Increased sodium channel use-dependent inhibition by a new potent analogue of tocainide greatly enhances in vivo antimyotonic activity.

Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers. The current study was performed to verify their potential as antimyotonic agents. Patch-clamp experiments show that both compounds, especially To042, are greatly more potent and use-dependent blockers of human skeletal muscle hNav1.4 channels compared to tocainide and mexiletine. Reduced effects on F1586C hNav1.4 mutant suggest that the compounds bind to the local anesthetic receptor, but that the increased hindrance and lipophilia of the N-substituent may further strengthen drug-receptor interaction and use-dependence. Compared to mexiletine, To042 was 120 times more potent to block hNav1.4 channels in a myotonia-like cellular condition and 100 times more potent to improve muscle stiffness in vivo in a previously-validated rat model of myotonia. To explore toxicological profile, To042 was tested on hERG potassium currents, motor coordination using rotarod, and C2C12 cell line for cytotoxicity. All these experiments suggest a satisfactory therapeutic index for To042. This study shows that, owing to a huge use-dependent block of sodium channels, To042 is a promising candidate drug for myotonia and possibly other membrane excitability disorders, warranting further preclinical and human studies.

[Treatment of tinnitus with lidocaine? A report of clinical experiences]. / Tinnitusbehandlung mit Lidocain? Ein klinischer Erfahrungsbericht.

The efficacy of intravenous lidocaine therapy in patients suffering from severe tinnitus aurium has been reported for many years although pharmacological mechanisms for its use are not fully understood. In order to evaluate the effectiveness of lidocaine therapy in the treatment of tinnitus we performed a retrospective study on 77 patients suffering from tinnitus. All patients were given a test dose of lidocaine after a saline placebo infusion. Suppression of tinnitus was classified according to a visual analogue scale. Our results showed that 19 of the 77 patients investigated experienced different degrees of reduced tinnitus. Fourteen of these latter patients also were treated with oral tocainide 3 x 400 mg/day. Treatment was stopped in 13 of the patients because of side-effects or an insufficient effect on tinnitus. Our findings suggest that lidocaine and tocainide do not have a significant role in pharmacological treatment of tinnitus except in certain cases of long-standing severe tinnitus.

[Diagnosis and treatment of the patient with trigeminal neuralgia]. / Diagnóstico y tratamiento del paciente con neuralgia del trigémino.

Neuralgia of the trigeminus (NT) is the most common of cranial nerve neuralgias. Its diagnosis is entirely clinical and its most common form of presentation is well understood. Questions of differential diagnosis can emerge with certain entities such as atypical trigeminal neuralgia, short-duration unilateral neuralgiform cephalea of the trigeminus (SUNCT) arising from injection to the conjunctival, lacrimal or other glands, cluster headache, chronic paroxymal hemicrania, pain arising in the teeth and myofacial pain syndrome. The three main causative factors of NT are compression of the nerve root by an artery in the prepontine space, thereby creating an area of demyelinization, compression of the nerve by a tumor, and multiple sclerosis. The first is the most common of the three. NT can be classified as essential in 10 to 30% of patients. Recent advances in magnetic resonance (MR), and its advantages over other imaging systems, have made MR the diagnostic method of choice. The first treatment is medical and the basic drugs involved can be considered classic. Other therapies have been suggested in recent years, however, and should probably be studied further. Two substances stand out among those proposed: tocainide, an antiarrhythmic drug, and pimozide, an antipsychotic. Surgical treatment of NT can address either the cause (tumor or vascular compression) or symptoms, the latter being indicated when medical treatment fails. Surgery can be performed on peripheral nerves, on the gasserian ganglion and on the posterior fossa. The indications, outcomes and possible complications are quite different for each approach, making choice controversial.

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%.

[The lidocaine test in tinnitus. Determination of its current status]. / Lidocaintest beim Tinnitus. Eine Standortbestimmung.

Intravenous administration of high doses of lidocaine has been used as a treatment modality for tinnitus. From 1991 to 1992 we treated 108 patients with high-dose lidocaine and had each patient complete a special tinnitus questionnaire. The effects of therapy were estimated on patients' subjective responses concerning loudness, suppression, stress relationships and mastering of tinnitus. These parameters were recorded before and after 5 days of lidocaine therapy. Quantification of tinnitus in acute and chronic disease showed significant temporary diminution of tinnitus in all patients. Complete alleviation of tinnitus was so impressive that personal attitudes concerning tinnitus were changed. These findings demonstrated that lidocaine was a useful strategy for significant relief of symptoms due to tinnitus.

Bone marrow granulomas, fever, pancytopenia, and lupus-like syndrome due to tocainide.

We describe the case of a patient in whom a syndrome of fever, pancytopenia, pleural effusion, hepatosplenomegaly, positive ANA antibodies, and bone marrow granulomas developed in association with tocainide therapy. Tocainide, a recognized, albeit rare, cause of fever, lupus-like syndrome, and cytopenias, should be added to the list of medications that can cause bone marrow granulomas.

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.

[Combination anti-arrhythmic drug therapy]. / Medikamentöse antiarrhythmische Kombinationstherapie.

Antiarrhythmic treatment with single agents is often ineffective and can be limited by dose-dependent side-effects. Therefore, combinations of antiarrhythmic drugs in smaller and well-tolerated doses are advocated in cases refractory to single antiarrhythmic drugs. Basically, substances belonging to the same electrophysiologic class should not be combined. A combination of beta-adrenoreceptor blockers with class I antiarrhythmic drugs may be effective, mainly in cases in which the arrhythmia is dependent on adrenergic stimulation. As shown in our study, the combination of class III and I B-substances can be useful in some cases, from the electrophysiological and clinical points of view. Among the successful combinations of this type are amiodarone and mexiletine, sotalol and mexiletine, and sotalol and tocainide. In patients refractory to amiodarone alone or to a combination with mexiletine, the combined treatment with amiodarone and class-I-C drugs such as flecainide and encainide prolongs the cycle length of ventricular tachycardia, but does not suppress induction of ventricular tachycardia during programmed stimulation. Combination therapy with amiodarone and encainide is associated with a remarkable incidence of proarrhythmic effects. Nevertheless, a combination of antiarrhythmic drugs improves efficacy of therapy in selected patients. However, a close monitoring is mandatory because of the risk of proarrhythmia.