Search

We present a case of double‐chambered right ventricle (DCRV) complicated by hypertrophic obstructive cardiomyopathy (HOCM) in KRAS mutation‐associated Noonan syndrome. The diagnosis was incidental and made during diagnostic testing for an intradural extramedullary tumour. Spinal compression, if not surgically treated, may cause paralysis of the extremities. We decided to pursue pharmacological therapy to control biventricular obstructions and reduce the perioperative complication rate. We initiated treatment with cibenzoline and bisoprolol; the doses were titrated according to the response. After 2 weeks, the peak pressure gradient of the two RV chambers decreased from 101 to 68 mmHg, and the LV peak pressure gradient decreased from 109 to 14 mmHg. Class 1A antiarrhythmic drugs and β‐blockers decreased the severe pressure gradients of biventricular obstructions caused by DCRV and HOCM. The patient was able to undergo surgery to remove the intradural extramedullary tumour, which was diagnosed as schwannoma.

Background The current report describes a case of stomach perforation, a rare but serious complication, that occurred during cardiopulmonary resuscitation following severe cibenzoline intoxication. Case Presentation A woman aged in her 30s was brought into our hospital while receiving cardiopulmonary resuscitation for pulseless electrical activity. After starting extracorporeal membrane oxygenation (ECMO), her abdominal X‐ray examination revealed free air in her abdomen. She was diagnosed with internal gastric perforation. An emergency operation was carried out while the circulation was maintained using ECMO. As the patient’s blood cibenzoline concentration on admission was 3,868 ng/mL, she was diagnosed with cibenzoline intoxication caused by the self‐intake of twice the prescribed dose. She was successfully weaned off ECMO and discharged alive with full recovery. Conclusion We successfully treated a case of gastric perforation after pulseless electrical activity requiring ECMO support due to cibenzoline intoxication. Abdominal surgery can be carried out even if ECMO support is needed., The current report describes a case of stomach perforation, a rare but serious complication, that occurred during cardiopulmonary resuscitation following severe cibenzoline intoxication. We successfully saved a case of gastric perforation after pulseless electrical activity requiring extracorporeal membrane oxygenation support due to cibenzoline intoxication.

This review aims to present an overview of the application of stable isotope technology in clinical pharmacology. Three main categories of stable isotope technology can be distinguished in clinical pharmacology. Firstly, it is applied in the assessment of drug pharmacology to determine the pharmacokinetic profile or mode of action of a drug substance. Secondly, stable isotopes may be used for the assessment of drug products or drug delivery systems by determination of parameters such as the bioavailability or the release profile. Thirdly, patients may be assessed in relation to patient-specific drug treatment; this concept is often called personalized medicine. In this article, the application of stable isotope technology in the aforementioned three areas is reviewed, with emphasis on developments over the past 25 years. The applications are illustrated with examples from clinical studies in humans.

An 83-year-old woman was admitted to our hospital because of palpitation. She had hypertension and paroxysmal atrial fibrillation, treated with digoxin and cibenzoline, and took dipyridamole for microalbuminuria. Before admission, she had taken pilsicainide pills in addition. On admission, electrocardiogram showed regular tachycardia with mildly prolonged QRS width. For the purpose of terminating tachycardia, 10 mg of adenosine triphosphate (ATP) was rapidly injected. About 20 sec later, atrioventricular block and ventricular standstill occurred. She presented loss of consciousness and convulsion, and chest compression was performed. About 30 sec later, the QRS complex reappeared, and she became alert. Serum concentration of digoxin, cibenzoline and pilsicainide was within therapeutic level, respectively. We should be cautious in using ATP for a patient taking dipyridamole and antiarrhythmic agents.

