Moricizine HCl Research Articles

Human moricizine metabolism. II. Quantification and pharmacokinetics of plasma and urinary metabolites

1. The metabolism of moricizine HCl was studied in 12 male volunteers dosed with 250 mg (300 μCi) 14C-radiolabelled drug. 2. Moricizine was biotransformed to many metabolites in humans (at least 35 plasma and 51 urine metabolites). 3. Urine and faecal combined mean (range) recovery accounted for 90.2% (73.4- 101.6%) of the administered radioactivity, with most of the recovered radioactivity present in faeces (mean 58.4%; range 45.6-64.7%). Mean (range) urinary recovery was 31.8% (26.2-36.9%), with <1% of the dose recovered as intact moricizine, and no one metabolite accounting for >2.5% of the dose. 4. Total radioactivity (TR) plasma t1/2 was 85.2 h, while that for moricizine was 2.4 h. Mean half-lives for plasma metabolites ranged from 2.9 to 23.6 h. The largest portion (11%) of TR AUC (area under the plasma concentration-time curve) was attributed to 2-amino-10-glucuronophenothiazine. Each of the other metabolites accounted for less of the TR AUC than parent drug except for two unidentified peaks which had comparable areas (~5% of the total radioactivity area). 5. Two identified moricizine metabolites, 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, possess the structural characteristics proposed for class 1 anti-arrhythmic activity (pendant amine functionality) and have plasma half-lives 4-7-fold longer than moricizine.

Experience with moricizine HCl in children with supraventricular tachycardia

Eight children, age between 4.5 and 19 years were treated with moricizine for supraventricular tachycardia during the last 3 years. The tachycardia was documented by surface electrocardiogram (ECG), and/or by ambulatory ECG in all the children and the mechanism of tachycardia was determined by previously published surface ECG and electrophysiologic criteria in all but one child. Of the eight children, three had atrial ectopic tachycardia, three had automatic junctional ectopic tachycardia, one had atrioventricular (AV) nodal reentry tachycardia and one had atrial reentry. All the children except one had failed trial of two or more antiarrhythmic drugs prior to moricizine therapy. The duration of moricizine therapy ranged from 4 days to 25 months. In three of the eight children (patients 3, 5 and 7), who presented with AV nodal reentrant tachycardia, automatic junctional ectopic tachycardia and atrial ectopic tachycardia, respectively, moricizine therapy was effective in restoring sinus rhythm and controlling the clinical tachycardia. Only one child (patient 1) developed proarrhythmia, an episode of fast, narrow-QRS supraventricular tachycardia lasting for 30 s, on the third day of therapy. This was subsequently confirmed by electrophysiologic study to be AV nodal reentrant tachycardia. The other side effects noted were non-cardiac, not dose-dependant and did not require dis-continuation of therapy. Based on our small series and those of others, moricizine, a newer class I anti-arrhythmic agent, has a limited but useful role in the management of recalcitrant type of supraventricular tachycardia, such as ectopic atrial and junctional tachycardia in children.

Effect of moricizine on heart rate variability in normal subjects

We investigated the effects of moricizine HCl, a type Ic anti-arrhythmic agent, on heart rate variability. Decreased heart rate variability is a risk factor for mortality in post-MI and other patient populations, and some antiarrhythmic drugs decrease heart rate variability. Normal volunteers (10 M, 11 F, age 19–39 years) received blinded placebo and moricizine HCl at 200 mg twice daily for 5 days. On day 4, a 24-h ECG was obtained, and time and frequency domain measures of heart rate variability based on normal-to-normal intervals were computed. Moricizine decreased both time and frequency domain measures of heart rate variability. Significant reductions were seen for SDNNIDX (the average S.D. for N-Ns for each 5-min interval in ms) and pNN50 (the proportion of successive N-N differences >50 ms in percent) in the time domain, and very low (0.0033–0.04 Hz), low (0.04–0.15 Hz) and high (0.15–0.4 Hz) frequency power. Similar patterns of change in heart rate variability were seen when data for daytime and nighttime periods were analyzed separately. rMSSD (the root mean square successive difference of N-N intervals in ms), pNN50 and high frequency power are primarily indices of parasympathetic tone. SDNNIDX, and very low and low frequency power reflect both sympathetic and parasympathetic tone and longer term variability. Thus, moricizine decreases both vagal tone and longer term components of heart rate variability. This decrease produced by moricizine is similar to that reported with other type 1 antiarrhythmics.

