piperidines and Arrhythmias--Cardiac

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus-host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown.. We systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's. As far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV.. May Tam Mak Mei Yin, The Shaw Foundation Hong Kong, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, The Hong Kong Hainan Commercial Association South China Microbiology Research Fund, The Jessie & George Ho Charitable Foundation, Perfect Shape Medical, The Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, The Theme-Based Research Scheme of the Research Grants Council, Sanming Project of Medicine in Shenzhen, and The High Level-Hospital Program, Health Commission of Guangdong Province, China.. Lower levels of total T3 were strongly correlated with in-hospital mortality in patients with SCMP. A low T3 level might suggest poor prognosis in patients with SCMP.

Topics: Adult; Aged; Aged, 80 and over; Animals; Antibodies, Bacterial; Anxiety Disorders; Arecaceae; Arrhythmias, Cardiac; Autonomic Nervous System; Bacterial Proteins; Behavior Therapy; Burkholderia pseudomallei; Caco-2 Cells; Campylobacter; Campylobacter Infections; Carbazoles; Carcinoma, Non-Small-Cell Lung; Case-Control Studies; Chickens; Computer Simulation; Coumarins; COVID-19; Cross-Sectional Studies; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Diabetes Mellitus, Type 1; Diarrhea; Dietary Supplements; Echocardiography; Educational Measurement; Electrocardiography, Ambulatory; Endoribonucleases; Exercise; Exercise Therapy; Faculty, Dental; Farms; Fear; Female; Flame Retardants; Florida; Gene Expression Regulation, Plant; Halogenated Diphenyl Ethers; Hearing Loss, Sudden; Heart Rate; HIV Infections; Hospital Mortality; Humans; Hypertension; Hypoglycemia; Immunity; In Situ Hybridization; Japan; Kinetics; Kuwait; Lung Neoplasms; Macaca mulatta; Macrophages; Male; Masked Hypertension; Melioidosis; Methyltransferases; Mice; Mice, Inbred BALB C; Middle Aged; Molecular Docking Simulation; Molecular Dynamics Simulation; Myocardium; Oryza; Patient Education as Topic; Peptide Hydrolases; Phosphoric Monoester Hydrolases; Piperidines; Plant Extracts; Plant Proteins; Platelet Count; Poultry Diseases; Prevalence; Protease Inhibitors; Protein Kinase Inhibitors; Protein Kinases; Rabbits; Rats; Rats, Sprague-Dawley; RAW 264.7 Cells; Resistance Training; Retrospective Studies; Risk Factors; SARS-CoV-2; Saudi Arabia; Severe acute respiratory syndrome-related coronavirus; Students; Substance-Related Disorders; Surveys and Questionnaires; Swine; Tachycardia, Ventricular; Takotsubo Cardiomyopathy; Thyroid Gland; Transcriptome; Transfection; Tropism; United Arab Emirates; Virulence; Virulence Factors; Writing

Inhibition of Bruton's tyrosine kinase (BTK) has revolutionized the treatment landscape for patients with chronic lymphocytic leukemia (CLL). By targeting this critical kinase in proximal B-cell receptor signaling, BTK inhibitors (BTKis) impair cell proliferation, migration, and activation of NF-κB. Clinically, because indefinite inhibition is a mainstay of therapy, there is an extended period of exposure in which adverse effects can develop. Given the impressive efficacy and activity of BTKis in the treatment of patients with CLL, appropriate management of treatment-emergent adverse events (AEs) is of paramount importance. Here we review the BTKi landscape and present the available toxicity and safety data for each agent. The long-term toxicity profile of ibrutinib, a first-in-class inhibitor, is well characterized and includes a clinically significant incidence of cardiac arrhythmias, bleeding, infection, diarrhea, arthralgias, and hypertension. Acalabrutinib, the initial second-generation BTKi to earn approval from the US Food and Drug Administration, demonstrates improved kinase selectivity for BTK, with commonly observed adverse reactions including infection, headache, and diarrhea. Mediated by both on-target inhibition of BTK and variable off-target inhibition of other kinases including interleukin-2-inducible T-cell kinase (ITK), tyrosine-protein kinase (TEC), and endothelial growth factor receptor (EGFR), the toxicity profile of BTKis is closely linked to their pattern of kinase binding. Other emerging BTKis include second-generation agents with variable degrees of kinase selectivity and third-generation agents that exhibit reversible noncovalent binding to BTK. We also highlight critical considerations for the prevention and monitoring of AEs and offer practical management strategies for treatment-emergent toxicities.

Topics: Adenine; Agammaglobulinaemia Tyrosine Kinase; Aged; Animals; Arrhythmias, Cardiac; Arthralgia; Benzamides; Diarrhea; Hemorrhage; Humans; Hypertension; Infection Control; Infections; Male; Piperidines; Protein Kinase Inhibitors; Pyrazines

Although the new second-generation nonsedative antihistamines terfenadine and astemizole were launched as highly selective and specific H(1)-receptor antagonists, they were later found to cause prolongation of the QT-interval and severe cardiac arrhythmias. The prolongation of the QT-interval is caused by the blockade of one or more of the cardiac potassium channels, among which the delayed rectifier I(Kr), encoded by the HERG-gene, appears to be the most significant. The potency of the prokinetic drug cisapride to block I(Kr) appears to be similar to that of terfenadine (IC(50) about 50 nmol/l). These drugs cause problems when overdosed, used in combination with inhibitors of their CYP3A4-mediated metabolism, or when given to individuals with altered drug kinetics (the aged) or patients with existing cardiac disease (congenitally long QT). Moreover, interactions with other QT-interval prolonging drugs require special attention. Active hydrophilic metabolites of the second-generation antihistaminic compounds (ebastine-carebastine, loratadine-desloratadine, terfenadine-fexofenadine, astemizole-norastemizole) are new compounds with probably reduced risk for drug interactions and cardiac toxicity.

Topics: Arrhythmias, Cardiac; Astemizole; Benzimidazoles; Butyrophenones; Cetirizine; Cisapride; Heart Diseases; Histamine H1 Antagonists; Humans; Loratadine; Piperidines; Serotonin Receptor Agonists; Terfenadine; Triprolidine

Cardiac intracellular Na+and Ca2+homeostasis is regulated by the concerted action of ion channels, pumps and exchangers. The Na+, K+-ATPase produces the electrochemical concentration gradient for Na+, which is the driving force for Ca2+removal from the cytosol via the Na+/Ca2+exchange. Reduction of this gradient by increased intracellular Na+concentration leads to cellular Ca2+overload resulting in arrhythmias and contractile dysfunction. Na+and Ca2+overload-associated arrhythmias can be produced experimentally by inhibition of Na+efflux (digitalis-induced intoxication) and by abnormal Na+influx via modulated Na+channels (veratridine, DPI 201-106; hypoxia) or via the Na+, H+exchanger. Theoretically, blockers of Na+and Ca2+channels, inhibitors of abnormal oscillatory release of Ca2+from internal stores or modulators of the Na+, Ca2+and Na+, H+exchanger activities could protect against cellular Na+and Ca2+overload. Three exemplary drugs that prevent Na+and Ca2+overload, i.e. the benzothiazolamine R56865, the methylenephenoxydioxy-derivative CP-060S, and the benzoyl-guanidine Hoe 642, a Na+, H+exchange blocker, are briefly reviewed with respect to their efficacy on digitalis-, veratridine- and ischaemia/reperfusion-induced arrhythmias.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzothiazoles; Calcium; Calcium Channel Blockers; Guanidines; Heart; Homeostasis; Humans; Piperidines; Sodium; Sodium Channel Blockers; Sodium Channels; Sodium-Hydrogen Exchangers; Sulfones; Thiazoles; Thiazolidines

Drugs can cause cardiac arrhythmias in a number of clinical situations, and many of the implicated agents are used to treat non-cardiac conditions. These adverse effects are frequently idiosyncratic, but are often mediated via triggered activity causing torsade de pointes. Drugs being used for treatment of cardiac conditions may promote arrhythmias by re-entrant mechanisms or via triggered activity. Many drugs may cause cardiac arrhythmic complications when taken in excessive amounts. Keys to reducing the incidence of drug-induced cardiac arrhythmias include increased awareness among the medical, pharmaceutical and nursing professions of the potential problems in using certain agents, especially in specific situations. Appropriate monitoring when such treatment is essential and, after diagnosis, prompt withdrawal of the offending agent and treatment for the arrhythmia should be initiated.

Topics: Amiodarone; Angiotensin-Converting Enzyme Inhibitors; Anti-Arrhythmia Agents; Anti-Infective Agents; Arrhythmias, Cardiac; Bradycardia; Cisapride; Digitalis Glycosides; Electrocardiography; Gastrointestinal Agents; Histamine H1 Antagonists; Humans; Incidence; Piperidines; Sotalol; Tachycardia, Ventricular; Torsades de Pointes

Topics: Anti-Ulcer Agents; Arrhythmias, Cardiac; Cisapride; Humans; Long QT Syndrome; Piperidines; Risk Factors

This is a brief review of agents that stabilize calcium release from the sarcoplasmic reticulum in cardiac muscle. An excess intracellular calcium concentration (calcium overload) is a common feature in a variety of cardiac cell injuries. Calcium overload elicits diastolic and systolic failure, and is involved in the genesis of arrhythmias. These abnormalities appear in part to be caused by the spontaneous release of calcium ions from the sarcoplasmic reticulum. Previous efforts to treat calcium overload were made with the intention to decrease the total intracellular content of calcium ions. However, such procedures would result in a decrease in contractility. Agents that stabilized calcium release from the sarcoplasmic reticulum may therefore be useful to correct abnormalities in calcium overload. In this review, after briefly describing intracellular calcium homeostasis, strategies against calcium overload, especially those involving magnesium ion, ryanodine, caffeine, dantrolene, phenytoin, R56865, KT361 and flunarizine will be discussed.

Topics: Animals; Anti-Arrhythmia Agents; Anticonvulsants; Arrhythmias, Cardiac; Benzothiazoles; Caffeine; Calcium; Calcium Channel Blockers; Dantrolene; Flunarizine; Homeostasis; Humans; Magnesium; Models, Cardiovascular; Muscle Relaxants, Central; Myocardial Contraction; Myocardium; Phenytoin; Piperidines; Ryanodine; Sarcoplasmic Reticulum; Thiazepines; Thiazoles

The present article presents an overview of the pharmacologic profile of the benzopyran derivative RP 58866, a racemic mixture, and of RP 62719 (terikalant), its active enantiomer. In normal cardiac tissues studied in vitro, both drugs dose-dependently prolonged the atrial and ventricular action potential but affected neither the upstroke of the action potential nor the diastolic potential. Patch-clamp experiments demonstrated that the prolongation of the action potential induced by the drugs is due to a specific blockade of the inward rectifier K+ current. In vivo, intravenous administration to anesthetized dogs of low doses of RP 62719 consistently induced bradycardia and prolonged the atrial, nodal, and ventricular refractory periods, but did not affect the conduction velocity. Because of these properties, RP 58866 and RP 62719 exert potent antiarrhythmic and antifibrillatory actions both at the atrial and ventricular levels in various experimental models of arrhythmia. Our results demonstrate that RP 58866 and RP 62719 are K(+)-channel blockers acting as pure class III antiarrhythmic drugs.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzopyrans; Chromans; Chromones; Electrophysiology; Humans; Models, Cardiovascular; Piperidines; Potassium Channels

The last ten years have been a period of extensive research and development of new agents for the treatment of cardiac rhythm abnormalities. Several new subclass Ic agents have been developed, and more recently the class III agents have become the focus of attention. These new agents are all remarkable for their potency and potential for producing side effects. While none of these agents offers the perfect cure for the treatment or prevention of cardiac arrhythmias, they all offer advantages and options that are valuable for clinical management of patients.

Topics: Amiodarone; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Encainide; Flecainide; Humans; Mexiletine; Piperidines; Propafenone; Propanolamines

Pirmenol, a novel pyridinemethanol derivative, is active in a variety of experimental arrhythmic models of diverse etiology. Animal pharmacology studies showed that pirmenol is highly efficacious whether the arrhythmias were atrial or ventricular in origin; chemically, mechanically, or electrically induced; or of the automaticity or reentrant types. The conscious coronary artery-ligated (Harris) dog model best allowed simulation of a variety of clinical situations in which pirmenol could be used either alone or in combination. Pirmenol was highly effective by both the intravenous and oral routes, causing immediate suppression, prevention, or termination of cardiac arrhythmias. Preclinical studies in the dog showed an excellent correlation between the dose of pirmenol, plasma levels, and antiarrhythmic efficacy. Administration of pirmenol in the dog at intentionally accelerated infusion rates suggested a relatively wide margin of safety for pirmenol compared with other class I agents. In vitro electrophysiologic studies in dog Purkinje fibers revealed possibly unique differences of pirmenol from other antiarrhythmic agents. It depresses fast and slow response automaticity and its electrophysiologic effects were less variable than other class I drugs over a spectrum of potassium levels. To test the relevance of the in vitro electrophysiologic results, pirmenol's antiarrhythmic efficacy was assessed in several in vivo dog models in which serum potassium was either increased or decreased. Studies comparing pirmenol and disopyramide clearly showed a relative lack of serum potassium dependence for pirmenol, suggesting a potential clinical advantage over disopyramide and other antiarrhythmics in variable potassium settings. The clinical relevance of these observations will have to be established in patients with variable potassium levels. Overall, pirmenol compared favorably with other reference agents in efficacy and safety in extensive preclinical investigations.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Drug Evaluation, Preclinical; Drug Interactions; Electrophysiology; Heart; Piperidines

Pirmenol hydrochloride is a promising antiarrhythmic agent with quinidine-like (Class Ia) properties presently undergoing evaluation. It's clinical pharmacology and pharmacokinetics are reviewed. The author outlines the effects of pirmenol on the sinus node, atrial tissue, A-V node, and ventricular tissue and describes its antiarrhythmic efficacy in clinical studies to date, including his own study in 21 patients with a history of sustained ventricular tachycardia. The author summarizes the hemodynamic and pharmacokinetic studies of pirmenol noting that its effects are relatively independent of potassium concentration. The drug's side effects profile is presented, and it is concluded that pirmenol is well tolerated. Hypotension has not been a significant problem with intravenous pirmenol. Precipitation or worsening of clinical heart failure appears to occur only rarely. The favorable pharmacokinetics of pirmenol permit dosage at less frequent intervals than with procainamide, quinidine, disopyramide. Pirmenol has shown efficacy for ventricular arrhythmias even in some patients refractory to Class Ia agents. Antiarrhythmic effects appear to be correlated with plasma levels, and a well-defined therapeutic minimum has been determined.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Evaluation; Half-Life; Humans; Injections, Intravenous; Piperidines

Topics: Adrenergic beta-Antagonists; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Disopyramide; Electric Countershock; Electric Stimulation; Electrocardiography; Exercise Test; Flecainide; Heart Ventricles; Humans; Lidocaine; Phenytoin; Piperidines; Procainamide; Quinidine; Risk; Tachycardia; Tocainide; United States; Ventricular Fibrillation; Verapamil

The frequency of ventricular arrhythmias increases with age. Several factors make elderly people more prone to antiarrhythmic drug toxicity. Familiarity with the changes in the pharmacokinetics and pharmacodynamics of antiarrhythmic agents may reduce or prevent adverse response in this patient population.

Topics: Aged; Amiodarone; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bretylium Compounds; Digoxin; Disopyramide; Encainide; Flecainide; Humans; Lidocaine; Mexiletine; Piperidines; Procainamide; Propranolol; Quinidine; Tocainide; Verapamil

Topics: Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bretylium Tosylate; Disopyramide; Flecainide; Heart Ventricles; Humans; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Phenytoin; Piperidines; Procainamide; Propafenone; Propiophenones; Quinidine; Sotalol; Tocainide; Verapamil

Flecainide acetate is a new class 1 c antiarrhythmic drug. It slows conduction in the working myocardium and the specialized conduction system and may depress sinus node activity in patients with pre-existing sinus node disease. Its hemodynamic effects are minimal. The drug is completely absorbed and shows a half-life of 7-22 hours. Elimination is mainly through the kidneys. Flecainide is highly effective in the treatment of ventricular arrhythmias, pre-excitation syndromes and AV reentry tachycardias. Side effects are mild and consist mostly of dizziness, visual disturbances, and nervousness. They rarely require discontinuation of therapy. Proarrhythmic effects have been reported. Caution is required in patients with congestive heart failure, AV block, and/or bundle-branch block or sinus node dysfunction.

Topics: Action Potentials; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrophysiology; Flecainide; Hemodynamics; Humans; Kinetics; Piperidines; Pre-Excitation Syndromes

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Interactions; Electrocardiography; Flecainide; Heart; Heart Rate; Hemodynamics; Humans; Kinetics; Metabolic Clearance Rate; Piperidines

Flecainide has been shown to be a relatively safe and effective antiarrhythmic agent. Its twice daily dosage schedule and demonstrated efficacy in suppression of ventricular ectopy suggest that it will be a valuable agent in the therapy of ventricular arrhythmias.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Flecainide; Heart Ventricles; Humans; Kinetics; Piperidines

Serotonergic receptors have been identified in the blood vessels of the heart and in myocardial tissue. We indirectly examined the potential significance of these receptors by studying the properties of ketanserin, an S2-serotonergic antagonist. In an isolated rat heart preparation, ketanserin at 10(-6) M slowed the heart rate, whereas at 10(-5) M it also decreased the cardiac output. Because the stroke volume rose, a negative inotropic effect could be excluded. Electrophysiologically, ketanserin (10(-7) M or more) increased the action potential duration of the superfused guinea-pig papillary muscle preparation. This Class III effect may account for the antiarrhythmic action of ketanserin (5 X 10(-6) M-10(-5) M) in an ischemic-reperfused rat heart preparation. The possibility of nonspecific effects of ketanserin such as an interaction with alpha 1-adrenergic receptors merits careful evaluation, but in the case of the Class III effect, ketanserin was approximately 100 times more active than prazosin in widening the action potential duration. These data suggest that even high concentrations of ketanserin are unlikely to have harmful effects on the myocardium and might, on the contrary, have beneficial effects in the context of myocardial ischemia.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Coronary Circulation; Coronary Disease; Heart; Heart Rate; Humans; In Vitro Techniques; Ketanserin; Myocardial Contraction; Piperidines; Serotonin; Serotonin Antagonists; Sinoatrial Node

A number of conventional and newer antiarrhythmic agents are available for the treatment and prophylaxis of ventricular tachycardia and sudden death. Using a multifaceted approach of programmed electrical stimulation studies, drug level determinations, exercise tolerance testing, and 24-hour ambulatory electrocardiographic monitoring, the physician can identify those patients who require therapy and then predict the likelihood of efficacy with each antiarrhythmic agent. This approach affords evaluation of both aspects of the sudden death equation-ectopy frequency (triggering mechanism) and vulnerability to development of sustained ventricular tachycardia (substrate). After institution of therapy, careful follow-up is necessary to document sustained drug efficacy and detect side effects. Serious adverse reactions necessitate a change in antiarrhythmic therapy, as opposed to lowering drug dosage to an ineffective level. The unacceptably high incidence of sudden death due to electrical instability can be reversed only by a rigorous and dedicated long-term approach to the management of serious ventricular arrhythmias.

