Search

Key Clinical Message: An 86‐year‐old geriatric patient with sepsis presented cibenzoline‐induced hypoglycaemia, although within the boundary range of cibenzoline blood concentration. An 86‐year‐old geriatric patient taking cibenzoline for ametropic hypertrophic cardiac tendinopathy was admitted to our hospital for the treatment of sepsis. Upon admission, blood cibenzoline levels of 400.1 ng/mL were observed. Antibiotic therapy was initiated and cibenzoline was discontinued. On Day 16, cibenzoline was administered orally at a reduced dose of 50 mg/day. Several days after restarting cibenzoline, the patient developed hypoglycaemia (64 mg/dL), prompting the administration of 20% glucose. The present case demonstrates a rational timeline for cibenzoline administration, considering the patient's renal dysfunction and sepsis. Clinicians should exercise caution when managing older patients with severe infections who are receiving cibenzoline, and should consider the possibility of blood glucose fluctuations regardless of cibenzoline blood levels. Further research is warranted to better understand and address the potential side effects of cibenzoline administration in geriatric populations. [ABSTRACT FROM AUTHOR]

Cibenzoline succinate is a renal-excretion type antiarrhythmic medication. There have been few reports on prescribing of cibenzoline succinate to elderly patients, whose renal function is expected to decline. Therefore, we estimated creatinine clearance based on body weight and serum creatinine levels by age group as reported in the “National Health and Nutrition Investigation in 2019” by the Ministry of Health, Labour and Welfare, and compared cibenzoline upper limit doses accordingly with optimal cibenzoline prescriptions in the processed receipt data of insurance pharmacies. We also investigated the occurrence of dose reduction over time in patients whose initial cibenzoline dose exceeded the upper limit. The study indicates that some patients over 75 years old may have exceeded the upper dose limit for age-related decline in Ccr. Patients who exceeded their initial cibenzoline dose were significantly more likely to experience subsequent dose reductions. As such, pharmacy pharmacists should check the renal function of patients and optimize cibenzoline doses accordingly. [ABSTRACT FROM AUTHOR]

Key Clinical Message An 86‐year‐old geriatric patient with sepsis presented cibenzoline‐induced hypoglycaemia, although within the boundary range of cibenzoline blood concentration. Abstract An 86‐year‐old geriatric patient taking cibenzoline for ametropic hypertrophic cardiac tendinopathy was admitted to our hospital for the treatment of sepsis. Upon admission, blood cibenzoline levels of 400.1 ng/mL were observed. Antibiotic therapy was initiated and cibenzoline was discontinued. On Day 16, cibenzoline was administered orally at a reduced dose of 50 mg/day. Several days after restarting cibenzoline, the patient developed hypoglycaemia (64 mg/dL), prompting the administration of 20% glucose. The present case demonstrates a rational timeline for cibenzoline administration, considering the patient's renal dysfunction and sepsis. Clinicians should exercise caution when managing older patients with severe infections who are receiving cibenzoline, and should consider the possibility of blood glucose fluctuations regardless of cibenzoline blood levels. Further research is warranted to better understand and address the potential side effects of cibenzoline administration in geriatric populations.

A 13-year-old girl was referred for closer examination of electrocardiographic abnormalities. She had a Levine 2/6 systolic murmur (SM) and a fourth heart sound. Electrocardiography findings showed poor R progression from V1 to V4 and negative T waves in the II, III, and aVF leads. Approximately 3.2 years later, her SM increased to Levine 3–4/6. Echocardiography indicated mitral regurgitation and left ventricular pressure gradient (LVPG) of 18.5 mmHg, together with a notch on the systolic wave in the apexcardiogram. We concluded that the electrocardiographic abnormalities were caused by hypertrophic cardiomyopathy. Approximately 6 months later, her SM further increased to Levine 4–5/6, and the voltage on the electrocardiogram increased. In carotid pulse tracing, steep upstroke and deflated percussion wave due to mitral regurgitation were noted. The LVPG was approximately 102 mmHg, and systolic anterior movement was confirmed. After the oral administration of 200 mg of cibenzoline, the LVPG decreased to approximately 48 mmHg. Subsequently, 300 mg/day of cibenzoline was administered. The LVPG further decreased, and her symptoms improved. Clinical symptoms and left ventricular pressure gradient decrease can be ameliorated by cibenzoline therapy in patients with hypertrophic obstructive cardiomyopathy. This finding applies not only to adult patients but also to teen-aged patients. [ABSTRACT FROM AUTHOR]

