- Email: [email protected]
Evaluation of disopyramide and mexiletine used alone and in combination for ventricular arrhythmias in patients with and without overt heart disease
International Journal of Cardiology, 32 (1991) 303-312 0 1991 Elsevier SciencePublishersB.V.0167~5273/91/$03.50 ADONIS 016752739100188V
CARD10
303
01334
Evaluation of disopyramide and mexiletine used alone and in combination for ventricular arrhythmias in patients with and without overt heart disease Teruhisa Tanabe, Kiyoshi Takahashi, Koichiro Yoshioka and Yuichiro Goto Department of Cardiology, Tokai University School of Medicine, Bohseidai, Isehara, Japan (Accepted
23 August
1990)
Teruhisa T, Kiyoshi T, Koichiro Y, Yuichiro G. Evaluation of disopyramide and mexiletine used alone and in combination for ventricular arrhythmias in patients with and without overt heart disease. Int J Cardiol 1991;32:303-312. The effkacies and side effects of disopyramide and mexiletine used alone and in combination were assessed in 29 patients with chronic ventricular arrhythmias. In combination therapy, one half or two thirds of the conventional doses of each drug were administered. Each patient underwent Holter electrocardiographic monitoring during 4 different periods: baseline, disopyramide alone, mexiletine alone and combination of the two drugs. The mean baseline number of ventricular premature complex per hour was 783 f 521 (mean + SD), which was significantly reduced with all three therapies. Disopyramide alone significantly reduced the ventricular premature complex frequency in patients with organic heart disease (P < 0.051, but did not significantly reduce the ventricular premature complex frequency in patients with no apparent heart disease. In contrast, mexiletine alone significantly decreased the ventricular premature complex frequency in no apparent heart disease patients (P < 0.09,but did not significantly reduce the ventricular premature complex frequency in organic heart disease patients. With disopyramide alone, patients having a significant reduction in ventricular premature complexes ( 2 83% reduction in ventricular premature complexes) or elimination of ventricular tachycardias tended to be more frequently found in organic heart disease than in no apparent heart disease. The opposite was observed with mexiletine alone. QTc interval with disopyramide alone was significantly prolonged, and the prematurity index of ventricular premature complexes was significantly lowered as compared to mexiletine alone or combination therapy (P < 0.01 for disopyramide versus mexiletine; P < 0.05for disopyramide versus combination therapy). During combination therapy, no patients withdrew from the study due to side effects. However, 3 patients receiving single drug therapy withdrew from the study due to severe side effects. Consequently, disopyramide is suggested to be more effective on ventricular premature complexes in organic heart disease than in no apparent heart disease patients, whereas the opposite was true for
Correspondence to: Teruhisa of Cardiology, Tokai University dai, Isehara 259-11, Japan.
Tanabe, M.D., Department School of Medicine, Bohsei-
304
mexiletine. A combination of disopyramide and mexiletine in smaller doses may provide almost the same or enhanced antiarrhythmic effects, no aggravation of electrocardiographical parameters and less incidence of side effects when compared to the conventional dose of each drug alone. Key words: Disopyramide and mexiletine; Single and combined tients with and without overt heart disease
Introduction The major electrophysiologic effect of the class I antiarrhythmic agents is to reduce the maximal rate of depolarization. However, these drugs have different effects on repolarization. Some drugs prolong the action potential duration and refractory period (and are subclassed as class Ia), and others shorten these intervals (and are subclassed as class Ib) [l-3]. Disopyramide is a class Ia antiarrhythmic agent and mexiletine is a class Ib agent. Both drugs are effective in the treatment of ventricular arrhythmias. However, disopyramide may cause side effects such as dysuria, aggravated heart failure and a prolongation of the QTc interval [4,5]. On the other hand, mexiletine may cause side effects such as gastrointestinal disturbances and tremors of the hands [6-S]. Thus, the side effects and the action on the QTc interval of disopyramide are different from those of mexiletine. In addition, these side effects are dose-related. Therefore, a combination of disopyramide and mexiletine in smaller doses may reduce the side effects and prevent the aggravation of electrocardiographic intervals while maintaining beneficial synergistic effects between the two agents [9-111. The objective of this study was to compare the benefits and side effects between a conventional dose of disopyramide or mexiletine used alone, and smaller doses of each drug used in combination.
therapy; Ventricular
arrhythmia;
Pa-
premature complexes per day had been also obtained from Holter electrocardiograms performed in the past studies as baseline recordings. Those past studies had started at least 6 months prior to, and had ended at least 2 weeks prior to initiation of this present study. These reflect the stable incidence of ventricular premature complexes in each patient. The baseline numbers of ventricular premature complexes per hour obtained from those past studies in each patient are compiled in Table 1. The mean age in this study was 56 years (ranging from 29 to 77). Six patients had old myocardial infarction, four had dilated cardiomyopathy, three had hypertensive heart disease, two had hypertrophic cardiomyopathy, one had car pulmonale due to chronic obstructive pulmonary disease and thirteen had no apparent heart disease (idiopathic ventricular premature complexes). Patients with unstable cardiac conditions, such as acute myocardial infarction, unstable angina pectoris, congestive heart failure, digitalis intoxications, advanced A-V block or electrolyte abnormality, were excluded from the study. Patients with a low left ventricular ejection fraction less than 30% as determined by radionuclide ventriculography or echocardiography were also excluded. The mean left ventricular ejection fraction was 54.6 k 14.6%. None of the patients had been treated with amiodarone. Patients receiving P-blocking agents, calcium antagonists and other antiarrhythmic agents were also excluded from the study.
Subjects and Methods Protocol Patient population The present study consisted of 29 patients (20 men and 9 women) with chronic, stable and frequent (2 3,000 day) ventricular premature complexes. In all of them, 3,000 or more ventricular
A baseline 24-hour Holter electrocardiogram was recorded within 1 week before the initiation of drug therapy. Next, either disopyramide or mexiletine was selected by the envelop method and administered for 1 week (the first single-drug
305
therapy). Then, a combination of disopyramide and mexiletine was administered for 1 week (combination therapy). Finally, the drug, which was not used in the first single-drug therapy, was administered for 1 week (the second single-drug therapy). Holter electrocardiograms were conducted on the day before termination of each therapy period. During single-drug therapy, 100 mg of disopyramide or 1.50 mg of mexiletine was orally administered every 8 hours three times daily. Although
TABLE
these doses are lower than those used in Western countries, they are the conventional doses for Japanese patients [8,12,131. During combination therapy, the dose of each drug was reduced: 50 mg of disopyramide and 100 mg of mexiletine were administered every 8 hours three times daily. Continuous 24-hour Holter electrocardiograms were recorded on an Avionics 447 two-channel recorder. Analysis of the tapes was performed with the computer assistance of a Del Mar-Avionics Dynamic Electrocardioscanner DCG VII.
1
The numbers of ventricular premature complexes (VPCs) per hour during baseline, disopyramide alone and combination therapy in the present study, and baseline in the past study in each patient Patient No.
