piperidines and Atrial-Flutter

To evaluate the efficacy and safety of refralon (niferidil), a new class III antiarrhythmic agent whose activity is related to the block of delayed rectifying potassium current and to the prolongation of atrial and ventricular action potential and refractory periods, when it is used as an agent for pharmacological cardioversion for atrial fibrillation (AF) and atrial flutter (AFL).. The efficacy of the drug as 3 intravenous boluses of 10 μg/kg was evaluated in 134 patients (90 men; 57.8 ± 11 years) with a mean AF duration of 3 (1.5; 6) months. Its effect was controlled by 24-hour Holter ECG monitoring. The criterion for its antiarrhythmic effect was 24-hour sinus rhythm (SR) recovery.. Niferidil restored SR in 47.7% of the patients with AF after administration of bolus 1, in 62% after bolus 2, and in 84.6% after bolus 3. SR was restored in all 100% patients with AFL. With the AF duration of less than 3 months, the efficacy of niferidil was 91.8%. There was nonsustained polymorphic ventricular tachycardia (VT) (torsade de pointes) in 1 (0.7%) patient and nonsustained monomorphic VT was stated in 5 (3.7%) patients. CONCLUSION> Pharmacological cardioversion with niferidil for persistent AF and VT may be regarded as a possible alternative to electrical cardioversion.. Цель исследования. Оценка эффективности и безопасности рефралона (ниферидила) - нового антиаритмического препарата III класса, действие которого связано с блокадой калиевых токов задержанного выпрямления, удлинением потенциала действия и рефрактерных периодов в предсердиях и желудочках, при его применении в качестве средства для медикаментозной кардиоверсии при фибрилляции предсердий (ФП) и трепетании предсердий (ТП). Материалы и методы. Эффективность препарата в виде 3 болюсов по 10 мкг/кг внутривенно оценена у 134 больных (57,8±11 лет, 90 мужчин) при средней длительности ФП 3 (1,5; 6) мес. Действие препарата контролировалось при 24-часовом холтеровском мониторировании электрокардиограммы. Критерием антиаритмического эффекта было восстановление синусового ритма (СР) в течение 24 ч. Результаты. Ниферидил восстановил СР у 47,7% больных с ФП после введения 1-го болюса, у 62% - после введения 2-го и у 84,6% - после введения 3-го болюса. СР восстановлен у всех 100% больных с ТП. При длительности ФП менее 3 мес эффективность ниферидила составила 91,8%. Неустойчивая полиморфная желудочковая тахикардия (ЖТ) типа torsades de pointes отмечена в 1 (0,7%) случае. Неустойчивая мономорфная желудочковая тахикардия (ЖТ) констатирована у 5 (3,7%) больных. Заключение. Медикаментозная кардиоверсия персистирующей ФП и ТП с использованием ниферидила может рассматриваться как возможная альтернатива электрической кардиоверсии.

Topics: Action Potentials; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Echocardiography; Electrocardiography, Ambulatory; Female; Heart; Humans; Male; Middle Aged; Piperidines; Potassium Channels; Treatment Outcome

To study the efficacy and safety of the new class III antiarrhythmic agent niferidil for pharmacological cardioversion in patients with persistent atrial fibrillation (AF) and atrial flutter (AFl).. One hundred thirty-four adults (aged 57.8 ± 11 years, 90 males) were included with median AF duration of 3 (1.5-6) months. All patients received a total of 10-30 μg/kg, niferidil, intravenously, in 1-3 (if needed) consecutive boluses at 15-minute intervals. Holter electrocardiogram monitoring was started before infusion and was continued for 24 hours. The criterion for an antiarrhythmic effect was sinus rhythm restoration within 24 hours of the initial bolus. Niferidil converted AF to sinus rhythm in 47.7% of cases after bolus 1, in 62% of cases after bolus 2, and in 84.6% of cases bolus 3. Niferidil induced a 100% recovery rate in patients with AFl and a 91.8% recovery rate in patients with AF of duration from 8 days to 3 months. Nonsustained torsade de pointes occurred in 1 patient (0.7%), and nonsustained monomorphic ventricular tachycardia was observed in 5 patients (3.7%).. The new intravenous class III drug niferidil demonstrated high conversion rates of 84.6% in patients with persistent AF and 100% in patients with persistent AFl. Niferidil may be used as a possible alternative to electrical cardioversion for pharmacological cardioversion of persistent AF/AFl.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Dose-Response Relationship, Drug; Electrocardiography, Ambulatory; Female; Humans; Male; Middle Aged; Piperidines; Treatment Outcome

