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Intravenous and oral mexiletine prophylaxis was compared with lignocaine supplemented placebo in a single blind trial in 240 high-risk patients with acute myocardial infarction. Although atrial fibrillation, supraventricular tachycardia and ventricular extrasystoles occurred less frequently in the mexiletine treated patients, ventricular tachycardia and primary ventricular fibrillation were not prevented. Mortality at 6 weeks was less in the mexiletine group (19%) than placebo (27%) but not significantly so (0.2 greater than p greater than 0.1). An 80% chance of showing a significant difference would require 860 high-risk patients. Low plasma mexiletine levels after 3 h treatment were due to diamorphine and may explain failure to prevent major arrhythmias. Pretreatment with intravenous metoclopramide tended to reverse this effect of diamorphine.

Mexiletine was given to 12 patients for different periods of time varying from 4 to 96 months, with a mean of 47.8 months. At the latest follow-up in August 1983, five patients had been taking mexiletine for 74 to 96 months (mean 85 months). Mexiletine was well tolerated and serious side effects were not seen. In particular, there was no rise in antinuclear factor titer. The serum level of mexiletine was easily maintained within the therapeutic range, and most side effects correlated closely with the drug level. It is concluded that mexiletine can be administered for a long time as a safe alternative to other antiarrhythmic drugs.

Forty patients with serious lidocaine-responsive ventricular arrhythmias were randomly assigned to treatment with either oral disopyramide (100 mg 4 times daily) or mexiletine (200 mg 4 times daily) for 3 weeks. A satisfactory arrhythmias control (greater than 75 % reduction of premature ventricular complexes per minute as compared to the control period prior to lidocaine administration) was achieved in 19 patients in the mexiletine group and in 16 in the disopyramide treated patients. Furthermore, disopyramide failed to maintain the reduction of the number of ventricular extrasystoles per minute obtained with lidocaine, while mexiletine succeeded. Finally, the number of ventricular extrasystoles per minute in the mexiletine treated group was significantly lower than in the other group. Gastrointestinal disturbances were more frequent during mexiletine administration.

A new antiarrhythmic agent, 1-(2,6- dimethylphenoxy )-2-aminopropane (mexiletine), was investigated in 10 patients with chronic premature ventricular contractions (PVCs) to evaluate the antiarrhythmic efficacy and the pharmacokinetics after single intravenous, single oral and repeated oral dosings of mexiletine 150 mg. Mexiletine was well absorbed from the intestinal tract. The relative bioavailability was 83.2 +/- 8.9% (mean +/- S.E.). The time-concentration curve of mexiletine fitted in well with two-compartment open model. Elimination half-life, volume of distribution and plasma clearance were 10.54 +/- 0.26 h, 2.10 +/- 0.49 l/kg, 6.01 +/- 0.63 ml/min/kg, respectively. The computer-simulated time-concentration curves of multiple oral dosings , which were based on the kinetic parameters from single oral dosing, conformed well with measured concentrations. This might be applied to predict the plasma level of mexiletine. The steady state of plasma mexiletine level was reached 4-5 days after 450 mg/day dosings and ranged 0.75-2.18 micrograms/ml. In 6 of 10 patients, the frequency of PVCs was suppressed more than 75% as compared with the pre-medication value. Mexiletine was well tolerated at a dose of 450 mg/day. However, of 4 patients with the dose increased to 600 mg/day, the administration was ceased in three patients due to gastrointestinal symptoms and tremor. All of these adverse reactions disappeared when the administration was stopped. These results suggest that mexiletine is effective against ventricular arrhythmias and the dosage should be carefully adjusted. The prediction of plasma level would be applied to the dosage regimen of mexiletine.

Mexiletine administered either intravenously or orally was found to be an effective antiarrhythmic agent. Unfortunately, important adverse effects occurred in approximately half of the patients. Adverse effects which appeared during oral therapy were dose related. Mexiletine controlled lignocaine-resistant ventricular dysrhythmias in more than half of the patients treated. Ventricular tachycardia and ventricular fibrillation occurred at plasma concentrations which were not significantly different from those associated with severe side-effects, suggesting that when mexiletine is used to control these major dysrhythmias the incidence of important side effects will be high.

