Ethmozine® (moricizine HCl) therapy for complex ventricular arrhythmias

Ethmorine”(MoricizineHCI)Therapyfor Complex VentricularArrhythmias MICHAEL

J.

HESSION,

MD, STEVEN LAMPERT, MD, and BERNARD LOWN, MD

Moricizine HCI (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 HCI 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 prevehted the induction of >2 repetitive responses. Of 75 patients completing noninvasive study, 30 (40 % ) responded to moricizine HCI therapy, whereas only 1 of 20 patients undergoing electrophysiologic testing responded. There was no

T

PHILIP J.

PODRID,

MD,

difference in moricizine HCI blood levels between responders and nonresponders (0.41 pg/ml vs 0.43 pg/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 HCI therapy was higher in patients with nonsustained VT (62 % ) compared with those with sustained VT (IgO/,) 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 HCI, 12 patients have continued the drug for a mean followup of 17 months. Four patients died suddenly after 24 months, and 4 patients had a nonfatal recurrence after 5 months. Moricizine HCI is a well-tolerated antiarrhythniic drug particularly effective in patients with nonsustained VT and intact left ventricular function. (Am J Cardiol 1987;60:59F-66F) stantial incidence of adverse reactions.l~z Moricizine HCl (Ethmozine@]* is a new antiarrhythmic agent undergoing clinical investigation. It is a phenothiazine derivative lacking the side effects usually associated with this class of drugs. A number of studies have reported it effective and well tolerated for the treatment of ventricular premature beats (VPBS].~,~Little is known about the action of moricizine HCl in supressing complex ventricular arrhythmias in patients with malignant ventricular arrhythmias. This article details our experience with moricizine HCl in patients with a history of life-threatening ventricular tachyarrhythmias.

reating patients with malignant ventricular arrhythmias remains a challenge for cardiologists. Although many of the newer antiarrhythmic drugs are potent, improved performance is coupled with a subFrom the Harvard School of Public Health, and the Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts. This study was supported in part by Grant No. HL07776 from the National Heart, Lung, and Blood Institute, National Institutes of Health, US Public Health Service, Bethesda, Maryland, and the Rappaport International Program in Cardiology, Boston, Massachusetts. Address for reprints: Philip J. Podrid, MD, Department of Nutrition, Harvard School of Public Health, 221 Longwood Avenue, Boston, Massachusetts 02115.

*Moricizine HCl is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozinem. 59F

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A SYMPOSIUM:

TABLE I

ETHMOZINE@ (MORICIZINE

Patient Population

HCI)-A

NEW ANTIARRHYTHMIC

(n = 102)

M F Mean age (years) Cardiac diagnosis CAD Previous MI Cardiomyopathy Valvular disease Congenital heart disease None Presenting arrhythmia VF VT Sustained Nonsustained Congestive heart failure Average LVEF (% )

79 23 58 (range 19 to 79) 67 56 16 10 2 7 31 71 46 25 52

37

CAD = coronary artery disease; LVEF = left ventricular ejection fraction; Ml = myocardial infarction; VF = ventricular fibrillation; VT = ventricular tachycardia.

Patientsand Methods The study population consisted of 102 patients referred for the management of recurrent ventricular tachyarrhythmias (Table I]. There were 79 men and 23 women, with a mean age of 58 years (range 19 to 79). Cardiac diagnosis included coronary artery disease in 67, of whom 56 had a previous myocardial infarction. Idiopathic cardiomyopathy was present in 16, valvular heart disease in 10 and congenital heart disease in 2; 7 patients had no structural heart disease, as determined by cardiac catheterization and echocardiography. Fifty-two patients were being treated for congestive heart failure, but each patient was hemodynamically stable at time of study, and medications were unaltered. The presenting arrhythmia was ventricular fibrillation (VF) in 31 patients, sustained ventricular tachycardia [VT) with syncope in 46 and runs of nonsustained VT associated with symptoms of lightheadedness or dizziness in the remaining 25. The ventricular arrhythmia was not the result of an acute myocardial infarction or precipitated by reversible factors. An average of 2.9 antiarrhythmic drugs had been ineffective before entry into the study. Upon admission to hospital, all antiarrhythmic agents were discontinued and patients were continuously monitored by a telemetric system [CAMS, American Optical). Digoxin and diuretic drugs were maintained if necessary for control of congestive heart failure, and antianginal regimens were not altered. Continuous ambulatory monitoring for 48 hours and a maximal symptom-limited exercise tolerance test [Bruce protocol) on a motorized treadmill were performed after at least 5 half-lives of washout from previous antiarrhythmic drug. 5,6A radionuclide ventriculogram was obtained in patients to determine ventricular function. This constituted the control period for establishing baseline frequency and type of arrhythmia, categorized according to the Lown grading system:6,7grade 0 = no VPBs; grade 1A = occasional, isolated VPBs (<30/h@ and
AGENT

