The electrophysiologic effects of oral cibenzoline

J. ELECTROCARDIOLOGY 17 (1), 1984, 15-24

The Electrophysiologic Effects of Oral Cibenzoline BY MARK KUSIINER, M . D . * , EVA MAGIROS, M . D . * , ROBERT PETERS, M.D.'~, NATIIAN CARLINER, M.D.**, GARY PLOTNICK, M.D.1-1"AND MICHAEL FISHER, M . D . * * *

SUMMARY F i v e m a l e p a t i e n t s w i t h chronic s t a b l e v e n t r i c u l a r a r r h y t h m i a s u n d e r w e n t a p l a c e b o c o n t r o l l e d a s c e n d i n g dose s t u d y w i t h oral cibenzoline, a n e w t y p e 1 a n t i a r r h y t h m i c d r u g . A m b u l a t o r y E C G (Holter) r e c o r d i n g s a n d e l e c t r o p h y s i o l o g i c s t u d i e s w e r e done while on p l a c e b o a n d on the m a x i m u m d o s e of cibenzoline. D r u g t o x i c i t y , m a n i f e s t e d b y v o m i t i n g and Q R S widening, a c c o m p a n i e d b y v e r y h i g h s e r u m cibenzoline c o n c e n t r a t i o n s , w a s seen in t w o p a t i e n t s . A m a j o r r e d u c t i o n (>85% in v e n t r i c u l a r p r e m a t u r e b e a t s o c c u r r e d in t h r e e p a t i e n t s including t w o in w h o m only r e l a t i v e l y low s e r u m c o n c e n t r a t i o n s h a d b e e n achieved. Cibenzoline c a u s e d s i g n i f i c a n t i n c r e a s e s in A H (97 _ 26 vs. 110 _ 23 m s e c , p <0.01) a n d H V (59 _ 7 vs. 78 ___ 7 m s e c , p <0.02), a m a j o r b u t s t a t i s t i c a l l y n o t s i g n i f i c a n t i n c r e a s e in Q R S (99 _ 12 vs. 128 4- vs. 128 _ 27 m s e e , NS) b u t Q T (38 _ 2 vs. 38 _ msec) and Q T c (42 _ 1 vs. 44 _ 3 msec) w e r e e s s e n t i a l l y u n c h a n g e d , e v e n in t o x i c p a t i e n t s . Cibenzoline h a d no c o n s i s t a n t e f f e c t on s i n u s cycle length, s i n u s n o d e r e c o v e r y time, or t h e relative, f u n c t i o n a l or e f f e c t i v e r e f r a c t o r y p e r i o d s of t h e a t r i u m a n d A V node. W e conclude t h a t cibenzoline h a s p o t e n t t y p e 1 e f f e c t s in p r o l o n g i n g H V b u t m a y be u n i q u e in n o t a f f e c t i n g Q T or QTc, e v e n a t t o x i c levels. I t s e f f e c t s u p o n A H w e r e unexpected and warrant further study.

s t r u c t u r a l l y u n r e l a t e d to t h e c o m m e r c i a l l y available t y p e 1 a g e n t s {quinidine, p r o c a i n a m i d e , a n d d i s o p y r a m i d e ) . I n t r a v e n o u s cibenzoline h a s b e e n s h o w n to p r o l o n g t h e i n f r a n o d a l c o n d u c t i o n t i m e (HV) a n d Q R S i n t e r v a l in c o n s c i o u s d o g s a n d in h u m a n s u b j e c t s 2.3, b u t t h e e l e c t r o p h y s i o l o g i c eff e c t s of oral cibenzoline h a v e n o t b e e n fully elucidated. R e p o r t e d herein are t h e r e s u l t s of elect r o p h y s i o l o g i c s t u d i e s u n d e r t a k e n in five pat i e n t s r e c e i v i n g oral cibenzoline for t r e a t m e n t of chronic f r e q u e n t p r e m a t u r e v e n t r i c u l a r b e a t s .

