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PubMed1982

Tocainide for refractory symptomatic ventricular arrhythmias.

Tocainide, an oral form of lidocaine, was employed in 120 patients with recurrent malignant ventricular arrhythmia refractory to conventional antiarrhythmic drugs. After discontinuation of all antiarrhythmic agents, patients underwent control studies including 48 hours of ambulatory electrocardiographic monitoring and maximal symptom-limited exercise testing. One hundred patients had frequent as well as repetitive ventricular premature beats whereas in 20 patients, because of infrequency of ectopic activity, invasive electrophysiologic studies were carried out to provoke a repetitive ventricular response. Tocainide therapy was begun at 1,200 mg daily and increased to 2,400 mg daily guided by drug efficacy and the occurrence of adverse effects. After 48 hours of treatment with a fixed dose, drug action was evaluated by repeat monitoring and exercise stress testing or electrophysiologic testing. Fifty-five patients (46 percent) responded to tocainide. The average daily dose of drug and peak blood levels were equivalent in responders and nonresponders. Adverse effects occurred in 42 patients (35 percent) and were primarily related to the central nervous system. Lidocaine predicted the response to tocainide in 78 percent of patients. Thirty-four patients were continued on long-term maintenance therapy. After an average follow-up period of 16 months (range 2 to 39), treatment with the drug was discontinued in nine patients. The remaining 25 patients have had no adverse effects and no recurrence of ventricular arrhythmia.

Adult↗
PubMed1988

Tocainide plus quinidine for treatment of ventricular arrhythmias.

Tocainide and quinidine were administered both as single agents and in combination to 14 patients with chronic ventricular arrhythmias. Therapy with tocainide was limited by the occurrence of dose-related adverse reactions in 8 patients, but could be titrated to a dose that was well-tolerated in 13 of 14 and effective in 2 of 13. The addition of quinidine gluconate to the tolerated dose of tocainide increased the number of patients with arrhythmia suppression from 2 to 6. After tocainide washout, quinidine alone suppressed arrhythmias in only 3 patients. Analysis of electrocardiogram intervals showed that the drugs had additive effects on the coupling interval of the sinus beat to the predominant ectopic beat, but exerted antagonistic effects on the corrected QT interval. These findings suggest that the combination may be clinically useful, exerting pharmacologic effects unlike either agent alone.

Aged↗
PubMed1986

Tocainide suppression of immune-complex-mediated dermal inflammation: comparison with prostaglandin E1.

Local anesthetic agents have been shown to alter a variety of polymorphonuclear leukocyte (PMN) functions and may be useful as anti-inflammatory agents. We compared the anti-inflammatory effects of therapeutic doses of the recently released local anesthetic-antiarrythmic drug tocainide to pharmacologic doses of prostaglandin E1 (PGE1) on immune-complex-mediated dermal inflammation in female Sprague-Dawley rats. Intense dermal inflammation was produced using a classic reverse passive Arthus reaction, and the inhibition of PMN accumulation in the subdermis was quantitated in biopsy samples taken 2.5 hr after the reaction was initiated and the drug was given. Using a light microscope with a counting grid, biopsy sections were randomly sampled in a blinded fashion and an inflammation index equal to the ratio of PMNs to fibroblasts was determined for each animal. The mean inflammation index in 10 animals given 25 mg of tocainide (mean serum level = 14.6 micrograms/ml) was 9.3 +/- 1.2 (+/- SEM), which was significantly less than the index of 17.7 +/- 2.5 in 10 control animals (P less than 0.025). Similarly, the five animals that received either 500 or 250 micrograms of PGE1 had a significantly reduced index, with the effect of 250 micrograms PGE1 comparable to the effect of the tocainide. These findings suggest that therapeutic levels of tocainide reduce the accumulation of PMNs in immune-complex-mediated dermal inflammation; thus, local anesthetic agents may be useful in the treatment of certain inflammatory disorders.

