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Ethmozine® (moricizine HCl): A promising drug for “automatic” atrial ectopic tachycardia
Ethmozine”(MoricizineHCI):A PromisingDrugfor “Automatic” Atrial EctopicTachycardia VICTORIA L. EVANS, MD, ARTHUR GARSON, Jr., MD, RICHARD T. SMITH, MD, JEFFREY P. MOAK, MD, PAT McVEY, RN, and DAN G. McNAMARA, MD
Atriai ectopic tachycardia is an uncommon iifethreatening supraventricuiar tachycardia in children and is resistant to usual anti&rhythmic drugs. Whereas the cellular mechanism of atriai ectopic tachycardia is unknown, atriai ectopic tachycardia may be due to a form of automaticity. Moricizine HCI 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
M
oricizine HCI (Ethmozine@)*, a phenothiazine derivative, was initially developed as an antiarrhythmic drug in the USSR, with preliminary results demonstrating efficacy against ventricular rhythm disturbances.*M3Results of investigations in the US indicate that moricizine HCI is an effective antiarrhythmic drug, producing significant reductions in the frequency of ventricular premature depolarizations4-6 and preventing recurrent ventricular tachycardia.7 Moricizine HCI also depresses abnormal automaticity and delayed after-depolarizations but has little effect on normal automaticity.* Whereas the cellular mechanism of atria1 ectopic tachycardia is unknown, atria1 ectopic tachycardia may be due to a form of abnormal automaticity. Due to moricizine HCl’s ability to suppress abnormal automaticity, we have used moricizine HCl in 4 patients with atria1 ectopic tachycardia.
Featuresof Atrial Ectopic Tachycardia Atria1 ectopic tachycardia has been defined by Goldreyer,g Gillette, lo Scheinmanll and their co-workers. The diagnosis of atria1 ectopic tachycardia may be suspected from the surface electrocardiogram. In all patients P waves are clearly visible. If a P wave is not visible, the rhythm is most likely not atria1 ectopic tachycardia. P wave rates vary from 100 to 250. The PR * Moricizine HCI is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozinem. 83F
this property, we have used moricizine HCI in 4 patients with atriai ectopic tachycardia. As evidenced by continuous 24-hour Hoiter monitoring, moricizine HCI was successful in suppressing atriai ectopic tachycardia in each patient. During a limited follow-up (6 months) no side effects have occurred. Moricizine HCI is a promising primary drug for atriai ectopic tachycardia. (Am J Cardioi 1987;60:83F-86F)
interval is usually normal. If the onset of supraventricular tachycardia is observed, there is a progressive shortening in cycle length. This “warmup” behavior is distinct from the oscillatory behavior of most types of reentry supraventricular tachycardia. The diagnosis of atria1 ectopic tachycardia is confirmed by intracardiac electrophysiologic studies. Atria1 ectopic tachycardia is neither induced nor terminated by rapid atria1 pacing or premature extrastimuli or cardioversion. Rapid atria1 pacing at a rate faster than the atria1 ectopic tachycardia will capture the atrium, but upon termination of pacing, the tachycardia resumes without an intervening sinus beat. The atria1 activation sequence and P wave of the first beat are identical to the subsequent beats of atria1 ectopic tachycardia. Unlike the usual types of supraventricular tachycardia in which the atrioventricular node is involved in sustaining supraventricular tachycardia, atrioventricular block can occur in the presence of atria1 ectopFrom Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas. This study was supported by grant HL07190 from the National Institutes of Health, Bethesda, Maryland; by HHS grant RR00188 from the US Public Health Service, Washington, D.C.; and by a grant from the J. S. Abercrombie Foundation, Houston, Texas. Address for reprints: Arthur Garson, Jr., MD, Pediatric Cardiology, Texas Children’s Hospital, 6621 Fannin, Houston, Texas 77030.
84F
A SYMPOSIUM:
ETHMOZINP
(MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
ic tachycardia. In atria1 ectopic tachycardia, atria1 cycle length is not a direct function of atrioventricular nodal conduction.
