- Email: [email protected]
Electrophysiologic effects of cibenzoline in humans related to dose and plasma concentration
12. 13. 14.
15.
16.
namic effects of ethmozine in patients with ventricular tachycardia and left ventricular dysfunction (abstr). J Am Co11 Cardiol 3:474, 1984. Josephson ME, Seides SF: Clinical cardiac electrophysiology. Philadelphia, 1979, Lea & Febiger, Publishers. Narula OS, Samet P, davier RP: Significance of sinus node recovery time. Circulation 45:140, 1972. Mason JW. Winkle RA: Electrode catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 58:971, 1978. Swerdlow CD, Gong G, Echt DS, Winkle RA, Griffith JC, Ross DL, Mason JW: Clinical factors predicting successful electrophysiologicpharmacologic study in patients with ventricular tachycardia. J Am Co11 Cardiol 1:409, 1983. Mason JW, Swerdlow CD. Winkle RA, Ross DL, Echt DS, Anderson KP. Mitchell LB, Clusin WT: Ventricular tachyarrhythmia induction for drug selection: Experience with 311 patients. In Lucchesi BR, Dingell JV, Schwarz RP, Jr, edit.ors: Clinical pharmacology of antiarrhythmic therapy. New York, 1984. Raven Press, p 229.
17. Podrid PJ, Lown B: Ethmozin therapy for luairgnant vrntricular arrhythmia (abstr). Am .J Cardiol 49: IOl?. 1982. 18. Platia EV. Reid PR: Comparison of prcqqammed electrical stimulation and ambulatory electroci~rdi~,graphic (Halter) monitoring in the management of vent ri(&+r tarhycardia and ventricular fibrillation. .J Am (‘011 (‘ardiol 4:49:1. 1984. 19. Ruff R, Rozenshtraukh LV. Elharrar \‘. %ipes DP: Electrc,physiological effects of ethmozin on (‘;ir incx myocardium (Iardiovasc Res 13:354. 1979. 20. ljangman KH, Hoffman RF: ‘I’hc e(ft*c:q iii EN-:Il:I on abnormal automaticity in canine cardia I’urkinie fibers lahstrl. Circulation 57&58:11-l&$, 197X. 21. Rinkenberger RL. Prystowsky EN. Jackmat) WM. Naccarelli (i\‘. Heger .Jd. Zipes DP: Drug 1%onversion I)!’ nonstustained ventricular tachycardia to sustained venlracular tacbvcardia during serial electrophysiologic studies: Identificaiion of drugs that exacerbate tachycardia and potratial mechanisms. AM HEART .I 103:177, 1982. 22. Whitnev CC, Weinst,ein SH. Gaylord ,I(‘: ~~i4h-performance liquid c:hromatographic determinat.ion $:I‘ -thmozin in plasma. .J Pharm Sci X1:462. 1981.
Electrophysiologic effects of cibenzoline humans related to dose and plasma concentration
in
The electrophysiologic effects of a new antiarrhythmic agent, cibenroline, were investigated in 25 patients with an average age of 62 years. The compound was administered intravenously, as a bolus given over 2 minutes, then as a slow infusion over 40 minutes. Each subject was randomly allocated to receive one of the following four doses: 1.55 mg/kg (six patients), 1.8 mg/kg (six patients), 2.2 mg/kg (six patients), or 2.6 mg/kg (seven patients). Plasma cibentoline concentrations at these doses were 378 t 80, 525 + 194, 618 + 72, and 731 I? 196 rig/ml, respectively. Administration of 1.55 mg/kg cibenzoline significantly shortened the sinus cycle (60 msec on average; p < 0.025) and increased intraatrial (+8 msec; p < 0.05) and His-Purkinje conduction times (HV interval +13 msec; p < 0.001). At 1.80 mg/kg, prolongation occurred in the HV interval (+9 msec; p < 0.02), the duration of the QRS complex (+20 msec; p > 0.05), and the QT interval (+18 msec; p < 0.025). At the higher doses these changes became more marked (maximum increase: HV = +16 msec, p < 0.001; QRS + 25 msec; p < 0.001; QT + 26 msec, p < 0.05), and additional effects on atrioventricular nodal conduction time (AH interval + 17 msec; p < 0.05) and atrial (+20 msec; p < 0.05) and ventricular (+lO msec; p > 0.05) effective refractory periods were observed. Prolongation of the QRS duration was the effect that correlated best with plasma cibenzoline levels (r = 0.47; p < 0.05). These results allow an understanding of the antiarrhythmic activity of cibenzoline in humans. (AM HEART J 112:333, 1986.)
Paul Touboul, M.D., George Atallah, M.D., Gilbert Kirkorian, M.D., Claudio de Zuloaga, M.D., Alain Dufour, Ph.D., Marie France Aymard, Pierre Lavaud, M.D., and Pierre Moleur, M.D. Lyon, France From the Hi)pital C’ardiwasrulaire et Pneumologique Louis Pradel. Received Lx puhlicatir,n Aug. ld. 19X5; revision received Oct. 30, 1985; xwptrd Ik. IO. 1985. Reprint requests: Paul l’ouhoul, M.D., HBpital Cardiovasculaire et Pneum~~lopique I~ctuk Pradel. HP Lyon Montchat, 69394 Lyon Cedex OR, France.
M.D.,
Cibenzoline is a new antiarrhythmic agent with an original chemical formula (Fig. 1). Published reports have shown it to be effective in ventricular arrhythmias with both intravenous and oral administration.l-I’ The electrophysiologic bases for the com333
334
Touboul
et al.
,/vI n U\ ’ Fig.
American
I
Ii + HOOC
1. Chemical
formula
- 1 CH&
COOH
of cibenzoline.