grade 2 = frequent VPBs (>3O/hr); grade 3 = multiform VPBs; grade 4A = repetitive VPBs (couplets]; grade 4B = repetitive VPBs (runs of VT]; grade 5 = early VPBs (abutting or interrupting the T wave]. Drug effectiveness was evaluated by either noninvasive methods, using monitoring and exercise testing, or by invasive electrophysiologic study. The decision as to which approach to use was based on frequency and reproducibility of ventricular arrhythmia during the control period.8 A noninvasive approach was used for evaluating drug effect if the following criteria were present: on ambulatory monitoring, grade 2 VP@ >5O% of each 24-hour period in association withgrade 4 arrhythmia for at least 3 hours; with exercise testing, at least 2 VPBs/min in association with grade 4 arrhythmia. Patients who failed to meet these criteria underwent electrophysiologic testing using programmed electrical stimulation. The protocol for electrophysiologic testing has been previously reported.g A 6Fr hexapolar electrode catheter (USCI] was inserted via the left subclavian vein under fluoroscopic guidance and positioned in the right ventricular apex. Up to 3 extrastimuli were added during both sinus and ventricular-paced rhythms, at cycle lengths of 500 ms. Current intensities of the extrastimuli were 2 and 3 times the mid-diastolic threshold. The endpoints for testing were the reproducible induction of nonsustained VT or sustained monomorphic VT. Nonsustained VT was defined as 13 repetitive responses lasting up to 30 seconds, whereas sustained VT lasted >30 seconds and required intervention for termination. When sustained VT was induced it occurred without any antecedent episodes of nonsustained VT. Of the 102 patients, 82 had an adequate density of spontaneous arrhythmia and underwent noninvasive evaluation. During control monitoring, 63 patients had grade 2 VPBs for all monitored hours; 7 had frequent VPBs for 75% to 99% of hours; whereas 12 had grade 2 VPBs for 50% to 75% of hours. The average number of hours of grade 2 VPBs was 18.4. Grade 4A arrhythmia was present in 79 patients, of whom 53 had these forms for >75% of hours; 9 patients had 4A for 50% to 75% of hours; 17 had 4A for 25% to 50% of hours. The average number of hours for couplets was 15, with an average of 20.3 episodes/hr. Grade 4B arrhythmia was present in 76 patients. Runs of VT were present for >75% of hours in 32 patients; for 50% to 75% of hours in 12 patients; whereas 32 patients had grade 4B arrhythmia for 25% to 50% of hours. Average number of hours of VT was 8.6, and there were, on average, 11.6 runs of VT per hour. During exercise testing, the average number of VPBs induced was 149; the average number of couplets was 12; the average number of runs of VT was 4.3. The average left ventricular ejection fraction in the group of 82 patients undergoing noninvasive evaluation was 36% (870 to 80%). Twenty patients did not have adequate arrhythmia and underwent invasive electrophysiologic testing. In 8 patients nonsustained VT with an average of 7 repetitive cycles was induced, whereas in 12 patients, sustained monomorphic VT occurred. In each case VT