Background Beta-blockers and Class 1A antiarrhythmics decrease the subaortic pressure gradient in hypertrophic obstructive cardiomyopathy. However, real-time monitoring of the pressure gradient transition during intravenous therapy, based on cardiac catheterization, has never been reported. Case summary A 52-year-old man, with an history of hypertension, was transferred to our hospital, complaining of angina. A 12-lead electrocardiogram showed diffuse ST-segment depression, and transthoracic echocardiography revealed a thickened left ventricular outflow tract (LVOT) septum, resulting in LVOT obstruction which had never been diagnosed. Besides, severe mitral regurgitation (MR) due to systolic anterior motion was detected. Emergent cardiac catheterization revealed normal coronary arteries and severe MR. Simultaneous pressure measurements were taken at the ascending aorta (using a coronary catheter) and left ventricle (using a pressure wire). The subaortic systolic pressure gradient was 147 mmHg: 251 mmHg in the left ventricle and 104 mmHg in the aorta. Intravenous cibenzoline, following propranolol, was administered to ameliorate the pressure gradient, following which his chest pain disappeared immediately; the pressure gradient decreased to 13 mmHg. Further, severe MR was diminished. Oral bisoprolol and cibenzoline administration effectively stabilized his condition after catheterization. Discussion Monitoring the simultaneous pressure between the left ventricle and aorta with a pressure wire revealed drastic improvement in the subaortic systolic pressure gradient. Owing to the soft, fine structure, the pressure wire allowed recording of the subaortic pressure gradient stably with less frequent premature ventricular contractions. Furthermore, this method could decrease the burden of catheter-related complications by eliminating the need for multiple atrial punctures. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to test regional pharmacological effects of an antiarrhythmic agents to predict ablative effects. Background: The vein of Marshall (VOM) providing vascular access to myocardial tissue has been used for ablative purposes using ethanol. Methods: A total of 35 patients (male 21, 63.2 ± 7.8 years old) were included. A balloon‐tipped infusion catheter was inserted into the VOM. Endocardial ultrahigh‐resolution mapping was performed along the VOM region to record the change in atrial electrograms (AEs) after VOM injection of cibenzoline of 3.5 mg during sustained atrial fibrillation (AF). Subsequently, ethanol was infused into the VOM and ablative region was mapped. Results: In 17 patients (49 %), cibenzoline reduced AEs amplitude by >50%, all of which had also complete elimination of AEs following ethanol (Group A). In 18 patients (Group B), cibenzoline failed to eliminate AEs; yet, in 13 of 18 AEs were eliminated by ethanol. In the remaining five patients, ethanol did not eliminate AE. Conclusions: Cibenzoline into the VOM could reliably predicts the results of subsequent ethanol infusion into the VOM using ultrahigh‐resolution mapping system, which leads to avoid unnecessary permanent lesion creation by ethanol infusion. [ABSTRACT FROM AUTHOR]

RASopathies - caused by mutations in the RAS/MAPK signaling pathway - are frequently associated with cardiac diseases, such as hypertrophic obstructive cardiomyopathy. Although cibenzoline is useful for adult hypertrophic obstructive cardiomyopathy patients, little is known about its effect in children. Here, we report two paediatric cases of hypertrophic obstructive cardiomyopathy associated with RASopathies where the condition was improved by cibenzoline.

We reviewed the natural history of patients with hypertrophic cardiomyopathy (HCM). The effect of medical treatments on natural history, left ventricular (LV) functions and LV remodeling was also evaluated. Sudden cardiac death and end-stage heart failure are the most serious complications of HCM. Age <30 years and a family history of sudden premature death are risk factors for sudden cardiac death in HCM patients. End-stage heart failure is not a specific additional phenomenon observed in patients with HCM, but is the natural course of the disease in most of those patients. After the occurrence of heart failure, the progression to cardiac death is very rapid. Young age at diagnosis, a family history of HCM, and greater wall thickness are associated with a greater likelihood of developing end-stage heart failure. Neither beta-blockers nor calcium antagonists can prevent this transition. The class la antiarrhythmic drugs, disopyramide and cibenzoline are useful for the reduction of LV pressure gradient. Unlike disopyramide, cibenzoline has little anticholinergic activity; therefore, this drug can be easily adapted to long-term use. In addition to the reduction in LV pressure gradient, cibenzoline can improve LV diastolic dysfunction, and induce regression of LV hypertrophy in patients with HCM. A decrease in intracellular Ca2+ concentration through the activation of the Na+/Ca2+ exchanger associated with cibenzoline therapy is likely to be closely related with the improvement in HCM-related disorders. It is possible that cibenzoline can prevent the progression from typical HCM to end-stage heart failure [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Background: Cibenzoline (CBZ), a class I antiarrhythmic drug, has been widely used to maintain sinus rhythm in patients with paroxysmal atrial fibrillation (P-AF). This agent has an anticholinergic action and will become the drug of first choice for vagally mediated P-AF. We assessed its efficacy quantitatively by analyzing the frequency-domain heart rate variability (FD-HRV) of the Holter electrocardiogram (ECG) in patients with vagal P-AF. Methods: We enrolled 65 consecutive patients with vagal P-AF, but 31 patients were excluded because of the occurrence of significant arrhythmias during the 24-h Holter recordings. Accordingly, CBZ was administered to the remaining 34 patients. After administration, a Holter ECG recording was made again. High frequency (HF) components, i.e., vagal tone index, on the FD-HRV analysis from 00:00h to 06:00h were used for assessment. In 14 patients, the treatment was changed to disopyramide (DSP) and the same analyses were performed. Results: In two patients, the FD-HRV analysis was not utilized after administration. Finally, 32 patients were available for evaluation. CBZ was considered effective for vagal P-AF in 24 patients (75%). After administration, the HF component levels decreased (1589±795ms2 vs. 850±524ms2, p <0.0001). Comparison of the pre-administration HF component levels between the CBZ-responsive group and the CBZ-non-responsive group showed higher levels in the CBZ-responsive group (1766±758ms2 vs. 1058±690ms2, p =0.026). Although no significant difference in the reduction of the HF component levels was found between CBZ and DSP, DSP had anticholinergic side effects in two patients (14%). Conclusions: In vagal P-AF patients, larger HF components on the FD-HRV analysis could be a hallmark of the antiarrhythmic action of CBZ. The reduction in the HF component levels after drug administration is useful for a quantitative assessment of anticholinergic action. [Copyright &y& Elsevier]