1 2
Age/sex
8 9 10 11 12 13 14 15 16
70 74 68 58 59 56 46 66 62 56 77 75 57 52 49 64
F F M M M M M F M F M M M F M M
17 18 19 20 21 22 23 24 25 26 27 28 29
29 50 33 61 34 59 64 62 44 58 65 54 44
F M M M M F M M F M M M F
4 6
Diagnosis
OMI OMI OMI OMI OMI OMI DCM DCM DCM DCM HHD HHD HHD HCM HCM Cor pulmonale NHD NHD NHD NHD NHD NHD NHD NHD NHD NHD NHD NHD NHD
(DP) alone, are shown
mexiletine
(MX)
No. of VPCs/hr Current baseline
DP
253 199 138 532 282 274 684 135 531 1112 1021 1388 510 658 907 491
15 12 180 489 67 75 226 51 10 397 415 5 710 167 1245 *
720 259 1356 221 1348 1514 916 1292 I 223 596 1901 552 263
1063 7 442 48 671 1253 196 1116 13 166 1393 ** **
MX
6 37 193 150 100 446 81 120 1631 437 567 * * 370 4 652 0.5 419 28 922 502 0.3 954 0.5 184 1353 974 287
OMI = old myocardial infarction; DCM = dilated cardiomyopathy; HHD = hypertensive cardiomyopathy; NHD = no apparent heart disease. * Patients withdrawing due to side effects; * * Patients not completing the protocol.
Combination
318 152 161 410 342 342 574 222 402 928 998 784 724 1028 1001 249
12 245 172 318 29 184 0.2 8 684 520 0.8 118 278 495 0.5 943 9
1020 711 1481 208 1011 899 804 1099 914 514 1485 858 364
184 205 556 492 134 1180 0.8 402 1514 363 27 heart
Past baseline
disease;
HCM = hypertrophic
306
Each tape was also analyzed using a FukudaDenshi sigmacorder TR-210, which was able to print all 24-hour electrocardiograms in 12 minutes and easily demonstrated ventricular tachycardia (as defined by three or more consecutive ventricular premature complexes at a rate greater than 120 beats/min). The total numbers of ventricular premature complexes and ventricular tachycardias were counted. The mean number of ventricular premature complexes/hour was calculated by dividing the total ventricular premature complexes/day by 24. An 83% or greater reduction in ventricular premature complex frequency and elimination of ventricular tachycardias were defined as significant responses to the therapy
[ill. Twelve-lead electrocardiograms were recorded during the periods of baseline, single-drug therapy and combination therapy. The PQ, QRS and QTc intervals during the drug therapies were compared to the baseline values. In addition, the prematurity index (PI) and vulnerability index (VI), which are known as indicators of the severity of ventricular premature complexes [14], were measured. PI is expressed as the ratio of the coupling interval (CI) to the QT interval of the normal beat (or CI/QT). VI reflects the ratio of the product of the basic QT interval and the preceding cycle length to the CI (or RR/PI) [141. The plasma levels of disopyramide and mexiletine were determined by the gaschromatographic method from blood samples taken before and 2 hours after drug administration on the final day of each treatment period. Evaluation of side effects Patients were instructed to withdraw from the administration of antiarrhythmic agents if they experienced any intolerable side effects. On the final day of each drug therapy, patients were questioned about side effects. Side effects were classified into two groups: mild and severe. Patients experiencing mild side effects were able to continue drug therapy despite symptoms. Those with severe side effects withdrew from the study due to intolerable symptoms.
Statistical analysis Statistical analyses of the data were performed using Student’s paired t-test or the X2-test. A P value smaller than 0.05 was considered significant. Results Antiarrhythmic effectiveness Table 1 summarizes the diagnosis, the number of ventricular premature complexes per hour during the current and past baselines, the number of ventricular premature complexes during singledrug therapies with disopyramide and mexiletine, and the number of ventricular premature complexes during combination therapy in the 29 patients. Twenty-four of the 29 patients completed the protocol. Three of the remaining 5 patients withdrew from disopyramide therapy alone or mexiletine therapy alone due to severe side effects. The 2 remaining patients did not participate in the disopyramide administration test due to an inability to schedule the Holter monitoring for that time period. At baseline, the mean number of ventricular premature complexes per hour in the 24 patients who completed the protocol was 783 _t 521 (mean _t SD). This was reduced significantly with all three therapies to: (1) 398 & 467 with disopyramide alone, (2) 394 & 447 with mexiletine alone and (3) 345 f 403 with the combination therapy (Fig. 1A). The mean number of ventricular premature complexes per hour in patients with organic heart disease, such as old myocardial infarction, dilated cardiomyopathy, hypertensive heart disease, hypertrophic cardiomyopathy and car pulmonale was 580 + 420 (mean f SD) at baseline. This was significantly reduced with disopyramide alone and with combination therapy (P < 0.05 in each). However, these organic heart disease patients showed no significant reduction of ventricular premature complexes with mexiletine alone (Fig. 1B). The mean number of ventricular premature complexes per hour in patients with no apparent
307
A h
VPCs
NHD Patients
OHD Patients
Total Patients B I-peo.0
c
,-
P
rpco.05
I -1
7
p < 0.017
1500
r
1400
rpcO.011 ,-p
1200 I IO0 ID00 1300 900
rpc0.05J
I
800 700 600 500 400 300 200 100 8L
DP
MX
comb
8L
DP
MX
8L
Comb.
8L: baseline, DP: disopyranude, MX: mexlletlne, Comb.: combination
DP
MX
Comb.
thempy
Fig. 1. Comparison of the ventricular premature complex frequency among baseline, disopyramide therapy alone, mexiletine therapy alone and combination therapy. Fig. 1A reflects all patients including patients with organic heart disease (OHD) and those with no apparent heart disease (NHD). Fig. IS and 1C demonstrate the ventricular premature complex frequency during baseline and each therapy in organic heart disease patients and patients with no apparent heart disease, respectively. Each column reflects the mean and standard deviation of ventricular premature complex frequency. BL = baseline; DP = disopyramide; MX = mexiletine: Comb. = combination therapy.
heart disease at baseline was 1,031 k 534 (mean k SD). This was significantly reduced with mexiletine alone and with combination therapy (P < 0.05 in each). However, these patients with no apparent heart disease showed no significant reduction of ventricular premature complexes with disopyramide alone (Fig. 10 The number of patients showing a significant reduction in ventricular premature complexes (>= 83%) or elimination of ventricular tachycardias did not differ significantly among the disopyramide alone, mexiletine alone and combination therapy (Fig. 2A, Fig. 3A). Disopyramide alone had a tendency to be more effective in patients with organic heart disease than in those with no apparent heart disease. Mexiletine alone tended to be more effective in patients with no apparent heart disease than in organic heart disease patients. Combination therapy demonstrated almost the same effectiveness in both organic heart disease patients and patients with no apparent heart disease (Fig. 2B).
