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PubMed1988

Tocainide for drug-resistant sustained ventricular tachyarrhythmias.

Eighty-two patients with drug-resistant ventricular tachycardia or fibrillation were treated with oral tocainide. Treatment in 54 patients, all with inducible ventricular tachycardia or fibrillation at baseline electrophysiologic testing, was based on the results of invasive electrophysiologic testing. Twenty-eight additional patients with frequent spontaneous ventricular tachycardia or no inducible arrhythmia during electrophysiologic testing were treated on the basis of the findings of electrocardiographic (ECG) Holter monitoring. Tocainide was effective in 7 (13%) and partially effective in 5 (8%) of the 54 patients in the electrophysiologic study group and was effective in 17 (61%) of the 28 patients in the ECG monitoring group. History of previous myocardial infarction and failure of response to lidocaine correlated with failure to respond to tocainide. Side effects were common both during initial therapy and during long-term treatment and necessitated discontinuation of tocainide therapy in 17% of the patients. At a mean follow-up period of 14 months, 13 patients are still receiving tocainide and are arrhythmia-free. In conclusion, the usefulness of oral tocainide in the management of drug-refractory sustained ventricular tachycardia or fibrillation is limited because of its low effectiveness and frequent side effects.

Anti-Arrhythmia Agents↗
PubMed1990

Tocainide and mortality after myocardial infarction: a prospective study in conscious dogs.

The production of an anterior myocardial infarction as part of an experimental animal model for sudden death was burdened by a persistently elevated mortality rate (30%) despite the use of traditional antiarrhythmic drugs. Mortality was reduced when tocainide (600 mg three times daily) was empirically administered for 4 days before and 4 days after myocardial infarction. Retrospective analysis showed that mortality at 4 days after infarction was significantly lower in the tocainide-treated dogs than in the preceding large group of dogs that had not been so treated (5 [9%] of 55, versus 64 [32%] of 199, p less than 0.01). This difference was still evident 30 days after myocardial infarction (13 [24%] of 55 versus 83 [42%] of 199; p less than 0.05). This observation led to the present prospective study in 106 dogs with a similar protocol but with a randomized sequence. At 4 days after myocardial infarction, the mortality rate was 55% lower in the tocainide group than in the control group (7 [12.5%] of 56 versus 14 [28%] of 50; p less than 0.05). During the 10 days after treatment withdrawal 9 (18%) of 49 dogs in the tocainide group died compared with only 2 (5%) of 36 in the control group. This rebound in mortality produced similar survival figures in the two groups at 14 and at 30 days after infarction when mortality was 30% (17 of 56) in the tocainide group and 34% (17 of 50) in the control group. The tocainide plasma levels were 7.4 +/- 4 micrograms/ml the day before infarction and 7.2 +/- 3 micrograms/ml 3 days after infarction.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Antimyotonic effects of tocainide enantiomers on skeletal muscle fibers of congenitally myotonic goats.

Tocainide is effective in the symptomatic treatment of myotonic syndromes for its ability to reduce the high frequency discharges of action potentials typical of the disease, by blocking voltage-gated sodium channels. However, its use is restricted by serious side effects. In spite of its chiral structure, tocainide is clinically used as a racemic mixture. Since the optical isomers may differ in their efficacy and toxicity, the present study was aimed at evaluating the antimyotonic activity of the pure R(-) and S(+) enantiomers of tocainide, on the abnormal membrane hyperexcitability of external intercostal muscle fibers of congenitally myotonic goats. The excitability parameters were recorded in vitro by means of the standard two-microelectrode current-clamp technique before and after the addition of the compounds. The R(-) enantiomer of tocainide at concentrations as low as 10 microM potently counteracted the abnormal excitability of myotonic fibers, by increasing the threshold current, and decreasing the latency of the action potential and firing capability. Also, this concentration of R-(-) tocainide almost completely abolished the abnormal spontaneous electrical activity occurring in about 70-80% of the myotonic fiber. The S(+) enantiomer was remarkably less potent since up to 100 microM did not restore the normal excitability pattern. The results show that most of the antimyotonic activity of tocainide resides in the R(-) enantiomer suggesting that its clinical use may allow a significant reduction of the doses and possibly of the side effects.

