Combination Of Mexiletine Research Articles

Interactions of Mexiletine with Novel Antiepileptic Drugs in the Maximal Electroshock Test in Mice: An Isobolographic Analysis

The aim of the study was to evaluate precisely the type of interactions between mexiletine (an antiarrhythmic drug) and four new generation antiepileptic drugs: lamotrigine, oxcarbazepine, topiramate and pregabalin in the maximal electroshock test in mice (MES). The isobolographic analysis was used to assess the nature of interactions between the tested drugs. Total brain concentrations of antiepileptics were also measured to detect possible pharmacokinetic interactions. The results obtained indicated that the mixture of mexiletine and pregabalin at the fixed ratios of 1:1 and 3:1 led to supra-additive interaction in terms of seizure suppression, while the proportion of 1:3 occurred additive. Synergism was also demonstrated for the combination of mexiletine and topiramate in all three proportions. Combinations of mexiletine with lamotrigine and mexiletine with oxcarbazepine were found to be additive. Adverse-effect profiles of mexiletine, antiepileptics and drug combinations were evaluated in the chimney test (motor coordination) and step-through passive-avoidance task (long-term memory). Mexiletine and drug combinations did not impair long-term memory. Moreover, all combinations of mexiletine with lamotrigine, oxcarbazepine and topiramate had no significant effect on motor coordination. However, the results from the chimney test indicated that pregabalin, administered alone at its ED50 dose from the MES-test, significantly impaired motor performance. Similar adverse effects were observed when mexiletine was co-administered with pregabalin at the fixed-dose ratio combinations of 1:1 and 1:3. However, reduction of pregabalin dose at the fixed ratio of 3:1 seems to prevent significant motor impairment. The results may indicate that mexiletine can be considered as an adjunctive drug in antiepileptic treatment, particularly in patients with concomitant cardiac arrhythmia.

SUCCESSFUL TREATMENT FOR PHANTOM PAIN

This article reports a series of 31 patients with true phantom pain. Mexiletine was used in an open-label study to evaluate its effectiveness in the treatment of this disorder. Eighteen of these patients had good to excellent results with mexiletine alone. Eleven other patients responded favorably with a combination of mexiletine and clonidine. Two patients did not respond to either drug alone or in combination. Three patients elected to discontinue use of the mexiletine because of persistent nausea, even at low doses.

Effect of the combination of mexiletine and midazolam on the electrical and mechanical activity of cardiac preparations

Effect of the combination of mexiletine and midazolam on the electrical and mechanical activity of cardiac preparations

Role of combination drug therapy with a class IC antiarrhythmic agent and mexiletine for ventricular tachycardia

The combination of mexiletine and a class IC antiarrhythmic agent (encainide, propafenone or flecainide) was evaluated by electrophysiologic testing in 14 patients with a history of sustained ventricular tachycardia whose tachycardia remained inducible during therapy with the class IC drug alone. During the control drug-free state, all patients had inducible ventricular tachycardia, with a mean cycle length of 260 ms (range 190 to 400). During monotherapy with the IC agent the tachycardia remained inducible in each patient, but there was a significant increase in the cycle length to 340 ms (240 to 500) (p less than 0.001). The effective refractory period of the ventricle was not altered. Treatment with mexiletine (oral in 13 and intravenous in 1) was begun and electrophysiologic testing was repeated. Ventricular tachycardia in one patient was rendered noninducible and one patient had arrhythmia aggravation. The tachycardia in the remaining 12 patients remained inducible but its average cycle length increased further to 392 ms (340 to 460) (p = NS). Nine patients had rate slowing and the average cycle length of the ventricular tachycardia in this group was significantly increased (302 to 388 ms, p less than 0.05). The average effective refractory period was significantly increased during combination therapy (267 ms) compared with no drug therapy (235 ms) and therapy with the class IC drug alone (247 ms) (p less than 0.05). After a mean follow-up interval of 22 months, seven patients continue on the combined treatment and have no ventricular tachycardia.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination of Flecainide and Mexiletine for the Treatment of Ventricular Tachyarrhythmias

