British Heart journal, 1979, 41, 89-98

Electrophysiological effects ofL 9394(benzoyl-indolizine) in manA. WALEFFE, A. BORDALO', P. BRUNINX, H. J. J. WELLENSa, ANDH. E. KULBERTUS

From the Laboratory of Electrocardiology, Institute of Medicine, University of Liege, Belgium;and the Department of Cardiology, University of Limburg, Maastricht, The Netherlands

SUMMARY The electrophysiological effects of L 9394 (benzoyl-indolizine), a substance chemicallyrelated to amiodarone, but devoid of iodine atoms, were investigated by programmed electrical stimula-tion ofthe heart in 12 patients with various forms of tachycardia. Four subjects had electrocardiographicevidence of the WPW syndrome and episodes of circus movement tachycardia. Paroxysmal supra-

ventricular tachycardia, confined to the atrioventricular (AV) node, was found in 3 patients. In 2 cases,

where a short PR interval was present, the main complaint was the occurrence of paroxysmal atrialfibrillation. In the remaining 3 instances, the arrhythmia consisted of slow ventricular tachycardia (1case), supraventricular tachycardia of the focal type (1 case), and episodes of primary ventricularfibrillation, not related to acute myocardial ischaemia (1 case).L 9394 injected intravenously was seen to lengthen the transnodal conduction time as well as the

effective and functional refractory periods of the node. Similar effects were found on the retrogradeVA pathway. The drug had no action on the infra-Hisian conduction system, on the refractory periodsof ventricular muscle, or on the refractory periods of accessory bypasses.The drug was injected during an episode of tachycardia in 6 cases with reproducible supraventricular

re-entrant tachycardia. Three had a tachycardia circuit confined to the node. In those instances, the drughad beneficial effects (slowing and interruption of tachycardia, decrease or abolition of echo zone; loss ofability to induce tachycardia). In the other 3 cases, an accessory pathway was incorporated in the circuit.L 9394 interrupted the tachycardia in 2 instances (by anterograde AV block), but failed to protect all3 patients against reinitiation of tachycardia by premature stimuli.

It is concluded that L 9394 does not share all the pharmacological properties of amiodarone and willnot replace it in all its indications.

Amiodarone has been reported to be an effectiveantiarrhythmic agent for different types of arrhyth-mia (Coumel et al., 1974; Rosenbaum et al., 1974;Touboul et al., 1975; Rosenbaum et al., 1976;Wellens et al., 1976; Waleffe et al., 1978). Side-effects however have limited wide acceptance of thedrug in clinical practice (Geerts, 1971; Verin et al.,1971; Babel and Stangos, 1973; Pritchard et al.,1975; Burger et al., 1976). L 9394, a benzoyl-indolizine derivative, is a new substance which ischemically related to amiodarone (Fig. 1) (Charlier

"Research Fellow of the Calouste Gulbenkian Foundation,Lisbon, Portugal.2This work was performed while H. J. J. Wellens was ChaireFranqui Professor at the University of Li6ge.

Received for publication 5 December 1977

et al., 1976, 1977). However, since L 9394 is not acarrier of iodine atoms, there are reasons to believethat the drug is likely to be devoid of at least someof the side-effects of amiodarone. We thereforedecided to investigate the electrophysiologicalproperties of L 9394 in man.

Subjects and methods

Twelve patients were studied. Data on age, sex,and type of arrhythmia are given in Table 1.

After obtaining informed consent, 4 catheterswere introduced into the femoral vein using theSeldinger technique. One quadripolar catheter waspositioned high on the lateral wall of the rightatrium: the two distal electrodes were used forstimulation and the proximal electrodes for re-

89

A. Waleffe, A. Bordalo, P. Bruninx, H. 7. J'. Wellens, and H. E. Kulbertus

L 9394if> CH2 CH3

s - C oCH2 CH2 CCHCHN~ H

,, 0O.-CH2 CH2 CH2-N\ CH2 CH2 C

AmiodaroneCH2 CH2 CH2 CH3

C1 O-CH2-CH2-N\ 2 3

CH2 CH3

Table 1 Clinicalfeatures

Case no. Age and sex Diagnosis

L1 20 F AVN RT2 23 F AVN RT3 38 F AVN RT4 55 M Short PR + AF5 27 F Intermittent WPW type A + CMT6 34 F WPW type B + CMT7 26 M WPW type A + CMT + AF8 51 M WPW type B9 18 M Short PR + AF