pound action have been established in vitro12-‘6 and in the whole ammaLl Studies in humans have demonstrated cardiac electrical changes following intravenous and oral cibenzoline.*s Ia,ls However, no special attention has been paid to the question of dose response. The purpose of the present study was to evaluate the electrophysiologic effects of intravenous cibenzoline in humans in relation to dose and plasma concentration. METHODS Patient selection. Twenty-five patients were studied, 11 men and 14 women, ages 62 + 16 years (mean & SD, range 24 to 85). The majority (22 patients) suffered from syncope, two from dizziness, and two from palpitations. No heart disease was demonstrable from historic features and clinical evaluation. ECGs were normal in 15 patients but showed right bundle branch block in nine patients (two of whom also showed left anterior hemiblock) and left bundle branch block in one. Electrophysiologic techniques. Electrophysiologic studies were performed in the catheterization laboratory. All subjects were studied in the postabsorptive, nonsedated state. All had been carefully screened before the study to ensure absence of any metabolic disorder or antiarrhythmic treatment. Informed consent was obtained. Percutaneous catheterization was employed via the right and left femoral veins. In each patient, two bipolar electrode catheters were positioned in the right atrium, one for recording (in the sinus node area) and the other for pacing (in the upper third of the interatrial septum). A tripolar catheter was used to record His bundle potentials.*O The remaining catheter served to pace the right ventricular apex. Recordings were made by means of an eight-channel ink-jet ECG (Elema, Stockholm, Sweden), at a paper speed of 100 mm/set. His bundle signals were transmitted to an ECG amplifier and filtered (recording frequencies: 50 to 700 Hz). In addition to the intracardiac electrograms, leads I, II, III, V1, and V, were also recorded simultaneously. Some of these were displayed on an oscilloscope to provide continuous patient monitoring. A programmable modular stimulator (Janssen, Belgium) was used for cardiac electrical pacing, delivering rectangular impulses, 1.5 msec in duration, at twice diastolic threshold intensity. Atrioventricular (AV) conduction intervals were measured during regular atrial pacing. Cardiac refractory periods were determined by the
August, 1986 Heart Journal
extrastimulus method.*] Atria1 and AV conduction tissue refractory periods were obtained by premature atria1 depolarizations (coupling intervals reduced by 10 msec decrements) after eight beats of regular atria1 pacing. The right ventricular refractory period was measured by the same technique, using ventricular pacing. Sinoatrial function was also evaluated. Sinus node recovery time was measured after rapid atria1 pacing by using four different pacing frequencies (90, 110, 130, and 150 min) each sustained for 30 seconds and separated by l-minute sinus rhythm periods.22 The extrastimulus method during sinus rhythm was chosen for determining the sinoatrial conduction time.2:J All data collected during electrophysiologic studies were stored on magnetic tape (Hewlett-Packard recorder). Cibenzoline administration. Once the control study was completed, cibenzoline was administered as follows: an 0.8 mg/kg bolus was injected intravenously over 2 minutes, followed by slow infusion over 40 minutes of 0.75, 1.0, 1.4, or 1.8 mg/kg. Each patient could therefore receive one of the four following doses: 1.55, 1.8, 2.2, or 2.6 mg/kg, determined at random. This infusion regimen for intravenous administration was designed from the pharmacokinetics of cibenzoline3,25 and predicted from the tenth minute on relatively stable plasma concentrations. Blood samples for assay of the compound by gas chromatography2” were taken at 1.50, 15, 25, 35, 45, 48, 53, 58, and 73 minutes after administration began. The electrophysiologic study was resumed after 15 minutes, and evaluation was completed within 20 to 25 minutes. Statistics. Student’s t test for paired data was used to analyze the effects of cibenzoline at each dose level. Dose response was assessed by calculating the slope of the regression line of the variable against the dose and comparing it to zero (t test). The effect of the concentration was established by calculating the correlation coefficient. Terminology. Sinus cycle length was calculated by taking the mean of five successive cycles before administration of the drug and then 15 minutes after the onset of cibenzoline administration. The SA interval, or intraatrial conduction time, was measured during atria1 pacing from the stimulation impulse to the first rapid deflection of the atria1 electrogram recorded from the His bundle lead. The AH interval, or intranodal condution time, was defined as the interval between the first rapid deflection of the atria1 electrogram and that of the His bundle potential. The HV interval, or His-Purkinje conduction time, was measured from the first rapid deflection of the His potential to that of the ventricular electrogram V recorded from the His bundle lead. QRS and QT duration and conduction intervals before and. after cibenzoline were compared in each patient by means of identical pacing frequencies. The Wenckebach cycle during rapid atria1 pacing is the longest atria1 cycle at which an intranodal Wenckebach phenomenon occurs. The refractory periods, measured by premature cardiac stimulation, are defined as follows: The atria1 effective refractory period is the longest S,-S, interval at which premature atria1 stimulus S, is not followed by atria1
Volume 112 Number 2
Etectrophysiology
of cihenzotint~
Table I. Cumulative data on AV conduction, QRS and QT duration, and sinus node function different doses of cibenzoline __ --__ 1.55 mg Jkg 1.80 mglkg 2.20 mglkg Data
in man
aft.er administration
--
----
335
of
~-. __-_~..-:!.til) mglkg -..._I_---..
Sinus cycle Mean change P No. of patients SNRT Mean change P No of patients SAC’1 Mean change
+ SD (msec)
-60 j: 45 <0.025 6
-:12 2 48 >O.lO 6
-15 I? 4.5 >0.40 6
-24
t SD (I’(, )
+25 k 44 >(I.20 6
+1.8 i >0.60 6
i-64 + 141 >0.30 6
-t 44 f 1 1L? ~0.30 7
+ SD (msec)
-18 t 52 >0.40 6
-4x 2 55 X.10 5
-37 + 8
-. t,3 -f 52 N.05 .-,
i SD (msec)
+8 + 6 <0.05 6
-3 i XI.60 6
+3 -t 30 >0.70 ti
t-6 f 8 :>0.10 7
+ SD (msec)
-2 I 20 >0.80 6
t7 k 13 X).20 6
+3 2 12 >0.50 6
+I7 ’ 13
P No. of patients SA interval Mean change
P AH
No. of patients interval Mean change
P HV
No. of patients interval Mean change + SD (msec)
P
No.
+13
+ SD (msec)
No. of patients interval Mean change
t16 * s
6
+20 -+ 17 >0.05 :’
+23 It 14
t25 2 10
t2 k 13 >0.70 6
+18 + 11 <0.025 s
+12 +- 12 10.05 6
+26 ‘+ 24 <0.05 7
0 + 45 >0.90 6
0 t 41 >0.90 7
t 8
<0.20
+ SD (msec)
No. of patients Wenckebach cycle Mean change f SD (msec)
+17 k 52 >0.40 6
P X0. of patients SNRT
6
+14 _t 6 <0.005 6
+5
P
= sinus node recwery
time; SACT
= sinoatrial
conduction
cycle.
f 7
-4 i BO.60 6
19
time.
depolarization. The atria1 functional refractory period is the shortest A,-A, interval between two atria1 responses that can be achieved. The AV nodal effective refractory period is the longest A,-A, interval at which the premature AZ atria1 response is not propagated to the bundle of His. The AV nodal functional refractory period is the shortest H,-H, interval achievable between two His bundle depolarizations. The His-Purkinje system relative refractory period is the longest HI-H2 interval at which premature His bundle depolarization is followed by prolongation of the HV interval or by an aberrant QRS complex. The His-Purkinje system effective refractory period is the longest H,-H, interval at which premature His bundle activity is not conducted to the ventricles. The right ventricular effective refractory period, measured during regular ventricular pacing, is the longest S,-S, interval at which premature stimulation fails to induce a ventricular response. The effect of cibenzoline on the refractory periods was evaluated in each patient at the same basic drive
s
6
P QT
+9
of patients
QRS duration Mean change
-t 3
11
i 69 ~0.40 -:
Sinus node recovery time was measured from the last paced P wave to the first poststimulation sinus activity. The result was expressed as the percentage of the length of the basic sinus cycle according to the formula: sinus node recovery time/sinus cycle length x 100, the sinus cycle length being the mean of five successive sinus cycles before atrial pacing. Only the highest value was retained out of the four determined for each patient. The sinoatrial conduction time studied by premature atria1 stimulation was measured by the difference between the length of the return cycles recorded from the reset zone and that of the mean sinus cycle. It represents the total sum of conduction time into and out of the sinus node. RESULTS
Six patients received a total dose of 1.55 mg/kg, six patients received 1.80 mg/kg, six received 2.20 mg/kg, and seven received 2.80 mg/kg. The results are shown in Tables I and II. The effects of ciben-
336
Touboul
et al.