Concerning the elimination of ventricular tachycardias, disopyramide alone tended to be more effective in patients with organic heart disease than in those with no apparent heart disease (Fig. 3B). Effects on electrocardiographic
intervals
Compared with the baseline value, no significant differences in the PQ or QRS intervals were noted during disopyramide alone, mexiletine alone and combination therapy. However, the QTc interval during disopyramide alone was significantly prolonged as compared to the combination therapy (P < 0.05), as shown in Fig. 4A. PI was significantly lowered and VI tended to be increased following DP therapy alone as compared to combination therapy (Fig. 4B,C). Adverse effects
Mexiletine therapy alone had a higher incidence of side effects than disopyramide alone or
morning of Holter monitoring in each therapy period. The average values shown in Table 2 represent the mean plasma levels obtained just prior to and 2 hours after administration. The average plasma value of disopyramide with combination therapy was 69% of that seen with disopyramide therapy alone, despite the fact that only 50% of the normal dose was given. On the other hand, plasma value of mexiletine achieved with combination therapy was two thirds of that with mexiletine alone. This level was expected for a dose which was two thirds the normal one.
A
Disopyromide
Mexiletine
Combinaticn
%
mOHD
cases
ONHD
OHD vs NHD
60 I
Discussion Efficacy in combination therapy
I
7/l 6 -WI3
40-
20.
Dwpyromlde
Mexiletine
Combination
Fig. 2. Comparison of the number of patients with a significant reduction of ventricular premature complexes ( 2 83%) among disopyramide alone, mexiletine alone and the combination therapy (A), and comparison of the effectiveness of each therapy between organic heart disease patients and patients with no apparent heart disease in each therapy (B). OHD = organic heart disease; NHD = no apparent heart dis ease.
the combination, but the difference was not significant (Fig. 5). Seven patients had gastrointestinal disturbance with mexiletine alone, and two of them withdrew from the study. Three patients had dysuria with disopyramide alone, and one of them withdrew from the study. Three patients had gastrointestinal disturbances with the combination, but none withdrew due to this side effect. Plasma levels The mean plasma levels before administration and 2 hours after administration are shown in Table 2. These values were obtained on the
The clinical usefulness of combining class Ia and Ib drugs has been reported by several investigators [7,9,11,15,161. Recently, Kim et al. [ll] observed that a combination of disopyramide (524 t- 135 mg/day) and mexiletine (652 f 146 mg/day) in smaller and well-tolerated doses avoided dose-related side effects and was more effective than either drug used alone at higher doses (disopyramide: 602 + 152 mg/day, mexiletine: 739 f 144 mg/day). Our study differs from previous studies in which it uses much smaller doses and constant dosing schedules of disopyramide and mexiletine in both single and combination therapies. In addition, we administered each drug regimen for 1 week while previous researchers conducted studies lasting only several days. In general, the therapeutic doses of antiarrhythmic drugs are lower in Japanese patients than in Western patients. In spite of such smaller doses, our single and combination therapies had comparable or better results compared to those of Kim et al. [ll]. Our present study shows a particularly interesting observation which has not been previously reported. Namely, disopyramide alone significantly reduced the ventricular premature complex frequency in patients with organic heart disease, but not in patients with no apparent heart disease. In contrast, mexiletine alone significantly decreased the ventricular premature complex fre-
309 Total
quency in patients with no apparent heart disease, but not in organic heart disease patients. A significant reduction in ventricuIar premature complexes (2 83% reduction in ventricular premature complexes) or elimination of ventricular tachycardias tended to be more frequently observed in organic heart disease patients than in no apparent heart disease patients with disopyramide alone, while the opposite was found with mexiletine alone. According to the theory of rate-dependency of class I antiarrhythmic drugs on Na channel receptors [17-221, disopyramide and mexiletine were cfassified into slow and fast kinetic drugs, respectively [20,21]. For this reason, particularly mexiletine is expected to have a more beneficia1 effect on ventricular premature complexes associated with short coupling intervals [20,22]. To our knowledge, previously published studies have not shown that the coupling intervals of ventricular premature complexes tended to be shorter in patients with no apparent heart disease (0.44 & 0.05 set) than in those with organic heart disease (0.46 1: 0.06 set). Therefore, mexiletine might be more effective in patients with no apparent heart disease than in those with organic heart disease. In contrast, this rate-dependent effect begins to be significant at slower driving rates (0.2 Hz) for slow drugs 1183. Therefore, disopyramide is expected to be effective not only
Patients
% cases 80
60 A
40
Disopymmide
Combination
Mexiletine
a %
OH0
vs NH0
OH0
aNHO
I
co&&s !A -
too-
21;
80. r
cl/9 :::::::: :.:.:.:.
:i:;:x :::::::: y::::: :::::::: ....‘*..
: UcsopyramkSe
Mextletlne
-
(;Om0tnation
Fig. 3. Comparison of the number of patients with elimination of ventricular tachycardia among disopyramide alone, mexiletine alone and the combination therapy (A), and comparison of the effectiveness of each therapy between organic heart disease patients and patients with no apparent heart disease in each therapy (B). OHD = organic heart disease, NHD = no apparent heart disease. Prematurity
Index
( PI )
DP
BL: baseline,
Fig. 4. Comparison
MX
Comb.
8L
DP: disopyromide, MX: mexiletine,
of electrocardiographic
DP
MX
Index
( VI )
C
TPCOCJ51
BL
Vulnerabtllty
Comb.
EL
DP
MX
Ccfnb.
Comb : combinatfon therapy
intervals among baseline, disopyramide therapy.
alone, mexiietine alone and combination
310 severity %
cases
0 m
mild severe
407/27 203/26
5
l-r 3/29
fibrillation [14]. In our present study, low PI and high VI, which were induced by disopyramide alone, were corrected by the combination therapy. Therefore, combination therapy with both drugs in smaller doses is beneficial in reducing the degree of prematurity of ventricular premature complexes. Side effects
3
Disopyramide
Mexiletine
Combination
Fig. 5. Comparison of the incidence and severity effects among disopyramide alone, mexiletine alone combination therapy.
of side and the
on ventricular premature complexes having short coupling intervals, but also on ventricular premature complexes having non-short coupling intervals. Nevertheless, the reason for the more beneficial effect of disopyramide on ventricular premature complexes in patients with organic heart disease than in those with no apparent heart disease remains unexplained. Electrocardiographic intervals Class Ia antiarrhythmic drugs prolong the QTc interval, while class Ib drugs shorten it. Our study supports previous results [7,111 with respect to having prevented prolongation of the QTc interval with a combination therapy. Low PI and high VI in ventricular premature complexes are reportedly indicators of the initiation of ventricular tachycardia and/or ventricular
TABLE
In the present study, the combination therapy used one half or two thirds of the normal dosage and resulted in the reduced incidence and degree of side effects. The side effects of each drug were different. The most frequent side effect of disopyramide when given alone was dysuria. The side effect of mexiletine when given alone was gastrointestinal disturbances. Therefore, the combination of both drugs in smaller doses reduced the dose-related side effects, as previously reported [7,8,11,151. Plasma levels Ohashi et al. [lo] reported that mexiletine at 450 mg/day in Japanese patients with ventricular premature complexes produced blood levels of 0.75 to 2.19 pg/ml. These plasma levels are reported by Campbell et al. [231 and Mehta et al. [24] to be the therapeutic ones. We previously observed that the average therapeutic plasma level of mexiletine (1.09 k 0.41 pg/ml) was almost the same as in Western reports even when half the dose (300 to 450 mg/dayl of Western use was given [8].