Serial Pharmacological Cardioversion of Persistent AF. Introduction: The success rate of pharmacological cardioversion of atrial fibrillation (AF) in patients depends on the duration of AF. It is unknown to what extent AF-induced structural atrial remodeling contributes to this loss of efficacy. Methods and Results: In 10 goats, persistent AF was induced by repetitive burst pacing. During a time period of 16 weeks, the efficacy of flecainide and cibenzoline to cardiovert AF was investigated by serial cardioversion. The drugs were administered intravenously at a rate of 0.1 mg/kg/min. AF cycle length (AFCL) was continuously monitored. Drug infusion was continued until AF was successfully cardioverted or the QRS duration was prolonged about twofold. The average atrial cycle length during persistent AF was 104 ± 10 msec and did not change during the 16-week period. The success rate of cardioversion by flecainide and cibenzoline decreased with the duration of AF from 60% to 17% and from 80% to 63%. In goats that failed to cardiovert, sinus rhythm was not restored despite a twofold prolongation of the AF cycle length (respectively from 96 ± 5 msec to 168 ± 30 msec (flecainide) and 203 ± 26 msec (cibenzoline)). The sensitivity of AF for Class IC drugs was not altered with time, and the dose-dependent effect on AFCL remained the same (flecainide: 8 ± 5 vs 7 ± 2 msec/mg/kg (P = 0.70) and cibenzoline: 13 ± 3 vs 13 ± 5 msec/mg/kg (P = 0.95)). In animals in which cardioversion remained possible, the critical AFCL at which cardioversion occurred increased from 96 ± 5 msec to 211 msec (flecainide) and 189 ± 24 msec (cibenzoline). Conclusions: The progressive loss of efficacy of Class IC drugs to cardiovert AF of longer duration is not due to a decrease in the sensitivity of remodeled atrial myocardium for Class IC drugs. Failure of cardioversion was due to an increase in the critical AF cycle length required for pharmacological cardioversion.

1. Cibenzoline, (+/-)-2-(2,2-diphenylcyclopropyl-2-imidazoline succinate, has been clinically used as one of the Class I type antiarrhythmic agents and also reported to block ATP-sensitive K(+) channels in excised membranes from heart and pancreatic beta cells. In the present study, we investigated if this drug inhibited gastric H(+),K(+)-ATPase activity in vitro. 2. Cibenzoline inhibited H(+),K(+)-ATPase activity of permeabilized leaky hog gastric vesicles in a concentration-dependent manner (IC(50): 201 microM), whereas no effect was shown on Na(+),K(+)-ATPase activity of dog kidney (IC(50): >1000 microM). Similarly, cibenzoline inhibited H(+),K(+)-ATPase activity of HEK-293 cells (human embryonic kidney cell line) co-transfected with rabbit gastric H(+),K(+)-ATPase alpha- and beta-subunit cDNAs (IC(50): 183 microM). 3. In leaky gastric vesicles, inhibition of H(+),K(+)-ATPase activity by cibenzoline was attenuated by the addition of K(+) (0.5 - 5 mM) in a concentration-dependent manner. The Lineweaver-Burk plot of the H(+),K(+)-ATPase activity shows that cibenzoline increases K(m) value for K(+) without affecting V(max), indicating that this drug inhibits H(+),K(+)-ATPase activity competitively with respect to K(+). 4. The inhibitory effect of H(+),K(+)-ATPase activity by cibenzoline with normal tight gastric vesicles did not significantly differ from that with permeabilized leaky gastric vesicles, indicating that this drug reacted to the ATPase from the cytoplasmic side of the membrane. 5. These findings suggest that cibenzoline is an inhibitor of gastric H(+),K(+)-ATPase with a novel inhibition mechanism, which inhibits gastric H(+),K(+)-ATPase by binding its K(+)-recognition site from the cytoplasmic side.

The effects of the antiarrhythmic drug flecainide on levcromakalim-induced hyperpolarization, macroscopic and unitary K(+) currents in pig urethra were investigated using patch-clamp techniques. The effects of flecainide were also examined on currents in inside-out patches of COS7 cells expressing carboxy terminus truncated inwardly rectifying K(+) channel (Kir6.2) subunits (i.e. Kir6.2DeltaC36) which form ATP-sensitive K(+) channels (K(ATP) channels). In current-clamp mode, application of flecainide (> or =100 microM) caused a significant depolarization after the membrane potential had been hyperpolarized by levcromakalim. In voltage-clamp experiments, the levcromakalim-induced outward current was suppressed by 300 microM flecainide in quasi-physiological K(+) conditions (K(i)=51 microM). In contrast, approximately 20% of the levcromakalim-induced inward current still remained even after application of 300 microM flecainide in symmetrical 140 mM K(+) conditions (K(i)=51 microM). In contrast, approximately 20% of the levcromakalim-induced inwar=126 microM). In cell-attached configuration, the channel activity of the levcromakalim-induced K(ATP) channels was reversibly inhibited by flecainide (> or =30 microM) at -50 mV. Their activity was also suppressed by either disopyramide or cibenzoline. Flecainide reversibly inhibited the channel activity of Kir6.2DeltaC36 expressed in COS7 cells using inside-out configuration. Inhibitory effects of flecainide on the levcromakalim-induced currents became more potent when the value of external pH increased, although this slightly reduced the proportion of drug molecules carrying a positive charge. These results suggest that flecainide inhibits channel activity through blocking the pore site of the K(ATP) channel in pig urethra.