Table
II. Cumulative
data on cardiac
Data ERP-RA Mean P No. of FRP-RA Mean P No. of ERP-AV Mean P No. of FRP-AV Mean P No. of ERP-HPS Mean P No. of RRP-HPS Mean P No. of ERP-RV Mean P No. of
August, 1966 Heart Journal
American
refractory
periods
after administration
1.55 mg/kg
of different
1.80 mg/kg
doses of cibenzoline*
2.20 mglkg
2.60 mglkg
(msec)
+3 + 15 >0.60 6
+4 + 11 >0.40 5
+20 * 17 <0.05 6
0 t 33 >0.90 7
change
I SD (msec)
patients node change
+3 + 15 >0.60 6
-4 k 17 >0.60 5
+21 k 25 .0.60 6
-1 + 35 >0.90 7
+ SD (msec)
+a
change
k SD
patients
patients node change
+- SD (msec)
patients change
k 45
-20
+- 26
+5 k 21
-10
3
3
1
2
+a ? 38 >0.60 6
-25 i 51 >0.30 5
+3 + 29 >0.70 6
-7 t 19 >0.30 7
-55
-85
+20
1
1
1
+ SD (msec)
patients change
+ SD (msec)
patients change patients
t SD (msec)
+2 k 10 >0.60 6
Abbreviations: ERP = effective refractory period; FRP = functional ventricle; HPS = His-Purkinje system; SD = standard deviation. *The effect of cibenzoline on the His-Purkinje system refractoriness
+3
k 5
+615 >0.05 6
>O.lO
6 refractory could
zoline in each group are expressed, for greater clarity, as mean change per parameter -t the standard deviation. Duration of QRS and QT intervals. The duration of the QRS interval increased markedly from the 1.80 mg/kg dose upward (+20 +- 17 msec; p > 0.05). Subsequent increases were +23 +- 14 msec at 2.20 mg/kg 0, < 0.01) and +25 t- 10 msec at 2.60 mg/kg (p < 0.001). Increase in the QT interval became apparent from the 1.80 mg/kg dose of cibenzoline (+18 ? 11 msec; p < 0.025). At higher doses, the increase was as follows: +12 -+ 12 msec at 2.20 mg/kg (p < 0.05) and +26 f 24 msec at 2.60 mg/kg 0, < 0.05). It should be noted that when the JT interval only was considered, the compound had no demonstrable effect. AV conduction. The SA interval increased, on average, by 8 -t 6 msec after administration of 1.55 mg cibenzoline (p < 0.05). No significant changes were seen at higher doses. The AH interval did not vary significantly up to the dose of 2.20 mg/kg. At 2.60 mg/kg, it showed an increase of 17 -+ 13 msec (p < 0.02). The HV interval increased significantly
period;
RRP = relative
not be assessed
because
refractory
of the small
period; number
+10 + 13 >0.05 7 RA = right
atrium;
RV = right
of patients.
at all doses used. The increase was +13 f 3 msec at the lowest dose (p < O.OOl), +14 + 6 msec at 2.20 mg/kg (p < 0.005), and +16 +- 5 msec at 2.60 mg/kg @ < 0.001). There was no greater prolongation of the HV interval in patients with bundle branch block. There were no significant changes in the Wenckebach cycle at any dose. Refractory periods. The effective atria1 refractory period increased at the 2.20 mg/kg dose (+20 + 17 msec; p < 0.05). There was no significant variation in the functional refractory period. There were no demonstrable effects on the AV nodal functional refractory period. The AV nodal effective refractory period could be measured before and after cibenzoline in only nine patients (distributed over the four groups). No conclusions can be drawn given the limited number of patients. The His-Purkinje system relative refractory period decreased by 55 and 85 msec in two patients given 1.55 and 1.80 mg/kg cibenzoline, respectively. It increased by 20 msec in a third patient given a dose of 2.20 mg/kg. No conclusion can be drawn from these results. There was no patient in whom
Volume 112 Number 2
(3,QRS r-----l . QT Q AH
l.OOO- -
A-H
(P
H-V (P--0.066)
:.I: 1, .1 I
2 800. y2 700-x 3 600--
8 I
1.55
1.8 DOSE
2.2 (MGIKG)
2.6 IV
Fig. 2. Mean change in QRS, QT, AH, and HV intervals and ventricular effective refractory period (VERP) at the different doses of cibenzoline studied. Dose response was analyzed by regression test.
the His-Purkinje system effective refractory period could be measured. The increase in right ventricular effective refractory period, which was insignificant at the lowest doses, rose to 6 -t 5 msec at 2.20 mg/kg (p < 0.05) and to 10 -+ 13 msec at 2.60 mg/kg (p < 0.05). Sinoatrial function. Sinus cycle length decreased significantly at the 1.55 mg/kg dose (-60 k 45 msec; p < 0.025). This effect was reduced and was no longer significant at the higher doses. Cibenzoline showed no effect on sinus node recovery time. A tendency toward increase was, however, noted at higher doses. The sinoatrial conduction time decreased following cibenzoline, with the change becoming significant at 2.20 mg/kg (-37 ‘r_ 8 msec; p < 0.001).
Regression test showed that changes in the AH interval (p < 0.05), QRS duration (p < 0.02), and QT interval (p < 0.05) were dose dependent. As for the HV interval and the right ventricular effective refractory period, the results obtained almost reached statistical significance (with values of p = 0.086 and 0.075, respectively). The dose-dependent changes in these parameters are shown in graph form in Fig. 2. Plasma cibenzoline levels during electrophysiologic evaluation were calculated for each patient from three separate determinations performed 15, 25, and 35 minutes after administration of the
L
I I
. I
1.55
1.8 DOSE
1
I I
2.2 (MGIKG)
Fig. 3. Mean plasma concentrations tion) for the four doses of cibenzoline
2.6 IV (*standard studied.
devia-
compound was begun. Mean values for each group were as follows: 378 + 80, 525 r 194,618 + 72, and 731 + 196 rig/ml on doses of 1.55,1.80,2.20, and 2.60 mg/kg, respectively (Fig. 3). Dependency on cibenzoline plasma levels could be demonstrated for changes in sinus cycle length (r = 0.42; p < 0.05) and duration of QRS (r = 0.47; p < 0.05). The results for the right ventricular effective refractory period just failed to reach statistical significance (p = 0.061). The administration of cibenzoline was well tolerated in all patients. Blood pressure did not change significantly. DlSCUSSlON Depression of intraventricuiar conduction. Studies on isolated cardiac tissue have shown that cibenzoline decreases the maximum rate of depolarization in myocardial and Purkinje cells.12-LGVoltage clamp analysis has confirmed depression of the fast inward sodium current.“j The resultant decrease in conduction velocity in fast-response tissues accounts for the prolongation of the HV interval and the increased duration of the QRS interval observed in humans.BJo*lX The changes in QRS duration in our series were dose dependent and constituted the best marker of plasma cibenzoline levels. The depressant
338
Touboul
et al.