Summary: Methods and results: This study included 68 patients (47 men, 21 women, mean age 69 years) in whom atrial fibrillation (AF) recurred immediately after electrical cardioversion (EC) was performed with no antiarrhythmic drugs. After administration of cibenzoline (Cib, 70mg) or pilsicainide (Pil, 50mg) on a randomized basis, all patients again underwent EC at the same energy as that prior to administration of antiarrhythmic drugs. We compared the efficacy of Cib (n =35) and Pil (n =33), and examined factors affecting successful cardioversion in patients treated with Cib. These patients were divided into a successful group (Group A) and an unsuccessful group (Group B). The success rate of EC at the same energy after intravenous Cib administration (77%) was significantly greater than that after intravenous Pil administration (42%) (p <0.01). In patients treated with Cib, AF duration was significantly greater in Group B (55.8±48.2h) than in Group A (29.1±17.0h) (p <0.05). Plasma concentrations of atrial natriuretic peptide (ANP) during AF and the ratio of ANP level during AF to that during sinus rhythm were also significantly greater in Group A (110.9±69.7pg/ml and 3.9±2.8, respectively) than in Group B (58.2±36.1pg/ml and 1.8±0.9, respectively) (both, p <0.05). In patients treated with Pil, AF duration was also significantly greater in Group B (59.7±44.6h) than in Group A (19.6±21.7h) (p <0.05), and the ratio of ANP level during AF to that during sinus rhythm was significantly greater in Group A (3.5±2.6) than in Group B (1.7±0.9) (p <0.05). Conclusions: In patients with AF previously refractory to conventional EC, intravenous Cib administration was more effective in restoring sinus rhythm with EC than intravenous Pil administration. The capacity of ANP secretion during AF tachycardia may be a predictive indicator for the prevention of AF recurrence in electrically remodeled atria. [Copyright &y& Elsevier]

Synthesis of (±)-cibenzoline and its analogs has been achieved by a simple sequence of reactions. The diaryl cyanoolefin intermediate 3 could be prepared by Knoevenagel condensation of benzophenone with ethylcyanoacetate to form the tetra-substituted olefin intermediate 2 followed by Krapcho deethoxycarbonylation or from β-hydroxynitrile intermediate 2' followed by the elimination of hydroxyl group respectively. The 2,2-diphenylcyclopropanecarbonitrile 4 was synthesized from intermediate 3 by cyclopropanation, which was converted to (±)-2-(2,2-diphenylcyclopropyl)-2-imidazoline 5 by reaction with ethylenediamine in the presence of a catalytic amount of sulfur. Moreover, the obtained 2-imidazolines were smoothly oxidized to the corresponding imidazoles 6 in good to moderate yields. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective The objective of the present study was to investigate the effectiveness of postoperative oral administration of cibenzoline for the prevention of atrial fibrillation (AF) in coronary artery bypass grafting (CABG). Methods: A total of 39 patients who underwent isolated CABG from September 2000 to February 2001 and who took oral cibenzoline (300 mg per day for 10 days beginning immediately after surgery) were compared to 59 patients who underwent surgery in our department 8 months prior to the study and who did not take cibenzoline for incidence of postoperative AF. Exclusion criteria encompassed age (>80 years), low ejection fraction (<30%), high serum creatinine level (>2.0 mg/dL), and history of supraventricular arrhythmia with or without treatment by anti-arrhythmic drugs. Results: Postoperative AF occurred in 2 patients in the cibenzoline group (2/35, 5.7%) and 20 patients in the control group (20/59, 33.9%). There were significant differences in the incidence of postoperative AF ( p=0.002). Multivariate analysis revealed that the administration of cibenzoline reduced the incidence of AF significantly, and that a large number of bypass grafts significantly contributed to postoperative AF in CABG. The number of bypass grafts was significantly larger in the cibenzoline group, indicating that cibenzoline administration significantly suppresses the incidence of AF after CABG in high-risk patients. Conclusions: Postoperative administration of oral cibenzoline for 10 days is one effective method for the prevention of AF after CABG. [ABSTRACT FROM AUTHOR]

