Efficacy of mexiletine in chronic ventricular arrhythmias: a multicentre double-blind medium-term trial

In a multicentre double-blind, inpatient, placebo-controlled trial the effects on premature ventricular beats (PVBs) of mexiletine in a standard, submaximal dose were studied by Holter monitoring in 144 outpatients. After wash-out, mexiletine was administered for 14 days. The effects were re-tested, after one week of a placebo, in a second 14-day period of mexiletine administration. Of the patients 73% in the first period and 82.5% in the second period responded to mexiletine (a reduction of 75% or more of PVBs/24 h--p less than 0.001 compared with the placebo for both periods). Mexiletine also significantly reduced the Lown class of PVBs and the frequence of paired PBVs, ventricular tachycardia, multiform beats and R on T wave phenomenon. Mexiletine showed an equivalent effectiveness in the four main aetiological groups of arrhythmias. Fifty nine patients complained of adverse effects (gastrointestinal or neurological) the intensity of which led to the stopping of the treatment in 16 of them. These results show that mexiletine is highly effective, even in submaximal doses, in preventing ventricular arrhythmias of whatever origin.     

Comparison of the antiarrhythmic efficacy of disopyramide and mexiletine against stimulus-induced ventricular tachycardia

Programmed ventricular stimulation was used to assess the effect of oral disopyramide (600 mg/day), mexiletine (600--1000 mg/day), and a combination of both drugs in a randomized cross-over study on 12 patients with documented ventricular tachycardia and/or fibrillation. In two cases, all three types of treatment were ineffective in that ventricular tachycardia could still be initiated under the same conditions. In four cases, disopyramide and mexiletine alone were ineffective or the change in inducibility was only slight. However, when both drugs were administered in combination, ventricular tachycardia was more difficult to induce or was no longer inducible. In two other cases, disopyramide was the more effective drug. In the remaining four patients, all three types of treatment were similarly effective. In patients whose ventricular tachycardia remained inducible its rate decreased from 188 +/- 45 bpm (control) to 170 +/- 40 bpm on disopyramide, 172 +/- 31 bpm on mexiletine, and 146 +/- 39 bpm on disopyramide plus mexiletine. Long-term therapy was based on the results of acute testing. Seven patients received both disopyramide and mexiletine and tolerated this therapy well during a follow-up of 42 +/- 23 weeks. Two sudden deaths occurred, one possibly due to dose reduction and one in a patient in whom short bursts of ventricular tachycardia remained inducible during acute testing. We conclude that the combined administration of disopyramide and mexiletine is effective and safe in patients with ventricular tachycardia. It is tolerated without major side effects even during long-term therapy.     

Pharmacokinetics and pharmacodynamics of the antiarrhythmic compound MD750819 in dogs with experimentally induced arrhythmias

Pharmacokinetics and pharmacodynamics were studied in three dogs with interventricular coronary artery ligatures (ligature of Harris) and in three control animals. Weighted nonlinear analysis was used to fit equations describing two and three compartment open models to the experimental data, obtained after intravenous injection (5 mg/kg) of the drug. The three compartment model gave a reduction in the weighted sum of squared residuals and an improvement in the randomness of scatter of the experimental points about the theoretical curve. The postdistribution elimination half-life was longer, the area under the plasma elimination curve larger, and the total body plasma clearance and apparent volume of distribution was reduced in the animals with arrhythmias. The pharmacological response was assessed by recording the ECG and calculating the percentage of normal sinus rhythm/min. A combined pharmacokinetic-pharmacodynamic model was used to analyze data from individual animals. k_e0, a measure of the lag time of pharmacological response behind changes in plasma concentration, and C_e (50), a measure of the sensitivity of the cardiac site of action of the drug, were determined.     

