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The aim of this study was to investigate the relationship between late gadolinium enhancement (LGE) and the effect of cibenzoline (CBZ) on left ventricular (LV) diastolic function in hypertrophic cardiomyopathy (HCM) patients. Echocardiography before and after intravenous CBZ (1.4 mg/kg over 5 minutes) and magnetic resonance imaging (MRI) were performed in 22 consecutive patients with HCM [mean age: 65 ± 14 years, obstructive HCM: 14, nonobstructive HCM (HNCM): 8]. The extent of LGE (%LGE = LGE volume/total LV volume) was obtained by contrast-enhanced MRI using custom software. LGE was observed in 19 patients (mean %LGE = 5.1% ± 3.9%). The propagation velocity of LV early filling flow (Vp) increased significantly in patients with obstructive HCM (26 ± 7 to 36 ± 14 cm/s, P = 0.001) and nonobstructive HCM (25 ± 9 to 36 ± 16 cm/s, P = 0.007). A significant negative correlation was observed between the change in Vp and %LGE in patients with HCM (r = 20.542, P = 0.009). Less extensive myocardial fibrosis, as demonstrated by LGE on contrast-enhanced MRI, may predict the ability of CBZ to improve LV diastolic function in HCM.

Background: It has been reported that approximately one-third of patients undergoing cardiovascular surgery experience paroxysmal atrial fibrillation (AF) during the postoperative period. There is, however, little information on the selection of anti-arrhythmic drugs for terminating postoperative paroxysmal AF. Methods and Results: Between April 2007 and March 2009, 118 patients (76 men, 42 women, mean age 68±10 years) who had postoperative paroxysmal AF lasting ≥30 min were randomly assigned to receive either iv cibenzoline (70 mg, n=60) or disopyramide (50 mg, n=58) for terminating postoperative paroxysmal AF. The success rate of iv cibenzoline therapy (47%) was significantly greater than that of iv disopyramide therapy (24%; P

Negative inotropic agents are often administered to decrease the left ventricular (LV) pressure gradient in patients with obstructive hypertrophic cardiomyopathy (HC). Little information is available regarding comparisons of the effects on LV pressure gradient among negative inotropic agents. The present study compared the decrease in the LV pressure gradient at rest in patients with obstructive HC after treatment with pilsicainide versus treatment with disopyramide or cibenzoline. The LV pressure gradient and LV function were assessed before and after the intravenous administration of each drug. In 12 patients (group A, mean pressure gradient 90 ± 24 mm Hg), the effects of disopyramide, propranolol, and verapamil were compared. In another 12 patients (group B, mean pressure gradient 98 ± 34 mm Hg), a comparison was performed among disopyramide, cibenzoline, and pilsicainide. In group A, the percentage of reduction in the LV pressure gradient was 7.7 ± 9.9% with verapamil, 19.0 ± 20.2% with propranolol, and 58.6 ± 15.0% with disopyramide, suggesting that disopyramide was more effective than either verapamil or propranolol. In group B, the percentage of reduction in the LV pressure gradient was 55.3 ± 26.6% with disopyramide, 55.3 ± 20.6% with cibenzoline, and 54.7 ± 15.4% with pilsicainide, suggesting an equivalent effect on the LV pressure gradient for these 3 agents. In conclusion, these results indicate that the acute efficacy for the reduction of the LV pressure gradient at rest by pilsicainide (a pure sodium channel blocker) was equivalent to that of disopyramide or cibenzoline (combined sodium and calcium channel blockers). Accordingly, sodium channel blockade might be more important for reducing the LV pressure gradient at rest in patients with obstructive HC than calcium channel blockade or β blockade.

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.

Cibenzoline is a class I antiarrhythmic drug with limited class III and IV activity which can be administered orally or intravenously. An elimination half-life of about 8 to 12 hours permits twice daily administration, although age and renal function must be considered when determining dosage. Cibenzoline has some activity in ventricular and supraventricular arrhythmias, including drug-refractory ventricular tachycardia or ventricular arrhythmias following recent acute myocardial infarction, although results in patients with sustained ventricular tachycardia are less promising. In comparative trials, cibenzoline has demonstrated efficacy similar to or better than that of a variety of other class I antiarrhythmic drugs and was at least as well tolerated, with a more convenient dosage schedule. However, further studies to clarify the proarrhythmic effects of cibenzoline and its use in patients with impaired left ventricular function are required, and the use of cibenzoline (and other class I antiarrhythmic agents) in patients with other than potentially lethal ventricular arrhythmias should be avoided following the results of the CAST studies. Thus, cibenzoline is an effective antiarrhythmic agent with a favourable pharmacokinetic profile that may be considered with other class I drugs in patients requiring therapy for high risk arrhythmias.

The effect of cibenzoline succinate, a new antiarrhythmic agent, was studied on insulin secretion in rats. Experiments were performed both in vivo and in vitro using two preparations: the isolated perfused pancreas and isolated islets. In anaesthetized rats, cibenzoline was able to increase plasma insulin levels and to reduce glycaemia. These effects were observed at 1 mg/kg i.v. in fed rats and at 3 mg/kg i.v. in fasted rats. In the isolated pancreas perfused in the presence of a slightly stimulating glucose concentration (8.3 mM), cibenzoline (2 and 6 microM) elicited a progressive and sustained insulin response in a concentration-dependent manner. In the presence of a non-stimulating glucose concentration (4.2 mM), cibenzoline was ineffective at 2 microM and slightly increased basal insulin release at 6 microM. In isolated islets incubated with 8.3 mM glucose, cibenzoline (6 and 20 microM) caused a concentration-dependent stimulation of insulin release. It is concluded that cibenzoline stimulates insulin secretion by a direct action on pancreatic B cells in rats.

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.

This report presents the case of an 8-year-old male with biventricular hypertrophic obstructive cardiomyopathy who achieved a successful reduction of the pressure gradients by treatment with cibenzoline. Ultrasound echocardiography showed marked intraventricular septal hypertrophy and left midventricular and right ventricular outflow obstructions. A cardiac catheterization revealed left midventricular and right outflow obstructions associated with pressure gradients of 100 and 35 mmHg, respectively. An intravenous injection of 28 mg (1.4 mg/kg) cibenzoline immediately improved the biventricular pressure gradients. Therefore, oral cibenzoline treatment was initiated, the dose was increased to 150 mg/day, and both pressure gradients remained low, without any complications at the time of discharge, 4 months later.

