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PubMed1976

Clinical efficacy and pharmacokinetics of a new orally effective antiarrhythmic, tocainide.

Tocainide, a new oral antiarrhythmic agent, was studied in man in a short-term protocol designed to evaluate the efficacy, kinetics, and toxicity of this compound. Premature ventricular contractions (PVCs) were suppressed by less than 70% in 11 of 15 patients compared with pre-drug placebo controls. For these 11 responders, there was an average PVC reduction of 91% +/- 10 (range 70 to 100%) at tocainide doses not associated with side effects. Mild transient central nervous system toxicity was observed in some patients near the time of peak concentrations during the highest dose administered. The drug was found to have linear kinetics over the dose range studied and a plasma half-life of 13.5 +/- 2 hours. Plasma concentration-response curves indicate antiarrhythmic activity over all plasma concentrations, with 70% PVC reduction above 6.0 mug/ml. This study suggests that tocainide is a safe and effective antiarrhythmic agent during short-term administration and is worthy of further clinical trials.

Administration, Oral↗
PubMed1977

Suppression of ventricular ectopic depolarizations by tocainide.

In a previous clinical study we demonstrated that tocainide is effective in the suppression of ventricular ectopic depolarizations (VEDs) after single oral doses. This information provided the basis for evaluating this drug's antiarrhythmic efficacy after multiple dose administration according to a loading-maintenance regimen. Twelve patients with stable VEDs were given loading doses of tocainide (400-600 mg) with maintenance doses every 12 hours. Every 48 hours the dose was increased until either arrhythmia suppression to less than 25% of VED frequency during placebo administration or side effects occurred. Computer analysis of 12-hr telemetric ECGs taken 24-36 hr after each dosage increment documented effective suppression (76-95%) in 8 of 12 patients. Those subjects demonstrating suppression were randomly assigned to a cross-over study of placebo or active drug at the dosage found effective in the dose-ranging phase. Dosages for the cross-over stage ranged from 400 to 1100 mg every 12 hours. Comparison of the two five-day periods documented suppression in these patients (mean +/- SE = 83.3 +/- 4%). No serious side effects or undue drug accumulation occurred during the study. The data indicate that tocainide can effectively suppress VEDs for 8-12 hours in many patients and that continuous suppression could be possible on an 8-12 hr dosage regimen.

Anti-Arrhythmia Agents↗
PubMed1978

Clinical electrophysiologic effects of tocainide.

The electrophysiologic properties of tocainide were evaluated by electrophysiologic studies in 11 patients before, during and after a constant intravenous infusion of the drug for 15 minutes. Peak plasma tocainide concentrations averaged 11.0 +/- 1.7 microgram/ml (SEM), range 3.7 to 22.7. AH, HV, QRS, QTc and RR intervals were measured every 5 minutes during sinus and atrial-paced rhythms and showed small changes which were not statistically significant for HV and QRS. Mild shortening of RR was significant (P less than 0.05) at 15 minutes only. AH tended to increase slightly for spontaneous (but not paced) rhythm, becoming significant at 15 minutes only (P less than 0.05). QTc decreased slightly, a change which was significant (P less than 0.05) for paced but not spontaneous rhythm. A progressive rise in mean arterial pressure occurred during infusion and persisted through 30 minutes (P less than 0.001). Comparison of electrophysiologic studies at 0 and 30 minutes showed decreased in mean effective refractory periods of atrium, A-V node, and right ventricle by 17, 22, and 23 msec, respectively (P less than 0.05, 0.01, 0.01). Functional refractory period of the A-V node showed an average decrease which was not significant. Sinus node recovery time and Wenckebach cycle length were unchanged. The drug was well tolerated in all 11 patients. Hypotension in a twelfth patient may or may not have been drug related. These results obtained at therapeutic plasma concentrations suggest qualitative similarities between the conduction system effects of tocainide and those published for lidocaine.

Aged↗
PubMed1978

The hemodynamic effects of intravenous tocainide in patients with heart disease.

In order to evaluate its hemodynamic actions, tocainide, a new orally effective antiarrhythmic drug, was given intravenously over a 15 minute period to 12 patients with compensated left ventricular dysfunction. Doses were 0.5 (4 patients) or 0.75 (8 patients) mg/kg/min. Hemodynamics and drug plasma concentrations were measured at the end and 15 minutes after the end of the infusion. Tocainide infusion produced small but statistically significant increases in the pulmonary and systemic vascular resistance, aortic and pulmonary arterial pressure, and left and right ventricular end-diastolic pressure. There was no significant change in left ventricular dp/dt, heart rate, or cardiac index. In patients with compensated left ventricular dysfunction, tocainide produces a small rise in vascular resistance and arterial pressure. Overall cardiac function is maintained with a small increase in left ventricular end-diastolic pressure.