The antiarrhythmic effects of controlled release disopyramide phosphate and long acting propranolol in patients with ventricular arrhythmias

The antiarrhythmic effect of slow-release disopyramide phosphate (DR) 300 mg twice daily and of long-acting propranolol (PR) 1 X 160 mg daily was compared in a randomized cross-over study in patients with premature ventricular beats (PVB). 12 patients with PVB (Lown Classes II-V) were given: placebo I for 3 days, DR or PR for 7 days, placebo II for 5 days and PR or DR for 7 days. During each study phase Holter-ECG recordings were taken over a period of 24 h. With DR 6 patients showed a positive qualitative effect, improving by at least one Lown class, whereas only 2 patients did so with PR. With DR reduction of PVB greater than 80% occurred in 7 patients, and with PR in 2 patients. In all patients with any reduction in PVB, the median decrease was 85% with DR and 59% with PR. The overall results suggest that the antiarrhythmic effect of disopyramide phosphate in the slow-release preparation is at least satisfactory and comparable to that of disopyramide phosphate in the standard capsule formulation given in the usual and more complicated regime of four divided doses. The antiarrhythmic effect of PR in the recommended dose as given was not convincing.     

Electrophysiological mechanisms for the antiarrhythmic action of mexiletine on digitalis-, reperfusion- and reoxygenation-induced arrhythmias.

The antiarrhythmic potency of mexiletine was evaluated on three groups of guinea-pig isolated hearts. Arrhythmias were induced (a) with digitalis intoxication, (b) with hypoxia followed by reoxygenation and (c) with ischaemia followed by reperfusion. Mexiletine 10 microM was found to be very effective against all three types of arrhythmias in all three groups. The electrophysiological effects of mexiletine were then studied on sheep cardiac Purkinje fibres manifesting oscillatory afterpotentials and triggered automaticity induced by barium or strophanthidin. Mexiletine 10 microM consistently decreased the amplitude of oscillatory afterpotentials and blocked subsequent triggered activity in sheep Purkinje fibres. In contrast, mexiletine 10 microM had no significant effect on Vmax in normal, barium- and strophanthidin-treated preparations. The results are discussed in relation to the mechanisms of antiarrhythmic action of mexiletine.     

Pharmacokinetics of intravenous mexiletine in patients with acute myocardial infarction

Acute myocardial infarction (AMI) is known to alter the pharmacokinetics of several antiarrhythmic agents. To study the effects of AMI on the kinetics of mexiletine (MEX), a single intravenous dose of 200 mg MEX HCl was infused over 30 min in 11 patients with AMI. The study was performed within 24 h of the onset of pain (study I) and repeated about 2 weeks later in seven patients at discharge (study II). MEX was quantitated in plasma and urine samples by a gas-liquid chromatographic method. The decline of MEX in plasma was three-exponential, with a terminal half-life of 14.7 +/- 3.4 (mean +/- SE) h in study I and 11.3 +/- 2.4 h (p less than 0.05) in study II, in the seven patients studied in both phases. The steady-state volume of distribution averaged 578 +/- 97 L in study I and 415 +/- 33 L in study II (p less than 0.05). The total plasma clearance, renal clearance, and recovery of MEX in urine were similar in the two studies, as was the plasma protein binding of MEX (64 +/- 2 vs. 57 +/- 3%, NS). Thus, an increase in the volume of distribution with consequent prolongation of the elimination half-life of MEX occurs in the acute phase of AMI, whereas the rate of elimination remains unchanged.     

Crossover comparison of cibenzoline and quinidine in ambulatory patients with chronic ventricular arrhythmias