Obstruction of the left ventricular outflow tract (LVOT) is usually complicated by hypertrophic cardiomyopathy or left ventricular hypertrophy. It occurs rarely in cases of sigmoid-shaped septum (SS), which are considered as a normal part of the aging process. The 2 cases of SS with obstruction of the LVOT were observed. Their complaints were dyspnea on effort and exercise increased the left ventricular pressure gradient. In both cases, atenolol administration decreased rest pressure gradient. Moreover, additional cibenzoline administration decreased the pressure gradient caused by exercise. It is emphasized that dual therapy with cibenzoline and atenolol is effective in resolving the obstruction of the LVOT caused by SS.

We report a patient in whom severe hemodynamic instability occurring after mitral valvoplasty (MVP) was successfully treated with cibenzoline. Left ventricular outflow tract obstruction (LVOTO) with mitral regurgitation (MR) resulting from the systolic anterior motion (SAM) of the mitral valve that occurs after MVP often leads to hemodynamic collapse. Patients who develop SAM after MVP have been managed with intravenous volume loading, reduction/discontinuation of inotropic drugs, and with increased afterload, but these strategies were often ineffective. Cibenzoline decreased myocardial contraction, attenuated SAM, and improved hemodynamics in our patient. We recommend that cibenzoline be administered before further surgical manipulation is considered for patients who develop SAM after MVP.

Introduction. Cibenzoline is an antiarrhythmic drug used to treat patients with supraventricular or ventricular arrhythmias. Cibenzoline overdose is associated with proarrhythmic and hemodynamic effects such as hypotension and congestive heart failure. Case Report. We report a case of cardiogenic shock due to cibenzoline overdose in a patient with progressive renal insufficiency. Discussion. The standard treatment of a cibenzoline intoxication is symptomatic, but we used combined hemoperfusion-hemodialysis to treat our patient. Conclusions. This was associated with a rapid decline in plasma cibenzoline concentration and improvement of the clinical condition. However, only 28.98 mg of an estimated body pool of cibenzoline (447.2 to 806.6 mg) was removed during the 8 hours of treatment.

The electrophysiologic effects of intravenous (i.v. 1.5 mg/kg) cibenzoline were investigated in 13 patients with organic heart disease and supraventricular arrhythmias (control group) and 13 patients with drug refractory sustained ventricular tachycardia (VT group). In both groups, cibenzoline increased the effective refractory period (ERP) of the right ventricle (p less than or equal to 0.05), QRS duration (p less than or equal to 0.01), and QTc duration (p less than or equal to 0.01). Cycle length of the VT was increased from 311 +/- 73 to 393 +/- 119 ms (p less than or equal to 0.05) as well. The increase in QTc duration was more pronounced (p less than or equal to 0.05) in the VT group as compared with the control group. In four patients in the VT group with the largest increase in QRS-, QTc duration and cycle length of the VT proarrhythmia was noted after i.v. cibenzoline. Cibenzoline plasma levels were not significantly different between the two study groups. In the VT group, induction of VT was prevented in 2 patients, more difficult in 2 patients, easier in 1 patient, and unchanged in 5 patients. Spontaneous occurrence of the VT or induction by atrial stimulation was noted in 4 patients. In the control group, ventricular vulnerability remained unchanged. Cibenzoline may be effective in selected patients with drug refractory VT. In such patients, the increase in QTc duration was more pronounced as compared with a control group.

The anticholinergic effects of cibenzoline, disopyramide, and atropine were compared on experimental models. Using inhibition of specific binding of 3H-quinuclidinyl benzylate (3H-QNB) in rat heart and cerebral cortex, Ki values were 15.8 +/- 1.6, 12 +/- 3.5, and 0.013 +/- 0.001 microM, respectively, for heart membranes and 31.6 +/- 1.5, 7.8 +/- 1.3, and 0.006 +/- 0.001 microM, respectively, for cerebral cortex membranes. In isolated guinea pig ileum, disopyramide was about 15 times more anticholinergic than cibenzoline but about 900 times less so than atropine. In anesthetized dogs, the three drugs administered by intravenous bolus reduced bradycardia caused by vagal stimulation. The effect of cibenzoline at 7 mg/kg i.v. (double the antiarrhythmic dose) was approximately the same as that of disopyramide at 2.5 mg/kg (half the antiarrhythmic dose). The drugs were infused for 1 h at 0.17 mg/kg/h for atropine, 11.6 mg/kg/h for disopyramide, and 5.5 mg/kg/h for cibenzoline. The maximal inhibition of the vagal stimulation was 98, 95, and 52%, respectively, for the three drugs. In nonanesthetized dogs, inhibition of the vagal-tone-induced tachycardia reached 33 +/- 4, 134 +/- 20, and 206 +/- 19% for cibenzoline, disopyramide and atropine, respectively. These results show cibenzoline to exert less potent anticholinergic effects than disopyramide.

The relationship between the negative inotropic effect and the effect on maximal upstroke velocity of action potentials (Vmax) induced by class 1 antiarrhythmic drugs [aprindine (A); cibenzoline (C); disopyramide (D); lidocaine (L); pirmenol (P); quinidine (Q)] was evaluated in the guinea-pig myocardium using electrophysiological techniques. Each drug reduced the force of contraction (Fc) and Vmax of fast action potentials dose-dependently. Tetrodotoxin and verapamil also decreased Fc in a dose-dependent manner. Class 1 an-tiarrhythmic drugs also reduced Vmax of the Ca-dependent slow response together with Fc. These drugs might be divided into three types according to the regression patterns of Fc. Type 1: The reduction of Fc was mainly due to Na channel blockade, resembling the pattern of tetrodotoxin (A). Drugs of this type show weaker negative inotropic than antiarrhythmic properties compared with drugs of types 2 and 3. Type 2: The reduction of Fc was predominantly due to Ca channel blockade, resembling the pattern of verapamil (Q). Type 3: Other type (C, D, L, P). This classification of class 1 antiarrhythmic drugs seems to be clinically useful in choice of drugs considering the patient's condition, such as cardiac function, and possible mechanism of arrhythmia.