Animals↗
PubMed2001

Increased rigidity of the chiral centre of tocainide favours stereoselectivity and use-dependent block of skeletal muscle Na(+) channels enhancing the antimyotonic activity in vivo.

1. Searching for the structural requirements improving the potency and the stereoselectivity of Na(+) channel blockers as antimyotonic agents, new derivatives of tocainide, in which the chiral carbon atom is constrained in a rigid alpha-proline or pyrrolo-imidazolic cycle, were synthesized as pure enantiomers. 2. Their ability to block Na(+) currents, elicited from -100 to -20 mV at 0.3 Hz (tonic block) and 2-10 Hz (use-dependent block) frequencies, was investigated in vitro on single fibres of frog semitendinosus muscle using the vaseline-gap voltage-clamp method. 3. The alpha-proline derivative, To5, was 5 and 21 fold more potent than tocainide in producing tonic and 10 Hz-use-dependent block, respectively. Compared to To5, the presence of one methyl group on the aminic (To6) or amidic (To7) nitrogen atom decreased use-dependence by 2- and 6-times, respectively. When methylene moieties were present on both nitrogen atoms (To8), both tonic and use-dependent block were reduced. 4. Contrarily to tocainide, all proline derivatives were stereoselective in relation to an increased rigidity. A further increase in the molecular rigidity as in pyrrolo-imidazolic derivatives markedly decreased the drug potency with respect to tocainide. 5. Antimyotonic activity, evaluated as the shortening of the time of righting reflexes of myotonic adr/adr mice upon acute drug in vivo administration was 3 fold more effective for R-To5 than for R-Tocainide. 6. Thus, constraining the chiral centre of tocainide in alpha-proline cycle leads to more potent and stereoselective use-dependent Na(+) channel blockers with improved therapeutic potential.

Animals↗
PubMed1992

Proarrhythmic effects of procainamide and tocainide in a canine infarction model.

A canine model of myocardial infarction (MI) was used to study the type and frequency of ventricular antiarrhythmic and proarrhythmic effects due to procainamide and tocainide and the risk factors associated with development of proarrhythmia. An anterior MI was created by a 2-h occlusion of the left anterior descending artery (LAD) with complete reperfusion. Programmed ventricular stimulation was performed on two occasions after MI, on days 4-6 and on days 8-10, before drug and during antiarrhythmic drug infusion at three dose levels. The antiarrhythmic drugs were given in a randomized cross-over design. Only procainamide caused a dose-dependent increase in QRS, JTc, and right ventricular effective refractory period (ERP). Neither procainamide nor tocainide made sustained ventricular tachycardia (VT) noninducible, but procainamide slowed the tachycardia rate. Both drugs successfully made ventricular fibrillation (VF) noninducible: procainamide in 78% of trials and tocainide in 50% of trials. Proarrhythmia (development of inducible VT during drug when not present before drug or inability to terminate VT during drug administration) developed in 29% of dogs that received procainamide and 25% of dogs that received tocainide. There was no apparent correlation of QRS, JTc, and right ventricular ERP after drugs and proarrhythmia due to procainamide or tocainide. There was no significant difference in the size of MI between dogs with one or more proarrhythmic response to either drug and dogs that had no proarrhythmia. In this model, procainamide and tocainide had no antiarrhythmic efficacy for VT, but had moderate proarrhythmia potential that was unpredictable.

Animals↗
PubMed1990

Comparative hemodynamic effects of procainamide, tocainide, and encainide in severe chronic heart failure.

