Pilsicainide hydrochloride (pilsicainide) is a newly synthesized oral antiarrhythmic agent developed in Japan. The chemical structure of pilsicainide [N-(2,6-dimethylphenyl)-8-pyrrolizidinylacetamide hydrochloride hemihydrate] is analogous to that of lidocaine (1) but has a unique feature, a "pyrrolizidine" structure (2), which is not present in other antiarrhythmic agents. It has been demonstrated that pilsicainide is effective in suppressing coronary ligated, ouabain- and epinephrine-induced ventricular arrhythmias in dogs (3,4). Cellular electrophysiologic study revealed that pilsicainide depresses the maximal rate of increase of phase 0 of guinea pig atrial and papillary muscles in a dose-dependent manner without affecting action-potential duration (5). It is thus considered a class 1c antiarrhythmic drug. Furthermore, the suppression of Vmax is rate dependent, and the onset and offset of Na channel-blocking action occur with very slow kinetics, the recovery time constant being ∼28 s (6). Although the antiarrhythmic effects of pilsicainide have been evaluated in various experimental studies (3,4,7-9), limited information is available concerning its clinical efficacy (10,11). In this study, we systematically investigated the antiarrhythmic, electrophysiologic, and hemodynamic effects of pilsicainide in patients with supraventricular tachycardia (SVT) and otherwise normal cardiac performance. The pharmacokinetics and pharmacodynamics of pilsicainide also were evaluated.
Eighteen patients (13 men and five women) aged 24 to 62 years (mean, 46 years) who underwent electrophysiologic study for evaluation of SVT took part in the study. Electrocardiography during sinus rhythm demonstrated an overt Wolff-Parkinson-White (WPW) pattern in seven patients including two with intermittent WPW syndrome. Because the findings of routine physical examinations, electrocardiography, chest radiography, and echocardiography were normal, all patients were considered to be free from organic heart disease. Moreover, the routine biochemical examination demonstrated normal hepatic and renal function. The study protocol was approved by the Nippon Medical School Committee on the Use of Human Subjects in Research. All patients were studied in a nonsedated postabsorption state after giving written informed consent. All antiarrhythmic drugs were discontinued at least five drug-elimination half-lives before the study.
Short-term electrophysiologic and hemodynamic effects
Electrophysiologic study was performed by using four quadripolar electrode catheters advanced fluoroscopically via femoral or subclavian veins and introduced into the heart. Two catheters were positioned, one at the high right atrium and one at the right ventricular apex. The two distal electrodes were used for pacing, and the two proximal electrodes, for recording of local electrograms. Another quadripolar catheter was positioned against the septal leaflet of the tricuspid valve to record low right atrial, His bundle, and proximal right ventricular electrograms. By way of the right subclavian vein, a quadripolar electrode was positioned in the proximal and distal regions of the coronary sinus. Intracardiac signals were filtered (30-500 Hz) and recorded on a multichannel recorder (VR-12; E for M, White Plains, NY, U.S.A.) simultaneously with surface electrocardiographic leads I, aVF, and V1, by using a paper speed of 100 mm/s. Intracardiac stimulation was achieved with a BC-02 "programmable" cardiac stimulator (Fukuda Denshi Co., Tokyo, Japan) by using a pulse amplitude that was twice the diastolic threshold and a pulse duration of 1 ms. Electrophysiologic variables measured included sinus cycle length, maximal corrected sinus node recovery time, sinoatrial conduction time by the Strauss method (12), AH and HV intervals, effective refractory period of the right atrium and right ventricle, assessment of AV and ventriculoatrial conduction and refractoriness, and inducibility of SVT. Refractory periods were determined with a single atrial or ventricular extrastimulus applied after an eight-beat basic drive with a cycle length of 600 or 500 ms. Induction of SVT was attempted by incremental atrial (high right atrium or proximal coronary sinus) or right ventricular pacing or by extrastimuli.
After electrophysiologic study, a Swan-Ganz catheter was introduced into the pulmonary artery to measure the hemodynamic parameters. The mean pulmonary arterial pressure and pulmonary capillary wedge pressure were recorded on a multichannel recorder. Cardiac output was calculated by using a cardiac-output computer by the thermodilution method (Baxter Healthcare Co., Irvine, CA, U.S.A.). Central venous pressure was measured with a water-filled manometer, and brachial arterial pressure was determined with a standard mercury manometer.