We have developed an enzyme-linked immunosorbent assay (ELISA) suitable for routine monitoring of serum levels of cibenzoline. Anti-cibenzoline antibody was obtained by immunizing rabbits with cibenzoline conjugated with bovine serum albumin using N-(4-maleimidobutyryloxy)succinimide as a heterobifunctional coupling agent. An enzyme marker was prepared by coupling 2,2-diphenylethylamine with beta-D-galactosidase using glutaraldehyde. The detection limit of cibenzoline by ELISA was approximately 640 pg/ml with 50-microl samples. Cross-reactivity data showed that the antibody well recognizes both the diphenyl and cyclopropyl moieties, and is thus specific enough to the structure of cibenzoline. The values for the cibenzoline concentrations detected using this assay were comparable with those detected using HPLC. There was a good correlation between the values determined by the two methods. Moreover, ELISA was about 15-fold more sensitive in detecting cibenzoline at lower concentrations. Using this assay, drug levels were easily measured in the serum of rabbits after oral administration of cibenzoline at a single dose of 3 mg/kg.

We describe the case of a 71-years-old man in chronic hospital hemodialysis who was admitted to the hospital because of symptomatic hypoglycemia. We discovered that this was due to a documented intoxication with cibenzoline, an antiarrhythmic drug , used to treat (supra-)ventricular tachyarrhythmia. In addition we made a short review of the literature concerning cibenzoline intoxication.

Using the whole-cell voltage clamp, we examined acute effects of various agents on Na+/Ca2+ exchange current (INCX) in guinea-pig cardiac ventricular cells and transfected cells. Among the antiarrhythmic drugs, amiodarone, bepridil, dronedarone, cibenzoline, azimilide, and aprindine inhibited INCX in a concentration-dependent manner. We also investigated the effects on NCX of 2,3-buanedione monoxim (BDM) and selective NCX inhibitors such as KB-R7943, SEA0400, and SN-6. The presence of trypsin in the pipette solution attenuated the inhibitory effects on NCX of amiodarone, bepridil, and BDM, suggesting that these drugs inhibit NCX from the cytosolic side. In contrast, the trypsin-insensitive NCX inhibitors were aprindine, azimilide, dronedarone, cibenzoline, KB-R7943, SEA0400, and SN-6. KB-R7943, SEA0400, and SN-6 suppressed the uni-directional outward INCX more potently than the uni-directional inward INCX. The mechanism of this mode-dependency is unknown, but is suggested to be related to intracellular Na+ concentration. Keywords:: antiarrhythmic drug, benzyloxyphenyl analogue, blocker, Na+/Ca2+ exchange current, pharmacophore model

The effect of cibenzoline, a class-Ia antiarrhythmic drug, on coronary flow velocity reserve (CFVR) was examined in patients with hypertrophic cardiomyopathy using transthoracic Doppler echocardiography. Coronary flow velocity reserve was assessed in 11 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 12 patients with hypertrophic nonobstructive cardiomyopathy (HNCM), before and after the intravenous administration of cibenzoline (1 mg/kg). Coronary hyperemia was induced by an intravenous infusion of adenosine triphosphate and CFVR was calculated as the ratio of hyperemic to basal mean coronary diastolic flow velocity. At baseline, CFVR was significantly correlated with left ventricular outflow tract pressure gradient (LVPG) in patients with HOCM (r = 0.67, P0.03). In patients with HOCM, administration of cibenzoline significantly improved impaired CFVR (2.0 +/- 0.8 to 3.0 +/- 1.0, P0.001), and reduced LVPG (55 +/- 30 to 23 +/- 18 mmHg, P0.001), while CFVR remained unchanged in patients with HNCM (2.6 +/- 0.9 to 2.9 +/- 0.8, P not significant). Cibenzoline not only reduces LVPG but also improves CFVR in patients with HOCM. In addition left ventricular outflow obstruction plays an important role in impaired coronary circulation in patients with HOCM.

We report a case of a 61-year-old female patient who presented with palpitations. The baseline electrocardiogram showed incomplete right bundle branch block with saddle back pattern of the ST segment in one precordial lead, but without any significant ST elevation. She was treated with oral cibenzoline. The subsequent ECG showed a coved Brugada ECG (type 1) pattern, which resolved following the discontinuation of cibenzoline. An ajmaline test reproduced the coved type Brugada ECG pattern. Our case is the first report of oral cibenzoline therapy unmasking the diagnostic coved Brugada ECG pattern in a patient with a baseline normal ECG. Cibenzotine, a class I sodium channel blocker antiarrhythmic drug, should probably be avoided in the treatment of patients with Brugada syndrome. (c) 2005 The European Society of Cardiology. Published by Elsevier Ltd. All rights reserved.

Summary Objective: In general, drugs are used in accordance with an approved dosage regimen in expectation of an appropriate balance between efficacy and toxicity. However, dose control of drugs with a narrow therapeutic range and marked intersubject variability in pharmacokinetics should be established through individualization of dosing based on therapeutic drug monitoring (TDM). The purpose of this study was to examine differences between the approved dosage regimen and the doses of antiarrhythmic drugs and digoxin used in clinical practice and to examine the influence of TDM on dosing. Methods: Prescription research of antiarrhythmic drugs was performed at five national hospitals in Japan. Prescriptions for antiarrhythmic drugs (cibenzoline, disopyramide, pirmenol, mexiletine, aprindine, flecainide, pilsicainide, amiodarone and digoxin) were counted for the study period. The mean dose and dose distribution of the drugs were determined in each hospital. Comparisons were made of mean dose obtained in the study with the dosage approved by the authority. In addition, the percentage of patients that received TDM was determined. Results: A difference was seen between the approved dosage and the actual dose. For all drugs except flecainide, the mean dose was smaller than the approved dosage. For all drugs except digoxin, remarkable variations were seen in the dose distribution among the hospitals. Digoxin showed a similar dose distribution among the five hospitals. Overall, the percentage of patients that received TDM was low except for Hospital A. However, TDM of digoxin was relatively common at four of the hospitals. Conclusions: It is concluded that, with the exception of digoxin, the appropriate dosing regimen for antiarrhythmic drugs is not yet established. The establishment of appropriate dosing regimens for antiarrhythmic drugs requires the more widespread adoption of TDM.