Cibenzoline (Diphenyl - 2:2' - c y c l o p r o p y l 2 imidazole succinate) is a p r o m i s i n g n e w a n t i a r r h y t h m i c d r u g w i t h t y p e 1 p r o p e r t i e s 1 t h a t is From the department of Medicine, University of Maryland School of Medicine and the Veterans Administration Medical Center, Baltimore, Maryland. *Fellow, Division of Cardiology, Department of Medicine, VA Medical Center, Baltimore, hiD. 1"Director, Coronary Care Unit, Division of Cardiology, VA Medical Center, Baltimore, hiD and Associate Professor of Medicine, University of Maryland School of Medicine, Baltimore, hiD. **Director, Electrocardiography, Division of Cardiology, VA Medical Center, Baltimore, hiD and Associate Professor of Medicine, University of Maryland School of Medicine, Baltimore, hiD. t~Director Noninvasive Laboratory, Division of Cardiology, VA Medical Center, Baltimore, hiD and Associate Professor of Medicine, University of Maryland School of Medicine, Baltimore, hiD. ***Chief, Division of Cardiology, VA Medical Center, Baltimore, hiD, and Associate Professor of Medicine, University of Maryland School of Medicine, Baltimore, hiD. Supported by Veterans Administration Research and by Hoffmann LaRoche Research Grant. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked " a d v e r t i s e m e n t " in accordance with 18 U.S.C. w 1734 solely to indicate this fact. Reprint requests to: Robert W. Peters. M.D., Division of Cardiology. Veterans Administration Medical Center, 3900 Loch Raven Blvd., Baltimore, Maryland 21218.

MATERIALS A N D METHODS As part of a multicenter dose-finding clinical trial, five male patients with chronic frequent PVC's (an average of >30 premature ventricular beats per hour on two consecutive 24 hour Holter monitor recordings) were treated with increasing doses of cibenzoline and underwent electrophysiologic study prior to and after a maximal dose of oral cibenzoline. Specifically excluded were patients with recent myocardial infarction, unstable angina pectoris, decompensated congestive heart failure, bundle branch block, second or third degree AV block, sinus node dysfunction or significant hepatic, renal, or thyroid disease. Cibenzoline Administration. Each patient was hospitalized in the telemetry unit and underwent an initial five day washout period during which all antiarrhythmic medications, including beta blockers, were discontinued. Digitalis therapy was continued, without change in dose, throughout the

15

16

KUSHNER ET AL

study period. The study was carried out in a single blind manner. During four consecutive 72 hours periods, the patients received placebo followed by 130 rag., 260 rag., and 325 rag. of cibenzoline daily in four divided doses. In the event of clinical signs of toxicity (nausea, vomiting, and QRS widening >25 % above control), the medication was discontinued. A final 72 hour placebo period followed termination of the drug. Four patients achieved the maximum dose of cibenzoline (325 reg./day) while one (patient #5) became clinically toxic and had the drug discontinued at a dose of 260 mg./day.

Serum Cibenzoline Concentrations. Venous blood samples were obtained during the placebo period and on the last day of each dosing interval, five hours after the final dose. Serum cibenzoline concentration was determined by a specific high performance liquid chromatography assay (data on file at Hoffmann LaRoche Company, Nutley, N.J.). Electrophysiologie Study. Electrophysiologic studies were performed in the postabsorptive, unsedated state. The initial study was performed on the last day of the pretreatment placebo period, and the second study was obtained within five hours of the final scheduled dose of cibenzoline. In the two patients who became clinically toxic, the second study was performed within 24 hours of the last dose of the drug. Electrophysiologic studies were performed using s t a n d a r d techniques 4. Using flouroscopic guidance, two multipolar electrode catheters were inserted percutaneously and positioned against the lateral wall of the high atrium and across the tricupsid valve in the region of the His bundle, respectively. Intracardiac electrograms and standard electrocardiographic leads I, AVF and V 1 were displayed s i m u l t a n e o u s l y on an Electronics for Medicine multichannel oscilloscope (DR-12) and recorded at paper speeds of 100 and 200 mndsec. Programmed electrical stimulation was performed using a multiprogrammable stimulator (Bloom Associates, Narbeth, Pa.) with 1.8 msec rectangular stimuli at two to three times late diastolic threshold current. The stimulation protocol incuded: 1) incremental high right atrial pacing beginning at a cycle length 10-25 msec shorter than the spontaneous cycle length with progressive shortening of the pacing cycle by 50 msec decrements until atrioventricular (AV) nodal block occurred; 2) atrial and AV nodal refractory period determinations by pacing the high right atrium at a constant cycle length (S1 S I ~- 600 msec) for eight paced complexes and introducing premature stimuli ($2) using 10 msec decrements until the effective refractory period of the right atrium was attained. The stimulus to atrial depolarization interval (S-A), intra-atriai conduction time (high right atrial to low septal right atrial interval), A V nodal conduction time (AH), infranodal conduction time (HV), QRS duration, QT and QTc (QT/ R-R) intervals were measured during sinus rhythm using standard techniques. Each interval

