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PubMed1985

Pharmacokinetics and metabolism of bepridil.

Bepridil hydrochloride differs from the other calcium antagonists in structure as well as in several clinical pharmacokinetic characteristics. The drug is completely absorbed from the gastrointestinal tract, but first-pass extraction reduces oral bioavailability to approximately 60%. After single-dose administration, the elimination half-life of bepridil averages 33 +/- 15 hours. However, upon multiple dosing, a half-life of 42 +/- 12 hours is found. As with verapamil and diltiazem, bepridil clearance is decreased after multiple dosing. Bepridil is completely metabolized, presumably by hepatic oxidative processes. A total of 17 metabolites have been identified, but the contribution of any of these metabolites to observed clinical response is currently unclear. The free fraction of bepridil in plasma is low, averaging only 0.23%. Despite this high protein binding, in vitro studies indicate that the potential for drug-to-drug interactions based on displacement of bepridil from its binding sites is low. Bepridil follows a linear dose/plasma concentration relation after single and multiple doses of the drug in both healthy volunteers and patients with angina. However, mean steady-state plasma bepridil concentrations are higher in patients, indicating a greater average decreased clearance. Food does not interfere with bepridil absorption. At this time, no significant pharmacokinetic interactions between bepridil and digoxin have been detected.

Animals↗
PubMed1985

Evaluation of bepridil for the treatment of angina pectoris: evidence for preservation of left ventricular function.

The efficacy of bepridil (400 mg once a day) was assessed in 15 patients with exertional angina pectoris. All 15 patients reported substantial clinical improvement during bepridil treatment compared with placebo treatment. Episodes of angina were 11.8 +/- 4.1 (mean +/- standard error of the mean)/week with placebo and 3.8 +/- 1.6 with bepridil (p less than 0.05); nitroglycerin use was 9.1 +/- 3.3 tablets/week with placebo and 3.5 +/- 1.7 with bepridil (p less than 0.05). Five of 15 patients receiving bepridil did not experience angina during treadmill exercise; in the remaining 10 patients, time to onset of angina during exercise was 5.7 +/- 0.9 minutes with bepridil as opposed to 4.5 +/- 0.8 minutes with placebo (p less than 0.05). Left ventricular (LV) performance at peak exercise as measured by first-pass radionuclide angiography revealed the ejection fraction to be 38 +/- 3% during placebo therapy and 47 +/- 4% during bepridil therapy (p less than 0.0025). End-diastolic LV volume was unchanged, but end-systolic volume was 136 +/- 11 and 117 +/- 13 ml (p less than 0.05) and stroke volume was 82 +/- 6 and 97 +/- 9 ml (p less than 0.05) during placebo and bepridil therapy, respectively. Heart rate at peak exercise was 136 +/- 3 beats/min with placebo and 128 +/- 3 beats/min with bepridil; however, blood pressure was unchanged. These studies demonstrate that bepridil results in significant clinical improvement and enhanced LV performance in patients with angina pectoris.

Angina Pectoris↗
PubMed1985

Electrophysiologic and antiarrhythmic properties of bepridil.

Bepridil has been shown to block both slow- and fast-channel activity in the heart. Electrophysiologic studies in man demonstrate that oral and intravenous bepridil prolongs sinus cycle length, PR interval and QT interval, without apparently changing the QRS interval. In addition, the drug depresses atrioventricular (AV) nodal conduction, resulting in an increased AH interval. Refractoriness in the AV node, atrium and ventricle is increased. There is usually little or no change in the HV interval. The antiarrhythmic properties of bepridil have been noted in patients with supraventricular tachycardia, ventricular premature complexes (VPCs) and sustained ventricular tachycardia (VT). In 17 patients, intravenous bepridil was compared with either verapamil or ajmaline. AV nodal reentrant tachycardia was terminated in all patients with bepridil and verapamil. However, ajmaline was somewhat more effective than bepridil in patients with AV reentry (8 of 8 versus 5 of 8). In 12 of these 17 patients, oral bepridil (500 mg/day for 3 days) suppressed the induction of tachycardia or slowed its rate. In 3 studies of oral bepridil for VPCs, the drug was effective in 68%, 69% and 70% of patients. Another group of studies evaluated bepridil in a total of 30 patients with sustained VT. Intravenous bepridil terminated VT in 17 of 26 patients. The induction of VT by programmed ventricular stimulation was also prevented in 7 of 17 patients. Although torsade de pointes has been reported, its incidence appears to be low.