After the baseline electrophysiologic and hemodynamic study, pilsicainide capsules (each containing 50 mg of pilsicainide hydrochloride) were administered orally with ∼180 ml of cold water with the patient in the supine position. The dose of pilsicainide given was 200 mg in five patients and 150 mg in 13 patients. Electrophysiologic and hemodynamic assessments were then repeated at 60 min and completed within 90 min after the administration. For refractory-period determinations, the same basic cycle length and pacing site as in the baseline study were used after pharmacologic intervention in each patient.
Serial reinduction study of SVT
After all the measurements had been completed, all catheters were removed except for a catheter electrode introduced from the subclavian vein in nine patients with inducible SVT in the baseline study. The tip of this catheter was located in the coronary sinus or at the right ventricular apex for later evaluation of suppressive efficacy on SVT induction. Reinduction of SVT was attempted with patients in the supine position in the ward by the same pacing procedure as in the baseline study. These attempts were repeated at 2, 4, 8, 12, and 24 h after administration by using standard 12-lead electrocardiography.
Plasma pilsicainide level determination
Peripheral venous blood for serum pilsicainide level determination was drawn before and 1, 2, 4, 8, 12, and 24 h after administration in all patients. The serum concentration of pilsicainide was determined by high-performance liquid chromatography.
Statistical data were analyzed by using Student's paired t test and nonpaired t test for paired and nonpaired data, respectively. Repeated measured analysis of variance (ANOVA) was used for analysis of electrocardiographic variables after pilsicainide. Correlation between electrocardiographic variables and the plasma pilsicainide level was analyzed by using linear-regression analysis. All values are expressed as means ± standard deviations.
The administration of both doses of pilsicainide was well tolerated by all patients, with no important adverse effects. Comparable electrophysiologic data are summarized in Table 1. Pilsicainide significantly shortened sinus cycle length. Corrected sinus node recovery time and sinoatrial conduction time were significantly prolonged after pilsicainide dosing. The AH interval during sinus rhythm, measured in all subjects but one, a patient with overt WPW syndrome that obscured the His potential, was significantly prolonged. Similarly, the HV interval during sinus rhythm, in cases other than those with overt WPW syndrome, was significantly prolonged. Anterograde conduction via accessory pathways during sinus rhythm was abolished, as indicated by the disappearance of the delta wave in the surface electrocardiogram (ECG) in six of seven patients with overt WPW syndrome. The right ventricular effective refractory period was significantly prolonged, and the mean plasma pilsicainide level when these electrophysiologic measurements were made was 1.00 ± 0.58 μg/ml (range, 0.21-1.88 μg/ml).
Ventriculoatrial conduction and suppression of SVT induction
Retrograde conduction during right ventricular pacing at an interstimulus interval slightly shorter than the sinus cycle length was abolished in 11 out of 18 patients after pilsicainide administration (Table 2). Of 12 patients with retrograde conduction via the accessory pathway, nine (75%) patients developed a retrograde conduction block, whereas of six patients with retrograde conduction via the AV node, just two (33%) patients developed retrograde block. Therefore one-to-one retrograde conduction at a ventricular cycle length of 600 ms was observed in only seven patients after administration. With regard to these seven patients, retrograde effective refractory periods were prolonged in two patients via the accessory pathway and in one patient via the AV node.
In the baseline study, SVT was reproducibly induced in 13 patients. The mechanism of SVT was determined as orthodromic atrioventricular reentrant tachycardia (AVRT) in seven patients and as common-type AVNRT in six patients. Among a group of seven patients with AVRT, induction of SVT was completely suppressed in six patients as a result of retrograde block through the accessory pathway. In the remaining one patient, slight prolongation of SVT cycle length was observed after pilsicainide administration. In contrast, one patient, whose SVT was not induced in the baseline study, developed inducible AVRT after pilsicainide administration. The cycle length of this induced SVT of 400 ms, however, was conspicuously longer than the previous spontaneous tachycardia cycle length of 260 ms.