This study was designed to compare the efficacy and safety of cibenzoline and quinidine in ambulatory patients with ventricular arrhythmias. Following washout of previous antiarrhythmic treatment, a 48-h ambulatory electrocardiographic (ECG) recording was obtained. Twenty-seven patients were screened, of whom 20 met the entry criteria of greater than or equal to 30 ventricular premature beats (VPBs)/h. Cibenzoline was started at 130 mg every 12 h and was increased to 160 mg every 12 h if necessary. Quinidine was started at 300 mg every 6 h and was increased to 400 mg every 6 h if necessary. Treatment was assessed by 24-h ambulatory ECG recording. Efficacy was defined as greater than 75% reduction in single VPBs, greater than 90% reduction in paired VPBs, and total abolition of ventricular tachycardia events. A 7-day washout with repeat 24-h ambulatory ECG recording to document return of ventricular arrhythmias was required prior to crossover. Efficacy was documented in 9 of 20 (45%) patients receiving cibenzoline and in 9 of 20 (45%) patients receiving quinidine. Response to cibenzoline 130 mg every 12 h was documented in 8 of 20 (40%) patients and in 1 of 11 (9%) patients receiving cibenzoline 160 mg every 12 h. Response to quinidine 300 mg every 6 h was documented in 8 of 20 (40%) patients and in 2 of 6 (33%) patients receiving 400 mg every 6 h. Dose-limiting side effects occurred in 1 of 20 (5%) patients receiving cibenzoline and in 7 of 20 (35%) patients receiving quinidine. Cibenzoline and quinidine are equal in efficacy, but cibenzoline is significantly better tolerated.     

索他洛尔治疗慢性室性和室上性心律失常44例

目的;观察索他洛尔（Ｓｏ）治疗难治性慢性室性早搏（ＶＰＣ）和症状性阵发性心房颤动（ＰＡＦ）的疗效,作用特点和不良反应。方法：２８例慢性ＶＰＣ患者和１６例ＰＡＦ患者接受Ｓｏ治疗,起始剂量１２０￣１６０ｍｇ／ｄ,无效则递增,最大剂量３２０ｍｇ／ｄ。     

慢性心力衰竭患者射血分数与室性心律失常相关性分析

目的观察慢性心力衰竭（CHF）患者室性心律失常（Ventricular Arrhythmias,VA）发生情况,探讨VA与射血分数（Ejection Fraction,EF）的关系,并对室性心动过速的影响因素进行分析。方法选取我院258例CHF患者,按左室射血分数（LVEF）值分为A组（〈30％）、B组（30％～40％）、C组（40％～50％）及D组（〉50％）,比较各组间VA发生率及严重程度差异。分析心力衰竭患者室性心动过速发生的可能影响因素。结果各组间VA发生率的差异均有统计学意义,EF与VA的发生率呈负相关（r=-0．618,P〈0．01）。EF、左室舒张末期内径（LVDd）与心衰患者室性心动过速相关,OR值分别为0．247（P〈0．01）及2．690（P〈0．05）。结论CHF患者EF与VA发生呈负相关,EF是CHF患者室性心动过速发生的重要影响因素。     

Long-term antiarrhythmic pharmaco-therapy guided by Holter monitoring in patients with malignant ventricular arrhythmias and ischemic heart disease.

In 126 patients with clinical ventricular tachycardia and/or fibrillation, ischemic heart disease and repetitive and/or frequent ventricular ectopic beats long-term therapy guided by Holter ecg was assessed. Criteria for efficacy of antiarrhythmic drugs were following: 1) > 75% decrease in ectopic beats, 2) elimination of salvos, 3) > 90% reduction of couples and R/T and 4) reduction of multiformity up to 2 forms. They were fulfilled in 71% of patients (responders). During follow-up 1-49 months, mean 20, rate of sudden death was lower in responders as compared with nonresponders (p < 0.05). However, suppression of ventricular ectopic beats was not predictive for a favorable outcome, because the incidence of arrhythmic events and total cardiac death was similar in the two groups.     

Pharmacokinetics of mexiletine in the elderly

The effect of advancing age on the kinetics of the antiarrhythmic agent mexiletine was studied by comparing various kinetic parameters calculated after administration of a single oral dose of mexiletine hydrochloride to seven elderly and eight young healthy volunteers. The rate of absorption of the drug from the gastrointestinal tract was significantly slower in the elderly (1.37 +/- 0.51 hr-1) than in the young group (2.25 +/- 0.79 hr-1). The mean values for elimination half-life and oral clearance were 12.3 +/- 3.7 hr and 10.3 +/- 5.4 mL/min/kg respectively in the young group and 14.4 +/- 4.5 hr and 8.5 +/- 2.9 mL/min/kg respectively in the elderly group. Neither of these parameters was significantly different between the two groups. The amount of mexiletine eliminated in urine up to 48 hours postdose was identical in both groups and represented less than 5% of the administered dose. It is concluded that the age-related modifications in the kinetics of mexiletine are not clinically important during chronic administration of the drug.     