Introduction: The aim of this study was to investigate the usefulness of the autocorrelation function (reversed fast Fourier transform analysis) in determining the atrial fibrillation cycle length (AFCL) during human atrial fibrillation (AF). Methods and Results: From 30 episodes of atrial electrograms recorded for 30 seconds from the high right atrium during type I AF in 16 patients, the mean, 5th percentile (p5), and 95th percentile (p95) of the AFCLs were measured by using a computer-picked activation time. The peak, minimum, and maximum AFCLs also were measured by using the autocorrelation function. The mean AFCL was retrieved at the point of the maximum peak of the coefficient of the first positive autocorrelogram. The minimum AFCL (min AFCL) was chosen as the point where the first positive autocorrelogram crossed the baseline from negative to positive, and the maximum AFCL (max AFCL) was chosen as the point where the first positive autocorrelogram crossed the baseline from positive to negative. There was a significantly strong correlation between the mean and peak AFCLs (r = 0.995, P < 0.0001), p5 and min AFCLs (r = 0.953, P < 0.0001), and p95 and max AFCLs (r = 0.98, P < 0.0001). Conclusion: The autocorrelation function was useful in determining the AFCLs, at least during type I AF. The min AFCL may be used as an index of the refractory period during AF when the p5 AFCL approximates the refractory period. (J Cardiovasc Electrophysiol, Vol. 14, pp. 965-970, September 2003) [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

We aimed to investigate whether the improvement of left ventricular (LV) diastolic function by cibenzoline, a class Ia antiarrhythmic drug, in hypertrophic obstructive cardiomyopathy (HOCM) is due to LV afterload reduction or a primary lusitropic effect on LV. Twenty-three patients with hypertrophic cardiomyopathy (11; HOCM, 12; non-obstructive HCM; HNCM) were examined. Pulsed-wave Doppler, color M-mode and tissue Doppler echocardiography were performed before and 90 minutes after oral administration of cibenzoline (300 mg), and were compared with a treatment of bisoprolol (5 mg/day, 10 days). Early (E) and late diastolic LV inflow velocity, E flow propagation velocity (FPV) and early diastolic mitral annulus velocity (Ea) were measured. E/FPV and E/Ea were calculated as indices of LV filling pressure. LV outflow pressure gradients estimated using continuous-wave Doppler in HOCM markedly decreased after cibenzoline (83 ± 42 to 40 ± 33 mmHg, p < 0.005) and bisoprolol (44 ± 40 mmHg, p < 0.005). Following cibenzoline, E/FPV and E/Ea were significantly decreased in both HOCM (1.75 ± 0.53 to 1.32 ± 0.28, p < 0.05, 18.9 ± 6.2 to 14.8 ± 5.0, p < 0.05, respectively) and HNCM (1.75 ± 0.58 to 1.41 ± 0.73, p < 0.05, 13.0 ± 4.3 to 9.7 ± 3.6, p < 0.01, respectively). Those in HNCM did not change by bisoprolol. Cibenzoline improved LV diastolic function in HCM, whereas bisoprolol did not affect it. Thus, the primary lusitropic effect of cibenzoline rather than LV after load reduction might have contributed to the improvement of diastolic function in HOCM. [ABSTRACT FROM AUTHOR]

While some antiarrhythmic agents have potential hypoglycemic effects and indeed some reports of hypoglycemic adverse effect of those drugs, no systematic reports have been issued. We studied the hypoglycemic effects of cibenzoline, a class I antiarrhythmic agent. Cibenzoline succinate (150–300 mg/day) was given orally for 12 weeks to 10 patients who had ventricular premature complexes (VPCs) of <1000 per 24 hours and abnormal glucose tolerance before treatment with cibenzoline. Abnormal glucose tolerance, judged by a 75-g oral glucose tolerance test (OGTT), was defined as the response designated as “diabetic” or “borderline” type according to the criteria specified by the Japan Diabetes Society. In OGTT, the insulinogenic index (defined as the ratio of the increment of IRI [immunoreactive insulin] to that of plasma glucose at 30 minutes after a glucose load) and the sum of IRI (ΣIRI) were also determined. Holter ECG recordings, OGTT, and measurements of fasting plasma glucose IRI, and HbA1 were performed before and during cibenzoline treatment. Cibenzoline caused VPC reduction of < 70% in 6 of the 10 patients. The drug significantly decreased fasting plasma glucose and HbAc (mean ± SD) 12 weeks after treatment, from 6.18 ± 0.92 mM/L to 5.54 ± 1.08 mM/L and from 6.17 ± 1.03% to 5.83 ± 0.96%, respectively ( P < 0.05). While it significantly increased fasting IRI from 4.99 ± 1.50 to 6.51 ± 1.47 μU/mL ( P < 0.01), the insulinogenic index from 0.33 ± 0.26 to 0.65 ± 0.38 ( P < 0.05), and ∑ IRI from 168 ± 67 μU/mL to 199 ± 46 ( P < 0.05). Cibenzoline exerted a hypoglycemic effect, facilitating insulin secretion in patients with abnormal glucose tolerance and ventricular arrhythmias. [ABSTRACT FROM AUTHOR]1 c (mean ± SD) 12 weeks after treatment, from 6.18 ± 0.92 mM/L to 5.54 ± 1.08 mM/L and from 6.17 ± 1.03% to 5.83 ± 0.96%, respectively ( P < 0.05). While it significantly increased fasting IRI from 4.99 ± 1.50 to 6.51 ± 1.47 μU/mL ( P < 0.01), the insulinogenic index from 0.33 ± 0.26 to 0.65 ± 0.38 ( P < 0.05), and ∑ IRI from 168 ± 67 μU/mL to 199 ± 46 ( P < 0.05). Cibenzoline exerted a hypoglycemic effect, facilitating insulin secretion in patients with abnormal glucose tolerance and ventricular arrhythmias. [ABSTRACT FROM AUTHOR]

