs associated with the rat cardiac sodium channel.

Amiodarone has multiple pharmacological effects in heart. Electrophysiological data suggest that among its other effects, amiodarone is a sodium channel blocker. Using a radioligand assay, we determined whether amiodarone interacted with a previously described receptor for type I agents associated with the cardiac sodium channel. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([ 3H]BTXB), a toxin that binds to the activated state of the sodium channel. We have previously shown that class I antiarrhythmic drugs inhibit [3H]BTXB binding. The purpose of this study was to assess whether amiodarone and other class III agents interact with this receptor. Amiodarone inhibited [3H]BTXB binding in a dose-dependent fashion, with an estimated IC50 value of 3.6 microM. This IC50 value is similar to reported clinically effective serum concentrations of amiodarone. In contrast to amiodarone, the IC50 values for other class III drugs (bretylium, sotalol, bethanidine, N-acetylprocainamide) were much higher than their therapeutic concentrations and bore no relation to them. Scatchard analysis of [3H]BTXB binding showed that amiodarone reduced the maximal binding for [3H]BTXB; this finding indicates irreversible inhibition or (more likely) allosteric inhibition by amiodarone. The latter agrees with electrophysiological data suggesting that amiodarone binds to inactivated sodium channels. Sodium channel blockade by amiodarone may contribute to its overall electrophysiological effect.

Allosteric Site↗

PubMed1989

Antiarrhythmic drugs and the cardiac sodium channel: current models.

The major electrophysiological effect of Class I antiarrhythmic 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 electrophysiological studies predict that a receptor for Class I drugs is associated with the sodium channel, and that occupancy of this receptor causes blockade of the sodium channel. Recent radioligand studies with [3H]batrachotoxinin-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.

Anti-Arrhythmia Agents↗

PubMed1989

Class I antiarrhythmic drug receptor: biochemical evidence for state-dependent interaction with quinidine and lidocaine.

The state-dependent binding of class I antiarrhythmic drugs to a receptor associated with the cardiac sodium channel was assessed using [3H]batrachotoxinin A 20-alpha-benzoate [( 3H]BTXB) binding. [3H]BTXB binds specifically to and stabilizes activated states of the sodium channel. Quinidine (IC50 = 40 microM) and lidocaine [IC50 = 61 microM) inhibited equilibrium [3H]BTXB binding to sodium channels present on freshly isolated rat cardiac myocytes. Scatchard analysis of [3H]BTXB binding in the presence of quinidine and lidocaine revealed two apparent patterns of inhibition. Quinidine (33 microM) increased the KD but had no significant effect on the Bmax, whereas lidocaine (91 microM) reduced the Bmax but had no significant effect on the KD. To address drug binding to activated and nonactivated states, we exploited the state-specific binding of [3H]BTXB. Drugs that increase the rate of dissociation (k-1) of [3H]BTXB must bind to sodium channels to which [3H]BTXB is already bound (i.e., activated channels). Therefore, drug-mediated increases in k-1 measure drug binding to activated states. Both quinidine and lidocaine increased the k-1 of [3H]BTXB, indicating drug binding to and destablization of activated sodium channels. However, the minimal affinities of quinidine and lidocaine for activated channels (KDact) were estimated to be 433 and 455 microM, respectively, concentrations much higher than the equilibrium IC50 values. Drugs that allosterically decrease the rate of association (k+1) of [3H]BTXB must bind to sodium channels to which [3H]BTXB is not already bound (i.e., nonactivated channels). Therefore, drug-mediated decreases in k+1 measures drug binding to nonactivated states. Quinidine and lidocaine decreased the k+1 of [3H]BTXB, indicating drug binding to and stablization of nonactivated sodium channels. The affinity of quinidine and lidocaine for nonactivated channels (KDnon) was estimated to be 10 and 35 microM, respectively, concentrations close to the equilibrium IC50 values. The markedly different KDact and KDnon values for both quinidine and lidocaine indicate state-dependent binding of quinidine and lidocaine to the class I receptor on the cardiac sodium channel. Both drugs destabilize activated channels and stabilize nonactivated channels. The Scatchard results suggest that quinidine and lidocaine may have different mechanisms of allosteric inhibition of [3H]BTXB binding.

