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Liquid chromatographic determination of mexiletine and tocainide in human plasma with fluorescence detection after reaction with a modified o-phthalaldehyde reagent.

A liquid chromatographic procedure for the determination of mexiletine or tocainide in human plasma is described. Plasma, after the addition of a homologue of mexiletine or of tocainide, is extracted with dichloromethane. The extract is evaporated and reconstituted in a non-aqueous o-phthalaldehyde--mercaptoethanol reagent. An aliquot of the solution is chromatographed on a reversed-phase Ultrasphere-octyl column. The peaks are detected by fluorescence (lambda ex = 350 nm and lambda em = 445 nm). The fluorescent derivatives of the drugs and internal standards are stable at room temperature and give symmetrical single peaks. Use of fluorescamine as a reagent to prepare fluorescent derivatives of mexiletine and tocainide prior to chromatography is also evaluated.

Chromatography, Liquid↗

Electron-capture gas-liquid chromatographic determination of tocainide in biological fluids using fused silica capillary columns.

Gas-liquid chromatography using capillary columns and electron-capture detection has been employed for the determination of a new antiarrhythmic drug, tocainide, in rat plasma and urine. The drug is extracted from a basified solution along with an internal standard, monoethylglycine xylidide, and subsequently reacted with heptafluorobutyric anhydride. The 50 m x 0.2 mm fused silica capillary column was coated in the laboratory with Carbowax 20M. Linearity of detector response was established in the range of 50-1000 ng of tocainide hydrochloride per 100 microliter of plasma or urine. This represented 14-270 pg of the free base at the detector, using a split ratio of 1:25 and an injection volume of 2 microliter. The derivatization method and chromatographic assay are well suited for monitoring of plasma or urine samples. The applicability of the method is demonstrated by the analysis of rat plasma collected over a period of 7 h after intravenous administration of 20 mg/kg of tocainide hydrochloride.

Animals↗

Mexiletine and tocainide: does response to one predict response to the other?

Mexiletine and tocainide were administered to 79 patients to determine whether the response to one of these drugs would predict the effect of the other. In 57 patients, the two agents were evaluated noninvasively with monitoring and exercise testing, and efficacy was judged by the suppression of spontaneous ventricular arrhythmia. In the remaining 22 patients, electrophysiologic testing was performed and efficacy was defined as the inability to induce more than two repetitive ventricular premature beats. An equal number of patients responded to mexiletine and tocainide (38 versus 39%). However, in only 42 patients (53%) were the results concordant. There was no difference in concordance when the results were analyzed by method of drug evaluation, left ventricular ejection fraction or etiology of presenting arrhythmia. It is concluded that mexiletine and tocainide have different clinical effects and must be evaluated individually.

Adult↗

Possible proarrhythmic effects of tocainide in dilated cardiomyopathy.

A patient with a dilated cardiomyopathy experienced a cardiac arrest when taking tocainide for asymptomatic nonsustained ventricular tachycardia. After successful resuscitation from ventricular fibrillation and exclusion of a myocardial infarction, an electrophysiological evaluation was performed. Drug-free study #1 revealed no induction of ventricular tachycardia. A tocainide study revealed induction of sustained monomorphic ventricular tachycardia. Drug-free study #2 revealed induction of nonsustained ventricular tachycardia. This report illustrates a possible proarrhythmic effect of tocainide.

Cardiomyopathy, Dilated↗

Antiarrhythmic effects of tocainide and lidocaine in dogs.

To compare the antiarrhythmic activities of tocainide and lidocaine in dogs, a protocol was designed where the drug plasma levels were increased stepwise. This was achieved by computerizing bolus doses and infusion rates, using pharmacokinetic equations with constants, derived from previous experiments in similar animals. In conscious coronary-ligated dogs with ischaemic arrhythmias both compounds were active, causing a 50% reduction in VPB's at plasma concentrations of 5.0 micrograms/ml (tocainide) and 3.5 micrograms/ml (lidocaine). "Clearing" of catecholamine-induced arrhythmias was not obtained in any of six dogs given tocainide and only in two out of six dogs given lidocaine.