Topics: Adrenergic beta-Antagonists; Ajmaline; Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Bepridil; Bethanidine; Bretylium Tosylate; Disopyramide; Drug Administration Schedule; Encainide; Flecainide; Heart Conduction System; Humans; Imidazoles; Lidocaine; Mexiletine; Moricizine; Myocardial Contraction; Phenothiazines; Phenytoin; Piperidines; Procainamide; Propafenone; Propiophenones; Pyrrolidines; Quinidine; Tocainide; Verapamil

Topics: Adrenergic beta-Antagonists; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Calcium Channel Blockers; Electrophysiology; Encainide; Flecainide; Heart Conduction System; Humans; Lidocaine; Moricizine; Phenothiazines; Piperidines; Quaternary Ammonium Compounds; Sotalol; Tocainide

Flecainide is a Class I antiarrhythmic drug of the local anaesthetic type. It can be given either intravenously or orally and its pharmacokinetic properties allow relatively long (12 hours) dosing intervals with oral administration. In several open and a few controlled therapeutic trials, orally administered flecainide has brought about a greater than 90% suppression of ventricular ectopic beats in about 80% of patients. A similar percentage of patients (83%) experienced at least an 80% suppression of their ventricular tachycardia in these trials. A slightly greater response rate was reported with intravenous infusion of flecainide. Initial results in arrhythmias complicating the Wolff-Parkinson-White syndrome have been favourable. Comparative trials are few in number but flecainide has proved to be more effective than quinidine, and possibly more effective than disopyramide, mexiletine, tocainide and propafenone, in suppressing ventricular ectopic activity. The most commonly reported extracardiac adverse effects have been dizziness and visual disturbances. Proarrhythmic effects have been reported in 7 to 8% of patients, with a higher incidence in patients with serious ventricular tachycardia and reduced myocardial function. The moderate negative inotropic effects of flecainide can become clinically significant in patients with impaired ventricular function. Thus flecainide, with its convenient dose schedule and apparently low incidence of serious side effects, would appear to be a useful addition to the antiarrhythmic agents available. Further studies are needed though, to confirm its long term tolerability when used prophylactically.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Biotransformation; Drug Interactions; Electrophysiology; Flecainide; Hemodynamics; Humans; Kinetics; Piperidines; Tissue Distribution

Flecainide acetate is a new orally active antidysrhythmic agent classified in the Ic category. Flecainide is effective in suppressing 88 to 100 percent of abnormal cardiac rhythms in the form of complex ventricular dysrhythmias, including couplets, ventricular tachycardia, reentrant junctional tachycardia, and Wolff-Parkinson-White syndrome. Flecainide appears to have a greater effect on conduction than on repolarization and only minimal effects on hemodynamic parameters. Flecainide is rapidly and completely absorbed after oral administration and has a 13-hour elimination half-life, allowing for twice-daily dosing regimens. Flecainide is generally well tolerated, with dizziness, blurred vision, nausea, and headache the most common side effects. Flecainide has been shown to be superior to quinidine and disopyramide in suppressing ventricular ectopic activity and may be considered a first-line oral agent for this indication. It is believe that flecainide has enough therapeutic advantages to be added to drug formularies.

Topics: Action Potentials; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Drug Interactions; Electrocardiography; Flecainide; Hemodynamics; Humans; Kinetics; Piperidines

Topics: Amiodarone; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Encainide; Flecainide; Humans; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Piperidines; Propafenone; Propiophenones; Tocainide

Effective antiarrhythmic therapy requires a carefully considered approach, including an understanding of the arrhythmia, the underlying cardiac disease and the drug's pharmacokinetics. Flecainide is a new antiarrhythmic drug that may soon be released for general use. Flecainide demonstrates unsurpassed efficacy in chronic ventricular arrhythmias in stable patients and may become a first-choice drug because of its ease of administration, efficacy and favorable tolerance. Twice-daily dosing with 100 to 200 mg usually provides effective therapy. Clinical experience suggests flecainide to be indicated in the treatment of uniform and multiform ventricular premature complexes, coupled ventricular premature complexes, and episodes of nonsustained ventricular tachycardia. A lower response rate is observed in preventing induction of sustained ventricular tachycardia, and these patients should be carefully selected. Flecainide is promising in the treatment of supraventricular tachycardias using atrioventricular nodal or extranodal reentrant pathways, although this use is still investigational in the United States. The drug's use for arrhythmias during acute myocardial infarction requires further study. Flecainide possesses modest negative inotropic potential. Proarrhythmic or other adverse reactions have occurred primarily in settings of high drug level, poor ventricular function or refractory, malignant arrhythmias, suggesting caution in these groups.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Flecainide; Hemodynamics; Humans; Piperidines

Lorcainide is a type I antiarrhythmic drug of the local anesthetic type. It can be given either intravenously or orally, and its pharmacokinetic properties allow relatively long (12 hours) dosing intervals with oral administration. A slowly eliminated metabolite, norlorcainide, probably contributes to the effects of orally administered lorcainide in chronically treated patients. In mainly short term studies, lorcainide has been shown to suppress ventricular ectopy in about 80% of patients treated either orally or intravenously. Preliminary evidence suggests that its efficacy in suppressing ectopy in the setting of acute myocardial infarction is comparable with that of lignocaine (lidocaine). It is of variable efficacy in preventing recurrent ventricular tachycardia and has been shown to be effective in some patients who have failed to respond to other antiarrhythmic drugs. Experience is limited in treating supraventricular arrhythmia, but initial results in patients with Wolff-Parkinson-White syndrome have been favourable. Adverse cardiac effects are infrequent. Abnormal sinus node function may be exacerbated by lorcainide treatment, however, and bundle branch block may be precipitated in patients with pre-existing conduction system disease. Exacerbation of pre-existing arrhythmias is uncommon, and clinically important myocardial depression has not been observed. The most frequent side effect is disturbed sleep during the initiation of oral treatment, which may occur in the majority of patients but usually responds to treatment with a benzodiazepine and subsides with time. Thus, lorcainide appears useful against a variety of arrhythmias. With its convenient dosage schedule and apparently low incidence of serious side effects it should become a useful addition to the antiarrhythmic agents available, although longer term studies are needed to confirm its continued efficacy and lack of unexpected side effects when used for long periods.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Biological Availability; Clinical Trials as Topic; Drug Interactions; Electrophysiology; Half-Life; Hemodynamics; Humans; Kinetics; Piperidines; Wolff-Parkinson-White Syndrome

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzofurans; Drug Interactions; Flecainide; Heart; Hemodynamics; Humans; In Vitro Techniques; Myocardial Contraction; Piperidines; Verapamil

The investigational antiarrhythmic agents available for use in this country are predominantly class I drugs with local anesthetic membrane effects. These drugs are often used successfully to control arrhythmias refractory to treatment with the standard antiarrhythmic drugs. Side effects often limit their use, and particular attention needs to be paid to their cardiac side effects, such as exacerbation of arrhythmia or enhanced conduction defects.

Topics: Amiodarone; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Encainide; Flecainide; Humans; Lidocaine; Mexiletine; Piperidines; Tocainide

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Coronary Disease; Encainide; Flecainide; Heart Ventricles; Humans; Lidocaine; Mexiletine; Myocardial Infarction; Piperidines; Tachycardia; Tocainide; Ventricular Fibrillation

Currently available antiarrhythmic drugs possess very poor therapeutic-to-toxic ratios, and therefore, there is a great deal of interest in the development of new investigational agents to suppress ventricular rhythm disturbances. This article includes most of the investigational ventricular antiarrhythmic drugs in which there has been a great deal of recent active investigation and interest. It stresses the different patient populations that have been tested with each of these antiarrhythmic drugs, pointing out those drugs that have been documented to be effective in nonsustained ventricular tachycardia or sustained ventricular tachycardia and sudden cardiac death.

Topics: Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Encainide; Flecainide; Humans; Imipramine; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Piperidines; Tocainide

Topics: Action Potentials; Ajmaline; Amiodarone; Anilides; Animals; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Bretylium Tosylate; Disopyramide; Encainide; Hemodynamics; Humans; Kinetics; Moricizine; Morpholines; Phenothiazines; Piperidines; Verapamil

This is a first review of lorcainide hydrochloride, a new antiarrhythmic agent with local anaesthetic activity. The antiarrhythmic actions of lorcainide are mediated by an impairment of fast sodium conductance. Pharmacologically, this drug appears effective in suppressing reentry phenomena and ectopic pacemaker activity, especially in the ventricles. Lorcainide has only negligible depressant effects on important haemodynamic parameters and its toxicity is minimal. The drug is well absorbed by the oral route and its elimination half-life is long when compared with other substances. Lorcainide-induced QRS widening is directly correlated with the plasma levels of the drug. Preliminary experience in supraventricular arrhythmias is promising but pre-excitation syndromes and the ventricular arrhythmias are the main indications for this drug since a very high response rate has been observed in these conditions. Side effects are harmless and dose-dependent, but may be clinically troublesome.

Topics: Absorption; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Dogs; Electrocardiography; Guinea Pigs; Half-Life; Heart Conduction System; Hemodynamics; Humans; Kinetics; Lethal Dose 50; Mice; Myocardial Contraction; Piperidines; Rats

Topics: Androstanes; Animals; Arrhythmias, Cardiac; Blood Pressure; Bromides; Carbamates; Cardiovascular System; Curare; Dogs; Electrocardiography; Gallamine Triethiodide; Guinea Pigs; Heart Rate; Histamine Release; Humans; Muscle Relaxants, Central; Piperidines; Succinylcholine; Toxiferine; Tubocurarine

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Arrhythmias, Cardiac; Asian People; Benzamides; Case-Control Studies; Cisapride; Cross-Over Studies; Double-Blind Method; Electrocardiography; Female; Humans; Indoles; Irritable Bowel Syndrome; Long QT Syndrome; Male; Morpholines; Moxifloxacin; Piperidines; Placebos; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Mixed mood states in bipolar disorder are difficult to treat and when present indicate worse illness trajectories. Several medications are US Food and Drug Administration approved to treat mixed episodes; however, the clinical trials have been short term and rarely reported depression response.. We conducted a 5-month open-label trial examining the tolerability and efficacy of iloperidone for bipolar disorder mixed episodes.. Mania and depression scores significantly improved over the course of the study for study completers (ie, 60%-68% improvement for manic symptoms and 41%-49% for depression symptoms). Improvements were observed early in the trial and after adjusting for concomitant medication effects. The average daily dose in completers was 15 mg. Thirty-nine percent (12/31) of the eligible sample discontinued early because of adverse effects. The adverse events most commonly associated with withdrawal were increased heart rate/palpitations (n = 5 of 12) and urinary incontinence/intense urge to urinate (n = 3 of 12).. In a subset of patients, iloperidone provides relief for classic manic, depression, and irritability symptoms associated with mixed episodes in a long-term trial. Adverse effect profiles are likely to be a major factor contributing to individualized medication use.

Topics: Adult; Antipsychotic Agents; Arrhythmias, Cardiac; Bipolar Disorder; Female; Humans; Isoxazoles; Male; Piperidines; Treatment Outcome; Urinary Incontinence; Urinary Incontinence, Urge; Young Adult

Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Anesthesia; Anesthetics, Inhalation; Arrhythmias, Cardiac; Double-Blind Method; Electrocardiography; Female; Humans; Hypotension, Controlled; Long QT Syndrome; Male; Methyl Ethers; Middle Aged; Nitroglycerin; Piperidines; Prospective Studies; Remifentanil; Rhinoplasty; Sevoflurane; Vasodilator Agents; Young Adult

Female sex and age more than 65 years are common risk factors for the development of torsades de pointes in association with heart rate-corrected QT (QTc) interval prolongation, which can be induced by tracheal intubation during general anaesthesia. However, the administration of remifentanil can prevent intubation-induced QTc interval prolongation. We compared sex-related differences in the effect-site concentration (Ce) of remifentanil for preventing QTc interval prolongation among elderly patients.. Twenty-two female and 22 male patients older than 65 years were enrolled. Anaesthesia was induced with remifentanil and propofol using a target-controlled infusion. The Ce of remifentanil for maintaining a QTc interval prolongation <15 ms following intubation was determined for each sex using the isotonic regression method and a bootstrapping approach following Dixon's up-and-down method.. The Ce of remifentanil for preventing QTc interval prolongation following intubation in 50 % of the population (EC50) and 95 % of the population (EC95) were significantly lower in females than in males. Isotonic regression revealed that the EC50 (83 % confidence interval) of remifentanil was 3.50 (2.95-4.08) ng/mL in females and 4.38 (4.08-4.63) ng/mL in males. The EC95 (95 % confidence interval) of remifentanil was 4.43 (4.25-4.48) ng/mL in females and 4.94 (4.78-4.98) ng/mL in males.. Target-controlled infusion of remifentanil is effective in attenuating QTc interval prolongation after intubation among elderly patients and the Ce of remifentanil is lower in females than in males.

Topics: Aged; Aged, 80 and over; Anesthesia, General; Anesthetics, Intravenous; Arrhythmias, Cardiac; Drug Administration Schedule; Female; Health Services for the Aged; Heart Conduction System; Humans; Inhibitory Concentration 50; Intubation, Intratracheal; Male; Piperidines; Postoperative Complications; Propofol; Remifentanil; Sex Factors

Patients with type 2 diabetes are at increased susceptibility to a prolonged QT interval. Furthermore, insulin secretagogues, drugs used to treat diabetes, may prolong QT interval and provoke arrhythmias. We evaluated whether secretagogues can affect QTc interval during cardiac stress test in 20 patients with type 2 diabetes treated with secretagogues. ECG stress test was performed in all patients. QTc interval was calculated both before cardiac stress test (BCST) and at acme of cardiac stress test (ACST). Diabetic patients treated with secretagogues showed longer QTc-ACST values than those treated with metformin only. QTc-ACST values resulted shorter than QTc-BCST values in control group. Diabetic patients treated with secretagogues showed QTc-ACST values significantly longer than QTc-BCST values. In our study, diabetic patients treated with secretagogues did not show the QTc physiologic decrease that is a protective against arrhythmias. These results suggest to evaluate, in these patients, QT length, even during routine cardiac stress test.

Topics: Aged; Arrhythmias, Cardiac; Carbamates; Diabetes Mellitus, Type 2; Electrocardiography; Exercise Test; Female; Glyburide; Heart Rate; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Piperidines

Donepezil is a widely used cholinesterase inhibitor for the treatment of Alzheimer's disease (AD), however its cholinergic adverse side effects on the cardiovascular system are still unclear. In this study, we aimed to examine the adverse side effects caused by donepezil on cardiac rhythm and postural blood pressure changes in elderly patients with Alzheimer Disease.. The ECG parameters including heart rate, PR, QT, QTc interval and QRS duration and postural blood pressure changes were recorded at the baseline and at each donepezil dose level (5 and 10 mg/d). Patients Seventy-one consecutive patients who were referred by primary care centers to a Geriatric Clinic were enrolled and underwent comprehensive geriatric assessment.. Fifty-two subjects completed the study. There were no significant changes relative to the baseline in any of the ECG parameters or arterial blood pressure at any of the investigated dosages of donepezil.. It was demonstrated that donepezil was not associated with increased negative chronotropic, arrhythmogenic or hypotensive effects for elderly patients with Alzheimer's disease.

Topics: Aged; Aged, 80 and over; Alzheimer Disease; Arrhythmias, Cardiac; Blood Pressure; Cholinesterase Inhibitors; Donepezil; Electrocardiography; Female; Gastrointestinal Diseases; Heart Rate; Humans; Hypotension; Indans; Male; Nootropic Agents; Piperidines

To compare their effects on cardiorespiratoy and recovery parameters and side effects.. This study was performed in The Ministry of Health Ankara Numune Research and Training Hospital, Ankara, Turkey, from January to May 2005. The 40 American Society of Anesthesiology II/III patients were randomized into 2 groups. All patients received remifentanil 0.75 microgram.kg(-1); and then received either etomidate 0.1 mg.kg(-1) (group E, n=20) or propofol 0.5 mg.kg(-1) (group P, n=20). Cardiorespiratory data, induction time, recovery parameters, pain scores, number of shocks (NS), total amount of energy used (TE), side effects, and patient/cardiologist satisfaction were recorded.. Induction time and recovery parameters were shorter in group P. No differences were seen between the groups in NS and mean TE required. In group P, a statistically significant decrease in mean blood pressure occurred after induction and returned to its baseline levels in 6 minutes. After cardioversion over 2 minutes, the respiratory rates were decreased significantly more in group P when compared with group E. Two patients in group P became apneic and needed assisted ventilation. Pain scores, side effects and patient/cardiologist satisfaction were similar in both groups. No patients in either group had myoclonus.. We can induce hypnosis with propofol 0.5 mg.kg(-1) or etomidate 0.1 mg.kg(-1) by adding remifentanil 0.75 microgram.kg-1 in cardioversion anesthesia. Although recovery parameters were longer in group E, and cardiorespiratory parameters were less stable in group P, their usage with remifentanil was both acceptable for cardioversion anesthesia.

Topics: Aged; Analgesics, Opioid; Anesthesia; Anesthetics, Intravenous; Arrhythmias, Cardiac; Electric Countershock; Etomidate; Female; Humans; Male; Middle Aged; Piperidines; Propofol; Remifentanil

The pharmacokinetic properties of the short-acting micro opioid receptor-agonist remifentanil makes it possible to give cardiac surgical patients a deep intraoperative anesthesia without experiencing postoperative respiratory depression and a prolonged stay in the intensive care unit (ICU). However, previous investigations have shown that patients who received remifentanil required additional analgesia during the early postoperative period as compared to patients who received fentanyl. The aim of the present study therefore was to investigate the effects of supplementing remifentanil to a standard fentanyl-based anesthesia in coronary artery bypass grafting (CABG).. The study was prospective, randomized, double-blind, and placebo-controlled. Twenty male patients aged 55-70 years were included. All patients received a standard fentanyl and isoflurane-based anesthesia. In addition, the patients were randomized to receive either remifentanil 0.5 micro g kg(-1) min(-1) or placebo during surgery. Hemodynamic recordings and measurements of blood glucose and plasma adrenaline and noradrenaline were performed intra- and postoperatively.. Remifentanil reduced the hemodynamic and metabolic response to surgical stress compared to the standard fentanyl-based anesthetic regimen. However, the patients in the remifentanil group had a lower cardiac output (CO), left ventricular stroke work index (LVSWI), and mixed venous oxygen saturation (SvO(2)), and a higher central venous pressure (CVP) than the patients in the placebo group during the early postoperative phase, indicating a postoperative cardiac depression in the remifentanil group.. In CABG, remifentanil reduces the hemodynamic and metabolic responses during surgery but seems to give a cardiac depression in the early postoperative phase.

