- Email: [email protected]
Aprindine
Appraisal Edited
and reappraisal
by Arthur
C. DeGraff
and Julian
of cardiac
therapy
Frieden
Aprindine
Peter Danilo,
Jr., Ph.D
New York, N. Y.
For many years clinicians have been limited by the availability of efficacious antiarrhythmic drugs. A major lack has been of agents that are effective by both the oral and parenteral routes, that have a sustained time course of action against a variety of arrhythmias, and a low toxicity. A recently developed drug purported to meet these requirements is aprindine, which was developed in Belgium (Fiboran, A. E. Christiaens). Its chemical structure is shown in Fig. 1. Aprindine possesses some structural similarities to procainamide, lidocaine, and propranolol in that all four agents consist of an aromatic residue, an intermediate chain, and an amino group with two ethyl groups attached. All four exert local anesthetic effects on cardiac transmembrane action potentials. Aprindine is now available in the United States as Fibocil (Eli Lilly & Co.) for clinical investigation. It has been the subject of a symposium’ and the current literature has been recently reviewed by Zipes and Troup.? 1. Clinical
use
In man, aprindine is effective against ventricular arrhythmias of diverse etiologies. Kesteloot and colleagues” found aprindine effective in treating ventricular premature depolarizations (VPDs) and ventricular tachycardia (VT). Aprindine was administered intravenously in doses of 20 mg. every 2 minutes until a therapeutic effect was observed or until a total dose of 140 mg. was administered. In some instances 25 mg. of aprindine was administered every 2 minutes (a total dose of 150 mg.). In others, 250 mg. was given more slowly by infusion. Aprindine was adminisFrom York,
Columbia N. Y.
Received
University
for publication
College
& Surgeons,
New
Aug. 7, 1978.
Reprint requests: Peter Danilo, College of Physicians & Surgeons, 10032.
0002-8703/79/010119
of Physicians
Jr., Ph.D., Columbia University 630 W. 168th St., New York, N. Y.
+ 06$00.60/O
0 1979 The
C. V. Mosby
Co.
tered orally to selected patients as a loading dose of 200 to 400 mg. on day 1, followed by 100 to 300 mg. on day 2 and then by a 100 to 150 mg. maintenance dose thereafter. Of 11 patients, aprindine completely abolished VPDs in eight, decreased VPDs by 50 to 75 per cent in two and had no effect in one. In the same study aprindine was administered to four patients with VT. The arrhythmia had occurred for “hours to weeks” and was diagnosed on the basis of the repeated occurrence of at least three sequential ventricular complexes at a rate of > loo/minute. In three of the four cases, intravenous administration of 100 to 150 mg. of aprindine was associated with complete abolition of VT and in the remaining case the incidence of VT was reduced by 80 per cent. In four patients with idioventricular tachycardia, two were completely cured of their arrhythmia by aprindine and two were refractory. Of the two aprindineresistant cases, one did not respond to intravenous aprindine, 200 mg., or to any other available antiarrhythmic agents. Van Durme and co-workers+ studied 129 patients with stable VPDs associated with coronary heart disease (64 per cent), valvular heart disease (11 per cent), hypertension (3 per cent), cardiomyopathy (3 per cent), non-cardiac causes (4 per cent), and unknown causes (15 per cent). Data were obtained by scanning electrocardiograms obtained for 5 minutes three times a day or by continuous monitoring for an unspecified period of time using a Holter system. All other antiarrhythmic therapy was stopped at least 3 days prior to aprindine administration. Complete suppression of VPDs was observed in 67 per cent of the cases and 50 per cent suppression of VPD’s with elimination of repetitive/multifocal VPD’s was observed in 14 per cent. No effect was noted in 19 per cent. More recently, Fasola and associates,” in a well-controlled study, evaluated the
American
Heart
Journal
119
Danilo
/
C2H5
’
C2’4,
A PRINDINE Fig.
1. N-[3-(diethylamino)propyl]-N-phenyl-2-indanamine.
effect of aprindine on recurrent VT and fibrillation (VF) in 23 patients who had not responded well to various combinations of procainamide, quinidine, lidocaine, propranolol, or diphenylhydantoin. Arrhythmias before administration of aprindine were evaluated by continuous monitoring of the electrocardiogram and/or continuous Holter monitoring. Holter monitoring before aprindine averaged 108 hours for each patient. Following administration of aprindine, Holter monitoring was continued for an average of greater than 900 hours/patient. Aprindine, administered orally, was given as an initial 200 mg. dose, followed by 100 mg. 1 hour later and again 4 to 10 hours later. On day 2 of oral aprindine therapy, a total dose of 300 mg. was administered and on day 3,400 mg. was given. On subsequent days the dose was adjusted for each patient to obtain the maximal antiarrhythmic effect with minimal side effects. Of 13 patients with recurrent VT/VF, 11 remained asymptomatic during chronic aprindine therapy. Five deaths occurred in this group, apparently unrelated to either cardiac arrhythmias or to aprindine administration. In 10 patients with recurrent VT, nine remained asymptomatic during chronic aprindine therapy. The effectiveness of aprindine in the treatment of ventricular arrhythmias as been demonstrated by others.‘, ‘-* Aprindine has also been used in the treatment of supraventricular arrhythmias, although with somewhat less success than with ventricular arrhythmias. Kesteloot found that aprindine was effective in the treatment of atria1 fibrillation of recent onset (four cases) but ineffective in chronic atria1 fibrillation associated with heart failure. Treatment of atria1 flutter with aprindine was unsuccessful (five of six cases). Although the flutter rate decreased, the ventricular response to flutter increased. Two of three cases of paroxysmal atria1 tachycardia responded favorably to aprindine (150 mg., intravenously), chronic atria1 tachycardia was successfully treated with aprin-
120