The electrophysiological effects of intravenous mexiletine in a dose of 200 to 250 mg given over 5 minutes, followed by continuous infusion of 60 to 90 mg per hour, were studied in 5 patients with normal conduction and in 20 patients with a variety of disturbances of impulse formation and conduction, by means of His bundle electrography, atrial pacing, and the extrastimulus method. In all but 2 patients the plasma level was above the lower therapeutic limit. Mexiletine had no consistent effects on sinus frequency and atrial refractoriness. The sinoatrial recovery time changed inconsistently in both directions; however, of the 5 patients in whom an increase was evident, 3 had sinus node dysfunction. In most patients mexiletine increased the AV nodal conduction time at paced atrial rates and shifted the Wenckebach point to a lower atrial rate. The effective refractory period of the AV node was not consistently influenced, while the functional refractory period increased in 12 out of 14 patients. The HV intervals increased by a mean of 11 ms in 8 patients and were unchanged in 17. Both the relative and effective refractory period of the His-Purkinje system increased after mexiletine. Non-cardiac side effects occurred in 7 out of 25 patients, and cardiac side effects, including one serious, in 2. The results indicate that mexiletine shares some electrophysiological properties with procainamide and quinidine, when given to patients with conduction defects, and that the drug should not be used in patients with pre-existing impairment of impulse formation or conduction. It has additional effects on AV nodal conduction which may be of value in the treatment of re-entrant tachycardias involving the AV node.

The antiarrhythmic efficacy of mexiletine was evaluated in 44 patients with drug-resistant ventricular tachyarrhythmias. In 33 of these patients, the efficacy of mexiletine was assessed on the basis of the results of programmed ventricular stimulation. Mexiletine did not alter the ventricular effective refractory period, the Q-Tc interval, or the methods of tachyarrhythmia induction and termination during programmed stimulation. The mean cycle length of ventricular tachycardia (VT) increased from 270 +/- 49 to 313 +/- 80 ms in 21 patients in whom VT remained inducible on mexiletine alone (p less than 0.002). Overall, VT remained inducible with methods similar to control (no drugs) inductions in 25 patients receiving mexiletine alone or in combination with a type I agent. VT induction was prevented in only 8 patients, 3 on mexiletine alone and 5 receiving mexiletine combined with another drug. Mexiletine alone (in 2 patients) or with another agent (in 3) suppressed clinical recurrence of VT in an additional 5 of 11 patients who did not undergo electrophysiologic study. These 13 patients were discharged on mexiletine alone (5 patients) or in combination with other drugs (8 patients), and remained arrhythmia-free over a mean follow-up period of 7.7 +/- 4.1 months. Adverse effects occurred in 27 of 44 patients (61%) and were gastrointestinal in 17 and/or neurologic in 22. The drug was discontinued because of adverse effects in 6 patients (14%). Thus, mexiletine has limited efficacy when used alone, but when combined with other drugs it may be useful in up to 30% of patients with drug-resistant ventricular arrhythmias. Adverse effects are relatively common.

In order to evaluate and compare slow-release mexiletine 360 mg 12 hourly and conventional mexiletine 200 mg 8 hourly, twelve patients with symptomatic ventricular arrhythmias have been studied. Ambulatory electrocardiographic monitoring was performed before treatment and at the end of two, two week long treatment periods during which slow-release mexiletine and conventional mexiletine were administered in random order. On the last day of each treatment period frequent blood samples for drug assay were collected during a dosage interval. Each formulation produced greater than 70% suppression of ventricular ectopic beats in 55% of patients. The variation between pre-dose and observed peak plasma concentration was 29.6% with slow-release mexiletine and 71.6% with mexiletine (P less than 0.01). The time from pre-dose to observed peak concentration was 4.0 h (+/- 1.6 SD) with slow-release mexiletine and 2.0 h (+/- 1.8 SD) with conventional mexiletine (P less than 0.05). Three patients were withdrawn from the study in the first treatment period because of central nervous system or gastric adverse effects. Overall, side-effects were marginally fewer on therapy with slow-release mexiletine. We conclude that, in the nearest equivalent dosage, the slow-release formulation is as effective as conventional mexiletine and at least as well tolerated. The fluctuations in plasma mexiletine concentration are less marked on the slow-release preparation despite the longer dosage interval, which allows effective oral therapy with a twice daily dosage.