Allosteric Regulation↗

PubMed1989

Mexiletine-quinidine combination: enhanced antiarrhythmic and electrophysiologic activity in the dog.

Combination treatment with mexiletine and quinidine has been shown to be more effective than either monotherapy in the treatment of ventricular tachycardia in humans. The purpose of this study was to assess the electrophysiologic changes which correlated with enhanced antiarrhythmic activity during treatment with the monotherapies and this combination. Twenty-seven dogs with inducible sustained ventricular tachyarrhythmias (VT) late after ischemic injury were treated with mexiletine and quinidine, alone and in combination. Conscious but sedated animals were assigned randomly to receive serial drug treatments. Sustained VT was consistently inducible during serial placebo studies. In 13 dogs who received all four drug treatments (mexiletine, quinidine, combination and placebo) significantly greater antiarrhythmic efficacy was seen with combination therapy (8 of 13) than was seen with mexiletine alone (1 of 13), quinidine alone (3 of 13) and saline (0 of 13) (P less than .005). This enhanced antiarrhythmic activity was paralleled by greater prolongation of intraventricular conduction to the border zone and increase in excitability threshold at the border zone and increase in ventricular effective refractory period in the infarct zone. Serum concentrations of quinidine were 19 +/- 5 microM when given alone and 15 +/- 5 microM when given in combination. Mexiletine concentrations were 3.6 microM when given alone and 4.2 microM when given in combination. In conclusion, mexiletine and quinidine in combination produced enhanced antiarrhythmic activity which was paralleled by electrophysiologic changes occurring in the perinfarct zone. These electrophysiologic changes appear to be correlates of enhanced antiarrhythmic activity.

Animals↗

PubMed1988

Right and left ventricular function during chronic amiodarone therapy.

Although chronic therapy with amiodarone is an effective means of suppressing ventricular tachycardia, its long-term effects on ventricular function have not been evaluated. Therefore, left ventricular (LV) and right ventricular (RV) ejection fraction (EF) as well as wall motion score were assessed in 21 patients with ventricular tachycardia before therapy and after 2, 6, 10 and 20 weeks of amiodarone therapy. Serum amiodarone levels after 2, 6, 10 and 20 weeks were 1.9 +/- 0.7, 1.7 +/- 0.6, 1.5 +/- 0.6 and 1.5 +/- 0.7 micrograms/ml, respectively. Drug therapy did not significantly affect the mean LVEF (0 weeks 38 +/- 17, 2 weeks 40 +/- 17, 6 weeks 40 +/- 17, 10 weeks 41 +/- 18 and 20 weeks 40 +/- 18%) or the mean RVEF. Neither LV wall motion score nor RV wall motion score were changed significantly during amiodarone therapy. Fourteen patients had a drug-free LVEF less than 40% (mean 28 +/- 7%). Ventricular function in this subgroup was not impaired after 20 weeks of amiodarone therapy (drug-free LVEF 28 +/- 7%, 20 weeks LVEF 29 +/- 9%; drug-free RVEF 42 +/- 13%, 20 weeks RVEF 41 +/- 12%). Ten patients who were evaluated 34 +/- 6 months after initiation of amiodarone therapy had no significant change in LVEF (drug-free 37 +/- 20%, 34 months 43 +/- 20%). Ventricular functional reserve was assessed after 20 weeks of therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1988

Usefulness of early positive technetium-99m stannous pyrophosphate scan in predicting reperfusion after thrombolytic therapy for acute myocardial infarction.