dine in three of five cases. Two cases of WolffParkinson-White syndrome with paroxysmal tachycardia showed improvement following aprindine administration. Similar effects of aprindine in the Wolff-Parkinson-White syndrome have been described.“‘, I1 Breithardt and colleagues” found that aprindine administered orally over 1 to 18 months reduced the frequency of APDs in four of four patients. Bollen and Enderle’ reported that aprindine (100 to 300 mg., total dose) completely abolished APDs in 12 of 16 cases and reduced the incidence of APDs by 50 per cent in two of 16. Paroxysmal atria1 tachycardia responded to aprindine (100 to 400 mg., total dose) in a similar manner-ten of 12 cases were converted to sinus rhythm. Atria1 flutter and fibrillation appeared to respond less favorably. Four of eight cases of atria1 fibrillation showed complete reversion to sinus rhythm and four were refractory to aprindine. Of two cases of atria1 flutter, one returned to sinus rhythm. Zipes and co-workers” studied 10 patients with supraventricular tachycardia who had failed to respond to conventional antiarrhythmic drugs. Nine of these patients had the Wolff-ParkinsonWhite syndrome. Before aprindine was administered, supraventricular tachycardia (SVT) was initiated in eight of 10 patients using properly timed stimuli. Aprindine was then administered according to the following schedule: 200 mg. (initial dose) followed by two additional doses of 100 mg., each; on day 2,300 mg., and on day 3,200 mg. of aprindine was administered. On subsequent days the dose was individualized according to the observed response. Following aprindine, paroxysmal SVT could not be elicited in four patients. In the remaining four, administration of aprindine did not prevent the induction of SVT. In this latter group aprindine reduced the ease with which SVT could be induced (two patients) or facilitated it (two patients). In the group of four patients in whom SVT could be in initiated during treatment with aprindine, the rate of the tachycardia was lower after administration of aprindine. Effects on experimental arrhythmias. In dogs subjected to two-stage ligation of the left anterior descending coronary artery, aprindine administered orally’” or intravenously”-” reduced the frequency of VPDs. However, VF occurring in dogs after single stage coronary artery occlusion and release responded less well to aprindine. Also,
January,
1979, Vol. 97, No. 1
Aprindine
pretreatment with aprindine (5 mg./Kg.) exerted no protective effect against VF associated with complete occlusion’” or complete occlusion and release in dogs.“. ” In pigs subjected to a 75 per cent decrease in flow through the left anterior descending coronary artery, aprindine, 2.8 mg./ Kg intravenously, decreased the mortality rate due to fibrillation from five of 22 animals in a control group, to one of 23 animals in the aprindine-treated group.“’ Aprindine, 0.5 to 2.0 mg./Kg., intravenously, did not prevent the occurrence in cats of ventricular arrhythmias induced by rapid intravenous administration of epinephrine 30 to 50 pg/Kg.‘” Aprindine is effective against digitalis-induced arrhythmias in experimental animals. Aprindine, 4.4 mg. administered intraduodenally as a single dose was effective against ouabain-induced venIntravenous tricular arrhythmias in dogs.” administration of aprindine, 2.9 mg./Kg., suppressed ouabain-induced arrhythmias in dogs in 14 of 14 experiments.” Similar effects of aprindine on ouabain-induced arrhythmias have been demonstrated by others in the dog,ll guinea pig, and cat.’ ’ 2. Pharmacokinetics
Aprindine is effective as an antiarrhythmic when administered orally or intravenously. It is 85 to 95 per cent protein bound. In dogs and man, it is metabolized in the liver by aromatic hydroxylabion and N-dealkylation and the major portion of these metabolites undergoes glucuronidation in the liver.“’ At least one metabolite, N-desethyl aprindine. possesses some antiarrhythmic activity.“’ In man, approximately 40 per cent”’ to 85 per cent”’ of a given dose of aprindine is eliminated in the urine, and as much as 35 per cent is eliminated in the feces.“’ Elimination of aprindine has been explained using a two compartment model.i” The early, rapid phase has a t,, of 0.5 to 2.7 hours and the later, slower phase has a t,? of 12.5 to 66 hours. Effective plasma levels of aprindine have been reported to range between 0.32 to 6.6 pg/ml. (1 to 3 pg/ml.. mean)“, I”, “I 3. Toxicity
Side effects of aprindine are reportedly doserelated and appear to be manifest mainly through the CNS and less frequently through the gastrointestinal system.“. ‘. ‘I’. I1 These toxic signs
American
Heart
Journal
include fine tremor and nervousness (most common), intention tremor, dizziness and ataxia. The following have also been reported, although less frequently: fatigue, headache, nausea and vomiting and, rarely, hallucinations and seizures. These untoward effects seldom occur at aprindine plasma levels of 5 1 pg/ml. and occur with increasing frequency when plasma levels exceed 2 pg/ml. For the most part, therapeutic effects of aprindine can be attained at plasma levels (i.e., between 1 and 2 ,ug/ml.) below those which induce toxicity of sufficient magnitude to require cessation of aprindine therapy. Agranulocytosis”, “.I and cholestatic jaundice” have also been reported to occur in association with aprindine therapy. Both of these side effects are thought to be idiosyncratic and unrelated to the dose of aprindine. Of eight patients with agranulocytosis, two died as a result of this side effect and the remainder showed signs of recovery 1 to 4 weeks after cessation of aprindine.” Of five patients with hepatotoxicity during treatment with aprindine,” two developed severe cholestatic jaundice within 2 to 3 weeks after beginning aprindine, three showed less severe signs. Following cessation of aprindine therapy, normal liver function returned. Three of these same patients submitted to subsequent challenges with aprindine and showed signs of abnormal liver chemistries. The incidence of agranulocytosis in Europe is on the order of one in several thousand, while in the United States it is currently three in 400 cases (Dr. J. G. Armstrong, personal communication). Additional data must be collected in the United States to determine whether the incidence is related to aprindine or to some other factor. 4. Hemodynamic aprindine
and autonomic
effects
of
Aprindine exerts a negative inotropic effect on isolated cat papillary muscle.” Aprindine, 2.5 to 5.0 pg/ml., decreases peak developed tension and the rate of tension development. Results obtained from intact animals have varied due in part, to species differences and variation in technique. Aprindine has been reported to decrease myocardial contractility slightly in conscious dogs in a dose-dependent manner unaccompanied by significant changes in LVEDP or LVSP.“; Effects of aprindine on cardiac contractility in anesthetized dogs’: and pigsICi.‘?ihave been reported as slight at low doses (0.3 to 4 mg./Kg). In open-chested
121
Danilo
dogs’” under halothane/N,O anesthesia, significant decreases in “LVP” were observed at aprindine doses of > 6 mg./Kg., while LV dp/dt was decreased at aprindine 4 mg./Kg. Stroke volume was decreased at relatively high aprindine doses (6 to 8 mg./Kg.). Studies of pentobarbital-anesthetized pigs showed that aprindine I 7.8 mg./ Kg., had little effect on LVEDP while induring a marked, dose-dependent decrease in LV dp/dt.” Cardiac output is decreased by relatively high doses of aprindine (3.8 to 6 mg./Kg.) in openchested dogs’” and in pigs.” Studies in humans have shown a similar effect of aprindine on LV dp/dt.‘” In both man and animals, aprindine has little effect on arterial blood pressure”. Z. “‘. jU except at high doses, i.e., 10 mg./Kg. in the dog.” Aprindine is reported to have little effect on autonomic responses mediated by adrenergic or cholinergic receptors. Georges and colleagues’i showed that intravenous aprindine, 0.5 to 3.0 mg./Kg., did not prevent the increase in blood pressure induced by epinephrine or norepinephrine, the tachycardia resulting from injection of isoproterenol, on the hypotension and bradycardia induced by intravenous acetylcholine. Elharrar and associates,” showed that the effects of aprindine can occur in the presence of adrenergic and cholinergic blockade. 5. Effects conduction