Topics: Aged; Anesthesia, General; Anesthesia, Intravenous; Anesthetics, Intravenous; Arrhythmias, Cardiac; Biomarkers; Blood Gas Analysis; Coronary Artery Bypass; Creatine Kinase; Depression, Chemical; Double-Blind Method; Electrocardiography, Ambulatory; Hemodynamics; Humans; Isoenzymes; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Postoperative Complications; Propofol; Prospective Studies; Remifentanil; Troponin I

S9788 is a triazineaminopiperidine derivative capable of reversing multidrug resistance (MDR) in vitro. In preclinical models S9788 was several fold more potent MDR inhibitor than verapamil or cyclosporine. At P-glycoprotein (Pgp) blocking concentrations, S9788 appeared to have only very little toxicity.. In a two step phase I trial we treated 39 patients with refractory cancer with S9788 and bolus doxorubicin. The steps differed mainly in the S9788 infusion duration; in the first part 23 patients received the MDR-reversing drug S9788 over 30 minutes, in the second step of the study 16 patients were administered S9788 over 150 minutes. The doses of S9788 were escalated in cohorts of three patients up to a dose level (DL) of 96 mg/m2 on the 30 minutes infusion, and to 144 mg/m2 on the 150 minutes infusion. The pharmacokinetics of S9788 were determined.. With the 30-minute infusion schedule symptomatic cardiac arrhythmia were found to be dose limiting. In all patients at the highest DL transient cardiac repolarization prolongation with a long QT-interval on ECG was demonstrated. With the 150-minute administration schedule, S9788 could be escalated up to 144 mg/m2 without subjective toxicity. However, transient QT prolongation was present in all patients. A third degree AV-block and a QT increase of about 40% occurred at the highest DL. Asymptomatic torsade de pointe (DL 96 mg/m2) was demonstrated on Holter recording in one patient. Theses repolarization disturbances with QT increase were considered dose limiting toxicity and the trial was closed. No arrhythmia related death was noted. Pharmacokinetics were similar with both infusion schedules with a mean alpha half life of 11.3 and 13.2 minutes, for the 30-minute and 150-minute infusion, and a terminal half life of 13.5 and 15 hours, respectively. QTc prolongation duration appeared to be dose-dependent.. With the tested infusion schedules, cardiac toxicity, in particular AV-blocks and QT prolongation, leading to ventricular arrhythmia and torsade de pointe, are the dose limiting toxicities of S9788. Our experience together with the observation of asymptomatic torsade de pointe in two other phase 1 trials of S9788 infused over six hours precluded the further clinical development of S9788.

Topics: Adult; Aged; Antineoplastic Agents; Arrhythmias, Cardiac; Doxorubicin; Drug Administration Schedule; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Torsades de Pointes; Triazines

Ninety-five patients with suspected acute myocardial infarction were randomly allocated on admission to hospital on a double blind basis to treatment with lorcainide, a Class 1C anti-arrhythmic drug, or matching placebo. Treatment was continued for 6 weeks. Twenty-four-hour ECG tape recordings were made immediately on admission, on the sixth or seventh day after admission, and again just before the end of the treatment period. Lorcainide was shown to be an effective anti-arrhythmic agent. The study was not designed to evaluate the effect of lorcainide on survival, but there were nine deaths among the 49 patients treated with lorcainide compared with only one in the patients given placebo. These findings are consistent with the results of the First and Second Cardiac Arrhythmia Suppression trials (CAST and CAST-II). This study was carried out in 1980 but was not published at the time: it now provides an interesting example of 'publication bias'.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Publishing; Survival Analysis; Time Factors

Previous reports have stated that pirmenol is a Class IA antiarrhythmic drug that prolongs the QT interval, but did not use computerized electrocardiography. We randomized 18 patients with frequent ventricular ectopic depolarizations to pirmenol (8 patients) or quinidine (10 patients). Pirmenol was effective and tolerated for suppression of arrhythmia in all 7 patients treated (1 patient withdrew for personal reasons) but quinidine was effective and tolerated for 4 weeks in only 5 of 10 patients (p less than 0.05). Using computerized 12-lead electrocardiography, the mean change in PR interval from placebo to treatment was 5 +/- 18 ms for quinidine and 5 +/- 11 ms for pirmenol (p = NS). The mean change in QRS interval was 5 +/- 14 ms for quinidine and 10 +/- 5 ms for pirmenol (p = NS). The mean change in QT interval was 46 +/- 30 ms for quinidine and 8 +/- 9 ms for pirmenol (p less than 0.01) and the mean change in JT interval was 41 +/- 36 ms for quinidine and -2 +/- 10 ms for pirmenol (p less than 0.01). After the double-blind phase, 4 quinidine patients had computerized electrocardiographic intervals measured on pirmenol; the above findings were confirmed. These electrocardiographic features of pirmenol clearly distinguish it from quinidine, the prototype Class IA drug. However, pirmenol has minimal effect on the PR and QRS intervals, and thus does not appear to be a Class IC drug either. Although its electrocardiographic features are closest to Class IB, its electrophysiology in isolated cells and its antiarrhythmic and side effect profile are atypical for a IB agent.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Double-Blind Method; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Quinidine; Stroke Volume

Intravenous lorcainide and lidocaine were administered to 25 patients with symptomatic ventricular tachyarrhythmias in a randomized single-blind crossover study. Prior to drug therapy, each patient underwent 48 hours of ambulatory monitoring and exercise testing on a motorized treadmill. At the completion of baseline studies, patients were randomized to receive either lidocaine or lorcainide intravenously. The dose of lidocaine was 1.0 mg/kg by bolus followed by an infusion of 2 to 3 mg/min. The dose of lorcainide was 2.0 mg/kg followed by a constant infusion of 200 to 300 mg over 24 hours. Two patients developed side effects on lidocaine and the infusion was discontinued prior to evaluation of efficacy. Of the remaining 23 patients, 11 (48%) had their arrhythmia controlled, defined as a greater than 90% reduction in repetitive forms (couplets and ventricular tachycardia) and a 50% reduction in ventricular premature beats. Lorcainide was effective in 8 of the 25 patients (32%). There was no correlation between the effect of lidocaine and the response to lorcainide (p = NS). Oral lorcainide therapy was administered to 17 patients who were free of side effects during the intravenous infusion. The oral drug was effective in nine patients (53%), five of whom had responded to the intravenous drug, and was ineffective in eight, seven of whom were also unresponsive to intravenous lorcainide. The intravenous drug predicted the response to the oral form in 71% of patients, but this was not statistically significant. Side effects occurred in 10 patients (59%) and were primarily neurologic.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Infusions, Intravenous; Lidocaine; Male; Middle Aged; Piperidines; Random Allocation

Suppression of premature atrial complexes by pirmenol, a new Class I antiarrhythmic agent, was examined following oral and intravenous routes of administration. In 4 patients, single intravenous doses of 50 to 150 mg reduced premature atrial beats greater than or equal to 90% for 2 to 4 h. Oral doses of 75 to 200 mg twice daily induced a mean arrhythmia reduction of greater than or equal to 80% in 5 out of 9 patients during a 24-h electrocardiographic recording compared with a baseline period of 48 h. No significant side-effects occurred. The results indicate that pirmenol effectively suppresses premature atrial complexes, which may be of value in the prevention of supraventricular tachyarrhythmias.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Heart Atria; Humans; Injections, Intravenous; Middle Aged; Piperidines

Thirty patients with frequent (greater than or equal to 30/hr) and repetitive ventricular premature beats (VPBs) unassociated with acute infarction were randomized to intravenous lorcainide (LOR) or lidocaine (LID). Following at least 2 hours of baseline Holter monitoring, patients received LOR, 2 mg/kg then 200 mg/24hr, or LID, 1 mg/kg then 2 mg/min, with rebolus if needed. Nonresponders detected by bedside telemetry were crossed over. Clinical response was 6 of 25 (24%) including two of nine crossovers with LOR and 8 of 26 (31%) including 3 of 12 crossovers with LID (p = NS). By computer analysis of 24-hour Holter monitors and asymptotic regression of success rates at hourly intervals, it was projected that greater than or equal to 80% reduction in VPBs occurred in 28% of LOR and in 25% of LID (p = NS), and complete suppression of repetitive VPBs occurred in 102% of LOR and in 92% of LID (p = NS). The mean drug levels were 405 ng/ml (range 371 to 463) with LOR and 3.4 micrograms/ml (range 2.1 to 3.6) with LID. Side effects were similar, occurring in 8 of 25 LOR trials and in 11 of 26 LID trials (p = NS). Thus, LOR and LID effectively suppress repetitive VPBs and to a lesser extent VPB frequency. However, neither drug is superior and each may be an effective alternative when resistance to the other is encountered.

Topics: Aged; Arrhythmias, Cardiac; Benzeneacetamides; Chronic Disease; Electrocardiography; Female; Humans; Infusions, Parenteral; Kinetics; Lidocaine; Male; Middle Aged; Monitoring, Physiologic; Myocardial Infarction; Piperidines; Random Allocation

Twenty-eight subjects underwent evaluation of drug toxicity and antiarrhythmic efficacy with oral and intravenous lorcainide. Lorcainide, a new type 1C antiarrhythmic drug, has an active metabolite, norlorcainide, which accumulates after oral but not significantly after intravenous administration. Group 1 consisted of 14 subjects who received intravenous lorcainide with an initial bolus of 2 mg/kg at a rate of 2 mg/min followed by 0.14 mg/min or 200 mg/24 hours. The lorcainide level after bolus was 0.432 micrograms/ml and fell to 0.178 micrograms/ml at 4 to 6 hours despite constant drug infusion. Prior work has demonstrated no detectable norlorcainide levels after intravenous infusion. Group II consisted of 14 subjects who received oral lorcainide, 100 mg orally every 8 hours. Mean lorcainide levels were 0.287 micrograms/ml and mean norlorcainide levels were 0.377 micrograms/ml. Only 2 of 12 subjects in group I experienced headache, dizziness, or sleep disturbance, compared to 12 of 14 subjects in group II (p less than 0.01). Intravenous lorcainide has a lower incidence of central nervous system side effects than oral lorcainide. These effects may be attributable to the accumulation of the norlorcainide metabolite with oral therapy.

Topics: Administration, Oral; Adolescent; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Central Nervous System; Female; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Monitoring, Physiologic; Piperidines

21 depressed patients of the Basle University Psychiatric Outpatient Clinic were treated in a double-blind study with paroxetine and amitriptyline. 11 of these patients did not continue the trial until the end of the 7th week. There was a significant difference in the number of dropouts between the two groups: 80% of the amitriptyline group did not continue until the end, while in the paroxetine group we found only 30% dropouts. The patients of both groups showed a gradual decrease of the median total scores on the Hamilton and the Montgomery and Asberg Depression Rating Scales. Although the number of patients who stayed in the trial for at least 4 weeks (8 with paroxetine, 6 with amitriptyline) is quite small, we see from the results of the clinical global impression that the members of the paroxetine group improved most of all in the somatic symptoms, while considering their moods we found no differences between the groups. Patients of both groups complained about side effects, most of all about dry mouth and tiredness. From the high rate of dropouts under amitriptyline we found that the side effects under this drug were more severe and therefore led to the dropouts.

Topics: Adolescent; Adult; Amitriptyline; Arrhythmias, Cardiac; Depressive Disorder; Double-Blind Method; Electroencephalography; Female; Humans; Male; Middle Aged; Paroxetine; Piperidines; Psychiatric Status Rating Scales

There is a need for effective, well tolerated, intravenous antiarrhythmic agents. The effects of lorcainide, a new class I antiarrhythmic agent, were compared with those of lidocaine in a randomized parallel study with cross-over option in 30 hospitalized patients with frequent (greater than 1/min) complex ventricular arrhythmias. Lorcainide loading dose was 2 mg/kg (at 2 mg/min) supplemented, if needed, with 100 mg in 1 hour; maintenance dose was 8 mg/h. Lidocaine loading dose was 1 mg/kg (at 25 mg/min) supplemented, if needed, with 50 mg in 2 minutes; maintenance dose was 2 or 3 mg/min (as needed). Arrhythmias were compared for 2 hours before and after drug loading. Initially responding patients (minimum of 70% arrhythmia suppression) were continued on maintenance therapy for 24 hours. Patients initially failing or with later arrhythmia escape crossed over to alternating therapy (seven to lidocaine, nine to lorcainide). The median frequency of premature ventricular complexes decreased by 76% after lidocaine (p less than 0.05) and by 93% after lorcainide (p less than 0.001); this difference approached significance (p = 0.06). More than 95% arrhythmia suppression was achieved by lorcainide in 47% of patients and by lidocaine in only 13% (p less than 0.05). Couplets decreased by a median of 100% after lorcainide and by 89% after lidocaine. Couplets were eliminated in 62% of the patients after lorcainide and in 27% after lidocaine (p = 0.06). There was 100% suppression of runs of premature beats in 11 patients after lorcainide and 99% suppression in 10 patients after lidocaine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Drug Administration Schedule; Electrocardiography; Female; Humans; Infusions, Parenteral; Lidocaine; Male; Middle Aged; Piperidines; Prospective Studies; Random Allocation; Time Factors

The effects on ventricular arrhythmias of a new class IA drug, flecainide, were compared with those of amiodarone in 10 patients with frequent, chronic, and stable ventricular ectopic beats (VEBs). The study consisted of an initial 1-week, placebo-controlled, baseline period followed by two 12-day, randomized, crossover, double-blind treatment periods with incremental dosage and 1 month of placebo between drug periods. Frequent VEBs, which were present in all 10 patients during both placebo control periods (30 or more VEBs/hour every hour, during 24-hour Holter monitoring), were markedly suppressed (reduction greater than 80%) in nine patients with both drugs (p less than 0.01). There was almost total abolition of the VEBs in six patients with flecainide, and the satisfactory results with a minimal dose in three demonstrate its fast onset of action. Side effects from either agent were infrequent and no discontinuation was necessary. We conclude from our study that flecainide is a highly effective antiarrhythmic agent.

Topics: Adult; Aged; Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzofurans; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Female; Flecainide; Heart Ventricles; Hemodynamics; Humans; Male; Middle Aged; Myocardial Contraction; Piperidines; Random Allocation

Flecainide acetate is a new orally active antidysrhythmic agent classified in the Ic category. Flecainide is effective in suppressing 88 to 100 percent of abnormal cardiac rhythms in the form of complex ventricular dysrhythmias, including couplets, ventricular tachycardia, reentrant junctional tachycardia, and Wolff-Parkinson-White syndrome. Flecainide appears to have a greater effect on conduction than on repolarization and only minimal effects on hemodynamic parameters. Flecainide is rapidly and completely absorbed after oral administration and has a 13-hour elimination half-life, allowing for twice-daily dosing regimens. Flecainide is generally well tolerated, with dizziness, blurred vision, nausea, and headache the most common side effects. Flecainide has been shown to be superior to quinidine and disopyramide in suppressing ventricular ectopic activity and may be considered a first-line oral agent for this indication. It is believe that flecainide has enough therapeutic advantages to be added to drug formularies.

Topics: Action Potentials; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Drug Interactions; Electrocardiography; Flecainide; Hemodynamics; Humans; Kinetics; Piperidines

The flecainide discovery and development process started in 1966 with the broad goal of investigating the effects of fluorine substitution in potential drug molecules. The overall process evolved slowly. The original goals of the project were translated into the 3 major phases: (1) the synthesis and evaluation of 2 major chemical series through the efforts of chemists who incorporated fluorine atoms into new compounds; (2) a change in focus from local anesthetic programs to the antiarrhythmic project through the efforts and advisement of pharmacologists; and (3) commitment to a flecainide development plan culminating in the new drug application for approval of flecainide in the suppression and prevention of ventricular arrhythmias.

Topics: Anesthetics, Local; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Drug Evaluation; Flecainide; Humans; Piperidines

In this multicenter trial, the efficacy and safety of flecainide, a new antiarrhythmic agent, were compared with those of quinidine, a standard antiarrhythmic agent in the United States. A randomized, parallel, placebo-controlled design was used. Flecainide was more effective than quinidine (p less than 0.0001) in reducing ventricular premature complexes, couplets and ventricular tachycardia. Flecainide continued to be effective in reducing ventricular arrhythmias during a 12-month follow-up period. The incidence of side effects was similar for the 2 drugs in both short- and long-term studies. Therefore, flecainide should be an excellent drug to use in treating patients with ventricular arrhythmias classified as either benign or potentially malignant.