10 19 M Slow VT11 56 F VF12 22 M SVT (focal type)

AF, atrial fibrillation; AVN RT, AV nodal re-entrant tachycardia;CMT, circus movement tachycardia; VF, ventricular fibrillation;VT, ventricular tachycardia; SVT, supraventricular tachycardia;WPW, Wolff-Parkinson-White syndrome.

cording the intra-atrial electrogram. A bipolarcatheter was placed close to the bundle of His torecord the His bundle electrogram. The third(bipolar) catheter was positioned in the apex of the

CH2 CH3.H Cl

ZH2 CH3

Fig. 1 Chemical structure ofL 9394 ascompared with amiodarone.

right ventricle and was used for ventricular stimu-lation.

In 6 patients, in order to record a left atrialelectrogram, a fourth quadripolar catheter wasadvanced into the coronary sinus or, through apatent foramen ovale, into the left atrial cavity.Using the extrastimulus technique, the effective

refractory period of the right atrium, the effectiveand functional refractory periods of the AV node,and the effective refractory period of the right ven-tricle and of the accessory pathway, when present,were measured. The zones of premature beatintervals resulting in atrial echoes or sustainedtachycardia were carefully determined. The rightventricle was paced up to its effective refractoryperiod. The pattern and refractory period of VAconduction were registered. Atrial and ventricularpacing were first done at rates slightly above thespontaneous rate, and thereafter at shorter cyclelengths.

Table 2 Effects of L 9394 on electrophysiological indices: comparison of control values with longest valuesobserved after drug administration

Case no. Pacing AH interval HV interval ERPRA (ms) AV node (A V direction)cycle (ms) (ms) ERP (ms)length (ms)

Before After A Before After Before After A Before After A

1 500 120 120 0 30 50 - - - 220 300 802 550 50 60 10 35 35 215 235 20 < 225 360 > 135

5003 470 70 100 30 40 40 210 230 20 < 230 330 > 1004 600 50 70 20 20 20 210 225 15 < 235 340 > 1055 470 100 115 15 30* 30* 175 215 40 < 200 420 22C6 500 80 85 5 30t 30t 195 210 15 240 > 280 > 4C7 600 100 ? ? -40 ? 250 270 20 ? ? ?8 550 ? ? ? 50* ? 210 210 0 < 240 > 310 > 7C9 500 110 120/240 10/130 30 30 240 280 40 250 380 13C10 500 110 140 30 30 30 170 190 20 230 330 lOC

55011 600 120 170 50 40 40 230 250 20 < 250 420 > 17C12 500 90 120 30 40 40 190 190 0 280 380 1OC

600

Mean difference +32 +19-10 > 113P < 0-05 < 0-001 < 0-0

ERP, effective refractory period; FRP, functional refractory period; RA, right atrium; RV, right ventricle;AP, accessory pathway. *Without pre-excitation; tDuring circus movement tachycardia.

90

Electrophysiological effects of L 9394 (benzoyl-indolizine) in man

The various measurements were made before andafter the injection of2 mg/kg ofL 9394, administeredintravenously over a 5-minute period. All measure-

ments were repeated at the end of the injection(time zero) and again every fifteenth minute,during 1 hour.

All data obtained during the stimulation studywere recorded on tape (HP 8868 A) and directlyregistered on an eight-channel Elema Mingografrecorder. Leads I, II, III, V1, V6, the intracavitaryright atrial lead, the left atrial lead (when available),and the His bundle electrogram were simultaneouslyrecorded. For recording the His bundle electro-gram, a 854 Universal Amplifier with input adapterwas used.The effective refractory period of the AV node

was defined as the longest A1-A2 interval failing toconduct through the AV node. The functionalrefractory period (FRP) of the AV node was con-sidered as the shortest H1-H2 interval that couldbe obtained. Since it was not always possible todetermine when the AV node became refractoryduring ventricular pacing (because of absence ofa retrograde H potential and/or because of a gapphenomenon in VA conduction), no values will begiven for the effective refractory period ofthe differ-ent parts of the VA conduction system. Statisticalanalysis was performed using the paired t test.Plasma levels of L 9394 were determined by usinga chromatographic method (J. Broekhuysen, 1977,personal communication).