on cardiac
impulse
initiation
and
Aprindine slows conduction in all cardiac tissues.? In experimental animals, aprindine has been variably reported to decrease’*. :I’ or increase” sinus rate. Aprindine slows intraatria1 conduction in man” and experimental animals.“’ In both man and animals, aprindine slows conduction through the atrioventricular (AV) node”, Zi. ‘?*.,iZ through an increase in A-H and H-V intervals.,“. 3L’Effective and functional refractory periods of the A-V node in man,‘:’ and animals”’ are increased and intraventricular conduction is slowed.“. X. Zn It is of interest that the effects of aprindine on the P-R interval and QRS duration have been reported to be antagonized partially by adrenergic stimulation’ (See “Hemodynamic effects of aprindine,” above). Aprindine has also been found to block conduction through pathways involved in the WolffParkinson-White syndrome.“. $?..i’
122
6. Cellular aprindine
electrophysiological
effects
of
Microelectrode studies of isolated cardiac preparations indicate that aprindine exerts local anesthetic effects. Aprindine, 0.5 to 5 pg/ml. decreases action potential amplitude and maximum rate of rise of phase 0 depolarization (q,;,,) of bovine Purkinje fibers in a concentrationdependent manner. :’ Steinberg and Greenspan iJ’ showed that aprindine (approximately 1 pg/ml.) significantly decreased \I,,, of isolated canine Purkinje fibers while exerting no significant effect on maximum diastolic potential. Aprindine decreased Purkinje fiber action potential duration by decreasing the time course of full repolarization and by decreasing the plateau height, suggesting that aprindine may alter potassium and other ionic currents (e.g., Ca- ) operating in the range of plateau potentials. Verdonck and co-workers:‘” showed that, for bovine Purkinje fibers, ([K’],, = 5.4 mM.) with a total action potential duration of approximately 600 msec., aprindine 1 microgram per milliliter decreased total duration approximately 22 per cent. Steinberg and Greenspan”; studied canine Purkinje fibers ([K+],, = 4 mM.) and showed that aprindine, 1 microgram per milliliter, decreased action potential duration (measured to 95 per cent repolarization) to 13 per cent, compared to control. This slight difference in effect of aprindine may be due to species variability, to effects of different [K’]<,, to temperature, or to different, n:tes of stimulation. Verdonck and colleagues” and Carmeliet and Verdonck”’ suggest that the effect of aprindine is not due to an effect on gK since al rindine had no effect on “K-efflux at a [K+]” of 0 or 5.4 mM. They further suggest that the “stabilizing” effect of aprindine may be due to a decrease in membrane permeability to Na rather than an increase in permeability to K . Aprindine may exert a different effect on the action potential of ventricular myocardium than on Purkinje fibers. Verdonck and associates,” compared the effects of aprindine on bovine Purkinje fibers to those on guinea pig ventricular muscle. They found that aprindine had less effect on action potential duration of guinea pig ventricle than that of bovine Purkinje fiber. The importance of this result depends upon the extent to which aprindine effects on ventricular myocar-
January,
1979, Vol. 97, No. 1
Aprindine
dium from one species compared to eff’ects on another (cow). Consistent with
the
(guinea Purkinje effect
of
pig) can be fibers from
cholamines, aprindine decreased the slope of phase 4 depolarization associated with each of the
aprindine
interventions,A’ affect action
on
action potential duration is its action on effective refractory period (ERP). Aprindine decreases the ERP of bovine,‘; and canine’“’ Purkinje fibers. These effects of aprindine on isolated cardiac preparations occurred rapidly and, for therapeutic concentrations, appear bo be readily reversible. Higher aprindine levels took longer to reverse. Aprindine has been reported to decrease Purkinje fiber automaticity:“-:‘: Verdonck and colleagues, +’ studying bovine Purkinje fibers at an unspecified temperature at a [K+], = 5.4 r&f., found that “normal” automaticity (i.e., that occurring at membrane potentials of approximately -90 mV.) is decreased by aprindine, 1 pg/ml.
These
authors
also state
(but
do not show)
that aprindine, 1 pg/ml., can completely reverse the effects of epinephrine, 1 pg/ml., on normal phase 4 depolarization (which at least suggests that aprindine may possess p blocking properties). Further, aprindine markedly decreased the slope of phase 4 depolarization of bovine Purkinje fiber when studied at a [K*], of 1.35 mM.“: In addition, fibers depolarized by a K- -free solution, aprindine, 2 pg/ml., induced a hyperpolarization from approximately -40 mV. to -65 mV. Steinberg and Greenspan,“’ also state that aprindine decreased Purkinje fiber automaticity. Slow response action potentials initiated at relatively low levels of membrane potential (-40 to -60 mV.) and having low upstroke velocities have been suggested to underlie certain types of cardiac arrhythmias.“’ Carmeliet and Verdonck:” have demonstrated a lack of effect of aprindine, 2 pg/ml. on slow response action potentials recorded from cat papillary muscle superfused with a solution containing 27 mM. K+. Similarly a lack of effect of aprindine on slow responses induced in canine Purkinje fibers by KC1 (22 mM.) and isoproterenol has been reported in preliminary fashion by Elharrar and colleagues.,” Transient &polarizations induced by acetylstrophanthidin were suppressed by aprindine. Preliminary results of others, however,“‘. ‘I suggest that aprindine may alter “abnormal, ” slow response automaticity of cardiac tissues superfused with Na+-free, Ca-* rich solutions. In canine Purkinje fibers depressed by stretch, hypoxia, digitalis or cate-
suggesting that potentials initiated
aprindine at lower
may than
normal membrane potentials. Further investigation is required to determine to what extent aprindine exerts effects on ionic currents underlying the slow response action potential. Conclusions
Aprindine is a long-acting antiarrhythmic agent, effective when administered orally or intravenously in the treatment of ventricular arrhythmias of varying etiologies. It may be especially useful in the treatment of the WolffParkinson-White syndrome. To a lesser extent, it may be useful in the treatment of atria1 arrhythmias. Side effects can be minimized by careful titration of the dose of aprindine. If the frequency of such serious side effects as cholestatic jaundice and agranulocytosis remains low enough, aprindine should prove to be a useful addition to currently available antiarrhythmic drugs. The author thanks Dr. Michael R. Rosen for excellent editorial assistance and Mrs. Cynthia Brandt for outstanding secretarial assistance. REFERENCES