Methodsand Patients Patients: Patients with a documented life-threatening supraventricular arrhythmia not controlled with currently available antiarrhythmic agents were included in the study. Excluded were patients with ventricular arrhythmias in the immediate postoperative period, patients with ventricular arrhythmias within 7 days of acute myocardial infarction, patients in cardiogenie shock and those known to be hypersensitive to moricizine HCl or other phenothiazines. Patients with congestive heart failure, preexisting second- or thirddegree atrioventricular block or severe gastrointestinal, renal, hepatic, hematologic or metabolic disorders, as well as patients receiving phenothiazines in addition to moricizine HCl, were treated with extra caution. Each patient was admitted to the Clinical Research Center at Texas Children’s Hospital. A complete medical history and physical examination, including neurological examination, body weight, height, temperature, blood pressure and pulse rate, were performed. A baseline 15-lead electrocardiogram, 24-hour electrocardiogram, &dimensional echocardiogram, M-mode echocardiogram and chest x-ray were obtained. Baseline laboratory studies were obtained before starting moricizine HCl therapy and included a complete blood count with differential, platelet count, urinalysis, serum lactic acid dehydrogenase, serum glutamicpyruvic transaminase, urea nitrogen, bilirubin, total protein, albumin, glucose, electrolytes, calcium, phosphorus, creatinine, uric acid, cholesterol, triglyceride levels, antinuclear antibody titer and moricizine HCl level. All antiarrhythmic drugs except digoxin were discontinued before starting therapy with moricizine HCl. After 5 half-lives had passed, moricizine HCl therapy was started. The initial loading dosage was 7 mg/kg/day administered in 3 equal doses at &hour intervals. After administering the initial loading dose, the subsequent dosage consisted of 3 equal doses of 5 mg/kg/day given at 8-hour intervals. Efficacy was
TABLE
I
Patient
AGENT
measured by 24-hour electrocardiographic readings. Moricizine HCl was considered effective if episodes of tachycardia were eliminated, as determined by readings from the 24-hour electrocardiogram. If moricizine HCl was not effective, the dosage was increased every 48 hours by 2.5 mg/kg/day in 3 divided doses, 3 times daily, up to a maximum dosage of 15.0 mg/kg/l2 hr in 3 divided doses, or 1,200 mg/day.
Results Four patients with incessant atria1 ectopic tachycardia were included in the study (Table I). Their ages were 3,4,5 and 18 years [average 7.5). They had documented tachycardia for 2.5, 3.5, 4.5 and 0.5 years, respectively, before starting moricizine HCl. Atria1 ectopic tachycardia had not been controlled by previous medical therapy. One patient (no. 2) had unsuccessful surgical cryoablation of the atria1 ectopic focus, Each patient had myocardial dysfunction, as evidenced by chronic cardiomyopathy and abnormal left ventricular shortening fraction: 21%, 10%,27% and 27%, respectively (mean 21%; normal shortening fraction 28% to 43%). No patient had evidence of structural heart disease. Each patient was started on 7 mg/kg/day. Final dosageswere 15 mg/kg/day for patients 1,2 and 3, and 9.75 for patient 4. The mean dose was 13.7 mg/kg/day. During moricizine HCl administration, continuous 24-hour Holter monitor readings were obtained. Each patient had atria1 ectopic tachycardia for the entire 24hour period before starting moricizine HCl. An initial effect of moricizine HCl was observed in the youngest patients at a dosage of 11 mg/kg/day: at maximum dosage, 3 of 4 patients were in sinus rhythm for 24 of 24 hours. The other patient is currently receiving a maximum dosage of 15 mg/kg/day. This patient is in sinus rhythm for 23 of 24 hours. No patient had exacerbation of atria1 ectopic tachycardia or other proarrhythmic effects while receiving moricizine HCl therapy. The drug had no effect on PR interval or QRS duration. The QT interval was slightly lengthened (Table II]. Average heart rate was significantly decreased. During moricizine HCl administration no abnormalities were noted on routine physical examination, including neurologic examination, body weight,
Characteristics Pt.