To test the hypothesis that scans with technetium-99m pyrophosphate (Tc-99m-PPi) are positive when performed early after successful thrombolytic therapy for acute myocardial infarction (AMI), 16 consecutive patients with AMI who received thrombolytic therapy within 5 hours after the onset of chest pain were studied. Patients were included if chest pain lasted for greater than 30 minutes, was unresponsive to sublingual nitroglycerin and was associated with at least 0.2 mV ST-segment elevation in at least 2 contiguous electrocardiographic leads. All patients received 1.5 million IU of streptokinase intravenously, a mean of 195 +/- 99 minutes after onset of chest pain. Tc-99m-PPi scans and coronary cineangiograms were recorded 491 +/- 156 minutes and 518 +/- 202 minutes, respectively, after the onset of symptoms. Effective reperfusion was present in 10 patients, 6 of whom had positive Tc-99m-PPi scans (sensitivity of 60% to detect reperfusion). Of the 6 patients without effective reperfusion, 3 had positive Tc-99m-PPi scans (specificity of 50%, p greater than 0.05). Analysis of the data using various definitions of effective reperfusion or artery patency yielded similar results. Thus, our findings indicate that early AMI scanning with Tc-99m-PPi does not accurately detect the presence or absence of reperfusion in patients with AMI after treatment with intravenous streptokinase. At this time, coronary cineangiography is the only reliable method to detect reperfusion promptly after thrombolytic therapy.

Aged↗

PubMed1988

Effect of oral combination therapy with mexiletine and quinidine on left and right ventricular function.

Combination therapy with mexiletine (MEX) and quinidine (Q) may be more efficacious than monotherapy with either drug in suppressing ventricular arrhythmias, but its effects on ventricular performance are not known. Thus, right ventricular ejection fraction (RVEF) and left ventricular ejection fraction (LVEF) and wall motion score (WMS) were assessed in 14 patients with ventricular tachycardia before antiarrhythmic therapy, during MEX and Q monotherapies, and during combination therapy. During monotherapy, the daily doses and serum drug levels were: MEX, 621 mg/day and 3.4 microM/L; Q, 1573 mg/day and 8.3 microM/L, respectively. With combination therapy, the daily doses and serum drug levels were: MEX, 636 mg/day and 3.3 microM/L; Q, 1643 mg/day and 9.5 microM/L, respectively. Drug therapy did not affect group LVEF (drug free = 36 +/- 19%, MEX = 34 +/- 18%, Q = 36 +/- 19%, and combination MEX-Q = 35 +/- 19%), RVEF (drug free = 34 +/- 11%, MEX = 35 +/- 11%, Q = 36 +/- 13%, and combination MEX-Q = 36 +/- 12%), or WMS. Ventricular function reserve was assessed in five patients. Drug therapy did not affect group exercise LVEF (drug free = 44 +/- 14%, MEX = 42 +/- 12%, Q = 43 +/- 13%, and MEX-Q = 45 +/- 12%), RVEF (drug free = 38 +/- 10%, MEX = 40 +/- 11%, Q = 39 +/- 12%, and MEX-Q = 40 +/- 12%), WMS, or exercise duration. Combination MEX-Q therapy did not have a significant effect on exercise performance or ventricular function in seven additional patients in whom no exercise studies were done during monotherapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac Pacing, Artificial↗

PubMed1988

Tetrodotoxin: sodium channel specific anti-arrhythmic activity.

Many Class I anti-arrhythmic drugs not only block the cardiac sodium channel but also block the calcium and/or potassium channels. The hypothesis tested in this study was that sodium channel blockade without blockade of calcium or potassium channels produced anti-arrhythmic activity in the treatment of malignant ventricular arrhythmias. The arrhythmia model consists of ventricular fibrillation induced by critically timed single extrastimuli at twice diastolic pacing threshold following 15 minutes of ischaemic injury in a rabbit heart perfused in vitro. Preparations were randomly assigned to either tetrodotoxin (a selective sodium channel blocking toxin) or vehicle. Ventricular fibrillation occurred in all vehicle treated preparations in response to single extrastimuli following ischaemic injury. Treatment with tetrodotoxin at concentrations of 0.1 to 1.0 micromolar protected some hearts from fibrillation, while at concentrations above 3 micromolar ventricular fibrillation was not inducible. Tetrodotoxin produced concentration dependent increases in ventricular effective refractory period and conduction time in the infarct zone which were associated with anti-arrhythmic activity. No concentration dependent change in action potential duration was seen with tetrodotoxin. Thus the electrophysiological and anti-arrhythmic activities of tetrodotoxin in this model demonstrate that the property of selective sodium channel blockade is sufficient to produce anti-arrhythmic activity.