An 83-year-old woman with hypertension was admitted to hospital with episodes of dyspnea on effort after having breakfast. Physical examination revealed a systolic murmur at the left sternal border in the third to fourth intercostal space. Cross-sectional echocardiography showed a sigmoid-shaped interventricular septum markedly protruding into the left ventricle, concentric left ventricular hypertrophy, systolic anterior motion of the mitral valve, and a resultant left ventricular outflow tract obstruction with a pressure gradient of 121.8 mmHg. She began daily treatment with 60 mg metoprolol. However, the chest symptoms were not relieved and the left ventricular outflow tract obstruction was still visible on echocardiography. She was then given 200 mg daily of cibenzoline, in addition to 40 mg metoprolol, and the left ventricular pressure gradient significantly decreased and she was free of symptoms without any complications. This case shows that cibenzoline may be useful in the treatment of left ventricular outflow tract obstruction caused by sigmoid septum. (Circ J 2004; 68: 968 - 971)

Introduction: During atrial fibrillation (AF), there is fractionation of extracellular potentials due to head-to-tail interaction and slow conduction of fibrillation waves. We hypothesized that slowing of the rate of AF by infusion of a Class I drug would increase the degree of organization of AF. Methods and Results: Seven goats were instrumented with 83 epicardial electrodes on the left atrium, left atrial appendage, Bachmann's bundle, right atrium, and right atrial appendage. AF was induced and maintained by an automatic atrial fibrillator. After AF had persisted for 4 weeks, the Class IC drug cibenzoline was infused at a rate of 0.1 mg/kg/min. AF cycle length (AFCL), the percentage of fractionated potentials, conduction velocity (CV), and direction of propagation of the fibrillation waves were measured during baseline, after AFCL was increased by 20, 40, 60, and 80 ms, and shortly before cardioversion. Infusion of cibenzoline increased the mean of the median AFCLs from 96 ± 6 ms to 207 ± 43 ms (P < 0.0001). The temporal variation in AFCL in different parts of the atria was 8% to 20% during control and, with the exception of Bachmann's bundle, was not significantly reduced during cibenzoline infusion. CV decreased from 76 ± 14 ms to 52 ± 9 cm/s (P < 0.01). Cibenzoline increased the percentage of single potentials from 81%± 4% to 91%± 4% (P < 0.01) and decreased the incidence of double potentials from 14%± 4% to 7 ± 5% (P < 0.01) and multiple potentials from 5%±% to 1%± 2% (P < 0.001). Whereas during control, linking (consecutive waves propagating in the same direction) during seven or more beats occurred in 9%± 15% of the cycles, after cibenzoline the degree of linking had increased to 40%± 33% (P < 0.05). During the last two beats before cardioversion, there was a sudden prolongation in AFCL from 209 ± 37 ms to 284 ± 92 ms (P < 0.01) and a strong reduction in fractionated potentials (from 22%± 12% to 6%± 5%, P < 0.05). Conclusion: The Class IC drug cibenzoline causes a decrease in fractionation of fibrillation electrograms and an increase in the degree of linking during AF. This supports the observation that Class I drugs widen the excitable gap during AF. (J Cardiovasc Electrophysiol, Vol. 15, pp. 572-580, May 2004)

Hypertrophic obstructive cardiomyopathy (HOCM), which shows left ventricular outflow pressure gradient (LVPG), is often complicated with mitral regurgitation (MR). We examined a 62-year-old Japanese female with HOCM and MR. Ultrasound echocardiography showed severe MR, asymmetrical septal hypertrophy, systolic anterior movement of the mitral valve anterior leaflet, and left ventricular outflow stenosis. Her LVPG, measured using continuous wave Doppler recording, was 118 mmHg. During heart catheterization, the aortic pressure and left ventricular pressure were simultaneously measured. An intravenous injection of 70 mg cibenzoline decreased the LVPG from 110 mmHg to 16 mmHg. Left ventriculography was performed immediately after the injection and did not show MR. This clearly demonstrates that cibenzoline decreases LVPG in patients with HOCM and also improves the MR that arises from LVPG.

A 29-year-old man was referred for electrophysiological testing and radiofrequency ablation because of repeated episodes of palpitation over 2 years. A 12-lead electrocardiogram during sinus rhythm showed manifest Wolff-Parkinson-White syndrome and during palpitation showed narrow QRS tachycardia at a rate of 213 beats/min. Following successful radiofrequency ablation of the left anterolateral accessory pathway, sustained atrial fibrillation was induced by atrial extrastimulation. Cibenzoline (2 mg/kg body weight) was injected to terminate atrial fibrillation. ST-T segment elevation in the right precordial leads was observed following cibenzoline administration. Ventricular fibrillation was reproducibly induced by ventricular extrastimuli (S1: 600 ms, S2: 220 ms, S3: 210 ms). (PACE 2004; 27:109–111)

Antiarrhythmic drugs have been considered to be transported by the organic cation transport system. The purpose of this study was to elucidate the molecular mechanism underlying the transport of antiarrhythmic drugs using cells from the second segment of the proximal tubule (S2) cells of mice expressing human-organic cation transporter 3 (S2 human-OCT3). The antiarrhythmic drugs tested were cibenzoline, disopyramide, lidocaine, mexiletine, phenytoin, pilsicanide, procainamide and quinidine. Human-OCT3 mediated a time- and dose-dependent uptake of quinidine and lidocaine, with Km values of 216 and 139 microM, respectively. Human-OCT3 also mediated the uptake of disopyramide and procainamide but not that of phenytoin. All antiarrhythmic drugs tested inhibited histamine uptake mediated by human-OCT3 in a dose-dependent manner. The IC50 values of antiarrhythmic drugs for human-OCT3 ranged between 0.75 and 656 microM. Kinetic analysis revealed that disopyramide, lidocaine, procainamide and quinidine inhibited histamine uptake mediated by human-OCT3 in a competitive manner. In conclusion, these results suggest that human-OCT3 mediates the transport of antiarrhythmic drugs, which may be the mechanism underlying the distribution and the elimination of these drugs.