In six patients with AVNRT, SVT was completely suppressed in three patients, in whom a retrograde block developed in two, and a retrograde refractory period of the AV node prolonged in one. Among three patients who failed to prevent the SVT induction, prolongation of the cycle length of AVNRT was observed in two patients after pilsicainide. The plasma pilsicainide level of the six patients with AVNRT was comparable to that of the patients with accessory pathways (1.04 ± 0.70 vs. 1.04 ± 0.58 μg/ml; NS).
The hemodynamic effects of pilsicainide are summarized in Table 3. No substantial changes were observed in mean arterial pressure, central venous pressure, cardiac index, and systemic vascular resistance. Similarly, pulmonary arterial wedge pressure and pulmonary vascular resistance were not altered. The stroke-volume index was, however, significantly decreased, and heart rate and mean pulmonary arterial pressure were significantly increased.
Pharmacokinetics of pilsicainide
After oral administration, pilsicainide was rapidly absorbed, and appeared in the plasma. Peak plasma levels were achieved at 1 h in seven patients, at 2 h in five patients, and at 4 h in four patients (Fig. 1). The process of elimination of pilsicainide from plasma was exponential and fitted a single-compartment model. The pharmacokinetic parameters of a single oral dose of pilsicainide were evaluated in 13 patients who were given 150 mg. Maximal concentration (Cmax) was 1.30 ± 0.30 μg/ml; time to peak concentration (Tmax) was 1.74 ± 1.31 h; the elimination half-life (T1/2) was 5.22 ± 0.62 h; and the area under the concentration curve (AUC) was 11.24 ± 3.96 μg·h/ml. In five patients who received 200 mg, Cmax was 1.6 ± 0.17 μg/ml, Tmax was 1.23 ± 0.69 h, T1/2 was 4.44 ± 0.59 h, and AUC was 11.80 ± 1.44 μg·h/ml.
Pharmacodynamics of pilsicainide
Effects on electrocardiographic variables. The effects of pilsicainide on electrocardiographic parameters are presented graphically in Fig. 2. Slight but significant acceleration of heart rate was observed at 1, 2, and 4 h after administration. The changes in PQ interval, QRS width, and QTc and JTc intervals are presented as percentage changes from the baseline values. Five patients with overt WPW syndrome were excluded from these comparisons. Substantial and significant increases of PQ interval and QRS width were observed <12 and 8 h after administration, respectively (maximal percentage change was 30.4 ± 20.5% for PQ interval and 26.6 ± 15.2% for QRS width). Both changes were significantly correlated to the plasma pilsicainide level (Fig. 3). Slight but significant prolongation of QTc (maximal percentage change, 5.8 ± 5.7%) was observed at 1-12 h. However, JTc was not significantly altered throughout the observation period.
Plasma level and induction of SVT. The relation between the plasma pilsicainide level and the suppressive effect of pilsicainide on SVT induction was assessed in 13 patients with inducible SVT in the baseline study: seven patients with AVRT and six patients with AVNRT (Table 4). At 1 h after administration, induction of SVT was suppressed in nine of 13 patients. The plasma pilsicainide level of the responders ranged from 0.21 to 1.66 μg/ml (1.20 ± 0.50 μg/ml), whereas that of nonresponders was 0.19-1.88 μg/ml (0.72 ± 0.78 μg/ml). At 2 h after administration, no SVT was induced in seven of nine tested patients. Subsequently, SVT was not induced in six of eight, three of seven, and three of seven tested patients at after 4, 8, and 12 h, respectively. At 24 h after administration, SVT was inducible in all seven tested patients. Plasma pilsicainide levels at these tested points are plotted in Fig. 4. The suppression of SVT induction was observed (23 of 28 tested points, 82%) mainly at the plasma pilsicainide levels > 0.5 μg/ml but did not occur in 18 (78%) of 23 tested points at levels < 0.5 μg/ml.