The aim of the study was to evaluate the efficacy and safety of administered intravenously niferidil in doses 10, 20 and 30 mkg per kg in patients with persistent atrial fibrillation (AF) and flutter (AFL) for pharmacological cardioversion. The study included 30 patients (22 male) with persistent AF (n = 28) and AFL (n = 2) without structural heart diseases with median arrhythmia duration 6.1 +/- 4.8 months (2 weeks to 24 months). Niferidil was administered as 3 bolus injections (10 mkg per kg each) performed with the interval of 15 minutes. Antiarrhythmic efficacy of niferidil in dose of 10 mkg per kg was 60%, in dose of 20 mkg per kg it was 70%, and in dose of 30 mkg per kg reached 90% prespectively. The part of the patients, in whom QTc prolongation exceeded potentionally dangerous value of 500 mc, was 22.2% (6 of 27). None of the patients developed proarrhythmic side effect as torsade de pointes.

Topics: Aged; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Depression, Chemical; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Approval; Drug Evaluation, Preclinical; Electrocardiography; Female; Heart Rate; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines; Rabbits; Rats; Time Factors; Torsades de Pointes; Treatment Outcome

Radio frequency treatment in cardiology generates short acute pain during the heating process. The present study evaluates two techniques used for sedation/analgesia for this procedure.. Two groups of 20 patients each were studied prospectively. Patients were randomized to receive sedation for the procedure using either a patient-controlled analgesia device with remifentanil (Group R), or a target controlled infusion of propofol (Group P). Patients in Group R had a basal infusion of remifentanil 0.02-0.04 microg x kg(-1) x min(-1) with self administered bolus doses of 0.3 microg x kg(-1) i.v. every minute as required, with a delivery time greater than 30 sec. Patients in Group P had an initial plasma target concentration set at 3-4 microg x mL(-1).. Sedation scores were significantly higher in Group P, and two patients required supplementation with remifentanil and insertion of an laryngeal mask airway. Pain scores were higher in Group R, and two patients experienced muscular rigidity, one with transient apnea. Systolic blood pressure decreased significantly in Group P, and at the end of the procedure, PaCO(2) values were higher in that group (P < 0.01). Recovery time was significantly longer in Group P. Patient and physician satisfaction scores were similar in the two groups.. A basal infusion of remifentanil plus remifentanil patient controlled analgesia and target controlled infusion of propofol were adequate but not optimal techniques for sedation/analgesia for radio frequency treatment of atrial flutter.

Topics: Aged; Analgesia, Patient-Controlled; Analysis of Variance; Anesthetics, Intravenous; Atrial Flutter; Blood Pressure; Catheter Ablation; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Length of Stay; Male; Pain; Pain Measurement; Patient Satisfaction; Piperidines; Propofol; Remifentanil; Time Factors

There is increasing evidence that rates of atrial arrhythmias (AA), specifically atrial fibrillation and flutter are elevated in patients treated with the tyrosine kinase inhibitor, ibrutinib; however, the exact risk of ibrutinib-associated AA is not definitively established. We conducted a retrospective study of 137 patients diagnosed with B-cell malignancies treated with ibrutinib compared with 106 patients treated with chemotherapy for the same cancers in order to quantify the rates and risk of AA in a "real-world" sample of cancer patients. Fisher's exact test was used to evaluate for any statistically significant differences between groups. Logistic regression was used to generate odds ratios, adjusting for potential confounders. Incidence of AA was 14% (n = 17) in ibrutinib-treated patients compared with 3% (n = 3) in patients treated with chemotherapy (p = 0.009). Ibrutinib-treated patients were significantly older (mean age 67 vs 63 years, p = 0.003); however, there were no other significant differences in baseline characteristics. Ibrutinib use, age, hypertension, and previous use of ACE inhibitors, angiotensin receptor blocker use, β blocker use, and aspirin use were independently associated with incident arrhythmias. In multivariable analysis, patients treated with ibrutinib were associated with a 5-fold increased risk of developing AA (odds ratio = 5.18, 95% confidence interval 1.42 to 18.89). In conclusion, the rates and risk of AA are higher in patients treated with ibrutinib compared with chemotherapy, and this study provides strong evidence that ibrutinib itself is an independent risk factor for the development of incident AA.