Many of the newer antiarrhythmic agents are said to cause minimal myocardial depression, but their hemodynamic effects have not been invasively evaluated and compared in patients with severe chronic heart failure. In a randomized, crossover study, the hemodynamic responses to single oral doses of procainamide (750 mg), tocainide (600 mg), and encainide (50 mg) given to 21 patients with severe chronic heart failure were compared. Cardiac performance decreased with all three drugs, but the magnitude of deterioration differed among the three agents. Stroke volume index decreased with procainamide (-5 +/- 1 ml/m2, p less than 0.001), tocainide (-7 +/- 1 ml/m2, p less than 0.001), and encainide (-8 +/- 1 ml/m2, p less than 0.001), but the decline was significantly greater with encainide than with procainamide (p less than 0.05). Similarly, left ventricular filling pressure increased with tocainide and encainide (+4 +/- 1 and +5 +/- 2 mm Hg, respectively; both p less than 0.05), but not with procainamide; the increase was significantly greater with tocainide and encainide than with procainamide (p less than 0.001). These deleterious hemodynamic effects were accompanied by worsening symptoms of heart failure in six patients with encainide and seven patients with tocainide but in only two patients with procainamide. Serum levels for all drugs were in the therapeutic range. In conclusion, although the three type I antiarrhythmic agents tested may all adversely affect left ventricular function in patients with heart failure, encainide and tocainide are more likely than procainamide to cause hemodynamic and clinical deterioration.

Aged↗
PubMed1990

Pulmonary fibrosis associated with tocainide: report of a case with literature review.

A report is presented of an 85-yr-old woman who developed severe pulmonary fibrosis while receiving tocainide for treatment of ventricular arrhythmias. Severe bilateral interstitial fibrosis was documented in this patient by open lung biopsy and at autopsy. Review of the literature revealed other cases with an association between the use of tocainide and the development of pulmonary complications such as pulmonary fibrosis and interstitial pneumonitis, and suggested that clinical improvement occurs when the correct diagnosis is made early and tocainide therapy is stopped immediately. Because tocainide is currently being widely used for the treatment of ventricular arrhythmias, the pulmonary status of patients receiving tocainide should be monitored closely. Hopefully, awareness of this potential complication of tocainide therapy will minimize the number of cases of serious pulmonary toxicity.

Aged↗
PubMed1980

Antiarrhythmic efficacy, pharmacokinetics and clinical safety of tocainide in convalescent myocardial infarction patients.

The antiarrhythmic efficacy and pharmacokinetics of tocainide, an oral analog of lidocaine, was evaluated in 18 hospitalized convalescing myocardial infarction patients. Holter ECG tapes were recorded daily during two-day placebo therapy preceding and succeeding two days of tocainide treatment. Left ventricular function was characterized from prior or subsequent arteriographic studies (ten cases) or from radionuclide scanning (eight cases). Tocainide dosage was 17.7 +/- 4.9 SD mg/kg/day. Plasma half-time of elimination was 19.1 +/- 6.8 hours (r = 0.9). Tocainide had no significant effect on heart rate, pulse rate, or QTC intervals and did not worsen chronic heart failure, even in patients with ejection fraction < 30%. In seven of 18 patients, tocainide significantly reduced ventricular premature beat (VPB) frequency as compared to predrug and postdrug placebo periods. Drug responders averaged a 200 to 545% reduction in VPB frequency at tocainide blood levels of > 3.5 microgram/ml.

Adult↗
PubMed1983

Tocainide. A review of its pharmacological properties and therapeutic efficacy.

Tocainide is an antiarrhythmic drug structurally related to lignocaine with similar electrophysiological, haemodynamic and antiarrhythmic effects. In contrast to lignocaine (lidocaine) it is well absorbed after oral administration and has a plasma half-life of about 15 hours. In several open and controlled therapeutic trials in patients with ventricular arrhythmias, often following a myocardial infarction, tocainide has been relatively effective and usually well tolerated. In treating ventricular ectopic beats and/or ventricular tachycardia tocainide has demonstrated effective suppression in 60 to 70% of patients in both open and controlled studies. It has an acute effect when infused in patients with ventricular arrhythmias complicating myocardial infarction, as well as a prophylactic effect when given orally. The majority of these studies have demonstrated tocainide to be more effective than placebo, but trials against other antiarrhythmic agents are few in number and vary in design. One study combining an infusion of tocainide with oral therapy compared to a bolus injection of lignocaine followed by a constant infusion in patients after myocardial infarction, found the two agents to be of similar efficacy. The most common adverse effects are neurological and gastrointestinal in nature, nausea and dizziness occurring most frequently. Adverse effects resulting in termination of therapy have been reported in about 16% of patients. Aggravation of pre-existing heart failure, increased ventricular arrhythmia, deterioration of conduction disturbances, convulsions, and cases of lupus erythematosus syndrome have occasionally been reported. Thus, tocainide appears to offer a worthwhile addition to the other antiarrhythmic agents available for ventricular arrhythmias. However, its relative place in therapy compared with other antiarrhythmic drugs is not yet clearly established.