1. International Symposium on Pathophysiology and Drug Treatment of Cardiac Arrhythmias. Preliminary experiences with a new antiarrhythmic agent (aprindine), Acta. Cardiol. (Brux.) Suppl. 18: 1974. 2. Zipes, D. P., Troup, P. J.: New antiarrhythmic agents, Am. J. Cardiol. 41:1005, 1978. 3. Kesteloot, H., Van Miegham. W., and De Geest, H.: Aprindine (AC 1802) a new antiarrhythmir drug, Acta. Cardiol. (Brux) 28:145, 1973. 4. Van Durme, J. P., Rousseau, M., and Mbuyamba, P.: Treatment of chronic ventricular dysrhythmia with a new drug: Aprindine (AC 1802). Acta Cardiol. (Brux) Suppl. 18:335, 1974. 5. Fasola, A. F., Noble, R. J., and Zipes, D. P.: Treatment of recurrent ventricular tachycardia and fibrillation with aprindine, Am. J. Cardiol. 39:903, 1977. 6. Breithardt, G., Gleichmann, U., Seipel, L., and Loogen. F.: Long term oral antiarrhythmic therapy with aprindine (AC 1802). Acta Cardiol. (Brux) Suppl. 18:341, 1974. 7. Bollen, G., and Enderle, J.: Preliminary experience in the treatment of cardiac arrhythmias with aprindine, Acta Cardiol. (Brux) Suppl. 18:355, 1974. 8. Pouleur, H., Chaudron, J. M., and Reyns, P.: Effects of disopyramide and aprindine on arrhythmias after acute mvocardial infarction, Eur. J. Cardiol. 5:397. 1977. ---a 9. Kesteloot, H.: General aspects of antiarrhythic treatment with aprindine. Acta Cardiol. (Brux) Suppl. 18:303, 1974. 10. Fasola. A. F.. and Carmichael, R.: The pharmacology
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American
Heart
Journal
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and clinical evaluation of aprindine. a new antiarrhythmic agent, Acta Cardiol. (Brux). Suppl. 18:317, 1974. Zipes, D. P., Gaum, W. E., Foster, P. R., Rosen, K. M., Wu, D., Amat-Y-Leon, F.. and Noble, R. J.: Aprindine for treatment of supraventricular tachycardias with particular application to Wolff-Parkinson-White syndrome, Am. J: Cardiol. 40:586. 1977. Guam, W. E., Elharrar, V., Walker, P. D., and Zipes. D. P.: Influence of excitability of the ventricular fibrillation threshold in dogs, Am. J. Cardiol. 40:929, 1977. Ueda. M., Kimoto, S.. Matsuda, S., Kawakomi, M., Morishiae. E.. Matsumuro, S.. and Tabela. H.: Antiarrhythmic effects of aprindine on several types of ventricular arrhythmias, Jap. J. Pharmacol. 25:549, 1975. Kroll, D. A., and Lucchesi, B. R.: Antiarrhgthmic and antifibrillatory properties of aprindine, J. Pharmacol. Exp. Ther. 194:427, 1975. Elharrar, V., Foster, P. R., and Zipes, D. P.: Effects of aprindine HCl on cardiac tissues, -7. Pharmacol. Exp. Ther. 195:201, 1975. Verdouw. I’. D.. Remme, W. J., and Hugenholtz, P. G.: Cardiovascular and antiarrhythmic effects of aprindine (AC 1802) during partial occlusion of a coronary artery in the pig, Cardiovasc. Res. 11:317, 1977. Georges, A., Hosslet, A., and Duvernay, G.: Pharmacological evaluation of aprindine (AC 1802) a new antiarrhythmic agent, Acta. Cardiol. (Brux) 28:166, 1973. Foster, P. R.. King, R. M., Nicoll, d. De. B., and Zipes, D. P.: Suppression of ouabain-induced ventricular rhythms with aprindine HCl, Circulation 53:315, 1976. Murphy. P. .J.: Metabolic pathways of aprindine, Acta. Cardiol. (Brux) Suppl. 18:131. 1976. Delcroix. C.. Martin, L.. Van Durme, J. P., Kesteloot, H., Hagemeijer, F., Mbuvamba, P., and Deblecker, M.: Model for exchange kinetics of aprindine in man after single and multiple doses, Acta. Cardiol. (Brux) Suppl. 18:177. 1974. Van Durme, J. P., Bogaert. M. G., and Rosseel. M-T.: Therapuetic effectiveness and plasma levels of aprindine, a new antiarrhythmic drug, Eur. J. Clin. Pharm. 7:343, 1974. van Leeuwen. R., and Meyboom, R. H. B.: Agranulocytosis and aprindine, Lancet 2:1137, 1976. Baedeker. W., and Rastetter, J.: Agranulozytose hach aprindine behandlung, Munch. Med. Wschr. 119:1047,
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Elewaut, A., Van Durme, J. P., Goethals, L., Kauffman, J. M., Mussche, M., Elinck, W., Roels, H.. Bogaert, M., and Barbier, F.: Aprindine-induced liver injury, Acta Gastroenterol. Belg. 40:236. 1977. Brutsaert, D. L.: Effects of aprindine on myocardial contractility, Acta Cardiol. (Brux) Suppl. 18:9I, 1974. Gerin. M., Gerin, Y., Duvernay, G., and Georges, A.: Effects of aprindine (AC 1802) on cardiac function in conscious dogs, Acta. Cardiol. (Brux) Suppl. 18:143, 1974. Remme. W. J., and Verdouw, P. D.: Cardiovascular
effects of aprindine, a new antiarrhythmic drug. Eur. .J. Cardiol. 3:307, 1975. Mertens, H. M., and Neuhaus, K-L.: Investigation on the cardiovascular effects of aprindine, Acta Cardiol. (Brux) Suppl. 18:163, 1974. Piessens, J., Willems. J., Kesteloot, H., and DeGust, H.: Effects of aprindine on left ventricular contractility in man, Acta. Cardiol. (Brux) Suppl. 18:203, 1974. Rousseau, M. F.. Brasseur, L. A., and Detry. J. M.: Hemodynamic effects of aprindine during upright exercise in normal subjects, Acta Cardiol. (Brux) Suppl.
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Elharrar, V., Foster, P. R.. and Zipes, D. P.: Effects of aprindine HCl on cardiac tissues, J. Pharmacol. Exp. Ther. 195:201, 1975. Seipel, L., Bath, A., Breithardt. G., Gieichmann, IT.. and Loogen, F.: Action of antiarrhythmic drugs on His bundle electrogram and sinus node function. Acta Cardiol. (Brux) Suppl. 18:251. 1974. Schlepper. M., and Neuss, H.: Changes of refractory periods in the A-V conduction system induced by antiarrhythmic drugs. A study using His bundle recordings, Acta. Cardiol. (Brux) Suppl. 18:269, 1974. Neuss. H., and Schlepper, M.: Influence of various antiarrhythmic drugs (Aprindine, Ajmaline, Verapamil, Oxpenolol. Orciprenaline) on functional properties of accessory A-V pathways, Acta Cardiol. (Brux) Suppl. 18:279, 1974. Verdonck, F., Vereecke, J., and Vleugels, A.: Electrophysiological effects of aprindine on isolat,ed heart preparations, Eur. J. Pharm. 26:338, 1974. Steinberg, M. I.. and Greenspan, K.: Intracellular electrophysiological alterations in canine cardiac conducting tissue induced by aprindine and lignocaine, Cardiovasc. Res. 10:236, 1976. Carmeliet, E., and Verdonck, F.: Effects of aprindine and lidocaine on transmembrane potentials and radioactive K efflux in different cardiac tissues, Acta Cardiol. (Brux) Suppl. 18:73, 1974. Cranefield, P. F.: The Conduction of the Cardiac Impulse. New York, 1975, Futura Publishing Company. Inc. Elharrar, V., Bailey, J. C., Lathrop, D. A., and Zipes, D. P.: Effects of anrindine on slow channel action potentials and transient depolarizations in canine Purkinje fibers, J. Pharmacol. Exp. Ther. 205:410, 1978. Reiser. J., Freeman, A. R., and Greenspan, K.: Aprindine-a calcium mediated antiarrhythmic (Abstr.). Fed. Proc. 33:476, 1974. Harker, R. .J.. and Greenspan, K.: Modification of calcium-dependent slow responses in canine Purkinje fibers by aprindine (Abstr.). Fed. Proc. 36:946, 1977. Greenspan, K., Steinberg, M., Holland, D.. and Freeman, A. R.: Electrophysiologic alterations in cardiac dvsrhythmias: antiarrhythmic effects of aprindine (Abstr.), Am. J. Cardiol. 33:140, 1974.