reflects the mean of five consecutive beats. The effective refractory periods of the atrium and AV node were defined as the longest S 1 S 2 and A 1 A 2 that failed to induce atrial or His bundle depolarization respectively. Similarly, the functional refractory periods of the atrium and AV node were defined as the shortest obtainable atrial (A1A2) and His b u n d l e (H1H 2) depolarizations respectively. The relative refractory periods of the atrium and AV node were defined as the longest S 1 S 2 interval at which S 2 A 2 exceeds S 1 A 1 (latency) and the longest A 1 A= at which A 2 H 2 exceeds A 1 H 1 respectively. Holter Moniter Recordings. Continuous Holter monitor recordings were obtained during the last 48 hours of the placebo period and during the last 48 hours of each dosing period. Data Analysis. Data are expressed as the mean __ one standard deviation. A major reduction in frequency of premature ventricular beats was defined as >85%. Student's t-test for paired data was used to assess the significance of changes from the placebo state.

RESULTS Clinical Characteristics. T h e clinical c h a r a c t e r i s t i c s of our p o p u l a t i o n are s h o w n in T a b l e I. T h e s e five male p a t i e n t s h a d chronic f r e q u e n t p r e m a t u r e v e n t r i c u l a r b e a t s t h a t h a d b e e n r e s i s t a n t to a t least one conventional a n t i a r r h y t h m i c agent. No p a t i e n t had clinical or l a b o r a t o r y evidence of h e p a t i c d y s f u n c t i o n . P a t i e n t s //4 a n d #5 had m o d e r a t e l y severe cong e s t i v e h e a r t failure and were r e c e i v i n g digoxin {0.25 mg. and 0.125 mg.), w i t h s e r u m levels of 1.0 ng/ml a n d 0.7 ng/ml r e s p e c t i v e l y d u r i n g the s t u d y . I n addition, p a t i e n t #5 had s t a b l e renal insufficiency (BUN ---- 57 mg/dl, Creatinine -- 2.6 mg/dl); all o t h e r s h a d n o r m a l renal function. Antiarrhythmic Efficacy and S e r u m

Drug Concentration. T a b l e II c o m p a r e s the a v e r a g e n u m b e r of p r e m a t u r e v e n t r i c u l a r b e a t s per h o u r o v e r the 24 h o u r m o n i t o r i n g period w i t h t h e t r o u g h s e r u m d r u g c o n c e n t r a t i o n . A m a j o r r e d u c t i o n in the freq u e n c y of p r e m a t u r e v e n t r i c u l a r b e a t s was seen in t h r e e of t h e five p a t i e n t s despite the fact t h a t two of these t h r e e only a c h i e v e d a s e r u m concent r a t i o n of cibenzoline t h a t was n e a r the lower limit of w h a t is c o n s i d e r e d " t h e r a p e u t i c " (>200 ng/ml). T h e r e d u c t i o n in high g r a d e v e n t r i c u l a r e c t o p y (couplets a n d v e n t r i c u l a r tachycardia) closely paralled the decrease in t o t a l p r e m a t u r e v e n t r i c u l a r beats. Of p a r t i c u l a r n o t e is the wide inter-individual v a r i a t i o n in s e r u m cibenzoline levels d e s p i t e the c o m m o n dose protocol. Clinical evidence of d r u g t o x i c i t y m a n i f e s t e d b y n a u s e a