The cellular electrophysiologic effect of a new amiodarone like antiarrhythmic drug GYKI 16638 in undiseased human ventricular muscle: comparison with sotalol and mexiletine

The cellular electrophysiologic effect of GYKI 16638, a new antiarrhythmic compound was studied and compared with that of sotalol and mexiletine in undiseased human right ventricular muscle preparation by applying the conventional microelectrode technique. GYKI 16638 (5 microM), at stimulation cycle length of 1000 ms, lengthened action potential duration (APD(90)) from 338.9 +/- 28.6 ms to 385.4 +/- 24 ms (n = 9, p > 0.05). This APD lengthening effect, unlike that of sotalol (30 microM), was rate-independent. GYKI 16638, contrary to sotalol and like mexiletine (10 microM), exerted a use-dependent depression of the maximal rate of depolarization (V(max)) which amounted to 36.4 +/- 11.7% at cycle length of 400 ms (n = 5, p < 0.05) and was characterised with an offset kinetical time constant of 298.6 +/- 70.2 ms. It was concluded that GYKI 16638 in human ventricular muscle shows combined Class IB and Class III antiarrhythmic properties, resembling the electrophysiological manifestation seen after chronic amiodarone treatment.     

Effects of an antiarrhythmic drug A-2545 on canine ventricular arrhythmia models; comparison with mexiletine and flecainide

We investigated effects of a new Na⁺ channel blocking antiarrhythmic drug, A-2545, N-3 (2,2,5,5-tetramethyl-3-pyrroline-3-carboxamido)-propyl-phthalimide-hydrochloride, on various canine ventricular automaticity arrhythmias induced by two-stage coronary ligation, digitalis and adrenaline, and compared them with those of mexiletine. A-2545 showed antiarrhythmic effects, significantly decreasing the arrhythmic ratio of 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced automaticity arrhythmias. The antiarrhythmic plasma concentrations (IC₅₀) of A-2545, 2 mg kg^–1 10 min^–1, i.v., for 24-h and 48-h coronary ligation-, digitalis- and adrenaline-induced arrhythmias were 1.8, 1.3, 5.8 and 3.7 μg ml^–1, respectively, and that calculated for oral A-2545 (25 mg kg^–1) in 24-h coronary ligation-induced arrhythmia was 1.8 μg ml^–1. A-2545 is specifically potent in suppressing coronary ligation-induced arrhythmias, i.e., decreasing the arrhythmic ratio nearly to zero by oral administration, and among the intravenously given experiments A-2545 was effective at lower concentrations than other arrhythmia models; A-2545, 2 mg kg^–1 10 min^–1, was equipotent to 5 mg kg^–1 10 min^–1 mexiletine in suppressing 24-h coronary ligation-induced arrhythmia, indicating that A-2545 is more potent than mexiletine. In order to determine whether A-2545 has arrhythmogenic effects, we used programmed electrical stimulation (PES)-induced reentry arrhythmias in dogs with old myocardial infarction and compared effects of A-2545 and flecainide. A-2545, 2 and 5 mg kg^–1 10 min^–1, significantly suppressed the PES-induced arrhythmias in all six dogs without aggravating them. These arrhythmias were not markedly suppressed by flecainide either with 1 or 3 mg kg^–1 10 min^–1; moreover even in one out of six dogs aggravation of arrhythmia was noted after 1 mg kg^–1 10 min^–1. In conclusion, A-2545 suppressed various canine ventricular arrhythmias, and the antiarrhythmic effect of A-2545 was more potent than that of mexiletine, and A-2545 did not show arrhythmogenic effects compared to flecainide. Received: 16 February 1998 / Accepted: 7 October 1998     