Ajmaline↗
PubMed1992

Comparative efficacy and concomitant use of bepridil and beta blockers in the management of angina pectoris.

The efficacy and safety of bepridil hydrochloride (HCl) and propranolol HCl monotherapy were investigated in a double-blind, parallel-group crossover study in 75 patients with chronic stable angina pectoris. For the first double-blind segment, both drugs reduced the frequency of weekly anginal attacks and nitroglycerin consumption. On exercise testing, bepridil was significantly more effective in terms of increasing time to angina and total work. Heart rate and ST-segment depression decreased to a greater degree with propranolol than bepridil. Bepridil produced a greater increase in QT interval than propranolol; corrected QT (QTc) interval was increased by bepridil and slightly decreased by propranolol. The incidence of adverse effects was roughly comparable for the two active drugs and higher than that for placebo during washout periods. It was concluded that bepridil, at a mean maintenance dosage of 324 mg/day, was at least as effective as propranolol in improving exercise tolerance--specifically time to angina and total work--and that tolerability of the 2 drugs was comparable. In another study, the efficacy and safety of bepridil combined with propranolol were compared with that of placebo plus propranolol in 56 patients who had not been well controlled on propranolol alone. The addition of bepridil significantly reduced the frequency of anginal attacks and weekly nitroglycerin consumption compared with baseline. The combination of propranolol and bepridil also produced significant improvements in total exercise time, time to angina, and total work compared with baseline. The QTc interval increased significantly from baseline in the bepridil combination group and decreased significantly in the propranolol plus placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1986

The binding of the calcium channel blocker, bepridil, to calmodulin.

Bepridil had the highest relative potency for inhibition of myosin light chain kinase (MLCK) activated by Ca2+-calmodulin of all the calcium channel blockers we examined. Kinetic analysis indicated that the primary effect of bepridil was mediated through a competitive inhibition of the enzyme activation by interaction with calmodulin and the apparent Ki value of this agent was 2.2 microM. We then examined the binding of bepridil to calmodulin, using the equilibrium column binding technique. [3H]bepridil bound to the calcium-calmodulin complex, but not to calmodulin in the presence of 2 mM EGTA. Scatchard analysis of the binding of bepridil to calmodulin demonstrated that the dissociation constant was 6.2 microM and the calculated number of specific binding sites was about 5 sites per molecule of calmodulin. The concentrations of unlabeled bepridil, W-7, prenylamine, verapamil and diltiazem producing 50% inhibition (IC50) of the binding of [3H]bepridil to calmodulin were 4 microM, 28 microM, 45 microM, 130 microM and 700 microM, respectively. However, nifedipine and nicardipine did not displace [3H]labeled bepridil from calmodulin. There was a good correlation between the displacement of [3H]bepridil from calmodulin and the inhibitory effect on MLCK by these calcium channel blockers and W-7. These results suggest that bepridil binds to calmodulin in the presence of calcium and potently inhibits the phosphorylation of myosin light chain.

Animals↗
PubMed1990

Effects of bepridil compared to those of its quaternary analogue on femoral arteries from spontaneously hypertensive rats.

The effects of bepridil and its quaternary analogue, methylated bepridil, were studied on femoral arterial strips from spontaneously hypertensive rats (SHR). Methylated bepridil relaxed precontracted strips more rapidly than did bepridil, but bepridil was a more potent vasorelaxant. Both drugs non-competitively inhibited arterial contraction evoked by voltage-dependent or alpha-adrenoceptor-operated Ca2+ influx with bepridil being more potent than methylated bepridil. In the absence of extracellular Ca2+, the contractile responses of Wistar-Kyoto rats (WKY) and SHR arteries to norepinephrine and caffeine were reduced similarly by methylated bepridil and bepridil. It is suggested that the effects of bepridil involve both extracellular and intracellular actions. The altered sensitivity of the contraction mechanism with norepinephrine-releasable Ca2+ to the Ca2+ antagonist may be due to an abnormality in the intracellular vasocontraction process distal to Ca2+ release from storage sites of the SHR blood vessels.