J. ELECTROCARDIOLOGY 17 (1), 1984

ELECTROPHYSIOLOGIC

EFFECTS OF ORAL CIBENZOLINE

17

TABLE I Clinical Descriptors of Population.

Type of Heart Disease

NYHA Class

Patient

Age

Sex

Race

1

66

M

W

ischemic heart disease sip IMI

II

2

51

M

W

ischemic heart disease sip CABG 5/81

II

EKG Diagnosis old IMI NSST-T changes

Other Cardiovascular Medications None None

NSST-T changes

3

65

M

B

ischemic heart disease angina pectoris minimal Aortic Sterosis

II

1 o AV Block NSST-T changes

None

4

58

M

W

ischemic heart disease, sip IMI, MR, CHF

III

old IMI old AMI LAHB NSST-T changes 1 o AV Block

Isosorbide dinitrate Digoxin Furosemide

5

70

M

B

sip mitral valve replacement for rheumatic heart disease, ischemic heart disease, CHF

III

LVH with secondary STT changes 1 o AV Block

Captopril Furosemide

AMI = Anterior wall myocardial infarction; 1 o A V Block = First degree AV block; CABG = Coronary artery bypass graft; CHF = Congestive Heart Failure; IMI = Inferior wall myocardial infarction; LAHB = Left Anterior Hemiblock; LVH = Left Ventricular Hypertrophy; MR = Mitral Regurgitation; NSST-T changes = Non-specific ST-T changes; NYHA = New York Association Functional Classification for Congestive Heart Failure; s/p = Status post.

and vomiting, was seen in the two patients with the highest serum cibenzoline levels. Electrophysiologic Data (See Table III). Spontaneous Sinus Cycle Length. In the two patients with clinical evidence of drug toxicity, mean cycle length decreased by 70 and 80 msec respectively. Of the non-toxic patients, two had no changes in sinus cycle length while one had an increase of 130 msec {20%}. Sinus Node Recovery Time. Mean sinus node recovery time was slightly but not significantly decreased during cibenzoline therapy {1210 __+236 msec vs. 1128 ___ 156 msec). Secondary pauses were not seen in any patient. Intraatrial Conduction. Intraatrial conduction could not be fully assessed because of difficulties in recording a technically adequate high right atrial electrogram during atrial pacing. The stimulus to low (septal) right atrial conduction time became prolonged during cibenzoline administration in four of the five patients and was particularly pronounced in the two toxic patients, in one of whom atrial Wenckebach developed during pacing. In the only patient in whom technically adequate high atrial depolarizations were record-

J. E L E C T R O C A R D I O L O G Y

17 (1), 1984

ed in both studies, the entire delay occurred between the high and low right atrial deflections. A V Nodal Conduction (See Figs. 1 & 2). After cibenzoline administration, A H prolongation occurred in all five patients with mean A H increasing 13% (97 __+ 26 msec vs. 110 ___ 23 msec p <0.01}. Because A H m a y be affected by alterations in sinus cycle length, we examined the changes in A H when cycle length was held constant by atrial pacing. A t a paced cycle length of 500 msec (600 msec in one patient who was limited by the development of type 1 second degree AV block}, A H was significantly prolonged by cibenzoline administration (146 __+ 76 vs. 166 _+ 64 msec, p <0.025). His-Purkinje Conduction (See Fig. 1 & 2). Cibenzoline was associated with a major increase in HV in all five patients (59 ___ 7 msec vs. 78 __+7 msec, p <0.02) and the increase was especially pronounced in the two toxic patients. Infranodal block was not observed in any patient during atrial pacing. QRSDuration (See Figs. 1 & 3). The QRS interval increased during cibenzoline therapy in four of the five patients. In the group as a whole, mean

18

KUSHNER ET AL

T

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I

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A

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i

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Fig. 1A. His bundle e l e c t r o g r a m d u r i n g placebo phase.