Objective: A case-control study was carried out to compare the risks of hypoglycemia caused by disopyramide and cibenzoline. Methods: We selected 91 subjects with hypoglycemia from among 14,156 outpatients who consulted the National Cardiovascular Center (NCVC) and received drug therapy between September 1997 and February 1998. We used the fasting blood sugar (FBS) level of 75 mg/dl or less as the cut-off level to screen for hypoglycemia. For each case, five controls matched for gender and age were selected from the clinical division consulted by relevant subjects. Results: Ninety-one cases and 455 controls were enrolled in this study. Of 91 cases with hypoglycemia, 8 (8.8%) were treated with cibenzoline and 3 (3.3%) with disopyramide. The percentage of cases treated with cibenzoline was greater than that in the controls (1.5%), and the prescription frequency of cibenzoline during the study period was 2%. With adjustment for potential confounding factors using conditional logistic regression, hypoglycemia was significantly correlated with the use of cibenzoline [OR 8.0 (95% CI 1.7–36.8)], insulin [OR 48.4 (95% CI 8.8–267.2)], and thyroid agents [OR 13.0 (95% CI 1.1–160.4)]. An increased risk of hypoglycemia associated with the use of sulfonylureas was not detected. In additional logistic regression analysis, including the variables with individual sulfonylureas, glibenclamide but not gliclazide significantly increased the risk of hypoglycemia. The use of disopyramide did not affect the risk of hypoglycemia. In separate analyses for diabetic and non-diabetic patients, the risks of hypoglycemia associated with the use of drugs other than β-blocking agents in non-diabetic patients were estimated to be lower than those in diabetic patients. Conclusion: The use of cibenzoline was significantly correlated with an increased risk of hypoglycemia. [ABSTRACT FROM AUTHOR]

An 84-year-old woman was urgently referred to our hospital owing to persistent malaise and chest pain. Takotsubo cardiomyopathy was diagnosed following transthoracic echocardiography, emergency coronary angiography, and left ventriculography. A left ventricular pressure tracing during cardiac catheterization revealed a 72 mmHg-intraventricular pressure gradient (LVPG). Although β-blockers are effective at reducing LVPG in takotsubo cardiomyopathy, such treatment was contraindicated in our patient owing to her history of bronchial asthma. Therefore, we administered intravenous cibenzoline succinate to attenuate her LVPG. The LVPG decreased to 18 mmHg within 10 min after intravenous cibenzoline succinate administration. During her subsequent hospitalization, the patient showed excellent functional recovery, without any complications. Left ventriculography, performed 21 days after admission, showed normal wall motion and a left ventricular ejection fraction of 68%. < Learning objective: The prognosis of takotsubo cardiomyopathy is generally good, however, fatal complications have been reported. Our case demonstrated a LVPG of 72 mmHg, and β-blockers were contraindicated because of bronchial asthma. Intravenous cibenzoline administration resulted in successful attenuation of the patient's LVPG. The present case suggests that cibenzoline might be effective for the treatment of takotsubo cardiomyopathy, especially in those contraindicated for β-blocker therapy.> [ABSTRACT FROM AUTHOR]

We examined the effects of cibenzoline, a new class Ia antiarrhythmic drug, on various membrane ionic currents and action potentials of guinea-pig single ventricular cells, using patch clamp techniques in whole-cell configuration. Action potentials and the membrane currents were evoked at a clamping rate of 0.2 Hz, and all experiments were performed at 32-33°C. From these findings, we conclude that apart from potent inhibitory effects on I, cibenzoline possesses multiple blocking effects on other currents, e.g., I, I and I, with a different potency (I > I > I > I) and with essentially the same efficacy. These effects may explain, at least in part, the alleged, potent antiarrhythmic effects of this drug. [ABSTRACT FROM AUTHOR]