October 16, 1987

resembled the clinical arrhythmia. The average rate of VT was 240 (160 to 300) Sustained VT was terminated by overdrive pacing in 6 patients, whereas 6 patients required defibrillation because of hemodynamic collapse. The endpoint was achieved with 1 extrastimulus in 4 patients, 7 patients required 2 extrastimuli, 9 patients required 3 extrastimuli. The average ejection fraction in those undergoing electrophysiologic study was 39% (12% to 80%). Phase l-acute drug testing: At completion of the control period, selected patients with a high density of spontaneous arrhythmia underwent acute drug testing, following a protocol previously reported.6J0 On the day of the test, a 30-minute baseline period of continuous electrocardiographic monitoring by trendscription established the density and type of ventricular arrhythmia. A l&lead electrocardiogram was recorded to establish PR, QRS and QT intervals. Control observations also included a brief period of exercise on a bicycle ergometer, which approximated a workload similar to that of routine daily activities. Rhythm was continuously recorded by trendscription during exercise. At conclusion of the baseline period, 600 mg of moricizine HCl was administered as a single oral dose. Monitoring by trendscription was continued for 3 hours with bicycle ergometry, vital signs, electrocardiographic intervals and blood drug levels obtained hourly. Phase 2: Upon completion of acute drug testing, multiple dosing was begun, with an additional dose of 200 mg moricizine HCl administered 8 hours after the end of the acute drug test. In patients not undergoing drug testing, therapy was initiated with 200 mg moricizine HCl administered 3 times on day 1. On the second day this dosing schedule was repeated, while on the third day, if arrhythmia persisted and no side effects occurred, dosage was increased to 250 mg 3 times daily. On day 4, dosage could be increased to 300 mg 3 times daily, with further increases of dosage every 24 hours to 350 and 400 mg 3 times daily, as guided by clinical response. Maximal permitted daily dosage was 15 mg/kg. During daily therapy, drug action was evaluated by continuous telemetric monitoring and 5minute bicycle ergometry. A l&lead electrocardiogram was obtained daily for measuring electrocardiographic intervals. After 5 or more days of therapy, 24hour continuous ambulatory monitoring and treadmill exercise test or electrophysiologic studies were repeated. Blood levels were obtained 2 hours after dosing with moricizine HCl at time of exercise testing or electrophysiologic study. Criteria for efficacy during phases 1 and 2 were a >90% reduction in 4A and 4B arrhythmia and a >5O% decrease of VPBs during both monitoring and exercise. With electrophysiologic testing, efficacy was defined as the inability to induce >2 repetitive ventricular beats with up to 3 extrastimuli during both sinus and a ventricular-paced rhythm. Aggravation of arrhythmia during noninvasive evaluation was defined as a >lO-fold increase in repetitive arrhythmia or the occurrence of a sustained ventricular tachyarrhythmia not present during control studies.11 During electro-

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physiologic testing, aggravation of arrhythmia was defined as the conversion of nonsustained VT to a sustained VT when using the same or less number of extrastimuli, the induction of an endpoint when using 2 fewer extrastimuli than in control or the induction of a tachyarrhythmia with a more rapid ventricular rate.12 Phase 3: Patients responding to moricizine HCI therapy who were without side effects and who preferred this drug were discharged while taking this agent as part of a long-term management program. Patients were seen every 3 months in follow-up at the Cardiovascular Laboratory at the Harvard School of Public Health. With each visit, a physical examination, la-lead electrocardiogram, blood level screening, 24hour ambulatory monitoring and a maximum symptom-limited exercise tolerance test were obtained. Dosage was adjusted depending on emergence of side effects. Data were analyzed using the t test for paired values or x2 test, where appropriate. The criterion for significance was p <0.05.

Results Phase 1: Thirty patients underwent acute drug testing with moricizine HCl. One patient developed an exacerbation of congestive heart failure 2 hours after dosing and did not complete the study. Of the 29 patients completing acute drug testing, arrhythmia was suppressed in 22 patients (76%). The average peak blood level achieved during the acute test was 1.72 f 1.19 pg/ml, occurring 1 hour after the 600-mg dose. Two and 3 hours after dosing, levels were 1.46 f 0.84 and 1.12 f 0.67 pg/ml, respectively. Phase 2: Of the 82 patients undergoing noninvasive study, 75 patients completed the protocol, whereas

EFFECTIVE (n=31)

24 1 20c’6f-

INEFFECTIVE (n=44)

I

+*-i t-**---

t-**-I

4A

48

4A

48

VEA GRADE % m

CONTRO L AMBULATORY MONITOR MORICIZINE HCI AMBULATORY MONITOR

* PC.05 ** p<.OOl FIGURE 1. Results of maintenance moricirine HCI therapy as evaluated by ambulatory monitoring. Among the 31 responders, there was a significant reduction in hours of couplets (4A) from 12.4 to 0.4, and in ventricular tachycardia (48) from 6.9 to 0.08. In the 44 nonresponders moricizine HCI significantly reduced the hours of 4A and 48, although criteria for efficacy were not achieved. VEA = ventricular ectopic activity.