Adult↗
PubMedDate not supplied

Chemistry, pharmacology, antiarrhythmic efficacy and adverse effects of tocainide hydrochloride, an orally active structural analog of lidocaine.

Tocainide is an orally effective antiarrhythmic agent, structurally and pharmacologically similar to lidocaine. It appears to be free of marked negative hemodynamic or electrophysiologic effects in patients with heart disease, despite a high frequency of minor and often transient central nervous system and gastrointestinal side effects. Tocainide is effective in suppressing ventricular arrhythmias in a variety of settings. This agent may be a useful addition to our antiarrhythmic armamentarium.

Animals↗
PubMed1991

Tocainide therapy in muscle cramps and spasms due to neuromuscular disease.

Significant improvement in symptoms of disabling cramps and muscle spasms was obtained in 9 patients with motor neuron diseases, tetany, and myotonic disorders who were treated with tocainide, a lidocaine analog. No significant side effects were observed except for light-headedness and fatigue in 1 patient, who also showed slight prolongation of intraventricular conduction time. Tocainide is useful in treating disabling muscle spasms and cramps associated with conditions characterized by neuromuscular irritability. This effect is probably based on stabilization of the membrane potential at various levels (motor neurons, peripheral nerve, or muscle fiber membrane).

Adult↗
PubMed1985

Antimyotonic therapy with tocainide under ECG control in the myotonic dystrophy of Curschmann-Steinert.

Ten patients suffering from advanced myotonic dystrophy with severe myotonic symptoms were treated with 800-1200 mg/day of the anti-arrhythmic drug tocainide (Xylotocan). All patients reported a marked subjective improvement of myotonia, which was confirmed by objective tests. Except for a slight QT-prolongation in one patient, the ECG was not significantly altered by the treatment. Twenty-four-hour ECG after treatment disclosed that pre-existing ventricular arrhythmia disappeared in three cases. The occurrence of complex ventricular arrhythmia in two patients under treatment was not necessarily due to specific effects of the drug but might be explained by the high spontaneous variability of rhythm disorders. In these patients suffering from myotonic dystrophy with typical cardiomyopathy no deleterious effects of the drug were observed, especially no cardiac arrhythmias which would have necessitated interruption of treatment. Therefore, the authors recommend symptomatic therapy with tocainide for myotonia and paramyotonia congenita, as well as in myotonic dystrophy patients suffering from marked myotonic stiffness. ECG and 24-h ECG should be carefully recorded as necessary in any treatment with anti-arrhythmic drugs.

Adult↗
PubMed1983

Clinical profiles of newer class I antiarrhythmic agents--tocainide, mexiletine, encainide, flecainide and lorcainide.

New class I antiarrhythmic drugs differ in potency, adverse effects and pharmacokinetics. Encainide and flecainide can totally suppress arrhythmias in some patients, but arrhythmia induction can also occur. At effective dose levels, neurologic and gastrointestinal adverse effects are uncommon. Flecainide pharmacokinetics are suitable for oral use but encainide disposition is complex with variable bioavailability and active metabolites that contribute substantially to activity. Lorcainide is also potent, but neurologic adverse effects are common and dose-dependent bioavailability and an active metabolite may complicate long-term oral therapy. Tocainide and mexiletine can suppress arrhythmias in acute myocardial infarction, during convalescence from myocardial infarction and in patients with arrhythmias resistant to other therapy. Dose-related neurologic and gastrointestinal adverse effects are common, but hemodynamic effects are minor and arrhythmia induction is rare. Tocainide disposition is reasonably predictable and stable in patients, but mexiletine disposition is less so because of variation in distribution and clearance. Although all of the newer agents have some disadvantages, their availability should increase the likelihood of success in the high-risk patient.

Administration, Oral↗
PubMed1983

Comparison of three beta-amino anilides: IQB-M-81, lidocaine and tocainide, on isolated rat atria.

The effects of a new beta-amino anilide, IQB-M-81, on electrical and mechanical activity of isolated rat atria were studied and compared with those of lidocaine and tocainide. In spontaneously beating right atria IQB-M-81 produced a dose-dependent decrease in rate, contractile force and maximum following frequency and prolonged the sinus node recovery time and the effective refractory period of atrial fibers. The negative inotropic effect was not modified by pretreating the atria with atropine or practolol. In isolated right atria IQB-M-81 did not block the positive chronotropic and inotropic responses to isoprenaline but shifted the dose-response curve to the right. IQB-M-81 and lidocaine, but not tocainide, reduced in a dose-dependent manner the slow contractions induced by isoprenaline in K-depolarized right atria. These results suggest that in contrast to other beta-amino anilides, IQB-M-81 exerted a negative chronotropic effect and that it presented a class I antiarrhythmic effect on isolated rat atria. A possible class IV antiarrhythmic effect is also discussed.

