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SUMMARY Mexiletine, an orally active lidocaine congener, was used to treat 21 patients whose ventricular arrhythmias were not responsive to conventional antiarrhythmic therapy (or in whom therapy produced limiting side effects). Seventeen of the 21 patients had ischemic heart disease; five had episodes of ventricular fibrillation, six had recurrent, sustained ventricular tachyeardia requiring cardioversion, and the remainder had episodic nonsustained ventricular tachycardia. As the dosage of mexiletine was gradually increased, only three patients' arrhythmias were controlled without limiting side effects. One patient continued to have episodic ventricular fibrillation during mexiletine therapy and was excluded from the remainder of the study. The other 17 patients had a partial antiarrhythmic response (the mean suppression of ventricular ectopic depolarizations [VEDs] was 62.5 + 25%) and 10 continued to have ventricular tachycardia), but dose-related side effects limited therapy (at a mean dose of 950 + 202 mg/day). These 17 patients had not responded to or did not tolerate quinidine (mean dose of 1042 + 362 mg/day). With the maximum well-tolerated dosage of quinidine, the mean suppression of VEDs was 59 16%. Eleven of 17 patients (64%) continued to have ventricular tachycardia with quinidine, and therapy was limited by side effects (diarrhea) in 11. In the group of 17 patients, the addition of a previously well-tolerated dosage of quinidine (824 + 298 mg) to a well-tolerated but only partially effective dosage of mexiletine (800 + 239 mg) produced a significantly greater antiarrhythmic response. The mean suppression of VEDs during combination therapy increased to 85.9 + 26%. Only one patient continued to have ventricular tachycardia, and limiting side effects occurred in only 12% of the patients. Continuation of quinidine and withdrawal of mexiletine was associated with recurrence of complex ventricular arrhythmias and documented the need for combination treatment in nine patients. Electrocardiographic intervals were measured at baseline, during mexiletine therapy and during combination therapy. The coupling interval of the predominant ectopic beat prolonged (p < 0.05) during mexiletine treatment and further prolonged (p < 0.05) with the addition of quinidine. After withdrawal of mexiletine from the combination treatment in nine patients, the QTc interval significantly prolonged (p < 0.05). Thus, mexiletine limited the quinidine-induced increase in QTc interval. During 18 5.2 months of follow-up, three patients have died, one with intractable congestive heart failure and two related to documented noncompliance to their medical regimen. The addition of quinidine, which prolongs repolarization of the action potential in vitro, enhanced the antiarrhythmic efficacy of mexiletine, which shortens the action potential duration in vitro. We conclude that combinations of drugs with different electrophysiologic properties may provide enhanced antiarrhythmic efficacy.ANTIARRHYTHMIC drugs are widely prescribed to suppress...