Age(yrs) Documented duration (yrs) of tachycardia before moricizine HCI therapy Previous medication
Previous surgery for arrhythmia Final dosage (mg/kg/day) Duration of follow-up (mo)
1
2
3
4
3 2.5
4 3.5
5 4.5
18 0.5
digoxin
verapamil
0 15 5
0 9.75 5
digoxin propranolol
0, 15 1
digoxin propranolol verapamil quinidine amiodarone + 15 12
October 16, 1987
TABLE II
Effect of Moricizine
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 60
85F
HCI on Electrocardiogram Pt. 1
EGG intervals (seconds) PR QRS QT 24-hour electrocardiogram Average heart rate (beatsjmin)
2
3
4
Pre
Post
Pre
Post
Pre
Post
Pre
Post
0.14 0.07 0.36
0.14 0.08 0.36
0.16 0.10 0.26
0.14 0.09 0.34
0.12 0.05 0.28
0.13 0.05 0.36
0.16 0.06 0.32
0.15 0.08 0.36
180
92
182
64
170
81
102
81
height, temperature, blood pressure and pulse rate. No abnormalities were noted on the aforementioned baseline laboratory tests. Cardiac function as determined by history, physical examination or echocardiogram did not deteriorate during treatment with moricizine HCl. Moricizine HCl was well tolerated in each patient with no adverse reactions. Length of follow-up has been 1 to 12 months (mean 6). No abnormalities in physical examination or baseline laboratory tests have occurred during moricizine HCI therapy. Cardiac function as determined by echocardiogram has improved in each patient. Echocardiographic measurement of left ventricular shortening fraction showed improvement (Table III). Each patient has had continual suppression of atria1 ectopic tachycardia while receiving maintenance therapy with moricizine HCl.
Discussion Possible “mechanism” of atria1 ectopic tachycardia: Moricizine HCl is a promising primary drug for the management of atria1 ectopic tachycardia. The precise mechanism of atria1 ectopic tachycardia is not known. However, atdal ectopic tachycardia may be due to abnormal automatic@. Abnormal automaticity occurs in depolarized cells with membrane potential of -50 to -70 mV. Abnormal automaticity occurs spontaneously and may be overdrive-suppressed or overdrive-enhanced. In some patients, overdrive suppression may have no effect. Theoretically, treatment with moricizine HCI could have caused exit block or have affected a reentry circuit. Microelectrode studies are needed to determine the precise mechanism of atria1 ectopic tachycardia in patients. Dosage of moricizine HCl: per kilogram or per m?: Complete suppression of atria1 ectopic tachycardia occurred in 3 of 4 patients. The other patient was in sinus rhythm for 23 of 24 hours. This patient is on the lowest dosage per m2. At present the maximum dosage used is calculated on the basis of kilogram of body weight, not by m2 of body surface area. All the parameters of pharmacology, absorption, distribution, metabolism and elimination, however, are dependent on body surface area rather than body weight.12 Since the younger child has a larger body surface area per kilogram than the older child or adult, drug dosage should be calculated on the basis of body surface, which would increase the dosage per kilogram. The maxi-
TABLE III Shortening
M-Mode Echocardiographic Fraction*
Left Ventricular
Patient
Before Moricizine HCI Therapy (%)
With Moricizine HCI Therapy (% )
1 2 3 4
21 IO 27 27
27 33 30 34
* normal = 28 % to 43 %
mum dosage of 15 mg/kg/day may be insufficient because all but 1 patient required the maximum dosage for suppression of tachycardia. If the dosage had been calculated on the basis of body surface area, the maximum dosage would have been higher. Tachycardia-induced cardiomyopathy: During atria1 tachycardia, and while in sinus rhythm immediately after successful treatment, each patient had myocardial dysfunction, as evidenced by chronic cardiomegaly and abnormal left ventricular shortening fraction. Each patient had improvement in cardiac function during moricizine HCl therapy, as documented by less cardiomegaly and normalization of left ventricular shortening fraction. Any chronic tachycardia may lead to myocardial dysfunction or cardiomyopathy and should be treated aggressively.13 Previously conventional medical therapy was only partially successful in treating atria1 ectopic tachycardia. Despite a slower rate of atria1 ectopic tachycardia and fewer symptoms, when atria1 ectopic tachycardia is left untreated, the patient is likely to go on to develop a cardiomyopathy. Successful treatment of atria1 ectopic tachycardia with moricizine HCI would eliminate tachycardia-induced cardiomyopathy in these patients. Surgical ablation or catheter electroablation is not always successful due to the presence of multiple ectopic foci among other factors.
References 1. Zaslovskaya RM, Skorobogatskya IF, Kolbanouskaya EY. Ethmozin therapy of patients with rhythm disturbances in heart activity. Sov Med 1969;5:5o54. 2. Gomzakova TG. Results of clinical study of the ontiarrhythmic drug corbazinc (Ethmozin). Viach Pelo 1970;4:62-64. 3. Votchal BY, Lozinskiy LG. Efficacy of a new antiarrhythmic drug, ethmozin. Klin Med (Mask) 171;10:16-22.