Alprostadil↗
PubMed1995

Assay of tocainide enantiomers in plasma by solid-phase extraction and indirect chiral high-performance liquid chromatography after derivatization with (-)-menthyl chloroformate.

A fast high-performance liquid chromatographic (HPLC) assay was developed for determination of tocainide enantiomers in plasma. Subsequent to solid-phase extraction of tocainide from plasma, homochiral derivatization with (-)-menthyl chloroformate enabled separation of the enantiomers by a conventional reversed-phase HPLC system. The detection was performed by UV absorption at 262 nm. An enantiomeric resolution of 1.0 was obtained. Linearity of the method was investigated and found to be good in the range from 1.0 to 20.0 micrograms/ml tocainide enantiomer and the limit of quantitation was 1.0 microgram/ml. The method was applied to a study of the distribution and elimination pharmacokinetics of tocainide enantiomers in the rabbit. No difference in distribution or elimination between the enantiomers was found nor did the enantiomers affect the disposition of one another when administered together as the racemate.

Animals↗
PubMed1984

Efficacy and safety of intravenous tocainide compared with intravenous lidocaine for acute ventricular arrhythmias immediately after cardiac surgery.

In this double-blind parallel study, 99 patients with acute ventricular tachyarrhythmias after open-heart surgery were given either tocainide (50 patients) or lidocaine (49 patients) intravenously as 2 bolus injections 15 minutes apart, plus a fixed-rate infusion that started at the first bolus. If needed, a third bolus was administered and simultaneously the infusion rate was doubled. The boluses and initial infusion rate for tocainide treatment were, respectively, 250, 250 and 125 mg and 1.04 mg/min, and for lidocaine treatment, 100, 50 and 50 mg and 2.08 mg/min. When efficacy was defined as 80% or greater reduction in single ventricular premature complexes (VPCs) or complete abolition of ventricular couplets or ventricular tachycardia, no difference in efficacy between the 2 treatments was found by bedside electrocardiographic monitoring. By computer analysis of 24-hour taped electrocardiograms and a regression analysis of the proportion of patients responding favorably to treatment, it was estimated that an 80% or greater reduction of single VPCs occurred in 55% of patients during tocainide treatment and in 48% of patients during lidocaine treatment; abolition of couplets occurred in 74% and 68% of patients, respectively; and abolition of ventricular tachycardia in 87% and 73% of patients, respectively. These treatment-related differences were different (p less than 0.004). Adverse reactions occurred in 5 patients (10%) given tocainide (hypotension in 4; junctional rhythm in 1 patient; and nausea-vomiting in 1) and led to discontinuation of treatment in 3 patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1986

Effects of tocainide on Purkinje fibers from normal and infarcted ventricular tissues.

The left anterior descending coronary artery was occluded in anesthetized dogs. Dogs were sacrificed after 24 hours and the experimental preparations, which included both normal and infarcted tissues, were dissected from the left ventricles. Effects of tocainide in concentrations of 15-40 mg/l on action potentials of Purkinje fibers from normal and infarcted zones were studied using conventional microelectrode techniques. In the normal zone cells, tocainide superfusion produced a significant decrease in maximum diastolic potential, action potential amplitude, action potential duration to 50% and 90% repolarization and the rate of phase O depolarization, and no significant change in effective and functional refractory periods. In the infarct zone cells, it produced a significant decrease in action potential amplitude and the rate of phase O depolarization, a significant increase in effective and functional refractory periods, and no significant changes in the other parameters. The unequal actions of tocainide resulted in selective depression of maximum diastolic potential and action potential duration to 50% repolarization in the normal cells only, reducing the disparity in these parameters between normal and infarcted tissues. Tocainide increased the refractoriness (ratio of effective refractory period to action potential duration) in both cell types but this change was greater in the infarct zone. This decreased disparity of membrane potential and repolarization combined with increased refractoriness may help to block the arrhythmias observed in infarcted preparations following closely coupled stimuli.

Animals↗
PubMed1999

Mechanism of inhibition of the Na current by tocainide in guinea-pig isolated ventricular cells.