Background: Cibenzoline, a class la antiarrhythmic drug, can be used to relieve left ventricular (LV) outflow obstruction in hypertrophic obstructive cardiomyopathy (HOCM). However, the mechanism of this agent in HOCM has been controversial. Hypothesis: This study was designed to investigate the effect of cibenzoline on regional LV function and the acoustic properties in HOCM using ultrasonic integrated backscatter. Methods: Ten patients with HOCM and 16 healthy volunteers were examined. In patients with HOCM, wall thickening (%WT) and the magnitude of cyclic variation of integrated backscatter (mag-CVIBS) in the interventricular septum (IVS) and LV posterior wall were measured before and after oral administration of cibenzoline. To assess asynchrony of contractile elements, the phase difference between CVIBS and%WT were measured from the LV posterior wall. Pressure gradients at the LV outflow tract were estimated using continuous-wave Doppler echocardiography. Results: Although%WT decreased significantly in the LV posterior wall, %WT and mag-CVIBS remained unchanged in the IVS. The phase difference in the LV posterior wall was significantly greater in patients with HOCM than in healthy volunteers (HOCM:healthy volunteers, 1.57 ± 0.23:1.00 ± 0.03, p < 0.001) at baseline. After administration of cibenzoline, the phase difference shifted to normal value (from 1.57 ± 0.23 to 1.28 ± 0.27, p = 0.0382), and pressure gradients at the LV outflow tract decreased (from 109 ± 55 to 58 ± 48 mmHg, p = 0.0063). Changes in pressure gradients at the LV outflow tract and the phase difference were closely related. Conclusions: Regional function and the acoustic properties of myocardium in HOCM were altered by cibenzoline in the LV posterior wall but remained unchanged in the IVS. The normalization of the phase difference in the LV posterior wall was closely related to the decrease in pressure gradients at the LV outflow tract. These findings suggest that negative inotropic action and the improvement of asynchrony in the LV posterior wall rather than in the IVS may contribute to the reduction of pressure gradients at the LV outflow tract in HOCM.

Pharmacologic Cardioversion of Chronic AF. Introduction: Recently, we reported that repetitive induction of atrial fibrillation (AF) in the goat causes electrical remodeling of the atria leading to the development of sustained AF. The aim of the present study was to compare Class IA, IC, and III drugs in their ability to cardiovert chronic AF in remodeled atria. Methods and Results: In 16 goats with sustained AF, hydroquinidine (HQ), cibenzoline (Ci), flecainide (FI), and d-sotalol (dS) were infused. HQ, Ci, FI, and dS restored sinus rhythm (SR) in 83%, 91%, 67%, and 92% of the cases, while adverse drug effects occurred in 17%, 36%, 56%, and 8%. Prior to restoration of SR, AF cycle length prolonged by 68%, 103%, 53%, and 20%, respectively. The QRS width increased by 14%, 64%, and 58% (HQ, Ci, and FI), and remained unchanged by administration of dS. RR intervals were slightly prolonged by HQ, Ci, and FI, and markedly prolonged by dS (48%). The QT interval was moderately prolonged by HQ, Ci, and FI, and considerably by dS (34%). QTc was only slightly prolonged by each of the drugs. Directly after cardioversion of AF, the atrial refractory period was 87 ± 29 (HQ), 119 ± 32 (Ci), 66 ± 10 (FI), and 73 ± 18 msec (dS) (control: 146 ± 18 msec). Atrial conduction velocity was 85 ± 6, 71 ± 11, 86 ± 12, and 110 ± 11 cm/sec compared with a control value of 116 ± 10 cm/sec. Because directly after cardioversion the atrial wavelength was still very short (5.7 to 8.4 cm), the vulnerability for AF was still very high, and a single premature beat reinduced AF in 71% (Ci) to 100% (HQ, FI, and dS) of the cases. Conclusion: In a goat model of sustained AF, Class IA, IC, and III drugs restored sinus rhythm in 67% to 92% of the cases. However, after cardioversion, the atrial wavelength was still abnormally short, and AF was readily inducible in 71% to 100% of the cases.