Combination Ethacizin and Ethmozin Treatment of Resistant Ventricular Ectopy

Ethmozin (Moricizine HCl) and ethacizin are two class I antiarrhythmic drugs with different rate constants of interaction with the sodium channel. Computer simulation using the "guarded-receptor" model predicted that the combination of ethacizin and ethmozin should exert a greater decrease in excitability and conduction at short coupling intervals, but little effect at normal heart rates (HR). To test this prediction, we measured intraventricular conduction delay in canine hearts in vivo. In agreement with the model, the combination more potently prolonged the delay only at intervals < 600 ms as compared with ethacizin alone. Combination therapy was tested in 6 patients with idiopathic ventricular ectopic depolarizations (VEDs). Three patients were resistant to either ethmozin or ethacizin monotherapy, and three could not tolerate effective doses because of side effects. Quantitative continuous ECG monitoring showed that total VEDs in the resistant group decreased 0 and 17 +/- 13% for 400 and 800 mg/day ethmozin and 18 +/- 12 and 55 +/- 12% for 100 and 200 mg/day ethacizin, respectively. Combined therapy with ethmozin (400 mg/day) and ethacizin (100 mg/day) reduced the number of VEDs by 78 +/- 2% in these patients without side effects. In the "nonresistant" but intolerant group of patients, use of the combination allowed relief of symptomatic ectopy without side effects. A theoretical model correctly predicted an effective combination of class I antiarrhythmic drugs, one with "fast-off" and one with "slow-off" kinetics, which may provide a general rationale for choosing drug combinations.

Combination Ethacizin and Ethmozin Treatment of Resistant Ventricular Ectopy

Summary: Ethmozin (Moricizine HCl) and ethacizin are two class I antiarrhythmic drugs with different rate constants of interaction with the sodium channel. Computer simulation using the “guarded-receptor” model predicted that the combination of ethacizin and ethmozin should exert a greater decrease in excitability and conduction at short coupling intervals, but little effect at normal heart rates (HR). To test this prediction, we measured intraventricular conduction delay in canine hearts in vivo. In agreement with the model, the combination more potently prolonged the delay only at intervals <600 ms as compared with ethacizin alone. Combination therapy was tested in 6 patients with idiopathic ventricular ectopic depolarizations (VEDs). Three patients were resistant to either ethmozin or ethacizin monotherapy, and three could not tolerate effective doses because of side effects. Quantitative continuous ECG monitoring showed that total VEDs in the resistant group decreased 0 and 17 ± 13% for 400 and 800 mg/day ethmozin and 18 ± 12 and 55 ± 12% for 100 and 200 mg/day ethacizin, respectively. Combined therapy with ethmozin (400 mg/day) and ethacizin (100 mg/day) reduced the number of VEDs by 78 ± 2% in these patients without side effects. In the “nonresistant” but intolerant group of patients, use of the combination allowed relief of symptomatic ectopy without side effects. A theoretical model correctly predicted an effective combination of class I antiarrhythmic drugs, one with “fast-off” and one with “slow-off” kinetics, which may provide a general rationale for choosing drug combinations.

The developmental electrophysiologic effects of moricizine HCl on the canine cardiac purkinje fiber

Using standard microelectrode techniques, the developmental cellular electrophysiologic effects of moricizine HCl on adult and neonatal canine Purkinje fibers were studied. Steady state and rate-related changes in the transmembrane action potentials produced by moricizine HCl in both age groups were characterized and compared. Also, the rate of barium-induced abnormal automaticity before and after drug was also investigated in neonatal and adult Purkinje fibers. The major findings of this study are as follows. (1) The steady state and rate-related depressant effecs of moricizine HCl on V max were similar in both age groups. (2) Moricizine HCl shortened APD 90 in the adult fibers to a greater extent than in the neonate. (3) The concentration of moricizine HCl required to significantly reduce the rate of abnormal automaticity was less in the neonate than in the adult. The effect of moricizine HCl on APD 90 of individual Purkinje fibers is influenced both by their control APD 90 value as well as by maturational factors. It is less clear whether developmental differences in the effects of moricizine HCl on abnormal automaticity are solely a result of differences in control rates of abnormal automaticity between the two age groups.