2
Mean plasma
levels
Treatment
Disopyramide Mexiletine Combination
Doses administered
alone alone therapy
Disopyramide Mexiletine
Mean plasma
100 mg t.i.d. 150 mg t.i.d.
Disopyramide 50 mg t.i.d. Mexiletine 100 mg t.i.d.
levels Fg/ml
Before administration
2 hours after administration
Average value
1.36 f 0.61
1.89 + 0.61
1.69 f 0.58
1.02 + 0.34
1.32 f 0.42
1.17 f 0.38
1.09 + 0.45 0.64 + 0.26
1.25 f 0.56 0.84 k 0.28
1.17 f 0.50 0.74 f 0.26
311
Therapeutic plasma levels of disopyramide were reportedly more than 2.0 pg/ml in Western patients administered 600 mg/day [24]. In Japan, approximately two thirds (1.76 + 0.54 wg/ml) of their therapeutic plasma level was attained when half of their dose (300 mg/day) was administered
9 10
Bl. The addition of a second antiarrhythmic agent to a patient’s drug regimen can produce various types of drug interactions [25,26]. This may be explained by the interaction of the second drug on the pharmacokinetics and pharmacodynamics of the first drug. The present study reveals that combination of mexiletine with disopyramide comparatively increased the plasma level of disopyramide, although it did not increase the plasma level of mexiletine. This finding explains the higher efficacy of the combination therapy over the single-drug therapy. However, further investigation will be needed of drug interactions in the combination therapy of disopyramide with mexiletine.
11
12
13
14 15
16
References 17 Vaughan Williams EM. Classification of antiarrhythmic drugs, In: Sandoe E, Flenstedt Jensen E, Olesen KH, eds: Symposium of cardiac arrhythmias. Sodertalje. Sweden: Astra Publishing, 1970:449-472. Singh BN. Hauswirth 0. Comparative mechanisms of action of antiarrhythmic drugs. Am Heart J 1974;87:367-382, Singh BN, Ikeda N, Nademanee K. Hauswirth 0. Cellular electrophysiology of the heart: basis for elucidating the origin of cardiac arrhythmias and the action of antiarrhythmic agents. In: Levy S, Scheinman M, eds. Cardiac arrhythmias. Mount Kisco, NY: Futura, 1984;15-32. Koch-Weser J. Disopyramide. N Engl J Med 1979;300: 957-962. Teichman SL. The antichohnergic side effects of norpace and norpace CR. Angiology 1985;36:767-771. Talbot RC, Julian DG. Prescott LF. Long-term treatment of ventricular arrhythmias with oral mexiletine. Am Heart J 1976;91:58-65. Duff HJ, Roden D, Primm RK. Oates JA, Woosley RL. Mexiletine in the treatment of resistant ventricular arrhythmias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine. Circulation 1983;67:1124-1128. Tanabe T, Yoshikawa H, Furuya H, Goto Y. Therapeutic
18
19
20
21
22
23
effectiveness and plasma levels of single or combination use of class I antiarrhythmic agents for ventricular arrhythmias. Jpn Circulation J 1988;52:298-305. Levy S. Combination therapy for cardiac arrhythmias. Am J Cardiol 1988;61:95A-101A. Ohashi K, Ebihara A. Hashimoto T, Hosoda S. Kondo K. Oka T. Pharmacokinetics and the antiarrhythmic effect of mexiletine in patients with chronic ventricular arrhythmias. Arzneim Forsch/Drug Res 1984;34:503-507. Kim SG, Mercando AD, Tam S. Fisher JD. Combination of disopyramide and mexiletine for better tolerance and additive effects for treatment of ventricular arrhythmia. J Am Coil Cardiol 1989;13:659-664. Kasanuki H. Onishi S, Hirosawa K. The usefulness of electrophysiological-pharmacologic studies in the longterm therapy of paroxysmal tachycardias. Jpn Circulation J 1985;49:351-361. Tanabe T, Yoshikawa H. Tagawa R, Furuya H, Ide M, Goto Y. Evaluation of antiarrhythmic efficacy using Holter electrocardiographic technique. Jpn Circ J 1985;49:337344. Han J, Gael BG. Electrophysiologic precursors of ventricular tachyarrhythmias. Arch Intern Med 1972;129:749-755. Breithardt G, Seipel L. Abendroth RR. Comparison of the antiarrhythmic efficacy of disopyramide and mexiletine against stimulus-induced ventricular tachycardia. J Cardiovast Pharm 1981;3:1026-1037. Greenspan AM, Spielman SR. Webb CR, Sokoloff NM, Rae AP, Harowitz LN. Efficacy of combination therapy with mexiletine and type IA agent for inducible ventricular tachyarrhythmias secondary to coronary artery disease. Am J Cardiol 1985;56:277-284. Hondeghem LM, Katzung BG. Time and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 1977:472:373-398. Hondeghem LM. Katzung BG. Test of a mode of antiarrhythmic drug action. Effects of quinidine and lidocaine on myocardial conduction. Circulation 1980:61:1217-1224. Courtney KR. Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium. J Mol Cell Cardiol 1980:12:1273-1286. Campbell TJ. Resting and rate-dependent depression of maximum rate of depolarization CV maxi in guinea pig ventricular action potentials by mexiletine, disopyramide. and encainide. J Cardiovasc Pharmacol 1983;5:291-296. Campbell TJ. Kinetics of onset of rate-dependent effects of class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res 1983;17:344-352. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Ann Rev Pharmacol Toxicol 1984;24:387-423. Campbell NPJ. Pantridge JF. Adgey AAJ. Long-term oral antiarrhythmic therapy with mexiletine. Br Heart J 1978:40:796-801.
312 24 Mehta J, Conti CR. Mexiletine, a new antiarrhythmic agent, for treatment of premature ventricular complexes. Am J Cardiol 1982;49:455-460. 25 Kjekshus K, Bethen J, Orning OM, Storstein LLV. A double blind, crossover comparison of flecainide acetate
and disopyramide phosphate in the treatment of ventricular premature complexes. Am J Cardiol 1984;53:72B-78B. 26 Tartini R, Kappenberger L, Steinbrunn W, Meyer UA. Dangerous interaction between amiodarone and quinidine. Lancet 1982;1:1327-1329.