Animals↗
PubMed1988

Tocainide blocks Na currents by accumulation of inactivated Na channels.

The effect of tocainide on the voltage-dependent parameters of Na permeability was studied in voltage clamp experiments performed in single myelinated rat and frog nerve fibres. The main effect of tocainide was a potential- and frequency-dependent block of Na channels in both species. There was no shift to the voltage-dependent parameters of steady state Na activation (m infinity) or of the time constants of Na activation (tau m) and inactivation (tau h) along the potential axis.

Animals↗
PubMed1985

The effect of systemic tocainide, lidocaine and bupivacaine on nociception in the rat.

The analgesic properties of systemically administered tocainide, a primary amine congener of lidocaine with a longer duration of action, were examined in rats. Significant antinociception, as assayed on the hot-plate test, was observed after i.p. tocainide at doses below toxic levels. No antinociception was seen with non-toxic doses of lidocaine or bupivacaine.

Animals↗
PubMed1989

The effect of intravenous lidocaine, tocainide, and mexiletine on spontaneously active fibers originating in rat sciatic neuromas.

The effects of intravenously administered subanesthetic concentrations of lidocaine, tocainide, and mexiletine on spontaneously active fibers (SAFs) originating in 7-day-old rat sciatic neuromas were studied. Control injections of normal saline caused no decrease in SAF or discharge rate. Lidocaine and tocainide given in incremental doses of 5, 10, 15, 20 and up to 25 mg/kg caused nearly all observed SAFs to stop firing. Mexiletine given in doses of 3, 5, 7, 10 and up to 15 mg/kg showed similar results at lower doses. All agents decreased the sensitivity of SAF to mechanical stimulation. No conduction blockade occurred at these doses of intravenously administered local anesthetics. The demonstrated reduction in firing rate of SAF may explain the pain relief observed in clinical trials of these orally available agents.

Action Potentials↗
PubMed1993

Relationship between negative inotropic and chronotropic effects of tocainide and five class I antiarrhythmic drugs in the coronary perfused guinea-pig heart.

1. The relationship between the negative inotropic and chronotropic effects of tocainide and 5 other class I antiarrhythmic drugs was evaluated in Langendorff-perfused guinea-pig hearts. 2. All 6 drugs reduced the contractile force (Fc) and the heart rate (HR) of spontaneously beating guinea-pig hearts in a dose-dependent manner. The order of crude negative inotropic potency was: quinidine (Qui) = aprinidine (Apr) > mexiletine (Mex) > lidocaine (Lid) > disopyramide (Dis) > tocainide (Toc); and the order of negative chronotropic effect was: Apr > Qui > Mex > Dis > Lid > Toc. 3. The order of the negative inotropic potency relative to chronotropic effect (expressed as a ratio: ID50 for Fc/ID50 for HR) was Lid > Qui > Dis > Toc > Mex > Apr (n = 6). 4. For heart electrically stimulated at a constant rate, the order of crude negative inotropic potency was: Apr > Qui > Mex > Dis > Lid > Toc, and the order of negative inotropic potency (determined by the ratio: ID50 for Fc in driven heart/ID50 for spontaneously beating HR) was: Mex > Apr > Toc > Dis > Qui > Lid (n = 6). 5. There was a significant influence of negative chronotropic effect on the inotropic potency and the order was: Lid > Qui > Dis > Toc > Apr > Mex. The potency of various drugs is clinically useful in the choice of drugs when considering cardiac function and heart rate.

Animals↗
PubMed2004

New potent mexiletine and tocainide analogues evaluated in vivo and in vitro as antimyotonic agents on the myotonic ADR mouse.

The antimyotonic activity of chiral derivatives of mexiletine and tocainide, selected as potent use-dependent blockers of skeletal muscle sodium channels, was evaluated in vivo acutely in myotonic ADR mice. The compounds had either aromatic (Me4 and Me6) or branched isopropyl groups (Me5 and To1) on the asymmetric centre, or had this latter one methylene apart from the amino group (Me2). Therapeutic doses of mexiletine (5-10 mg/kg) and tocainide (7-20 mg/kg) significantly reduced the long time of righting reflex (TRR), typical of ADR mice. Me4, Me5 and Me6 were 2-fold more potent than mexiletine. To1 fully normalised the TRR at 7 mg/kg. The electromyographic analysis confirmed a muscle-based activity for drug effectiveness on TRR. All the compounds reduced the myotonic hyperexcitability of intercostal muscle fibres when tested in vitro by current-clamp recordings, with a potency correlated with their action on sodium channels. On stimulus-evoked firing, the isopropyl analogues were 2-4-fold more potent than parent compounds, while the aromatic analogues were about 10-fold more potent than mexiletine. Patch-clamp recordings confirmed a normal-like pharmacological sensitivity of sodium channels of native ADR muscle fibres. Finally, the in vivo antimyotonic activity is due to the block of sodium channels and divergences with in vitro potency can be related to structure-based changes in drug pharmacokinetics.