Classification of the Antiarrhythmic Action of Moricizine

The subdivisiion of class 1 antiarrhythmic agents into groups a, b, and c was originally based on clinical electrophysiologic findings. Class 1b compounds did not alter QRS or HV interval in sinus rhythm, but the compounds did lengthen ERP in spite of shortening JT. Class 1c agents widened QRS and prolonged HV at low concentrations in sinus rhythm, but had little effect on ERP or JT. Cellular electrophysiologic studies provided an explanation for these clinical effects by frequency-dependent onset/offset kinetics. Class 1b drugs became rapidly attached to sodium channels after depolarization, which rendered them nonconducting, but the drugs also dissociated rapidly after repolarization so that by the end of a normal diastole nearly all channels were back to their conducting state. In contrast, class 1c drugs became more slowly attached, and more slowly detached, so that a proportion of sodium channels was permanently eliminated as long as the drug was present. This caused slow conduction in the His-Purkinje system and ventricle. Both clinical and cellular electrophysiologic studies show that moricizine HCl is a class 1c agent.

Antiarrhythmic efficacy of ethmozine ® (moricizine HCl) compared with disopyramide and propranolol

In the investigation of new antiarrhythmic drugs, comparative trials with clinically available antiarrhythmic agents provide a perspective from which to judge the new investigational agent. Two clinical investigations of moricizine HCl, each using a placebo-controlled, double-blind, crossover design, are summarized. In the first study, 18 patients with ≥ 30 ventricular premature complexes (VPCs) per hour (mean 369 ± 95) were given propranolol (120 mg daily) compared with moricizine HCl (816 ± 103 mg daily). Propranolol suppressed 38% of VPCs in the study group, moricizine HCl, 81% of VPCs, and the combination of both drugs, 87%. Moricizine HCl was more effective than propranolol in suppressing VPCs at all individual levels > 70% (p < 0.05, McNemar's test). The combination of moricizine HCl and propranolol was well tolerated. The second investigation used a placebo-controlled, double-blind, crossover design to compare the efficacy of disopyramide (600 mg daily) and moricizine HCl (800 mg daily) in 27 patients. Patients had ≥ 40 VPCs/hr on a 24-hour ambulatory electrocardiogram. During moricizine HCl administration, the mean VPC frequency decreased from 524 to 151 VPCs/hr (71.2% reduction). In contrast, disopyramide reduced VPC frequency from 535 to 253 VPCs/hr (52.8% reduction) and demonstrated significantly greater side effects (p < 0.05). Moricizine HCl was more effective than disopyramide in suppressing VPCs at all individual percent reduction levels >70% (p < 0.05, McNemar's test). Moricizine HCl was more effective in suppressing VPCs than either disopyramide or propranolol, with significantly fewer side effects.

Clinical, electrophysiologic and antiarrhythmic efficacy of moricizine HCl

The electrophysiologic effects and antiarrhythmic efficacy of moricizine HCl (1.5 to 2.0 mg/kg intravenously, and 600 to 800 mg orally/24 hours) were studied using electrophysiologic testing, ambulatory electrocardiographic monitoring, exercise stress testing and transesophageal stimulation of the left atrium. Moricizine HCl had no significant effects on the sinus node in patients with normal nodal function and did not depress sinoatrial conduction time even in patients with serious node dysfunction. Moricizine HCl significantly lengthened the following intervals: PA (32 ± 5 to 40 ± 5 ms), AH (82 ± 13 to 92 ± 12 ms), HV (45 ± 12 to 50 ± 12 ms), paced cycle length 1:1 atrioventricular node conduction (340 ± 14 to 352 ±14 ms) and paced cycle length 1:1 ventriculoatrial conduction (300 ± 14 to 400 ± 13 ms). The refractory periods of atrium, atrioventricular node and ventricular myocardium did not change significantly, and there was no alteration of the QRS or QT intervals. The drug abolished anterograde and retrograde conduction over the accessory pathway and increased the refractory period of accessory pathway in all patients. Intravenous moricizine HCl terminated and prevented tachycardia in 72% and 68 % of the patients, respectively. Oral moricizine HCl (600 to 800 mg/24 hours) prevented tachycardia in 40% of patients with a preexcitation syndrome. Intravenous moricizine HCl terminated atrioventricular nodal reentrant paroxysmal tachycardia in 66% of patients, whereas 40% responded to the oral drug. Moricizine HCl 600 to 800 mg/24 hours suppressed ventricular premature beats in 60 % of patients. A similar drug, Ethacizine, had the same electrophysiologic effects as moricizine HCl but was more potent. Ethacizine suppressed ventricular premature beats in 78% of patients. Moricizine HCl and Ethacizine, which are both phenothiazine derivatives, have similar electrophysiologic and antiarrhythmic effects in patients with cardiac arrhythmia.