effect on intraventricular conduction did not produce complications, even at the highest doses. However, all of our patients had a normal HV interval, Further studies are required in subjects with abnormal His-Purkinje conduction. Increase in ventricular refractoriness. The increase in right ventricular effective refractory period became significant at the 2.20 mg/kg dose. This effect is similar to data from in vitro studies. Cibenzoline has been shown to produce a significant increase in the duration of the the action potential in the ventricle.12-I4 The effects on the QT interval would appear to corroborate the concept of a prolongation of ventricular repolarization. Like others,18 we noted a prolongation of the QT interval after cibenzoline, an effect which was dose dependent. However, the JT interval was not significantly altered, suggesting that the QT changes reflected only the increase in the duration of the QRS complex. One can therefore imagine that the effect of cibenzoline on the ventricular refractory period was more probably related to a slowing of the fast inward sodium current reactivation process-a mechanism which has been demonstrated in vitro.16 This might also account for the increased refractoriness of the atrium seen in our series at the 2.20 mg/kg dose.16 Restriction of the slow inward current. Administration of cibenzoline was associated at the 1.55 mg/kg dose with a significant increase in sinus rate. Possible mechanisms include sympathetic stimulation secondary to cardiac depression or the intervention of vagolytic effects. 24That this effect should fall off as the dosage is increased suggests the development of a direct depressant action on the sinus node partially counterbalancing the changes brought about by the autonomic nervous system. Studies on isolated sinoatrial node have shown that cibenzoline produces bradycardia as a result of prolongation of the action potential and reduction in maximum rate of depolarization.12 The latter effect suggests restriction of the slow inward current.16 As for the decrease in sinoatrial conduction time in our patients, it could also be explained by the action of autonomic nervous system. Slow inward current depression also accounts for the changes in AV nodal conduction time. Prolongation of the AV interval was dose dependent and became significant at 2.60 mg/kg. Variations in autonomic tone associated with cibenzoline activity might well be contributing to the minimization of direct AV nodal depressant effects. Cibenzolineinduced increase in AV nodal conduction time has been observed in isolated cardiac tissue studies.12 Additional effects on the AV nodal functional
American
August, 1986 Heart Journal
refractory period have also been reported.12 By facilitating the development of AV nodal block, such changes could provide a basis for the drug efficacy in supraventricular arrhythmias. Cibenzoline can thus be expected to have a wide clinical spectrum. It should be stressed that some studies have shown similar electrophysiologic results after oral administration.‘O In humans the compound shows over 90% bioavailability.25 Furthermore, the antiarrhythmic effect of oral cibenzoline has been demonstrated to be proportional to plasma concentration.? Such features aid in managing the drug. The present study reports the electrical properties of cibenzoline at different dose levels. The purpose is to individualize cibenzoline therapy by establishing a relationship between plasma drug concentration and therapeutic effect. This should make for more rational use of cibenzoline in clinical practice. REFERENCES
1. Baligadoo S, Chiche P: Beneficial effects of UP 339-01, a new antiarrhythmic agent against ventricular premature beats. Circulation 56179, 1978. 2. Heger JJ, Prystowsky EN, Browne KF, Chilson DA, Lloyd EA, Zipes DP: Cibenzoline treatment of patients with chronic ventricular arrhythmias. Clin Res 30:709, 1982. 3. Desoutter P, Dufour A, Aymard MF, Haiat R: Etude pharmacocinetique d’un nouvel antiarythmique la cibenzoline a la phase aigu& d’un infarctus myocardique. Correlations therapeutiques. Therapie 36237, 1983. 4. Kostis JB, Krieger S, Cosgrove N, Burns J, Saviano G, Moreyra A: Cibenzoline in ventricular ectopic activity. Circulation 66214, 1983. 5. Miura DS, Keren G, Siegel L, Tepper D, Butler B, Aogaichi A, Somberg JC: Effect of cibenzoline in suppressing ventricular tachycardia induced by programmed stimulation. J Am Co11 Cardiol 1:699, 1983. 6. Tepper D, Butler B, Keren G, Somberg JC, Tagarin M, Siegel L, Aogaichi K, Miura DS: Effects of oral cibenzoline therapy on ventricular ectopic activity. Clin Res 31:634A, 1983. 7. Brazzell RK, Aogaichi K, Heger JJ, Somberg JC, Carliner NH, Morganroth J: Cibenzoline plasma concentration and antiarrhythmic effect. Clin Pharmacol Ther 35:307, 1984. 8. Browne KF, Prystowsky EN, Zipes DP, Chilson DA, Heger JJ: Clinical efficacy and electrophysiologic effects of cibenzoline therapy in patients with ventricular arrhythmias. J Am Co11 Cardiol 3:857, 1984. 9. Cocco G, Strozzi C, Pansini R, Rochat N, Bulgarelli L, Padula A, Sfrisi C, Kamal Al Yassini A: Antiarrhythmic use of cibenzoline, a new class 1 antiarrhythmic agent with class 3 and 4 properties in patients with recurrent ventricular tachycardia. Eur Heart J 5:108, 1984. 10. Kushner M, Magiros E, Peters R, Carliner N, Plotnick G, Fisher M: The electronhvsioloeic effects of oral cibenzoline. J Electrocardiol 17:15, i984. ” 11. Saksena S, Rothbarts S, Shah Y, Liptak K: Chronic effects of oral cibenzoline in refractory ventricular tachycardia. Clin Pharmacol Ther 35:271, 1984. 12. Millar JS, Vaughan-Williams EM: Effects on rabbit nodal, atrial, ventricular and Purkinje cell potentials of a new antiarrhythmic drug, cibenzoline, which protects against action potential shortening in hypoxia. Br J Pharmacol 75469, 1982. 13. Ikeda N, Singh BN: Electrophysiological profile of a new
Volume 112 Number 2
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antiarrhythmic drug, in isolated cardiac tissues. Fed Proc Fed Am Sot Exp Biol 42:2908, 1983. Ohta M, Sugi K, McCullen A, Mandel WJ, Peter T, Karagueuzian H: Electrophysiologic effects of cibenzoline, a new antiarrhythmic drug, on isolated cardiac tissue. Circulation 66:220, 1983. Dangman KH: Cardiac effects of cibenzoline. J Cardiovasc Pharmacol 6:300, 1984. Masse C, Cazes M, Sassine A: Effects of cibenzoline, a novel antiarrhythmic drug, on action potential and transmembrane currents in frog atria1 muscle. Arch Int Pharmacodyn Ther 26:219, 1984. Sassine A, Masse C, Dufour A, Hirsch JL, Cazes M, Puech P: Cardiac electrophysiological effects of cibenzoline by acute and chronic administration in the anesthetized dog. Arch Int Pharmacodyn Ther 269:201, 1984. Thizy JF, Jandot V, Andre-Fouet X, Viallet M, Pont M: Etude Clectrophysiologique de 1’UP 339-01 chez l’homme. Lyon Med 245:119, 1981. Magiros E, Kushner M, Peters R, Carliner N, Fisher M, Plotnick G: Electrophysiology of oral cibenzoline. Clin Res 30:674A, 1982.
of cihr.r?:oiine in marl
20. Scherlag BJ, Lau SH, Helfant RH, Berkowitz WD, Stein E, Damato AN: Catheter technique for rectbrding His hundle activity in man. Circulation 39:13, 1969 21. Wit AL, Weiss MB, Berkowitz WD, Rosen KM, Steiner C. Damato AN: Pattern of atrioventricular t.clnduction in t.hc human heart. Circ Res 28:679, 1970. 22. Mandel W, Hayakawa H, Danzig R, Marcus HS: Evaluation of sino-atria1 node function in man by overdrive suppression Circulation 44:59, 1971. 23. Strauss HC, Saroff AC, Bigger JT *it-, Giartlina EGV: f’remature atria1 stimulation as a key to the understanding ol sinoatrial conduction in man. Circulation 47:86, 1973. 24. Furuta T, Toyama J, Yamada K: Comparative study of cibenzoline and disopyramide on fast channel blocking and anticholinergic action in isolated guinea pig cardiac muscle. Environ Med 27:99, 1983. 25. Canal M, Flouvat B, Tremblay D, Dufour :I: F’harmacokinetits in man of a new antiarrhythmic drug. ~‘ibrnzolinr. Em .I Pharmacol 24:509, 1983.
Continuous 24-hour electrocardiography in thyrotoxicosis before and after treatment Ten thyrotoxic individuals, who otherwise had no evidence of cardiovascular disease, underwent continuous ambulatory 24-hour ECG monitoring, before and after antithyroid treatment. The mean age of the subjects was 41 + 14.4 years (mean + SD) with a range of 22 to 66 years. When subjects were thyrotoxic, the mean heart rate for the group was 104 + 10.8 bpm. This fell to 82 i 6.8 bpm when the subjects were rendered euthyroid (p < 0.001). Circadian rhythm of heart rate response was maintained in the thyrotoxic state, although heart rate variability was significantly increased (p < 0.001). The prevalence of ventricular premature contractions was not significantly different before and after treatment, although premature atrial contractions were more prevalent during the middle third of the day (p < 0.01) when subjects were euthyroid. These findings support the view that normal adrenergic responsiveness persists in hyperthyroidism, and for most individuals treatment does not significantly alter the prevalence of ectopic activity. (AM HEART J 112:339, 1986.)