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Electrocardiography; Flecainide; Humans; Piperidines; Quinidine; Random Allocation

Lorcainide is a type I antiarrhythmic drug of the local anesthetic type. It can be given either intravenously or orally, and its pharmacokinetic properties allow relatively long (12 hours) dosing intervals with oral administration. A slowly eliminated metabolite, norlorcainide, probably contributes to the effects of orally administered lorcainide in chronically treated patients. In mainly short term studies, lorcainide has been shown to suppress ventricular ectopy in about 80% of patients treated either orally or intravenously. Preliminary evidence suggests that its efficacy in suppressing ectopy in the setting of acute myocardial infarction is comparable with that of lignocaine (lidocaine). It is of variable efficacy in preventing recurrent ventricular tachycardia and has been shown to be effective in some patients who have failed to respond to other antiarrhythmic drugs. Experience is limited in treating supraventricular arrhythmia, but initial results in patients with Wolff-Parkinson-White syndrome have been favourable. Adverse cardiac effects are infrequent. Abnormal sinus node function may be exacerbated by lorcainide treatment, however, and bundle branch block may be precipitated in patients with pre-existing conduction system disease. Exacerbation of pre-existing arrhythmias is uncommon, and clinically important myocardial depression has not been observed. The most frequent side effect is disturbed sleep during the initiation of oral treatment, which may occur in the majority of patients but usually responds to treatment with a benzodiazepine and subsides with time. Thus, lorcainide appears useful against a variety of arrhythmias. With its convenient dosage schedule and apparently low incidence of serious side effects it should become a useful addition to the antiarrhythmic agents available, although longer term studies are needed to confirm its continued efficacy and lack of unexpected side effects when used for long periods.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Biological Availability; Clinical Trials as Topic; Drug Interactions; Electrophysiology; Half-Life; Hemodynamics; Humans; Kinetics; Piperidines; Wolff-Parkinson-White Syndrome

Lorcainide, a new class I antiarrhythmic agent, was administered intravenously to eight patients with acute myocardial infarction for 24 hours, and thereafter given by mouth, 200 mg daily for ten days. Ten control infarction patients were given lidocaine 3 mg/min during the first 24 hours and the oral betablocking agent, pindolol, for the following ten days. The two groups were comparable with respect to age, sex, onset-admission interval, and site and size of infarction. Ventricular premature beats were monitored with a 24-hour continuous ECG recording on days 1, 6 and 10. Complex ventricular premature beats were common during the first 24 hours of infarction; their occurrence and severity were similar in both groups, as judged by the Lown grading system. The plasma levels of lorcainide after the 24-hour infusion ranged 72-144 ng/ml (mean 95 ng/ml). On the sixth day, 12 hours after previous oral dose, lorcainide plasma levels ranged 11-82 ng/ml (mean 42 ng/ml). No major adverse effects were noticed, mild insomnia being the most disturbing reaction. It is concluded that lorcainide is an acceptable alternative to lidocaine in the treatment of ventricular arrhythmias in the acute stage of myocardial infarction. It has the advantage of being effective by oral route, too.

Topics: Administration, Oral; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Female; Humans; Infusions, Parenteral; Lidocaine; Male; Middle Aged; Myocardial Infarction; Pindolol; Piperidines; Random Allocation

Lorcainide, 100 mg twice daily was compared with placebo in 39 patients with frequent ventricular arrhythmias in a randomized double-blind crossover trial. A mean frequency of ventricular premature beats (VPBs) of at least 30 VPBs/hour was required during a drug-free period of 48 hours. Holter monitoring and a maximal symptom-limited exercise test were performed at the end of each of the 2-week double-blind treatment phase. The group averaged 350 +/- 361 (standard deviation) VPBs/hour. Lorcainide decreased the mean VPB frequency of the group by 46% (p less than 0.01), with VPB reduction beyond the expected variation in 22 of 39 patients. In 13 patients VPBs were unchanged and in 4 they increased. Eight additional patients responded during drug titration, for an overall response rate of 77% (30 of 39). Lorcainide did not significantly reduce the exercise-related VPB frequency. At 6 months 61% of patients had significant VPB suppression. Thus, lorcainide was effective in reducing the frequency and grade of spontaneous ventricular arrhythmias during short- and long-term evaluation.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Exercise Test; Female; Follow-Up Studies; Heart Ventricles; Hemodynamics; Humans; Male; Middle Aged; Piperidines; Random Allocation

The efficacy of a new antiarrhythmic agent, lorcainide, was compared with that of quinidine gluconate in a fixed-dose, randomized, crossover trial. Of 26 previously untreated patients with frequent ventricular ectopic beats documented by 24-hour ambulatory monitoring, 17 completed four weeks of therapy with quinidine and 12 with lorcainide. Of 22 patients receiving both drugs, early termination of therapy due to side effects occurred in ten (45 percent) patients receiving lorcainide and five (23 percent) receiving quinidine. Lorcainide (100 mg twice daily or three times daily, dependent on body weight) effectively suppressed ventricular arrhythmias in seven of 12 (58 percent) patients completing four weeks of therapy, and suppression by quinidine gluconate (324 mg three times daily) occurred in five of 12 (59 percent) patients. We conclude that in a dose of 100 mg twice or three times daily, lorcainide is as effective as quinidine gluconate, 324 mg three times daily, for the suppression of chronic ventricular arrhythmias. However, the high incidence of adverse reactions experienced with lorcainide make it an unacceptable agent for first-line antiarrhythmic therapy.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Female; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Quinidine; Random Allocation

The effectiveness and safety of intravenous flecainide was evaluated in 33 patients with chronic high frequency premature ventricular complexes (mean value of PVCs 23.7 min-1). Flecainide was injected intravenously at a rate of 20 mg per 2 min until complete disappearance of ventricular arrhythmias or up to a total dose not exceeding 200 mg. Total suppression of PVCs occurred in 31 out of 33 patients at the end of the injection (mean dose 132 mg). The overall reduction of PVCs was 94 per cent (P less than 0.001) at the end of infusion and 74 per cent (P less than 0.001) 1 h later. The mean plasma drug level attained 1 h after administration was 287 ng ml-1 (range 82-984). Heart rate and blood pressure did not change, but a significant increase (P less than 0.001) in PR (+12%), QRS (+13%) and QTc (+4%) duration occurred after drug administration. Flecainide was well tolerated. An idioventricular tachycardia was induced in one patient and two patients experienced side effects of the central nervous type: dizziness, blurring of vision and a sensation of warmth. In view of its activity flecainide appears to be a valuable addition to the antiarrhythmic armamentarium.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Clinical Trials as Topic; Electrocardiography; Female; Flecainide; Heart Rate; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines

Lorcainide, a new type I antiarrhythmic agent, was compared to quinidine in respect to antiarrhythmic efficacy and clinical safety. Thirteen subjects completed an open, randomized, crossover study with analysis of 24-hour ambulatory ECG monitoring and drug blood levels. The QRS and Q-T intervals increased with both lorcainide and quinidine. The mean reduction in total ventricular premature beats (VPBs) with quinidine was 16 percent compared to 68 percent with lorcainide (p less than .05). With lorcainide eight of 13 subjects had a significant (greater than 82 percent) reduction in VPBs compared to only three of 13 subjects taking quinidine (p less than .05). This same relationship was observed when mean VPB/1,000 heartbeats was analyzed. Ventricular tachycardia was no longer present in five of nine subjects taking lorcainide and in two of nine taking quinidine. No relationship could be established between drug level and arrhythmia suppression in this small population. Some CNS effects were reported in both groups, but no significant hematologic, chemical, or urinary adverse effects were seen with either drug. Thus, lorcainide compares favorably to quinidine in regard to arrhythmia suppression, but was limited in its clinical utility by CNS side effects.

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Male; Middle Aged; Piperidines; Quinidine; Tachycardia

The antiarrhythmic efficacy and safety of oral flecainide acetate and quinidine sulfate were compared in a double-blind, 16-center parallel trial involving 280 patients with chronic premature ventricular complexes (PVCs). Eighty-five percent of the flecainide patients had at least 80% suppression of PVCs, vs 57% of the quinidine patients (p less than 0.0001). Sixty-eight percent of the flecainide patients met the above criterion and also had complete suppression of couplets and beats of ventricular tachycardia, vs 33% of the quinidine patients (p less than 0.0001). PR and QRS intervals were prolonged by flecainide without clinical consequence, but they were not substantially affected by quinidine (p less than 0.0001). Quinidine prolonged JT (QT minus QRS) intervals significantly more than flecainide (p less than 0.05). Nineteen of 141 flecainide patients and 21 of 139 quinidine patients discontinued therapy because of side effects (p greater than 0.50). Flecainide side effects included dizziness, blurred vision, headache and nausea. Quinidine side effects included diarrhea, nausea, headache and dizziness. Flecainide was more effective than quinidine in suppressing chronic ventricular arrhythmias (especially complex forms), and thus is an important new antiarrhythmic agent.

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Quinidine; Random Allocation; Tachycardia

In a randomized placebo-controlled double-blind trial, we compared flecainide to quinidine for treatment of ventricular ectopic depolarizations in 19 patients. The mean percent suppression of total ventricular ectopic depolarizations was 95% for flecainide and 56% for quinidine (p less than 0.05). A greater than 80% reduction of total ventricular ectopic depolarizations was obtained in eight of nine patients given flecainide and in five of ten patients given quinidine (p = 0.09). After the randomized protocol, the patients who had received quinidine were given flecainide; 9 of the 10 patients had greater than 80% reduction of total ventricular ectopic depolarizations. Flecainide produced 100% suppression of nonsustained ventricular tachycardia and 99.5% suppression of paired ventricular depolarizations. Flecainide prolonged the PR and QRS intervals; quinidine prolonged the PR and JTC intervals. Side effects were commoner with quinidine than flecainide (p = 0.06). Three other patients failed to complete the protocol because of serious adverse experiences.

Topics: Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Double-Blind Method; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Quinidine; Random Allocation

Topics: Administration, Oral; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Double-Blind Method; Heart Ventricles; Humans; Injections, Intravenous; Piperidines

The authors report their clinical experience with flecainide, a new Class I antiarrhythmic drug, in 44 patients classified into three groups. The first group (7 cases) comprised patients with a wide range of arrhythmias sensitive to the usual antiarrhythmic agents. The second (17 cases) were atrial arrhythmias resistant to the usual antiarrhythmic agents and were mainly vagal atrial arrhythmias. The last group (20 cases) comprised patients with resistant VT, 14 of whom had underlying cardiac disease (8 chronic infarcts). The results obtained were analysed by a score test because of the wide range of arrhythmias and the wide variations in their spontaneous recurrent rate. The antiarrhythmic effect was checked by repeated Holter monitoring correlated with the results of interrogation. Provocative pacing studies were performed in 5 cases of inducible VT under therapy. The results with flecainide were compared with those obtained with reference Class I antiarrhythmics: quinidine, 700 to 1100 mg/day or disopyramide, 600 mg/day. Amiodarone was often associated with each Class I antiarrhythmic because of the resistant nature of these arrhythmias. In group I the results with flecainide were equivalent to those of quinidine. In the other two groups the results were significantly better than those of the reference antiarrhythmic: mean scores: group II 3,20 +/- 0,5 compared to 1,9 +/- 0,4 (p less than 0,01); group III 3,70 +/- 0,37 compared to 1,85 +/- 0,22 (p less than 0,001). Tolerance was good apart from neurosensory side effects (loss of accomodation, vertigo) which were dose dependent and which led to the withdrawal of therapy in only 4 cases. Four types of cardiac side effects were observed: aggravation of existing sinoatrial block (1 case); aggravation of existing intraventricular block (2 cases); aggravation of contractile function which was very poor before therapy (2 cases); and sudden death during therapy in patients with ischemic heart disease in cardiac failure and with incessant resistant VT (2 cases). In these instances the role of the drug cannot be confirmed. These complications were observed with doses of more than 5 mg/kg/day and in patients with cardiac failure. Two of these patients had serum flecainide levels which were very high. It may therefore be possible to reduce the incidence of these complications by adapting dosage to the patient's clinical state and to the serum drug levels.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Drug Tolerance; Electrocardiography; Female; Flecainide; Humans; Male; Middle Aged; Piperidines

A 3-stage, concentration-maintaining intravenous infusion regimen of pirmenol, a new antiarrhythmic agent, was tested for efficacy and safety in 8 subjects with chronic, stable premature ventricular beats. The regimen, which consisted of (1) a priming bolus of 50 mg over 2 minutes, followed by (2) a rapid loading infusion of 2.5 mg/min for 1 hour, and (3) a maintenance infusion of 0.25 mg/min, rapidly achieved and maintained stable plasma pirmenol levels from 0.94 to 2.75 micrograms/ml, during infusions lasting up to 48 hours. Therapeutic efficacy was evaluated during 4-hour infusions in 5 patients utilizing a randomized, double-blind, placebo-controlled study design. Pirmenol suppressed average premature ventricular beat frequency 93 +/- 6% compared with control values (p = 0.03). Pirmenol infusions were unassociated with toxicity. There were slight but significant increases in diastolic blood pressure, QRS duration, and corrected Q-T interval. No significant changes occurred in systolic blood pressure, heart rate, P-R interval, or laboratory variables. Pirmenol is a promising therapeutic agent that warrants further evaluation. The 3-stage infusion satisfactorily achieves and maintains therapeutic plasma pirmenol levels.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Double-Blind Method; Drug Evaluation; Electrocardiography; Female; Heart Rate; Humans; Infusions, Parenteral; Kinetics; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Random Allocation

Several therapeutic approaches have sought to prevent the occurrence of sudden cardiac death. Many sudden deaths are presumed to be due to an arrhythmia, but the drugs best known for antiarrhythmic activity, the local anesthetic agents, have not been suitable prophylactic agents because of their toxicities and other undesirable pharmacologic characteristics. Several new drugs in this class have been synthesized and are currently being tested for antiarrhythmic activity in clinical trials. One of them may prove to be worthy of a large-scale clinical trial to determine whether chronic arrhythmia suppression reduces the risk of sudden death. The characteristics of the "ideal" antiarrhythmic agent are discussed, and a brief summary of the drugs currently being tested in the United States is presented. The discussion of each drug emphasizes the characteristics that might make it suitable--or unsuitable--for use in a sudden-death trial. Many agents being tested are clearly not satisfactory for such a trial. However, they may be prototypes for an ideal drug or combination of drugs that might yet be developed.

Topics: Acecainide; Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Bretylium Compounds; Clinical Trials as Topic; Death, Sudden; Encainide; Flecainide; Humans; Kinetics; Lidocaine; Mexiletine; Moricizine; Morpholines; Phenothiazines; Piperidines; Tocainide; Verapamil

In a blind cross-over study, 12 patients with ventricular arrhythmias (VPC's; Lown Grades II-IVB) resistant to a daily dose of quinidine 1.2 g, disopyramide 0.8 g, N-propyl-ajmaline 0.1 g were randomly given, each dose for one week, placebo (PL), mexiletine (MEX; 400, 600, 800 mg daily) and lorcainide (LOR; 200, 300, 400 mg daily). On the last day of each treatment period, patients were evaluated by 24-h continuous ambulatory monitoring, 6-channel surface ECG, plasma concentrations and side-effects. During PL I (before) and PL II (after drug treatment), the mean number of VPCs per hour was 670 and 701. VPCs were reduced in 5 of the 12 patients with MEX by 43% (400 mg), 74% (600 mg) and 91% (800 mg). VPCs were reduced in 10 patients with LOR by 60% (200 mg), 78% (300 mg) and 93% (400 mg). Log. lin. plasma conc. effect relationships were constructed for MEX and LOR. Vomiting, nausea, and abdominal pain were seen in 2 patients with MEX; insomnia and feeling heat in 10 patients with LOR. At the end of the LOR-treatment, these side-effects were less in 5 and absent in 5 patients. In this study, LOR seems superior to MEX in refractory ventricular arrhythmias.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Coronary Disease; Dose-Response Relationship, Drug; Electrocardiography; Female; Heart Failure; Heart Ventricles; Humans; Male; Mexiletine; Middle Aged; Mitral Valve Prolapse; Piperidines; Propylamines; Random Allocation

Flecainide acetate, a new antiarrhythmic agent, was given orally to 11 hospitalized patients with chronic high-frequency ventricular ectopic depolarizations. Drug effectiveness was evaluated with a dose-ranging single-blind protocol, which included placebo control and washout periods. Twice-daily dosing (average daily dose 436 mg) completely suppressed all ventricular ectopic activity in five of 11 patients; average suppression in the 11 patients was 96.3%. Complex ventricular arrhythmias, which were present in all 11 patients during the placebo control period, were completely suppressed in eight patients and markedly suppressed in the other three patients during flecainide therapy. Ejection fraction and velocity of circumferential fiber shortening measured by M-mode echocardiography did not change significantly during flecainide dosing. Ventricular arrhythmias returned in all patients during the placebo washout period. During subsequent outpatient therapy with flecainide, significant suppression was present after 1 and 2 weeks of treatment (94.4% and 93.3%, respectively). Drug elimination was slow (average plasma half-life 20 hours). Ninety-five percent suppression of ventricular ectopic depolarization during dosing and 5% reappearance of arrhythmias during washout occurred with flecainide concentrations of 200-800 ng/ml. Side effects occurred in five of 11 patients, but did not require discontinuation of the drug. These results indicate that flecainide is a very effective antiarrhythmic agent that merits further clinical investigation.

Topics: Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Humans; Kinetics; Male; Middle Aged; Piperidines; Stroke Volume

The effectiveness and safety of oral flecainide for suppression of complex ventricular arrhythmias was tested in nine patients in a short-term (4 wk), single-blind, placebo-controlled experiment. The prevalence of multiform premature ventricular complexes (PVCs), couplets and nonsustained ventricular tachycardia (VT) (less than 3 PVCs at rate less than 100/min) was determined by 48-hr Holter monitoring on placebo and flecainide (200 to 300 mg b.i.d.) therapy. Multiform PVCs/hr were reduced by 96% in eight of nine patients (P less than 0.001). Couplets per 24-hr period were suppressed entirely in six patients (P less than 0.001). Couplets per 24-hr period were suppressed entirely in six patients (P less than 0.001) and reduced by 92% in the remaining two patients. VT runs per 24 hr were abolished in six patients (P less than 0.02) and reduced by 91% in one. As a group the frequency of PVCs per hour, couplets per 24 hr and VT per 24 hr was reduced by 96% (P less than 0.01) over than in the preceding placebo period. Flecainide (P less than 0.02) slowed heart rate by 10% and prolonged PR, QRS, and QTc intervals by 31%, 47% and 6%. No hematologic, hepatic, or renal abnormalities were found. Side effects were mild, transient, and central nervous system related; blurring of vision was the most frequent effect and was reported in four patients.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Drug Evaluation; Electrocardiography; Female; Flecainide; Heart Rate; Humans; Male; Middle Aged; Piperidines

The antiarrhythmic efficacy and safety of oral flecainide acetate were assessed during a controlled, short-term dosage-maintenance study. Thirteen patients with chronic ventricular ectopy entered a placebo control period, and 11 with persistent, frequent (greater than 600 per 12 hours) premature ventricular complexes (PVCs) advanced to drug therapy. Of 10 patients completing a trial of different doses, nine responded completely, with a mean PVC suppression of 98,3 per cent. Repetitive PVCs were eliminated. The mean effective dose was 189 mg per 12 hours, and the effective plasma concentration before administration of a dose averaged 635 ng per milliliter. One patient responded partially (68 per cent of PVCs suppressed). Flecainide continued to be effective and well tolerated at the end of a two-week outpatient trial in the nine complete responders, maintaining an average PVC suppression of 94.6 per cent. The PR and QRS intervals were mildly prolonged. The echocardiographic ejection fraction was unchanged during treatment. The elimination half-life was long - 18.8 +/- 3.8 hours. Flecainide thus appears to be a highly effective and well-tolerated antiarrhythmic agent with favorable pharmacokinetics.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Electrocardiography; Female; Flecainide; Half-Life; Heart Ventricles; Hemodynamics; Humans; Kinetics; Male; Middle Aged; Piperidines; Time Factors

A new anti-arrhythmic agent, lorcainide, has been compared with lignocaine in patients with acute myocardial infarction. Lorcainide has been shown to be as effective as lignocaine in suppressing ventricular ectopy. Lorcainide is unusually free of side-effects and has the great advantage over lignocaine of being effective when given orally.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Drug Evaluation; Humans; Lidocaine; Piperidines; Time Factors

We studied the antiarrhythmic effect of a range of oral doses of encainide in 11 patients with stable high-frequency ventricular arrhythmias. Total suppression of arrhythmia was documented in 10 patients at a wide range of doses and plasma concentrations, and the suppression was subsequently verified in a placebo-controlled crossover study. Drug elimination was rapid (the half-life was 1.9 to 3.8 hours), but the margin between efficacy and side effects was sufficiently wide for therapy every six to 12 hours to be feasible in all 10 patients, with continuing outpatient treatment at six to 12 months. Marked prolongation of PR (mean, 44 per cent) and QRS (mean, 47 per cent) durations coincided with abolition of arrhythmia, but no evidence that these effects were detrimental was observed in radionuclide ventriculograms, exercise testing, or prolonged monitoring. A single patient whose arrhythmia and electrocardiogram were unchanged during therapy eliminated the drug much more slowly than the others and was the only patient in whom no O-demethyl form could be detected in plasma, suggesting that this metabolite may be active. In this study, encainide was a highly effective, well-tolerated antiarrhythmic agent.