Action Potentials↗

PubMed1988

Time-dependent change in electrophysiologic milieu after myocardial infarction in conscious dogs.

This study was designed to assess the time-dependent change in propensity to induction of malignant ventricular tachyarrhythmia after myocardial infarction. Instrumented conscious dogs were assessed during serial drug-free electrophysiologic studies over 26 +/- 9 days (range 17 to 35 days) after 2 hr occlusion-reperfusion of the left anterior descending coronary artery. Of the 19 animals studied, 11 continued to have sustained ventricular tachyarrhythmias inducible (group I) over this time period. In the eight remaining animals, spontaneous loss in the ability to induce sustained ventricular tachycardia occurred (group II). Myocardial infarct size in group I animals (18 +/- 8%) was significantly greater than that in group II dogs (12.5 +/- 5%; p less than .05). Even in group I animals, time-dependent changes occurred in the number of extrastimuli required to induce ventricular tachycardia and the frequency with which left ventricular stimulation was necessary. A differential pattern of time-dependent changes in electrophysiologic variables was observed when comparing group I and II animals. The conduction time to the infarct zone was prolonged during follow-up in group I animals, while in group II animals this variable was unchanged. Repolarization time recorded in the border zone remained unchanged in group I animals, but it was significantly shortened in group II animals. In addition, ventricular effective refractory period in the infarct zone shortened over time in group I animals but did not change in group II animals. In conclusion, time-dependent changes occur in electrophysiologic variables that are associated with a progressive decrease in propensity to induction of ventricular tachycardia after myocardial infarction. A critical determinant of whether propensity to ventricular tachycardia resolves over time is size of myocardial infarction.

Animals↗

PubMed1988

Amiloride. Antiarrhythmic and electrophysiological activity in the dog.

Amiloride, a widely used diuretic, has multiple pharmacological actions, including inhibition of the sodium-hydronium ion and the sodium-calcium exchanger in heart. In terms of cardiac electrophysiology, amiloride prolongs action potential duration without alteration in upstroke velocity of phase 0 in Purkinje fibers. The antiarrhythmic efficacy of amiloride was assessed in a model of inducible sustained ventricular tachyarrhythmias in 16 dogs late after 2-hour occlusion-reperfusion of the left anterior descending coronary artery. Sixteen animals were studied: Four were randomly assigned to placebo, and 12 were assigned to amiloride treatment. Prolonged loading and maintenance infusions were designed to produce amiloride concentrations over the range achievable in humans. Animals were chronically instrumented to allow electrophysiological measures of conduction and refractoriness in the left ventricular infarct and border zones. Of the 12 animals treated with amiloride, six responded with inability to induce ventricular tachyarrhythmias, whereas of the four animals treated with placebo, none responded. The mean infarct size of the six animals responding to amiloride (12 +/- 5%) was significantly less than that of the six animals not responding to amiloride (20 +/- 8%). Overall, the only electrophysiological effect of amiloride observed in this study was prolongation of border zone ventricular refractoriness. This electrophysiological effect was accentuated in animals responding to amiloride. In addition, when animals were subdivided into responders, partial responders, or nonresponders, the border zone repolarization time was prolonged in responders and partial responders, whereas this measure shortened in nonresponding animals. Amiloride has antiarrhythmic activity in the suppression of sustained ventricular tachyarrhythmias in this postinfarction model.

Amiloride↗

PubMed1988

Stereospecific interaction of tocainide with the cardiac sodium channel.