A 67-year-old man was transferred to hospital because of acute circulatory failure resulting from sustained left ventricular tachycardia (LVT) and dysfunction. Transthoracic echocardiography revealed severely impaired left ventricular contraction and dyskinesis of the apical wall. Neither anti-arrhythmic agents nor direct current cardioversion was effective; the patient was resuscitated by immediate use of percutaneous cardiopulmonary support and intraaortic balloon counterpulsation. Ventricular contraction returned to normal following restoration of normal sinus rhythm with amiodarone and cibenzoline. The pathogenesis of LVT accompanied by transient ventricular dyskinesis is discussed with regard to the efficient use of a mechanical circulatory support system in resuscitation.

A Na(+)-channel blocker, cibenzoline, blocks the delayed rectifier potassium current ( I(k)), but its detailed action on the rapidly activating component ( I(kr)) of I(k) encoded by the human ether-a-go-go-related gene ( HERG) has not been clarified. We examined the effects of cibenzoline on stably expressed HERG current in HEK293 cells recorded by the patch-clamp technique of whole-cell configuration. Cibenzoline blocked HERG current expressed in HEK293 cells with IC(50) = 3.7 +/- 0.963 micro M and Hill coefficient = 0.74 +/- 0.12. Voltage-depended activation was shifted in a negative direction by cibenzoline. No block or minor block was induced at test depolarization of -40 to -30 mV, and the block increased with depolarization reaching a plateau at 0 mV without a further increase at positive voltages. Voltage-dependent activation of HERG currents became faster at negative test voltages but there were no changes at positive voltages after cibenzoline. No frequency-dependent block of HERG tail current by cibenzoline after equilibration was noted between 1.33 and 0.2 Hz. Steady-state inactivation of the HERG current was shifted in a negative direction by approximately 8 mV but the time constants of fast inactivation were little affected by cibenzoline. Cibenzoline blocks the I(kr)-like current reconstituted by HERG clone transfection with an IC(50) value comparable to therapeutic concentrations. Cibenzoline has a preferential affinity, at least, to the open state of the HERG channel with a rapid access to the binding site.

An increased spatial heterogeneity in refractory period duration is involved in the origin of ventricular arrhythmias. Spatial correlation and fractal analysis were introduced to describe the spatial order within epicardial maps of activation-recovery-intervals before and after application of antiarrhythmic drugs. Electrograms were simultaneously recorded with a 24/spl times/10 array of electrodes. Standard variability parameters as well as correlation and fractal dimension were computed. Disopyramide mainly prolonged the mean effective refractory period duration, accompanied by an increased variability. Contrarily, cibenzoline improved the spatial correlation strength of activation-recovery-intervals. The antiarrhythmic had a "smoothing" effect on activation-recovery-maps. The results imply that pharmacological treatment may influence the spatial organization of epicardial refractoriness.

Aims To ascertain if an electrophysiological study could predict long-term efficacy of anti-arrhythmic drugs in the treatment of lone atrial fibrillation. Methods and results Forty-four patients (36 males, 8 females, age 55·5±10·6) with paroxysmal atrial fibrillation were enroled to undergo serial electrophysiological studies at the bedside. Two quadripolar catheters were inserted via the subclavian vein. Disopyramide (D: 2 mg/kg iv), cibenzoline (C: 1·4 mg/kg iv), aprindine (A: 2 mg/kg iv), pilsicainide (P: 2 mg/kg po) and flecainide (F: 3 mg/kg po) were tested. Atrial fibrillation threshold (AFT) was measured as the lowest current amplitude of rapid pacing (50 Hz for 1 s) to induce atrial fibrillation lasting more than 30 s. Before drug treatment, AFT was 3·9±0·3 mA. Pharmacological treatment raised AFT as follows: D 5·9±0·9 mA, C 7·6±1·2 mA, A 8·1±1·1 mA, P 6·0±0·8 mA, F 7·3±1·1 mA. Recurrence of atrial fibrillation was observed during 1-year follow-up in 12% of cases when they were treated with a drug that raised AFT by 5 mA or more. On the other hand, the recurrence rate was 87% when patients were treated with a drug that raised AFT by less than 5 mA ( P =0·001). Conclusion AFT was a good predictor of long-term efficacy of pharmacological treatment against atrial fibrillation.

A 46 year-old man with hypertrophic obstructive cardiomyopathy (HOCM) was referred to this clinic complaining of shortness of breath. His symptoms remained even after he had been treated with bisoprolol, lisinopril, and verapamil. We started treating him with cibenzoline, instead of verapamil. Continuous-wave Doppler examination revealed a marked decrease from 95.9 mm Hg to 8.8 mmHg in the left ventricular outflow tract pressure gradient after administration of cibenzoline, and the symptom disappeared. The electrical axis of the electrocardiogram deviated from +53 to +95 degrees, and the QRS interval was increased from 0.095 to 0.114 seconds. By the M-mode echocardiogram, the interventricular septum was observed moved paradoxically in the early, systolic phase. We suggest the possibility that cibenzoline modifies intraventricular conduction and causes asynchronous contraction of the left ventricle, resulting in decrease in the left ventricular outflow tract pressure gradient.

Objective: The purpose of this study was to evaluate the efficacy of our therapeutic drug monitoring (TDM) services in cibenzoline therapy using the risk of hypoglycemia as an end point. Methods: The TDM services of cibenzoline were introduced in March 1998. If the serum concentrations of cibenzoline deviated from the therapeutic range, adjustment of dosage was recommended. In addition, the physicians were recommended to pay attention to the hypoglycemia induced by cibenzoline. A series of case-control studies were performed before and after introduction of TDM services. After introduction of TDM services of cibenzoline, four case-control studies were performed every 6 months between March 1998 and February 2000 (stage 2 between March 1998 and August 1998; stage 3 between September 1998 and February 1999; stage 4 between March 1999 and August 1999; stage 5 between September 1999 and February 2000) using the same method as in the previous study which had been performed between September 1997 and February 1998 (stage 1). The TDM data of inpatients and outpatients between March 1998 and February 2000 were reviewed. Results: A significantly increased risk of hypoglycemia was observed for users of cibenzoline during stage 1 [crude odds ratio (OR) 10.4; 95% confidence interval (CI) 2.7–40.3], stage 2 (crude OR 3.1; 95% CI 1.0–9.0), and stage 3 (crude OR 3.8; 95% CI 1.2–12.7). However, during stage 4 and stage 5, no significantly increased risk of hypoglycemia was observed. There was no significant difference between the mean doses during stage 1 and stage 5. However, there was a significant difference in the distributions of the trough levels among the four stages. During stage 4 and stage 5, the percentage of samples with a trough level of 200–400 ng/ml was higher than during stage 2 and stage 3. During stage 2, the percentage of samples with a trough level over 400 ng/ml was 42.9%. Furthermore, the risk of hypoglycemia associated with cibenzoline use decreased together with the increase in the percentage of outpatients whose serum concentrations of cibenzoline had been measured in the past. The risk of hypoglycemia associated with cibenzoline use decreased after introduction of TDM of cibenzoline. Conclusion: Dose adjustment based on TDM and the physicians' increased recognition of hypoglycemia associated with cibenzoline use were beneficial for those patients treated with cibenzoline in order to prevent hypoglycemia.