Robin J. Northcote, M.D., M.R.C.P., Peter MacFarlane, M.R.C.P., and David Ballantyne, M.D., F.R.C.P.(Glasg).
Thyroid hormone has positive chronotropic and inotropic effects on the heart, causing an increase in heart rate and cardiac output in hyperthyr0idism.l Controversy has existed as to whether the cardiovasFrom the Departments of Medical Cardiology and Clinical Medicine, The Victoria infirmary. and the Department of Medical Cardiology, The Royal Infirmary. Received accepted
for publication Dec. 6. 1985.
Reprint requests: ogy, The Victoria
Dr. Robin Infirmary.
April
16, 1985; revision
received
Oct.
J. Northcote, Department of Medical Glasgow G42 9TY, Scotland.
29, 1985; Cardiol-
Ph.D., Colin M. Kesson, Glasgow, Scotland
cular abnormalities occurring in hyperthyroidism are secondary to the direct action of thyroid hormones on the heart2v3 or to increased adrenergic activity of catecholamines,4 the former hypothesis being currently favored .5 Since hyperthyroidism affects about 1% of the population at some stage in their lives6 and can be associated with sudden death,7 ventricular arrhythmias,8 and myocardial infarction,g it is important to understand the ECG abnormalities associated with the disease. The cardiovascular manifestations of thyrotoxico339
15.
16.
namic effects of ethmozine in patients with ventricular tachycardia and left ventricular dysfunction (abstr). J Am Co11 Cardiol 3:474, 1984. Josephson ME, Seides SF: Clinical cardiac electrophysiology. Philadelphia, 1979, Lea & Febiger, Publishers. Narula OS, Samet P, davier RP: Significance of sinus node recovery time. Circulation 45:140, 1972. Mason JW. Winkle RA: Electrode catheter arrhythmia induction in the selection and assessment of antiarrhythmic drug therapy for recurrent ventricular tachycardia. Circulation 58:971, 1978. Swerdlow CD, Gong G, Echt DS, Winkle RA, Griffith JC, Ross DL, Mason JW: Clinical factors predicting successful electrophysiologicpharmacologic study in patients with ventricular tachycardia. J Am Co11 Cardiol 1:409, 1983. Mason JW, Swerdlow CD. Winkle RA, Ross DL, Echt DS, Anderson KP. Mitchell LB, Clusin WT: Ventricular tachyarrhythmia induction for drug selection: Experience with 311 patients. In Lucchesi BR, Dingell JV, Schwarz RP, Jr, edit.ors: Clinical pharmacology of antiarrhythmic therapy. New York, 1984. Raven Press, p 229.
17. Podrid PJ, Lown B: Ethmozin therapy for luairgnant vrntricular arrhythmia (abstr). Am .J Cardiol 49: IOl?. 1982. 18. Platia EV. Reid PR: Comparison of prcqqammed electrical stimulation and ambulatory electroci~rdi~,graphic (Halter) monitoring in the management of vent ri(&+r tarhycardia and ventricular fibrillation. .J Am (‘011 (‘ardiol 4:49:1. 1984. 19. Ruff R, Rozenshtraukh LV. Elharrar \‘. %ipes DP: Electrc,physiological effects of ethmozin on (‘;ir incx myocardium (Iardiovasc Res 13:354. 1979. 20. ljangman KH, Hoffman RF: ‘I’hc e(ft*c:q iii EN-:Il:I on abnormal automaticity in canine cardia I’urkinie fibers lahstrl. Circulation 57&58:11-l&$, 197X. 21. Rinkenberger RL. Prystowsky EN. Jackmat) WM. Naccarelli (i\‘. Heger .Jd. Zipes DP: Drug 1%onversion I)!’ nonstustained ventricular tachycardia to sustained venlracular tacbvcardia during serial electrophysiologic studies: Identificaiion of drugs that exacerbate tachycardia and potratial mechanisms. AM HEART .I 103:177, 1982. 22. Whitnev CC, Weinst,ein SH. Gaylord ,I(‘: ~~i4h-performance liquid c:hromatographic determinat.ion $:I‘ -thmozin in plasma. .J Pharm Sci X1:462. 1981.
Electrophysiologic effects of cibenzoline humans related to dose and plasma concentration
in
The electrophysiologic effects of a new antiarrhythmic agent, cibenroline, were investigated in 25 patients with an average age of 62 years. The compound was administered intravenously, as a bolus given over 2 minutes, then as a slow infusion over 40 minutes. Each subject was randomly allocated to receive one of the following four doses: 1.55 mg/kg (six patients), 1.8 mg/kg (six patients), 2.2 mg/kg (six patients), or 2.6 mg/kg (seven patients). Plasma cibentoline concentrations at these doses were 378 t 80, 525 + 194, 618 + 72, and 731 I? 196 rig/ml, respectively. Administration of 1.55 mg/kg cibenzoline significantly shortened the sinus cycle (60 msec on average; p < 0.025) and increased intraatrial (+8 msec; p < 0.05) and His-Purkinje conduction times (HV interval +13 msec; p < 0.001). At 1.80 mg/kg, prolongation occurred in the HV interval (+9 msec; p < 0.02), the duration of the QRS complex (+20 msec; p > 0.05), and the QT interval (+18 msec; p < 0.025). At the higher doses these changes became more marked (maximum increase: HV = +16 msec, p < 0.001; QRS + 25 msec; p < 0.001; QT + 26 msec, p < 0.05), and additional effects on atrioventricular nodal conduction time (AH interval + 17 msec; p < 0.05) and atrial (+20 msec; p < 0.05) and ventricular (+lO msec; p > 0.05) effective refractory periods were observed. Prolongation of the QRS duration was the effect that correlated best with plasma cibenzoline levels (r = 0.47; p < 0.05). These results allow an understanding of the antiarrhythmic activity of cibenzoline in humans. (AM HEART J 112:333, 1986.)
Paul Touboul, M.D., George Atallah, M.D., Gilbert Kirkorian, M.D., Claudio de Zuloaga, M.D., Alain Dufour, Ph.D., Marie France Aymard, Pierre Lavaud, M.D., and Pierre Moleur, M.D. Lyon, France From the Hi)pital C’ardiwasrulaire et Pneumologique Louis Pradel. Received Lx puhlicatir,n Aug. ld. 19X5; revision received Oct. 30, 1985; xwptrd Ik. IO. 1985. Reprint requests: Paul l’ouhoul, M.D., HBpital Cardiovasculaire et Pneum~~lopique I~ctuk Pradel. HP Lyon Montchat, 69394 Lyon Cedex OR, France.
M.D.,
Cibenzoline is a new antiarrhythmic agent with an original chemical formula (Fig. 1). Published reports have shown it to be effective in ventricular arrhythmias with both intravenous and oral administration.l-I’ The electrophysiologic bases for the com333
334
Touboul
et al.
,/vI n U\ ’ Fig.