Animals↗

The antifibrillatory potency of aprindine, mexiletine, tocainide and lignocaine compared on Langendorff-perfused hearts of rabbits and guinea-pigs.

The effectiveness of three new antiarrhythmic drugs, aprindine, mexiletine and tocainide in elevating ventricular fibrillation threshold measured in the Langendorff-perfused rabbit heart and in protecting against ouabain-induced arrhythmias in the Langendorff-perfused guinea-pig heart has been compared with that of lignocaine. All these drugs have produced a significant rise in the threshold but quantitatively mexiletine was about equal to, tocainide five times less and aprindine thirty-eight times more potent than lignocaine in this effect. Aprindine differed from the other three drugs in that it had a slow onset of action and its effect was not entirely removed upon reperfusion with the drug-free solution. Only aprindine and mexiletine provided complete protection against ouabain-induced ventricular fibrillation while 3 of 6 and 4 of 6 hearts fibrillated in the presence of lignocaine or tocainide respectively.

Anilides↗

Optimal requirements for high affinity and use-dependent block of skeletal muscle sodium channel by N-benzyl analogs of tocainide-like compounds.

Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (INa) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position alpha [N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide (To5)] or beta [N-(2,6-dimethylphenyl)pyrrolidine-3-carboxamide (To9)] in a proline-like cycle and/or linked to a lipophilic benzyl moiety as in N-benzyl-tocainide (Benzyl-Toc), 1-benzyl-To5 (Benzyl-To5), and 1-benzyl-To9 (Benzyl-To9). INa were elicited with pulses to -20 mV from different holding potentials (-140, -100, and -70 mV) and stimulation frequencies (2 and 10 Hz). All compounds were voltage-dependent and use-dependent channel blockers. The presence of a proline-like cycle increased the potency; i.e., To5 was 3- and 10-fold more effective than Toc in blocking INa at the holding potential of -140 and -70 mV, respectively. The benzyl group on the amine further enhanced drug effectiveness with the following scale: Benzyl-To9 >/= Benzyl-Toc > Benzyl-To5. At a holding potential of -100 mV and 10-Hz stimulation, Benzyl-To9 blocked INa with a half-maximal concentration of 0.5 microM, being 60 and 400 times more potent than To9 and Toc, respectively. The similar effectiveness of Benzyl-Toc and Benzyl-To9 was paralleled by a similar spatial arrangement by equilibrium geometry modeling. In addition, the latter had a higher pKa value that probably contributed to a slow kinetic during its high use-dependent behavior. Benzyl-To5 had its lowest energy level at a more folded conformation that justifies the less favorable profile among the N-benzylated analogs. The new compounds are the most potent tocainide-like sodium channel blockers so far described and have high therapeutic potentials.

Animals↗

Tocainide and tinnitus. Clinical effect and site of action.

Tocainide, an amine analogue of lidocaine, which can be taken orally, was tested on 9 patients with severe tinnitus. 6 patients responded to the drug. In 4 patients the effect ceased after about 2 weeks despite continuous medication. 2 patients are still on this medication after more than 2 years. The binding of tocainide to melanin was analysed in vitro and in vivo in rats. It was concluded that the effect of tocainide on tinnitus is mediated by a peripheral mechanism possibly related to the accumulation on inner ear melanin.

Animals↗

A seizure induced by concurrent lidocaine-tocainide therapy--is it just a case of additive toxicity?

A 79-year-old white male was admitted to the hospital for treatment of a right-lower-lobe pneumonia. His past medical history included: mild congestive heart failure, asymptomatic ventricular tachycardia, and ethanol abuse. He was initially treated with furosemide for his heart failure, lidocaine for his arrhythmias, and Bactrim for his pneumonia. On day 13 of hospitalization he experienced a tonic-clonic seizure during the time he was being converted from lidocaine to tocainide. At the time of the seizure both tocainide and lidocaine were well within their respective therapeutic ranges. Since the seizure, the patient has tolerated treatment with each drug separately, and at serum concentrations similar to those preceding the seizure, without neurological complications, indicating the possibility of a tocainide-lidocaine induced seizure.

Aged↗

Tocainide: a severe adverse reaction.