Animals↗
PubMed2002

Structure of the regulatory N-domain of human cardiac troponin C in complex with human cardiac troponin I147-163 and bepridil.

Cardiac troponin C (cTnC) is the Ca(2+)-dependent switch for contraction in heart muscle and a potential target for drugs in the therapy of heart failure. Ca(2+) binding to the regulatory domain of cTnC (cNTnC) induces little structural change but sets the stage for cTnI binding. A large "closed" to "open" conformational transition occurs in the regulatory domain upon binding cTnI(147-163) or bepridil. This raises the question of whether cTnI(147-163) and bepridil compete for cNTnC.Ca(2+). In this work, we used two-dimensional (1)H,(15)N-heteronuclear single quantum coherence (HSQC) NMR spectroscopy to examine the binding of bepridil to cNTnC.Ca(2+) in the absence and presence of cTnI(147-163) and of cTnI(147-163) to cNTnC.Ca(2+) in the absence and presence of bepridil. The results show that bepridil and cTnI(147-163) bind cNTnC.Ca(2+) simultaneously but with negative cooperativity. The affinity of cTnI(147-163) for cNTnC.Ca(2+) is reduced approximately 3.5-fold by bepridil and vice versa. Using multinuclear and multidimensional NMR spectroscopy, we have determined the structure of the cNTnC.Ca(2+).cTnI(147-163).bepridil ternary complex. The structure reveals a binding site for cTnI(147-163) primarily located on the A/B interhelical interface and a binding site for bepridil in the hydrophobic pocket of cNTnC.Ca(2+). In the structure, the N terminus of the peptide clashes with part of the bepridil molecule, which explains the negative cooperativity between cTnI(147-163) and bepridil for cNTnC.Ca(2+). This structure provides insights into the features that are important for the design of cTnC-specific cardiotonic drugs, which may be used to modulate the Ca(2+) sensitivity of the myofilaments in heart muscle contraction.

Actin Cytoskeleton↗
PubMedDate not supplied

Bepridil blockade of Ca2+-dependent action potentials in vascular smooth muscle of dog coronary artery.

The effect of the new vasodilatory and antianginal compound, bepridil (CERM-1978), was examined on the electrical activity of the vascular smooth muscle of isolated dog coronary arteries. Tetraethylammonium (10 mM) was used to induce excitability in the muscle in the form of Ca2+-dependent overshooting action potentials, whose inward current is carried almost exclusively by Ca2+ ion through voltage-dependent slow channels. Bepridil (5 X 10(-7)--1 X 10(--5) M) produced a dose-dependent depression of the rate of rise and amplitude of these Ca2+ spikes. Complete blockade of the action potentials occurred at 1 X 10(-5) M bepridil. These effects of bepridil were antagonized by elevation of external Ca2+ concentration ([CA]o). The effects of bepridil were substantially reversed by washout after about 30 min. Bepridil (10(-5) M) also produced a small but significant (p less than 0.05) increase in resting membrane resistance (input resistance increased from a mean of 10.1 to 12.4 m omega), accompanied by a small but significant (p less than 0.05) depolarization of 6 mV (from a mean of --51 to --45 mV). These latter effects are consistent with a diminution of the resting K+ conductance (gK) by bepridil. It is concluded that the vasodilatory and antianginal properties of bepridil may be explained by the action of this drug in depressing and blocking the Ca2+ influx into the cells, presumably by acting directly on the voltage-dependent slow channels in the cell membrane, and thereby lowering [Ca]i and thus the degree of contraction. Bepridil has Ca2+-antagonistic (or Ca2+ entry blocking or slow channel blocking) properties much like verapamil, but it is somewhat less potent than verapamil in this action (i.e., complete blockade occurred at 10(-5) M bepridil vs. 2 X 10(-6) M verapamil).

Action Potentials↗
PubMed2005

Bepridil, an antiarrhythmic drug, opens mitochondrial KATP channels, blocks sarcolemmal KATP channels, and confers cardioprotection.