American
I
Ii + HOOC
1. Chemical
formula
- 1 CH&
COOH
of cibenzoline.
pound action have been established in vitro12-‘6 and in the whole ammaLl Studies in humans have demonstrated cardiac electrical changes following intravenous and oral cibenzoline.*s Ia,ls However, no special attention has been paid to the question of dose response. The purpose of the present study was to evaluate the electrophysiologic effects of intravenous cibenzoline in humans in relation to dose and plasma concentration. METHODS Patient selection. Twenty-five patients were studied, 11 men and 14 women, ages 62 + 16 years (mean & SD, range 24 to 85). The majority (22 patients) suffered from syncope, two from dizziness, and two from palpitations. No heart disease was demonstrable from historic features and clinical evaluation. ECGs were normal in 15 patients but showed right bundle branch block in nine patients (two of whom also showed left anterior hemiblock) and left bundle branch block in one. Electrophysiologic techniques. Electrophysiologic studies were performed in the catheterization laboratory. All subjects were studied in the postabsorptive, nonsedated state. All had been carefully screened before the study to ensure absence of any metabolic disorder or antiarrhythmic treatment. Informed consent was obtained. Percutaneous catheterization was employed via the right and left femoral veins. In each patient, two bipolar electrode catheters were positioned in the right atrium, one for recording (in the sinus node area) and the other for pacing (in the upper third of the interatrial septum). A tripolar catheter was used to record His bundle potentials.*O The remaining catheter served to pace the right ventricular apex. Recordings were made by means of an eight-channel ink-jet ECG (Elema, Stockholm, Sweden), at a paper speed of 100 mm/set. His bundle signals were transmitted to an ECG amplifier and filtered (recording frequencies: 50 to 700 Hz). In addition to the intracardiac electrograms, leads I, II, III, V1, and V, were also recorded simultaneously. Some of these were displayed on an oscilloscope to provide continuous patient monitoring. A programmable modular stimulator (Janssen, Belgium) was used for cardiac electrical pacing, delivering rectangular impulses, 1.5 msec in duration, at twice diastolic threshold intensity. Atrioventricular (AV) conduction intervals were measured during regular atrial pacing. Cardiac refractory periods were determined by the
August, 1986 Heart Journal
extrastimulus method.*] Atria1 and AV conduction tissue refractory periods were obtained by premature atria1 depolarizations (coupling intervals reduced by 10 msec decrements) after eight beats of regular atria1 pacing. The right ventricular refractory period was measured by the same technique, using ventricular pacing. Sinoatrial function was also evaluated. Sinus node recovery time was measured after rapid atria1 pacing by using four different pacing frequencies (90, 110, 130, and 150 min) each sustained for 30 seconds and separated by l-minute sinus rhythm periods.22 The extrastimulus method during sinus rhythm was chosen for determining the sinoatrial conduction time.2:J All data collected during electrophysiologic studies were stored on magnetic tape (Hewlett-Packard recorder). Cibenzoline administration. Once the control study was completed, cibenzoline was administered as follows: an 0.8 mg/kg bolus was injected intravenously over 2 minutes, followed by slow infusion over 40 minutes of 0.75, 1.0, 1.4, or 1.8 mg/kg. Each patient could therefore receive one of the four following doses: 1.55, 1.8, 2.2, or 2.6 mg/kg, determined at random. This infusion regimen for intravenous administration was designed from the pharmacokinetics of cibenzoline3,25 and predicted from the tenth minute on relatively stable plasma concentrations. Blood samples for assay of the compound by gas chromatography2” were taken at 1.50, 15, 25, 35, 45, 48, 53, 58, and 73 minutes after administration began. The electrophysiologic study was resumed after 15 minutes, and evaluation was completed within 20 to 25 minutes. Statistics. Student’s t test for paired data was used to analyze the effects of cibenzoline at each dose level. Dose response was assessed by calculating the slope of the regression line of the variable against the dose and comparing it to zero (t test). The effect of the concentration was established by calculating the correlation coefficient. Terminology. Sinus cycle length was calculated by taking the mean of five successive cycles before administration of the drug and then 15 minutes after the onset of cibenzoline administration. The SA interval, or intraatrial conduction time, was measured during atria1 pacing from the stimulation impulse to the first rapid deflection of the atria1 electrogram recorded from the His bundle lead. The AH interval, or intranodal condution time, was defined as the interval between the first rapid deflection of the atria1 electrogram and that of the His bundle potential. The HV interval, or His-Purkinje conduction time, was measured from the first rapid deflection of the His potential to that of the ventricular electrogram V recorded from the His bundle lead. QRS and QT duration and conduction intervals before and. after cibenzoline were compared in each patient by means of identical pacing frequencies. The Wenckebach cycle during rapid atria1 pacing is the longest atria1 cycle at which an intranodal Wenckebach phenomenon occurs. The refractory periods, measured by premature cardiac stimulation, are defined as follows: The atria1 effective refractory period is the longest S,-S, interval at which premature atria1 stimulus S, is not followed by atria1
Volume 112 Number 2
Etectrophysiology
of cihenzotint~
Table I. Cumulative data on AV conduction, QRS and QT duration, and sinus node function different doses of cibenzoline __ --__ 1.55 mg Jkg 1.80 mglkg 2.20 mglkg Data
in man
aft.er administration
--
----
335
of
~-. __-_~..-:!.til) mglkg -..._I_---..
Sinus cycle Mean change P No. of patients SNRT Mean change P No of patients SAC’1 Mean change
+ SD (msec)
-60 j: 45 <0.025 6
-:12 2 48 >O.lO 6
-15 I? 4.5 >0.40 6
-24
t SD (I’(, )
+25 k 44 >(I.20 6
+1.8 i >0.60 6
i-64 + 141 >0.30 6
-t 44 f 1 1L? ~0.30 7
+ SD (msec)
-18 t 52 >0.40 6
-4x 2 55 X.10 5
-37 + 8
-. t,3 -f 52 N.05 .-,
i SD (msec)
+8 + 6 <0.05 6
-3 i XI.60 6
+3 -t 30 >0.70 ti
t-6 f 8 :>0.10 7
+ SD (msec)
-2 I 20 >0.80 6
t7 k 13 X).20 6
+3 2 12 >0.50 6
+I7 ’ 13
P No. of patients SA interval Mean change
P AH
No. of patients interval Mean change
P HV
No. of patients interval Mean change + SD (msec)
P
No.
+13
+ SD (msec)
No. of patients interval Mean change
t16 * s
6
+20 -+ 17 >0.05 :’
+23 It 14
t25 2 10
t2 k 13 >0.70 6
+18 + 11 <0.025 s
+12 +- 12 10.05 6
+26 ‘+ 24 <0.05 7
0 + 45 >0.90 6
0 t 41 >0.90 7
t 8
<0.20
+ SD (msec)
No. of patients Wenckebach cycle Mean change f SD (msec)
+17 k 52 >0.40 6
P X0. of patients SNRT
6
+14 _t 6 <0.005 6
+5
P
= sinus node recwery
time; SACT
= sinoatrial
conduction
cycle.
f 7
-4 i BO.60 6
19
time.
depolarization. The atria1 functional refractory period is the shortest A,-A, interval between two atria1 responses that can be achieved. The AV nodal effective refractory period is the longest A,-A, interval at which the premature AZ atria1 response is not propagated to the bundle of His. The AV nodal functional refractory period is the shortest H,-H, interval achievable between two His bundle depolarizations. The His-Purkinje system relative refractory period is the longest HI-H2 interval at which premature His bundle depolarization is followed by prolongation of the HV interval or by an aberrant QRS complex. The His-Purkinje system effective refractory period is the longest H,-H, interval at which premature His bundle activity is not conducted to the ventricles. The right ventricular effective refractory period, measured during regular ventricular pacing, is the longest S,-S, interval at which premature stimulation fails to induce a ventricular response. The effect of cibenzoline on the refractory periods was evaluated in each patient at the same basic drive
s
6
P QT
+9
of patients
QRS duration Mean change
-t 3
11
i 69 ~0.40 -:
Sinus node recovery time was measured from the last paced P wave to the first poststimulation sinus activity. The result was expressed as the percentage of the length of the basic sinus cycle according to the formula: sinus node recovery time/sinus cycle length x 100, the sinus cycle length being the mean of five successive sinus cycles before atrial pacing. Only the highest value was retained out of the four determined for each patient. The sinoatrial conduction time studied by premature atria1 stimulation was measured by the difference between the length of the return cycles recorded from the reset zone and that of the mean sinus cycle. It represents the total sum of conduction time into and out of the sinus node. RESULTS
Six patients received a total dose of 1.55 mg/kg, six patients received 1.80 mg/kg, six received 2.20 mg/kg, and seven received 2.80 mg/kg. The results are shown in Tables I and II. The effects of ciben-
336
Touboul
et al.