124
January,
1979, Vol. 97, NO.
I
and reappraisal
by Arthur
C. DeGraff
and Julian
of cardiac
therapy
Frieden
Aprindine
Peter Danilo,
Jr., Ph.D
New York, N. Y.
For many years clinicians have been limited by the availability of efficacious antiarrhythmic drugs. A major lack has been of agents that are effective by both the oral and parenteral routes, that have a sustained time course of action against a variety of arrhythmias, and a low toxicity. A recently developed drug purported to meet these requirements is aprindine, which was developed in Belgium (Fiboran, A. E. Christiaens). Its chemical structure is shown in Fig. 1. Aprindine possesses some structural similarities to procainamide, lidocaine, and propranolol in that all four agents consist of an aromatic residue, an intermediate chain, and an amino group with two ethyl groups attached. All four exert local anesthetic effects on cardiac transmembrane action potentials. Aprindine is now available in the United States as Fibocil (Eli Lilly & Co.) for clinical investigation. It has been the subject of a symposium’ and the current literature has been recently reviewed by Zipes and Troup.? 1. Clinical
use
In man, aprindine is effective against ventricular arrhythmias of diverse etiologies. Kesteloot and colleagues” found aprindine effective in treating ventricular premature depolarizations (VPDs) and ventricular tachycardia (VT). Aprindine was administered intravenously in doses of 20 mg. every 2 minutes until a therapeutic effect was observed or until a total dose of 140 mg. was administered. In some instances 25 mg. of aprindine was administered every 2 minutes (a total dose of 150 mg.). In others, 250 mg. was given more slowly by infusion. Aprindine was adminisFrom York,
Columbia N. Y.
Received
University
for publication
College
& Surgeons,
New
Aug. 7, 1978.
Reprint requests: Peter Danilo, College of Physicians & Surgeons, 10032.
0002-8703/79/010119
of Physicians
Jr., Ph.D., Columbia University 630 W. 168th St., New York, N. Y.
+ 06$00.60/O
0 1979 The
C. V. Mosby
Co.
tered orally to selected patients as a loading dose of 200 to 400 mg. on day 1, followed by 100 to 300 mg. on day 2 and then by a 100 to 150 mg. maintenance dose thereafter. Of 11 patients, aprindine completely abolished VPDs in eight, decreased VPDs by 50 to 75 per cent in two and had no effect in one. In the same study aprindine was administered to four patients with VT. The arrhythmia had occurred for “hours to weeks” and was diagnosed on the basis of the repeated occurrence of at least three sequential ventricular complexes at a rate of > loo/minute. In three of the four cases, intravenous administration of 100 to 150 mg. of aprindine was associated with complete abolition of VT and in the remaining case the incidence of VT was reduced by 80 per cent. In four patients with idioventricular tachycardia, two were completely cured of their arrhythmia by aprindine and two were refractory. Of the two aprindineresistant cases, one did not respond to intravenous aprindine, 200 mg., or to any other available antiarrhythmic agents. Van Durme and co-workers+ studied 129 patients with stable VPDs associated with coronary heart disease (64 per cent), valvular heart disease (11 per cent), hypertension (3 per cent), cardiomyopathy (3 per cent), non-cardiac causes (4 per cent), and unknown causes (15 per cent). Data were obtained by scanning electrocardiograms obtained for 5 minutes three times a day or by continuous monitoring for an unspecified period of time using a Holter system. All other antiarrhythmic therapy was stopped at least 3 days prior to aprindine administration. Complete suppression of VPDs was observed in 67 per cent of the cases and 50 per cent suppression of VPD’s with elimination of repetitive/multifocal VPD’s was observed in 14 per cent. No effect was noted in 19 per cent. More recently, Fasola and associates,” in a well-controlled study, evaluated the
American
Heart
Journal
119
Danilo
/
C2H5
’
C2’4,
A PRINDINE Fig.
1. N-[3-(diethylamino)propyl]-N-phenyl-2-indanamine.
effect of aprindine on recurrent VT and fibrillation (VF) in 23 patients who had not responded well to various combinations of procainamide, quinidine, lidocaine, propranolol, or diphenylhydantoin. Arrhythmias before administration of aprindine were evaluated by continuous monitoring of the electrocardiogram and/or continuous Holter monitoring. Holter monitoring before aprindine averaged 108 hours for each patient. Following administration of aprindine, Holter monitoring was continued for an average of greater than 900 hours/patient. Aprindine, administered orally, was given as an initial 200 mg. dose, followed by 100 mg. 1 hour later and again 4 to 10 hours later. On day 2 of oral aprindine therapy, a total dose of 300 mg. was administered and on day 3,400 mg. was given. On subsequent days the dose was adjusted for each patient to obtain the maximal antiarrhythmic effect with minimal side effects. Of 13 patients with recurrent VT/VF, 11 remained asymptomatic during chronic aprindine therapy. Five deaths occurred in this group, apparently unrelated to either cardiac arrhythmias or to aprindine administration. In 10 patients with recurrent VT, nine remained asymptomatic during chronic aprindine therapy. The effectiveness of aprindine in the treatment of ventricular arrhythmias as been demonstrated by others.‘, ‘-* Aprindine has also been used in the treatment of supraventricular arrhythmias, although with somewhat less success than with ventricular arrhythmias. Kesteloot found that aprindine was effective in the treatment of atria1 fibrillation of recent onset (four cases) but ineffective in chronic atria1 fibrillation associated with heart failure. Treatment of atria1 flutter with aprindine was unsuccessful (five of six cases). Although the flutter rate decreased, the ventricular response to flutter increased. Two of three cases of paroxysmal atria1 tachycardia responded favorably to aprindine (150 mg., intravenously), chronic atria1 tachycardia was successfully treated with aprin-
120