CARD10
303
01334
Evaluation of disopyramide and mexiletine used alone and in combination for ventricular arrhythmias in patients with and without overt heart disease Teruhisa Tanabe, Kiyoshi Takahashi, Koichiro Yoshioka and Yuichiro Goto Department of Cardiology, Tokai University School of Medicine, Bohseidai, Isehara, Japan (Accepted
23 August
1990)
Teruhisa T, Kiyoshi T, Koichiro Y, Yuichiro G. Evaluation of disopyramide and mexiletine used alone and in combination for ventricular arrhythmias in patients with and without overt heart disease. Int J Cardiol 1991;32:303-312. The effkacies and side effects of disopyramide and mexiletine used alone and in combination were assessed in 29 patients with chronic ventricular arrhythmias. In combination therapy, one half or two thirds of the conventional doses of each drug were administered. Each patient underwent Holter electrocardiographic monitoring during 4 different periods: baseline, disopyramide alone, mexiletine alone and combination of the two drugs. The mean baseline number of ventricular premature complex per hour was 783 f 521 (mean + SD), which was significantly reduced with all three therapies. Disopyramide alone significantly reduced the ventricular premature complex frequency in patients with organic heart disease (P < 0.051, but did not significantly reduce the ventricular premature complex frequency in patients with no apparent heart disease. In contrast, mexiletine alone significantly decreased the ventricular premature complex frequency in no apparent heart disease patients (P < 0.09,but did not significantly reduce the ventricular premature complex frequency in organic heart disease patients. With disopyramide alone, patients having a significant reduction in ventricular premature complexes ( 2 83% reduction in ventricular premature complexes) or elimination of ventricular tachycardias tended to be more frequently found in organic heart disease than in no apparent heart disease. The opposite was observed with mexiletine alone. QTc interval with disopyramide alone was significantly prolonged, and the prematurity index of ventricular premature complexes was significantly lowered as compared to mexiletine alone or combination therapy (P < 0.01 for disopyramide versus mexiletine; P < 0.05for disopyramide versus combination therapy). During combination therapy, no patients withdrew from the study due to side effects. However, 3 patients receiving single drug therapy withdrew from the study due to severe side effects. Consequently, disopyramide is suggested to be more effective on ventricular premature complexes in organic heart disease than in no apparent heart disease patients, whereas the opposite was true for
Correspondence to: Teruhisa of Cardiology, Tokai University dai, Isehara 259-11, Japan.
Tanabe, M.D., Department School of Medicine, Bohsei-
304
mexiletine. A combination of disopyramide and mexiletine in smaller doses may provide almost the same or enhanced antiarrhythmic effects, no aggravation of electrocardiographical parameters and less incidence of side effects when compared to the conventional dose of each drug alone. Key words: Disopyramide and mexiletine; Single and combined tients with and without overt heart disease
Introduction The major electrophysiologic effect of the class I antiarrhythmic agents is to reduce the maximal rate of depolarization. However, these drugs have different effects on repolarization. Some drugs prolong the action potential duration and refractory period (and are subclassed as class Ia), and others shorten these intervals (and are subclassed as class Ib) [l-3]. Disopyramide is a class Ia antiarrhythmic agent and mexiletine is a class Ib agent. Both drugs are effective in the treatment of ventricular arrhythmias. However, disopyramide may cause side effects such as dysuria, aggravated heart failure and a prolongation of the QTc interval [4,5]. On the other hand, mexiletine may cause side effects such as gastrointestinal disturbances and tremors of the hands [6-S]. Thus, the side effects and the action on the QTc interval of disopyramide are different from those of mexiletine. In addition, these side effects are dose-related. Therefore, a combination of disopyramide and mexiletine in smaller doses may reduce the side effects and prevent the aggravation of electrocardiographic intervals while maintaining beneficial synergistic effects between the two agents [9-111. The objective of this study was to compare the benefits and side effects between a conventional dose of disopyramide or mexiletine used alone, and smaller doses of each drug used in combination.
therapy; Ventricular
arrhythmia;
Pa-
premature complexes per day had been also obtained from Holter electrocardiograms performed in the past studies as baseline recordings. Those past studies had started at least 6 months prior to, and had ended at least 2 weeks prior to initiation of this present study. These reflect the stable incidence of ventricular premature complexes in each patient. The baseline numbers of ventricular premature complexes per hour obtained from those past studies in each patient are compiled in Table 1. The mean age in this study was 56 years (ranging from 29 to 77). Six patients had old myocardial infarction, four had dilated cardiomyopathy, three had hypertensive heart disease, two had hypertrophic cardiomyopathy, one had car pulmonale due to chronic obstructive pulmonary disease and thirteen had no apparent heart disease (idiopathic ventricular premature complexes). Patients with unstable cardiac conditions, such as acute myocardial infarction, unstable angina pectoris, congestive heart failure, digitalis intoxications, advanced A-V block or electrolyte abnormality, were excluded from the study. Patients with a low left ventricular ejection fraction less than 30% as determined by radionuclide ventriculography or echocardiography were also excluded. The mean left ventricular ejection fraction was 54.6 k 14.6%. None of the patients had been treated with amiodarone. Patients receiving P-blocking agents, calcium antagonists and other antiarrhythmic agents were also excluded from the study.
Subjects and Methods Protocol Patient population The present study consisted of 29 patients (20 men and 9 women) with chronic, stable and frequent (2 3,000 day) ventricular premature complexes. In all of them, 3,000 or more ventricular
A baseline 24-hour Holter electrocardiogram was recorded within 1 week before the initiation of drug therapy. Next, either disopyramide or mexiletine was selected by the envelop method and administered for 1 week (the first single-drug
305
therapy). Then, a combination of disopyramide and mexiletine was administered for 1 week (combination therapy). Finally, the drug, which was not used in the first single-drug therapy, was administered for 1 week (the second single-drug therapy). Holter electrocardiograms were conducted on the day before termination of each therapy period. During single-drug therapy, 100 mg of disopyramide or 1.50 mg of mexiletine was orally administered every 8 hours three times daily. Although
TABLE
these doses are lower than those used in Western countries, they are the conventional doses for Japanese patients [8,12,131. During combination therapy, the dose of each drug was reduced: 50 mg of disopyramide and 100 mg of mexiletine were administered every 8 hours three times daily. Continuous 24-hour Holter electrocardiograms were recorded on an Avionics 447 two-channel recorder. Analysis of the tapes was performed with the computer assistance of a Del Mar-Avionics Dynamic Electrocardioscanner DCG VII.
1
The numbers of ventricular premature complexes (VPCs) per hour during baseline, disopyramide alone and combination therapy in the present study, and baseline in the past study in each patient Patient No.