Tocainide blocked the Na current (I(Na)) in ventricular myocytes in either a tonic or a phasic block manner, having a higher affinity for the inactivated state (K(di) = 18 microM) than for the rested state (Kd(rest) = 606 microM). The degree of phasic block was enhanced and the onset of phasic block was faster with an increase in pulse duration as well as at less-negative holding potential (HP). The recovery-time constant from the phasic block of I(Na) induced by tocainide was independent of either the HP or the removal of fast inactivation. After removal of fast inactivation, tocainide showed the pulse-duration dependency of phasic block but not the voltage dependency. These results suggest that tocainide could bind to the inactivated-state receptor through the hydrophilic pathway and leave the receptor through the hydrophobic pathway, producing the tonic and phasic block of I(Na).

Animals↗
PubMed2000

Synthesis of new 2,6-prolylxylidide analogues of tocainide as stereoselective blockers of voltage-gated Na(+) channels with increased potency and improved use-dependent activity.

A series of tocainide chiral analogues were designed, synthesized, and evaluated in vitro, in pure enantiomeric form, as use-dependent blockers of skeletal muscle sodium channels to better understand the structural requirements responsible for the antimyotonic activity. The voltage clamp recordings showed a remarkable increase of both potency and use-dependent behavior with the analogue N-(2, 6-dimethylphenyl)-2-pyrrolidinecarboxamide (1a). In fact (R)-1a was 5-fold more potent than (R)-tocainide in producing the tonic block, i.e., the reduction of peak sodium current in resting conditions after application of the compound, but it was 21-fold more potent in condition of high frequency of stimulation (phasic block). Furthermore, as opposite to tocainide, this compound was also stereoselective, (S)-1a being 2-3-fold less potent than (R)-1a. The introduction in 1a of a methyl group in place of the hydrogen bonded to either the aminic nitrogen atom [N-(2, 6-dimethylphenyl)-1-methyl-2-pyrrolidinecarboxamide (2a)] or the amidic nitrogen atom [N-(2, 6-dimethylphenyl)-N-methyl-2-pyrrolidinecarboxamide (3a)] led unexpectedly to an inversion of stereoselectivity, the (S)-enantiomers being 3-fold more potent than the (R)-ones. The comparison between eutomers showed that (S)-2a and (S)-3a are almost equieffective to (R)-1a in producing a tonic block, the half-maximal concentrations being about 100 microM; however, the use-dependent behavior was remarkably decreased by the presence of the methyl group: i.e., the gain of potency observed at high frequency of stimulation amounted to 3 and 1.6 times for 2a and 3a, respectively. The replacement of both hydrogens bonded to the aminic and amidic nitrogen atoms resulted in N-(2,6-dimethylphenyl)-N, 1-dimethyl-2-pyrrolidinecarboxamide (4a) in which the (S)-isomer was still twice as potent as the (R)-one, but the absolute potency and mostly the use-dependent behavior were strongly reduced, showing therefore no clear advantages with respect to tocainide. The use-dependent behavior, which plays a pivotal role for antimyotonic activity, is strongly reduced by the presence of methyl groups on the nitrogen atoms, likely for modification of pK(a) and/or for constraint of molecular conformation.

Animals↗
PubMed1986

The pharmacokinetics of R- and S-tocainide in patients with acute ventricular arrhythmias.

The pharmacokinetics of R(-) and S(+)- tocainide were studied in twelve patients requiring intravenous tocainide. In all patients, a progressive increase in the S(+):R(-) ratio was observed during the infusion. Mean +/- s.d. ratios increased from 1.03 +/- 0.05 at 2 min to 1.76 +/- 0.35 at 48.5 h. Data from eight patients were fitted to a two-compartment model and there was a significant difference (Wilcoxon matched-pairs test P less than 0.01) in the clearance estimates for the two enantiomers. The median values were: S(+)-tocainide = 6.25 l h-1 and R(-)-tocainide = 9.31 l h-1. There was no differences in V1 or Vss.