A double blind randomised study was undertaken comparing the effects of oral mexiletine and placebo given by general practitioners at home in the early stages of suspected acute myocardial infarction, and continued for six weeks. The study comprised 216 patients. In 59 the diagnosis of acute myocardial infarction was not confirmed. Of the 72 patients with confirmed myocardial infarction treated with mexiletine, 11 (15.3%) died, compared with 19 (22.4%) of the 85 patients given the placebo, and significantly fewer of the former compared with the latter had frequent ventricular ectopics or ventricular tachycardia recorded on 24 hour electrocardiograms. Numbers of patients transferred to hospital or withdrawn from the trial because of arrhythmia or heart failure were similar in the two treated groups. Ten (13.9%) of the patients taking mexiletine had the drug withdrawn because of side effects attributed to it, compared with three (3.5%) of the group taking the placebo. A further five patients (all on mexiletine) also had treatment withdrawn because of side effects but infarction was not later confirmed. The results indicate that oral mexiletine can be given safely to patients with suspected myocardial infarction at home by their general practitioners in the absence of a positive electrocardiographic diagnosis. The frequency of ventricular tachycardia is significantly reduced; but there is no evidence of reduced mortality.

This single-blind, randomized study was designed to evaluate the efficacy and safety of oral mexiletine compared with oral quinidine in suppressing premature ventricular contractions (PVCs). Fifty-one patients were studied for less than or equal to 12 weeks; 26 patients were randomized to the mexiletine group and 25 to the quinidine group. The drugs were administered in an increasing dose regimen to suppress the PVCs by 70% from the baseline value in both groups. Mexiletine reduced the average number of PVCs by 70% of the baseline number in a comparable fashion to quinidine; 69% in the mexiletine group vs 70% in the quinidine group (p greater than 0.05). There was a comparable reduction (greater than or equal to 50%) of ventricular couplets from the baseline value in the 2 groups, 78% in the mexiletine group vs 86% in the quinidine group (p greater than 0.05). The effect of mexiletine on suppression of ventricular tachycardia was also similar, 72% in the mexiletine group vs 71% in the quinidine group (p greater than 0.05). There was no significant difference in the 2 groups in side effects. This study shows the comparable efficacy and tolerance of mexiletine and quinidine for the control of ventricular arrhythmias in a large number of patients with diverse forms of heart diseases.

The anti-arrhythmic drug mexiletine caused an oesophageal ulcer, confirmed by endoscopy and biopsy, in a 72-year-old woman. This side-effect has not previously been published. The clinical course was similar to that observed after oesophageal ulceration caused by other drugs. An ulcer in the piriform recess also developed in a 63-year-old man who was taking both acetylsalicylic acid and mexiletine: it cleared up after mexiletine had been discontinued.

Mexiletine is a type 1B antiarrhythmic drug similar to lidocaine. Prolongation of ventricular depolarization has not been previously reported with the usual oral dosage of mexiletine. We describe a patient with renal failure and heart failure on low-dose oral therapy who developed mexiletine toxicity, which was manifested by ECG prolongation of ventricular depolarization. This was confirmed by elevated plasma concentration of mexiletine. This case illustrates that contrary to the usual belief, mexiletine pharmacokinetics are altered by renal failure. It is important to monitor mexiletine therapy by plasma levels in patients with impaired renal function to avoid mexiletine toxicity.

Drug-drug interactions can be adverse or beneficial and can be classified as pharmacokinetic or pharmacodynamic. Several adverse pharmacokinetic drug interactions have been described for mexiletine. Because it is a weak base, mexiletine undergoes several pH-dependent drug interactions in the gastrointestinal tract and kidney. Since mexiletine is metabolized by hepatic mixed-function oxidases, its metabolic rate can be altered by drugs that induce or inhibit this drug metabolizing system. Phenytoin and rifampin have been shown to increase mexiletine clearance and decrease its plasma concentration. Striking examples of beneficial pharmacodynamic interactions occur with mexiletine. Combining mexiletine with either beta-adrenergic blocking drugs or with quinidine markedly increases antiarrhythmic efficacy and substantially decreases the incidence of adverse effects. These beneficial interactions will have a major impact on the clinical use of mexiletine.