1 2
Age/sex
8 9 10 11 12 13 14 15 16
70 74 68 58 59 56 46 66 62 56 77 75 57 52 49 64
F F M M M M M F M F M M M F M M
17 18 19 20 21 22 23 24 25 26 27 28 29
29 50 33 61 34 59 64 62 44 58 65 54 44
F M M M M F M M F M M M F
4 6
Diagnosis
OMI OMI OMI OMI OMI OMI DCM DCM DCM DCM HHD HHD HHD HCM HCM Cor pulmonale NHD NHD NHD NHD NHD NHD NHD NHD NHD NHD NHD NHD NHD
(DP) alone, are shown
mexiletine
(MX)
No. of VPCs/hr Current baseline
DP
253 199 138 532 282 274 684 135 531 1112 1021 1388 510 658 907 491
15 12 180 489 67 75 226 51 10 397 415 5 710 167 1245 *
720 259 1356 221 1348 1514 916 1292 I 223 596 1901 552 263
1063 7 442 48 671 1253 196 1116 13 166 1393 ** **
MX
6 37 193 150 100 446 81 120 1631 437 567 * * 370 4 652 0.5 419 28 922 502 0.3 954 0.5 184 1353 974 287
OMI = old myocardial infarction; DCM = dilated cardiomyopathy; HHD = hypertensive cardiomyopathy; NHD = no apparent heart disease. * Patients withdrawing due to side effects; * * Patients not completing the protocol.
Combination
318 152 161 410 342 342 574 222 402 928 998 784 724 1028 1001 249
12 245 172 318 29 184 0.2 8 684 520 0.8 118 278 495 0.5 943 9
1020 711 1481 208 1011 899 804 1099 914 514 1485 858 364
184 205 556 492 134 1180 0.8 402 1514 363 27 heart
Past baseline
disease;
HCM = hypertrophic
306
Each tape was also analyzed using a FukudaDenshi sigmacorder TR-210, which was able to print all 24-hour electrocardiograms in 12 minutes and easily demonstrated ventricular tachycardia (as defined by three or more consecutive ventricular premature complexes at a rate greater than 120 beats/min). The total numbers of ventricular premature complexes and ventricular tachycardias were counted. The mean number of ventricular premature complexes/hour was calculated by dividing the total ventricular premature complexes/day by 24. An 83% or greater reduction in ventricular premature complex frequency and elimination of ventricular tachycardias were defined as significant responses to the therapy
[ill. Twelve-lead electrocardiograms were recorded during the periods of baseline, single-drug therapy and combination therapy. The PQ, QRS and QTc intervals during the drug therapies were compared to the baseline values. In addition, the prematurity index (PI) and vulnerability index (VI), which are known as indicators of the severity of ventricular premature complexes [14], were measured. PI is expressed as the ratio of the coupling interval (CI) to the QT interval of the normal beat (or CI/QT). VI reflects the ratio of the product of the basic QT interval and the preceding cycle length to the CI (or RR/PI) [141. The plasma levels of disopyramide and mexiletine were determined by the gaschromatographic method from blood samples taken before and 2 hours after drug administration on the final day of each treatment period. Evaluation of side effects Patients were instructed to withdraw from the administration of antiarrhythmic agents if they experienced any intolerable side effects. On the final day of each drug therapy, patients were questioned about side effects. Side effects were classified into two groups: mild and severe. Patients experiencing mild side effects were able to continue drug therapy despite symptoms. Those with severe side effects withdrew from the study due to intolerable symptoms.
Statistical analysis Statistical analyses of the data were performed using Student’s paired t-test or the X2-test. A P value smaller than 0.05 was considered significant. Results Antiarrhythmic effectiveness Table 1 summarizes the diagnosis, the number of ventricular premature complexes per hour during the current and past baselines, the number of ventricular premature complexes during singledrug therapies with disopyramide and mexiletine, and the number of ventricular premature complexes during combination therapy in the 29 patients. Twenty-four of the 29 patients completed the protocol. Three of the remaining 5 patients withdrew from disopyramide therapy alone or mexiletine therapy alone due to severe side effects. The 2 remaining patients did not participate in the disopyramide administration test due to an inability to schedule the Holter monitoring for that time period. At baseline, the mean number of ventricular premature complexes per hour in the 24 patients who completed the protocol was 783 _t 521 (mean _t SD). This was reduced significantly with all three therapies to: (1) 398 & 467 with disopyramide alone, (2) 394 & 447 with mexiletine alone and (3) 345 f 403 with the combination therapy (Fig. 1A). The mean number of ventricular premature complexes per hour in patients with organic heart disease, such as old myocardial infarction, dilated cardiomyopathy, hypertensive heart disease, hypertrophic cardiomyopathy and car pulmonale was 580 + 420 (mean f SD) at baseline. This was significantly reduced with disopyramide alone and with combination therapy (P < 0.05 in each). However, these organic heart disease patients showed no significant reduction of ventricular premature complexes with mexiletine alone (Fig. 1B). The mean number of ventricular premature complexes per hour in patients with no apparent
307
A h
VPCs
NHD Patients
OHD Patients
Total Patients B I-peo.0
c
,-
P
rpco.05
I -1
7
p < 0.017
1500
r
1400
rpcO.011 ,-p
1200 I IO0 ID00 1300 900
rpc0.05J
I
800 700 600 500 400 300 200 100 8L
DP
MX
comb
8L
DP
MX
8L
Comb.
8L: baseline, DP: disopyranude, MX: mexlletlne, Comb.: combination
DP
MX
Comb.
thempy
Fig. 1. Comparison of the ventricular premature complex frequency among baseline, disopyramide therapy alone, mexiletine therapy alone and combination therapy. Fig. 1A reflects all patients including patients with organic heart disease (OHD) and those with no apparent heart disease (NHD). Fig. IS and 1C demonstrate the ventricular premature complex frequency during baseline and each therapy in organic heart disease patients and patients with no apparent heart disease, respectively. Each column reflects the mean and standard deviation of ventricular premature complex frequency. BL = baseline; DP = disopyramide; MX = mexiletine: Comb. = combination therapy.
heart disease at baseline was 1,031 k 534 (mean k SD). This was significantly reduced with mexiletine alone and with combination therapy (P < 0.05 in each). However, these patients with no apparent heart disease showed no significant reduction of ventricular premature complexes with disopyramide alone (Fig. 10 The number of patients showing a significant reduction in ventricular premature complexes (>= 83%) or elimination of ventricular tachycardias did not differ significantly among the disopyramide alone, mexiletine alone and combination therapy (Fig. 2A, Fig. 3A). Disopyramide alone had a tendency to be more effective in patients with organic heart disease than in those with no apparent heart disease. Mexiletine alone tended to be more effective in patients with no apparent heart disease than in organic heart disease patients. Combination therapy demonstrated almost the same effectiveness in both organic heart disease patients and patients with no apparent heart disease (Fig. 2B).