Acute Disease↗
PubMed1993

The effect of tocainide on theophylline metabolism.

The effect of 5 days of oral tocainide (400 mg every 8 h) on the kinetics of theophylline given as a single 5 mg kg-1 i.v. infusion over 30 min was investigated in eight healthy male nonsmokers. Treatment with tocainide decreased the plasma clearance of theophylline from 37.5 +/- 6.9 (mean +/- s.d.) to 33.7 +/- 5.0 ml kg-1 h-1 (difference -3.8, 95% CI, -1.7 to -5.9; P = 0.004) and increased its terminal elimination half-life from 9.7 +/- 2.5 to 10.4 +/- 2.1 h (difference 0.7, 95% CI, 0.2 to 1.2; P = 0.011). Tocainide decreased the formation clearances of 3-methylxanthine and 1-methyluric acid, but the formation clearance of 1,3-dimethyluric acid was unaltered. These data indicate that tocainide exerts a modest inhibitory effect on theophylline metabolism. The magnitude of this change is substantially smaller than that reported to be produced by mexiletine.

Adult↗
PubMed1985

A sequential double blind cross-over trial of tocainide hydrochloride in tinnitus.

A sequential double blind cross-over trial of tocainide hydrochloride, an oral analogue of lignocaine, is reported. The dosage of tocainide hydrochloride ranged from 200-600 mg daily. Of the 32 patients who completed the trial, 1 had complete relief and 2 had partial relief of their tinnitus whilst taking tocainide. An increased incidence of side-effects in patients taking tocainide was noted, in particular, headache, dizziness, nausea and skin rashes.

Adult↗
PubMed1986

Efficacy and safety of oral tocainide in refractory ventricular arrhythmia: a preliminary report on an open label study.

The preliminary data on efficacy and safety of oral tocainide in refractory ventricular dysrhythmia in 8 patients is described. Two patients died; one within 15 days and the other after 1750 days of continuous tocainide therapy. The cause of death in both patients was unclear. During initial administration and acute titration, oral tocainide was extremely effective in lidocaine-sensitive ventricular dysrhythmia and in patients with Q-T prolongation syndrome. Four out of 8 patients received tocainide in presence of left ventricular dysfunction and 2 out of 4 such patients died suddenly. Minor central nervous system side effects were seen in 2 patients and dermatologic adverse reaction was seen in one patient only.

Aged↗
PubMed1987

Mental changes associated with tocainide, a new antiarrhythmic.

A case is reported in which tocainide, a relatively new cardiac antiarrhythmic for oral use, is believed to have caused a delirium. The patient had been admitted to a coronary intensive care unit for the treatment of ventricular arrhythmia and had developed confusion, impairment in concentration and severe anxiety. Her EEG was compatible with metabolic encephalopathy. The clinical picture varied with the use of tocainide so closely that it appeared to be the most likely cause of the delirium. Other factors were taken into consideration but did not seem to adequately disprove this impression. Tocainide has been known to cause minor, transient and treatable side effects in the form of gastrointestinal and central nervous symptoms--mainly nausea, tremor and dizziness. There have also been three case reports of paranoid psychoses. It is suggested that psychiatrists be aware of the above complications as they may have occasion to see patients taking tocainide, especially in consultation-liaison work. A table with the more common side effects and their frequencies is included.

Affective Symptoms↗
PubMedDate not supplied

The effect of intra-venous lidocaine and several different doses oral tocainide HCl on tinnitus. A dose-finding study.

As part of preliminary studies for an investigation to assess the place of some drugs, including tocainide HCl, in the treatment of tinnitus, the present study was performed to establish the appropriate dose for tocainide. The effect of lidocaine HCl on tinnitus was studied in a double-blind controlled cross-over study in 22 patients. Lidocaine appeared to give significant relief. To select an optimal daily dose for the lidocaine analog tocainide HCl, this drug was administered orally to 19 patients with obstructive tinnitus in seven 4-day periods. This could be done in a single-blind controlled trial. A different dose was given in each period. Comparison of the effect on tinnitus and the associated side effects led to the choice of a daily dose of 900 mg. The effect of lidocaine HCl appeared to have no prognostic value for the effect of tocainide HCl on the tinnitus in the individual patient.