The antiarrhythmic action of type I antiarrhythmic drugs may be mediated via binding of the drugs to a receptor associated with the cardiac sodium channel. This suggested that the effects of type I drugs might be stereospecific. We measured the effect of the tocainide stereoisomers (which have stereospecific antiarrhythmic effects) on conduction time and on radioligand binding to the cardiac sodium channel. The concentration-dependent effects of the individual enantiomers of tocainide on interventricular conduction time measured during constant rate ventricular pacing at 350 msec were assessed in 47 isolated perfused rabbit heart preparations. Significant increases (p less than 0.05) in conduction time occurred for both R-(-)-tocainide (75 microM, 10 +/- 5 msec) and S-(+)-tocainide (150 microM, 4 +/- 1 msec). R-(-)-Tocainide was more potent than the S-(+)-tocainide in prolonging conduction time (p less than 0.05). This stereospecific prolongation of conduction time suggested a stereospecific interaction with the sodium channel. The affinities of the enantiomers for the channel were measured with a radioligand binding assay using [3H]batrachotoxinin benzoate and freshly isolated cardiac myocytes. Both enantiomers inhibited [3H]batrachotoxin benzoate binding, but the IC50 (+/- SD) values were different: R-(-)-tocainide 184 +/- 8 microM; S-(+)-tocainide, 546 +/- 37 microM (p less than 0.003). Tocainide isomers are stereospecific in terms of prolonging conduction time and in binding to the sodium channel. The stereospecific electrophysiologic effects of tocainide may result from binding to a receptor associated with the cardiac sodium channel.

Animals↗

PubMed1988

Determinants of stereospecific binding of type I antiarrhythmic drugs to cardiac sodium channels.

The determinants of stereospecific binding of type I antiarrhythmic drugs to specific sites associated with the sodium channel were assessed using rat cardiac myocytes. The asymmetric carbon atoms of stereoisomers may be located at two sites within type I drugs. The structure of these drugs can be schematically illustrated as Aromatic-C1-link-C2-Amine, where C1 and C2 represent potentially asymmetric carbon atoms. We used enantiomeric pairs with either C1 or C2 asymmetric carbon atoms to assess the importance of conformation at these sites to drug binding. The affinities of enantiomers of seven sodium channel blockers were measured with a radioligand binding assay using [3H]batrachotoxinin benzoate [( 3H]BTXB) and freshly isolated cardiac myocytes. The enantiomers inhibited [3H]BTXB binding in a dose-dependent manner, with a mean Hill number of 1.0 +/- 0.1. The ratios of affinities [IC50 of (+)-isomer/IC50 of (-)-isomer] were, for the C1 pairs: quinidine, 0.29; cinchonidine, 0.55; disopyramide, 1.11; RAC 109, 5.33; and for C2 pairs: flecainide, 1.03; mexiletine, 2.15; tocainide, 3.01. The stereospecific differences in drug binding suggest that the orientations of both the aromatic and the amine groups to the rest of the drug molecule are important determinants of drug binding to the cardiac sodium channel. This also suggests the presence of at least two stereospecific domains within the binding sites for type I antiarrhythmic drugs.

Animals↗

PubMed1988

Procainamide in vivo modulates suppressor T lymphocyte activity.

Autoantibodies to histone and denatured DNA have been found in 80% of patients treated with procainamide. Of these 10 to 20% will eventually develop a Systemic Lupus Erythematosus-like syndrome. Although the mechanism by which procainamide exerts its effect is unknown, in vitro studies suggest that procainamide may inhibit suppressor T cell activity. We have studied the immune function of 18 patients receiving a two hour infusion of procainamide during transvenous catheter electrophysiologic studies. There was no difference between pre and post infusion samples with respect to T and B cell mitogenesis or pokeweed mitogen-induced immunoglobulin secretion. However, in seventeen of eighteen patients, there was a marked decrease in Concanavalin A-inducible suppressor cell activity. This decrease appeared to be related to the amount of procainamide infused as high dose samples showed less suppressor activity than low dose samples. Thus the data show that procainamide, when given in vivo, leads to a rapid and dose dependent decrease in suppressor cell activity.

Adult↗