The effects of three I antiarrhythmic drugs, flecainide, propafenone and cibenzoline, were investigated in anaesthetized, open-chest pigs, in a left ventricular area, during pacing at a constant high rate (180 beats min), in the absence and the presence of ischaemia. Ischaemia was produced by transient complete occlusion of the left anterior descending coronary artery 1-1.5 cm from its origin. In addition to surface electrocardiogram, conduction time and monophasic action potential were recorded in the contractile fibres. Measurement of the effective refractory period was added in the absence of ischaemia. In this event, flecainide and propafenone, each in a dose of 2.5 mg kg i. v. and cibenzoline, 2.0 mg kg, i.v., considerably lengthened (by 50-90%) conduction time, but did not affect or hardly affected the duration of the monophasic action potential or the effective refractory period. Thus, it seems that these I antiarrhythmic drugs enhance the prolongation of conduction time by 60% and do not prevent the 30% shortening of monophasic action potential caused by ischaemia: contrary to expectation, they produced a large reduction (from about 120 to 25 s) in the onset time of fibrillation due to ischaemia. Thus, they manifested profibrillatory properties (more pronounced than those of other class I antiarrhythmic drugs), which might be explained by their potent action on depolarization with almost total absence of action on repolarization. [ABSTRACT FROM AUTHOR]

The effects of cibenzoline, rightly known as a sodium channel inhibitor (class IC antiarrhythmic drug), were investigated in anaesthetized, closed-chest dogs, on conduction in the contractile fibres, ventricular and atrial, the His-Purkinje system and the atrioventricular node. In ventricular muscle, conduction time was measured between base and apex by two endocavitary electrodes. The other conduction times were obtained from the recording of the His bundle potentials. In addition, effective refractory period was determined by the extrastimulus method in ventricular and atrial muscle and in the atrioventricular node, and sinus rate monitored in the intervals of pacing periods. In the absence of vagal tone, cibenzoline in 4 mg - kg dose prolonged conduction times in the ventricular contractile tissue, His-Purkinje system and atrial contractile tissue to a large extent, but decreasingly from the former to the latter. This prolongation was antagonized by hypernatremia (174 mmol. 1). In contrast, conduction time in the atrioventricular node, effective refractory periods and sinus rate were very little influenced. In the presence of vagal tone, the prolongation of conduction times in the ventricular contractile tissue, His-Purkinje system and atrial contractile tissue did not differ substantially from previously. It was the same for ventricular effective refractory period. But atrial effective refractory period was then considerably lengthened, while conduction time and effective refractory period in the atrioventricular node were greatly shortened and sinus rate notably accelerated. All these latter changes, independent of any hypotension which might have reflexly reduced vagal tone, and counteracted by hypercalcaemia (38 mmol. 1), are probably to be imputed to some blockade of calcium channel the role of which becomes preeminent in the atrial electrogenesis under vagal tone. [ABSTRACT FROM AUTHOR]

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 μM) or an ATP-sensitive potassium (KATP) channel blocker glibenclamide (10 μM), the shortening of the APD90 during ischemia was significantly attenuated. However, the recovery of developed tension was significantly inhibited. Class Ic drug pilsicainide (10 μM) 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 μM), 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 KATP channels inhibit contractile recovery after reperfusion by attenuating the shortening of APD during ischemia. In contrast, mexiletine, which activates KATP channels (in addition to blockade of Na+ channels) improves contractile recovery by facilitating the shortening of APD during ischemia. [ABSTRACT FROM AUTHOR]

Introduction: Anisotropic conduction characteristics, expressed as the ratio of conduction velocities in the longitudinal (V1) 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 subclassified) 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 V1 and Vt determined from 128 electrograms recorded with a plaque electrode on the anterior left ventricle of isolated perfused hearts (spacing 2.5 mm). V1 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 (Vmax) of action potentials were obtained from ventricular muscle exposed to the same drugs. Flecainide [1 μM] and cibenzoline [0.3 μM] did not alter V1 and Vt significantly. Quinidine [3 μM] predominantly depressed V1 at rapid pacing rates, but the V1/Vt ratio was not significantly altered. Quinidine [10 μM] and flecainide [3 μM] reduced V1 and Vt in a frequency-dependent fashion. Conversely, cibenzoline [1 μM] mostly decreased Vt and thus decreased the V1/Vt ratio and increased the V1/Vt at all pacing rates. This different effect was not related to a greater depressant effect on &Vdot;max. Conclusion: Quinidine and flecainide act similarly on the anisotropic pattern of conduction (both drugs increase the &Vdot;1/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. [ABSTRACT FROM AUTHOR]