Drug interactions with ethmozine ® (moricizine HCl)

Moricizine HCl, a phenothiazine derivative synthesized in the USSR in 1964, has been shown to be an orally effective antiarrhythmic drug. Moricizine HCl has demonstrated a low incidence of generally mild and transient side effects. Studies of possible drug interaction between it and other drugs most likely to be administered to cardiovascular patients are currently being conducted in US drug trials. Possible interactions between moricizine HCl and cimetidine, and between moricizine HCl and digoxin, are reviewed. The coadministration of moricizine HCl had no effect on the pharmacokinetics of cimetidine; in contrast, cimetidine administration slowed the elimination of moricizine HCl. The implications of greater therapeutic and/or toxic effects of moricizine HCl must be considered for patients receiving cimetidine and moricizine HCl concomitantly. No significant interactions were observed when monitoring serum levels of moricizine HCl and digoxin in patients with normal renal function receiving digoxin therapy for congestive heart failure or atrial fibrillation. Moricizine HCl in therapeutic dosages (10 mg/kg daily) demonstrated antiarrhythmic efficacy without significant alterations in serum digoxin levels.

Electrophysiologic aspects of moricizine HCl

Moricizine HCl, a phenothiazine derivative, is a new antiarrhythmic drug that has quinidine-like effects on the myocardium. Moricizine HCl, 1 × 10 −7 g/ml, significantly decreases V max of the transmembrane action potential of canine Purkinje fibers and reduces the duration of the action potential at 50% and 90% of repolarization, whereas resting potential is unchanged. The drug decreases the fast inward sodium current (I Na), as measured by the double sucrose gap technique in frog atrium trabeculae; the processes of activation, inactivation and reactivation of current did not change even when a high concentration of drug (5 × 10 −6 g/ml) was used. At the same dose, the slow inward calcium current (I Ca) increased, but the total outward current did not change. Using the patch-clamp technique, it was shown that moricizine HCl, 1 × 10 −4 g/ml, did not alter single-channel conductance, but essentially decreased the mean open tonic and open-state probability of potassium channels either at positive or negative holding potentials. I Na measured in a single myocyte preparation decreased faster when drug was administered in the external bath compared with intracellular injection. Moricizine HCl action on I Na of the single cell and on V max of the action potential is frequency dependent. When I Na was recorded directly, there was a cumulative effect of drug. Similar to other quinidine-like agents, moricizine HCl enhanced arrhythmogenicity within the first few minutes after coronary artery occlusion, but prevented arrhythmias 24 hours after acute myocardial infarction. Moricizine HCl exerts a direct antiarrhythmic effect on the myocardium and produces identical changes of electrophysiologic parameters (SA, AH and HV intervals and refractory periods) in the isolated and intact heart. An analog of moricizine HCl, Ethacizine, has more potent depressive effects of I Na and reduces I Ca in cardiac tissue. Preliminary experimental and clinical data have demonstrated that Ethacizine has a more potent effect than moricizine HCl and a longer duration of antiarrhythmic action.