Animals↗
PubMed1999

Inhibition of human liver cytochrome P-450 1A2 by the class IB antiarrhythmics mexiletine, lidocaine, and tocainide.

Mexiletine, lidocaine, and tocainide are class IB antiarrhythmic drugs that are used for the treatment of ventricular arrhythmias and are known to inhibit drug metabolism. The objectives of this study were to characterize the inhibitory effects of mexiletine, lidocaine, and tocainide on cytochrome P-450 1A2 (CYP1A2) activity in human liver microsomes and to evaluate their relative inhibitory potencies by using a molecular model of this P-450 isozyme. The inhibitory effect of mexiletine, lidocaine, and tocainide on cytochrome CYP1A2 in human liver microsomes was examined with methoxyresorufin O-demethylase activity as an index of the catalytic activity of this P-450 isozyme. The kinetic inhibition types and Ki values were determined by Lineweaver-Burk plots and Dixon plots, respectively. Molecular modeling was used to assess the interaction of these agents with the CYP1A2 active site. Methoxyresorufin O-demethylase activity was inhibited 67 +/- 8%, 20 +/- 5%, and 7 +/- 4% by 2 mM mexiletine, lidocaine, and tocainide, respectively. Mexiletine and lidocaine exhibited competitive inhibition with Ki values of 0.28 +/- 0.12 mM and 1.54 +/- 0.74 mM, respectively, whereas the inhibition type of tocainide could not be determined because of its weak potency. A charge interaction between mexiletine and the Asp313 side chain in the CYP1A2 active site was found, and varying degrees of hydrogen bond formation between these three compounds and the CYP1A2 active site were observed. The in vitro inhibitory potencies in human liver microsomes (mexiletine > lidocaine > tocainide) are consistent with the structural interactions found in a molecular model of the active site of CYP1A2.

Anti-Arrhythmia Agents↗
PubMed1989

Influence of rifampin on tocainide pharmacokinetics in humans.

The effects of metabolic enzyme induction by rifampin on the pharmacokinetics of tocainide were studied in eight healthy volunteers. In an open, unrandomized fashion, volunteers received tocainide hydrochloride 600 mg orally. Blood samples were obtained immediately before and at various time intervals up to 48 hours after the dose. Urine samples were collected before and at various intervals up to 72 hours after the dose. Serum and urine samples were assayed for tocainide content by high-performance liquid chromatography. After a four-week washout period, volunteers ingested 300 mg of rifampin by mouth every 12 hours. After 10 doses, subjects received a second oral dose of tocainide hydrochloride 600 mg, and blood and urine samples were collected as before. During the sampling period, subjects continued to ingest rifampin 300 mg orally every 12 hours. Significant differences in elimination rate constant (average increase, 0.0545 to 0.0748 hr-1), elimination half-life (average reduction, 13.2 to 9.4 hours), oral clearance, and area under the concentration-time curve (average reduction, 76.8 to 55.0 mg.hr/L) between the control and rifampin treatment phases were observed. Volume of distribution and renal clearance of tocainide were not significantly different after rifampin treatment. Tocainide appears to be susceptible to significant drug-drug interactions mediated by metabolic enzyme induction.

Adult↗
PubMed1985

[Tinnitus therapy with lidocaine and tocainide].