dine in three of five cases. Two cases of WolffParkinson-White syndrome with paroxysmal tachycardia showed improvement following aprindine administration. Similar effects of aprindine in the Wolff-Parkinson-White syndrome have been described.“‘, I1 Breithardt and colleagues” found that aprindine administered orally over 1 to 18 months reduced the frequency of APDs in four of four patients. Bollen and Enderle’ reported that aprindine (100 to 300 mg., total dose) completely abolished APDs in 12 of 16 cases and reduced the incidence of APDs by 50 per cent in two of 16. Paroxysmal atria1 tachycardia responded to aprindine (100 to 400 mg., total dose) in a similar manner-ten of 12 cases were converted to sinus rhythm. Atria1 flutter and fibrillation appeared to respond less favorably. Four of eight cases of atria1 fibrillation showed complete reversion to sinus rhythm and four were refractory to aprindine. Of two cases of atria1 flutter, one returned to sinus rhythm. Zipes and co-workers” studied 10 patients with supraventricular tachycardia who had failed to respond to conventional antiarrhythmic drugs. Nine of these patients had the Wolff-ParkinsonWhite syndrome. Before aprindine was administered, supraventricular tachycardia (SVT) was initiated in eight of 10 patients using properly timed stimuli. Aprindine was then administered according to the following schedule: 200 mg. (initial dose) followed by two additional doses of 100 mg., each; on day 2,300 mg., and on day 3,200 mg. of aprindine was administered. On subsequent days the dose was individualized according to the observed response. Following aprindine, paroxysmal SVT could not be elicited in four patients. In the remaining four, administration of aprindine did not prevent the induction of SVT. In this latter group aprindine reduced the ease with which SVT could be induced (two patients) or facilitated it (two patients). In the group of four patients in whom SVT could be in initiated during treatment with aprindine, the rate of the tachycardia was lower after administration of aprindine. Effects on experimental arrhythmias. In dogs subjected to two-stage ligation of the left anterior descending coronary artery, aprindine administered orally’” or intravenously”-” reduced the frequency of VPDs. However, VF occurring in dogs after single stage coronary artery occlusion and release responded less well to aprindine. Also,
January,
1979, Vol. 97, No. 1
Aprindine
pretreatment with aprindine (5 mg./Kg.) exerted no protective effect against VF associated with complete occlusion’” or complete occlusion and release in dogs.“. ” In pigs subjected to a 75 per cent decrease in flow through the left anterior descending coronary artery, aprindine, 2.8 mg./ Kg intravenously, decreased the mortality rate due to fibrillation from five of 22 animals in a control group, to one of 23 animals in the aprindine-treated group.“’ Aprindine, 0.5 to 2.0 mg./Kg., intravenously, did not prevent the occurrence in cats of ventricular arrhythmias induced by rapid intravenous administration of epinephrine 30 to 50 pg/Kg.‘” Aprindine is effective against digitalis-induced arrhythmias in experimental animals. Aprindine, 4.4 mg. administered intraduodenally as a single dose was effective against ouabain-induced venIntravenous tricular arrhythmias in dogs.” administration of aprindine, 2.9 mg./Kg., suppressed ouabain-induced arrhythmias in dogs in 14 of 14 experiments.” Similar effects of aprindine on ouabain-induced arrhythmias have been demonstrated by others in the dog,ll guinea pig, and cat.’ ’ 2. Pharmacokinetics
Aprindine is effective as an antiarrhythmic when administered orally or intravenously. It is 85 to 95 per cent protein bound. In dogs and man, it is metabolized in the liver by aromatic hydroxylabion and N-dealkylation and the major portion of these metabolites undergoes glucuronidation in the liver.“’ At least one metabolite, N-desethyl aprindine. possesses some antiarrhythmic activity.“’ In man, approximately 40 per cent”’ to 85 per cent”’ of a given dose of aprindine is eliminated in the urine, and as much as 35 per cent is eliminated in the feces.“’ Elimination of aprindine has been explained using a two compartment model.i” The early, rapid phase has a t,, of 0.5 to 2.7 hours and the later, slower phase has a t,? of 12.5 to 66 hours. Effective plasma levels of aprindine have been reported to range between 0.32 to 6.6 pg/ml. (1 to 3 pg/ml.. mean)“, I”, “I 3. Toxicity
Side effects of aprindine are reportedly doserelated and appear to be manifest mainly through the CNS and less frequently through the gastrointestinal system.“. ‘. ‘I’. I1 These toxic signs
American
Heart
Journal
include fine tremor and nervousness (most common), intention tremor, dizziness and ataxia. The following have also been reported, although less frequently: fatigue, headache, nausea and vomiting and, rarely, hallucinations and seizures. These untoward effects seldom occur at aprindine plasma levels of 5 1 pg/ml. and occur with increasing frequency when plasma levels exceed 2 pg/ml. For the most part, therapeutic effects of aprindine can be attained at plasma levels (i.e., between 1 and 2 ,ug/ml.) below those which induce toxicity of sufficient magnitude to require cessation of aprindine therapy. Agranulocytosis”, “.I and cholestatic jaundice” have also been reported to occur in association with aprindine therapy. Both of these side effects are thought to be idiosyncratic and unrelated to the dose of aprindine. Of eight patients with agranulocytosis, two died as a result of this side effect and the remainder showed signs of recovery 1 to 4 weeks after cessation of aprindine.” Of five patients with hepatotoxicity during treatment with aprindine,” two developed severe cholestatic jaundice within 2 to 3 weeks after beginning aprindine, three showed less severe signs. Following cessation of aprindine therapy, normal liver function returned. Three of these same patients submitted to subsequent challenges with aprindine and showed signs of abnormal liver chemistries. The incidence of agranulocytosis in Europe is on the order of one in several thousand, while in the United States it is currently three in 400 cases (Dr. J. G. Armstrong, personal communication). Additional data must be collected in the United States to determine whether the incidence is related to aprindine or to some other factor. 4. Hemodynamic aprindine
and autonomic
effects
of
Aprindine exerts a negative inotropic effect on isolated cat papillary muscle.” Aprindine, 2.5 to 5.0 pg/ml., decreases peak developed tension and the rate of tension development. Results obtained from intact animals have varied due in part, to species differences and variation in technique. Aprindine has been reported to decrease myocardial contractility slightly in conscious dogs in a dose-dependent manner unaccompanied by significant changes in LVEDP or LVSP.“; Effects of aprindine on cardiac contractility in anesthetized dogs’: and pigsICi.‘?ihave been reported as slight at low doses (0.3 to 4 mg./Kg). In open-chested
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dogs’” under halothane/N,O anesthesia, significant decreases in “LVP” were observed at aprindine doses of > 6 mg./Kg., while LV dp/dt was decreased at aprindine 4 mg./Kg. Stroke volume was decreased at relatively high aprindine doses (6 to 8 mg./Kg.). Studies of pentobarbital-anesthetized pigs showed that aprindine I 7.8 mg./ Kg., had little effect on LVEDP while induring a marked, dose-dependent decrease in LV dp/dt.” Cardiac output is decreased by relatively high doses of aprindine (3.8 to 6 mg./Kg.) in openchested dogs’” and in pigs.” Studies in humans have shown a similar effect of aprindine on LV dp/dt.‘” In both man and animals, aprindine has little effect on arterial blood pressure”. Z. “‘. jU except at high doses, i.e., 10 mg./Kg. in the dog.” Aprindine is reported to have little effect on autonomic responses mediated by adrenergic or cholinergic receptors. Georges and colleagues’i showed that intravenous aprindine, 0.5 to 3.0 mg./Kg., did not prevent the increase in blood pressure induced by epinephrine or norepinephrine, the tachycardia resulting from injection of isoproterenol, on the hypotension and bradycardia induced by intravenous acetylcholine. Elharrar and associates,” showed that the effects of aprindine can occur in the presence of adrenergic and cholinergic blockade. 5. Effects conduction