62F

A SYMPOSIUM:

ETHMOZINE@ (MORICIZINE

HCI)-A

NEW ANTIARRHYTHMIC

side effects compelled drug discontinuation in 7 patients. Thirty-one patients (44%) met the criteria for drug efficacy as evaluated with monitoring, with a reduction in the number of hours of 4A from 12.4 to 0.4

INEFFECTIVE

EFFECTIVE

4A

4B

VEA GRADE m w

CONTROL EXERCISE TEST MORICIZINE

HCI EXERCISE

TEST

* PC.05 ** PC.01

FIGURE 2. Results of maintenance therapy with moricizine HCI as evaluated by exercise testing. In the 35 responders, moricirlne HCI significantly reduced frequency of couplets (4A) per test from 18.9 to 0.3 and runs of ventricular tachycardla from 5.1 to 0.07. In nonresponders, there was a significant reduction in 4A, but not In 4B. VEA = ventricular ectopic activity.

AGENT

(9770, p
October

16, 1987

Mean moricizine HCI blood levels in patients undergoing noninvasive studies were nearly identical in responders and nonresponders: 0.41 f 0.31 and 0.43 f 0.19 pg/ml [difference not significant], respectively. With invasive therapy, the blood level for nonresponders was 0.47 pg/ml, whereas in the 1 responder, the drug level was 0.30 pg/ml. Twenty-five patients underwent both phase 1 and phase 2 drug testing (Fig. 4). The acute drug test correlated with the results in 14 patients (56%] (difference not significant]. Results of the acute drug test were not predictive of drug effect during maintenance therapy. Side effects: Twenty-eight of the 102 patients (27%) developed side effects during moricizine HCl therapy (Table II]. Aggravation of arrhythmia occurred in 12 patients. In 9, this consisted of sustained tachyarrhythmia with syncope, occurring spontaneously in 6, whereas in 3 it was provoked by exercise stress testing [Fig. 5). Electrical reversion was necessary in each. The remaining 3 patients had nonsustained VT converted to sustained VT with syncope during electrophysiologic study;_ in_ each the VT was induced with fewer extrastimuli than were required to induce nonsustained VT during control testing. Congestive heart failure was exacerbated in 3 patients. Nausea and vomiting occurred in 5 patients, necessitating discontinuation in 1. Anticholinergic side effects, common to

CONTROL

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Bide Effects (n = 28/102 [27%])

TABLE II

Cardiac Aggravation of arrhythmia CHF Gastrointestinal Anticholinergic (urinary retention, dry mouth, blurred vision) Central nervous system Rash CHF = congestive

heart

(+I

phase

C-1 I

4 1

failure.

I

2

15 12 3 5 3

10

I I

9

Total

19

2

12

4

13

6

I

25

FIGURE 4. Correlation of results of acute drug testing (ADT). Twenty-five patients completed both ADT and phase 2 testing with moricizine HCI. The ADT predicted the response to moricizine HCI in 14 patients (56%), whereas discordant results were observed in 11 patients (44%).

REST

MORICIZINE

HCI

EXERCISE

POST

EXERCISE

#DEFIBRILLATION

FIGURE 5. Example of aggravation of arrhythmia resulting from treatment with moricizine HCI. The patient presented clinically with recurrent episodes of sustained ventricular tachycardia always easily cardioverted. During baseline exercise testing there were frequent couplets and one 3-beat run of ventricular tachycardia. During therapy with moricizine HCI, exercise induced ventricular tachycardia, which rapidly degenerated into ventricular fibrillation, requiring 3 defibrillation attempts before a sinus mechanism was restored. Ventricular tachycardia and ventricular fibrillation recurred 2 more times before the rhythm stabilized.

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A SYMPOSIUM:

TABLE III Correlation of Moricizine HCI

ETHMOZINE@ (MORICIZINE

Between

Clinical

HCI)-A

Parameters

NEW ANTIARRHYTHMIC

AGENT

and Efficacy

20-

Response (%) Presenting arrhythmia Nonsustained VT Sustained VT VF LVEF >40% <40% Cardiac diagnosis CAD Cardiomyopathy Valvular disease None Abbreviations

TABLE IV

T r w 2 F

62 19 33 35 16

842

4A VEA GRADE

45

m MORICIZINE HCI EFFECTIVE R / MORICIZINE HCI INEFFECTIVE

* PC.05

Results No.

Total pts. Dead Sudden death Congestive failure Nonfatal recurrence Side effects Continued therapy

12-

28 36 70 17

as in Table I.