86F
A SYMPOSIUM:
ETHMOZINEB
(MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
4. Morganroth J, Pearlman AS, Dunkman WB, Horowitz LN, Josephson ME, Michelson EL. Ethmozine: a new antiarrhythmic agent developed in the USSR. Efficacy and tolerance. Am Heart fl979;98:621-628. 5. Podrid PJ, Lyakishev A, Lown B, Masur N. Ethmozin, a new ontiarrhythmic drug for suppressing ventricular premature complexes. Circulation 1980;61:450-457. 6. Singh SN, DiBianco R, Gottdierer JS, Ginsberg R, Fletcher RD. Effect of moricizine hydrochloride in reducing chronic high frequency ventricular arrhythmia: results of a prospective, controlled trial. Am 1 Cardiol 1984; 53:745-748. 7. Pratt CL, Yepsen SC, Taylor AA, Mason DT, Miller RR, Quinones MA, Lewis RA. Ethmozine suppression of single and repetitive ventricular premature depolarizations during therapy: documentation of efficacy and long-term safety. Am Heart J 1983;106:85-91.
AGENT
8. Ilvento JP, Provet J, Danilo P Jr, Rosen MR. Fast and slow idioventricular rhythms in the canine heart: a study of their mechanism using antiarrhythmic drugs and electrophysiologic testing. Am J Cardiol1982;49:1909-1916. 9. Goldreyer BN, Gallagher JJ, Damato AN. The electrophysiologic demonstration of atrial ectopic tachycardia in man. Am Heart 1 1973;85:205-210. 10. Gillette PC, Garson A Jr. Electrophysiologic and pharmacologic characteristics of automatic ectopic atrial tachycardia. Circulation 1977:5&V-574. 11. Scheinman MM, Basu D, Hollenberg M. Efectrophysiologic studies in patients with persistent atria1 tachycordia. Circulation 1976;50:266-271. 12. Maxwell GM. Principles of Pediatric Pharmacology. New York: Oxford University Press, 1984:89-99. 13. Gillette PC, Smith RT, Garson A, Cooley DA, Reul GJ, McNamara DC. Chronic supraventricular tachycardia: a curable cause of congestive cardiomyopathy. [AMA 1985;253:391-392.
Atriai ectopic tachycardia is an uncommon iifethreatening supraventricuiar tachycardia in children and is resistant to usual anti&rhythmic drugs. Whereas the cellular mechanism of atriai ectopic tachycardia is unknown, atriai ectopic tachycardia may be due to a form of automaticity. Moricizine HCI 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
M
oricizine HCI (Ethmozine@)*, a phenothiazine derivative, was initially developed as an antiarrhythmic drug in the USSR, with preliminary results demonstrating efficacy against ventricular rhythm disturbances.*M3Results of investigations in the US indicate that moricizine HCI is an effective antiarrhythmic drug, producing significant reductions in the frequency of ventricular premature depolarizations4-6 and preventing recurrent ventricular tachycardia.7 Moricizine HCI also depresses abnormal automaticity and delayed after-depolarizations but has little effect on normal automaticity.* Whereas the cellular mechanism of atria1 ectopic tachycardia is unknown, atria1 ectopic tachycardia may be due to a form of abnormal automaticity. Due to moricizine HCl’s ability to suppress abnormal automaticity, we have used moricizine HCl in 4 patients with atria1 ectopic tachycardia.