Concerning the elimination of ventricular tachycardias, disopyramide alone tended to be more effective in patients with organic heart disease than in those with no apparent heart disease (Fig. 3B). Effects on electrocardiographic
intervals
Compared with the baseline value, no significant differences in the PQ or QRS intervals were noted during disopyramide alone, mexiletine alone and combination therapy. However, the QTc interval during disopyramide alone was significantly prolonged as compared to the combination therapy (P < 0.05), as shown in Fig. 4A. PI was significantly lowered and VI tended to be increased following DP therapy alone as compared to combination therapy (Fig. 4B,C). Adverse effects
Mexiletine therapy alone had a higher incidence of side effects than disopyramide alone or
morning of Holter monitoring in each therapy period. The average values shown in Table 2 represent the mean plasma levels obtained just prior to and 2 hours after administration. The average plasma value of disopyramide with combination therapy was 69% of that seen with disopyramide therapy alone, despite the fact that only 50% of the normal dose was given. On the other hand, plasma value of mexiletine achieved with combination therapy was two thirds of that with mexiletine alone. This level was expected for a dose which was two thirds the normal one.
A
Disopyromide
Mexiletine
Combinaticn
%
mOHD
cases
ONHD
OHD vs NHD
60 I
Discussion Efficacy in combination therapy
I
7/l 6 -WI3
40-
20.
Dwpyromlde
Mexiletine
Combination
Fig. 2. Comparison of the number of patients with a significant reduction of ventricular premature complexes ( 2 83%) among disopyramide alone, mexiletine alone and the combination therapy (A), and comparison of the effectiveness of each therapy between organic heart disease patients and patients with no apparent heart disease in each therapy (B). OHD = organic heart disease; NHD = no apparent heart dis ease.
the combination, but the difference was not significant (Fig. 5). Seven patients had gastrointestinal disturbance with mexiletine alone, and two of them withdrew from the study. Three patients had dysuria with disopyramide alone, and one of them withdrew from the study. Three patients had gastrointestinal disturbances with the combination, but none withdrew due to this side effect. Plasma levels The mean plasma levels before administration and 2 hours after administration are shown in Table 2. These values were obtained on the
The clinical usefulness of combining class Ia and Ib drugs has been reported by several investigators [7,9,11,15,161. Recently, Kim et al. [ll] observed that a combination of disopyramide (524 t- 135 mg/day) and mexiletine (652 f 146 mg/day) in smaller and well-tolerated doses avoided dose-related side effects and was more effective than either drug used alone at higher doses (disopyramide: 602 + 152 mg/day, mexiletine: 739 f 144 mg/day). Our study differs from previous studies in which it uses much smaller doses and constant dosing schedules of disopyramide and mexiletine in both single and combination therapies. In addition, we administered each drug regimen for 1 week while previous researchers conducted studies lasting only several days. In general, the therapeutic doses of antiarrhythmic drugs are lower in Japanese patients than in Western patients. In spite of such smaller doses, our single and combination therapies had comparable or better results compared to those of Kim et al. [ll]. Our present study shows a particularly interesting observation which has not been previously reported. Namely, disopyramide alone significantly reduced the ventricular premature complex frequency in patients with organic heart disease, but not in patients with no apparent heart disease. In contrast, mexiletine alone significantly decreased the ventricular premature complex fre-
309 Total
quency in patients with no apparent heart disease, but not in organic heart disease patients. A significant reduction in ventricuIar premature complexes (2 83% reduction in ventricular premature complexes) or elimination of ventricular tachycardias tended to be more frequently observed in organic heart disease patients than in no apparent heart disease patients with disopyramide alone, while the opposite was found with mexiletine alone. According to the theory of rate-dependency of class I antiarrhythmic drugs on Na channel receptors [17-221, disopyramide and mexiletine were cfassified into slow and fast kinetic drugs, respectively [20,21]. For this reason, particularly mexiletine is expected to have a more beneficia1 effect on ventricular premature complexes associated with short coupling intervals [20,22]. To our knowledge, previously published studies have not shown that the coupling intervals of ventricular premature complexes tended to be shorter in patients with no apparent heart disease (0.44 & 0.05 set) than in those with organic heart disease (0.46 1: 0.06 set). Therefore, mexiletine might be more effective in patients with no apparent heart disease than in those with organic heart disease. In contrast, this rate-dependent effect begins to be significant at slower driving rates (0.2 Hz) for slow drugs 1183. Therefore, disopyramide is expected to be effective not only
Patients
% cases 80
60 A
40
Disopymmide
Combination
Mexiletine
a %
OH0
vs NH0
OH0
aNHO
I
co&&s !A -
too-
21;
80. r
cl/9 :::::::: :.:.:.:.
:i:;:x :::::::: y::::: :::::::: ....‘*..
: UcsopyramkSe
Mextletlne
-
(;Om0tnation
Fig. 3. Comparison of the number of patients with elimination of ventricular tachycardia among disopyramide alone, mexiletine alone and the combination therapy (A), and comparison of the effectiveness of each therapy between organic heart disease patients and patients with no apparent heart disease in each therapy (B). OHD = organic heart disease, NHD = no apparent heart disease. Prematurity
Index
( PI )
DP
BL: baseline,
Fig. 4. Comparison
MX
Comb.
8L
DP: disopyromide, MX: mexiletine,
of electrocardiographic
DP
MX
Index
( VI )
C
TPCOCJ51
BL
Vulnerabtllty
Comb.
EL
DP
MX
Ccfnb.
Comb : combinatfon therapy
intervals among baseline, disopyramide therapy.
alone, mexiietine alone and combination
310 severity %
cases
0 m
mild severe
407/27 203/26
5
l-r 3/29
fibrillation [14]. In our present study, low PI and high VI, which were induced by disopyramide alone, were corrected by the combination therapy. Therefore, combination therapy with both drugs in smaller doses is beneficial in reducing the degree of prematurity of ventricular premature complexes. Side effects
3
Disopyramide
Mexiletine
Combination
Fig. 5. Comparison of the incidence and severity effects among disopyramide alone, mexiletine alone combination therapy.
of side and the
on ventricular premature complexes having short coupling intervals, but also on ventricular premature complexes having non-short coupling intervals. Nevertheless, the reason for the more beneficial effect of disopyramide on ventricular premature complexes in patients with organic heart disease than in those with no apparent heart disease remains unexplained. Electrocardiographic intervals Class Ia antiarrhythmic drugs prolong the QTc interval, while class Ib drugs shorten it. Our study supports previous results [7,111 with respect to having prevented prolongation of the QTc interval with a combination therapy. Low PI and high VI in ventricular premature complexes are reportedly indicators of the initiation of ventricular tachycardia and/or ventricular
TABLE
In the present study, the combination therapy used one half or two thirds of the normal dosage and resulted in the reduced incidence and degree of side effects. The side effects of each drug were different. The most frequent side effect of disopyramide when given alone was dysuria. The side effect of mexiletine when given alone was gastrointestinal disturbances. Therefore, the combination of both drugs in smaller doses reduced the dose-related side effects, as previously reported [7,8,11,151. Plasma levels Ohashi et al. [lo] reported that mexiletine at 450 mg/day in Japanese patients with ventricular premature complexes produced blood levels of 0.75 to 2.19 pg/ml. These plasma levels are reported by Campbell et al. [231 and Mehta et al. [24] to be the therapeutic ones. We previously observed that the average therapeutic plasma level of mexiletine (1.09 k 0.41 pg/ml) was almost the same as in Western reports even when half the dose (300 to 450 mg/dayl of Western use was given [8].