Topics: Adenine; Age Factors; Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Antineoplastic Agents; Aspirin; Atrial Fibrillation; Atrial Flutter; Female; Humans; Hypertension; Incidence; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Male; Middle Aged; Multivariate Analysis; Piperidines; Platelet Aggregation Inhibitors; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Risk Factors; Waldenstrom Macroglobulinemia

It is well known that vagal stimulation increases the vulnerability to atrial fibrillation via muscarinic receptor-mediated shortening of refractory period. Recently it has been reported that some class III antiarrhythmic drugs effectively terminate or prevent atrial flutter and fibrillation by prolonging atrial effective refractory period. However, effects of class III antiarrhythmic drugs on the muscarinic acetylcholine receptor-operated K+ current (IK.ACh), which is important for the repolarization phase of the action potential in atrial cells, have not been thoroughly examined.. Effects of three class III antiarrhythmic drugs, d,l-sotalol, E-4031, and MS-551, on the carbachol (1 mumol/L)-induced action potential shortening and outward K+ current were examined in guinea pig atrial cells by conventional microelectrode and patch clamp techniques. In isolated left atria, d,l-sotalol (100 mumol/L), E-4031 (3 mumol/L), and MS-551 (30 mumol/L) partially reversed the carbachol-induced action potential shortening. In isolated single atrial cells, IK.ACh was activated by extracellular application of carbachol (1 mumol/L) or adenosine (10 mumol/L) or by intracellular loading of GTP gamma S (100 mumol/L). Sotalol (3 to 1000 mumol/L), E-4031 (1 to 100 mumol/L), and MS-551 (1 to 100 mumol/L) inhibited the carbachol-induced IK.ACh in a concentration-dependent manner, and their IC50 (half-maximal inhibition) values were 35.5, 7.8, and 11.4 mumol/L, respectively. However, the GTP gamma S-induced and adenosine-induced IK.ACh were inhibited by high concentrations of E-4031 and MS-551 but not by sotalol.. Sotalol may inhibit IK.ACh by the blockade of the atrial muscarinic receptors, whereas E-4031 and MS-551 may inhibit the current not only by blocking the muscarinic receptors but also by depressing the function of the K+ channel itself and/or G proteins. These drugs may potentially be useful for the prevention and termination of atrial flutter and fibrillation through their inhibitory action on IK.ACh.

Topics: Acetylcholine; Action Potentials; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Atrial Function, Left; Cells, Cultured; Guinea Pigs; Heart Atria; In Vitro Techniques; Myocardial Contraction; Patch-Clamp Techniques; Piperidines; Potassium Channels; Pyridines; Pyrimidinones; Receptors, Muscarinic; Sotalol

To characterize slow abnormal conduction in the low right atrium, which is known to be responsible for atrial flutter, electrophysiologic findings were correlated with anatomic features in a canine model of atrial flutter with ligation of the crista terminalis in the midright atrium. Activation in the low right atrium was mapped with a patch electrode containing 52 bipolar electrodes and a multiplexing system. A particular region in the low right atrium showed atrioventricular node-like electrophysiologic properties, a rate-dependent conduction delay, and Wenckebach periodicity. This area coincided with an area responsible for slow conduction during atrial flutter and unidirectional block at its initiation. Both pilsicainide and E-4031 preferentially blocked conduction in the specific area, leading to the termination of atrial flutter. Although refractoriness could not explain the abnormal conduction, anatomic studies consistently found the specific region to be in or around a thick muscle bundle, that is, the crista terminalis, or a thick pectinate muscle branching from the crista, located perpendicular to the wavefront of the pacing impulse and atrial flutter. These electrophysiologic and anatomic findings suggest that slow abnormal and atrioventricular node-like conduction over a thick muscle bundle, which is a normal anatomic feature of the low right atrium, plays a role in the initiation, maintenance, and termination of atrial reentry.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Flutter; Atrial Function, Right; Dogs; Electric Stimulation; Electrocardiography; Female; Heart Atria; Heart Block; Heart Conduction System; Lidocaine; Male; Piperidines; Pyridines; Refractory Period, Electrophysiological; Time Factors