Topics: Adult; Aged; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Dose-Response Relationship, Drug; Electrocardiography; Encainide; Exercise Test; Female; Heart; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Tachycardia; Time Factors

In vitro animal studies suggest melperone, a neuroleptic butyrophenone, to be a type III antiarrhythmic drug according to the classification of Vaughan Williams. It has no negative inotropic effect on cardiac muscle. A double-blind trial of 3 hours' duration was carried out with melperone and placebo in 26 patients admitted to the CCU with suspected acute myocardial infarction (AMI) and ventricular arrhythmias. Melperone, 50 mg i.v., was superior to placebo in reducing the total number of ventricular ectopic beats (VEB) as well as the number of minutes with either frequent, multifocal, R-on-T-type or runs of VEB. The reduction became statistically significant in the second treatment hour in patients with definite AMI. Melperone induced sedation and reduction of systemic BP in most of the patients. Two patients with low initial systolic BP achieved a further reduction and had BP levels below 90 mmHg. Two patients experienced minor side-effects. In conclusion, melperone administered in large i.v. doses to patients with AMI induced sedation, acute BP reduction and some reduction of ventricular arrhythmia. X

Topics: Aged; Arrhythmias, Cardiac; Blood Pressure; Butyrophenones; Double-Blind Method; Female; Heart Rate; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Placebos

Encainide is a new anti-arrhythmic drug, which is highly effective against ventricular extrasystoles, both single and coupled, in the dose range of 80--140 mg i.v. Ventricular extrasystoles were abolished in 31 out of 33 cases treated. The drug is also relatively effective against supraventricular extrasystoles, but has little effect on atrial fibrillation. Both subjects with clinically normal hearts and those with ischaemic heart disease have been successfully treated. The drug prolongs the QRS and QT duration. Its effectiveness appears to be of the same order of magnitude and the range of indications similar to those of aprindine and lorcainide. Further study of the drug seems to be warranted.

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Clinical Trials as Topic; Heart Ventricles; Humans; Middle Aged; Piperidines; Tachycardia; Time Factors

The disposition and the antiarrhythmic effect of lorcainide (R 15,889) were investigated in 11 patients with ventricular premature beats (VPB) after a single intravenous dose of 100 mg or 2 mg/kg and after multiple intravenous and oral dosing. Pharmacokinetic parameters were computed according to the two-compartment open model. The half-life of the initial phase, t 1/2 (alpha), was calculated as 0.3 +/- 0.1 hr (mean +/- SD) and the terminal half-life, t 1/2 (beta), varied independently of the dose and route of administration between 5.8 and 12.5 hr (7.8 +/- 2.5 hr). After the single intravenous dose total plasma clearance (Cl) ranged from 570 to 1670 ml/min (988 +/- 425 ml/min) while after multiple dosing Cl decreased to 666 +/- 27 ml/min. Comparison of the area under the curves during steady state (ss) indicated a complete bioavailability of multiple oral doses. After the single intravenous dose, VPB were diminished or reduced for about 4 hr if the plasma concentrations exceeded 120 to 150 ng/ml. During ss-therapy plasma levels fluctuated between 200 and 550 ng/ml with an effective prevention of arrhythmias. Thus, the new drug demonstrates a therapeutic range of approximately 150 to 400 ng/ml and oral therapy seems to be effective with 100 mg t. i. d.

Topics: Acetanilides; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Dealkylation; Electrocardiography; Female; Half-Life; Heart Ventricles; Humans; Kinetics; Male; Middle Aged; Piperidines

The effectiveness of perhexiline maleate in the suppression of ventricular ectopic activity has been studied in 10 patients after myocardial infarction. Before treatment all patients exhibited frequent ectopic beats, i.e. more than 8 per hour. Numerous Holter magnetic tape recordings were made over a 9 - 10-month period of treatment. During the entire period of monitoring significant suppression of ectopic activity was observed in 5 patients and transient suppression in 4, of whom 3 subsequently showed a transient increase. The drug was discontinued in 1 patient because of nausea, anorexia and weight loss. No other adverse effects were encountered.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Clinical Trials as Topic; Humans; Male; Middle Aged; Myocardial Infarction; Perhexiline; Piperidines; Ventricular Fibrillation

Lorcainide is a promising antiarrhythmic agent that belongs to the class of local anesthetics. It was tested in 7 patients with malignant ventricular arrhythmias that were resistant to other antiarrhythmic agents. Lorcainide was effective in all cases (complete disappearance of arrhythmias in 6 cases and more than 50% disappearance in the 7th case), and the tolerance was within acceptable limits. The drug was effective at rest, as assessed by 24-h dynamic electrocardiographic monitoring, and during physical exercise. Longer studies with more patients are warranted, since the drug appears to be a promising antiarrhythmic agent.

Topics: Acetanilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Clinical Trials as Topic; Exercise Test; Female; Humans; Male; Middle Aged; Piperidines

Topics: Administration, Oral; Aged; Alanine Transaminase; Angina Pectoris; Animals; Arrhythmias, Cardiac; Aspartate Aminotransferases; Clinical Trials as Topic; Coronary Disease; Dose-Response Relationship, Drug; Drug Evaluation; Electrocardiography; Female; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Contraction; Nitroglycerin; Oxygen Consumption; Perhexiline; Piperidines; Prognosis

The antiarrhythmic activity of diphenidol, an antiemetic, has been demonstrated both in electrophysiologic studies of patiens and in experimental arrhythmias in animals. Accordingly, 18 patients with tachyarrhythmias were treated with intravenous diphenidol in doses of 0.5 to 1.5 mg/kg. In six patients with atrial arrhythmias, there was no notable effect. Similarly, 12 patients with premature ventricular contractions were treated and studied. In six of them, ectopic beats were abolished, at least transiently; in three the number of ventricular premature contractions decreased; in two there was no effect; and in one, the number of premature beats was increased. Of the total number of 18 patients, 14 suffered adverse effects related to the central nervous system. These adverse effects were of such severity as to suggest that further studies with diphenidol as an antiarrhythmic are not warranted.

Topics: Aged; Arrhythmias, Cardiac; Butanols; Central Nervous System; Clinical Trials as Topic; Confusion; Digitalis Glycosides; Dyspnea; Electrocardiography; Electrophysiology; Hemodynamics; Humans; Injections, Intravenous; Middle Aged; Piperidines; Placebos

Topics: Angina Pectoris; Animals; Arrhythmias, Cardiac; Clinical Trials as Topic; Dogs; Hemodynamics; Humans; Perhexiline; Piperidines; Placebos; Rats

Topics: Aggression; Analysis of Variance; Arrhythmias, Cardiac; Basal Ganglia Diseases; Benzoates; Butyrophenones; Chronic Disease; Clinical Trials as Topic; Dose-Response Relationship, Drug; Handwriting; Humans; Male; Piperidines; Placebos; Psychiatric Status Rating Scales; Schizophrenia; Statistics as Topic; Tranquilizing Agents; Tremor

Topics: Aged; Angina Pectoris; Arrhythmias, Cardiac; Aspartate Aminotransferases; Clinical Trials as Topic; Drug Evaluation; Electrocardiography; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Placebos; Time Factors; Vasodilator Agents

Topics: Aged; Arrhythmias, Cardiac; Clinical Trials as Topic; Coronary Disease; Electrocardiography; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Vasodilator Agents

Topics: Adult; Aged; Arrhythmias, Cardiac; Clinical Trials as Topic; Electrocardiography; Female; Humans; Male; Middle Aged; Monitoring, Physiologic; Perhexiline; Piperidines; Vasodilator Agents

Antihistamines are among the most widely used medications in the world. Ebastine is an antihistaminic which is long-acting, second-generation, and selective H1-receptor inverse agonist. I report a twelve-year-and-six-month-old girl with temporary prolongation of the QTc interval caused by acute ebastine intoxication due to TikTok challenge. Initial electrocardiogram showed sinus arrhythmia (72 beats/min) and prolongation of the QTc interval (QTc 482 milliseconds). Gastric lavage was performed. Intravenous fluid was administered, and activated charcoal (1 g/kg/per dose) was given. Electrocardiogram 9 h after drug ingestion showed sinus rhythm and normal QTc interval (QTc 414milliseconds). During follow-up, no electrocardiogram abnormalities were detected with electrocardiogram monitoring. She was discharged on day 2 without any complications. This case report is the first in the literature to show acute intoxication with ebastine due to challenge video on TikTok, which leads to a temporary prolongation of the QTc interval. Also, with this case report, I assert the fact that it is important to properly supervise the use of social media, such as TikTok and to review the content of TikTok videos.

Topics: Arrhythmias, Cardiac; Drug Inverse Agonism; Electrocardiography; Female; Histamine H1 Antagonists; Humans; Infant; Long QT Syndrome; Piperidines; Social Media

(No abstract allowed for commentary).

Topics: Arrhythmias, Cardiac; Humans; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Tyrosine Kinase Inhibitors

Sudden cardiac death (SCD) remains a major cause of global mortality. In addition to modern interventions, botanical folk medicines have long been used to treat cardiovascular disease, although the efficacy and underlying mechanisms are often unresolved. Aloperine, a bioactive quinolizidine alkaloid isolated from Sophora alopecuroides plants, exhibits antioxidant, anti-inflammatory, antitumor, and vasorelaxant properties, but possible antiarrhythmic effects of aloperine in SCD are unclear. Here, we examined whether aloperine protects against ischemia and reperfusion injury-associated lethal ventricular arrhythmia and sudden cardiac death. Rats were divided into sham, control, and aloperine groups, and reperfusion-provoked ventricular arrhythmogenesis, cardiac damage markers, and signaling pathways quantified following left main coronary artery ischemia and reperfusion. In vitro studies of effects of aloperine on hERG and Kv4.3 cardiac voltage-gated potassium (Kv) channels were performed using two-electrode voltage clamp analysis of cloned channels expressed in Xenopus laevis oocytes. Aloperine pretreatment (10 mg/kg) did not affect baseline cardiac electrical stability; yet, it reduced ventricular arrhythmogenesis and susceptibility to SCD (mortality rate: control: 64.3%; aloperine: 0%) induced by reperfusion injury. Aloperine also reduced serum levels of LDH, CK-MB, α-HBDH, and cTnI post-I/R, and stimulated phosphorylation of ventricular ERK1/2 and STAT-3, which are key components of RISK and SAFE signaling pathways. Inhibition of either ERK1/2 (with U0126) or STAT-3 (with Ag490) abolished aloperine-induced anti-arrhythmic effects and ERK1/2 and STAT-3 phosphorylation. Interestingly, while aloperine (100 μM) had no effect on cloned Kv4.3 activity, aloperine (1 μM and up) negative-shifted the voltage dependence of hERG activation by ~10 mV and increased peak hERG current by 35%. Thus, aloperine exerts striking anti-arrhythmic effects against myocardial ischemia and reperfusion injury-induced severe lethal ventricular arrhythmia and sudden cardiac death via the ERK1/2/STAT-3 signaling pathway, with potential additional contribution from increased cardiac myocyte repolarization capacity via augmented hERG activity.

Topics: Alkaloids; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Myocardial Reperfusion Injury; Myocytes, Cardiac; Piperidines; Rats

hERG is a voltage-gated potassium channel involved in the heart contraction whose defections are associated with the cardiac arrhythmia Long QT Syndrome type 2. The activator RPR260243 (RPR) represents a possible candidate to pharmacologically treat LQTS2 because it enhances the opening of the channel. However, the molecular detail of its action mechanism remains quite elusive. Here, we address the problem using a combination of docking, molecular dynamics simulations, and network analysis. We show that the drug preferably binds at the interface between the voltage sensor and the pore, enhancing the canonical activation path and determining a whole-structure rearrangement of the channel that slightly impairs inactivation.

Topics: Arrhythmias, Cardiac; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Heart; Humans; Piperidines

Cardiotoxicity by tyrosine kinase inhibitors remains an important concern. Nilotinib and vandetanib clinically carry high proarrhythmic risk and the exact mechanism underlying arrhythmogenesis is not fully understood. In this study, we investigated the effects of nilotinib and vandetanib on the abundance of human ether-á-go-go-related gene (hERG) K

Topics: Arrhythmias, Cardiac; Down-Regulation; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Quinazolines

Background Ibrutinib and acalabrutinib are Bruton tyrosine kinase inhibitors used in the treatment of B-cell lymphoproliferative disorders. Ibrutinib is associated with new-onset atrial fibrillation. Cases of sinus bradycardia and sinus arrest have also been reported following ibrutinib treatment. Conversely, acalabrutinib is less arrhythmogenic. The basis for these different effects is unclear. Methods and Results The effects of ibrutinib and acalabrutinib on atrial electrophysiology were investigated in anesthetized mice using intracardiac electrophysiology, in isolated atrial preparations using high-resolution optical mapping, and in isolated atrial and sinoatrial node (SAN) myocytes using patch-clamping. Acute delivery of acalabrutinib did not affect atrial fibrillation susceptibility or other measures of atrial electrophysiology in mice in vivo. Optical mapping demonstrates that ibrutinib dose-dependently impaired atrial and SAN conduction and slowed beating rate. Acalabrutinib had no effect on atrial and SAN conduction or beating rate. In isolated atrial myocytes, ibrutinib reduced action potential upstroke velocity and Na

Topics: Action Potentials; Adenine; Animals; Arrhythmias, Cardiac; Atrial Fibrillation; Benzamides; Cardiac Electrophysiology; Mice; Myocytes, Cardiac; Piperidines; Pyrazines; Sinoatrial Node

Acetylcholinesterase inhibitors such as donepezil delay the progression of Alzheimer's dementia by increasing acetylcholine concentrations in the central nervous system. However, it is becoming apparent that cholinesterase inhibition by donepezil is not confined to the brain. This is supported by previous case reports of peripheral cholinergic side effects and adverse cardiac arrhythmias such as Torsades de Pointes which are reversible upon cessation of donepezil. The augmented acetylcholine concentrations and I

Topics: Alzheimer Disease; Animals; Arrhythmias, Cardiac; Atrioventricular Block; Cholinesterase Inhibitors; Dogs; Donepezil; Halothane; Indans; Piperidines

Repolarization alternans, a periodic oscillation of long-short action potential duration, is an important source of arrhythmogenic substrate, although the mechanisms driving it are insufficiently understood. Despite its relevance as an arrhythmia precursor, there are no successful therapies able to target it specifically. We hypothesized that blockade of the sodium‑calcium exchanger (NCX) could inhibit alternans. The effects of the selective NCX blocker ORM-10962 were evaluated on action potentials measured with microelectrodes from canine papillary muscle preparations, and calcium transients measured using Fluo4-AM from isolated ventricular myocytes paced to evoke alternans. Computer simulations were used to obtain insight into the drug's mechanisms of action. ORM-10962 attenuated cardiac alternans, both in action potential duration and calcium transient amplitude. Three morphological types of alternans were observed, with differential response to ORM-10962 with regards to APD alternans attenuation. Analysis of APD restitution indicates that calcium oscillations underlie alternans formation. Furthermore, ORM-10962 did not markedly alter APD restitution, but increased post-repolarization refractoriness, which may be mediated by indirectly reduced L-type calcium current. Computer simulations reproduced alternans attenuation via ORM-10962, suggesting that it is acts by reducing sarcoplasmic reticulum release refractoriness. This results from the ORM-10962-induced sodium‑calcium exchanger block accompanied by an indirect reduction in L-type calcium current. Using a computer model of a heart failure cell, we furthermore demonstrate that the anti-alternans effect holds also for this disease, in which the risk of alternans is elevated. Targeting NCX may therefore be a useful anti-arrhythmic strategy to specifically prevent calcium driven alternans.

Topics: Acetamides; Action Potentials; Animals; Arrhythmias, Cardiac; Calcium; Calcium Signaling; Chromans; Dogs; Heart Conduction System; Myocytes, Cardiac; Piperidines; Sodium-Calcium Exchanger

Human Ether-à-go-go (hERG) channels contribute to cardiac repolarization, and inherited variants or drug block are associated with long QT syndrome type 2 (LQTS2) and arrhythmia. Therefore, hERG activator compounds present a therapeutic opportunity for targeted treatment of LQTS. However, a limiting concern is over-activation of hERG resurgent current during the action potential and abbreviated repolarization. Activators that slow deactivation gating (type I), such as RPR260243, may enhance repolarizing hERG current during the refractory period, thus ameliorating arrhythmogenicity with reduced early repolarization risk. Here, we show that, at physiological temperature, RPR260243 enhances hERG channel repolarizing currents conducted in the refractory period in response to premature depolarizations. This occurs with little effect on the resurgent hERG current during the action potential. The effects of RPR260243 were particularly evident in LQTS2-associated R56Q mutant channels, whereby RPR260243 restored WT-like repolarizing drive in the early refractory period and diastolic interval, combating attenuated protective currents. In silico kinetic modeling of channel gating predicted little effect of the R56Q mutation on hERG current conducted during the action potential and a reduced repolarizing protection against afterdepolarizations in the refractory period and diastolic interval, particularly at higher pacing rates. These simulations predicted partial rescue from the arrhythmic effects of R56Q by RPR260243 without risk of early repolarization. Our findings demonstrate that the pathogenicity of some hERG variants may result from reduced repolarizing protection during the refractory period and diastolic interval with limited effect on action potential duration, and that the hERG channel activator RPR260243 may provide targeted antiarrhythmic potential in these cases.