Table
II. Cumulative
data on cardiac
Data ERP-RA Mean P No. of FRP-RA Mean P No. of ERP-AV Mean P No. of FRP-AV Mean P No. of ERP-HPS Mean P No. of RRP-HPS Mean P No. of ERP-RV Mean P No. of
August, 1966 Heart Journal
American
refractory
periods
after administration
1.55 mg/kg
of different
1.80 mg/kg
doses of cibenzoline*
2.20 mglkg
2.60 mglkg
(msec)
+3 + 15 >0.60 6
+4 + 11 >0.40 5
+20 * 17 <0.05 6
0 t 33 >0.90 7
change
I SD (msec)
patients node change
+3 + 15 >0.60 6
-4 k 17 >0.60 5
+21 k 25 .0.60 6
-1 + 35 >0.90 7
+ SD (msec)
+a
change
k SD
patients
patients node change
+- SD (msec)
patients change
k 45
-20
+- 26
+5 k 21
-10
3
3
1
2
+a ? 38 >0.60 6
-25 i 51 >0.30 5
+3 + 29 >0.70 6
-7 t 19 >0.30 7
-55
-85
+20
1
1
1
+ SD (msec)
patients change
+ SD (msec)
patients change patients
t SD (msec)
+2 k 10 >0.60 6
Abbreviations: ERP = effective refractory period; FRP = functional ventricle; HPS = His-Purkinje system; SD = standard deviation. *The effect of cibenzoline on the His-Purkinje system refractoriness
+3
k 5
+615 >0.05 6
>O.lO
6 refractory could
zoline in each group are expressed, for greater clarity, as mean change per parameter -t the standard deviation. Duration of QRS and QT intervals. The duration of the QRS interval increased markedly from the 1.80 mg/kg dose upward (+20 +- 17 msec; p > 0.05). Subsequent increases were +23 +- 14 msec at 2.20 mg/kg 0, < 0.01) and +25 t- 10 msec at 2.60 mg/kg (p < 0.001). Increase in the QT interval became apparent from the 1.80 mg/kg dose of cibenzoline (+18 ? 11 msec; p < 0.025). At higher doses, the increase was as follows: +12 -+ 12 msec at 2.20 mg/kg (p < 0.05) and +26 f 24 msec at 2.60 mg/kg 0, < 0.05). It should be noted that when the JT interval only was considered, the compound had no demonstrable effect. AV conduction. The SA interval increased, on average, by 8 -t 6 msec after administration of 1.55 mg cibenzoline (p < 0.05). No significant changes were seen at higher doses. The AH interval did not vary significantly up to the dose of 2.20 mg/kg. At 2.60 mg/kg, it showed an increase of 17 -+ 13 msec (p < 0.02). The HV interval increased significantly
period;
RRP = relative
not be assessed
because
refractory
of the small
period; number
+10 + 13 >0.05 7 RA = right
atrium;
RV = right
of patients.
at all doses used. The increase was +13 f 3 msec at the lowest dose (p < O.OOl), +14 + 6 msec at 2.20 mg/kg (p < 0.005), and +16 +- 5 msec at 2.60 mg/kg @ < 0.001). There was no greater prolongation of the HV interval in patients with bundle branch block. There were no significant changes in the Wenckebach cycle at any dose. Refractory periods. The effective atria1 refractory period increased at the 2.20 mg/kg dose (+20 + 17 msec; p < 0.05). There was no significant variation in the functional refractory period. There were no demonstrable effects on the AV nodal functional refractory period. The AV nodal effective refractory period could be measured before and after cibenzoline in only nine patients (distributed over the four groups). No conclusions can be drawn given the limited number of patients. The His-Purkinje system relative refractory period decreased by 55 and 85 msec in two patients given 1.55 and 1.80 mg/kg cibenzoline, respectively. It increased by 20 msec in a third patient given a dose of 2.20 mg/kg. No conclusion can be drawn from these results. There was no patient in whom
Volume 112 Number 2
(3,QRS r-----l . QT Q AH
l.OOO- -
A-H
(P
H-V (P--0.066)
:.I: 1, .1 I
2 800. y2 700-x 3 600--
8 I
1.55
1.8 DOSE
2.2 (MGIKG)
2.6 IV
Fig. 2. Mean change in QRS, QT, AH, and HV intervals and ventricular effective refractory period (VERP) at the different doses of cibenzoline studied. Dose response was analyzed by regression test.
the His-Purkinje system effective refractory period could be measured. The increase in right ventricular effective refractory period, which was insignificant at the lowest doses, rose to 6 -t 5 msec at 2.20 mg/kg (p < 0.05) and to 10 -+ 13 msec at 2.60 mg/kg (p < 0.05). Sinoatrial function. Sinus cycle length decreased significantly at the 1.55 mg/kg dose (-60 k 45 msec; p < 0.025). This effect was reduced and was no longer significant at the higher doses. Cibenzoline showed no effect on sinus node recovery time. A tendency toward increase was, however, noted at higher doses. The sinoatrial conduction time decreased following cibenzoline, with the change becoming significant at 2.20 mg/kg (-37 ‘r_ 8 msec; p < 0.001).
Regression test showed that changes in the AH interval (p < 0.05), QRS duration (p < 0.02), and QT interval (p < 0.05) were dose dependent. As for the HV interval and the right ventricular effective refractory period, the results obtained almost reached statistical significance (with values of p = 0.086 and 0.075, respectively). The dose-dependent changes in these parameters are shown in graph form in Fig. 2. Plasma cibenzoline levels during electrophysiologic evaluation were calculated for each patient from three separate determinations performed 15, 25, and 35 minutes after administration of the
L
I I
. I
1.55
1.8 DOSE
1
I I
2.2 (MGIKG)
Fig. 3. Mean plasma concentrations tion) for the four doses of cibenzoline
2.6 IV (*standard studied.
devia-
compound was begun. Mean values for each group were as follows: 378 + 80, 525 r 194,618 + 72, and 731 + 196 rig/ml on doses of 1.55,1.80,2.20, and 2.60 mg/kg, respectively (Fig. 3). Dependency on cibenzoline plasma levels could be demonstrated for changes in sinus cycle length (r = 0.42; p < 0.05) and duration of QRS (r = 0.47; p < 0.05). The results for the right ventricular effective refractory period just failed to reach statistical significance (p = 0.061). The administration of cibenzoline was well tolerated in all patients. Blood pressure did not change significantly. DlSCUSSlON Depression of intraventricuiar conduction. Studies on isolated cardiac tissue have shown that cibenzoline decreases the maximum rate of depolarization in myocardial and Purkinje cells.12-LGVoltage clamp analysis has confirmed depression of the fast inward sodium current.“j The resultant decrease in conduction velocity in fast-response tissues accounts for the prolongation of the HV interval and the increased duration of the QRS interval observed in humans.BJo*lX The changes in QRS duration in our series were dose dependent and constituted the best marker of plasma cibenzoline levels. The depressant
338
Touboul
et al.