A H = 65 msec, HV = 65 msec, Q R S = 90 msec.

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patients.

QT and QTc Duration (See F i g . 2). C i b e n z 0 1 i n e had no consistent effect upon QT and QTc interJ. ELECTROCARDIOLOGY 17 (1), 1984

ELECTROPHYSIOLOGIC EFFECTS OF ORAL CIBENZOLINE

19

..~176

130.

I00.

mslmr 70,

Fig. 2. Graphic representation of AV nodal conduction time (AH}, infranodal conduction time (HV) and QT interval corrected for heart rate (QTc) during placebo (P) and Cibenzoline (CBZ} administration. Individual values for each of the five patients are shown along with the mean __ one standard deviation.

.....~

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o....""

....... g

9

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40, P

CBZ

P

AH

vals (38 __ 2 vs. 38 • 3 m s e c a n d 42 • 1 vs. 44 • 3 msec respectively} and only minor changes were seen in all five patients. Refractory Periods. There was no significant change in the relative, functional, or effective refractory periods of the atrium or AV node between studies although all values prolonged in the two clinically toxic patients. One patient was demonstrated to have dual AV nodal pathways; the effective refractory period of both p a t h w a y s was prolonged slightly following cibenzoline administration. His-Purkinje s y s t e m refractory periods could not be assessed because of atrial or AV nodal refractoriness.

CBZ

P

HV

CBZ

QTc

DISCUSSION Despite the recent development of a variety of new antiarrhythmic agents, these drugs, as a group, remain both relatively toxic and only partially effectiveS. A n t i a r r h y t h m i c d r u g s are grouped together because of common electrophysiologic properties with type 1 agents being characterized b y a tendency to prolong phase zero and phase 3 of the membrane action potential. Hence, type 1 agents produce widening of both the QRS complex and QT intervaP. QT prolongation, however, is a potentially dangerous characteristic and m a y predispose to malignant ventricular arrhythmias6. Quinldine, in particular, has

180"

140-

.....o..K-'~K ........................ K-... QRS INTERVAL (,...r I00-

"""" . X-'~

. . . Z ..... 0 ................

.~

.

.

"~

60-

Fig. 3. Graphic representation of QRS intervals during placebo (P) and cibenzoline (CBZ) administration. Individual values for each of the five patients are shown, J. ELECTROCARDIOLOGY 17 (1), 1984

o

PLACEBO

128mg

260mg

325mg

CIBENZOLINE

PLACEBO

20

KUSHNER ET AL

TABLE II The total number of ventricular premature beats, couplets and episodes of ventricular tachycardia found on 24 hour Holter Monitor during placebo and cibenzoline administration. Patient #

1 Placebo

Maximum CBZ

2 CBZ

Placebo

3 CBZ

Placebo

4 CBZ

Placebo

5 CBZ

Placebo

325

325

325

325

260

387

271

277

862

913

CBZ

Dose (mg/day) Serum Level CBZ (nglml) Total PVB's

7,344

11,858

1,320

144

5,184

Couplets

732

704

Total VT

35

81

10

27

0

336

3,936

6

4

0

0

0

2,112

23,352

0

2

9

0

2

0

72

24

4

2,638

2

6

4

940

0

2

1

305

0

Beats VT Events

VT = Ventricular tachycardia; CBZ = Cibenzoline; PVB's = Premature ventricular beats.