Topics: Arrhythmias, Cardiac; ERG1 Potassium Channel; Ether; Ether-A-Go-Go Potassium Channels; Humans; Long QT Syndrome; Piperidines; Quinolines

Human ether-à-go-go related gene (hERG) K

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Heart Rate; Kinetics; Myocytes, Cardiac; Oocytes; Piperidines; Quinolines; Refractory Period, Electrophysiological; Signal Transduction; Xenopus laevis; Zebrafish; Zebrafish Proteins

Mutations in KCNH2 can lead to long QT syndrome type 2. Variable disease manifestation observed with this channelopathy is associated with the location and type of mutation within the protein, complicating efforts to predict patient risk. Here, we demonstrated phenotypic differences in cardiomyocytes derived from isogenic human induced pluripotent stem cells (hiPSC-CMs) genetically edited to harbor mutations either within the pore or tail region of the ion channel. Electrophysiological analysis confirmed that the mutations prolonged repolarization of the hiPSC-CMs, with differences between the mutations evident in monolayer cultures. Blocking the hERG channel revealed that the pore-loop mutation conferred greater susceptibility to arrhythmic events. These findings showed that subtle phenotypic differences related to KCNH2 mutations could be captured by hiPSC-CMs under genetically matched conditions. Moreover, the results support hiPSC-CMs as strong candidates for evaluating the underlying severity of individual KCNH2 mutations in humans, which could facilitate patient risk stratification.

Topics: Arrhythmias, Cardiac; Cell Line; Electrophysiology; ERG1 Potassium Channel; Gene Editing; Genetic Predisposition to Disease; Humans; Induced Pluripotent Stem Cells; Long QT Syndrome; Models, Biological; Mutation; Myocytes, Cardiac; Patch-Clamp Techniques; Piperidines; Pyridines

Topics: Animals; Arrhythmias, Cardiac; Benzodiazepinones; Disease Models, Animal; Hypoglycemia; Male; Mecamylamine; Muscarinic Antagonists; Nicotinic Antagonists; Parasympathetic Nervous System; Piperidines; Rats; Rats, Sprague-Dawley; Sympathectomy, Chemical; Vagotomy

The physiological role of cardiac late Na

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Disease Models, Animal; Female; Heart Rate; Heart Ventricles; In Vitro Techniques; Isolated Heart Preparation; Kinetics; Myocytes, Cardiac; Piperidines; Pyridines; Rabbits; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin; Triazoles

Topics: Adenine; Adverse Drug Reaction Reporting Systems; Aged; Arrhythmias, Cardiac; Drug Monitoring; Female; Humans; Incidence; Lymphoproliferative Disorders; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Adenine; Arrhythmias, Cardiac; Humans; Piperidines; Pyrazoles; Pyrimidines

Human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes hold great potentials to predict pro-arrhythmic risks in preclinical cardiac safety screening, although the hiPSC cardiomyocytes exhibit rather immature functional and structural characteristics, including spontaneous activity. Our physiological characterization and mathematical simulation showed that low expression of the inward-rectifier potassium (I

Topics: Action Potentials; Arrhythmias, Cardiac; Drug Evaluation, Preclinical; HEK293 Cells; Humans; Induced Pluripotent Stem Cells; Models, Biological; Myocytes, Cardiac; Patch-Clamp Techniques; Piperidines; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Pyridines

Short QT syndrome (SQTS) is an inherited disorder associated with abnormally abbreviated QT intervals and an increased incidence of atrial and ventricular arrhythmias. SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels. Pro-arrhythmogenic effects of SQT1 have been well characterized, but less is known about the possible pharmacological antiarrhythmic treatment of SQT1. Therefore, this study aimed to assess the potential effects of E-4031, disopyramide and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology.. The ten Tusscher et al. biophysically detailed model of the human ventricular action potential (AP) was modified to incorporate IKr Markov chain (MC) formulations based on experimental data of the kinetics of the N588K mutation of the KCNH2-encoded subunit of the IKr channels. The modified ventricular cell model was then integrated into one-dimensional (1D) strand, 2D regular and realistic tissues with transmural heterogeneities. The channel-blocking effect of the drugs on ion currents in healthy and SQT1 cells was modeled using half-maximal inhibitory concentration (IC50) and Hill coefficient (nH) values from literatures. Effects of drugs on cell AP duration (APD), effective refractory period (ERP) and pseudo-ECG traces were calculated. Effects of drugs on the ventricular temporal and spatial vulnerability to re-entrant excitation waves were measured. Re-entry was simulated in both 2D regular and realistic ventricular tissue.. At the single cell level, the drugs E-4031 and disopyramide had hardly noticeable effects on the ventricular cell APD at 90% repolarization (APD90), whereas quinidine caused a significant prolongation of APD90. Quinidine prolonged and decreased the maximal transmural AP heterogeneity (δV); this led to the decreased transmural heterogeneity of APD across the 1D strand. Quinidine caused QT prolongation and a decrease in the T-wave amplitude, and increased ERP and decreased temporal susceptibility of the tissue to the initiation of re-entry and increased the minimum substrate size necessary to prevent re-entry in the 2D regular model, and further terminated re-entrant waves in the 2D realistic model. Quinidine exhibited significantly better therapeutic effects on SQT1 than E-4031 and disopyramide.. The simulated pharmacological actions of quinidine exhibited antiarrhythmic effects on SQT1. This study substantiates a causal link between quinidine and QT interval prolongation in SQT1 and suggests that quinidine may be a potential pharmacological agent for treating SQT1 patients.

Topics: Action Potentials; Arrhythmias, Cardiac; Cell Line; Disopyramide; Electrocardiography; ERG1 Potassium Channel; Heart Ventricles; Humans; Models, Biological; Piperidines; Polymorphism, Single Nucleotide; Pyridines; Quinidine

Donepezil is the most commonly prescribed acetylcholinesterase inhibitor for the treatment of Alzheimer's disease, an ailment that affects millions of older adult patients. By inhibiting the breakdown of acetylcholine in the central nervous system, donepezil has been shown to slow cognitive decline and improve patients' functional status. While donepezil is well-tolerated and generally considered safe at therapeutic doses, taking more than the prescribed dose could result in adverse cholinergic effects that range from mild gastrointestinal distress to serious cardiac dysrhythmias. We present a case of an 84-year-old man who developed gastrointestinal and cardiac disturbances after ingesting seven-times his daily dose of donepezil. As no specific antidote is available for donepezil overdose, this case highlights the importance of supportive care with particular attention to the management of cardiac dysrhythmias in patients displaying signs of toxicity.

Topics: Aged, 80 and over; Alzheimer Disease; Arrhythmias, Cardiac; Cholinesterase Inhibitors; Donepezil; Drug Overdose; Electrocardiography; Humans; Indans; Male; Piperidines

Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current I. The ten Tusscher et al model of human ventricular myocyte action potential (AP) was modified to recapitulate the changes in I. At the single cell level, the drugs quinidine, disopyramide, and E-4031 prolonged APD at 90% repolarization (APD. This study substantiates a causal link between quinidine and QT interval prolongation in SQT3 Kir2.1 mutations and highlights possible pharmacological agent quinidine for treating SQT3 patients.

Topics: Action Potentials; Arrhythmias, Cardiac; Disopyramide; Heart Conduction System; Heart Defects, Congenital; Heart Ventricles; Humans; Models, Biological; Piperidines; Pyridines; Quinidine

We evaluated the concordance of results from two sets of nonclinical cardiovascular safety studies on pitolisant.. Nonclinical studies envisaged both in the International Conference on Harmonization (ICH) S7B guideline and Comprehensive in vitro Pro-arrhythmia Assay (CiPA) initiative were undertaken. The CiPA initiative included in vitro ion channels, stem cell-derived human ventricular myocytes, and in silico modelling to simulate human ventricular electrophysiology. ICH S7B-recommended assays included in vitro hERG (K. Both sets of nonclinical data consistently excluded pitolisant from having clinically relevant QT-liability or pro-arrhythmic potential. CiPA studies revealed pitolisant to have modest calcium channel blocking and late I. Our findings support the CiPA initiative but suggest that sponsors should consider investigating drug effects on EADs and the use of pro-arrhythmia models when the results from CiPA studies are ambiguous.

Topics: Animals; Arrhythmias, Cardiac; Computer Simulation; Disease Models, Animal; Dogs; Electrocardiography; Female; Humans; Ion Channels; Male; Myocytes, Cardiac; Piperidines; Purkinje Fibers; Rabbits; Research Design

Topics: Adenine; Arrhythmias, Cardiac; Death, Sudden, Cardiac; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Piperidines; Pyrazoles; Pyrimidines

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Male; Myocardial Infarction; Piperidines

Topics: Arrhythmias, Cardiac; Cholinesterase Inhibitors; Dementia; Donepezil; Electrocardiography; Female; Humans; Indans; Middle Aged; Piperidines

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Evidence-Based Medicine; Humans; Myocardial Infarction; Piperidines; Publication Bias

Reverse-mode of the Na(+)/Ca(2+) exchanger (NCX) stimulation provides cardioprotective effects for the ischemic/reperfused heart during ischemic preconditioning (IP). This study was designed to test the hypothesis that pretreatment with an inhibitor of cardiac delayed-rectifying K(+) channel (IKr), E4031, increases reverse-mode of NCX activity, and triggers preconditioning against infarct size (IS) and arrhythmias caused by ischemia/reperfusion injury through mitoKCa channels.. In the isolated perfused rat heart, myocardial ischemia/reperfusion injury was created by occlusion of the left anterior descending coronary artery for 30 min followed by 120 min reperfusion. Two cycles of coronary occlusion for 5 min and reperfusion were performed, or pretreatment with E4031 or sevoflurane (Sevo) before the 30 min occlusion with the reversed-mode of NCX inhibitor (KB-R7943) or not.. E4031 or Sevo preconditioning not only markedly decreased IS but also reduced arrhythmias, which was significantly blunted by KB-R7943. Furthermore, these effects of E4031 preconditioning on IS and arrhythmias were abolished by inhibition of the mitoKCa channels. Similarly, pretreatment with NS1619, an opener of the mitoKCa channels, for 10 min before occlusion reduced both the infarct size and arrhythmias caused by ischemia/reperfusion. However, these effects weren't affected by blockade of the NCX with KB-R7943.. Taken together, these preliminary results conclude that pretreatment with E4031 reduces infarct size and produces anti-arrhythmic effect via stimulating the reverse-mode NCX, and that the mitoKCa channels mediate the protective effects.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Ischemic Preconditioning; Male; Mitochondria; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Piperidines; Potassium Channels, Calcium-Activated; Pyridines; Rats; Rats, Sprague-Dawley; Sodium-Calcium Exchanger

A prospective comparison study across 3 independent research laboratories of a pure IKr blocker E-4031 was conducted by using the same batch of human iPS cell-derived cardiomyocytes in order to verify the utility and reliability of our original standard protocol. Field potential waveforms were recorded with a multi-electrode array system to measure the inter-spike interval and field potential duration. The effects of E-4031 at concentrations of 1 to 100 nM were sequentially examined every 10 min. In each facility, E-4031 significantly prolonged the field potential duration corrected by Fridericia's formula and caused early afterdepolarizations occasionally resulting in triggered activities, whereas it tended to decrease the rate of spontaneous contraction. These results were qualitatively and quantitatively consistent with previous non-clinical in vitro and in vivo studies as well as clinical reports. There were inter-facility differences in some absolute values of the results, which were not observed when the values were normalized as percentage change. Information described in this paper may serve as a guide when predicting the drug-induced repolarization delay and arrhythmias with this new technology of stem cells.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cells, Cultured; Depression, Chemical; Dose-Response Relationship, Drug; Electrophysiologic Techniques, Cardiac; Heart Rate; Humans; Induced Pluripotent Stem Cells; Myocytes, Cardiac; Piperidines; Prospective Studies; Pyridines

Enhanced dispersion of action potential duration (APD) is a major contributor to long QT syndrome (LQTS)-related arrhythmias.. To investigate spatial correlations of regional heterogeneities in cardiac repolarization and mechanical function in LQTS.. Female transgenic LQTS type 2 (LQT2; n = 11) and wild-type littermate control (LMC) rabbits (n = 9 without E4031 and n = 10 with E4031) were subjected to phase contrast magnetic resonance imaging to assess regional myocardial velocities. In the same rabbits' hearts, monophasic APDs were assessed in corresponding segments.. In LQT2 and E4031-treated rabbits, APD was longer in all left ventricular segments (P < .01) and APD dispersion was greater than that in LMC rabbits (P < .01). In diastole, peak radial velocities (Vr) were reduced in LQT2 and E4031-treated compared to LMC rabbits in LV base and mid (LQT2: -3.36 ± 0.4 cm/s, P < .01; E4031-treated: -3.24 ± 0.6 cm/s, P < .0001; LMC: -4.42 ± 0.5 cm/s), indicating an impaired diastolic function. Regionally heterogeneous diastolic Vr correlated with APD (LQT2: correlation coefficient [CC] 0.38, P = .01; E4031-treated: CC 0.42, P < .05). Time-to-diastolic peak Vr were prolonged in LQT2 rabbits (LQT2: 196.8 ± 2.9 ms, P < .001; E4031-treated: 199.5 ± 2.2 ms, P < .0001, LMC 183.1 ± 1.5), indicating a prolonged contraction duration. Moreover, in transgenic LQT2 rabbits, diastolic time-to-diastolic peak Vr correlated with APD (CC 0.47, P = .001). In systole, peak Vr were reduced in LQT2 and E4031-treated rabbits (P < .01) but longitudinal velocities or ejection fraction did not differ. Finally, random forest machine learning algorithms enabled a differentiation between LQT2, E4031-treated, and LMC rabbits solely based on "mechanical" magnetic resonance imaging data.. The prolongation of APD led to impaired diastolic and systolic function in transgenic and drug-induced LQT2 rabbits. APD correlated with regional diastolic dysfunction, indicating that LQTS is not purely an electrical but an electromechanical disorder.

Topics: Action Potentials; Animals; Animals, Genetically Modified; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Diastole; Female; Long QT Syndrome; Magnetic Resonance Imaging; Piperidines; Pyridines; Rabbits

Abnormal enhanced transmural dispersion of repolarization (TDR) plays an important role in the maintaining of the severe ventricular arrhythmias such as torsades de pointes (TDP) which can be induced in long-QT (LQT) syndrome. Taking advantage of an in vitro rabbit model of LQT2, we detected the effects of KN-93, a CaM-dependent kinase (CaMK) II inhibitor on repolarization heterogeneity of ventricular myocardium. Using the monophasic action potential recording technique, the action potentials of epicardium and endocardium were recorded in rabbit cardiac wedge infused with hypokalemic, hypomagnesaemic Tyrode's solution. At a basic length (BCL) of 2000 ms, LQT2 model was successfully mimicked with the perfusion of 0.5 μmol/L E-4031, QT intervals and the interval from the peak of T wave to the end of T wave (Tp-e) were prolonged, and Tp-e/QT increased. Besides, TDR was increased and the occurrence rate of arrhythmias like EAD, R-on-T extrasystole, and TDP increased under the above condition. Pretreatment with KN-93 (0.5 μmol/L) could inhibit EAD, R-on-T extrasystole, and TDP induced by E-4031 without affecting QT interval, Tp-e, and Tp-e/QT. This study demonstrated KN-93, a CaMKII inhibitor, can inhibit EADs which are the triggers of TDP, resulting in the suppression of TDP induced by LQT2 without affecting TDR.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzylamines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Electrocardiography; Electrophysiologic Techniques, Cardiac; Endocardium; Heart; In Vitro Techniques; Long QT Syndrome; Pericardium; Piperidines; Protein Kinase Inhibitors; Pyridines; Rabbits; Sulfonamides; Torsades de Pointes

Cardiotoxicity is a common side effect of a large variety of drugs that is often caused by off-target human ether-à-go-go-related gene (hERG) potassium channel blockade. In this study, we designed and synthesized a series of derivatives of the class III antiarrhythmic agent E-4031. These compounds where evaluated in a radioligand binding assay and automated patch clamp assay to establish structure-activity relationships (SAR) for their inhibition of the hERG K(+) channel. Structural modifications of E-4031 were made by altering the peripheral aromatic moieties with a series of distinct substituents. Additionally, we synthesized several derivatives with a quaternary nitrogen and modified the center of the molecule by introduction of an additional nitrogen and deletion of the carbonyl oxygen. Some modifications caused a great increase in affinity for the hERG K(+) channel, while other seemingly minor changes led to a strongly diminished affinity. Structures with quaternary amines carrying an additional aromatic moiety were found to be highly active in radioligand binding assay. A decrease in affinity was achieved by introducing an amide functionality in the central scaffold without directly interfering with the pK(a) of the essential basic amine. The knowledge gained from this study could be used in early stages of drug discovery and drug development to avoid or circumvent hERG K(+) channel blockade, thereby reducing the risk of cardiotoxicity, related arrhythmias and sudden death.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Ether-A-Go-Go Potassium Channels; HEK293 Cells; Humans; Piperidines; Pyridines; Structure-Activity Relationship

Anandamide is an endocannabinoid that has antiarrhythmic effects through inhibition of L-type Ca(2+) channels in cardiomyocytes. In this study, we investigated the electrophysiological effects of anandamide on K(+) channels in rat ventricular myocytes. Whole cell patch-clamp technique was used to record K(+) currents, including transient outward potassium current (I(to)), steady-state outward potassium current (I(ss)), inward rectifier potassium current (I(K1)), and ATP-sensitive potassium current (I(KATP)) in isolated rat cardiac ventricular myocytes. Anandamide decreased I(to) while increasing I(KATP) in a concentration-dependent manner but had no effect on I(ss) and I(K1) in isolated ventricular myocytes. Furthermore, anandamide shifted steady-state inactivation curve of I(to) to the left and shifted the recovery curve of I(to) to the right. However, neither cannabinoid 1 (CB(1)) receptor antagonist AM251 nor CB(2) receptor antagonist AM630 eliminated the inhibitory effect of anandamide on I(to). In addition, blockade of CB(2) receptors, but not CB(1) receptors, eliminated the augmentation effect of anandamide on I(KATP). These data suggest that anandamide suppresses I(to) through a non-CB(1) and non-CB(2) receptor-mediated pathway while augmenting I(KATP) through CB(2) receptors in ventricular myocytes.