Mexiletine is a type I antiarrhythmic drug that is structurally similar to lidocaine. Mexiletine has considerable potential for causing neurologic, cardiac, or gastrointestinal side effects. However, mexiletine does not undergo clinically significant first-pass metabolism and, thus, has good oral bioavailability. Mexiletine has a large and variable volume of distribution and an elimination half-life ranging from 6 to 12 hours. Mexiletine disposition is probably altered in patients with heart failure, liver disease, and severe renal dysfunction. Efficacy and toxicity are not well correlated with mexiletine serum concentrations. Mexiletine is as effective as traditional antiarrhythmics in the treatment of premature ventricular contractions. However, in patients with drug-refractory inducible ventricular tachycardia, mexiletine is usually ineffective when used alone. When mexiletine is combined with other antiarrhythmic agents, a significantly higher percentage of patients with this difficult arrhythmia have a good response. Mexiletine is a potentially important addition to the existing antiarrhythmic drugs currently available, but its place in the clinical setting and in therapeutic drug monitoring is not well defined at this time.

Lidocaine, Mexiletine, Procainamide, and Phenytoin were administered intravenously to anaesthesized rabbits. BERA alterations showed two different patterns. If the intoxication dose was exceeded, amplitude depression, threshold elevation, desynchronization, and severe cumulative prolongation of all latencies and interpeak latencies appeared. Below this dose Lidocaine and Mexiletine induced a single, reversible, dose related, cumulative prolongation of all latencies and interpeak latencies. Procainamide induced counterrelated shiftings of interpeak latencies I-III and III-V, whereas Phenytoin showed no influence. One should, therefore, take into account these effects when BERA is used clinically, since otherwise serious errors can occur. On the other hand, there are diagnostic and therapeutic aspects for the tinnitus patient.

Each antiarrhythmic agent can cause side effects, but most of these are easily recognised by the patient or physician. However, one potentially serious side effect common to all of these drugs is aggravation of ventricular arrhythmia. Often this is without symptoms and goes unrecognised by the patient. It occurs in 11 to 16% of drug tests depending upon the method of drug evaluation employed. There are no ECG changes which predict its occurrence and blood concentrations of drug are usually within a therapeutic range. There are no clinical patient features which are associated with this toxic reaction and it does not correlate with the presence or extent of underlying heart disease, the nature of the presenting arrhythmia or the known electrophysiological properties of the antiarrhythmic drug. Careful evaluation of these drugs is therefore essential.

Aggravation of ventricular arrhythmia is a serious, potentially lethal, side effect that can occur with all antiarrhythmic agents. The purpose of this retrospective case-controlled study was to identify clinically useful parameters that would predict aggravation of arrhythmia. Patients in whom arrhythmia worsened while taking either quinidine, mexiletine or encainide were selected and matched to 2 similar patients who never developed this drug complication with any antiarrhythmic tested. A number of hemodynamic, electrophysiologic and pharmacologic parameters were compared. Only the presenting arrhythmia and a left ventricular ejection fraction less than 35% identified patients at risk for drug-induced aggravation of arrhythmia. Patients who presented with either sustained ventricular tachycardia or ventricular fibrillation were 3.4 times more likely to have arrhythmia aggravation compared with patients presenting with nonsustained ventricular tachycardia or ventricular premature beats. Patients with a left ventricular ejection fraction less than 35% were 2.2 times more likely to develop this drug complication compared with patients with an ejection fraction greater than 35%. There was no association between other clinical parameters, electrocardiographic intervals, ventricular arrhythmia density, drug dose or drug levels and aggravation of arrhythmia. In addition, drug aggravation to 1 drug did not predict its occurrence with another drug of the same class. Patients with a history of a sustained ventricular arrhythmia, especially when left ventricular dysfunction is present, are at high risk for the development of aggravation of arrhythmia.

The incidence of drug-induced congestive heart failure with several newer antiarrhythmic agents including encainide, ethmozine, lorcainide, mexiletine, propafenone and tocainide was determined in a group of 407 patients who underwent 1,133 drug tests. The incidence rate ranged from 0.7% with lorcainide to 4.7% with propafenone. Congestive heart failure was present in 167 patients (41%) who underwent 491 drug trials. Congestive failure was induced in 15 (9%) of these 167 patients and involved 19 (3.9%) of the 491 tests. Left ventricular ejection fraction was 20 +/- 8% in patients who developed congestive failure, in contrast to 39 +/- 19% in those who did not (p less than 0.001). It is concluded that each of the six antiarrhythmic drugs examined has the potential to aggravate congestive heart failure in patients with reduced left ventricular ejection fraction or a history of congestive heart failure, but the incidence rate is low and its occurrence unpredictable.

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.

