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.

Efficacy and toxicity of tocainide for the treatment of ventricular tachyarrhythmias in Doberman pinschers with occult cardiomyopathy.

Tocainide was administered to 23 cardiomyopathic Doberman Pinschers at doses of 15 to 25 mg/kg tid. These doses produced peak (2-hour) serum concentrations of 6.2 to 19.1 mg/L and trough (8-hour) serum concentrations of 2.3 to 11.1 mg/L. Anorexia and gastrointestinal disturbances occurred in 8 dogs (35%) at doses (15.6 to 25.0 mg/kg) that were not different from those (16.0 to 26.0 mg/kg) received by dogs that did not experience toxicity. Doses producing peak serum concentrations that were either greater or less than 14 mg/L were not different. Likewise, doses producing trough values that were either greater or less than 6 mg/L were not different. The mean dose that produced peak serum concentrations of 10 to 13.6 mg/L and trough concentrations of 4.2 to 10.0 mg/L was 17.9 mg/kg, and was associated with anorexia in 4 dogs. Mean peak serum concentrations associated with toxicity (14.4 mg/L) were significantly higher (P = .02) than dogs not experiencing toxicity (11.8 mg/L). Serious adverse effects occurred in 7 of 12 dogs (58%) receiving tocainide for longer than 4 consecutive months. Progressive corneal endothelial dystrophy occurred in 3 dogs. Although a causal effect could not be proven, 6 dogs experienced renal dysfunction during treatment. Drug doses in these 7 dogs were similar to those received by other dogs. At least a 70% reduction of the total numbers of ventricular premature contractions occurred in 80% of dogs treated, and ventricular tachycardia was eliminated in 90% of affected dogs by the time of the first posttreatment Holter recording. Long-term control of ventricular tachyarrhythmias was difficult to achieve in some dogs when the left ventricular shortening fraction was less than approximately 17%.

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.

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.