Background: The efficacy and safety of antiarrhythmic drugs for the prevention of atrial arrythmias are controversial because previous studies were nonrandomized or involved nonselected patients. The aim of this study was to evaluate the efficacy and tolerance of two Class I antiarrythmic drugs, cibenzoline, and flecainide, for the treatment of atrial arrhythmias in carefully selected patients. Patients and Methods: One hundred thirty-nine patients suffering from documented atrial arrhythmias (mean age 63 ± 12 years, 80 males, 59 females) were enrolled in randomized, double-blind, parallel clinical trials. Seventy patients received cibenzoline and 69 received flecainide; they were followed for a period of 6 months. All patients had good systolic ventricular function. The recurrence of atrial arrhythmias was diagnosed on symptoms, resting ECG, and 24-hour ambulatory ECG 3 and 6 months after commencing treatment. Results: Twenty-seven patients were withdrawn during the study, 13 for adverse side effects, 4 for proarrhythmic effects, and 3 for medical events; 7 were lost to follow-up. Forty-three patients had one recurrence of atrial arrhythmias (23 in the cibenzoline group, 20 in the flecainide group). The cumulative percentage of patients free from recurrence was not significantly different in either group at 6 months (63.7% in the cibenzoline group and 66.8% in the flecainide group). Cardiac adverse side effects were more frequent with flecainide than cibenzoline (5 vs. 2). One atrial proarrhythmic effect was observed. Conclusion: Cibenzoline and flecainide are both Class I antiarrhythmic agents which are well tolerated and may be safely administered to prevent alrial arrhythmias. A.N.E. 1999;4(1):53–59

Aims To test the existence of an association between reports of hypoglycaemia and angiotensin converting enzyme inhibitors, in a spontaneous reports database. Methods The French Pharmacovigilance database was examined for an association between adverse drug reaction reports mentioning hypoglycaemia, and angiotensin converting enzyme inhibitors (ACEI) using the case/non-case methodology, with reports of hypoglycaemia as cases and all other reports as comparators. The association between ACEI or other chosen drugs and hypoglycaemia was also tested in the subgroups of patients taking or not antidiabetic agents (ADA). Results 428 of 93338 reports mentioned hypoglycaemia (202/2227 with ADA (OR 40, 95% CI 33–48)). 46/5717 reports mentioned ACEI (OR 1.8 (1.25–2.54)). Other study drugs associated with hypoglycaemia were cibenzoline (OR 80 (57–112)), disopyramide (OR 32 (22–46)), nifedipine (OR 2.16 (1.32–3.51)), diltiazem (OR 1.76 (1.01–3.06)) nitrates (nitroglycerin, molsidomine) (OR 1.91 (1.16–3.16)) and frusemide (OR 1.89 (1.31–1.76)), but not nicardipine, amlodipine, felodipine or nitrendipine, diazepam, atenolol or combination thiazide diuretics. However, ACEI and other drugs were associated with ADA, so that in the subgroups of patients taking or not ADA, the association of ACEI with hypoglycaemia disappeared (OR 0.9 (0.5–1.4) and 1.2 (0.7–2.2), respectively). The same was found for other drugs except cibenzoline. Conclusion The association between reporting of hypoglycaemia and ACE inhibitors was related to concomitant use of antidiabetic agents. This was true also for other drugs used in arterial disease or renal failure, such as calcium channel blockers, nitrates, and frusemide.

1. We investigated the effect of cibenzoline (a class Ia antiarrhythmic drug) on basal insulin secretory activity of rat pancreatic islets and ATP-sensitive K+ channels (KATP) in single pancreatic beta cells of the same species, using radioimmunoassay and patch clamp techniques. 2. Micromolar cibenzoline had a dose-dependent insulinotrophic action with an EC50 of 94.2 +/- 46.4 microM. The compound inhibited the activity of the KATP channel recorded from a single beta-cell in a concentration-dependent manner. The IC50 was 0.4 microM in the inside-out mode and 5.2 microM in the cell-attached mode, at pH 7.4. 3. In the cell-attached mode, alkalinization of extracellular solution increased the inhibitory action of cibenzoline and the IC50 was reduced from 26.8 microM at pH 6.2 to 0.9 microM at pH 8.4. On the other hand, the action of cibenzoline in the excised inside-out mode was acute in onset with a small IC50, indicating that the drug attains its binding site from the cytoplasmic side of the cell membrane. 4. In the inside-out mode, micromolar ADP reactivated the cibenzoline-blocked KATP channels in a manner similar to that by which ADP restored ATP-dependent block of the channel. 5. The binding of [3H]-glibenclamide to pancreatic islets was inhibited by glibenclamide but not by cibenzoline. In contrast, the [3H]-cibenzoline binding was displaced by unlabelled cibenzoline but not by glibenclamide. It is concluded that cibenzoline blocks pancreatic KATP channels via a binding site distinct from the sulphonylurea receptor.