Long-Term

16-

23 5 4 1 4 2 12

Follow-Up

(months)

13 (l-57) 24 (3-44)

5 (2-8) 4 17 (l-57)

phenothiazine drugs, were noted in 3, including urinary retention in 2 and a combination of blurred vision, dry mouth and agitation in 1 patient. Three patients experienced central nervous system side effects, including dizziness, fatigue and paresthesias. One additional patient developed a rash, necessitating drug discontinuation. The average blood level of those patients with side effects was 0.54 pg/ml(O.l5 to 1.1) and was not different than the average level in those without side effects (difference not significant]. Correlation between clinical parameters and drug response: The response to moricizine HCl was correlated with a number of clinical characteristics to determine if any would predict response to this drug. The response rate in patients who experienced sustained VT was 19% compared with 33% in patients with a history of primary VF (difference not significant, Table III]. In contrast, patients presenting with nonsustained VT had a significantly higher response rate (62%, p 40% (mean 58%) (p <0.05]. When drug respond-

FIGURE 6. Correlation between density of ventricular arrhythmia (VEA) and response to moricizine HCI therapy. There was no significant difference in the hours of ventricular premature beats (grade 2) or runs of ventricular tachycardia (4B) between responders and nonresponders. Although the hours of couplets (4A) were greater in nonresponders, this was not a clinically important difference.

ers were compared with nonresponders, mean left ventricular ejection fractions were 46% and 3170, respectively (p 0.05), it was not clinically important. Long-term therapy: Long-term moricizine HCl therapy was continued in 23 patients who responded to the drug, were free of side effects during short-term use and who preferred this agent (Table IV). After a mean follow-up of 13 months, 11 patients have discontinued moricizine HCl therapy. Four patients died suddenly after an average of 24 months of therapy (3 to 44), whereas 1 patient died of progressive congestive heart failure unrelated to drug. Four patients had nonfatal recurrence of arrhythmia after an average of 5 months (2 to 8). Side effects occurred in 2 patients, requiring drug discontinuation. The remaining 12 patients have continued to receive moricizine HCl therapy for an average of 17 months (1 to 571(Fig. 7).

Discussion This study reviews our experience using moricizine HCl in patients with a history of malignant ventricular tachyarrhythmia refractory to conventional drugs. The intent was to determine its effectiveness and safety, as