Pilsicainide is a novel class 1c antiarrhythmic agent synthesized in Japan. A preliminary report concerning single oral administration in healthy volunteers revealed several characteristic features (13). These were (a) rapid and efficient absorption from the gastrointestinal tract (maximal plasma concentration is obtained in 1-2 h, and estimated bioavailability is 75-86%), (b) pharmacokinetics described by a single-compartment model with first-order absorption kinetics, and (c) almost complete excretion from the kidney within 24 h in unmetabolized form. These features will contribute to a rapid antiarrhythmic effect after oral administration. For these reasons, we conducted electrophysiologic and hemodynamic evaluations at 1 h after oral administration a single dose.
Electrophysiologic effects of pilsicainide
Effects on sinus node automaticity. Our results indicated that pilsicainide significantly shortened sinus cycle length. In vitro study revealed that pilsicainide did not affect the sinus node firing rate at low concentrations of 1 × 10−7 to 10−6 g/ml, but suppressed at the higher concentration of 1 × 10−5 g/ml (5). It has been well recognized that some antiarrhythmic agents, such as disopyramide, accelerate the heart rate as a result of their anticholinergic action. Pilsicainide, however, has no anticholinergic action, as evidenced by its lack of action on pilocarpine-induced hypersalivation, on pupil size, and on acetylcholine-induced contraction of isolated ileum in animal experiments (14). Alternative explanations will be required, such as increased sympathetic tone as a result of stress from prolonged invasive procedures.
Effects on cardiac conduction. Preliminary experimental study revealed that pilsicainide depresses intraatrial and intraventricular conduction in anesthetized dog or rabbit Langendorff heart (15). Microelectrode studies have shown that pilsicainide specifically decreases the maximal rate of increase of action potentials in canine Purkinje fibers and guinea-pig atrial and ventricular papillary muscles (5,16). Moreover, the suppressive effects on fast sodium current have been demonstrated in guinea-pig ventricular myocytes (1,16). Toyama et al. (17) demonstrated that the mode of sodium-channel blocking by pilsicainide shows quinidine-like slow kinetics. In our study, pilsicainide significantly prolonged the PQ interval, QRS width, sinoatrial conduction time, and AH and HV intervals. Conduction through the accessory pathway in both directions and retrograde conduction through the AV node were potentially depressed with pilsicainide. Similar results have been shown by previously reported clinical studies (10,11). Prolongation of the HV interval and the suppression of conduction in the accessory pathway manifest the potent sodium channel-blocking properties of this agent. Because the AH interval is accounted for mainly by the conduction through the AV node, it is usually prolonged under the influence of a calcium channel blocker such as verapamil. Although in vitro study has demonstrated that pilsicainide depresses the membrane calcium current only at higher concentrations, it is difficult to explain the prolongation of the AH interval as being a result of a calcium channel block, because the plasma concentration of our patients was one tenth of that in an in vitro study (16). Rather, it should be considered that the prolongation of the AH interval is caused by the prolongation of the intraatrial and proximal His region conduction times, which are regarded as showing sodium channel-dependent conduction. Of particular clinical importance is that pilsicainide caused a high incidence of conduction blocks through the accessory pathways (86% in an anterograde direction and 75% retrograde). This incidence is apparently higher than that of other class 1c antiarrhythmic agents, which have been reported as being of ≤ 50% (18-22). In contrast, retrograde block through the fast pathway of the AV node was observed in only two (33%) of six patients at plasma levels comparable to those in AVRT. Although some authors (23,24) have suggested the electrophysiologic resemblance of retrograde fast pathways to the accessory connections, our results demonstrated the functional differences between these pathways.
Effects on cardiac repolarization and refractoriness. Pilsicainide shortens the action-potential duration of canine Purkinje fibers but does not alter those of guinea pig atrial and papillary muscles (5). In our study, pilsicainide did not alter the effective refractory period of the right atrium but lengthened that of the right ventricle and the QTc. The magnitude of the prolongation, however, seemed clearly smaller than the changes of the other variables altered. Terazawa et al. (11) reported that pilsicainide did not affect the QTc or the effective refractory periods of the right atrium and the right ventricle at 1 h after single oral administration. The discrepancies between our results and these may have been caused by the difference of dose levels, because those authors used lower doses (100-150 mg) than we did. Additionally, as clearly shown by lack of prolongation in JTc, the prolongation of QRS measured as a part of QTc must have contributed to QTc prolongation. These clinical electrophysiologic properties of pilsicainide are compatible with those of class 1c agents proposed by cellular electrophysiologic studies (5,6).