The aim of this study was to use fast Fourier transform analysis to clarify the characteristics of human atrial fibrillation (AF) waves with respect to the duration of AF and the effect of class I antiarrhythmic drugs. Twenty-two patients (10 paroxysmal AF, 12 persistent AF) without organic heart disease were studied by conventional electrophysiological methods. Electrograms were recorded from the right atrial free wall during AF and spectral analysis was performed for 35 s (16 consecutive 4096-ms epochs with 50% overlap) and the fibrillation cycle length (FCL) was calculated from the peak frequency. Mean FCL and SD were determined from 16-epoch data, and the temporal variability of FCL was defined as the SD of FCL. Paroxysmal AF had a longer mean FCL than persistent AF (178 ±26 ms vs 139±16 ms, p

Summary Background and objective Although there is concern that cibenzoline, an antidysrhythmic drug for the treatment of ventricular and supraventricular dysrhythmias, may be associated with dose-dependent inhibition of myocardial contractility there are few reports about the relationship between myocardial metabolism and cardiac function when it is used. The present study was designed to investigate the effects of cibenzoline on cardiac function and metabolism. The effects of cibenzoline on cardiac function and myocardial metabolism were assessed in the isolated rat heart–lung preparation. Methods Thirty-two male Wistar-ST rats were divided into four groups: control, and those to receive cibenzoline, either 300, 900 or 3000 ng mL−1. The cibenzoline was administered into the perfusate 5 min after the start of perfusion. Heart rates in the 3000 ng mL−1 group were significantly lower than those in the control group. Cardiac output in the 3000 ng mL−1 group at 15 and 30 min was significantly lower than in the control group. In all groups, values for %LV dP/dt max (the ratio of values at each time to those at 5 min) at 20, 25, 30 min were significantly higher than at 5 min. Myocardial adenosine triphosphate concentration in the 3000 ng mL−1 group was significantly lower than in controls. There was no difference between groups in the lactate/pyruvate ratio. Conclusion The therapeutic range of cibenzoline has few effects on cardiac function and metabolism, although concentrations 10 times greater may cause a deterioration in myocardial metabolism.

We cared for a patient with progressive renal impairment who presented with blurred vision, QRS broadening and cardiac failure due to chronic cibenzoline intoxication. Treatment consisted of catecholamines and repetitive infusions of Ringer lactate. Cardiac function and symptoms recovered completely.

Modulation by class Ia antiarrhythmic drugs, cibenzoline and disopyramide, of the pacemaking activity and the underlying ionic currents in rat sino-atrial nodal cells was investigated using current-clamp and whole-cell patch-clamp techniques. Both drugs depressed the spontaneous activity and often caused sinus arrest. The negative chronotropic effect was significant at 10 microM cibenzoline and 30 microM disopyramide. The L-type Ca(2+) current (I(Ca)) and the hyperpolarization-activated inward current decreased by 69.7+/-3.2% and by 45.8+/-3.0% at 30 microM cibenzoline and by 51. 2+/-3.3% and by 48.3+/-2.7% at 100 microM disopyramide, respectively. The delayed rectifier K(+) current, which is composed of rapidly and slowly activated currents (I(Kr) and I(Ks)), also decreased. The IC(50) values of I(Kr) for cibenzoline and disopyramide were 8.8+/-1. 1 and 25.1+/-2.3 microM, respectively. In the presence of 5 microM E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonylaminobenzoyl) piperidine), the IC(50) values of I(Ks) for cibenzoline and disopyramide were 12.3+/-1.8 and 81.1+/-2.3 microM, respectively. The I(Ks) was completely blocked by 30 microM 293B (trans-6-cyano-4-(N-ethylsulphonyl-N-methtamino)-3-hydroxy-2 , 2-dimethyl-chromane). These results indicate that the ionic currents are more sensitive to cibenzoline than disopyramide in rat sino-atrial nodal cells, and that I(Ca) and I(Kr) make major contributions to pacemaking activity.

We investigated the effects of class I antiarrhythmic drugs on corrected QT (QTc) interval and adrenaline-induced arrhythmias in halothane-anaesthetized, closed-chest dogs. For this purpose, we plotted a dose–response curve for adrenaline by calculating the arrhythmic ratio, which is the number of ventricular ectopic beats induced by adrenaline divided by the total heart rate, and observed the changes in the arrhythmic ratio–adrenaline dose relation before and after administration of class I drugs. Disopyramide and cibenzoline decreased the arrhythmic ratio induced by adrenaline. Disopyramide prolonged the QTc interval by 20% (P

Because most anti-arrhythmic drugs are eliminated from the kidney, anti-arrhythmic drug therapy is largely restricted in patients undergoing hemodialysis (HD). Cibenzoline is a widely used antiarrhythmic drug excreted mainly from the kidney. The present study evaluated the safety and efficacy of reduced doses of cibenzoline (25 and 50 mg/day chronically) in 8 patients with maintenance HD. Cibenzoline was administered for more than 3 months without any problems in 7 of the 8 patients, although the medication was discontinued in 1 patient due to nausea and anorexia. With cibenzoline administration, the incidence and duration of atrial fibrillation decreased or disappeared in 6 of 7 patients and the frequency of complex ventricular arrhythmias was also reduced in 3 of 4 patients. No adverse side effects were noted. Plasma concentration of cibenzoline ranged from 169 to 220 ng/ml with the 25-mg/day dosage, and from 408 to 500 ng/ml with the 50-mg/day dosage. The concentrations remained stable during the study. In conclusion, low doses of cibenzoline are safe and effective in patients undergoing maintenance HD. However, intermittent monitoring is essential to ensure therapeutic drug concentrations.