on cardiac
impulse
initiation
and
Aprindine slows conduction in all cardiac tissues.? In experimental animals, aprindine has been variably reported to decrease’*. :I’ or increase” sinus rate. Aprindine slows intraatria1 conduction in man” and experimental animals.“’ In both man and animals, aprindine slows conduction through the atrioventricular (AV) node”, Zi. ‘?*.,iZ through an increase in A-H and H-V intervals.,“. 3L’Effective and functional refractory periods of the A-V node in man,‘:’ and animals”’ are increased and intraventricular conduction is slowed.“. X. Zn It is of interest that the effects of aprindine on the P-R interval and QRS duration have been reported to be antagonized partially by adrenergic stimulation’ (See “Hemodynamic effects of aprindine,” above). Aprindine has also been found to block conduction through pathways involved in the WolffParkinson-White syndrome.“. $?..i’
122
6. Cellular aprindine
electrophysiological
effects
of
Microelectrode studies of isolated cardiac preparations indicate that aprindine exerts local anesthetic effects. Aprindine, 0.5 to 5 pg/ml. decreases action potential amplitude and maximum rate of rise of phase 0 depolarization (q,;,,) of bovine Purkinje fibers in a concentrationdependent manner. :’ Steinberg and Greenspan iJ’ showed that aprindine (approximately 1 pg/ml.) significantly decreased \I,,, of isolated canine Purkinje fibers while exerting no significant effect on maximum diastolic potential. Aprindine decreased Purkinje fiber action potential duration by decreasing the time course of full repolarization and by decreasing the plateau height, suggesting that aprindine may alter potassium and other ionic currents (e.g., Ca- ) operating in the range of plateau potentials. Verdonck and co-workers:‘” showed that, for bovine Purkinje fibers, ([K’],, = 5.4 mM.) with a total action potential duration of approximately 600 msec., aprindine 1 microgram per milliliter decreased total duration approximately 22 per cent. Steinberg and Greenspan”; studied canine Purkinje fibers ([K+],, = 4 mM.) and showed that aprindine, 1 microgram per milliliter, decreased action potential duration (measured to 95 per cent repolarization) to 13 per cent, compared to control. This slight difference in effect of aprindine may be due to species variability, to effects of different [K’]<,, to temperature, or to different, n:tes of stimulation. Verdonck and colleagues” and Carmeliet and Verdonck”’ suggest that the effect of aprindine is not due to an effect on gK since al rindine had no effect on “K-efflux at a [K+]” of 0 or 5.4 mM. They further suggest that the “stabilizing” effect of aprindine may be due to a decrease in membrane permeability to Na rather than an increase in permeability to K . Aprindine may exert a different effect on the action potential of ventricular myocardium than on Purkinje fibers. Verdonck and associates,” compared the effects of aprindine on bovine Purkinje fibers to those on guinea pig ventricular muscle. They found that aprindine had less effect on action potential duration of guinea pig ventricle than that of bovine Purkinje fiber. The importance of this result depends upon the extent to which aprindine effects on ventricular myocar-
January,
1979, Vol. 97, No. 1
Aprindine
dium from one species compared to eff’ects on another (cow). Consistent with
the
(guinea Purkinje effect
of
pig) can be fibers from
cholamines, aprindine decreased the slope of phase 4 depolarization associated with each of the
aprindine
interventions,A’ affect action
on
action potential duration is its action on effective refractory period (ERP). Aprindine decreases the ERP of bovine,‘; and canine’“’ Purkinje fibers. These effects of aprindine on isolated cardiac preparations occurred rapidly and, for therapeutic concentrations, appear bo be readily reversible. Higher aprindine levels took longer to reverse. Aprindine has been reported to decrease Purkinje fiber automaticity:“-:‘: Verdonck and colleagues, +’ studying bovine Purkinje fibers at an unspecified temperature at a [K+], = 5.4 r&f., found that “normal” automaticity (i.e., that occurring at membrane potentials of approximately -90 mV.) is decreased by aprindine, 1 pg/ml.
These
authors
also state
(but
do not show)
that aprindine, 1 pg/ml., can completely reverse the effects of epinephrine, 1 pg/ml., on normal phase 4 depolarization (which at least suggests that aprindine may possess p blocking properties). Further, aprindine markedly decreased the slope of phase 4 depolarization of bovine Purkinje fiber when studied at a [K*], of 1.35 mM.“: In addition, fibers depolarized by a K- -free solution, aprindine, 2 pg/ml., induced a hyperpolarization from approximately -40 mV. to -65 mV. Steinberg and Greenspan,“’ also state that aprindine decreased Purkinje fiber automaticity. Slow response action potentials initiated at relatively low levels of membrane potential (-40 to -60 mV.) and having low upstroke velocities have been suggested to underlie certain types of cardiac arrhythmias.“’ Carmeliet and Verdonck:” have demonstrated a lack of effect of aprindine, 2 pg/ml. on slow response action potentials recorded from cat papillary muscle superfused with a solution containing 27 mM. K+. Similarly a lack of effect of aprindine on slow responses induced in canine Purkinje fibers by KC1 (22 mM.) and isoproterenol has been reported in preliminary fashion by Elharrar and colleagues.,” Transient &polarizations induced by acetylstrophanthidin were suppressed by aprindine. Preliminary results of others, however,“‘. ‘I suggest that aprindine may alter “abnormal, ” slow response automaticity of cardiac tissues superfused with Na+-free, Ca-* rich solutions. In canine Purkinje fibers depressed by stretch, hypoxia, digitalis or cate-
suggesting that potentials initiated
aprindine at lower
may than
normal membrane potentials. Further investigation is required to determine to what extent aprindine exerts effects on ionic currents underlying the slow response action potential. Conclusions
Aprindine is a long-acting antiarrhythmic agent, effective when administered orally or intravenously in the treatment of ventricular arrhythmias of varying etiologies. It may be especially useful in the treatment of the WolffParkinson-White syndrome. To a lesser extent, it may be useful in the treatment of atria1 arrhythmias. Side effects can be minimized by careful titration of the dose of aprindine. If the frequency of such serious side effects as cholestatic jaundice and agranulocytosis remains low enough, aprindine should prove to be a useful addition to currently available antiarrhythmic drugs. The author thanks Dr. Michael R. Rosen for excellent editorial assistance and Mrs. Cynthia Brandt for outstanding secretarial assistance. REFERENCES