A randomised clinical cross-over study was performed to evaluate the therapeutic value of lidocaine, tocainide infusion and oral application of tocainide against placebo in the treatment of tinnitus. 40 patients with sensory hearing loss of different origin and otherwise not treatable constant tinnitus were included. Lidocaine infusion showed a tinnitus suppression of more than 50 per cent in about 70 per cent of patients; in comparison, tocainide infusion in 55 per cent of the patients. Oral tocainide therapy was successful only in about 35 per cent of patients. This fact depends partially on the high proportion of side effects. Therefore, tocainide therapy should be used in such patients only, who suffer severely from their tinnitus. Patient selection can be done by the lidocaine test. Oral tocainide therapy is advisable only if the lidocaine test result is positive. The methodical problems in the assessment of the value of drugs in tinnitus treatment are discussed: Evaluation and elimination of placebo effects and spontaneous fluctuations of tinnitus intensity, as well as selection of patients included in the study.

Administration, Oral↗
PubMedDate not supplied

Disposition of (R,S)-tocainide. Some stereoselective aspects.

We have undertaken to study the stereoselective disposition of (R,S)-tocainide, a new antiarrhythmic agent. To determine the enantiomeric composition of tocainide extracted from urine or blood serum, the drug was converted to diastereomeric derivatives by reaction with (S)-alpha-methoxy-alpha-trifluoromethylphenylacetyl chloride, and the diastereomers were separated by gas chromatography. The stereoselective excretion of tocainide in the 24-hr urine of male and female rats and mice was studied after 20-mg/kg ip doses of the racemic drug. The (R)/(S) ratio of excreted drug was greater than 1.0 in mice and less 1.0 in rats. Sex differences were also found. Pretreatment with phenobarbital significantly reduced the excretion of the (S) isomer in male and female mice and in male rats, and significantly reduced the excretion of the (R) enantiomer in male rats only. The (R)/(S) ratio of circulating tocainide in the serum of patients receiving the drug was significantly different from 1.0 in several samples analyzed. The reduction of 2-oxopropiono-2',6'-xylidide, the product of the oxidative deamination of tocainide, to 2-hydroxypropiono-2',6'-xylidide, a known circulating metabolite of tocainide in humans, was catalyzed by rabbit- and rat-liver cytosol, and the reduction proceeded with high stereoselectivity to give predominantly or exclusively the (S)-alcohol.

Animals↗
PubMed1980

Inhibition of leukocyte locomotion by tocainide, a primary amine analog of lidocaine: at study with 111indium-labeled leukocytes and scanning electron microscopy.

The ability of tocainide (a primary amine derivative of lidocaine, 2-amino 2, 6-propionoxylidide) to inhibit leukocyte adhesion to and invasion of canine jugular veins was investigated. Leukocyte adhesion and migration were quantitated by use of 111indium-labeled leukocytes, and the morphologic characteristics of leukocytes and vessel lumen were studied by scanning electron microscopy. The morphologic characteristics of adhering and migrating 111indium-labeled leukocytes were similar to leukocytes that had not been manipulated, thus establishing their suitability for use as a marker for flammation. Exposure of leukocytes to 200 micrograms. per ml. of tocainide in autologous plasma in vitro inhibited adhesion and migration by 68 per cent. When labeled leukocytes were returned to the donor and exposed to intravenously infused tocainide the extent of reduction in adhesion and migration depended on whether tocainide infusion was started before or after neck dissection. Inhibition was only 46 per cent when dissection and injection of 111indium-labeled leukocytes preceded the start of infusion of tocainide but was 87 per cent when tocainide infusion was started before dissection and injection of leukocytes. The plasma level ranged from 25 to 47 microM over the 3 hour, 20 minute-infusion period, being 35 to 40 microM for the last hour. Migration of leukocytes across interendothelial junctions and their accumulation between the endothelial sheet and the basement membrane caused extensive damage to the endothelial lining of these veins. This was reduced when leukocyte migration was reduced. These observations suggest that the leukocyte-induced damage occurring in some sterile inflammations might be reduced by the use of local anesthetic drugs.

Anilides↗
PubMed1995

Relative potency of mexiletine, lidocaine, and tocainide as inhibitors of rat liver CYP1A1 activity.