Objective: Actions of cibenzoline and disopyramide, agents with Vaughan-Williams class la antiarrhythmic action, on ATP sensitive K+ (KATP) channels were examined in heart and pancreatic β cells. Methods: Single ventricular myocytes and β cells were prepared enzymatically from adult Wistar rat hearts and pancreatic islets. Using patch clamp techniques, KATP channel activities were recorded in whole cell and single channel modes. In whole cell experiments, myocytes were bathed with Tyrode's medium (34°C); inside out patches were bathed with internal solutions (22-24°C) containing 1 (μM ATP and varying concentrations of cibenzoline or disopyramide. Myocytes were voltage clamped at -40 mV and glibenclamide blockable conductance was produced by cromakalim. Results: Micromolar concentrations of both cibenzoline and disopyramide suppressed cromakalim induced conductance. When applied to the cytosolic surface of the cell membrane in inside out configuration, both drugs reversibly inhibited single KATP channel activities. Neither unitary conductance nor intraburst fast kinetics was affected by the compounds. At a holding potential of -40 mV under symmetrical ∼ 150 mM K+ conditions, half maximum doses (IC50) were 0.9 μM [Hill coefficient (h)=1.3] for cibenzoline induced block of cardiac KATP channels and 1.8 μM (h=1.0) for disopyramide block. At +40 mV, IC50 for cibenzoline block was 1.4 μM (h=0.9). Thus there was little voltage dependence in cibenzoline induced channel block. A similar IC50 value of 2.5 μM (h=1.2 at -60 mV under symmetrical ∼ 150 mM K+) was observed for cibenzoline induced block of KATP channels. Conclusions: Near therapeutic concentrations of cibenzoline and disopyramide inhibit KATP channel activities in both heart and pancreatic β cells. This may be causally related to the fasting hypoglycaemia which is sometimes reported in patients receiving the drugs. These antiarrhythmic agents may also modulate myocardial electrical properties during hypoxia or ischaemia.Cardiovascular Research 1992;26:1087-1094 [ABSTRACT FROM PUBLISHER]

The goal of this study was to test the hypothesis that class 1 drugs modify the electrophysiological substrate of atrial fibrillation. The effects of a single intravenous dose (1.4±0.3mg. kg) of the new class 1 drug, cibenzoline, were studied in 20 patients with spontaneous (n = 11) or induced (n = 9) atrial fibrillation, during an electrophysiological study. In one additional patient with chronic atrial fibrillation, the effects of a single intravenous dose of 2mg. kg of cibenzoline were studied intra-operativelv before undergoing a ‘corridor’ operation. High resolution epicardial mapping (248 channels) was used to reconstruct the atrial activation patterns before and after administration of the drug. In 18 out of 20 patients administration of cibenzoline resulted in conversion of atrial fibrillation into regular monomorphic atrial tachycardia. In these 18 patients, the mean atrial cycle length was prolonged from 147±34 ms during atrial fibrillation to 302±34 ms after cibenzoline ( <0.001). In eight out of the 18 patients, spontaneous (n = 3) or pacing induced (n = 5) conversion into sinus rhythm was observed after administration of the drug. In the patient undergoing the ‘corridor’ operation, epicardial mapping of both atria showed that the multiple wavelets present during atrial fibrillation fused in to a single broad wavefron circulating counterclockwise around the caval veins after cibenzoline. In conclusion, cibenzoline transforms random re-entry into ordered re-entry in the atria. This effect seems related to the depression of conduction produced by the drug. [ABSTRACT FROM PUBLISHER]

Cibenzoline, an imidazoline derivative is a new antiarrhythmic agent. Its electrophysiologicaleffects and antiarrhythmic properties were studied with programmed electrical stimulation of the heart in 12 patients with recurrent episodes of reentrant supraventricular tachycardia; atrionodal (5 cases), circus movement tachycardia involving an accessory pathway (6 cases), intraatrial reentry (one case). Cibenzoline was infused intravenously at a dose of 1 mg kg to 1.75 mg kg during sustained episodes of tachycardia and over 9 to 15 min. Cibenzoline shortened the sinus cycle length, moderately increased the transnodal conduction time and markedly lengthened the HV interval. The refractory periods of the atrioventricular (A–V) node, the atrium and the ventricle did not change. The effects of cibenzoline on accessory pathways used in the anterograde direction were measurable in 4 cases. Complete blockade of the bypass was seen in every case. In the retrograde direction the refractory period of the bypass could be evaluated; in 5 patients it lengthened systematically. Infused intravenously during epidoses of tachycardia, the drug terminated the rhythm disorder in 9 out of 12 cases. Tachycardia could still be initiated in 8 patients after i.v. cibenzoline (2 out of 5 A-V nodal tachycardias, 6 out of 6 circus movement tachycardias). The distribution of the drug followed a bicompartment pharmacokinetic model. The plasma levels at the end of infusion ranged from 1.34 to 3.19 μg ml. Cibenzoline, primarily has class I antiarrhythmic properties and its well-understood pharmacokinetics should be of help in tailoring the treatment to the individual needs of the patient. [ABSTRACT FROM PUBLISHER]