Tocainide is a primary analog of lidocaine with antiarrhythmic properties used to treat ventricular rhythm disorders. A 76-year-old man with benign paroxysmal premature ventricular contractions was treated with tocainide and developed a generalized maculopapular lupoid eruption, bleeding from the lips and gingivae, vertigo, gross tremors of the extremities, fever, and short-term memory loss, which required hospitalization. The patient recovered slowly over three months with no permanent sequelae after discontinuing the drug and receiving rigorous supportive care. His excellent physical status and absence of concomitant illness contributed to an uneventful recovery. Tocainide is a potent cardioactive drug with a long biological half-life and should be used with caution.

Aged↗

Auditory brainstem-evoked response after single-dose injection of lidocaine and tocainide.

In order to investigate the effects of tocainide and lidocaine on the auditory brainstem-evoked response (ABR), 10 healthy male subjects 20-40 years of age were given a single i.v. dose of 250 mg of tocainide and of 100 mg of lidocaine on separate occasions in a trial with a double-blind cross-over design. Neither drug produced any significant change in absolute or interpeak intervals, or in latency-intensity functions (wave V). The results fail to indicate that lidocaine and tocainide in the doses given influence the synaptic transmission and conduction velocity in the cochlear nerve or in the brainstem.

Adult↗

Tocainide: a new oral antiarrhythmic agent.

Tocainide, a newly released class 1B antiarrhythmic agent, has membrane stabilizing and electrophysiologic characteristics similar to those of lidocaine, but it can be prescribed for oral administration. Investigational studies in both animals and humans have shown tocainide's effectiveness for the treatment of ventricular arrhythmias in chronic and acute settings. The drug has nearly 100% bioavailability after oral administration and an effective half-life of 9 to 37 hours (mean, 15 hours). Antiarrhythmic efficacy is similar to that of other class I medications currently in use. Serious side effects most frequently involve the central nervous or gastrointestinal system and occur in 10% to 20% of patients. Tocainide has minimal negative inotropic effects and a tendency to shorten effective refractory periods.

Administration, Oral↗

[Interactions of quinidine and propranolol with mexiletine, encainide, flecainide and tocainide].

Blood serum quinidine sulphate and propranolol levels have been measured in patients with cardiac arrhythmias treated simultaneously with mexiletine, flecainide, encainide and tocainide. It was found that mexiletine and encainide increase quinidine sulphate serum concentrations. Propranolol serum concentrations have been increased by mexiletine, encainide flecainide, and tocainide. Flecainide ant tocainide have not changed quinidine sulphate serum concentrations.

Adult↗

[Combination of sotalol with the class I B substances mexiletine or tocainide in complex ventricular extrasystole].

In 34 patients with ventricular tachyarrhythmias the effect of the antiarrhythmic therapy of sotalol (160-320 mg p.o.) in combination with the type-I-B-agent mexiletine (600-800 mg p.o.) or tocainide (800-1200 mg p.o.) was studied by Holter monitoring. In all patients 2.2 +/- 1.1 drugs trials had failed, including amiodarone in 8 patients and beta blocking substances in 15 patients. The combination of sotalol with mexiletine or tocainide reduced ventricular ectopic beats by 79% and complex ventricular arrhythmias (pairs and salvoes) by 85%. A significant reduction of ventricular ectopic beats (greater than 80%) was reached in 74% of the patients, of pairs and salvoes (greater than 90%) in 79%. There was no difference in the antiarrhythmic efficacy between the combination of sotalol/mexiletine and sotalol/tocainide. Intervals of the resting ECG or laboratory values did not change significantly. In 5 patients with sotalol/tocainide and 1 patient with sotalol/mexiletine, side effects were observed which necessitated discontinuation of the treatment. The results show that sotalol, in combination with mexiletine or tocainide, has a potent antiarrhythmic effect in patients with otherwise drug-refractory ventricular arrhythmias.

Adult↗

Assay of free and total tocainide by high performance liquid chromatography (HPLC) with ultraviolet (UV) detection.