Action Potentials↗
PubMed2003

Enantiomeric separation of tocainide and its analogues on an optically active crown ether-based stationary phase by liquid chromatography.

Tocainide and its 14 analogues were resolved on a chiral stationary phase (CSP) based on (3,3'-diphenyl-1,1'-binaphthyl)-20-crown-6 covalently bonded to silica gel. The resolution was quite good, the separation (alpha) and resolution factors (Rs) being 1.84-15.32 and 1.34-13.78, respectively. Especially, the result for the resolution of tocainide on the CSP turns out to be the best one among others reported so far. The chromatographic resolution behaviors were demonstrated to be dependent on the content and the type of organic and acidic modifiers and the ammonium acetate concentration in aqueous mobile phase.

Acetates↗
PubMed1987

New antiarrhythmic drugs: tocainide, mexiletine, flecainide, encainide, and amiodarone.

Tocainide, mexiletine, flecainide, encainide, and amiodarone are antiarrhythmic agents that have recently been approved by the Food and Drug Administration for general use in the treatment of ventricular arrhythmias. All five agents are effective in the treatment of patients with ventricular arrhythmias, whereas encainide, flecainide, and amiodarone are also useful in patients with supraventricular arrhythmias and the Wolff-Parkinson-White syndrome (although not yet approved for these indications). Tocainide and mexiletine are similar to lidocaine and are as effective as quinidine in patients with ventricular arrhythmias. Encainide and flecainide are superior to quinidine for the control of ventricular ectopic beats and as effective as quinidine for patients with ventricular tachycardia. Amiodarone is the most effective agent available for treating patients with ventricular tachycardia, but it is also the most toxic antiarrhythmic agent and should be used only when other antiarrhythmic drugs have not been effective or tolerated.

Administration, Oral↗
PubMed1983

Gas--liquid chromatographic resolution and assay of tocainide enantiomers using a chiral capillary column and study of their selective disposition in man.

Tocainide is a new antiarrhythmic agent that is used clinically as the racemic mixture. In order to study the disposition of the individual enantiomers in man, a gas--liquid chromatographic assay was developed based on the resolution of the R-(-)- and S-(+)-enantiomers as their heptafluorobutyryl derivatives on a capillary column coated with a chiral stationary phase. Two healthy male volunteers ingested an oral solution dose of racemic tocainide hydrochloride at a dose of 3 mg/kg and plasma and urine were collected at intervals for up to 54 h. Analysis of the plasma samples revealed a stereoselective disappearance of the R-(-)-enantiomer, such that the apparent half-life for the S-(+)- and R-(-)-enantiomers were 25.6 and 20.5 h, respectively in one subject and 11.1 and 9.0 h in the second subject. Similar relationships were observed in urine, where the ratio of the S-(+)- to R-(-)-enantiomers varied from 0.98 in 1 h to 3.03 in the 54-h samples in one subject over the same time period.

Adult↗
PubMed1984

The clinical pharmacology of lidocaine congeners--review of encainide, flecainide, lorcainide and tocainide.

Among the newer antiarrhythmic drugs currently being evaluated are the four so-called lidocaine congeners, encainide, flecainide, lorcainide and tocainide. A knowledge of the pharmacokinetic properties of these agents may help to distinguish between them and may also be important for rational patient prescribing. Encainide and lorcainide both undergo predominantly hepatic elimination: both appear to form metabolites which have antiarrhythmic activity of their own and which have longer elimination half-lives than the parent compounds, resulting in accumulation with chronic administration. Flecainide and tocainide are cleared mainly by the kidneys, do not have active metabolites and have long elimination half-lives. All of the drugs have significant antiarrhythmic activity and this is proportionate to the plasma concentration of either the drug alone or combined with the active metabolites. Comparative effectiveness between the drugs has not been established. In general, all four drugs have only minor adverse effects, principally gastrointestinal or neurological, which may disappear with small dose reductions. However, cardiac effects can also occur and rarely pro-arrhythmic effects have been described, particularly with encainide and flecainide. All four drugs are suitable for long-term administration on a twice-daily basis.

Anilides↗