Antiarrhythmic effect of a new class 1 antiarrhythmic drug, nicainoprol, on canine ventricular arrhythmias

Using two-stage coronary ligation-, digitalis- and adrenaline-induced canine ventricular arrhythmias, antiarrhythmic effects of nicainoprol were examined in dogs, and the minimum effective plasma concentration for each arrhythmia model was determined. Nicainoprol suppressed the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 48 hr coronary ligation, digitalis and adrenaline were 8.9 micrograms/ml (by 5 mg/kg, i.v.), 3.0 micrograms/ml (by 3 mg/kg, i.v.) and 2.7 micrograms/ml (by 3 mg/kg, i.v.), respectively. The concentration for coronary ligation arrhythmia was higher than those for the digitalis and adrenaline arrhythmias. This pharmacological profile is similar to those of aprindine and propafenone. Nicainoprol induced some central nervous system effect including vomiting in conscious coronary ligated dogs. Though intravenous nicainoprol (5 mg/kg) was not effective on 24 hr coronary ligation arrhythmia, an oral dose of 30 to 40 mg/kg was effective. These results indicate that it may become a clinically useful antiarrhythmic drug.     

Pharmacokinetics and antiarrhythmic efficacy of intravenous ajmaline in ventricular arrhythmia of acute onset

21 patients with acute myocardial infarction and ventricular arrhythmia of Lown class II-IIIB of acute onset received a short infusion of (50 mg/5 min) ajmaline (Gilurytmal). 6 of the patients had normal kidney and liver function (Group 1), 4 patients had acute renal failure and hemodialysis treatment (Group 2), 4 patients had impaired hepatic function (Group 3), 3 patients had cardiogenic shock (Group 4), and 4 patients had been pretreated with phenobarbital for seizures for at least 5 days (Group 5). A distribution half-life of 6 +/- 1 min and an elimination half-life of 95 +/- 6 min was determined in Group 1. The total plasma clearance was significantly lower in patients with impaired liver or cardiac function and significantly higher in Group 5, whereas impaired renal function did not affect total plasma clearance. After short infusion, ventricular arrhythmia of Lown II-IIIB completely disappeared for at least 16 to 36 min (mean: 19 min), which was associated with an ajmaline plasma level of 0.1-0.45 micrograms/ml. Additionally, steady-state plasma levels of ajmaline were determined after continuous infusion of 10-50 mg/h to 16 patients (Group 6) with ventricular arrhythmia of acute onset (Lown class IVA-V). Ventricular arrhythmia completely disappeared or at least changed to lower Lown classes at ajmaline plasma levels of 0.4-2.0 micrograms/ml. The ajmaline plasma protein binding was 76 +/- 9%. Ajmaline had a special affinity to alpha 1-acid glycoprotein.     

Antioxidant action of the antiarrhythmic drug mexiletine in brain membranes

Mexiletine is a class Ib antiarrhythmic drug used in the treatment of ventricular arrhythmias. The Na+ channel blocker mexiletine inhibits calcium influx in cells via decreasing reverse operation of the Na+-Ca2+ exchanger. Thus this drug is shown to protect the CNS white matter against anoxic/ischemic injury. The aim of our study was to investigate if this drug could act as an antioxidant drug as well. The antioxidant action of this drug was studied under different oxidant conditions in vitro, and thiobarbituric acid-reactive substances were measured to follow lipid peroxidation. Mexiletine inhibited iron-ascorbate-H2O2-induced lipid peroxidation in brain membranes, liver microsomes and phospholipid liposomes, being most effective in brain membranes. The inhibition was dose- and time-dependent. Mexiletine also inhibited copper-ascorbate-H2O2-induced lipid peroxidation but to a lesser extent. It is concluded that mexiletine has a dual effect toward oxidative injury in brain, both by inhibiting Na+-Ca2+ exchanger-dependent Ca2+ influx and by acting as an inhibitor of lipid peroxidation. However, as this drug is effective at millimolar concentrations, it should be considered less active than natural antioxidants that are effective at micromolar concentrations.