A rapid high performance liquid chromatographic (HPLC) method for the determination of tocainide, using N-(2,6-dimethylphenyl)-2-amino-butanimide as an internal standard, was developed. A methylene chloride extraction involving salting out at pH 9.0 was employed. An 85:15 mixture of 0.025M monobasic potassium phosphate at pH 3.0 and acetonitrile was used as the mobile phase. The separation and quantitative analysis of tocainide was performed on a mixed phase column with a 1.0-mL/min flow rate and detection at 210 nm. Separation of tocainide from some of its metabolites required the use of heptane sulfonic acid as an ion-pairing reagent. For the free-drug assay, the specimen was centrifuged through an Amicon Centrifree filter before being processed.

Anti-Arrhythmia Agents↗

Treatment of tinnitus with lidocaine and tocainide.

The efficacy of lidocaine and tocainide in the rational treatment of tinnitus aurium was evaluated in a double-blind randomized cross over study against saline as placebo. Forty patients with severe long lasting (more than six months) tinnitus and sensorineural hearing loss were included in the study. In 24 patients treated with lidocaine (loading dose: 3 mg/kg body weight in 10 min; maintenance dose: 1 mg/kg in 20 min), in 19 patients treated with tocainide infusion (750 mg in 30 min), and 10 patients treated with tocainide orally (400 to 2,400 mg per day), tinnitus intensity was reduced by more than 50%, compared with placebo (designated as a positive result). In some patients, ABRs showed prolongation of interpeak latencies (IPLs) indicating a retrochlear site of drug action. This hypothesis is supported by our own animal experiments with lidocaine in rabbits. IPLs showed a dose dependent reversible prolongation without hearing loss.

Administration, Oral↗

Influence of dietary fat on the pharmacodynamics of quinidine, procainamide and tocainide in isolated perfused rabbit hearts.

We have reported previously that propafenone decreased ventricular excitability and prolonged ventricular conduction time in hearts from rabbits treated with a lard diet compared to those from rabbits treated with a safflower oil diet. We hypothesized that these effects might be modulated by the lipid solubility of the drug. Accordingly, we studied the effects of dietary fat on the pharmacodynamics of the hydrophilic drugs, procainamide and tocainide, and the lipophilic drug, quinidine. Weanling rabbits were fed diets of 10% w/w lard or safflower oil for 40 days. Differences in electrophysiological variables were compared at base line and during drug perfusion. The linoleic acid content of isolated sarcolemma was significantly higher in the safflower oil group (31.1 +/- 5.6%) than in the lard group (18.8 +/- 3.9%, P < .001). During quinidine (3 microM) perfusion, the threshold current was significantly greater in the lard group (0.44 +/- 0.18 mA) compared to the safflower oil group (0.24 +/- 0.11 mA, P < .05). During procainamide and tocainide perfusion, the threshold current was similar in the lard and safflower oil groups. During quinidine perfusion, greater prolongation of the endocardial monophasic action potential duration was observed in the safflower oil group (217 +/- 15 msec) compared to the lard group (196 +/- 24 msec, P < .05). Procainamide and tocainide effects on monophasic action potential duration were similar in the lard and safflower oil groups. Thus, dietary fat modulates the effects of the lipophilic drug quinidine on ventricular excitability and repolarization.

Action Potentials↗

[Anti-arrhythmic effect of tocainide (lidocaine congener) on ventricular arrhythmias (author's transl)].

The antiarrhythmic effect of tocainide, an amine analogue of lidocaine, was tested in the course of a double-blind trial on 12 patients with ventricular arrhythmias. Daily dose was 400 or 600 mg every eight hours. In all tested patients the frequency of ventricular extrasystoles, analysed by means of ambulatory 24-hour ECG monitoring, decreased by an average of 70%. In four of nine patients the severity of the ventricular extrasystoles (Lown's classification) was improved by at least one functional class. There was no correlation between the anti-arrhythmic effect and the plasma level of tocainide, which was between 4.1 and 9.7 micrograms/ml. Four patients had side effects in the form of CNS symptoms, but the drug did not have to be discontinued. Tocainide is an orally effective antiarrhythmic drug, an alternative in the treatment of ventricular arrhythmias.

Adult↗