been implicated as a cause of ventricular tachycardia and sudden deathT. Other serious adverse effects may occur with the commercially available preparations of this group of drugs 8"x~ Preliminary studies with cibenzoline have suggested antiarrhythmic efficacy comparable to disopyramide and that it is generally well toleratedn. In particular, cibenzoline seemed to lack the negative inotropic and anticholinergic side effects that characterize the commercially available type 1 drugs. The present investigation was done as part of a multi-center dose-finding study using oral cibenzoline in patients with chronic stable ventricular arrhythmJas. We found that cibenzoline tended to prolong conduction times throughout the conduction system, especially in individuals who became clinically toxic. Refractory periods of the atrium and AV node could not be fully evaluated but also tended to be prolonged in the toxic patients. In contrast to the other type 1 drugs, cibenzoline had negligible effects upon QT and QTc intervals, even in patients with clinical evidence of drug toxicity and serum concentrations well above the therapeutic range. The clinical importance of this finding is presently unknown but suggests that cibenzoline may be less arrhythmogenic than quinidine or other type 1 antiarrhythmic agents. The most prominent effect of cibenzoline upon conduction occurred within the His-Purkinje system and in the ventricles. The HV interval was prolonged considerably (mean increase =

32%) and to at least 70 msec in all five patients. This finding suggests that cibenzoline should be used with caution in patients with bundle branch block or extensive infranodal disease. It should be pointed out, however, that three of the five patients had prolonged HV during the control study so that our data may not be applicable to a population with totally normal infranodal conduction. As seen in Fig. 3, the effects of cibenzoline on intraventricular conduction were also quite pronounced, especially in the toxic patients, and suggest that, as with quinidine, QRS prolongation may indirectly reflect serum drug concentration and portend developing toxicity. Cibenzoline's effects on the AV node appear to be unlike those of quinidine, procainamide and disopyramide whose anticholinergic properties prevent prolongation of conduction and refractoriness. In contrast, cibenzoline's actions may reflect direct depression of conduction unopposed by anticholinergic effects. Thus, cibenzoline has potential value in the treatment of supraventricular tacharrhythmJas and might be safe to use in some patients without concomitant digitalis therapy in patients with atrial flutter or fibrillation. The efficacy of cibenzoline in the suppression of ventricular arrhythmias is difficult to assess using a dose finding protocol and a small sample size. However, it is of interest that three of our five patients demonstrated greater than 85% reduction in the number of total and complex forms of premature ventricular beats, despite the fact J. ELECTROCARDIOLOGY 17 (1), 1984

ELECTROPHYSIOLOGIC EFFECTS OF ORAL CIBENZOLINE

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22

KUSHNER ET AL

that only two of these three had serum concentrations within the "therapeutic" range. The single patient who showed no reduction in premature ventricular beats had a sub-therapeutic serum concentration. The wide range of serum cibenzoline concentrations despite identical dosing regimens in each patient also deserves comment. In normal volunteers, cibenzoline is well absorbed orally with almost 100% bioavailability12. Following a single oral dose, serum level peaks at one and one-half hours and approximately 55% is excreted unchanged in the urinel2. The serum half-life after oral administration is ordinarily 7 to 22 hours and is a function of renal function and age. However, only one of our patients had moderate renal insufficiency, thus, the cause of the wide variation in serum levels is unknown. It is noteworthy that the two patients with high serum cibenzoline concentrations had a history of congestive heart failure and were concomitantly taking digitalis. The possibility of a digitalis cibenzoline interaction warrants further investigation. Our data suggest that careful dose titration with monitoring of QRS duration and serum cibenzoline concentration will be needed to use this drug safely and effectively in clinical practice. Our s t u d y should be interpreted in light of certain methodologic limitations. First, the small number of patients precludes definitive conclusions. Second, it can be argued that the inclusion of subjects with only 30 premature ventricular beats per hour does not satisfy universal criteria for " f r e q u e n t " ventricular ectopy. However, as can be seen in Table II, all of our patients had considerably more premature ventricular beats than the defined minimum and at least two of the five had frequent complex forms. Third, it can also be argued that cibenzoline's greatest potential value will be for patients with s y m p t o m a t i c ventricular arrhythmias and that our population was asymptomatic. However, we believe that our s t u d y is clinically relevant because it is a common practice for patients with known organic heart disease and frequent premature ventricular beats to receive antiarrhythmic medications. Last, our s t u d y design did not include programmed ventricular stimulation for induction of ventricular arrhythmias. We feel that this type of procedure might be premature in a dose-finding s t u d y such as ours. Recently, Browne et al. described preliminary results of induction studies in eight patients receiving cibenzoline for t r e a t m e n t of r e c u r r e n t ventricular t a c h y c a r d i a 13. In their