Thirty patients received one of the lidocaine analogues--mexiletine or tocainide--orally for treatment of symptomatic ventricular arrhythmias. Crossover to the other analogue was allowed if initial drug treatment was unsuccessful, and the controlled use of other marketed oral antiarrhythmic agents was permitted. After follow-up of 7 +/- 3 months (SD), mexiletine was successful in 5 of 13 patients initially and in 5 of 14 patients who failed to respond to tocainide. Tocainide was successful in 1 of 17 patients initially and in 2 of 7 who did not respond to mexiletine. Combination therapy was used in nearly half of all ultimately successful drug trials. A common cause of drug trial failure for both drugs was the occurrence of adverse effects that frequently appeared well after hospital discharge. Response to lidocaine was a sensitive but nonspecific predictor of clinical outcome with mexiletine or tocainide that helped to identify drug-resistant patients. Finally, although mexiletine provided effective antiarrhythmic therapy more often than tocainide, response to one lidocaine analogue did not predict response to the other.

The antiarrhythmic effects of mexiletine (n = 14) were compared to procainamide (n = 16) by a double-blind parallel protocol in 30 patients (group I) with frequent premature ventricular contractions (PVCs) (greater than 20/hr), and to amiodarone by an open-label sequential approach in 25 patients (mean left ventricular ejection fraction of 32.6 +/- 13.4%) with life-threatening ventricular arrhythmias (group II) resistant to two or more conventional agents. The predetermined end point of therapy in group I patients was met in 6 of 14 (43%) given mexiletine, with 7 (50%) requiring drug discontinuation for severe gastrointestinal or central nervous system side effects and only 3 of 16 patients (19%) given procainamide, with 5 (31%) developing limiting side effects. Increases in dose led to a higher efficacy rate for PVC suppression with a corresponding increase in side effects with mexiletine; with procainamide, the higher dose was not associated with greater PVC suppression. In group II patients, mexiletine was effective in 4 (16%), with one patient discontinuing the drug during long-term therapy; mexiletine was ineffective in 16 (64%) and early side effects developed in 5 (20%). Patients not responding to or not tolerating mexiletine were given amiodarone; 20 of 21 (95%) responded with arrhythmia control after the loading dose. During a mean follow-up period of 2 years, sudden death occurred in two patients, death from heart failure in two, and death from subarachnoid hemorrhage in one patient; 15 (75%) patients are alive and free of arrhythmia.(ABSTRACT TRUNCATED AT 250 WORDS)

Cimetidine, a commonly used H2 receptor antagonist, was found to adversely interact with many drugs metabolized by the liver, including class I antiarrhythmic agents, lidocaine and quinidine. Mexiletine is a new class I antiarrhythmic agent similar to lidocaine which when used orally may have significant gastric side effects. Since some patients with peptic ulcer disease or gastric hyperacidity on mexiletine may benefit from the addition of cimetidine, it was important to rule out any significant adverse interaction between the two drugs in such patients. Eleven patients currently receiving long-term oral mexiletine for the treatment of complex ventricular arrhythmia underwent a double-blind crossover trial where they were maintained on their usual dose of mexiletine, and cimetidine, 300 mg orally every 6 hours, or placebo were added for a 1-week period each. Peak and trough mexiletine blood levels were not significantly altered by cimetidine. Similarly, there was no significant change in the frequency and severity of ventricular arrhythmia when cimetidine was added to mexiletine. Cimetidine reduced gastric side effects of mexiletine in 50% of patients who had complained of such symptoms on mexiletine alone or on mexiletine and placebo. We conclude that cimetidine can effectively reduce gastric side effects of mexiletine in many patients without adversely affecting the plasma concentration or the efficacy of the drug.

Mexiletine is an antiarrhythmic agent, structurally similar to lidocaine, but useful orally as well as intravenously. The safety and efficacy of mexiletine was compared with quinidine in a double-blind, parallel, randomized study of patients with chronic ventricular ectopia of various causes. Mexiletine was statistically more effective (P less than .05) than quinidine, though the total number of patients studied was small. Like quinidine, side effects limited the usefulness of mexiletine in certain patients, but these side effects are quite distinct from those of quinidine and other type I antiarrhythmic drugs. Mexiletine should be a useful addition to the armamentarium of antiarrhythmic drugs when it is released for clinical use in the United States.