Bidisomide (SC-40230) is a unique new antiarrhythmic agent. In this study the canine intravenous (i.v.) antiarrhythmic doses of bidisomide (9 ± 1 mg/kg), disopyramide (8 ± 1 mg/kg), cibenzoline (8 ± 2 mg/kg), and propafenone (6 ± 0.5 mg/kg) were established in a 24 h coronary ligation ventricular arrhythmia model. Based on the canine therapeutic doses of the four agents, three cumulative i.v. doses (load/maintenance infusions) of each of these drugs and placebo were then studied in normal anesthetized dogs to evaluate their general cardiovascular effects. Propafenone (0.7-3.0 μg/ml plasma concentration) caused potent reductions in cardiac output and increases in QRS duration relative to the other agents. Cibenzoline (0.9-7.0 μg/ml) and disopyramide (1.4-12.9 μg/ml), at matched plasma concentrations, caused very similar cardiac output reductions, but cibenzoline caused nearly double the QRS increase. Bidisomide (1.9-16.1 μg/ml) had the least potent effects on cardiac output and QRS duration. All four drugs increased PR and QT in addition to QRS, but only disopyramide and propafenone increased IT (QT-QRS). These experiments suggest that the antiarrhythmic plasma concentrations of bidisomide, in contrast to those of selected reference agents, do not cause prominent ventricular conduction slowing or prolongation of ventricular repolarization, and in addition, cause only modest hemodynamic effects in normal dogs. © 1995 Wiley-Liss, Inc.

1. Cibenzoline, a class I antiarrhythmic agent, was investigated for its effect on the ATP-sensitive K+ channel of pancreatic beta-cells by the patch clamp technique. 2. In perforated patch clamp experiments, cibenzoline depolarized the membrane of single beta-cells and thereafter, caused firing of action potentials in the presence of 2.8 mM glucose. 3. Cibenzoline inhibited the activity of the ATP-sensitive K+ channel in cell-attached recordings in the presence of 2.8 mM glucose and evoked repetitive fluctuations of the baseline current, apparently reflecting the action potentials of the beta-cell. 4. In whole-cell clamp experiments, time-independent outward current was induced by depleting cytoplasmic ATP with 0.1 mM ATP and 0.1 mM ADP in the solution contained in the pipette. The outward current was inhibited by cibenzoline in a dose-dependent manner in the concentration range of 1 microM to 100 microM and half maximum inhibition occurred at 1.5 microM. 5. Cibenzoline blocked substantially the ATP-sensitive K+ channel current when applied at the inner side of the membrane in isolated inside-out membrane patches. 6. It is concluded that cibenzoline blocks the ATP-sensitive K+ channel of pancreatic beta-cells and, thereby, stimulates insulin secretion at sub-stimulatory levels of glucose.

1. The novel K+ channel opener, Y-26763 induced outward K+ currents in voltage-clamped follicle-enclosed Xenopus oocytes in a concentration-dependent manner with an EC50 value of 58 microM. 2. The Y-26763-induced K+ current was completely and reversibly blocked by glibenclamide (an ATP-sensitive K+ channel blocker) in a concentration-dependent manner (IC50 140 nM). Effects of several antiarrhythmic drugs on Y-26763-induced glibenclamide-sensitive K+ currents were investigated. 3. (+/-)-Cibenzoline, RS-2135, pirmenol, lorcainide and KW-3407 (class I antiarrhythmic drugs, Na+ channel blockers) suppressed Y-26763 responses in a concentration-dependent manner with IC50 values (in microM) of 6.6, 54, 68, 71 and 370, respectively. 4. Clofilium, E-4031, MS-551 and bretylium (class III antiarrhythmic drugs which increase the action potential duration) also suppressed Y-26763 responses concentration-dependently, IC50 values (in microM) were 3.3, 660, 980 and > or = 2000, respectively. N-acetylprocainamide (class III antiarrhythmic drug) scarcely suppressed Y-26763 responses. 5. The glibenclamide-sensitive K+ currents elicited by KRN2391 were also suppressed by all these antiarrhythmic drugs. 6. The antiarrhythmic drugs, clofilium and (+/-)-cibenzoline block glibenclamide-sensitive K+ channels in Xenopus oocytes at concentrations comparable to their therapeutic plasma levels.