The present study was designed to assess the negative chronotropic and inotropic effects of 10 class I antiarrhythmic drugs, using isolated canine blood-perfused sinoatrial node and papillary muscle preparations. Each drug showed negative chronotropic and inotropic effects in a dose-related manner. The potency of the suppressive effect on the sinoatrial automaticity was in the order of aprindine, quinidine, flecainide, lidocaine, mexiletine, cibenzoline, disopyramide, procainamide, tocainide, and phenytoin, while the effect on the ventricular contraction was in the order of aprindine, flecainide, cibenzoline, lidocaine, mexiletine, disopyramide, tocainide, phenytoin, quinidine, and procainamide. The differences in the suppressive effects could not necessarily be explained by their subclassification, based either on action potential duration or kinetic properties of dissociation or association with sodium channels. On the other hand, we found a good correlation between the negative inotropic effects of class I drugs in this study and the canine antiarrhythmic plasma concentrations for the digitalis- and coronary ligation-induced ventricular arrhythmia models in our previous studies. However, the negative chronotropic effects of the drugs showed a poor correlation with the antiarrhythmic plasma drug concentrations. The data shown in this paper may provide a convenient guideline for predicting acute cardiosuppressive effects of antiarrhythmic drugs, especially in patients with reduced cardiac function.

A clinically available racemic mixture of the optical isomers of cibenzoline possesses a potent sodium channel-blocking action in addition to the moderate calcium channel-blocking action. It has been reported that the S(-)-isomer inhibits sodium channels more potently than calcium channels, whereas the R(+)-isomer suppresses the sodium channels as well as calcium channels, and that the calcium channel-blocking potency of these isomers is similar. This study was designed to assess the effects of each optical isomer of cibenzoline on ventricular contraction, coronary blood flow, and sinus node automaticity by using the canine isolated, blood-perfused papillary muscle and sinoatrial node preparations. Each isomer showed negative inotropic and chronotropic effects as well as coronary vasodilator action in a dose-dependent manner. The negative inotropic effect of S(-)-cibenzoline was 1.8 times more potent than that of R(+)-cibenzoline, whereas there was no significant difference between the isomers in the negative chronotropic and coronary vasodilator effects. These results suggest that the difference of the inotropic effects between the optical isomers of cibenzoline is mainly derived from the extent of the sodium channel-blocking action, whereas the vasodilator and negative chronotropic effects may chiefly depend on the calcium channel inhibition.

The binding characteristics of the class 1 antiarrhythmic agents, cibenzoline, disopyramide, disopyramide metabolite (the main active metabolite of disopyramide in humans), and pirmenol, for human muscarinic receptors (m1-m3) stably expressed in Chinese hamster ovary cells (CHO) were investigated by binding assay with [3H]N-methylscopolamine ([3H]NMS) as a ligand. All of these agents inhibited the specific [3H]NMS binding to membrane preparations in a concentration-dependent manner. The potencies of affinity of these agents for m1, m2, and m3 receptors (compared by IC50) were disopyramide > pirmenol > disopyramide metabolite > cibenzoline, pirmenol > cibenzoline > disopyramide > disopyramide metabolite, and disopyramide > disopyramide metabolite > pirmenol > cibenzoline, respectively. Some competition curves of cibenzoline, disopyramide, and pirmenol were shallow, and Hill coefficients of these curves differed from unity, suggesting that these agents have allosteric binding characteristics for human muscarinic receptors. The m2-selective ratios to m1 (IC50 m1/IC50 m2) and m3 (IC50 m3/IC50 m2) of cibenzoline were 4.0 and 16, and those of pirmenol were 6.5 and 43, respectively, whereas those of disopyramide and its metabolite ranged from 0.46 to 1.6, suggesting that cibenzoline and pirmenol exerted high selectivity to the m2 receptor. We conclude that (a) all class 1 antiarrhythmic agents in this study have inhibitory effects on human m1, m2, and m3 receptors, and some of those binding may show allosteric characterization; (b) disopyramide and its metabolite have similar affinity to m1 to m3 receptors; and (c) cibenzoline and pirmenol have high m2-selective ratios to m1 and m3.

To the Editor: We read with interest the paper of Hamada et al.1 They used M-mode and Doppler echocardiography in patients with hypertrophic obstructive cardiomyopathy (HOCM) to show that the antiarrhythmic drug cibenzoline, in addition to reducing left ventricular (LV) systolic pressure gradient and LV contractility, also altered the LV diastolic filling profile. Two hours after oral administration of 150 mg of the drug, E-wave velocity increased insignificantly (from 79 to 83 cm/s) and A-wave velocity decreased significantly (from 82 to 55 cm/s), with a significant increase of the E/A ratio (from 1.2 to 2.0).1 Furthermore, prolongation of isovolumic relaxation time (LV-IVRT) from 73 to 101 ms was noticed. The authors interpreted their findings as the result of a decrease in both left atrial (LA) and LV diastolic pressures.1 Data on deceleration time of early mitral inflow or on other Doppler indexes of LV filling, such as pulmonary venous flow velocities, were not given, and hemodynamic studies were not performed. Despite these shortcomings and considering the limitations of Doppler echocardiography in these patients,2 we would …

A 57-year-old woman was admitted for examination because of chest discomfort. Transthoracic echocardiography was performed and she was diagnosed as having hypertrophic cardiomyopathy. An echocardiogram also revealed that she had midventricular obstruction with a pressure gradient of 125 mmHg determined by Doppler echocardiography. A phonocardiogram showed an early systolic sound and the beginning of the sound coincided with the time of septal-posterior wall contact. In addition, the timing also corresponded to the sudden obstruction of blood flow in the region of the midventricular narrowing. Furthermore, this sound markedly decreased with the reduction in pressure gradient caused by cibenzoline treatment. Thus, it was concluded that the early systolic sound was associated with midventricular obstruction and produced by a rapid deceleration of the interventricular flow caused by midventricular obstruction.