Ethmozine ® (moricizine HCl) therapy for complex ventricular arrhythmias

Moricizine HCl (Ethmozine ®), a new antiarrhythmic agent, was administered to 102 patients with refractory ventricular fibrillation (n = 31), sustained ventricular tachycardia (VT) (n = 46) or symptomatic nonsustained VT (n = 25). A noninvasive approach utilizing monitoring and exercise testing was used in 82 patients who had a high density of reproducible spontaneous arrhythmia, whereas 20 patients without such arrhythmia required invasive electrophysiologic testing. The dosage of moricizine HCl was 200 mg 3 times daily, and during 5 to 6 days was titrated up to a maximum of 400 mg 3 times daily or 15 mg/kg daily, based on arrhythmia suppression and occurrence of side effects. Criteria for efficacy were a > 90% reduction in repetitive ventricular premature beats (couplets and runs of VT) and a > 50% reduction in ventricular premature beats when noninvasive methods were used. When electrophysiologic testing was used, the drug was judged effective if it prevented the induction of > 2 repetitive responses. Of 75 patients completing noninvasive study, 30 (40%) responded to moricizine HCl therapy, whereas only 1 of 20 patients undergoing electrophysiologic testing responded. There was no difference in moricizine HCl blood levels between responders and nonresponders (0.41 μg/ml vs 0.43 μg/ml, difference not significant). Side effects occurred in 28 patients (27%). Most frequent were aggravation of arrhythmia (n = 12), nausea and vomiting (n = 5), central nervous system toxicity (n = 3) and anticholinergic side effects (n = 3). The response rate to moricizine HCl therapy was higher in patients with nonsustained VT (62%) compared with those with sustained VT (19%) or ventricular fibrillation (33%). The response rate was 35% in patients with a left ventricular ejection fraction > 40% and 18% in those with an ejection fraction < 40% (p < 0.05). There was no difference in the density of arrhythmia during baseline studies between responders and nonresponders. Of 23 patients discharged while taking moricizine HCl, 12 patients have continued the drug for a mean follow-up of 17 months. Four patients died suddenly after 24 months, and 4 patients had a nonfatal recurrence after 5 months. Moricizine HCl is a well-tolerated antiarrhythmic drug particularly effective in patients with nonsustained VT and intact left ventricular function.

Efficacy and tolerance of ethmozine ® (moricizine HCl) in placebo-controlled trials

To investigate the tolerance and efficacy of moricizine HCl, single-blind placebo-controlled trials were conducted. The early protocols involved patients hospitalized for 14 days, and daily Holter monitoring was used to document efficacy and the degree of spontaneous variability of ventricular premature complexes (VPCs). Moricizine HCl was given orally from 2.9 to 15.3 mg/kg 3 times daily. Patients with lethal ventricular arrhythmias were excluded. Additional outpatient trials were conducted to define long-term efficacy and safety. A dose-response relation between moricizine HCl and the percentage of reduction in frequency of benign or potentially lethal ventricular arrhythmias was documented. Eighty-five percent of patients achieved a reduction in VPCs > 75% with daily dosages ranging from 10.1 to 15 mg/kg. This corresponded to a 95% decrease in mean frequency of VPCs. Long-term studies demonstrated no evidence of compromise in left ventricular function, and the proarrhythmic rate was only 2%. Symptomatic side effects were mild and usually well tolerated. Nausea, the most common, occurred in 11% of patients and dizziness in 9%. These results indicate that moricizine HCl is an effective and well-tolerated antiarrhythmic agent.

Ethmozine ® (moricizine HCl): A promising drug for “automatic” atrial ectopic tachycardia

Atrial ectopic tachycardia is an uncommon life-threatening supraventricular tachycardia in children and is resistant to usual antiarrhythmic drugs. Whereas the cellular mechanism of atrial ectopic tachycardia is unknown, atrial ectopic tachycardia may be due to a form of automaticity. Moricizine HCl has been used primarily for ventricular rhythm disturbances; the drug depresses abnormal automaticity and delayed after-depolarizations but has little effect on normal automaticity. Because of this property, we have used moricizine HCl in 4 patients with atrial ectopic tachycardia. As evidenced by continuous 24-hour Hotter monitoring, moricizine HCl was successful in suppressing atrial ectopic tachycardia in each patient. During a limited follow-up (6 months) no side effects have occurred. Moricizine HCl is a promising primary drug for atrial ectopic tachycardia.

Effects of ethmozine ® (moricizine HCl) on ventricular function using echocardiographic, hemodynamic and radionuclide assessments

Ventricular arrhythmias combined with left ventricular (LV) dysfunction in patients portend a poor prognosis. Most antiarrhythmic agents have not been sufficiently investigated to adequately describe detrimental effects on LV function; we report the effects of moricizine HCl on ventricular function in 4 trials highlighting patients with LV dysfunction. Quantitative 2-dimensional echocardiography was used to evaluate 81 patients pre- and posttreatment. There was no change in mean global LV ejection fraction (EF) during placebo compared with moricizine HCl therapy (47 ± 15% vs 46 ± 14%, p > 0.05). In a separate trial, radionuclide LVEF at rest and exercise tolerance testing were performed in 24 patients with life-threatening ventricular arrhythmias who had a mean control LVEF of 40 ± 19%. No significant change during moricizine HCl therapy (38 ± 19%, p > 0.05) was detected and exercise parameters were unchanged. Rest and exercise LV function was measured during right-sided heart catheterization in a placebo-controlled study of 20 patients with ventricular tachycardia. Moricizine HCl was well tolerated without hemodynamic deterioration in all but 3 patients, who could be identified by their inability to increase stroke volume index during exercise. Finally, the relation between initial LV function and resultant antiarrhythmic efficacy indicates that moricizine HCl controls arrhythmias best in patients with LVEF > 30%.