Numerous studies have shown that E-4031 generally prolongs the atrial effective refractory period (AERP) without affecting cardiac conduction. The effects of E-4031 on AERP and cardiac conduction at short cycle lengths (CLs) close to the AERP were measured in 12 dogs with sterile pericarditis. Three pairs of electrodes were sutured at three sites in the atria 4 days after the model was created. We measured AERP and maximum conduction delay (MCD) after 8 beats train at CLs of 400, 300, 200 and 150 ms before and during continuous infusion of E-4031 (0.1 microgram/kg/min) that followed an initial dose of 10 micrograms/kg/min/5 min. E-4031 interrupted sustained atrial flutter (AF) (> or = 10 min) in 4 of 5 episodes and atrial fibrillation (> or = 10 min) in 4 of 4. The CL of AF defined as a rapid atrial rhythm (rate > or = 240 beats/min) in five episodes studied in the sterile pericarditis model was significantly (p < 0.005) prolonged from 120 +/- 8 to 160 +/- 17 ms. There were significant (p < 0.005) increases in AERP at each CL, and prolongation of AERP was 39 +/- 18, 31 +/- 14, 23 +/- 14, and 16 +/- 14 ms at CL 400, 300, 200, and 150 ms, respectively. E-4031 produced less prolongation of AERP at short pacing CLs and had no effect on conduction time during atrial rapid pacing at CLs > 150 ms. E-4031 did not prolong MCD at CL 400 ms, but did prolong MCD at CLs of 300, 200, and 150 ms, despite prolongation of AERP.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Dogs; Electric Stimulation; Electrophysiology; Heart; Heart Conduction System; Models, Cardiovascular; Pericarditis; Piperidines; Pyridines

Effects of new antiarrhythmic drugs, pentisomide [3.5 +/- 0.5 mg/kg intravenously (i.v.) n = 8], and E-4031 (5.6 +/- 1.0 micrograms/kg, n = 8), a class III drug, on atrial flutter (AF) caused by reentry were compared with those of disopyramide (1.6 +/- 0.2 mg/kg, n = 8) and propafenone (2.2 +/- 0.2 mg/kg, n = 8). AF was induced with burst atrial pacing after we made an intercaval crush in anesthetized, open-chest dogs. Termination of AF did not differ among test drugs (8 of 8 with disopyramide, 7 of 8 with propafenone, 6 of 8 with pentisomide, and 8 of 8 with E-4031). Cycle length (CL) of AF was prolonged more with propafenone (57 +/- 10%) and pentisomide (41 +/- 5%) than with E-4031 (12 +/- 3%, p less than 0.05). This was also true for increase in interatrial conduction time determined at a pacing CL of 150 ms. Increase in atrial effective refractory period (ERP) determined at a basic pacing CL of 300 ms did not differ among test drugs. Changes in CL of AF correlated significantly with those in interatrial conduction time (r = 0.84, p less than 0.001), but not with those of ERP (r = 0.10, NS). Reinitiation of AF was significantly greater in propafenone (7 of 7) and pentisomide (5 of 6) groups than in disopyramide (1 of 8) and E-4031 (0 of 8) groups (p less than 0.001). Pentisomide and E-4031 were effective in terminating canine AF due to reentry, as were disopyramide and propafenone. Reinitiation of AF was greater in dogs treated with antiarrhythmic drugs that had more prominent effects on conduction time than on ERP.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Flutter; Disopyramide; Dogs; Electrocardiography; Electrophysiology; Heart Conduction System; Piperidines; Propafenone; Propylamines; Pyridines; Refractory Period, Electrophysiological

The aim was to test whether antiarrhythmic drugs preferentially suppressed conduction in the area of slow conduction in the re-entrant circuit.. Intravenous disopyramide [n = 8, plasma concentrations: 1.4 (SEM 0.2) micrograms.ml-1], flecainide [n = 8, 0.6(0.1) micrograms.ml-1], and E-4031, a new class III antiarrhythmic drug [n = 8, 5.6(1.0) ng.ml-1], were investigated for their effects on atrial flutter due to re-entry in dogs with intercaval crush. In three dogs, detailed atrial activation sequence during atrial flutter was determined with a hand held bipolar electrode and an epicardial isochronal map was drawn.. 24 anaesthetised adult mongrel dogs were used.. There was an area of slow conduction during atrial flutter in the low right atrium. Atrial flutter was terminated in all dogs except for one treated with flecainide. In 92% of the dogs, conduction block occurred in the low right atrium in which the area of slow conduction was located. Increase in local conduction time was greater in the area of slow conduction than other parts of the atria (percent ratio to the increase in cycle length of atrial flutter: 63% with disopyramide, 52% with flecainide, and 99% with E-4031).. These data suggested antiarrhythmic drugs preferentially suppressed conduction at the area of slow conduction in the re-entrant circuit leading to termination of atrial flutter in this canine model, irrespective of electrophysiological effects of antiarrhythmic drugs.