Topics: Animals; Anti-Arrhythmia Agents; Arachidonic Acids; Arrhythmias, Cardiac; Cardiac Electrophysiology; Dose-Response Relationship, Drug; Endocannabinoids; Heart Ventricles; Indoles; KATP Channels; Male; Myocytes, Cardiac; Patch-Clamp Techniques; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2

QT interval prolongation on the electrocardiogram (ECG) has extensively been reported with iloperidone, a novel antipsychotic drug. The objective of the present study was to evaluate the effects of iloperidone on cardiac ventricular repolarization at three different levels; in vitro, ex vivo and in vivo. (1) In vitro level: whole-cell patch-clamp experiments were performed on HERG-transfected HEK293 cells exposed to iloperidone 0.01-1 μmol/L (n = 35 cells, total) to assess drug effect on HERG current. (2) Ex vivo level: Langendorff retroperfusion experiments were performed on isolated hearts from male Hartley guinea pigs (n = 7) exposed to iloperidone 100 nmol/L with/without chromanol 293B 10 μmol/L to assess drug-induced prolongation of monophasic action potential duration measured at 90% repolarization (MAPD(90)). (3) In vivo level: ECG recordings using wireless cardiac telemetry were performed in guinea pigs (n = 5) implanted with radio transmitters and treated with a single oral gavage dose of iloperidone 3 mg/kg. (1) Patch-clamp experiments revealed an estimated IC50 for iloperidone on HERG current of 161 ± 20 nmol/L. (2) While pacing the hearts at stimulation cycle lengths of 200 or 250 ms, or during natural sinus rhythm (no external pacing), iloperidone 100 nmol/L prolonged MAPD(90) by respectively 9.2 ± 0.9, 11.2 ± 1.6 and 21.4 ± 2.3 ms. After adding chromanol 293B, MAPD(90) was further prolonged by 7.3 ± 3.3, 11.5 ± 2.3 and 29.2 ± 6.7 ms, respectively. (3) Iloperidone 3mg/kg p.o. caused a maximal 42.7 ± 10.2 ms prolongation of corrected QT interval (QTc(F)), 40 min after administration. Iloperidone prolongs the QT interval, the cardiac action potentials and is a potent HERG blocker. Patients are at increased risk of cardiac proarrhythmia during iloperidone treatment, as this drug possesses significant cardiac repolarization-delaying properties at clinically relevant concentration.

Topics: Action Potentials; Animals; Antipsychotic Agents; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Electrocardiography, Ambulatory; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Guinea Pigs; Heart Conduction System; HEK293 Cells; Humans; Isoxazoles; Male; Patch-Clamp Techniques; Perfusion; Piperidines; Potassium Channel Blockers; Risk Assessment; Telemetry; Time Factors; Transfection

We tested a hypothesis that an enhancement of I(Ks) may play a pivotal role in ventricular proarrhythmia under high sympathetic activity. A 2-dimensional ventricular muscle layer was prepared in rabbit hearts, and action potential signals were analyzed by optical mapping. During constant stimulation, isoproterenol (ISP, 0.1 µM) significantly shortened action potential duration (APD); chromanol 293B (30 µM), a selective I(Ks)-blocker, reversed the APD shortening. VTs induced in the presence of ISP lasted longer than in the control, and this was reversed by 293B. E-4031 (0.1 µM), a selective I(Kr)-blocker, did not cause such reversal. Spiral-wave (SW) reentry with ISP was characterized by more stable rotation around a shorter functional block line (FBL) than in the control. After application of 293B, SW reentry was destabilized, and rotation around a longer FBL with prominent drift reappeared. The APD abbreviation by ISP close to the rotation center was more pronounced than in the periphery, leading to an opposite APD gradient (center < periphery) compared with controls. This effect was also reversed by 293B. In conclusion, β-adrenergic stimulation stabilizes SW reentry most likely though an enhancement of I(Ks). Blockade of I(Ks) may be a promising therapeutic modality in prevention of ventricular tachyarrhythmias under high sympathetic activity.

Topics: Action Potentials; Adrenergic Agents; Animals; Arrhythmias, Cardiac; Chromans; Heart Ventricles; Isoproterenol; Myocardium; Piperidines; Potassium Channel Blockers; Potassium Channels; Pyridines; Rabbits; Sulfonamides; Sympathetic Nervous System

Pacemaker interactions can lead to complex wave dynamics seen in certain types of cardiac arrhythmias. We use experimental and mathematical models of pacemakers in heterogeneous excitable media to investigate how pacemaker interactions can be a mechanism for wave break and reentrant wave dynamics. Embryonic chick ventricular cells are cultured in vitro so as to create a dominant central pacemaker site that entrains other pacemakers in the medium. Exposure of those cultures to a potassium channel blocker, E-4031, leads to emergence of peripheral pacemakers that compete with each other and with the central pacemaker. Waves emitted by faster pacemakers break up over the slower pacemaker to form reentrant waves. Similar dynamics are observed in a modified FitzHugh-Nagumo model of heterogeneous excitable media with two distinct sites of pacemaking. These findings elucidate a mechanism of pacemaker-induced reentry in excitable media.

Topics: Animals; Arrhythmias, Cardiac; Chick Embryo; Heart; Models, Cardiovascular; Pacemaker, Artificial; Piperidines; Pyridines; Tissue Culture Techniques; Tissue Engineering

Electrical stability in the heart depends on two important factors; restitution of action potential duration (APD) and memory. Repolarization currents play an important role in determining APD and also affect memory. We determined the effects of blocking the rapid component of the delayed rectifier (I(Kr)) on a quantifiable measure of memory, i.e. hysteresis in restitution of APD, in swine. Transmembrane potentials were recorded from right ventricular endocardial tissues. Two pacing protocols with explicit control of diastolic interval (DI) were used to change DIs in a sequential and sinusoidal pattern to quantify hysteresis in restitution of APD. E-4031 (5 µM/L) was used to block I(Kr). Measures of memory and restitution were quantified by calculating hysteresis loop thickness, area, overall tilt, and maximum and minimum delays between DIs and APDs. Blocking I(Kr) with E-4031 increased the baseline APD, loop thickness, area, and tilt (p<0.05). However, loop thickness did not increase beyond what could be predicted by the increase in baseline APD after block of I(Kr). The substantial change in APD after blocking I(Kr) suggests that this current plays a major role in repolarization in the swine. Loop thickness is a measure of memory, an increase in which is predicted by theory to reduce instability in activation. In our study, the substantial increase in loop thickness could be accounted for by an equally substantial increase in APD and therefore does not necessarily indicate increased memory after blocking I(Kr). Our results also suggest that factors based on restitution and memory need to be considered in the context of operating point, i.e. baseline APD, when they are used to explore mechanisms that affect electrical stability in the heart.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Diastole; Electrophysiological Phenomena; Endocardium; Heart Conduction System; Models, Cardiovascular; Piperidines; Potassium Channels, Inwardly Rectifying; Pyridines; Swine

The majority of human ether-a-go-go-related gene (hERG) screens aiming to minimize the risk of drug-induced long QT syndrome have been conducted using heterologous systems expressing the hERG 1a subunit, although both hERG 1a and 1b subunits contribute to the K+ channels producing the repolarizing current I(Kr) . We tested a range of compounds selected for their diversity to determine whether hERG 1a and 1a/1b channels exhibit different sensitivities that may influence safety margins or contribute to a stratified risk analysis.. We used the IonWorks™ plate-based electrophysiology device to compare sensitivity of hERG 1a and 1a/1b channels stably expressed in HEK293 cells to 50 compounds previously shown to target hERG channels. Potency was determined as IC₅₀ values (µM) obtained from non-cumulative, eight-point concentration-effect curves of normalized data, fitted to the Hill equation. To minimize possible sources of variability, compound potency was assessed using test plates arranged in alternating columns of cells expressing hERG 1a and 1a/1b.. Although the potency of most compounds was similar for the two targets, some surprising differences were observed. Fluoxetine (Prozac) was more potent at blocking hERG 1a/1b than 1a channels, yielding a corresponding reduction in the safety margin. In contrast, E-4031 was a more potent blocker of hERG 1a compared with 1a/1b channels, as previously reported, as was dofetilide, another high-affinity blocker.. The current assays may underestimate the risk of some drugs to cause torsades de pointes arrhythmia, and overestimate the risk of others.

Topics: Action Potentials; Arrhythmias, Cardiac; Cell Line, Transformed; Drug Evaluation, Preclinical; Ether-A-Go-Go Potassium Channels; Fluoxetine; HEK293 Cells; Humans; Inhibitory Concentration 50; Long QT Syndrome; Piperidines; Protein Subunits; Pyridines; Sensitivity and Specificity; Torsades de Pointes

Acute effects of sex steroid hormones likely contribute to the observation that post-pubescent males have shorter QT intervals than females. However, the specific role for hormones in modulating cardiac electrophysiological parameters and arrhythmia vulnerability is unclear. Here we use a computational modeling approach to incorporate experimentally measured effects of physiological concentrations of testosterone, estrogen and progesterone on cardiac ion channel targets. We then study the hormone effects on ventricular cell and tissue dynamics comprised of Faber-Rudy computational models. The "female" model predicts changes in action potential duration (APD) at different stages of the menstrual cycle that are consistent with clinically observed QT interval fluctuations. The "male" model predicts shortening of APD and QT interval at physiological testosterone concentrations. The model suggests increased susceptibility to drug-induced arrhythmia when estradiol levels are high, while testosterone and progesterone are apparently protective. Simulations predict the effects of sex steroid hormones on clinically observed QT intervals and reveal mechanisms of estrogen-mediated susceptibility to prolongation of QT interval. The simulations also indicate that acute effects of estrogen are not alone sufficient to cause arrhythmia triggers and explain the increased risk of females to Torsades de Pointes. Our results suggest that acute effects of sex steroid hormones on cardiac ion channels are sufficient to account for some aspects of gender specific susceptibility to long-QT linked arrhythmias.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cells, Cultured; Computer Simulation; Disease Susceptibility; Electrocardiography; Estrogens; Female; Gonadal Steroid Hormones; Guinea Pigs; Male; Markov Chains; Menstrual Cycle; Myocytes, Cardiac; Piperidines; Potassium Channels; Progesterone; Pyridines; Testosterone

The hERG (Kv11.1) potassium channel underlies cardiac I(Kr) and is important for cardiac repolarization. Recently, hERG agonists have emerged as potential antiarrhythmic drugs. As modulation of outward potassium currents has been suggested to modulate cardiac conduction, we tested the hypothesis that pharmacological activation of I(Kr) results in impaired cardiac conduction.. Cardiac conduction was assessed in Langendorff-perfused guinea pig hearts. Application of the hERG agonist NS3623 (10 microM) prolonged the QRS rate dependently. A significant prolongation (16 +/- 6%) was observed at short basic cycle length (BCL 90 ms) but not at longer cycle lengths (BCL 250 ms). The effect could be reversed by the I(Kr) blocker E4031 (1 microM). While partial I(Na) inhibition with flecainide (1 microM) alone prolonged the QRS (34 +/- 3%, BCL 250 ms), the QRS was further prolonged by 19 +/- 2% when NS3623 was added in the presence of flecainide. These data suggest that the effect of NS3623 was dependent on sodium channel availability. Surprisingly, in the presence of the voltage sensitive dye di-4-ANEPPS a similar potentiation of the effect of NS3623 was observed. With di-4-ANEPPS, NS3623 prolonged the QRS significantly (26 +/- 4%, BCL 250 ms) compared to control with a corresponding decrease in conduction velocity.. Pharmacological activation of I(Kr) by the hERG agonist NS3623 impairs cardiac conduction. The effect is dependent on sodium channel availability. These findings suggest a role for I(Kr) in modulating cardiac conduction and may have implications for the use of hERG agonists as antiarrhythmic drugs.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Ether-A-Go-Go Potassium Channels; Flecainide; Guinea Pigs; Heart Conduction System; In Vitro Techniques; Male; Perfusion; Phenylurea Compounds; Piperidines; Potassium; Potassium Channel Blockers; Pyridines; Sodium Channel Blockers; Tetrazoles; Time Factors; Voltage-Sensitive Dye Imaging

This study was designed to evaluate the effects of pilocarpine and explore the underlying ionic mechanism, using both aconitine-induced rat and ouabain-induced guinea pig arrhythmia models. Confocal microscopy was used to measure intracellular free-calcium concentrations ([Ca(2+)](i)) in isolated myocytes. The current data showed that pilocarpine significantly delayed onset of arrhythmias, decreased the time course of ventricular tachycardia and fibrillation, reduced arrhythmia score, and increased the survival time of arrhythmic rats and guinea pigs. [Ca(2+)](i) overload induced by aconitine or ouabain was reduced in isolated myocytes pretreated with pilocarpine. Moreover, M(3)-muscarinic acetylcholine receptor (mAChR) antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) partially abolished the beneficial effects of pilocarpine. These data suggest that pilocarpine produced antiarrhythmic actions on arrhythmic rat and guinea pig models induced by aconitine or ouabain via stimulating the cardiac M(3)-mAChR. The mechanism may be related to the improvement of Ca(2+) handling.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Disease Models, Animal; Female; Guinea Pigs; Male; Microscopy, Confocal; Muscarinic Agonists; Muscarinic Antagonists; Myocytes, Cardiac; Ouabain; Pilocarpine; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M3; Time Factors

Interspecies differences can limit the translational value of excitable cells isolated from model organisms. It can be difficult to extrapolate from a drug- or mutation-induced phenotype in mice to human pathophysiology because mouse and human cardiac electrodynamics differ greatly. We present a hybrid computational-experimental technique, the cell-type transforming clamp, which is designed to overcome such differences by using a calculated compensatory current to convert the macroscopic electrical behavior of an isolated cell into that of a different cell type. We demonstrate the technique's utility by evaluating drug arrhythmogenicity in murine cardiomyocytes that are transformed to behave like human myocytes. Whereas we use the cell-type transforming clamp in this work to convert between mouse and human electrodynamics, the technique could be adapted to convert between the action potential morphologies of any two cell types of interest.

Topics: Action Potentials; Algorithms; Animals; Animals, Newborn; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cells, Cultured; Computers; Heart; Mice; Models, Cardiovascular; Myocytes, Cardiac; Patch-Clamp Techniques; Piperidines; Pyridines

Opioids may exert a protective effect against ventricular arrhythmias via a vagally mediated mechanism. This study evaluated the effects of the opioid remifentanil on arrhythmogenicity of epinephrine during halothane anesthesia. Eight dogs were assigned to 2 treatments in a randomized crossover design, with 1-week intervals between treatments. Anesthesia was maintained with 1.3% end-tidal halothane in oxygen and mechanical ventilation to maintain eucapnia. A constant rate infusion of remifentanil (0.72 microg/kg/min) was administered throughout the study in the experimental treatment, while control animals received physiologic saline as placebo. The arrhythmogenic dose of epinephrine (ADE), defined as 4 premature ventricular complexes (PVCs) within 15 s, was determined by administering progressively increasing infusion rates of epinephrine (2.5, 5.0, and 10 microg/kg/min), allowing 20 min intervals between each infusion rate. In both treatments, epinephrine infusions induced bradyarrhythmias and atrioventricular conduction disturbances, which were followed by escape beats and PVCs. In the remifentanil treatment, mean +/- s ADE values (11.3 +/- 4.9 microg/kg) did not differ from values observed in control animals (9.9 +/- 6.1 microg/kg). On the basis of the ADE model for assessing the arrhythmogenity of drugs during halothane anesthesia, the present study did not demonstrate a protective effect of remifentanil (0.72 microg/kg/min) against ventricular arrhythmias in dogs.

Topics: Analgesics, Opioid; Anesthesia; Anesthetics, Inhalation; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cross-Over Studies; Dog Diseases; Dogs; Electrocardiography; Epinephrine; Female; Halothane; Heart Rate; Infusions, Parenteral; Piperidines; Random Allocation; Remifentanil

To detect the function and expression of ventricular M3 receptor (M3R) in cerebral-cardiac syndrome (CCS) model rats and to explore the relationship between the expression of M3R and the arrhythmia resulted from CCS, CCS model rats were induced by occluding right middle cerebral artery. ECG was monitored. Intracellular calcium ([Ca2+]i) changes after agitating M3R were recorded by laser scanning confocal microscope. Changes of M3R expression in the ventricular tissue were detected by Western blotting. QRS and QT intervals in CCS group were remarkably longer than that in sham group. According to the results of Western blotting, the level of M3R expression was remarkably lower in CCS group compared with that in the normal group. KCl induced [Ca2+]i increasing in CCS group could be depressed by choline and the effect of choline could be blocked by 4-DAMP. The lower expression of M3R in CCS group may be one of important reasons of arrhythmia resulted from CCS. M3R that depressed the [Ca2+]i increasing agitated by choline may become a new target to cure arrhythmia resulted from CCS.

Topics: Animals; Arrhythmias, Cardiac; Calcium; Choline; Electrocardiography; Heart Ventricles; Infarction, Middle Cerebral Artery; Male; Muscarinic Antagonists; Myocardium; Myocytes, Cardiac; Piperidines; Potassium Chloride; Random Allocation; Rats; Rats, Wistar; Receptor, Muscarinic M3

It is well known that choline has protective effects on ischemic arrhythmias. We designed the present study to evaluate the antiarrhythmic effects of choline and to detect its related mechanisms in aconitine-induced rat and ouabain-induced guinea pig models of arrhythmia. Laser scanning confocal microscopy and patch-clamp technique were utilized to study the action of choline on intracellular calcium concentration and L-type calcium current (ICa-L) of cardiac myocytes. M3 receptor antagonist 4-DAMP (4-diphenylacetoxy-N-methylpiperidine-methiodide) was applied preliminarily to evaluate the role of the M3 receptor. Choline significantly increased the survival time of arrhythmic rats and guinea pigs, delayed the onset of arrhythmias and ventricular tachycardia, and decreased the arrhythmia score. The overload of intracellular Ca2+ induced by aconitine or ouabain was reduced in isolated myocytes pretreated with choline. Choline reduced the increased density of ICa-L induced by aconitine or ouabain. Moreover, the beneficial effects of choline were reversed by 4-DAMP. Choline produced antiarrhythmic actions on arrhythmia models by stimulating the cardiac M3 receptor. The mechanism may be related to the improvement of Ca2+ handling.