The use-dependent effects of cibenzoline, a new anti-arrhythmic drug, on the maximal rate of rise (Vmax) of the action potential and on conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea pigs under normal and hypoxic conditions. Standard microelectrode techniques were applied to monitor the action potential of the muscles and their conduction. Under control conditions, the amount of use-dependent block of Vmax, conduction velocity, and square of conduction velocity, induced by 10 mumol/L cibenzoline were 26.5 +/- 3.9, 13.8 +/- 1.4, and 25.6 +/- 2.4%, respectively; under hypoxic conditions, these values increased to 32.3 +/- 4.8, 19.7 +/- 1.2, and 35.5 +/- 2.0%, respectively. In the presence of 10 mumol/L cibenzoline, the mean values of time constants for the onset of the use-dependent inhibition of Vmax, conduction velocity, and the square of conduction velocity, during a 2-Hz stimulation, were 3.65 +/- 0.27, 2.77 +/- 0.33, and 2.56 +/- 0.26 seconds, respectively. Under hypoxic conditions, these values changed to 5.10 +/- 0.96, 3.05 +/- 0.44, and 2.84 +/- 0.39 seconds, respectively. The recovery time constants averaged 14.72 +/- 4.08 seconds (for Vmax), 22.23 +/- 3.78 seconds (for conduction velocity), and 23.17 +/- 13.38 seconds (for the square of conduction velocity) in the presence of 10 mumol/L cibenzoline, and 17.19 +/- 8.59 seconds (for Vmax), 15.77 +/- 2.37 seconds (for conduction velocity), and 16.82 +/- 2.61 seconds (for the square of conduction velocity) under hypoxic conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Classification of antiarrhythmic actions is reviewed in the context of the results of the Cardiac Arrhythmia Suppression Trials, CAST 1 and 2. Six criticisms of the classification recently published (The Sicilian Gambit) are discussed in detail. The alternative classification, when stripped of speculative elements, is shown to be similar to the original classification. Claims that the classification failed to predict the efficacy of antiarrhythmic drugs for the selection of appropriate therapy have been tested by an example. The antiarrhythmic actions of cibenzoline were classified in 1980. A detailed review of confirmatory experiments and clinical trials during the past decade shows that predictions made at the time agree with subsequent results. Classification of the effects drugs actually have on functioning cardiac tissues provides a rational basis for finding the preferred treatment for a particular arrhythmia in accordance with the diagnosis.

We describe a patient with Brugada syndrome in whom J point and ST-segment elevation in leads V1 and V2 were augmented by atrial pacing and intravenous administration of propranolol or cibenzoline. Significant T wave alternans with a 2:1 appearance of terminal negative T wave was observed in the absence and presence of atrial pacing after the administration of cibenzoline. The cellular mechanism responsible for T wave alternans, beat-to-beat appearance of terminal negative T wave and augmented J point and ST-segment elevation is discussed.

We experienced an ablation case of drug refractory ventricular parasystole. Case: A 73-year-old man presented with complete atrioventricular block. Conduction failure was in the distal to the His bundle and escape QRS complexes were right bundle branch block with inferior axis. After DDD pacemaker implantation, electrocardiogram showed paced QRS beat (R) and broad QRS complexes (X) same morphology as the escape beats. There was no fixed relationship in R-X intervals, as would be expected if the broad beats (X) were linked to paced beats (R). A parasystole was the most likely explanation. Intravenous injection of 5 mg verapamil suppressed this broad complexes (X) only for some minutes. Application of 8 mg adenosine triphosphate prolonged and then shortened the cycle length. Cibenzoline (1.4 mg/kg) was not effective. Catheter ablation was performed for this highly symptomatic parasystole. The earliest activation site was located at the left antero-septal region and the fractionated intracardiac electrograms were recorded. No purkinje potentials were observed. Delivery of radiofrequency energy at a successful site resulted in a rapid ventricular response. Distance between successful site and His bundle region was 2.5 cm. Conclusions: The detailed pharmacological testing and intracardiac mapping may be helpful to better understand the ventricular parasysytole. Catheter ablation could be a choice of therapy.

The case is an 87 years old woman. For brady-tachycardia syndrome due to the paroxysmal atrial fibrillation, she was implanted dual-chamber Biotronik pacemaker. She didnot have the problem of the pacemaker one or two months later. She was followed up in Home Monitoring (remote monitoring). We detected the pacing failure of the atrium and ventricle in IEGM, high frequency of ventricular pacing and the increase of premature ventricular contraction (PVC) by Home Monitoring. The cause of pacing failure was a rise in threshold by the cibenzoline. The pacemaker misrecognized the self-QRS to PVC by the crosstalk. As correspondence to each problems, we turned on AV hysteresis, changed the pacing output and the ventricular blanking period after atrium pacing.