1. International Symposium on Pathophysiology and Drug Treatment of Cardiac Arrhythmias. Preliminary experiences with a new antiarrhythmic agent (aprindine), Acta. Cardiol. (Brux.) Suppl. 18: 1974. 2. Zipes, D. P., Troup, P. J.: New antiarrhythmic agents, Am. J. Cardiol. 41:1005, 1978. 3. Kesteloot, H., Van Miegham. W., and De Geest, H.: Aprindine (AC 1802) a new antiarrhythmir drug, Acta. Cardiol. (Brux) 28:145, 1973. 4. Van Durme, J. P., Rousseau, M., and Mbuyamba, P.: Treatment of chronic ventricular dysrhythmia with a new drug: Aprindine (AC 1802). Acta Cardiol. (Brux) Suppl. 18:335, 1974. 5. Fasola, A. F., Noble, R. J., and Zipes, D. P.: Treatment of recurrent ventricular tachycardia and fibrillation with aprindine, Am. J. Cardiol. 39:903, 1977. 6. Breithardt, G., Gleichmann, U., Seipel, L., and Loogen. F.: Long term oral antiarrhythmic therapy with aprindine (AC 1802). Acta Cardiol. (Brux) Suppl. 18:341, 1974. 7. Bollen, G., and Enderle, J.: Preliminary experience in the treatment of cardiac arrhythmias with aprindine, Acta Cardiol. (Brux) Suppl. 18:355, 1974. 8. Pouleur, H., Chaudron, J. M., and Reyns, P.: Effects of disopyramide and aprindine on arrhythmias after acute mvocardial infarction, Eur. J. Cardiol. 5:397. 1977. ---a 9. Kesteloot, H.: General aspects of antiarrhythic treatment with aprindine. Acta Cardiol. (Brux) Suppl. 18:303, 1974. 10. Fasola. A. F.. and Carmichael, R.: The pharmacology
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and clinical evaluation of aprindine. a new antiarrhythmic agent, Acta Cardiol. (Brux). Suppl. 18:317, 1974. Zipes, D. P., Gaum, W. E., Foster, P. R., Rosen, K. M., Wu, D., Amat-Y-Leon, F.. and Noble, R. J.: Aprindine for treatment of supraventricular tachycardias with particular application to Wolff-Parkinson-White syndrome, Am. J: Cardiol. 40:586. 1977. Guam, W. E., Elharrar, V., Walker, P. D., and Zipes. D. P.: Influence of excitability of the ventricular fibrillation threshold in dogs, Am. J. Cardiol. 40:929, 1977. Ueda. M., Kimoto, S.. Matsuda, S., Kawakomi, M., Morishiae. E.. Matsumuro, S.. and Tabela. H.: Antiarrhythmic effects of aprindine on several types of ventricular arrhythmias, Jap. J. Pharmacol. 25:549, 1975. Kroll, D. A., and Lucchesi, B. R.: Antiarrhgthmic and antifibrillatory properties of aprindine, J. Pharmacol. Exp. Ther. 194:427, 1975. Elharrar, V., Foster, P. R., and Zipes, D. P.: Effects of aprindine HCl on cardiac tissues, -7. Pharmacol. Exp. Ther. 195:201, 1975. Verdouw. I’. D.. Remme, W. J., and Hugenholtz, P. G.: Cardiovascular and antiarrhythmic effects of aprindine (AC 1802) during partial occlusion of a coronary artery in the pig, Cardiovasc. Res. 11:317, 1977. Georges, A., Hosslet, A., and Duvernay, G.: Pharmacological evaluation of aprindine (AC 1802) a new antiarrhythmic agent, Acta. Cardiol. (Brux) 28:166, 1973. Foster, P. R.. King, R. M., Nicoll, d. De. B., and Zipes, D. P.: Suppression of ouabain-induced ventricular rhythms with aprindine HCl, Circulation 53:315, 1976. Murphy. P. .J.: Metabolic pathways of aprindine, Acta. Cardiol. (Brux) Suppl. 18:131. 1976. Delcroix. C.. Martin, L.. Van Durme, J. P., Kesteloot, H., Hagemeijer, F., Mbuvamba, P., and Deblecker, M.: Model for exchange kinetics of aprindine in man after single and multiple doses, Acta. Cardiol. (Brux) Suppl. 18:177. 1974. Van Durme, J. P., Bogaert. M. G., and Rosseel. M-T.: Therapuetic effectiveness and plasma levels of aprindine, a new antiarrhythmic drug, Eur. J. Clin. Pharm. 7:343, 1974. van Leeuwen. R., and Meyboom, R. H. B.: Agranulocytosis and aprindine, Lancet 2:1137, 1976. Baedeker. W., and Rastetter, J.: Agranulozytose hach aprindine behandlung, Munch. Med. Wschr. 119:1047,
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Elewaut, A., Van Durme, J. P., Goethals, L., Kauffman, J. M., Mussche, M., Elinck, W., Roels, H.. Bogaert, M., and Barbier, F.: Aprindine-induced liver injury, Acta Gastroenterol. Belg. 40:236. 1977. Brutsaert, D. L.: Effects of aprindine on myocardial contractility, Acta Cardiol. (Brux) Suppl. 18:9I, 1974. Gerin. M., Gerin, Y., Duvernay, G., and Georges, A.: Effects of aprindine (AC 1802) on cardiac function in conscious dogs, Acta. Cardiol. (Brux) Suppl. 18:143, 1974. Remme. W. J., and Verdouw, P. D.: Cardiovascular
effects of aprindine, a new antiarrhythmic drug. Eur. .J. Cardiol. 3:307, 1975. Mertens, H. M., and Neuhaus, K-L.: Investigation on the cardiovascular effects of aprindine, Acta Cardiol. (Brux) Suppl. 18:163, 1974. Piessens, J., Willems. J., Kesteloot, H., and DeGust, H.: Effects of aprindine on left ventricular contractility in man, Acta. Cardiol. (Brux) Suppl. 18:203, 1974. Rousseau, M. F.. Brasseur, L. A., and Detry. J. M.: Hemodynamic effects of aprindine during upright exercise in normal subjects, Acta Cardiol. (Brux) Suppl.
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Elharrar, V., Foster, P. R.. and Zipes, D. P.: Effects of aprindine HCl on cardiac tissues, J. Pharmacol. Exp. Ther. 195:201, 1975. Seipel, L., Bath, A., Breithardt. G., Gieichmann, IT.. and Loogen, F.: Action of antiarrhythmic drugs on His bundle electrogram and sinus node function. Acta Cardiol. (Brux) Suppl. 18:251. 1974. Schlepper. M., and Neuss, H.: Changes of refractory periods in the A-V conduction system induced by antiarrhythmic drugs. A study using His bundle recordings, Acta. Cardiol. (Brux) Suppl. 18:269, 1974. Neuss. H., and Schlepper, M.: Influence of various antiarrhythmic drugs (Aprindine, Ajmaline, Verapamil, Oxpenolol. Orciprenaline) on functional properties of accessory A-V pathways, Acta Cardiol. (Brux) Suppl. 18:279, 1974. Verdonck, F., Vereecke, J., and Vleugels, A.: Electrophysiological effects of aprindine on isolat,ed heart preparations, Eur. J. Pharm. 26:338, 1974. Steinberg, M. I.. and Greenspan, K.: Intracellular electrophysiological alterations in canine cardiac conducting tissue induced by aprindine and lignocaine, Cardiovasc. Res. 10:236, 1976. Carmeliet, E., and Verdonck, F.: Effects of aprindine and lidocaine on transmembrane potentials and radioactive K efflux in different cardiac tissues, Acta Cardiol. (Brux) Suppl. 18:73, 1974. Cranefield, P. F.: The Conduction of the Cardiac Impulse. New York, 1975, Futura Publishing Company. Inc. Elharrar, V., Bailey, J. C., Lathrop, D. A., and Zipes, D. P.: Effects of anrindine on slow channel action potentials and transient depolarizations in canine Purkinje fibers, J. Pharmacol. Exp. Ther. 205:410, 1978. Reiser. J., Freeman, A. R., and Greenspan, K.: Aprindine-a calcium mediated antiarrhythmic (Abstr.). Fed. Proc. 33:476, 1974. Harker, R. .J.. and Greenspan, K.: Modification of calcium-dependent slow responses in canine Purkinje fibers by aprindine (Abstr.). Fed. Proc. 36:946, 1977. Greenspan, K., Steinberg, M., Holland, D.. and Freeman, A. R.: Electrophysiologic alterations in cardiac dvsrhythmias: antiarrhythmic effects of aprindine (Abstr.), Am. J. Cardiol. 33:140, 1974.
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