A combination of oral flecainide and mexiletine was given to 11 patients in whom monotherapy with one of these drugs was ineffective for the suppression of inducible ventricular tachycardia or fibrillation. In eight of 11 studies, combination therapy prevented inducibility of a sustained ventricular tachycardia or resulted in induction of only nonsustained tachycardia (P = 0.0003, when compared to monotherapy). In one patient, a slow ventricular tachycardia was induced. During exercise testing ventricular tachycardia occurred in two of these nine patients, and ventricular fibrillation in another patient. Seven patients received combination on the long term, for a mean of 18 months. One patient had recurrences of ventricular tachycardia which was well tolerated. Another patient had a recurrent episode of ventricular fibrillation, but was successfully resuscitated. Severe congestive heart failure occurred in two patients. ACE inhibitors were given to them and to another four patients. No other important unwanted effects occurred. The combination of mexiletine and flecainide is very effective in suppressing inducible sustained ventricular tachycardia. The efficacy of this combination to prevent recurrences of ventricular tachyarrhythmias is acceptable. Exercise testing is of importance to unmask proarrhythmic effects before discharge from hospital.

Electrophysiologic Interactions Between Mexiletine-Quinidine and Mexiletine-Ropitoin in Guinea Pig Papillary Muscle

The effects of quinidine alone, ropitoin alone, and in combination with mexiletine at the sodium channel level were studied in isolated guinea pig papillary muscles using a sucrose gap technique. The maximum upstroke velocity (Vmax) was used as an indirect index of the magnitude of the sodium current. With quinidine (24 microM) and ropitoin (1 microM) added, trains of stimuli led to an exponential decline of Vmax to a new steady-state level (use-dependent block). The combination of mexiletine and quinidine decreased use-dependent Vmax block and magnitude of the slow component of reactivation induced by quinidine without modifying its time-constant of recovery. When we studied the interaction between mexiletine and ropitoin, we obtained similar results. Therefore, we conclude that mexiletine, quinidine, and ropitoin may bind to the same receptor site in the sodium channel. In addition, these antagonistic effects appeared only at frequencies greater than 0.5 Hz, whereas at very slow frequencies of stimulation we observed a synergistic effect in both interactions studied.

Electrophysiologic Interactions Between Mexiletine and Propafenone in Guinea Pig Papillary Muscles

The effects of propafenone alone, mexiletine alone, and their combination at the sodium channel level were studied in isolated guinea pig papillary muscles. The maximum upstroke velocity (Vmax) was used as an indirect index of the magnitude of the sodium inward current. In muscles driven at 0.02 Hz, neither mexiletine (10(-5) M) nor propafenone (5 X 10(-6) M) had any effect on action potential characteristics, but their combination decreased Vmax. In the presence of mexiletine and propafenone, trains of stimuli at 1 Hz led to a use-dependent block (onset rate 0.11 +/- 0.008 and 0.19 +/- 0.02 per action potential, respectively). The combination of mexiletine plus propafenone increased the onset rate of the use-dependent Vmax block (0.32 +/- 0.04 per action potential), but did not modify the time-constant of recovery of Vmax block or the magnitude of the slow component of reactivation induced by propafenone. Moreover, the combination of both drugs was more effective in suppressing early test stimuli than either drug alone. We conclude that the combination of mexiletine and propafenone is a synergistic one that affects only the onset kinetics of use-dependent Vmax block without detracting from the characteristics of the propafenone.

Mexiletine-quinidine in isolated hearts: an interaction involving the sodium channel