Administration, Oral↗
PubMed1986

Dose finding of tocainide in the treatment of tinnitus.

A dose finding study was performed for the use of oral tocainide in the treatment of tinnitus. In a single-blind study, increasing doses of tocainide hydrochloride ranging from 0 to 1800 mg and back to 0 mg were administered to 19 patients. Each dose was given for 4 days and the effects as well as the serum concentrations were recorded on the 4th day. In 8 patients the symptoms regressed to a non-troublesome level. In most instances this effect was seen at doses of 900 and 1800 mg, respectively. Side effects were frequent. The most important side effect, which was an absolute indication for termination of the study, was an exanthema that developed in 7 of the patients (37%). Taking into account all side effects observed, it was concluded that no justification exists for doses over 900 mg daily for the treatment of tinnitus. However, in comparison with lidocaine, which can only be given intravenously, the therapeutic score of tocainide is low and in fact tocainide is no satisfactory alternative to lidocaine.

Administration, Oral↗
PubMed1983

Comparison of tocainide and prajmalium bitartrate for the treatment of ventricular arrhythmias.

The antiarrhythmic efficacy of tocainide, a new antiarrhythmic substance, has been compared with that of prajmalium bitartrate, a drug in clinical use for many years in the German speaking countries. The investigation was performed as a double-blind cross-over study in 20 patients with ventricular arrhythmias (VA) of various origin. The efficacy was assessed by serial Holter monitoring. Plasma levels were measured to study the dose-effect relationship. Applying to the criterion of a reduction of VA of more than 75% or an improvement according to the Lown grading 8 pts. under tocainide and 7 under prajmalium bitartrate were responders. Side effects were few and under tocainide only 2 pts. had to discontinue the therapy. From the present findings tocainide and prajmalium bitartrate have the same efficient antiarrhythmic effects in the majority of patients.

Adult↗
PubMed1982

Serum binding of tocainide and its enantiomers in human subjects.

Serum from five healthy male volunteers aged 25-36 years was dialyzed against a series of buffer solutions containing varying amounts of racemic tocainide. The concentration of each enantiomer of the drug in the post-dialysis buffer and serum was determined using a specific gas-liquid-chromatographic method. The concentration of total tocainide in the post-dialysis sera ranged from 1.16 to 19.73 micrograms/ml. The percentage of total unbound tocainide ranged from 84.9 +/- 3.3 to 89.9 +/- 2.2 (mean +/- S.D.) whereas the percentages of unbound R-(-) and S-(+) enantiomers ranged from 86.3 +/- 4.0 to 91.0 +/- 2.3 and 83.3 +/- 5.4 to 88.9 +/- 2.2 respectively. Although the binding of the S-(+) enantiomer was slightly but statistically significantly greater than that of the R-(-) isomer, the difference would be of little clinical significance. Binding appeared independent of serum tocainide concentration within the therapeutic range of 4 to 12 micrograms/ml.

Adult↗
PubMedDate not supplied

Treatment of tinnitus with tocainide hydrochloride.

Intravenous (IV) injection of lidocaine was used in patients with tinnitus for combined treatment with oral anticonvulsants carbamazepine (Tegretol) and primidone (Mysoline). In most cases, the high complication rate with these drugs precluded their long-term use. Tocainide hydrochloride (HCl), a primary amine analog of lidocaine, can be taken orally and was evaluated for the use in the treatment of tinnitus. A double-blind study in which one group received 200 mg tocainide HCl four times a day and one group received a placebo revealed no significant differences in tinnitus relief between the two groups. A single-blind study in which 600 mg tocainide HCl four times a day was administered showed 80% to 98% tinnitus relief in five of the six patients who tolerated the drug. Tocainide HCl treatment of tinnitus is promising.

Adult↗