Pharmacokinetics of moricizine HCl

Moricizine HCl is a phenothiazine derivative with antiarrhythmic properties. It was developed in the USSR and is now undergoing clinical evaluation. Although preliminary work has shown moricizine HCl to be effective in treating both atrial and ventricular arrhythmias, little is known of its pharmacokinetics. There is a 4-fold variability in range for its elimination half-life and in volumes of distribution and clearance. There is a linear relation for peak plasma levels and area under the plasma concentration/time curve with regard to single-dose administration of moricizine HCl. The bioavailability of moricizine HCl connotes extensive first-pass effect, or presystemic metabolism. Very little of moricizine is excreted unchanged; it is extensively metabolized to certain compounds that are present in plasma for extended periods. Moricizine is extensively (92% to 95%) bound to plasma protein. Its coadministration with cimetidine leads to additive systemic effects; however, there is no evidence of alterations in steady-state levels when moricizine HCl is coadministered with digoxin. Because moricizine is a drug with active metabolites, its concentration/effect profile is complex; this poses a challenge for accurate dose titration. This may, however, be a helpful challenge in that the metabolites may one day prove useful in therapy. This surmise warrants further study.

Electrophysiology of ethmozine ® (moricizine HCl) for ventricular tachycardia

Moricizine HCl, an antiarrhythmic phenothiazine drug, was investigated for its efficacy against ventricular tachycardia (VT) in a group of 60 patients from 8 institutions using electrophysiologic testing before and after oral administration. Moricizine HCl significantly prolonged PR, QRS, AH and HV intervals and cycle length for atrioventricular nodal block, but had minimal or no effect on repolarization or cardiac refractory periods. Induction of sustained VT (in 33 patients) and nonsustained VT (in 14 patients) occurred at baseline. During moricizine HCl therapy, sustained VT was induced in 31 patients and nonsustained VT in 7 patients. In individual patients, suppression of VT induction was obtained in 18% of patients with sustained VT and in 27% of patients with nonsustained VT. Cycle length of induced VT was significantly prolonged by moricizine HCl therapy. During prospective follow-up of 37 patients, electrophysiologic study predicted recurrence or nonrecurrence of VT with a sensitivity value of 82% and specificity of 65%.

Reflections on reentry and focal activity

Initiation and maintenance of reentrant arrhythmias, such as ventricular tachycardia and fibrillation in the acute phase of myocardial ischemia, may be due to different mechanisms. The characteristics of circus movement reentry, both with and without involvement of an anatomic obstacle, are discussed. The concept of wavelength of a reentrant circuit as calculated by the product of refractory period and conduction velocity is emphasized. To maintain circus movement tachycardia in an acutely ischemic myocardium, the ischemic tissue mass must be larger than the wavelength. For maintenance of fibrillation, several independent reentrant wavelets must be simultaneously present. Agents that prolong wavelength (by lengthening refractory period, increasing conduction velocity or both) may prevent reentry. Experiments are described that show the effectiveness of lidocaine, which depresses action potentials of ischemic myocardial cells, in preventing ventricular fibrillation when administered before coronary artery occlusion in isolated pig hearts. Ventricular premature depolarizations or beats are usually necessary to initiate reentrant rhythms. They may be caused by reflection, a type of reentrant excitation involving slow conduction, or by electronic transmission over short segments of depressed or unexcitable tissue. An example of microreentry in a 4 mm segment of papillary muscle exposed to elevated extracellular K + concentrations, resulting in a ventricular premature beat, is shown. Focal mechanisms, such as abnormal automaticity or triggered activity, may also be responsible for premature impulses. Agents that suppress premature depolarizations may be effective against reentrant arrhythmias, even when they do not affect the reentrant mechanism itself. Experiments are described, showing that moricizine HCl suppresses abnormal automaticity in isolated papillary muscle, partially depolarized by application of electric current.