Cibenzoline is a new antiarrhythmic agent with class 1 properties, and additional class 3 and 4 effects. We treated 28 patients with drug-refractory and recurrent ventricular tachycardia with up to 700 mg/day cibenzoline for periods up to 5-5 months. Cibenzoline prevented the recurrence of ventricular tachycardia in five patients (18%). In three patients (11%) the arrhythmia may have been worsened, in 23 patients (82%) cibenzoline was ineffective. Cibenzoline increased the PR interval by 18% and the QRS duration by 33%; the effect on the QT was variable and the corrected QT interval did not change significantly. Side-effects were observed in 21% of patients. We conclude that cibenzoline does not appear to be superior to conventional class I antiarrhythmic agents and that it cannot be recommended for general use in patients with ventricular tachycardia. Additional pharmacokinetic and electrophysiologic studies are required before cibenzoline is used in outpatients with severe ventricular arrhythmias. [ABSTRACT FROM PUBLISHER]

A 69-year-old man was admitted to our kidney center with endstage renal failure. We started intermittent peritoneal dialysis immediately because of severe azotemia, hyperkalemia, and metabolic acidosis. Two weeks after admission, he developed uremic pericarditis with frequent ventricular premature contractions and supraventricular premature contractions. The intermittent peritoneal dialysis was then replaced by intensive hemodialysis, and oral administration of 300 mg/d of cibenzoline was started. Four days later, he developed thirst, weakness, and dyspnea due to respiratory muscular paralysis. We initiated respiratory support with a respirator because analysis of his blood gases revealed marked hypercapnia and hypoxia. He also developed hypoglycemia and prolonged PQ and QRS intervals on the electrocardiogram, which we believed were due to cibenzoline intoxication; we discontinued the cibenzoline immediately. All symptoms improved, and he was extubated 5 days later. After 2 months, his pericardial effusion disappeared. He now continues maintenance hemodialysis as an outpatient. We suspect that the cibenzoline induced the respiratory muscular paralysis for 2 reasons: 1) the patient experienced the respiratory muscular paralysis, at the same time he also experienced thirst, weakness, hypoglycemia, and prolonged PQ and QRS intervals on electrocardiogram, and all of these symptoms improved after the discontinuation of cibenzoline, and 2) his plasma concentration of cibenzoline became remarkably elevated, to 20 times above the standard therapeutic level. This patient's clinical course indicates that hemodialysis might be superior to intermittent peritoneal dialysis for treatment of cibenzoline intoxication. [ABSTRACT FROM AUTHOR]

The effect of a single dose of cibenzoline ((diphenyl 2,2 cyclopropyl) -2 imidazoline, Cipralan), a new compound with antiarrhythmic properties was studied in 14 patients undergoing routine heart catheterization for suspected coronary artery disease. The effect of the drug on dP/dt, V TP, Vce, negative dP/dt, heart rate (HR), left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), cardiac index (CI) and systemic vascular resistance (SVR) was measured before and after drug administration. A significant decrease in left ventricular isometric contraction parameters was manifested immediately after injection, with its maximal effect 2 to 5 min after injection. An increase in HR, a decrease in LVSP, a decrease in CI and an increase in SVR were observed; LVEDP was not significantly altered, nor was negative dP/dt. The effect of the drug on V TP and LVEDP was also examined during two atrial pacing stress tests (APST) done before and 10 to 20 min after drug administration. Although the negative inotropic action of the drug was apparent during the second APST, the effect was less pronounced at higher paced heart rates. No difference in the two tests was found between the maximal paced heart rate, nor was there a difference in the angina threshold. Finally the plasma level of the drug and the changes in certain parameters were compared. A positive correlation was found between the plasma level and dP/dt, V TP and cardiac index. [ABSTRACT FROM AUTHOR]

The kinetics of cibenzoline (UP 339.01), a new antiarrhythmic drug, was studied after i.v. and oral administration to 5 healthy subjects. Cibenzoline levels in plasma and urine cibenzoline were measured by a GLC method. After i.v. administration, the total clearance was 826 ml · min. The fraction of cibenzoline excreted unchanged in the urine was 0.602 and it was correlated with the creatinine clearance. After i.v. and oral administration, the renal clearances were 499 ml · min and 439 ml · min, and the half-lives were 4 h 01 min and 3 h 24 min, respectively. The differences were not significant. Availability by the oral route was 0.92, the maximum plasma concentration being observed at 1 h 36 min. The results were compared with those for other antiarrhythmic drugs. [ABSTRACT FROM AUTHOR]

The efficacy and safety of a single infusion of cibenzoline, a class I antiarrhythmic drug, were assessed in 86 patients presenting with a supraventricular tachyarrhythmia following heart surgery in a placebo-controlled double-blind parallel study. Cibenzoline was effective in 13 patients (30%) vs three patients (6.9%) with placebo (P<0.05). In the non-converted patients, ventricular rate was significantly slowed by cibenzoline (P<0.05), which also significantly increased the duration of QRS and QT intervals. Transient adverse events were seen in nine patients receiving cibenzoline: moderate hypotension, sweating, right bundle branch block. One patient with decreased left ventricular function had an increased ventricular rate and QRS duration associated with hypotension. There were no severe adverse events. These results suggest that cibenzoline is effective for the treatment of postoperative supraventricular tachyarrhythmias in patients without impairment of ventricular function. [ABSTRACT FROM PUBLISHER]