A 35-year-old man who had shown intermittent Wolf-Parkinson-White (WPW) syndrome and a history of syncope in the early morning was admitted to our hospital for the treatment of WPW syndrome. Ventricular fibrillation (Vf) as the cause of syncope was confirmed by the emergency crews and he was successfully resuscitated using an automatic external defibrillator. He fortunately recovered without any neurological complication. Ischemic heart disease had already been ruled out. He had been suspected as Vf due to atrial fibrillation associated with WPW syndrome and amiodarone had been started. Terminal QRS notches (J wave) in V3–V5 without delta wave were observed in his ECG upon admission. Electrophysiological study revealed the appearance of delta wave after isoproterenol infusion. Effective refractory period of antegrade Kent bundle was more than 600 msec, suggesting that intermittent WPW syndrome could not be a cause of Vf. Vf was easily induced by right ventricular extrastimuli after Kent ablation. We finally diagnosed idiopathic Vf with J wave. Therefore, we implanted an intracardiac defibrillator (ICD) and substituted cibenzoline for amiodarone. He has never experienced shock during 10 months after ICD implantation. We report a case here that the cause of syncope was thought to be an idiopathic Vf associated with J waves rather than a Vf due to atrial fibrillation associated with intermittent WPW syndrome.

Pharmacokinetic values of cibenzoline, a new, investigational, antiarrhythmic drug, were determined in 13 patients with varying degree of renal impairment, creatinine clearance range between 5 and 53 mL/min. Cibenzoline plasma levels were measured after direct intravenous injection of one single 1 mg/kg dose. The apparent volume of distribution of the drug (276 1) was similar to that reported in healthy subjects. Total body clearance decreased with creatinine clearance, and there was a close correlation between cibenzoline renal clearance and creatinine clearance (r = 0.956; P less than 0.001). Plasma elimination half-life was prolonged, with values ranging from 7:4 to 23.6 hours. This study showed that cibenzoline total body clearance correlated with the degree of renal impairment, and it is suggested that in patients with chronic renal failure dosage should be adjusted according to creatinine clearance values.

The plasma concentration and antiarrhythmic effect data following multiple, ascending oral doses of cibenzoline in four patients with frequent premature ventricular contractions (PVCs) were analyzed using pharmacokinetic and pharmacodynamic modeling. Three methods of data analysis were tested in the analysis of the large amount of arrhythmia frequency data gathered during the study: as total-data set, average-data set, and grouped-data set. We have shown that the antiarrhythmic effect profile of the drug could be characterized by average data when a large number of PVC measurements are involved. Using the average-data sets, the plasma concentration of the drug at steady state could be correlated to the antiarrhythmic response using pharmacokinetic and pharmacodynamic modeling.

Fifteen patients with ventricular premature complexes (VPCs) were included in this open study designed to assess the relative efficacy of bid (two times daily) and tid (three times daily) dosing regimens for cibenzoline as compared with qid (four times daily) administration. Patients started therapy with qid administration; this was followed in sequence by tid and bid administration at the maximum effective total daily dose determined during the qid administration. Of the nine patients evaluated for efficacy for suppression of VPCs, eight demonstrated a 75% or greater suppression of VPCs with cibenzoline administered qid (total daily dose of 130-325 mg). This effectiveness was maintained in four patients with a bid regimen and in three with a tid regimen. All four patients who had ventricular tachycardia (VT) had a decrease in the number of VT episodes while receiving cibenzoline (only one of these patients had satisfactory suppression of VPCs at the same dosage regimen). Twelve patients continued to receive extended therapy with cibenzoline for up to two years, as this was considered to be the optimum antiarrhythmic treatment for these patients. Two patients had to be removed from the study and two had the dosage lowered because of adverse reactions (dry mouth, blurred vision, dizziness, congestive heart failure) although in one instance, the congestive heart failure was subsequently considered to be unrelated to cibenzoline. One patient was able to complete the short-term phase of the trial, but was not given extended treatment because of persistent dry mouth. Two patients had treatment discontinued during the extended therapy phase because of adverse reactions (fever, nausea, vomiting, asthenia).(ABSTRACT TRUNCATED AT 250 WORDS)