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well as to define the type of patient who might benefit from this agent. A number of studies have reported that moricizine HCI is a highly effective antiarrhythmic agent for suppressing VPBs in patients without a history of malignant arrhythmia. Morganroth et al4 :...... :. . .NONFATAL . . . . . . . . . . . . . .RECURRENCES . . . . . . . . . . . . . . . . . . . . . .j reported that 70% of patients with frequent VPBs had a >60% reduction in arrhythmia. Moricizine HCI was reported to be as effective as quinidine for suppressing VPBs,13whereas in a comparative study Pratt et all4 found moricizine HCl to be more effective than disopyramide for abolition of VPBs, although the 2 agents were equally active on complex forms. A 1; lh 2h i0 $6 In our experience 600 mg daily of moricizine HCl, FOLLOW-UP (mo) when compared to placebo, was effective in 54% of FIGURE 7. Life-table analysis of survival among 23 patients receivpatients with frequent VPBs3 However, the value of ing long-term moricizine HCI therapy. During an average follow-up of 7 months, there were 4 sudden-death patients (12 %/year) and 4 moricizine HCl in treating patients with malignant ventricular arrhythmia remains undefined. As as- who had a nonfatal recurrence (12 %/year). sessedby means of monitoring and exercise testing, we found moricizine HCl effective in 40% of such patients. Other, newer agents, when evaluated with a feet. It is possible that the maximum daily dosage (15 mg/kg) currently used is suboptimal. It is uncertain similar protocol, exhibited a range of effectiveness varying from 35% to 60% .15-18Of interest: only 1 of 20 whether the administration of larger doses will be limpatients (5%) was rendered noninducible during elec- ited by side effects. In an attempt to determine the type of patient who trophysiologic testing, whereas in an additional 2 patients (lO%] with inducible sustained VT, only nonsus- would respond to moricizine HCl therapy, a number of tained VT could be provoked during moricizine HCI clinical parameters and their relation to drug effectiveness were analyzed. Although response to drug therapy. This low incidence of drug efficacy during electrophysiologic study has been reported with other was not related to the density of spontaneous arrhythinvestigational drugs .lgJo Although the present study mia documented on baseline ambulatory monitoring, was not designed to assessthe predictive accuracy of there was a relation to the presenting clinical arrhythmia. The drug was more effective in patients who electrophysiologic testing, it is possible that moricizine presented with nonsustained VT compared with those HCl can be added to the growing list of antiarrhythmic agents whose efficacy cannot be determined by elec- who had a history of sustained VT or VF. This suggests that moricizine HCI is more effective in patients who trophysiologic methods.21~22 Of note was the failure of acute drug testing to have less severe electrical instability, which is also suggested by the higher efficacy rates observed in papredict the effect of maintenance therapy. Although moricizine HCl was effective in 76% of subjects dur- tients without a history of serious arrhythmia who have ing acute drug testing, only 40% of these patients re- frequent VPBs. Although there was some correlation between the nature of the underlying heart disease sponded during short-term maintenance therapy. Acute drug testing was not predictive of response dur- and response to drug, the degree of left ventricular ing maintenance therapy. This is in sharp contrast to dysfunction was more strongly predictive of drug effiour results with other antiarrhythmic drugs.15J8The cacy. In patients with a left ventricular ejection frachigher response rate during phase 1 testing was sur- tion >40%, moricizine HCI was significantly more effective than for the group with a depressed left ventricprising. Moricizine HCl is a phenothiazine derivative that exhibits electrophysiologic effects on atria1 and ular ejection fraction (35% responding vs 18%). Thus, ventricular myocardial tissueaz3It interferes with sodi- patients with a left ventricular ejection fraction >40% um conductance and is thus classified as a membrane requiring therapy for nonsustained VT are most likely stabilizing agent. Onset of antiarrhythmic effect is re- to respond to moricizine HCl. The overall incidence of side effects with moriciportedly delayed for up to 48 to 72 hours.3*4A possible explanation is that metabolites of moricizine HCl pos- zine HCl was 27%, but in many patients adverse reacsessantiarrhythmic properties. Therefore, a higher re- tions were mild and resolved with a reduction in dose. sponse rate would be expected during phase 2 therapy As with other agents, moricizine HCl can aggravate compared with results after a single large oral dose. An ventricular arrhythmia; in the present study, the incialternative explanation is that the parent compound dence was 10%. We found no clinical parameter preexerts the major antiarrhythmic effects, but that these dictive of this side effect. Previous studies with moroare concentration related. During acute drug testing, cizine HCl in patients without a history of sustained the peak blood level of moricizine HCl at 1 hour after arrhythmia did not report this type of toxic reacdose administration was 3- to 4-fold higher than levels tion.3f4J4It is likely that drug-induced aggravation of achieved during maintenance therapy. With long-term arrhythmia is a complication observed in patients who therapy the drug is metabolized. Although metabolite have a history of malignant ventricular arrhythmias.24 levels may be high, the level of the parent compound is Moricizine HCl was well tolerated in patients with low-perhaps accounting for less antiarrhythmic ef- impaired left ventricular function, and in only 3 pa-

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tients with severely depressed left ventricular function did congestive failure occur. These results are in agreement with the observation that moricizine HCl does not significantly alter cardiac reserve as determined by exercise tolerance testing, even in patients with impaired ventricular function. Nonetheless, moricizine HCl exerts a mild negative inotropic effect and must be used with caution in patients with significant left ventricular dysfunction. In summary, moricizine HCl is a well-tolerated antiarrhythmic agent that suppresses repetitive ventricular arrhythmia in some groups of patients. It is particularly effective in patients with symptomatic runs of nonsustained VT, especially when left ventricular function is normal or only slightly impaired. The drug is less effective in patients with a history of sustained tachyarrhythmia, especially in the presence of marked left ventricular dysfunction. Further studies using higher maintenance doses may demonstrate improved response rates.

References 1. Podrid PJ. Antiarrhythmic

drug therapy. Benefits and hazards. Chest

1984;88:452-460.