Results

The results are summarised in Table 2.

AV CONDUCTIONAs indicated in the Table, the AH interval length-ened after the L 9394 injection in all but 1 of the10 patients in whom it could be measured. Meanincrease in AH interval was 32 ms (range 0 to 130ms) (P < 0.05). In case 9, a sudden and distinctlengthening of the AH interval (jump from 120 to240 ms) was transiently observed 30 minutes afterthe administration of L 9394.

Because some patients had the WPW syndrome,the refractory periods of the AV node could not bemeasured in all studies. 'The effective refractoryperiod measured in 11 patients increased by an

average of more than 113-6 ms (P < 0.001). Thefunctional refractory period increased by an average

of more than 89-4 ms (P < 0-001).A pattern suggestive of a dual AV nodal pathway

was present before L 9394 administration in 2patients (cases 1 and 9). L 9394 did not alter thebroken aspect of the AV conduction curve in case 9,the electrophysiological properties of both pathwaysbeing similarly affected by the drug. But in case 1, asmooth curve was observed during the initial20 minutes after drug injection. In 2 patients(cases 3 and 5), the injection of L 9394 revealed adual AV nodal pathway curve that had not beendepicted before drug administration. In case 5,this dual pathway curve appeared 20 minutes afterinjection and persisted until the end of the investi-gation. In case 2, a patient with AV nodal re-entranttachycardia, a smooth AV conduction curve wasconsistently obtained both before and after theadministration of L 9394.

In patients without pre-excitation no change wasobserved in the HV interval.

VA conduction system ERPRV (ms) ERPAP (ms):ms) ERP (ms) AV direction VA direction

After A Before After A Before After A Before After A Before After A

420 80 240 410 170 220 230 10> 360 > 10 .220 300 > 80 200 210 10

> 410 > 90 .230 .230 ? 0 220 220 0450 50 <275 .270 ? 265 255 - 10430 105 ? ? ? 215 225 10 440 ? ? < 225 < 240 ?

? ? ? ? ? 240 230 -10 280 280 0 280 290 10? ? ? ? ? 230 220 - 10 < 270 < 290 ? < 240 260 > 20? ? < 260 < 260 ? 240 240 0 290 310 20 340 350 10540 100 <230 410 >180 210 210 0460 100

270 410 140 200 210 10530 170 290 block x0 280 290 10440 100

360 500 140 330 220 -110

> 89-4 > 142 -7-5 > 13-3< 0-001 < 0-01 NS NS NS

91

92 A. Waleffe, A. Bordalo, P. Bruninx, H. J. J7. Wellens, and H. E. Kulbertus

Table 3 Effects of L 9394 on tachycardia

Case no. CL Tachycardia type Initiation Tachycardia zone RR interval during(ins) tachycardia (mns)

Before After Before After Before After

1 500 AVN RT 1 APB - 250-230 - 360 -

500 AF 1 APR - 210-180 400 -2 300 AV R Rapid atrial pacing - 330 -

300 AVR Rapid ventricular - 330 -

pacing3 SR AVNRT2APB 3 APB - 310 -

270 fV RTrapid atrial pacing -

5 470 2 APR 1 APB 320-265k 290-380 450470 CMT (WPW) 3 VPB 1 VPB 390-300f290 rapid atrial pacing -

6 500 CM} (P1 APR - 280-255 - 300 390500 CM(W ) - 1 VPB - 290

7 600 CMT (WPW) 1 VPB 1 VPB 310-300 350 320-360 450

CL, cycle length; AVN RT, AV nodal re-entrant tachycardia; AF, atrial flutter; CMT, circua movement tachycardia; APR, atrial prematurebeat; VPR, ventricular premature beat; SR, ainua rhythm.

VA CONDUCTION characteristics through the His AV nodal axis.In 3 patients (cases 5, 6, 7), the presence of an In 3 patients (cases 3, 4, 8), VA conduction per-accessory pathway (with an effective refractory sisted after drug administration up to the functionalperiod in VA direction shorter than that of the refractory period of the ventricle.ventriculoatrial conducting system) did not permit In 1 patient, after L 9394, a complete VA blockaccurate evaluation of changes in VA conduction occurred (case 11). Finally, in the remaining 5

~~~~~~~~~~~~~ ..A..~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~...... ~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~.......

£~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..... .....

81 PVI'...u......o.N.....A.......A.A..TV

......... ...- -..... t .'....v .............I .K... ..