Effects on SVT induction. In our study, single oral administration of pilsicainide was highly effective in preventing SVT induction. At 1 h after administration, SVT could no longer be induced in nine (69%) of 13 patients tested. Compared with other antiarrhythmic agents (18,22,25-27), pilsicainide has a promising suppressive effect on SVT induction. In six patients in whom AVRT was suppressed after administration, suppression of SVT was always mediated by a retrograde block of accessory pathway conduction. In contrast, in one of the five patients in whom AVRT was not induced in the baseline study, reproducible induction of AVRT was observed after pilsicainide. This paradoxical effect has been recognized in other antiarrhythmic agents (28) and could be attributed to the greater depression of accessory conduction in an anterograde direction and to the conduction slowing in the reentry circuit.
Hemodynamic effects of pilsicainide
As shown in the Cardiac Arrhythmia Suppression Trial (CAST; 29,30), administration of class 1c agents, despite obvious reduction of ventricular arrhythmia, increased mortality in a postinfarction population. Although the exact mechanism responsible for this failure is still under investigation, there has been speculation on the role of the negative inotropic effects of these agents (31). In normal anesthetized dogs, pilsicainide showed no appreciable changes in cardiovascular performance after intravenous injection of 1.0-3.0 mg/kg, but cardiovascular performance appeared to be suppressed at a higher dose of 6.0 mg/kg (32). Kihara et al. (33) reported the subcellular mechanisms of the negative inotropic action of flecainide and pilsicainide. They found that both agents reduced intracellular Ca2+ transients responsible for cardiac contraction and resulted in negative inotropic effects. This effect was more prominent with flecainide than with pilsicainide at equal concentrations. In our study, pilsicainide decreased the stroke-volume index without reducing cardiac output in patients with normal cardiac performance. Because no hemodynamic evaluation has been made in patients with impaired cardiac performance, caution is necessary regarding administration to such patients.
Pharmacokinetics and pharmacodynamics of pilsicainide
Orally administered pilsicainide was rapidly absorbed, and the time taken to reach peak concentration was 1-2 h. The elimination process was fitted to a single-compartment model, of which the plasma half-life was 4-5 h. These values were comparable to previously reported data obtained from normal healthy volunteers (13). Among the electrocardiographic variables measured, changes of PQ interval were well correlated with the plasma pilsicainide levels. This may allow us to predict the plasma pilsicainide level by measuring prolongation of PQ intervals. Suppression of SVT induction was achieved at a plasma level of > 0.5 μg/ml in most patients but did not occur at lower levels. These results suggested that the minimal plasma concentration required to suppress induction of SVT is 0.5 μg/ml. PQ prolongation and QRS widening of ≤120% of baseline value will frequently be observed at such therapeutic plasma concentrations.
In our study we assessed the suppressive effects of pilsicainide on SVT by using serial-induction studies after pilsicainide administration. Autonomic activity may have substantially altered during the 24 h of the study, as seen in the changes of heart rate. The changes of autonomic activity may have affected the electrical inducibility of SVT. Similar limitations can be applied to the changes of electrocardiographic variables. Plasma pilsicainide levels measured in this study demonstrated considerable variation, especially in the patients who received 150 mg (Fig. 1). The peak plasma level and the time taken to reach it were not negligibly varied. Because the patients remained supine for ∼12 h after administration, reduced gastrointestinal function may have greatly affected the absorption process. Higher absorption can be presumed when the drug is administered to ambulatory patients.
A single oral dose of pilsicainide can be administered safely to patients with SVT. At 1 h after administration, electrophysiologic effects on retrograde conduction systems efficiently suppressed the induction of SVT. Electrophysiologic effects and favorable pharmacokinetics of pilsicainide presented in this study predict that a single oral dose of this agent may be an effective regimen for patients with supraventricular tachyarrhythmias. The hemodynamic effects reflecting a negative inotropic action suggest that caution may be required in the administration of pilsicainide to patients with impaired left ventricular function. Further study is needed to verify the clinical effects of pilsicainide presented in this study.
Acknowledgment: We thank Mr. C.W.P. Reynolds for assistance with the English of the manuscript.
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