Featuresof Atrial Ectopic Tachycardia Atria1 ectopic tachycardia has been defined by Goldreyer,g Gillette, lo Scheinmanll and their co-workers. The diagnosis of atria1 ectopic tachycardia may be suspected from the surface electrocardiogram. In all patients P waves are clearly visible. If a P wave is not visible, the rhythm is most likely not atria1 ectopic tachycardia. P wave rates vary from 100 to 250. The PR * Moricizine HCI is manufactured by Du Pont Pharmaceuticals under the trade name of Ethmozinem. 83F
this property, we have used moricizine HCI in 4 patients with atriai ectopic tachycardia. As evidenced by continuous 24-hour Hoiter monitoring, moricizine HCI was successful in suppressing atriai ectopic tachycardia in each patient. During a limited follow-up (6 months) no side effects have occurred. Moricizine HCI is a promising primary drug for atriai ectopic tachycardia. (Am J Cardioi 1987;60:83F-86F)
interval is usually normal. If the onset of supraventricular tachycardia is observed, there is a progressive shortening in cycle length. This “warmup” behavior is distinct from the oscillatory behavior of most types of reentry supraventricular tachycardia. The diagnosis of atria1 ectopic tachycardia is confirmed by intracardiac electrophysiologic studies. Atria1 ectopic tachycardia is neither induced nor terminated by rapid atria1 pacing or premature extrastimuli or cardioversion. Rapid atria1 pacing at a rate faster than the atria1 ectopic tachycardia will capture the atrium, but upon termination of pacing, the tachycardia resumes without an intervening sinus beat. The atria1 activation sequence and P wave of the first beat are identical to the subsequent beats of atria1 ectopic tachycardia. Unlike the usual types of supraventricular tachycardia in which the atrioventricular node is involved in sustaining supraventricular tachycardia, atrioventricular block can occur in the presence of atria1 ectopFrom Baylor College of Medicine and Texas Children’s Hospital, Houston, Texas. This study was supported by grant HL07190 from the National Institutes of Health, Bethesda, Maryland; by HHS grant RR00188 from the US Public Health Service, Washington, D.C.; and by a grant from the J. S. Abercrombie Foundation, Houston, Texas. Address for reprints: Arthur Garson, Jr., MD, Pediatric Cardiology, Texas Children’s Hospital, 6621 Fannin, Houston, Texas 77030.
84F
A SYMPOSIUM:
ETHMOZINP
(MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
ic tachycardia. In atria1 ectopic tachycardia, atria1 cycle length is not a direct function of atrioventricular nodal conduction.
Methodsand Patients Patients: Patients with a documented life-threatening supraventricular arrhythmia not controlled with currently available antiarrhythmic agents were included in the study. Excluded were patients with ventricular arrhythmias in the immediate postoperative period, patients with ventricular arrhythmias within 7 days of acute myocardial infarction, patients in cardiogenie shock and those known to be hypersensitive to moricizine HCl or other phenothiazines. Patients with congestive heart failure, preexisting second- or thirddegree atrioventricular block or severe gastrointestinal, renal, hepatic, hematologic or metabolic disorders, as well as patients receiving phenothiazines in addition to moricizine HCl, were treated with extra caution. Each patient was admitted to the Clinical Research Center at Texas Children’s Hospital. A complete medical history and physical examination, including neurological examination, body weight, height, temperature, blood pressure and pulse rate, were performed. A baseline 15-lead electrocardiogram, 24-hour electrocardiogram, &dimensional echocardiogram, M-mode echocardiogram and chest x-ray were obtained. Baseline laboratory studies were obtained before starting moricizine HCl therapy and included a complete blood count with differential, platelet count, urinalysis, serum lactic acid dehydrogenase, serum glutamicpyruvic transaminase, urea nitrogen, bilirubin, total protein, albumin, glucose, electrolytes, calcium, phosphorus, creatinine, uric acid, cholesterol, triglyceride levels, antinuclear antibody titer and moricizine HCl level. All antiarrhythmic drugs except digoxin were discontinued before starting therapy with moricizine HCl. After 5 half-lives had passed, moricizine HCl therapy was started. The initial loading dosage was 7 mg/kg/day administered in 3 equal doses at &hour intervals. After administering the initial loading dose, the subsequent dosage consisted of 3 equal doses of 5 mg/kg/day given at 8-hour intervals. Efficacy was
TABLE
I
Patient
AGENT
measured by 24-hour electrocardiographic readings. Moricizine HCl was considered effective if episodes of tachycardia were eliminated, as determined by readings from the 24-hour electrocardiogram. If moricizine HCl was not effective, the dosage was increased every 48 hours by 2.5 mg/kg/day in 3 divided doses, 3 times daily, up to a maximum dosage of 15.0 mg/kg/l2 hr in 3 divided doses, or 1,200 mg/day.