2
Mean plasma
levels
Treatment
Disopyramide Mexiletine Combination
Doses administered
alone alone therapy
Disopyramide Mexiletine
Mean plasma
100 mg t.i.d. 150 mg t.i.d.
Disopyramide 50 mg t.i.d. Mexiletine 100 mg t.i.d.
levels Fg/ml
Before administration
2 hours after administration
Average value
1.36 f 0.61
1.89 + 0.61
1.69 f 0.58
1.02 + 0.34
1.32 f 0.42
1.17 f 0.38
1.09 + 0.45 0.64 + 0.26
1.25 f 0.56 0.84 k 0.28
1.17 f 0.50 0.74 f 0.26
311
Therapeutic plasma levels of disopyramide were reportedly more than 2.0 pg/ml in Western patients administered 600 mg/day [24]. In Japan, approximately two thirds (1.76 + 0.54 wg/ml) of their therapeutic plasma level was attained when half of their dose (300 mg/day) was administered
9 10
Bl. The addition of a second antiarrhythmic agent to a patient’s drug regimen can produce various types of drug interactions [25,26]. This may be explained by the interaction of the second drug on the pharmacokinetics and pharmacodynamics of the first drug. The present study reveals that combination of mexiletine with disopyramide comparatively increased the plasma level of disopyramide, although it did not increase the plasma level of mexiletine. This finding explains the higher efficacy of the combination therapy over the single-drug therapy. However, further investigation will be needed of drug interactions in the combination therapy of disopyramide with mexiletine.
11
12
13
14 15
16
References 17 Vaughan Williams EM. Classification of antiarrhythmic drugs, In: Sandoe E, Flenstedt Jensen E, Olesen KH, eds: Symposium of cardiac arrhythmias. Sodertalje. Sweden: Astra Publishing, 1970:449-472. Singh BN. Hauswirth 0. Comparative mechanisms of action of antiarrhythmic drugs. Am Heart J 1974;87:367-382, Singh BN, Ikeda N, Nademanee K. Hauswirth 0. Cellular electrophysiology of the heart: basis for elucidating the origin of cardiac arrhythmias and the action of antiarrhythmic agents. In: Levy S, Scheinman M, eds. Cardiac arrhythmias. Mount Kisco, NY: Futura, 1984;15-32. Koch-Weser J. Disopyramide. N Engl J Med 1979;300: 957-962. Teichman SL. The antichohnergic side effects of norpace and norpace CR. Angiology 1985;36:767-771. Talbot RC, Julian DG. Prescott LF. Long-term treatment of ventricular arrhythmias with oral mexiletine. Am Heart J 1976;91:58-65. Duff HJ, Roden D, Primm RK. Oates JA, Woosley RL. Mexiletine in the treatment of resistant ventricular arrhythmias: enhancement of efficacy and reduction of dose-related side effects by combination with quinidine. Circulation 1983;67:1124-1128. Tanabe T, Yoshikawa H, Furuya H, Goto Y. Therapeutic
18
19
20
21
22
23
effectiveness and plasma levels of single or combination use of class I antiarrhythmic agents for ventricular arrhythmias. Jpn Circulation J 1988;52:298-305. Levy S. Combination therapy for cardiac arrhythmias. Am J Cardiol 1988;61:95A-101A. Ohashi K, Ebihara A. Hashimoto T, Hosoda S. Kondo K. Oka T. Pharmacokinetics and the antiarrhythmic effect of mexiletine in patients with chronic ventricular arrhythmias. Arzneim Forsch/Drug Res 1984;34:503-507. Kim SG, Mercando AD, Tam S. Fisher JD. Combination of disopyramide and mexiletine for better tolerance and additive effects for treatment of ventricular arrhythmia. J Am Coil Cardiol 1989;13:659-664. Kasanuki H. Onishi S, Hirosawa K. The usefulness of electrophysiological-pharmacologic studies in the longterm therapy of paroxysmal tachycardias. Jpn Circulation J 1985;49:351-361. Tanabe T, Yoshikawa H. Tagawa R, Furuya H, Ide M, Goto Y. Evaluation of antiarrhythmic efficacy using Holter electrocardiographic technique. Jpn Circ J 1985;49:337344. Han J, Gael BG. Electrophysiologic precursors of ventricular tachyarrhythmias. Arch Intern Med 1972;129:749-755. Breithardt G, Seipel L. Abendroth RR. Comparison of the antiarrhythmic efficacy of disopyramide and mexiletine against stimulus-induced ventricular tachycardia. J Cardiovast Pharm 1981;3:1026-1037. Greenspan AM, Spielman SR. Webb CR, Sokoloff NM, Rae AP, Harowitz LN. Efficacy of combination therapy with mexiletine and type IA agent for inducible ventricular tachyarrhythmias secondary to coronary artery disease. Am J Cardiol 1985;56:277-284. Hondeghem LM, Katzung BG. Time and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 1977:472:373-398. Hondeghem LM. Katzung BG. Test of a mode of antiarrhythmic drug action. Effects of quinidine and lidocaine on myocardial conduction. Circulation 1980:61:1217-1224. Courtney KR. Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium. J Mol Cell Cardiol 1980:12:1273-1286. Campbell TJ. Resting and rate-dependent depression of maximum rate of depolarization CV maxi in guinea pig ventricular action potentials by mexiletine, disopyramide. and encainide. J Cardiovasc Pharmacol 1983;5:291-296. Campbell TJ. Kinetics of onset of rate-dependent effects of class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea pig ventricle, and provide a theoretical basis for their subclassification. Cardiovasc Res 1983;17:344-352. Hondeghem LM, Katzung BG. Antiarrhythmic agents: the modulated receptor mechanism of action of sodium and calcium channel-blocking drugs. Ann Rev Pharmacol Toxicol 1984;24:387-423. Campbell NPJ. Pantridge JF. Adgey AAJ. Long-term oral antiarrhythmic therapy with mexiletine. Br Heart J 1978:40:796-801.
312 24 Mehta J, Conti CR. Mexiletine, a new antiarrhythmic agent, for treatment of premature ventricular complexes. Am J Cardiol 1982;49:455-460. 25 Kjekshus K, Bethen J, Orning OM, Storstein LLV. A double blind, crossover comparison of flecainide acetate
and disopyramide phosphate in the treatment of ventricular premature complexes. Am J Cardiol 1984;53:72B-78B. 26 Tartini R, Kappenberger L, Steinbrunn W, Meyer UA. Dangerous interaction between amiodarone and quinidine. Lancet 1982;1:1327-1329.