Bepridil, which is clinically useful in the treatment of arrhythmias, has been reported to inhibit sarcolemmal ATP-sensitive K(+) (sarcK(ATP)) channels. However, the effect of bepridil on mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels remains unclear. The objective of the present study was to determine whether bepridil activates mitoK(ATP) channels and confers cardioprotection. SarcK(ATP) channels composed of Kir6.2+SUR2A in human embryonic kidney (HEK) 293 cells were examined using the patch-clamp technique. Flavoprotein fluorescence in guinea pig ventricular cells and matrix volume in isolated rat heart mitochondria were measured to assay mitoK(ATP) channel activity. Mitochondrial Ca(2+) concentration ([Ca(2+)](m)) was measured by loading cells with rhod-2 fluorescence. Coronary-perfused guinea pig ventricular muscles were subjected to 35-min no-flow ischemia followed by 60-min reperfusion. Bepridil (10 microM) completely inhibited the pinacidil-induced Kir6.2+SUR2A channel current expressed in HEK 293 cells. Bepridil reversibly oxidized the flavoprotein and increased mitochondrial matrix volume in a concentration-dependent manner. Furthermore, bepridil significantly attenuated the ouabain-induced increase of [Ca(2+)](m). Pretreatment with bepridil for 5 min before ischemia improved the recovery of developed tension measured after 60 min of reperfusion. These effects of bepridil were abolished by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microM) and by the nonselective K(ATP) channel blocker glisoxepide (10 microM). Our results indicate that bepridil is an opener of mitoK(ATP) channels but an inhibitor of sarcK(ATP) channels and exerts a direct cardioprotective effect on native cardiac myocytes. This is the first report of a unique modulator of K(ATP) channels; bepridil would be expected to mitigate ischemic injury while blunting arrhythmias.

Algorithms↗
PubMed1986

Stimulation of cardiac myofilament force, ATPase activity and troponin C Ca++ binding by bepridil.

We report that bepridil, a Ca++ channel blocker and calmodulin antagonist, which has been shown to enter myocytes, stimulates the mechanical and biochemical activity of cardiac myofilaments. Bepridil increased significantly the level of Ca++-dependent actomyosin Mg++-ATPase activity of myofibrils and the submaximal force developed by chemically skinned trabeculae of pig heart. In the range of concentrations (10-100 microM) in which bepridil showed this stimulatory activity, diltiazem and verapamil were without effect. The effect of bepridil on myofilament force and ATPase activity was higher at relatively low free Ca++ concentrations, and myofibrils lacking troponin-tropomyosin were not affected by bepridil. Associated with the stimulation of force and ATPase activity by bepridil was an increase in the amounts of Ca++ bound to troponin C (TnC). That bepridil stimulates TnC Ca++ binding was also shown in experiments using pure TnC labeled with 2-(4'-iodoacetamidoanilo)naphthalene-6-sulfonic acid, a fluorescent probe that reports Ca++ bound to the single "regulatory" site. Effects of bepridil on the fluorescence of a felodipine-cardiac TnC complex indicate that bepridil binds to TnC over the same range of doses where it affects myofilament activity. Our results indicate that the inotropic action of bepridil may result from a net response of heart cells to influences on the delivery of Ca++ to the myofilaments and their response to Ca++.

Actin Cytoskeleton↗
PubMed1985

Hemodynamic effects of intravenous bepridil in patients with normal left ventricular function.