Topics: Animals; Anti-Arrhythmia Agents; Atrial Flutter; Disopyramide; Dogs; Flecainide; Heart Conduction System; Piperidines; Pyridines

Antiarrhythmic drugs prolong the effective refractory period and depress conduction. To determine the exact role played by these two electrophysiologic effects in the termination of reentry, the effects of disopyramide, flecainide, propafenone and E-4031, a new class III drug, were examined in a canine model of atrial flutter (cycle length 120 +/- 4 to 131 +/- 3 ms) caused by reentry. Atrial flutter was induced in 32 anesthetized open chest dogs after placement of an intercaval crush. The excitable gap ranged from 9 +/- 2% to 11 +/- 4% of the basic flutter cycle length. The effective refractory period in the reentrant circuit during atrial flutter was estimated by subtracting the excitable gap from the basic flutter cycle length. Prolongation of flutter cycle length by the test drugs was proportional to the interatrial conduction time (r = 0.87, p less than 0.001). Atrial flutter was terminated by each test drug in all dogs except for flecainide and propafenone in one dog each. E-4031 prolonged the refractory period during atrial flutter to 129 +/- 6 ms, which did not differ significantly from the flutter cycle length immediately before termination (134 +/- 4 ms). The refractory period during atrial flutter after injection of the other drugs was shorter than the flutter cycle length before termination of atrial flutter (for example, flecainide 126 +/- 5 vs. 179 +/- 11 ms, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Atrial Flutter; Cardiac Pacing, Artificial; Disopyramide; Dogs; Electrocardiography; Flecainide; Heart Conduction System; Piperidines; Propafenone; Pyridines; Refractory Period, Electrophysiological

Flecainide acetate (Flecaine) is a new antiarrhythmic which has recently become available; its efficacity in treatment of ventricular rhythm disorders has been amply demonstrated. In this study we have evaluated its efficacity per os in treatment of auricular rhythm disorders refractory to the usual therapies, and its effects on the accessory routes of atrioventricular conduction. The results are very promising and better than those obtained with amiodarone in auricular disorders. They show that flecainide is a drug of importance among therapeutic agents used in treatment of auricular arrhythmia, and its action on Kent's bundle makes it a drug of choice in management of Wolff-Parkinson-White syndrome, especially as it seems equally efficacious in its action on the accessory routes with a short refractory period. Most of our patients did not present organic cardiopathy and the side-effects were generally benign. A non-negligible number of cases of paroxysmal hypertension were noted, in disagreement with literature data, and this point needs to be clarified by further study.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Flutter; Female; Flecainide; Heart Atria; Humans; Male; Middle Aged; Piperidines; Wolff-Parkinson-White Syndrome

Sixteen patients were investigated by means of programmed atrial stimulation at 2 different driving rates: 100/min and 120/min. All patients had an increased atrial vulnerability at both driving rates. After the administration of intravenous flecainide (1 mg/kg bodyweight as a bolus, followed by the same amount infused over a period of 20 minutes), the increased vulnerability was abolished in 11 and 9 patients, respectively. In the remaining patients the rate of induced atrial tachyarrhythmia decreased. These findings correlate with a significant prolongation of the effective refractory period of the right atrium and a corresponding significant shortening of its relative refractory period. It is concluded that flecainide may be effective in the treatment of atrial arrhythmias in humans.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Flutter; Electrocardiography; Female; Flecainide; Heart Atria; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Refractory Period, Electrophysiological

Sixteen patients were investigated by means of programmed atrial stimulation at two different driving rates: 100 and 120/min. All patients had an increased atrial vulnerability at both driving rates. After intravenous flecainide application (1 mg/kg body weight as a bolus followed by the same amount given by infusion over a period of 20 min) the increased vulnerability was abolished in 11 and 9 patients respectively. In the remaining patients the rate of induced atrial tachyarrhythmia decreased. These findings correlate with a significant prolongation of the effective refractory period of the right atrium and a significant shortening of the relative refractory period of the right atrium. It is concluded that flecainide may be effective in the treatment of atrial arrhythmias in man.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Cardiac Pacing, Artificial; Electrocardiography; Female; Flecainide; Heart Conduction System; Humans; Male; Middle Aged; Piperidines