effect on intraventricular conduction did not produce complications, even at the highest doses. However, all of our patients had a normal HV interval, Further studies are required in subjects with abnormal His-Purkinje conduction. Increase in ventricular refractoriness. The increase in right ventricular effective refractory period became significant at the 2.20 mg/kg dose. This effect is similar to data from in vitro studies. Cibenzoline has been shown to produce a significant increase in the duration of the the action potential in the ventricle.12-I4 The effects on the QT interval would appear to corroborate the concept of a prolongation of ventricular repolarization. Like others,18 we noted a prolongation of the QT interval after cibenzoline, an effect which was dose dependent. However, the JT interval was not significantly altered, suggesting that the QT changes reflected only the increase in the duration of the QRS complex. One can therefore imagine that the effect of cibenzoline on the ventricular refractory period was more probably related to a slowing of the fast inward sodium current reactivation process-a mechanism which has been demonstrated in vitro.16 This might also account for the increased refractoriness of the atrium seen in our series at the 2.20 mg/kg dose.16 Restriction of the slow inward current. Administration of cibenzoline was associated at the 1.55 mg/kg dose with a significant increase in sinus rate. Possible mechanisms include sympathetic stimulation secondary to cardiac depression or the intervention of vagolytic effects. 24That this effect should fall off as the dosage is increased suggests the development of a direct depressant action on the sinus node partially counterbalancing the changes brought about by the autonomic nervous system. Studies on isolated sinoatrial node have shown that cibenzoline produces bradycardia as a result of prolongation of the action potential and reduction in maximum rate of depolarization.12 The latter effect suggests restriction of the slow inward current.16 As for the decrease in sinoatrial conduction time in our patients, it could also be explained by the action of autonomic nervous system. Slow inward current depression also accounts for the changes in AV nodal conduction time. Prolongation of the AV interval was dose dependent and became significant at 2.60 mg/kg. Variations in autonomic tone associated with cibenzoline activity might well be contributing to the minimization of direct AV nodal depressant effects. Cibenzolineinduced increase in AV nodal conduction time has been observed in isolated cardiac tissue studies.12 Additional effects on the AV nodal functional
American
August, 1986 Heart Journal
refractory period have also been reported.12 By facilitating the development of AV nodal block, such changes could provide a basis for the drug efficacy in supraventricular arrhythmias. Cibenzoline can thus be expected to have a wide clinical spectrum. It should be stressed that some studies have shown similar electrophysiologic results after oral administration.‘O In humans the compound shows over 90% bioavailability.25 Furthermore, the antiarrhythmic effect of oral cibenzoline has been demonstrated to be proportional to plasma concentration.? Such features aid in managing the drug. The present study reports the electrical properties of cibenzoline at different dose levels. The purpose is to individualize cibenzoline therapy by establishing a relationship between plasma drug concentration and therapeutic effect. This should make for more rational use of cibenzoline in clinical practice. REFERENCES
1. Baligadoo S, Chiche P: Beneficial effects of UP 339-01, a new antiarrhythmic agent against ventricular premature beats. Circulation 56179, 1978. 2. Heger JJ, Prystowsky EN, Browne KF, Chilson DA, Lloyd EA, Zipes DP: Cibenzoline treatment of patients with chronic ventricular arrhythmias. Clin Res 30:709, 1982. 3. Desoutter P, Dufour A, Aymard MF, Haiat R: Etude pharmacocinetique d’un nouvel antiarythmique la cibenzoline a la phase aigu& d’un infarctus myocardique. Correlations therapeutiques. Therapie 36237, 1983. 4. Kostis JB, Krieger S, Cosgrove N, Burns J, Saviano G, Moreyra A: Cibenzoline in ventricular ectopic activity. Circulation 66214, 1983. 5. Miura DS, Keren G, Siegel L, Tepper D, Butler B, Aogaichi A, Somberg JC: Effect of cibenzoline in suppressing ventricular tachycardia induced by programmed stimulation. J Am Co11 Cardiol 1:699, 1983. 6. Tepper D, Butler B, Keren G, Somberg JC, Tagarin M, Siegel L, Aogaichi K, Miura DS: Effects of oral cibenzoline therapy on ventricular ectopic activity. Clin Res 31:634A, 1983. 7. Brazzell RK, Aogaichi K, Heger JJ, Somberg JC, Carliner NH, Morganroth J: Cibenzoline plasma concentration and antiarrhythmic effect. Clin Pharmacol Ther 35:307, 1984. 8. Browne KF, Prystowsky EN, Zipes DP, Chilson DA, Heger JJ: Clinical efficacy and electrophysiologic effects of cibenzoline therapy in patients with ventricular arrhythmias. J Am Co11 Cardiol 3:857, 1984. 9. Cocco G, Strozzi C, Pansini R, Rochat N, Bulgarelli L, Padula A, Sfrisi C, Kamal Al Yassini A: Antiarrhythmic use of cibenzoline, a new class 1 antiarrhythmic agent with class 3 and 4 properties in patients with recurrent ventricular tachycardia. Eur Heart J 5:108, 1984. 10. Kushner M, Magiros E, Peters R, Carliner N, Plotnick G, Fisher M: The electronhvsioloeic effects of oral cibenzoline. J Electrocardiol 17:15, i984. ” 11. Saksena S, Rothbarts S, Shah Y, Liptak K: Chronic effects of oral cibenzoline in refractory ventricular tachycardia. Clin Pharmacol Ther 35:271, 1984. 12. Millar JS, Vaughan-Williams EM: Effects on rabbit nodal, atrial, ventricular and Purkinje cell potentials of a new antiarrhythmic drug, cibenzoline, which protects against action potential shortening in hypoxia. Br J Pharmacol 75469, 1982. 13. Ikeda N, Singh BN: Electrophysiological profile of a new
Volume 112 Number 2
14.
15. 16.
17.
18.
19.
Electrophysiolog?
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Continuous 24-hour electrocardiography in thyrotoxicosis before and after treatment Ten thyrotoxic individuals, who otherwise had no evidence of cardiovascular disease, underwent continuous ambulatory 24-hour ECG monitoring, before and after antithyroid treatment. The mean age of the subjects was 41 + 14.4 years (mean + SD) with a range of 22 to 66 years. When subjects were thyrotoxic, the mean heart rate for the group was 104 + 10.8 bpm. This fell to 82 i 6.8 bpm when the subjects were rendered euthyroid (p < 0.001). Circadian rhythm of heart rate response was maintained in the thyrotoxic state, although heart rate variability was significantly increased (p < 0.001). The prevalence of ventricular premature contractions was not significantly different before and after treatment, although premature atrial contractions were more prevalent during the middle third of the day (p < 0.01) when subjects were euthyroid. These findings support the view that normal adrenergic responsiveness persists in hyperthyroidism, and for most individuals treatment does not significantly alter the prevalence of ectopic activity. (AM HEART J 112:339, 1986.)
Robin J. Northcote, M.D., M.R.C.P., Peter MacFarlane, M.R.C.P., and David Ballantyne, M.D., F.R.C.P.(Glasg).
Thyroid hormone has positive chronotropic and inotropic effects on the heart, causing an increase in heart rate and cardiac output in hyperthyr0idism.l Controversy has existed as to whether the cardiovasFrom the Departments of Medical Cardiology and Clinical Medicine, The Victoria infirmary. and the Department of Medical Cardiology, The Royal Infirmary. Received accepted
for publication Dec. 6. 1985.
Reprint requests: ogy, The Victoria
Dr. Robin Infirmary.
April
16, 1985; revision
received
Oct.
J. Northcote, Department of Medical Glasgow G42 9TY, Scotland.
29, 1985; Cardiol-
Ph.D., Colin M. Kesson, Glasgow, Scotland
cular abnormalities occurring in hyperthyroidism are secondary to the direct action of thyroid hormones on the heart2v3 or to increased adrenergic activity of catecholamines,4 the former hypothesis being currently favored .5 Since hyperthyroidism affects about 1% of the population at some stage in their lives6 and can be associated with sudden death,7 ventricular arrhythmias,8 and myocardial infarction,g it is important to understand the ECG abnormalities associated with the disease. The cardiovascular manifestations of thyrotoxico339