Calcium-channel blockers are known to have depressant effects on atrioventricular (AV) nodal conduction and myocardial contractility. Because of these known depressant effects, bepridil hydrochloride, a new, long-acting, antianginal and antiarrhythmic calcium-channel blocker, was administered intravenously to patients without heart failure to determine acute hemodynamic effects. The patients studied had normal ventricular function, were without electrocardiographic conduction disturbances and were taking no drug except sublingual nitroglycerin for at least 24 hours before bepridil infusion. The study protocol included right- and left-sided cardiac catheterization with infusion of bepridil at 2 mg/kg for 15 minutes followed by 1 mg/kg for 15 minutes in 10 patients, and infusion of bepridil at 3 mg/kg for 15 minutes followed by 1 mg/kg for 15 minutes in 8 patients. Pressures, Fick cardiac output, resistances, left ventricular (LV) dP/dt, LV stroke work index and rate-pressure product of the left ventricle were monitored. There were no significant changes during bepridil infusion at either dose for cardiac output, systemic vascular and pulmonary vascular resistances, LV stroke work index, heart rate, arterial blood pressure and rate-pressure product. There was mild depression of LV dP/dt during bepridil infusion. Further, LV end-diastolic pressure, pulmonary capillary wedge pressure and pulmonary arterial pressures were significantly increased during bepridil infusion. There were no apparent changes in AV nodal or intraventricular conduction during bepridil infusion. We conclude that bepridil appears to be a safe drug for intravenous administration despite mild depression of myocardial function in patients with normal baseline hemodynamic function who are not receiving concomitant beta-blocker therapy.

Adult↗
PubMed1985

Electrophysiologic and antiarrhythmic actions of bepridil. Comparison with verapamil and ajmaline for atrioventricular reentrant tachycardia.

Bepridil (2 mg/kg intravenously) was given to 20 patients with atrioventricular (AV) reentrant tachycardia and its effects were compared with those of verapamil (0.15 mg/kg intravenously) in 8 patients and ajmaline (0.75 mg/kg intravenously) in 12. After baseline electrophysiologic measurements, the drugs were given during sustained AV reentrant tachycardia (8 patients had dual AV nodal pathways and 12 had an accessory AV pathway). Verapamil terminated AV reentrant tachycardia in 7 patients and bepridil terminated it in 6. In 8 of the patients who received ajmaline, AV reentrant tachycardia was terminated and in 6 of this group bepridil did so. Bepridil was more successful in terminating AV reentrant tachycardia in those with dual AV nodal pathways than in those with an accessory AV pathway. Bepridil slowed sinus rate by 10% (p less than 0.0001), whereas verapamil did not change it significantly. Both verapamil and bepridil administration prolonged AV nodal conduction (39% and 44%, respectively), lengthened AV nodal effective refractory period (18% and 17% respectively) and increased the Wenckebach cycle length of the AV node (24% and 25%, respectively) to a significant degree (p less than 0.05). Bepridil also lengthened atrial and ventricular effective refractory periods (p less than 0.01) and QT interval (p less than 0.0001) in the group as a whole; in those receiving ajmaline and bepridil only atrial refractoriness was significantly altered (p less than 0.05). After treatment for 3 to 5 days with oral bepridil, 19 patients underwent repeat study.(ABSTRACT TRUNCATED AT 250 WORDS)

Ajmaline↗
PubMed1992

Bepridil hydrochloride compared with placebo in patients with stable angina pectoris.

Bepridil is a calcium antagonist with a unique chemical composition and a long elimination half-life (42 hours). We evaluated the efficacy of bepridil 300 mg once/day in a crossover comparison with placebo in 45 patients with angina. Patients had an average of 7.6 anginal episodes/week during the placebo baseline phase of the trial. After 4 weeks of bepridil therapy, anginal frequency decreased to 2.9 episodes/week (p less than 0.05). Likewise, mean nitroglycerin consumption declined from 7.4 tablets/week during the placebo baseline phase to 4.0 tablets/week during bepridil therapy (p less than 0.05). Statistically significant increases over the previous period (placebo baseline or double-blind placebo) were seen in total exercise time, time to angina, and total work (p less than 0.05). During bepridil therapy, 13 of 45 patients (29%) no longer experienced angina as an exercise end point despite the increase in work and exercise time. Bepridil significantly prolonged both the QT and corrected QT (QTc) intervals; the mean increases were 10.0% and 5.6%, respectively. Side effects were reported with equal frequency in the placebo and bepridil arms of the trial, and no serious side effects were reported. In an intermediate fixed dose of 300 mg/day, bepridil relieved anginal symptoms with few side effects. Bepridil appears to be a safe and effective treatment for stable angina.

Analysis of Variance↗
PubMedDate not supplied

Supraventricular antidysrhythmic and electrophysiological effects of bepridil, a new antianginal agent.