The effects of various class I antiarrhythmic drugs and glibenclamide were examined on the recovery of contraction during reperfusion, in relation to the action potential duration (APD) seen during ischemia. Action potential and contractile tension were recorded from isolated guinea pig right ventricular muscles perfused with oxygenated Tyrode solution via the coronary artery. Ten minutes of no-flow ischemia shortened the APD at 90% of repolarization level (APD90) to 58% of control (pre-ischemic values). The APD90 was completely restored after 60 min of reperfusion. The developed tension was abolished during ischemia and recovered to 87% of control after 60 min of reperfusion. In the presence of Vaughan Williams class Ia drug cibenzoline (5 microM) or an ATP-sensitive potassium (K(ATP)) channel blocker glibenclamide (10 microM), the shortening of the APD90 during ischemia was significantly attenuated. However, the recovery of developed tension was significantly inhibited. Class Ic drug pilsicainide (10 microM) did not affect the ischemia-induced shortening of the APD90 or the recovery of developed tension after reperfusion. In the presence of class Ib drug mexiletine (10 microM), the shortening of the APD90 during ischemia was significantly facilitated. The recovery of developed tension in the presence of mexiletine tended to be improved, although the difference was not statistically significant. The developed tension measured after the 60 min reperfusion period following 20 min of no-flow ischemia was markedly depressed, indicating the presence of myocardial stunning. Mexiletine and pilsicainide significantly improved the recovery of developed tension and diminished the stunning. We conclude that cibenzoline and glibenclamide, which block cardiac K(ATP) channels inhibit contractile recovery after reperfusion by attenuating the shortening of APD during ischemia. In contrast, mexiletine, which activates K(ATP) channels (in addition to blockade of Na+ channels) improves contractile recovery by facilitating the shortening of APD during ischemia.

Differential Drug Effects on Anisotropic Conduction. Introduction:Anisotropic conduction characteristics, expressed as the ratio of conduction velocities in the longitudinal (Vl) and transverse (Vt) fiber directions, may play a role in the mechanism of some ventricular tachycardias and is influenced by pharmacologic interventions. Discrepancies exist among the reported orientation-dependent effects of available Class I antiarrhythmic drugs. The aim of this study was to assess the respective effects of quinidine (Class IA), flecainide (Class IC), and cibenzoline (not subclassifled) on the anisotropic conduction of porcine hearts, in corroboration of their effects on ventricular action potentials. Methods and Results: We studied the actions of 3 and 10 μM quinidine, 1 and 3 μM flecainide, and 0.3 and 1 μM cibenzoline on Vl and Vt determined from 128 electrograms recorded with a plaque electrode on the anterior left ventricle of isolated perfused hearts (spacing 2.5 mm). Vl and Vt were computed from isochronal maps displaying ellipsoid activation during stimulation from the center of the plaque. The effects on the maximal rate of depolarization (V˙max) of action potentials were obtained from ventricular muscle exposed to the same drugs. Flecainide [1 μM] and cibenzoline [0.3 μM] did not alter Vl, and Vt, significantly. Quinidine [3 μM] predominantly depressed Vl at rapid pacing rates, hut the Vl/Vt ratio was not significantly altered. Quinidine [10 μM] and flecainlde [3 μM] reduced Vl and Vt in a frequency dependent fashion. Conversely, cibenzoline [1 μM] mostly decreased Vl and thus decreased the Vl/Vt ratio and increased the Vl/Vt at all pacing rates. This different effect was not related to a greater depressant effect on V˙max. Conclusion: Quinidine and flecainide act similarly on the anisotropic pattern of conduction (both drugs increase the Vl/Vt ratio), whereas cibenzoline exerts opposite effects. Orientation dependent effects are different among Class I antiarrhythmic drugs and may be of importance in their therapeutic efficacy or proarrhythmic potential.

Background The class Ia antiarrhythmic drug disopyramide relieves the outflow tract obstruction of hypertrophic obstructive cardiomyopathy (HOCM). Disopyramide, however, has several adverse effects, such as dysuria and thirst, resulting from its anticholinergic activity. A new class Ia antiarrhythmic drug, cibenzoline, has little anticholinergic activity. The aim of this study is to elucidate whether cibenzoline attenuates left ventricular pressure gradient (LVPG) in patients with HOCM. Methods and Results Ten patients with HOCM (mean age, 59±12 years) participated in this study. LVPG and left ventricular functions were measured before and 2 hours after administration of a single oral dose of 150 or 200 mg cibenzoline. LVPG decreased from 123±60 to 39±33 mm Hg ( P =.0026). The E/A ratio in transmitral Doppler flow increased from 1.20±0.84 to 2.00±1.72 ( P =.029). Isovolumic relaxation time increased from 73±16 to 101±23 ms ( P =.0026). Left ventricular diastolic dimension remained unchanged, but left ventricular systolic dimension enlarged significantly, from 21.6±2.4 to 26.2±3.3 mm ( P =.0004). Fractional shortening decreased from 47.6±6.1% to 34.6±8.8% ( P =.0007). Left ventricular ejection time index decreased significantly, and preejection period index increased in all the patients. Decreased LVPG remained maintained even in the long-term treatment with cibenzoline. Conclusions These results indicate that cibenzoline can markedly attenuate LVPG in patients with HOCM. A decrease in myocardial contractility seems to be closely related to a marked decrease in LVPG.

Cibenzoline is a class Ic antiarrhythmic agent that can be used to treat supraventricular arrhythmias. A case is reported of cibenzoline overdose in a patient with impaired renal function, leading not only to the usual cardiac and metabolic symptoms (bradycardia and hypoglycaemia), but also to a myastheniform syndrome with acute respiratory failure. Neuromuscular blockade was demonstrated by repetitive supramaximal stimulation of the median nerve, and diaphragmatic involvement was evidenced by applying the same protocol to the phrenic nerve. Muscle strength recovered as serum cibenzoline levels decreased, allowing the patient to be weaned from the ventilator. This observation suggests that cibenzoline, like other antiarrhythmic agents, can be responsible for neuromuscular blockade, and should therefore be used with caution in patients with neuromuscular and respiratory diseases or with impaired renal function.