Mexiletine and tocainide are lidocaine congeners that share similar chemical structures. Clinical studies suggest that the in vivo inhibitory effect of mexiletine on the CYP1A family of isoforms is substantially greater than that of tocainide. We investigated the inhibitory property of mexiletine, lidocaine, and tocainide on the in vitro activity of the cytochrome P4501A1 (CYP1A1) isozyme in the rat. Hepatic microsomes were prepared from rat livers induced with 3-methylcholanthrene. The rate of ethoxyresorufin-O-dealkylation (EROD) was used as an index of CYP1A1 activity. Vmax and KM of the reactions were determined from Lineweaver-Burk plots. The Ki values for the inhibitors were derived from Dixon plots. Results showed that mexiletine is a competitive inhibitor, lidocaine is a mixed inhibitor, and tocainide is a noncompetitive inhibitor of EROD. The Ki values for mexiletine and tocainide were 0.30 +/- 0.02 mM and 12.4 +/- 0.7 mM, respectively. Two Ki values for lidocaine were determined. They were 0.65 +/- 0.07 mM and 4.1 +/- 1.3 mM, respectively. The relative inhibitory potency of these agents on rat CYP1A1 activity is mexiletine > lidocaine > tocainide. This difference in potency, which is most likely attributable to the change in the chemical composition in the aliphatic chain among the compounds, suggests that these compounds may be useful probes for studying the mechanism of the interaction with the active site of CYP1A1.

Animals↗
PubMed1980

Tocainide conjugation in humans: novel biotransformation pathway for a primary amine.

The metabolism of tocainide, an experimental antiarrhythmic drug, was studied in humans. Urinary excretion of unchanged drug was 28-55% in 24 hr after oral dosing. Urine hydrolysis with hydrochloric acid or beta-glucuronidase increased tocainide recovery to 55-79%. Saccharo-1,4-lactone inhibited the beta-glucuronidase-mediated tocainide recovery increase. Adjustment of urine to pH 13 produced a compound identified as 3-(2,6-xylyl)-5-methylhydantoin. Evidence suggests that it was derived from the same metabolite that formed the additional tocainide after acid or beta-glucuronidase treatment. Tocainide carbamoyl O-beta-D-glucuronide is the structure proposed for the metabolite. The suggested pathway for its formation involves the addition of carbon dioxide to the amino nitrogen of tocainide followed by uridine diphosphate-glucuronic acid conjugation.

Anilides↗
PubMed1987

The effects of general anaesthesia on tocainide clearance in the sheep.

The haemodynamic effects and regional clearances of tocainide were investigated in sheep with chronic intravascular cannulae to measure blood flow through, and drug extraction by, lungs, kidneys, liver and gut. 2. Tocainide, at arterial blood concentrations in the therapeutic range, caused no haemodynamic effects and was significantly extracted only by the liver. 3. In the presence of general anaesthesia with halothane, the mean hepatic blood flow and tocainide extraction ratio were each reduced by approximately 25% so that the mean hepatic clearance and intrinsic clearance of tocainide each were reduced by approximately 50%. Thus arterial blood tocainide concentrations were increased by 50%. 4. While the clinical implications of this interaction are unclear because of insufficient information about the margin of safety of tocainide, the pharmacological implications are plain. Because general anaesthesia may alter the relationship between dose and blood drug concentrations, pharmacokinetic and pharmacodynamic data should not be interchanged between awake and anaesthetized subjects.

Anesthesia, General↗
PubMed1993

Stereoselectivity in central analgesic action of tocainide and its analogs.

The antiarrhythmic drug tocainide (5a) and some related chiral alpha-amino and alpha-imino anilides (5b-e) were synthesized in optically active form. The antinociceptive effects of the different stereoisomers of these compounds were examined and it was found that the analgesic effect of tocainide is due only to its (-)-(R)-enantiomer. Benzyl replacement for methyl group at the stereogenic centre of tocainide causes loss of activity while both enantiomers of the alpha-iminoxilidide 5e and of the strictly related tocainide analog 5d produce an analgesic effect without any stereoselectivity. Pharmacological tests and [3H] quinuclidinyl benzilate ([3H]QNB) binding assay, taken together, seem to show that the antinociceptive effect of (-)-(R)-tocainide, like the analgesia induced by lidocaine, procaine, and mexiletine, is due to a central presynaptic cholinergic mechanism of action.

Analgesics↗