We analyzed the incidence of adverse reactions to antiarrhythmic drugs in 123 consecutive patients with a history of sustained ventricular tachycardia or ventricular fibrillation. Blood levels were measured serially and were maintained within the usual therapeutic range. Minor reactions were defined as those that required dosage reduction and major reactions as those that required drug discontinuation or permanent pacing for bradycardia. A total of 237 individual, oral drug trials were evaluated in the 123 patients. Adverse reactions were noted in 79 trials (33%). Fifty-nine (48%) of the 123 patients had one or more adverse reaction. Major reactions were noted in 36 patients (29%). Adverse effects occurred during 49% of trials with mexiletine hydrochloride, 44% of trials with amiodarone, 24% of trials with procainamide hydrochloride, and 18% of trials with quinidine sulfate or gluconate. In conclusion, clinically significant adverse reactions are common during drug therapy for ventricular arrhythmias. These observations indicate that with the drugs used in this study, an acceptable risk-benefit ratio will be possible only in patients at a significant risk for a symptomatic arrhythmia. Antiarrhythmic drug therapy in patients at low risk for serious arrhythmia should be discouraged.

Tocainide, mexiletine, flecainide, encainide, and amiodarone are antiarrhythmic agents that have recently been approved by the Food and Drug Administration for general use in the treatment of ventricular arrhythmias. All five agents are effective in the treatment of patients with ventricular arrhythmias, whereas encainide, flecainide, and amiodarone are also useful in patients with supraventricular arrhythmias and the Wolff-Parkinson-White syndrome (although not yet approved for these indications). Tocainide and mexiletine are similar to lidocaine and are as effective as quinidine in patients with ventricular arrhythmias. Encainide and flecainide are superior to quinidine for the control of ventricular ectopic beats and as effective as quinidine for patients with ventricular tachycardia. Amiodarone is the most effective agent available for treating patients with ventricular tachycardia, but it is also the most toxic antiarrhythmic agent and should be used only when other antiarrhythmic drugs have not been effective or tolerated.

In 52 patients, KO 1173 (Mexiletin) administered intravenously and/or orally has been used for the treatment of rhythm disorders of ventricular origin. The disturbances of rhythm studied included ventricular extrasystoles, ventricular tachycardia and by DC-cardioversion abolished ventricular fibrillation. By intravenously administered KO 1173, 31 of the 32 patients had a more than 75% reduction of their ventricular extrasystoles or complete abolition of the arrhythmia. In 5 patients with ventricular tachycardia, rhythm disorder was terminated by administration of a total dose of 125 to 250 mg. When used prophylactically in patients with ventricular fibrillation terminated by electrical means, KO 1173 was successful in 10 of the 11 patients. Oral administration was carried out in a total of 32 patients. In 26 of the 32 patients optimum dosage for maximum beneficial effect appeared to be 200 mg 3 times daily. 6 patients responded unsatisfactory to KO 1173. The intravenous administration of KO 1173 induced side-effects, primarily manifested by central nervous system disturbances, which we have partly attributed to the dosage and the time of injection. No noteworthy side-effects have been reported at the oral administration. In 1 patient complaining of gastric irritation KO 1173 was withdrawn.

To study the effects of cirrhosis of the liver on the pharmacokinetics of mexiletine a single i.v. dose of 200 mg was administered to six cirrhotic patients and to six healthy controls. The distribution of mexiletine in both study groups was similar, as indicated by similar values of V1 and Vss, but it tended to occur more slowly in the cirrhotics. The plasma protein binding of mexiletine was unchanged in the patients with cirrhosis. The elimination of mexiletine was markedly retarded in the cirrhotics, as indicated by its lower total clearance (2.31 vs. 8.27 ml/kg/h,) lower total elimination rate constant (0.059 vs 0.353 h-1), and longer elimination half-life (28.7 vs 9.9 h). The antipyrine half-life was 38.3 h in the patients and 14.7 h in the controls. One healthy volunteer had a Morgagni-Stokes-Adams type of syncopal attack 5 min after administration of mexiletine due to disturbance of AV conduction induced by the drug. Thus, on a pharmacokinetic basis the loading dose of mexiletine need not be modified in cirrhotic patients, whereas the maintenance dosage should be reduced to one fourth - one third of the usual dose.