Combination therapy with mexiletine and quinidine has been shown to be more effective than either monotherapy in treating patients with ventricular tachycardia. This enhanced efficacy was associated with prolongation of ventricular refractoriness and conduction time in the infarct zone. As sodium channel activity is a determinant of both conduction time and refractoriness we formed the hypothesis that the mexiletine-quinidine interaction was due at least in part to interactions involving the sodium channel. To assess the role of sodium channel blockade in the enhanced anti-arrhythmic activity of mexiletine-quinidine combination we determined whether the electrophysiological and anti-arrhythmic effects of tetrodotoxin combined with mexiletine or quinidine mimicked the effect seen with mexiletine combined with quinidine. Eighty isolated perfused rabbit hearts were treated with mexiletine, quinidine and tetrodotoxin either alone or in combination before and after circumflex occlusion-reperfusion. Ventricular fibrillation occurred in response to single extrastimuli in all 24 hearts treated with a saline control infusion. Combinations of mexiletine and quinidine at concentrations which alone had little electrophysiological activity produced anti-arrhythmic activity greater than that seen with high concentrations of mexiletine or quinidine alone. The combination of similarly low concentrations of tetrodotoxin and quinidine also produced enhanced anti-arrhythmic efficacy and enhanced prolongation of ventricular refractoriness and conduction which mimicked the effect of mexiletine and quinidine in combination. In contrast, the combination of mexiletine and tetrodotoxin did not produce enhanced anti-arrhythmic and electrophysiological activity. Since tetrodotoxin is a highly specific sodium channel blocker, these data suggest that the enhanced antiarrhythmic activity of mexiletine-quinidine combination therapy involves, at least in part, blockade of the cardiac sodium channel.

A Comparison of the Cellular Electrophysiology of Mexiletine and Sotalol, Singly and Combined, in Canine Purkinje Fibers

To determine if combinations of mexiletine and sotalol retain Class I and III electrophysiologic actions, using standard microelectrode techniques, we examined the electrophysiologic effects on canine Purkinje fibers of solutions of mexiletine (3.1-100 microM), sotalol (3.1-400 microM), and combinations of the two drugs, at stimulation frequencies of 1.5 and 2.0 Hz. The combinations consisted of 12.5 microM of one drug combined with 3.1, 12.5, and 50 microM of the other. Mexiletine caused a concentration dependent depression of Vmax, the degree of depression always being greater at the more rapid frequency. At concentrations above 50 microM, sotalol depressed Vmax slightly. Increasing the stimulation frequency did not result in further Vmax depression. The addition of sotalol did not alter the Vmax depression produced by mexiletine but prior exposure to sotalol attenuated the effect of subsequent mexiletine. Both drugs reduced action potential amplitude and in combination their effects on this parameter were additive. Sotalol prolonged and mexiletine shortened action potential duration. Low concentrations of mexiletine reversed the prolongation caused by sotalol, whereas the addition of sotalol did not alter the effect of mexiletine. Mexiletine shortened the effective refractory period at low concentrations and prolonged it at high concentrations. Sotalol prolonged the effective refractory period at all concentrations. Exposure to a low concentration of sotalol did not alter the effects on the effective refractory period of subsequent exposure to mexiletine but a low concentration of mexiletine reduced the prolongation from subsequent sotalol. Thus, the combination of mexiletine and sotalol may add a Class II action to the Class I effects of mexiletine but the mexiletine prevents the Class III effects of sotalol.

Effects of Simultaneous Administration of Mexiletine and Quinidine on the Electrophysiologic Parameters of Canine Purkinje Fibers

The electropharmacologic effects of an equimolar combination of mexiletine and quinidine on canine Purkinje action potential parameters were compared with the effects of either drug alone in concentrations ranging from 0.31 to 5.0 X 10(-5) M. Six separate experiments were performed with mexiletine alone, quinidine alone, and the combination. At low concentrations, all three shortened action potential duration (APD) and effective refractory period (ERP) to the same degree; however, the combination depressed Vmax to the same extent as did solutions containing twice the concentration of quinidine alone even though mexiletine alone, in these concentrations, had no effect on the maximum rate of depolarization of phase 0 of the action potential Vmax. In higher concentrations, the combination depressed Vmax and prolonged the ERP to values midway between that achieved by the two drugs separately. Although increasing concentrations of mexiletine alone progressively shortened APD, the combination prolonged this parameter to values similar to those seen with twice the concentration of quinidine alone. The electropharmacologic effects of mexiletine and quinidine in combination are not simply additive and cannot be entirely predicted on the basis of a knowledge of their effects in isolation.