Results Four patients with incessant atria1 ectopic tachycardia were included in the study (Table I). Their ages were 3,4,5 and 18 years [average 7.5). They had documented tachycardia for 2.5, 3.5, 4.5 and 0.5 years, respectively, before starting moricizine HCl. Atria1 ectopic tachycardia had not been controlled by previous medical therapy. One patient (no. 2) had unsuccessful surgical cryoablation of the atria1 ectopic focus, Each patient had myocardial dysfunction, as evidenced by chronic cardiomyopathy and abnormal left ventricular shortening fraction: 21%, 10%,27% and 27%, respectively (mean 21%; normal shortening fraction 28% to 43%). No patient had evidence of structural heart disease. Each patient was started on 7 mg/kg/day. Final dosageswere 15 mg/kg/day for patients 1,2 and 3, and 9.75 for patient 4. The mean dose was 13.7 mg/kg/day. During moricizine HCl administration, continuous 24-hour Holter monitor readings were obtained. Each patient had atria1 ectopic tachycardia for the entire 24hour period before starting moricizine HCl. An initial effect of moricizine HCl was observed in the youngest patients at a dosage of 11 mg/kg/day: at maximum dosage, 3 of 4 patients were in sinus rhythm for 24 of 24 hours. The other patient is currently receiving a maximum dosage of 15 mg/kg/day. This patient is in sinus rhythm for 23 of 24 hours. No patient had exacerbation of atria1 ectopic tachycardia or other proarrhythmic effects while receiving moricizine HCl therapy. The drug had no effect on PR interval or QRS duration. The QT interval was slightly lengthened (Table II]. Average heart rate was significantly decreased. During moricizine HCl administration no abnormalities were noted on routine physical examination, including neurologic examination, body weight,
Characteristics Pt.
Age(yrs) Documented duration (yrs) of tachycardia before moricizine HCI therapy Previous medication
Previous surgery for arrhythmia Final dosage (mg/kg/day) Duration of follow-up (mo)
1
2
3
4
3 2.5
4 3.5
5 4.5
18 0.5
digoxin
verapamil
0 15 5
0 9.75 5
digoxin propranolol
0, 15 1
digoxin propranolol verapamil quinidine amiodarone + 15 12
October 16, 1987
TABLE II
Effect of Moricizine
THE AMERICAN
JOURNAL
OF CARDIOLOGY
Volume 60
85F
HCI on Electrocardiogram Pt. 1
EGG intervals (seconds) PR QRS QT 24-hour electrocardiogram Average heart rate (beatsjmin)
2
3
4
Pre
Post
Pre
Post
Pre
Post
Pre
Post
0.14 0.07 0.36
0.14 0.08 0.36
0.16 0.10 0.26
0.14 0.09 0.34
0.12 0.05 0.28
0.13 0.05 0.36
0.16 0.06 0.32
0.15 0.08 0.36
180
92
182
64
170
81
102
81
height, temperature, blood pressure and pulse rate. No abnormalities were noted on the aforementioned baseline laboratory tests. Cardiac function as determined by history, physical examination or echocardiogram did not deteriorate during treatment with moricizine HCl. Moricizine HCl was well tolerated in each patient with no adverse reactions. Length of follow-up has been 1 to 12 months (mean 6). No abnormalities in physical examination or baseline laboratory tests have occurred during moricizine HCI therapy. Cardiac function as determined by echocardiogram has improved in each patient. Echocardiographic measurement of left ventricular shortening fraction showed improvement (Table III). Each patient has had continual suppression of atria1 ectopic tachycardia while receiving maintenance therapy with moricizine HCl.