The electrophysiologic effects of cibenzoline were studied using programmed electrical stimulation (PES) techniques and were compared to those of quinidine. Cibenzoline, like the conventional class 1 agent quinidine, was effective in preventing arrhythmia induction. Twelve dogs were given 0.02 mg/kg digoxin intravenously for seven days to achieve a steady-state digoxin level. On the eighth day, cibenzoline was administered in incremental doses (0.5 to 10.5 mg/kg) and PES was performed at 30-minute intervals. A mean dose of 2.6 +/- 0.8 mg/kg cibenzoline prevented ventricular tachycardia induction. At this dose, cibenzoline had no significant effect on mean arterial blood pressure, but PR interval increased by 17 +/- 9 per cent, QRS duration by 27 +/- 14 per cent, and the ventricular refractory period (ERP) for the first extra stimulus increased by 35 +/- 9 per cent. A gradual decrease in heart rate and an increase in PR interval and QRS duration was caused by incremental doses of cibenzoline. In six additional animals, quinidine was administered in incremental doses (1 to 30 mg/kg) and PES performed at 30-minute intervals. A mean of 15 +/- 5 mg/kg prevented induction of ventricular tachycardia in five animals. No significant change in heart rate, PR, QRS, and ERP was found at the effective dose.

Summary— The cardiac adrenergic system is known to have practically no influence on conduction velocity in the ventricles under normal conditions. The effects of isoproterenol and propranolol were investigated on depression of intraventricular conduction induced by a class IC antiarrhythmic drug, cibenzoline, in anaesthetized, closed-chest dogs. In addition to electrocardiogram for measurement of QRS duration in sinus rhythm, conduction time was measured in the ventricular contractile tissue between an electrode advanced to the apex and a pacing electrode near the base, at 400- and 200-ms pacing periods. Effective refractory period (ERP) was measured concurrently according to the extrastimulus method. After intraventricular conduction had been slowed down by cibenzoline IV administered (loading dose of 3 mg/kg plus infusion of 0.2 mg/kg/min over 15 min), isoproterenol was infused or propranolol injected by the intravenous route also (0.5 mn/μg/kg/min over 5 min and 0.4 mg/kg, respectively). When conduction time has been raised by 75/150% (depending on the pacing rate), isoproterenol appears to attenuate and propranolol to aggravate substantially the impairment of conduction, whereas the reduction undergone by ERP does not differ from usual. Thus, reentrant arrhythmias might be prevented by isoproterenol and triggered by propranolol. Intraventricular conduction, when depressed, therefore, is sensitive to adrenergic drugs, probably because of the enhanced influence of polarization of the fibres in the presence of a sodium conductance impairment.

Single oral doses of cibenzoline were administered to eight healthy volunteers on two different occasions, once at 8.00 am and once at 10.00 pm, in a randomized crossover design with at least one week separating treatments. A fast was maintained for 12 hours prior to and for 2 hours after the morning dose and the subjects did not lie down for at least 12 hours after dosing. A standard dinner was eaten 3 hours prior to the evening dose, and a fast was maintained for 10 hours after dosing; the subjects laid down 2 hours after dosing for at least 6 hours. Blood was collected at specific times for 72 hours and the total volume of urine voided was collected through 72 hours. Cibenzoline concentrations in plasma and urine were measured by HPLC. Cibenzoline absorption was slower in 7 of the 8 volunteers following the evening dose relative to the morning dose. Mean +/- S.D. tmax for the evening dose was 2.6 +/- 0.5 hours compared to 1.7 +/- 0.8 for the morning dose. The corresponding mean +/- S.D. Cmax following the morning dose was 446 +/- 124 ng ml-1 compared to 402 +/- 114 ng ml-1 after the evening dose. The mean +/- S.D. AUC was 3328 +/- 1101 ng . h . ml-1 after the morning dose and 3561 +/- 1430 ng . h . ml-1 after the evening dose. The harmonic mean half-life was 7.4 hours after both treatments. These data indicated that the total amount of drug absorbed and the elimination rate constant of the drug had not varied between treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Bei fruheren Untersuchungen zum Metabolismus des als Antiarrhythmicum in klinischer Prufung befindlichen Cibenzolins (I) wurden neben dem Imidazol (II) die hydroxylierten Derivate (VII) als Metaboliten des tierischen (Hund, Ratte) Stoffwechsels isoliert und identifiziert.

Following treatment with cibenzoline, a new antiarrhythmic agent, 23 of 53 patients showed positive proteinuria reactions. In all cases, these results were obtained with bromphenol reagent strips. Subsequent exposure of serial dilutions of cibenzoline to these reagent strips showed positive protein reactions at concentrations as low as 1 mg/ml. Treatment of these same solutions with acetic acid-sodium acetate heat coagulation technique produced negative findings. Specimens from 14 of the above patients were then retested employing both techniques, and in all cases the reagent strips produced positive results while the heat coagulation technique (or sulfosalicylic acid) produced negative results. Therefore, it appears that cibenzoline produces false-positive proteinuria results when bromphenol reagent strips are employed for analysis.