~~~~ 2~J,~~~~~~~~~~~~~~~~~~

Fig.2(a)~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..Fig.2Case 1. Eight leads~~~~~~~~~~~~... ...ar siutneul recorded: .IV,V,HA(ihih tilla) CS.. andCS(twocoronarysinus leads), and the HEE (His bundle electrogram).~~~~~~~~~~~~~~~~~~~~~....... ...Ina)beordrgdmnitraio, t AAa ntrvl f 20 ns alon A iteva isobered(Hia 50 nsan neioeo oa eenrn ahcri wt rniet21AVbok siiitdIn~~~~~~~.(bn c fe diitaino 34 wpi tecrepotn h 12itrasaantteAAintervalsisstillobserved(H1H2 equals 410 ms for an A1A2 of 350 ins, and 550 ins for an A1A, of 340 ins). Inspite~~~~~~~~~~~~~~~~~~~~~~~~~~~..ofthis,noecho beat or tachycardia is elicited, the fast conducting pathway beingnow.blocked.in.the.retrogradedirection.~~~~~~~~~~~~~~~~~

Electrophysiological effects of L 9394 (benzoyl-indolizine) in man 93

Fig. 2(b)*

| .~~~~~~~~~~~~~~~~~~~~~~~~~~.. ..... ^_.I,_W..

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X,'y.f ~ N ... -..........- f

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tiR:-Ajk2 M.

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... ...HS EM P U . SS -- -- A -X

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vs14~~~~~~~~~~~~~~~~~~~~~~~~~........*~~~~~~~I A~~~~~~~..........t.

94 A. Waleffe, A. Bordalo, P. Bruninx, H. J. 7. Wellens, and H. E. Kulbertus

:-P.....

Yr~~~~~~~~~~~~~~~~~~~:. :.: ........... ..... . .. .... ..............

f JN

v.. ... .. .. ... ......

330> MOJ< 38OJ

-4~~ ~ ~~~~-

*N v

HEtA 1* H H HS...g .t. .., M2y J

H~~A*e ..S-- .......... .'t.l X 0 _. X - X~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~........u-1 r -@t AA ^ws

Fig. 3(a)

_=~~~~~~~ A

...~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~......

...:...:.:....:

*; ,j . .... , ,. <---b~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~A --.*. .......

...... -A........

~~ ~ ~ ~ ......SZ

*os o~~~~~~~~~~~~~..c.|S... . SJ .....

.......A A

Fig3(b).j%.,^,s. jfx t, . .. ... ..

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Fig..3....).

Fig. 3 Case 2. (a) Before drug administration, atrial pacing at a cycle length of 300 ms

results in a Wenckebach type of response and its interruption is followed by the initiationof an episode of tachycardia (AV nodal re-entrant tachycardia). (b) After administrationof L 9394, the Wenckebach type of block is more obvious during atrial pacing. Afterinterruption of pacing, one AV nodal re-entry cycle is completed, but this is not followed bytachycardia, the slow conducting pathway being now blocked in the anterograde direction.

Electrophysiological effects of L 9394 (benzoyl-indolizine) in man

subjects (cases 1, 2, 9, 10, 12), the effective re-fractory period of the VA conduction systemlengthened by an average of at least 142 ms.

EFFECTIVE REFRACTORY PERIOD OF RAAND RVIn all but 2 cases, the ERP of the right atriumslightly lengthened. The changes were statisticallysignificant (P < 0 001) but, in absolute values, theyappeared trivial. The ERP of the right ventriclefailed to show any consistent alteration.

ERP OF ACCESSORY PATHWAYAn accessory pathway was present in 4 cases(2 right-sided; 2 left-sided). The drug was found tohave no effect on its effective refractory periodeither in anterograde or retrograde direction.

MECHANISM OF TACHYCARDIAIn the 3 patients with AV nodal re-entrant tachy-cardia (cases 1 to 3), and in 3 of the 4 subjects withWPW (cases 5 to 7), episodes of tachycardia couldbe initiated by electrical stimulation (Table 3).