Discussion Possible “mechanism” of atria1 ectopic tachycardia: Moricizine HCl is a promising primary drug for the management of atria1 ectopic tachycardia. The precise mechanism of atria1 ectopic tachycardia is not known. However, atdal ectopic tachycardia may be due to abnormal automatic@. Abnormal automaticity occurs in depolarized cells with membrane potential of -50 to -70 mV. Abnormal automaticity occurs spontaneously and may be overdrive-suppressed or overdrive-enhanced. In some patients, overdrive suppression may have no effect. Theoretically, treatment with moricizine HCI could have caused exit block or have affected a reentry circuit. Microelectrode studies are needed to determine the precise mechanism of atria1 ectopic tachycardia in patients. Dosage of moricizine HCl: per kilogram or per m?: Complete suppression of atria1 ectopic tachycardia occurred in 3 of 4 patients. The other patient was in sinus rhythm for 23 of 24 hours. This patient is on the lowest dosage per m2. At present the maximum dosage used is calculated on the basis of kilogram of body weight, not by m2 of body surface area. All the parameters of pharmacology, absorption, distribution, metabolism and elimination, however, are dependent on body surface area rather than body weight.12 Since the younger child has a larger body surface area per kilogram than the older child or adult, drug dosage should be calculated on the basis of body surface, which would increase the dosage per kilogram. The maxi-
TABLE III Shortening
M-Mode Echocardiographic Fraction*
Left Ventricular
Patient
Before Moricizine HCI Therapy (%)
With Moricizine HCI Therapy (% )
1 2 3 4
21 IO 27 27
27 33 30 34
* normal = 28 % to 43 %
mum dosage of 15 mg/kg/day may be insufficient because all but 1 patient required the maximum dosage for suppression of tachycardia. If the dosage had been calculated on the basis of body surface area, the maximum dosage would have been higher. Tachycardia-induced cardiomyopathy: During atria1 tachycardia, and while in sinus rhythm immediately after successful treatment, each patient had myocardial dysfunction, as evidenced by chronic cardiomegaly and abnormal left ventricular shortening fraction. Each patient had improvement in cardiac function during moricizine HCl therapy, as documented by less cardiomegaly and normalization of left ventricular shortening fraction. Any chronic tachycardia may lead to myocardial dysfunction or cardiomyopathy and should be treated aggressively.13 Previously conventional medical therapy was only partially successful in treating atria1 ectopic tachycardia. Despite a slower rate of atria1 ectopic tachycardia and fewer symptoms, when atria1 ectopic tachycardia is left untreated, the patient is likely to go on to develop a cardiomyopathy. Successful treatment of atria1 ectopic tachycardia with moricizine HCI would eliminate tachycardia-induced cardiomyopathy in these patients. Surgical ablation or catheter electroablation is not always successful due to the presence of multiple ectopic foci among other factors.
References 1. Zaslovskaya RM, Skorobogatskya IF, Kolbanouskaya EY. Ethmozin therapy of patients with rhythm disturbances in heart activity. Sov Med 1969;5:5o54. 2. Gomzakova TG. Results of clinical study of the ontiarrhythmic drug corbazinc (Ethmozin). Viach Pelo 1970;4:62-64. 3. Votchal BY, Lozinskiy LG. Efficacy of a new antiarrhythmic drug, ethmozin. Klin Med (Mask) 171;10:16-22.
86F
A SYMPOSIUM:
ETHMOZINEB
(MORICIZINE
HCI)-A
NEW ANTIARRHYTHMIC
4. Morganroth J, Pearlman AS, Dunkman WB, Horowitz LN, Josephson ME, Michelson EL. Ethmozine: a new antiarrhythmic agent developed in the USSR. Efficacy and tolerance. Am Heart fl979;98:621-628. 5. Podrid PJ, Lyakishev A, Lown B, Masur N. Ethmozin, a new ontiarrhythmic drug for suppressing ventricular premature complexes. Circulation 1980;61:450-457. 6. Singh SN, DiBianco R, Gottdierer JS, Ginsberg R, Fletcher RD. Effect of moricizine hydrochloride in reducing chronic high frequency ventricular arrhythmia: results of a prospective, controlled trial. Am 1 Cardiol 1984; 53:745-748. 7. Pratt CL, Yepsen SC, Taylor AA, Mason DT, Miller RR, Quinones MA, Lewis RA. Ethmozine suppression of single and repetitive ventricular premature depolarizations during therapy: documentation of efficacy and long-term safety. Am Heart J 1983;106:85-91.
AGENT
8. Ilvento JP, Provet J, Danilo P Jr, Rosen MR. Fast and slow idioventricular rhythms in the canine heart: a study of their mechanism using antiarrhythmic drugs and electrophysiologic testing. Am J Cardiol1982;49:1909-1916. 9. Goldreyer BN, Gallagher JJ, Damato AN. The electrophysiologic demonstration of atrial ectopic tachycardia in man. Am Heart 1 1973;85:205-210. 10. Gillette PC, Garson A Jr. Electrophysiologic and pharmacologic characteristics of automatic ectopic atrial tachycardia. Circulation 1977:5&V-574. 11. Scheinman MM, Basu D, Hollenberg M. Efectrophysiologic studies in patients with persistent atria1 tachycordia. Circulation 1976;50:266-271. 12. Maxwell GM. Principles of Pediatric Pharmacology. New York: Oxford University Press, 1984:89-99. 13. Gillette PC, Smith RT, Garson A, Cooley DA, Reul GJ, McNamara DC. Chronic supraventricular tachycardia: a curable cause of congestive cardiomyopathy. [AMA 1985;253:391-392.