short-term follow-up (one to six months), cibenzoline was both effective and well tolerated. It will be extremely important to confirm their findings with a larger number of patients and a longer follow-up. In summary, cibenzoline is a new type 1 antiarrhythmic agent that has potential application in the treatment of both ventricular and supraventricular arrhythmias. Its effects on ventricular repolarization and possibly also on AV nodal conduction make it unique among the type 1 drugs and m a y have important therapeutic implications. Further studies are needed to examine the pharmacokinetics and electrophysiologic effects of this promising drug.

REFERENCES i. VAUGIIANWILLIAMS, E M: Classification of antiarrhythmic drugs. In: Symposium on Cardiac Arrhythmias (Elsinore, Denmark, 1970), E SANDE, E FLENSTED-JENSENANDK H OLSEN,Eds. AB Astra, Sodertalje, Sweden, pp 449-472, 1970 2. Cibenzoline: Investigator's Brochure. Nutley, New Jersey, Hoffmann LaRoche Inc., Ill2-11125, 1981 3. Cibenzoline: Investigator's Brochure, Nutley, New Jersey, Hoffmann LaRoche Inc., IV40-1V41, 1981 4. SCIIERLAG, B J, LAU, S H, BERKOWITZ, W D, ROSEN, K M, STEINER, C AND DAMATO, A N: Catheter technique for recording His bundle activity in man. Circulation 39:13, 1969 5. V~.LEBIT,V, Poomo, P, LOWN,B, COHEN, D H AND GRABOYS, T D: Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 65:886, 1982 6. Moss, A J AND SCIIWAB.TZ,P J: Delayed repolarization (QT or QTu prolongation) and malignant ventricular arrhythmias. Mod Concepts Cardiovasc Dis 51:85, 1982 7. KLOSTER, R W AND WELLENS, H J J: Quinidineinduced ventricular flutter and fibrillation without digitalis therapy. Am J Cardiol 38:519, 1976 8. STRASBERG,B, SCLAROVSKY, S, ERDBERG,A, DUFrY, C E, LAM,W, SWmYN,S, AGMON,J ANDROSEN, K M: Procainamide-induced polymorphousventricular tachycardia. Am J Cardiol 47:1309, 1981 9. DESAI, J M, SCHEINMAN, h~ M, HIRSCIIFELD, D,

GONZALEZ, R AND PETERS, R W: Cardiovascular collapse associated with disopyramide therapy. Chest 79:545, 1981 10. NICIIOI.SON,W J, MARTIN, C E, GRACEY, J G AND KNocli, H R: Disopyramide-induced ventricular fibrillation. Am J Cardiol 43:1053, 1979

J. ELECTROCARDIOLOGY 17 (1), 1984

ELECTROPHYSIOLOGIC EFFECTS OF ORAL CIBENZOLINE

11. HERPIN, D, GAUDEAU, B, AMIEL, A, BAUPLE, J L, BOWTAND, P H AND DEMANGE, J: Etude de l'activitdet de la tolerance d'un nouvel anti-arythmique, la cibenzoline, administrg par vole orale. Acta Cardiologica 36:131, 1981 12. Cibenzoline: Investigator's Brochure, Nutley,

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New Jersey, Hoffmann LaRoche Inc. IV-12, 1981 13. BROWNE,K F, ZXPES, D P, HEGER, J J, CHmSON, D A, LLOYD,E A AND PRYSTOWSKY,E N: Clinical efficacy and electrophysiologic effects of cibenzoline in patients with ventricular tachycardia. Clin Res 30:705A (Abstr), 1982