Fifty-one patients were treated with mexiletine over 10.4 +/- 16 months. The clinical arrhythmia in 25 (49%) was ventricular fibrillation (VF), 11 (22%) had sustained ventricular tachycardia (VT), and 15 (29%) had symptomatic nonsustained VT. Ischemic heart disease was present in 33 patients (66%), cardiomyopathy in nine (17%), and valvular or congenital heart disease in nine (17%). Only six (12%) remain on the drug. Arrhythmias recurred in 21 patients (41%): seven (14%) with VF, three (5%) with sustained VT, and 11 (22%) with symptomatic nonsustained VT. Intolerable side effects occurred in another 17 (33%). Seven patients (14%) died from nonarrhythmic-related deaths while taking mexiletine. Mexiletine was combined with a conventional type IA antiarrhythmic agent in 25 patients (49%). In 12 of these 25 patients (48%), ventricular arrhythmias recurred. These findings were not significantly different from those of the group treated with mexiletine alone, where arrhythmias recurred in 9 of 26 patients (35%) (p = NS). Thus mexiletine, alone or in combination with a type IA antiarrhythmic agent, has limited clinical utility in patients with life-threatening ventricular arrhythmias.

Mexiletine, an oral lidocaine-like drug, was initially thought to be effective treatment for recurring ventricular arrhythmias. Recent work has cast doubt on its efficacy. We administered mexiletine to 32 patients with chronically recurring ventricular arrhythmias. In 22 patients with no history of syncope or documented sustained ventricular arrhythmia (group 1), mexiletine was effective in only 27% (six patients) as assessed by 24-hour ambulatory ECG recordings before and during mexiletine treatment. Ten other patients had a history of syncope or documented sustained ventricular tachycardia or ventricular fibrillation. Only 10% (one patient) responded to mexiletine based on sequential electrophysiologic studies with programmed ventricular stimulation. Four of the seven patients responding to mexiletine had not received prior antiarrhythmic therapy. We conclude that mexiletine has limited efficacy in the treatment of recurring drug-refractory ventricular arrhythmias.

We evaluated the safety and efficacy of intravenous mexiletine and a method for converting from intravenous to oral mexiletine therapy. Fifteen patients with repetitive ventricular ectopy (13 had ventricular tachycardia) received intravenous mexiletine at a rate of 10 mg/min for 30 to 60 minutes. Ventricular ectopy was suppressed with minimal side effects in 10 of 15 subjects. Oral mexiletine was begun immediately after completion of the intravenous infusion at a dose of 10 mg/kg/24 hr in the 10 responders to intravenous therapy. In eight, the oral dose was effective in suppressing the arrhythmia, but it induced side effects in three of them. In one of these three, dose reduction resulted in adequate arrhythmia control with acceptable toxicity. In the two who did not respond to the original dose, a larger dose (15 mg/kg/24 hr) induced arrhythmia control with acceptable side effects in one subject. Thus rapid control of nonsustained repetitive ventricular arrhythmia can be achieved with intravenous mexiletine in about two thirds of patients, and conversion to oral therapy can often be achieved smoothly without significant arrhythmia recurrence.

The author reports a case of drug induced esophagitis secondary to mexiletine hydrochloride. At the time of gastroscopy, the patient is asymptomatic. Ulcerations are located at the level of the cervical esophagus and are reddish in color. The evolution is favorable. Prevention of such incidents is easy: ingestion of the medication while standing up with enough water (60 ml).

The antiarrhythmic efficacy and safety of oral mexiletine hydrochloride and quinidine sulfate were compared at 29 clinical centers in a double-blind, parallel-group trial involving 491 patients with benign or potentially lethal ventricular arrhythmias. Responders were defined as those who had at least a 70% reduction in the frequency of ventricular premature complexes (VPCs) that persisted for 12 weeks, and who experienced no intolerable side effects that required discontinuation of therapy. Of the patients available for analysis, 71 of 232 (31%) in the mexiletine and 73 of 225 (32%) in the quinidine group met these criteria. The dose range used for mexiletine was 200 to 400 mg every 8 hours, and that for quinidine 200 to 400 mg every 6 hours. More than half of the patients in each group were successfully treated with the smallest dose (200 mg every 8 hours mexiletine vs 200 mg every 6 hours for quinidine). Quinidine significantly prolonged the QT interval, whereas mexiletine did not. Proarrhythmic reactions were recorded in 18 of 221 (9%) patients taking quinidine and 10 of 217 (5%) patients taking mexiletine. There was no difference in the incidence of adverse reactions between the 2 groups; in both, the most common side effects were related to the gastrointestinal and central nervous systems. Mexiletine thus represents an alternative to quinidine for the treatment of patients with ventricular arrhythmias.