We investigated the potential antidysrhythmic effects of bepridil, a new antianginal agent, on dysrhythmias of supraventricular origin. Intravenous bepridil (5 mg/kg) suppressed dysrhythmias evoked by local application of aconitine to the left atria of anesthetized cats. After the aconitine-induced dysrhythmias had subsided, cardiac function was better maintained in animals given bepridil than in the controls. The effects of bepridil on the maximum following frequency (MFF) and transmembrane action potentials of isolated guinea pig atria and on cells displaying phase 4 depolarization were also examined. Both bepridil (5--120 microM) and verapamil (0.02--1 microM) induced a dose-dependent reduction in contractility of driven left atria, whereas only bepridil reduced MFF. The effects of bepridil (10--40 microM) on the cellular action potentials of left atria were a dose-dependent decrease in the maximum rate of depolarization of phase 0 associated with a reduction in action potential height and a marked prolongation of the action potential duration. In similar concentrations, bepridil reduced the spontaneous rate of the right atrium and reduced the slope of phase 4 depolarization. We conclude that the action of bepridil in suppressing supraventricular dysrhythmias may be partly explained by depression of automaticity together with a reduction in the intensity of the inward sodium current.

Aconitine↗
PubMedDate not supplied

Profile of coronary vasodilator and cardiac actions of bepridil revealed by use of isolated, blood-perfused heart preparations of the dog.

We investigated the coronary vasodilator and cardiac actions of bepridil in various isolated, blood-perfused dog heart preparations. Intra-arterial bepridil increased blood flow in all preparations. In sinoatrial (SA) node preparations bepridil decreased sinus rate and produced atrial standstill in large doses. In paced atrioventricular (AV) node preparations, bepridil injected into the posterior septal artery (which supplies the AV node) increased AV conduction time (i.e., AV nodal conduction time) and in large doses produced second- or third-degree AV block. In the same preparations, bepridil in large doses injected into the anterior septal artery (which supplies the His-Purkinje ventricular system) prolonged AV conduction time (i.e., intraventricular conduction time). In paced papillary muscle preparations, bepridil reduced force of contraction only in large doses. In spontaneously beating papillary muscle preparations, bepridil decreased the rate of automaticity and the force of contraction as well. The order of effectiveness of bepridil on the above cardiovascular variables is as follows: coronary blood flow greater than AV nodal conduction greater than SA nodal automaticity much greater than ventricular automaticity ventricular muscle contraction much greater than intraventricular conduction. The results indicate bepridil to have a pharmacological profile different from that of verapamil, diltiazem, nifedipine, nicardipine, or KB-944.

Animals↗
PubMed1995

Mechanism of inhibition of the sodium current by bepridil in guinea-pig isolated ventricular cells.

1. Effects of bepridil, a sodium-, calcium-, and potassium-antagonistic agent, on the Na+ current were studied by the whole cell voltage clamp technique (tip resistance = 0.5 MOhm, [Na]i and [Na]o 10 mmol l-1 at 20 degrees C). 2. Bepridil produced tonic block (Kdrest = 295.44 mumol l-1, Kdi = 1.41 mumol l-1; n = 4). 3. Bepridil (100 mumol l-1) shifted the inactivation curve in the hyperpolarization direction by 13.4 +/- 2.7 mV (n = 4) without change in the slope factor. 4. In the presence of 50 mumol l-1 bepridil, bepridil showed use-dependent block at 2 Hz, whereas changes in pulse duration did not significantly effect this use-dependent block (81% +/- 2% at 10 ms, 84% +/- 3% at 30 ms, 86% +/- 3% at 100 ms; n = 4). 5. After removal of fast inactivation of the Na+ current by 3 mmol l-1 tosylchloramide sodium, bepridil (50 mumol l-1) still showed use-dependent block which was independent of the holding potential. 6. The recovery time constant from the bepridil-induced use-dependent block was 0.48 s at holding potential of -100 mV and 0.51 s at holding potential of -140 mV. 7. These results indicate that bepridil could bind to the receptor in the sodium channel through the hydrophobic and the hydrophilic pathway and leave the receptor through the hydrophobic pathway in the lipid bilayer. The binding and dissociation kinetics of this drug were shown to be fast, and the accumulation of the drug in the sodium channel appeared to be small. Bepridil is presumed to be safe in terms of adverse effects that result from drug-accumulation in the sodium channel.