In case 1 (Fig. 2), before the administration of thedrug, a single atrial extrastimulus (S2) delivered be-tween 250 and 230 ms after the preceding stimulus(Si) initiated an AV nodal re-entrant tachycardiawith a cycle length of 360 ms. In addition, S2stimuli, delivered from 210 ms to 180 ms after Si,started episodes of atrial flutter with a ventricularcycle length of 400 ms. After L 9394 administration,the jump in the curve plotting the H1H2 againstthe A1A2 intervals transiently disappeared; it wasagain observed after a 20-minute period; extra-stimuli however could induce only one or two re-entrant echo beats, but no sustained tachycardia.Atrial flutter could not be elicited.

In case 2, AV nodal re-entrant tachycardia couldbe started only by rapid atrial or ventricular pacing(Fig. 3). After L 9394, no tachycardia could beinduced.

In case 3, supraventricular tachycardia could beinitiated by 2 or 3 atrial extrastimuli or by rapidatrial pacing. After drug administration, the abilityto induce tachycardia was lost in spite of theunmasking effect of a previously concealed dualAV nodal pathway.

In case 5 (Fig. 4), a left-sided accessory pathwaywas associated with a dual AV nodal pathway curveunmasked by L 9394 injection. Episodes of tachy-cardia with two different cardiac rates (suggestingcircuits with AV conduction over either the fast,or the slow AV nodal pathway, and VA conductionover the accessory pathway) could be initiatedbefore drug administration by giving a salvo of atleast 3 ventricular extrastimuli, more rarely by 2atrial premature beats, or by rapid atrial pacing

at a rate producing a Wenckebach phenomenon.After the drug, a jump in the AV conduction curvebecame clearly apparent. Initiation and terminationof tachycardia were facilitated. Circus movementtachycardia, using the accessory pathway retro-gradely, could be started by either a single ventri-cular or atrial premature beat with relatively largetachycardia zones (at that time the fast AV nodalpathway had become refractory), by rapid atrialpacing at rates producing a second degree AVblock, and by ventricular pacing. The tachycardiacould easily be terminated by 2 ventricular pre-mature beats and, with greater difficulty, by asingle ventricular extrastimulus, or by 3 atrialpremature beats. The tachycardia cycle length was,significantly prolonged after L 9394 (410 ms ascompared with 290 or 380 before the injection),this lengthening being in part the result of theexclusive use of the slow AV nodal pathway foranterograde conduction.

In 6 patients with reproducible paroxysmalre-entrant tachycardias, L 9394 was administeredduring an episode of tachycardia. The injectionresulted in termination of the rhythm disorder inall patients with the intranodal type of tachycardiaand in 2 of the 3 cases with the WPW syndrome(cases 5 and 7). The heart rate during tachycardiadecreased in each subject; this was related to slowingof conduction along the AV node and not to pro-longation of the VA conduction time.

OTHER INDICESSinus node function tests were not performed duringthis investigation because of a lack of time duringthe procedure.

In 2 of the cases, the threshold for atrial stimu-lation was noted to increase after L 9394 adminis-tration. In case 9, for example, the threshold at theend of injection rose to 20 mA. This value was5 times greater than the control value. It fell to7 mA 22 minutes later and to 5 mA after 30 minutes.In case 2, the threshold was measured at 7 mA atthe end of the injection and at 4 mA 30 minuteslater.

In the remaining subjects, no attempt was madeto measure systematically the threshold for atrialstimulation. Since stimulation was done at twicethe threshold value, any increase of less than 100per cent would have passed unnoticed.

Arterial blood pressure was monitored through-out the study, in 4 cases by continuous intra-arterial pressure recording, and in the remaininginstances by repeated measurements by sphygmo-manometer. No significant change was observed.The plasma level ofL 9394 was 3-0 ng/ml ± 2.0

at the end of injection and 0 47 ± 0-21 15 minutes

95

A. Waleffe, A. Bordalo, P. Bruninx, H. J. J. Wellens, and H. E. Kulbertus

later. After the end of injection, the plasmalevels showed an exponential decrease. Nocorrelation was observed between the pharma-cological effects and the plasma levels of the drugduring this initial distribution period (Wellens andDurrer, 1974).