2. Zipes DP, Troup PJ. New antiarrhythmic agents: amiodarone, aprindine, disopyromide, ethmozine, mexilitine, tocainide, verapamif. Am J Cardiol 1978;41:1005-1024. 3. Podrid PJ,Lyakishev A, Lown B, Mazur N. Ethmozine, o new ontiarrhythmic drug for suppressing ventricular premature complexes. Circulation 1380;61:450-457. 4. Morganroth J, Pearlman AS, Dunkman WB, Horowitz LN, Josephson ME, Michelson EL. Ethmozine: 01new antiarrhythmic developed in the USSR. Efficacy and tolerance. Am Heart J 1979;98:621-628. 5. Graboys TB, Lown B, Podrid PJ, DeSilva R. Long term survival of patients with mahgnont ventricular arrhythmia treated with antiarrhythmic drugs. Am J Cardioll982;59:437-443. 6. Lown B, Podrid PJ,DeSilva R, Graboys TB. Sudden cardiac death. Monagement of the patient at risk. Curr Probl Cordial 1980;4:1-62. 7. Lown B, Wolf M. Approaches to sudden death from coronary heart disease. Circulation 1971;44:130-142.

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8. Podrid PJ, Treatment of ventricular arrhythmia: noninvasive versus invaand limitations. Chest 1985;86:121-128. 9. Podrid PJ, Schoenberger A, Lampert S, Mates J, Porterfield J. Raeder E, Lown B, Corrigan E. The use of nonsustained ventricular tachycardio os o guide to ontiarrhythmic drug therapy in patients with malignant ventricular arrhythmia. Am Heart J 1983;105:181-188. 10. Gaughan CE, Lown B, Corrigan J, Voukydis J, Besser W. Acute oral testing for determining antiarrhythmic drug efficacy. I. Quinidine. Am J Cordiof 1976;38:677-682. 11. Velebit V, Podrid PJ, Lown B, Cohen BH, Graboys TB. Aggravation and provocation of ventricular arrhythmias by antiorrhythmic drugs. Circulation 1982;65:886-894. 12. Poser RF, Podrid PJ, Lombardi F, Lown B. Aggravation of induced arrhythmia with ontiarrhythmic electrophysiologic testing. Am Heart J 1985; 110:9-16. 13. Morganroth J, Orth D, Michelson E, Dunkman B, Pearlman A, Horowitz L, Josephson M, Kastor J. Comparative antiorrhythmic efficacy and tolerance of ethmozine and quinidine (abstr). Circulation 1978;57:II-103. 14. Pratt CM, Young JB, Francis MJ, Taylor AA, Norton HJ, English L, Mann DE, Kopelen H, Quinones MA, Roberts N. Comparative effect of disopyramide and ethmozine in suppressing complex ventricular arrhythmios by use of a double blind, placebo controlled, longitudinal crossover design. Circulotion 1984;69:288-297. 15. Podrid PI. Lown B. Mexilitine for ventricular arrhythmias. Am J Cardiol sive approach-applications

1981;47:895-902. 16. Podrid PJ, Lown B. Tocainide therapy for refractory symptomatic ventricular arrhythmias. Am J Cardiol1982;49:127-129. 17. Chesnie B, Lampert S, Podrid PI, Lown B. Lorcoinide for refractory

ventricular arrhythmias. JACC 1984;3:1531-1534. 18. Podrid PJ, Cytryn R, Lown B. Propafenone--a noninvosive evaluation of efficacy. Am J CardioJ1984;54:53D-59D. 19. Morady F, Scheinman MM, Hess DS, Sung RJ, Shen E, Shapiro W. Electrophysiologic testing in the management of survivors of out of hospital cardiac arrest. Am J CardioI1983;51:85-92. 20. Spielman SR, Schwartz JS,McCarthy DM, Horowitz LN, Greenspan AM, Sadowski LM, Josephson ME, Waxman HL. Predictors of successor foilure of medical therapy in patients with chronic recurrent sustained ventricular tachycordio: (I discriminant analysis. JACC 1983;1:403-408. 21. Hamer AW, Finerman WB, Peter T, Mandel WJ. Disparity between the clinical and electrophysiologic effects of amiodarone in the treatment of recurrent ventricular tochyarrhythmias. Am Heart J 1981;102:992-999. 22. Kingman H, Brugada P, Paulussen G, Wellens HJJ. Intravenous and oral uroaofenone in aatients with ventricular tochvcardia or fibrillation. Circulaiion 1984;70:11-55.

23. Danilo P, Langan WB, Rosen MR. Effects of the phenothiazine analog, EN313, on ventricular arrhythmias in the dog. Eur J PharmocoJ1977;45:127133. 24. Slater W, Podrid P, Lampert J, Lown B. Are there clinical predictors for arrhythmia aggravation? [abstr]. JACC 1986;suppJA:158A.