Animals↗
PubMed2003

Evaluation of the effect of bepridil on paroxysmal atrial fibrillation: relationship between efficacy and the f-f interval in surface ECG recordings.

Bepridil, a multi-ion channel blocker, is effective for some types of cardiac arrhythmias, and so its effect on the paroxysmal atrial fibrillation (PAF) was evaluated in the present study, comparing it with class Ic antiarrhythmic drugs. The relationship between efficacy and the f-f interval in the surface ECG recording was also analyzed. Sixty-one symptomatic PAF patients were randomized to a bepridil group (200 mg/day, n=23) or class Ic drug group (flecainide 100-200 mg/day or pilsicainide 75-150 mg/day, n=38). The drug was considered effective for PAF prevention when symptomatic episodes of PAF were decreased to less than 50% during the follow-up period of 2-6 months. The f-f interval in the surface 12-lead ECG trace was evaluated during a PAF episode. Both bepridil and the class Ic drugs were effectively prevented PAF (15/23 (65.2%) vs 24/38 (63.1%) patients, NS). In the class Ic drug group, the f-f interval was longer in the effective cases (114+/-48 ms) than in the non-effective cases (68+/-26 ms, p=0.0002). In contrast, in the bepridil group the f-f interval was shorter in the effective cases (85+/-26 ms) than in the non-effective ones (152+/-45 ms, p=0.0005). When comparing the non-effective cases in the 2 groups, the bepridil group showed a significantly longer f-f interval than the class Ic drug group (p=0.0003). As a result of drug administration, the class Ic drugs prolonged the f-f interval from 78+/-33 ms to 128+/-46 ms (p=0.0004) whereas bepridil showed no change (109+/-39 ms vs 135+/-47 ms). For clinical PAF prevention, the effect of bepridil matched that of class Ic antiarrhythmic drugs. Because bepridil was effective in PAF patients with relatively shorter f-f intervals without prolonging the f-f interval, bepridil is considered to work mainly as a class III antiarrhythmic drug.

Aged↗
PubMed2004

Drug-induced changes in fibrillation cycle length and organization index can predict chemical cardioversion of long-lasting atrial fibrillation with bepridil alone or in combination with aprindine.

BACKGROUND: The aim of this study was to investigate whether drug-induced changes in fibrillation wave characteristics can predict pharmacological conversion of long lasting persistent atrial fibrillation (AF). METHODS AND RESULTS: The study group comprised 23 consecutive patients with AF lasting > or =1 month. Patients first received bepridil (200 mg/day) for 2-4 weeks. When sinus rhythm was not restored with bepridil, oral aprindine (40 or 60 mg/day) was added to bepridil. Fast Fourier transform analysis of fibrillation waves using lead V1 was performed to calculate the fibrillation cycle length (FCL). The spectral areas were measured and the maximum area divided by the total area was termed the fibrillation organization index (FOI). Sinus rhythm was restored in 16 of 23 patients (70%); 8 of these 16 patients received only bepridil (Group I) and the other 8 responders received bepridil and aprindine (Group II). In Group I bepridil increased both FCL (p<0.001) and FOI (p<0.01) and terminated AF after 20+/-12 days. In Group II bepridil increased FCL (p<0.001), but did not change FOI. The addition of aprindine terminated AF in association with an increase in both FCL (p<0.005) and FOI (p<0.005) within 19+/-8 days. In the remaining 7 patients who did not have restoration of sinus rhythm, bepridil increased both FCL and FOI significantly, but less than in Group I, and the addition of aprindine did not further increase either of them. Chemical cardioversion of AF occurred in all patients with FCL > or =190 ms and FOI > or =45% after drug administration. CONCLUSION: Bepridil alone or in combination with aprindine converted long lasting persistent AF in association with an increase in both FCL and FOI. The combination of FCL and FOI after drug administration is helpful in predicting chemical cardioversion of persistent AF.

Aged↗