Discussion

The results of our investigation show that L 9394is a substance which acts mainly on the AV node.It lengthens the transnodal conduction time aswell as the effective and functional refractoryperiods of the node. As opposed to amiodarone(Touboul et al., 1975; Wellens et al., 1976; Waleffeet al., 1978), it has no effect on anterograde con-duction over the intraventricular conduction system,on ventricular muscle, and accessory pathways.The observed changes are of the same order of

magnitude as those which have been reportedpreviously with ouabain (Wellens et al., 1975;Wu et al., 1975), propranolol (Wu et al., 1974), andverapamil (Wellens et al., 1977).

In contrast to verapamil (Wellens et al., 1977),L 9394 had some effect on the retrograde VApathway in several patients. This may of coursereflect an action on the AV node but functionalchanges within the His-Purkinje system usedretrogradely cannot be ruled out.Our observations indicate that L 9394 is a

potentially interesting drug for the treatment oftachycardias confined to the AV node. In the 3patients whom we studied, the episodes of tachy-cardia were ended by the intravenous injection ofthe drug. In addition, L 9394 decreased or totallyeliminated the echo zones and made the patients

500

450

I

I 400.

350-

300C.

atrial pacing CL 470

efore ( After550-500

450

400.0Y

00

FRPA *0 350*000000- .

300

200 20 300 350 400A1 A2

lose their ability to develop sustained paroxysmalsupraventricular tachycardia during programmedelectrical stimulation.The effects in patients with circus movement

tachycardia associated with pre-excitation are lessclear. In the 3 patients studied, the drug producedslowing of transmission through the anterogradeAV nodal part of the tachycardia circuit whichresulted in a significant slowing of the cardiac rateduring circus movement tachycardia. L 9394interrupted tachycardia in 2 instances, but failed toprotect all 3 patients against reinitiation of tachy-cardia by premature stimuli. These observationsresemble those made in patients with concealedbypasses after administration of ouabain (Wellenset al., 1975; Wu et al., 1975), propranolol (Wu et a!.,1974), and verapamil (Wellens et al., 1977). Aspointed out by others (Wellens et al., 1975;Wu etal.,1975), by producing selective slowing of conductionwithin the AV node, these drugs, like L 9394, mayactually favour the initiation and perpetuation ofcircus movement tachycardia in the presence of aventriculoatrial accessory pathway. Delaying con-duction through the node increases the chance for apremature impulse to reach the ventricular endofthe bypass when it is excitable and thus promotesVA conduction over this pathway and initiation aswell as perpetuation of tachycardia. This wasclearly shown in case 5 of this series in whom anaccessory bypass as well as a dual nodal pathwaywere simultaneously present. Prolongation of theconduction time especially along the slow nodalpathway made it much easier to induce the tachy-cardia after drug administration.Drug induced changes of the pattern of atrio-

ventricular conduction have previously been re-

00

0.0.00 0

200 250 300 350 400A1 A2

Fig. 4(a)

96

i) B45501

Blectrophysiological effects of L 9394 (benzoyl-indolizine) in man 9

Before L9394

U.

fiCL4W~~~~~9jj0j

Fi. 4(b)....

After L9394

.t7........

U~~~~~~~~~~~~~~~~~~~~~~~~~~~~...

7-~~~~~~~~~~~~~~~

H182 420

LRtA

A A .AA..

Fig. 4(c)

~~~~~~~~~~~~~~~~.....A..

....~~~~~**~~~~~~~~~~~~~~~~~~~.....

/4 j I ~~~~~~~~~~~~~ .~~~~~~ A~~.,..' W Y~~~~~~~~~~~~. ......

LO A A..

U I~~~~~~~~~~~~~~~~~~~~~~.......'jji .....,...!...-A.......C5 A~~~~~~~~~~~~~~~~~~~~~~~~~~~......

.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..

Vs~~~~~~~~~~~~~~~~~~~~~~~~~~A. A A S~~~~~~~~~~~~~~~~~~~~~~~~.........

Fig. 4 Case 5. (a) The curve plotting the H1H2 against the A 1A2 intervals is smooth in the control state, but showsafter administration of L 9394 a typical jump at 320 ins. Tracings were obtained before (b) and after (c) administrationof the drug. Before L9394 (b) single ectopic beats elicited at A1IA2 intervals of 330 and 320 ms failed to initiatetachycardia. After L9394 (c) the ectopic beat elicited at an A 1A, interval of 320 ms produced a sudden increaseof the AH time and initiated an episode of tachycardia with a longer cycle length (410 ins) than in the basicconditions (290 to 380 ins). LRA: low right atrial lead.

97

A. Waleffe, A. Bordalo, P. Bruninx, H. J. J7. Wellens, and H. E. Kulbertus

ported (Wu et al., 1974; Wellens et al., 1975, 1977).Two different situations were encountered in thisseries. In 2 patients, a dual AV nodal pathway wasshown only after administration of L 9394. In oneother case, a dual pathway curve was identifiedbefore drug administration, but changed into asmooth curve afterwards. The possible explana-tions for such a phenomenon have been discussedpreviously (Wellens et al., 1975).

In summary, it is apparent that L 9394 does notshare all the pharmacological properties of amio-darone and in spite of its possibly bettertolerance, it will not completely replace amiodarone.As it has little effect on the atrial and ventricularmuscles and on the accessory pathways it is unlikelythat L 9394 will be as effective as amiodarone on alarge spectrum of arrhythmias. We want to stresshowever that our data were obtained after intra-venous administration of L 9394. Little is known ofthe pharmacokinetics ofthis substance in the human.In addition, previous experience has indicated thatthe effect of intravenous amiodarone is differentfrom that obtained after long-term oral adminis-tration (Berkman et al., 1975). In view of this,chronic studies (Wu et al., 1977) on the effect ofL 9394 administered orally are needed before anydefinite conclusion can be drawn regarding theclinical usefulness of this drug.

We thank Mr Broekhuysen (Labaz S.A., Brussels),who performed the blood level determinations, andLabaz S.A. (Brussels) who provided the L 9394for this investigation.

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Verin, Ph., Gendre, Ph., and Barchewitz, G. (1971).Thesaurismose corneenne par amiodarone. Donneesrecentes. Archives d'Ophtalmologie et Revue Generaled'Ophtalmologie, 31, 581-595.

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Wellens, H. J. J., Duren, D. R., Liem, K. L., and Lie, K. I.(1975). Effect of digitalis in patients with paroxysmalatrioventricular nodal tachycardia. Circulation, 52, 779-788.

Wellens, H. J. J., and Durrer, D. (1974). Effect of procaineamide, quinidine and ajmaline in the Wolff-Parkinson-White syndrome. Circulation, 50, 114-120.

Wellens, H. J. J., Lie, K. I., Bar, F. W., Wesdorp, J. C.,Dohmen, H. J., Duren, D. R., and Durrer, D. (1976).Effects of amiodarone in the Wolff-Parkinson-Whitesyndrome. American J7ournal of Cardiology, 38, 189-194.

Wellens, J. H. H., Tan, S. L., Bar, F. W. H., Duren, D. R.,Lie, K. I., and Dohmen, H. M. (1977). Effect of verapamilstudied by programmed electrical stimulation of the heartin patients with paroxysmal re-entrant supraventriculartachycardia. British Heart Journal, 39, 1058-1066.

Wu, D., Denes, P., Dhingra, R. C., Khan, A., and Rosen,K. M. (1974). The effects of propranolol on induction ofA-V nodal reentrant paroxysmal tachycardia. Circulation,50, 665-667.

Wu, D., Wyndham, C., Amat-y-Leon, F., Denes, P., Dhingra,R. C., and Rosen, K. M. (1975). The effects of ouabain oninduction of atrioventricular nodal reentrant paroxysmalsupraventricular tachycardia. Circulation, 52, 201-207.

Wu, D., Wyndham, C. R., Denes, P., Amat-y-Leon, F.,Millet, R. H., Dhingra, R. C., and Rosen, K. M. (1977).Chronic electrophysiological study in patients with recurrentparoxysmal tachycardia: a new method for developingsuccessful oral antiarrhythmic therapy in re-entrantarrhythmias. In Reentrant Arrhythmias, Mechanisms andTreatment, pp. 294-311. Ed. by H. E. Kulbertus. MTPPress, Lancaster.

Requests for reprints to Professor Henri Kulbertus,Division of Cardiology, Institute of Medicine,University of Liege School of Medicine, 66 Bvdde la Constitution, B-4020 Liege, Belgium.

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