Topics: Aconitine; Animals; Arrhythmias, Cardiac; Calcium; Choline; Disease Models, Animal; Female; Guinea Pigs; Male; Myocytes, Cardiac; Ouabain; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M3

The role of K(ATP) channels in the antiarrhythmic effect of Escherichia coli endotoxin-induced nitric oxide synthase (iNOS) was examined in an anesthetised rat model of myocardial ischemia and reperfusion arrhythmia by using glibenclamide (1 mg kg(-1)), nateglinide (10 mg kg(-1)) and repaglinide (0.5 mg kg(-1)). Endotoxin (1 mg kg(-1)) was administered intraperitoneally 4 h before the occlusion of the left coronary artery and glibenclamide, nateglinide or repaglinide was administered 30 min before coronary artery occlusion. We also evaluated the effects of K(ATP) channel blockers and nonselective K(+) channel blocker tetraethylammonium (TEA) on cardiac action potential configuration in the atria obtained from endotoxemic rats. The mean arterial blood pressure of rats receiving endotoxin was lower during both the occlusion and reperfusion periods. Endotoxin significantly reduced the total number of ectopic beats and the duration of ventricular tachycardia. Glibenclamide, but not nateglinide and repaglinide, prevented the hypotension and antiarrhythmic effects of endotoxin. Atria obtained from endotoxin-treated rats had prolonged action potential duration. This effect was abolished with pretreatment of iNOS inhibitors, l-canavanine and dexamethasone and perfusion of glibenclamide, but not with TEA and non-sulfonylurea drug, nateglinide. We demonstrated that glibenclamide inhibits the antiarrhythmic effect of endotoxin and this effect does not appear to involve K(ATP) channels.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Arrhythmias, Cardiac; Blood Pressure; Carbamates; Cyclohexanes; Disease Models, Animal; Drug Interactions; Endotoxemia; Glyburide; Heart Atria; Heart Conduction System; Lipopolysaccharides; Male; Myocardial Ischemia; Nateglinide; Phenylalanine; Piperidines; Potassium Channel Blockers; Potassium Channels; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Tetraethylammonium; Time Factors; Ventricular Fibrillation; Ventricular Premature Complexes

Delayed cardiac repolarization and fatal proarrhythmia have been linked to block of the repolarizing current, Ikr or hERG (human ether-a-go-go related gene) current. Thus, determining the potency of hERG block is critical in evaluating cardiac safety during preclinical development. Hydroxypropyl beta-cyclodextrins (HbetaC) are cyclic oligosaccharides used to enhance drug solubility. To evaluate the utility of HbetaC to enhance drug solubility in hERG screening assays, we studied the effect of HbetaC on hERG current and the sensitivity of the hERG assay to 3 structurally different hERG blocking drugs using whole-cell voltage clamp technique and HEK-293 cells expressing the hERG channel. HbetaC inhibited hERG activation and tail current and accelerated current deactivation in a concentration-dependent manner. HbetaC (6%) reduced the apparent potency of block by terfenadine (IC50 12000 nM vs 45 nM), cisapride (IC50 281 nM vs 28 nM), and E-4031 (163 nM vs 26 nM). Reduced potency of block was consistent with loss of activity as a result of complexation with HbetaC by terfenadine and cisapride (demonstrated in solubility studies) and interactions with HbetaC by E-4031 (demonstrated in absorbance studies). These results demonstrate that HbetaC is an unsuitable agent for enhancing compound solubility in the in vitro hERG current assay and may mask drug effects, allowing potentially dangerous drugs to advance into clinical development.

Topics: 2-Hydroxypropyl-beta-cyclodextrin; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; beta-Cyclodextrins; Biological Assay; Cisapride; Dose-Response Relationship, Drug; Electrophysiology; Ether-A-Go-Go Potassium Channels; Excipients; Gastrointestinal Agents; Histamine H1 Antagonists; Humans; Inhibitory Concentration 50; Myocytes, Cardiac; Piperidines; Potassium Channel Blockers; Pyridines; Solubility; Terfenadine; Time Factors

The analysis of cardiac electrical restitution (the relationship between an action potential duration and its preceding diastolic interval) has been used to predict arrhythmia liability. However, the procedure to measure restitution is invasive and disrupts normal physiological autonomic balance. Dynamic analysis of sequential beat-to-beat ECG data was used to study restitution under normal sinus rhythm and to quantify changes in temporal hysteresis with heart rate acceleration/deceleration during QT prolongation. Congenital long QT (LQT) 1 and LQT2 syndromes during sympathetic stimulation were modeled because of their association with increased risk of ventricular arrhythmia. Temporal heterogeneity and hysteresis of restitution were examined in the conscious dog under varying conditions of delayed repolarization using either the selective inhibitors of the slowly activating delayed rectifier potassium current (R)-2-(4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]acetamide (L-768,673); the rapidly activating delayed rectifier potassium current (1-[2-(6-methyl-2-pyridyl)ethyl]-4-methyl-sulfonylaminobenzoyl)-piperidine (E-4031); or a combination of both at rest and during heart rate acceleration with sympathetic stimulation using isoproterenol challenges. Impaired repolarization with the combination of E-4031 and L-768,673 increased heterogeneity of restitution at rest 55 to 91%, increased hysteresis during heart rate acceleration after isoproterenol challenge by approximately 40 to 60%, and dramatically reduced the minimum TQ interval by 72% to only 28 ms. Impaired repolarization alters restitution during normal sinus rhythm and increases hysteresis/heterogeneity during heart rate acceleration following sympathetic stimulation. Thus, dynamic beat-to-beat measurements of restitution could lead to clinically applicable ECG obtained biomarkers for assessment of changes associated with arrhythmogenic risk.

Topics: Acetamides; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzodiazepinones; Dogs; Electrocardiography; Female; Heart Rate; Long QT Syndrome; Male; Myocardial Contraction; Piperidines; Potassium Channels, Voltage-Gated; Pyridines

Sinus node inhibitors reduce the heart rate presumably by blocking the pacemaker current If in the cardiac conduction system. This pacemaker current is carried by four hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. We tested the potential subtype-specificity of the sinus node inhibitors cilobradine, ivabradine, and zatebradine using cloned HCN channels. All three substances blocked the slow inward current through human HCN1, HCN2, HCN3, and HCN4 channels. There was no subtype-specificity for the steady-state block, with mean IC50 values of 0.99, 2.25, and 1.96 microM for cilobradine, ivabradine, and zatebradine, respectively. Native If, recorded from mouse sinoatrial node cells, was slightly more efficiently blocked by cilobradine (IC50 value of 0.62 microM) than were the HCN currents. The block of I(f) in sinoatrial node cells resulted in slower and dysrhythmic spontaneous action potentials. The in vivo action of these blockers was analyzed using telemetric ECG recordings in mice. Each compound reduced the heart rate dose-dependently from 600 to 200 bpm with ED50 values of 1.2, 4.7, and 1.8 mg/kg for cilobradine, ivabradine, and zatebradine, respectively. beta-Adrenergic stimulation or forced physical activity only partly reversed this bradycardia. In addition to bradycardia, all three drugs induced increasing arrhythmia at concentrations greater than 5 mg/kg for cilobradine, greater than 10 mg/kg for zatebradine, or greater than 15 mg/kg for ivabradine. This dysrhythmic heart rate is characterized by periodic fluctuations of the duration between the T and P wave, resembling a form of sick sinus syndrome in humans. Hence, all available sinus node inhibitors possess an as-yet-unrecognized proarrhythmic potential.

Topics: Animals; Arrhythmias, Cardiac; Benzazepines; Bradycardia; Cardiotonic Agents; Cloning, Molecular; Electrocardiography; Humans; Ivabradine; Mice; Mice, Inbred C57BL; Piperidines; Sinoatrial Node; Up-Regulation

We designed the present study to examine whether diabetes mellitus affects the antiarrhythmic effect of flecainide, a sodium channel blocker, E-4031, a potassium channel blocker, and verapamil, a calcium channel blocker, in diabetic rats. The experiments were performed in intact and diabetic rats 2, 4, and 6 wk after administration of streptozotocin. Rats were anesthetized with halothane and monitored continuously for arterial blood pressure and premature ventricular contractions. The arrhythmogenic dose of epinephrine was defined as the smallest dose producing 3 or more premature ventricular contractions within a 15-s period. The arrhythmogenic doses of epinephrine in the presence of flecainide were 8.2 +/- 2.2 (mean +/- sd), 7.4 +/- 6.1, 5.5 +/- 2.8, and 2.0 +/- 0.5 microg/kg in intact and diabetic rats 2, 4, and 6 wk after streptozotocin administration, respectively. Similarly, the arrhythmogenic doses of epinephrine in the presence of E-4031 were 7.7 +/- 2.6, 2.3 +/- 0.7, 2.0 +/- 0.7, and 1.2 +/- 0.5 microg/kg, and those in the presence of verapamil were 8.2 +/- 2.1, 3.1 +/- 1.2, 2.3 +/- 0.9, and 1.5 +/- 0.5 microg/kg. Insulin partially recovered the antiarrhythmic effect of the blockers. We concluded that diabetes mellitus reduces the antiarrhythmic effects of flecainide, E-4031, and verapamil.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Diabetes Mellitus; Diabetes Mellitus, Experimental; Epinephrine; Flecainide; Halothane; Ion Channels; Male; Piperidines; Potassium Channel Blockers; Pyridines; Rats; Rats, Sprague-Dawley; Sodium Channel Blockers; Verapamil

The K(+) channel encoded by the human ether-a-go-go-related gene (HERG) is crucial for repolarization in the human heart. In order to investigate the impact of HERG current (I(Kr)) on the incidence of cardiac arrhythmias, we generated a transgenic mouse expressing HERG specifically in the heart.. ECG recordings at baseline showed no obvious difference between transgenic and wild-type (WT) mice with the exception of the T wave, which was more negative in transgenic mice than in WT mice. E4031 (20 mg/kg) prolonged the QTc interval and flattened the T wave in transgenic mice, but not in WT mice. Injection of BaCl(2) (25 mg/kg) induced short runs of ventricular tachycardia in 9/10 WT mice, but not in transgenic animals. Atrial pacing reproducibly induced atrial tachyarrhythmias in 11/15 WT mice. In contrast, atrial arrhythmia was inducible in only 2/11 transgenic mice. When pretreated with dofetilide (10 mg/kg), transgenic mice were as sensitive to experimental arrhythmias as WT mice. Microelectrode studies showed that atrial action potentials have a steeper slope of duration-rate adaptation in WT than in transgenic mice. Transgenic mice were also characterized by a post-repolarization refractoriness, which could result from the substantial amount of I(Kr) subsisting after repolarization as assessed with action potential-clamp experiments and simulations with a model of the transgenic mouse action potential.. HERG expression in the mouse heart can protect against experimental induction of arrhythmias. This is the first report of such a protective effect of HERG in vivo.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blotting, Western; Cardiac Pacing, Artificial; Cation Transport Proteins; Computer Simulation; Electrocardiography; Ether-A-Go-Go Potassium Channels; Genetic Engineering; Humans; Immunohistochemistry; Mice; Mice, Transgenic; Microelectrodes; Models, Cardiovascular; Myocardium; Patch-Clamp Techniques; Piperidines; Potassium Channels, Voltage-Gated; Pyridines

Clinical doses of available H(1) antihistamines are limited mainly by sedative side effects. However, higher doses are often required to obtain optimal therapeutic activity, especially in dermatology. We report the synthesis of three norpiperidine imidazoazepines representative of a new class of selective and nonsedating H(1) antihistamines. The compounds were at least as potent as cetirizine and loratadine as measured by H(1) receptor binding affinity, by protection against compound 48/80- and histamine-induced lethality in rats and guinea pigs, respectively, and by skin reaction tests in rats, guinea pigs, and dogs. The compounds, in particular 3a, were less prone than the reference compounds to penetrate the brain and to occupy central H(1) receptors, suggesting absence of sedative side effects. In vitro and in vivo cardiovascular safety tests showed that 3a had no intrinsic potential to prolong ventricular repolarization or induce cardiac arrhythmias. Compound 3a has been selected for further clinical development, mainly for application in dermatology.

Topics: Anaphylaxis; Animals; Arrhythmias, Cardiac; Benzazepines; Blood-Brain Barrier; CHO Cells; Cricetinae; Cricetulus; Dermatitis; Dermatologic Agents; Dogs; Drug Stability; Female; Guinea Pigs; Histamine H1 Antagonists, Non-Sedating; Hydrogen-Ion Concentration; Imidazoles; In Vitro Techniques; Male; Passive Cutaneous Anaphylaxis; Piperidines; Radioligand Assay; Rats; Rats, Wistar; Solubility; Spiro Compounds; Structure-Activity Relationship; Ventricular Function

Topics: Arrhythmias, Cardiac; Butyrophenones; Histamine H1 Antagonists; Humans; Piperidines; Rhinitis; Treatment Outcome; Urticaria

Topics: Animals; Arrhythmias, Cardiac; Automobile Driving; Butyrophenones; Electrocardiography; Histamine H1 Antagonists; Humans; Models, Animal; Piperidines; Potassium Channels; Time Factors

To investigate the relationship between M3-R/IK(M3) and arrhythmia in order to find a new target for antiarrhythmic agents.. Using the acute ischemic model of rats and patch-clamp techniques, the effects of the M3 receptor on the occurrence of arrhythmias and its possible mechanisms were studied.. In acute ischemic model of rats, the M3 receptor antagonist 4-diphenylacetoxy-N-methylpiperidine-methiodide (4DAMP) increased the occurrence of arrhythmias, and the M3 receptor agonist choline suppressed the onset and the development of arrhythmias (P < 0. 01). No change was observed after treatment with other receptor antagonists (M1, M2, and M4). With patch-clamp techniques, it was found that choline induced K+ current could be inhibited by 4DAMP. Antagonists toward M1, M2, and M4 receptors all failed to alter the current.. Choline modulates the cellular electrical properties of the heart, probably by activating a K+ current via stimulation of the M3 receptor. M3-R/IK(M3) may act as a new target for antiarrhythmic agents.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cell Separation; Choline; Guinea Pigs; Heart Ventricles; Male; Myocytes, Cardiac; Piperidines; Rats; Rats, Wistar; Receptor, Muscarinic M3

The present study was designed to determine whether a novel cyclohexane dicarboximide derivative, ST-6, 2-[4-[4-(chlorophenyl)-4-hydroxy-1-piperidinyl]butyl]hexahydro-1H-isoindol-1,3(2H)-dione, prevents reperfusion-induced ventricular arrhythmias. Pentobarbital-anesthetized rats were subjected to left coronary artery occlusion for 4 min followed by 4-min reperfusion, and the incidence of their ventricular arrhythmias was examined. The coronary occlusion of control rats induced ventricular tachycardia and fibrillation, eventually leading to sudden death. The intravenous injection of 0.1 to 2 mg/kg ST-6 prior to the occlusion resulted in a dose-dependent suppression of the ventricular arrhythmias. The suppression of ventricular fibrillation was also observed on the intraperitoneal and intradoudenal administration of 2 to 10 mg/kg ST-6 15 min prior to coronary occlusion. Antiarrhythmic effects of this agent (0.5 mg/kg per min) were compared with those of other antiarrhythmic agents including lidocaine (0.1 mg/kg per min), sematilide (0.3 mg/kg per min), and diltiazem (0.5 mg/kg per min) by administrating the agents from 1 min after the coronary occlusion to the end of 4-min reperfusion. Antiarrhythmic effects of ST-6 were similar in degree to those of lidocaine and diltiazem, whereas no significant prevention by sematilide was seen. The results suggest that ST-6 may be capable of suppressing reperfusion-induced arrhythmias following oral or intravenous administration.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Cyclohexanes; Heart Rate; Imides; Isoindoles; Male; Myocardial Reperfusion Injury; Piperidines; Rats; Rats, Sprague-Dawley

The aims of this study were to determine if endothelin-1 (ET-1) under normal and ischaemic conditions exhibits a direct arrhythmogenic effect that is independent of its ability to cause coronary vasoconstriction, and to determine the contribution of the ET(A) and ET(B) receptor subtype. ET(A/B) (with ET-1) and ET(A) (ET-1 in the presence of BQ-788) receptor activation resulted in a significant reduction in both epi- and endocardial monophasic action potential duration (MAPD(90)). ET(A) receptor activation reduced both epi- and endocardial effective refractory period (ERP). This MAPD(90) and ERP shortening were associated with a reduction in coronary flow, myocardial contractility and induction of ventricular fibrillation (VF) during ERP measurement. The ET(B) agonist sarafotoxin (S6c) had no marked, or concentration-dependent, effect on MAPD(90), ERP, myocardial contractility or induction of arrhythmias. Neither ET-1 nor S6c, given prior to coronary artery occlusion, significantly changed the ischaemia-induced dispersion of MAPD(90), ERP or the % incidence of VF. In conclusion, neither ET(A) nor ET(B) receptor stimulation has a direct arrhythmogenic effect in isolated rabbit hearts under normal or ischaemic conditions. The ET-1-induced arrhythmogenic effect observed in nonischaemic hearts is likely to be the result of the associated coronary vasoconstriction caused by ET(A) receptor stimulation resulting in myocardial ischaemia.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Circulation; Disease Models, Animal; Endocardium; Endothelin B Receptor Antagonists; Endothelin-1; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Ischemia; Oligopeptides; Pericardium; Piperidines; Rabbits; Receptor, Endothelin A; Receptor, Endothelin B; Ventricular Fibrillation; Viper Venoms

1. The aim of this study was to analyse the effects of eliprodil, a noncardiac drug with neuroprotective properties, on the cardiac repolarisation under in vitro circumstances, under normal conditions and after the attenuation of the 'repolarisation reserve' by blocking the inward rectifier potassium current (I(K1)) current with BaCl(2). 2. In canine right ventricular papillary muscle by applying the conventional microelectrode technique, under normal conditions, eliprodil (1 microm) produced a moderate reverse rate-dependent prolongation of the action potential duration (7.4+/-1.5, 8.9+/-2.1 and 9.9+/-1.8% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=9). 3. This effect was augmented in preparations where I(K1) was previously blocked by BaCl(2) (10 microm). BaCl(2) alone lengthened APD in a reverse frequency-dependent manner (7.0+/-1.3, 14.2+/-1.6 and 28.1+/-2.1% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). When eliprodil (1 microm) was administered to these preparations, the drug induced a marked further lengthening relative to the APD values measured after the administration of BaCl(2) (12.5+/-1.0, 17.6+/-1.5 and 20.5+/-0.9% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). 4. In the normal Langendorff-perfused rabbit heart, eliprodil (1 microm) produced a significant QT(c) prolongation at 1 Hz stimulation frequency (12.7+/-1.8%, n=9). After the attenuation of the 'repolarisation reserve' by the I(K1) blocker BaCl(2) (10 microm), the eliprodil-evoked QT(c) prolongation was greatly enhanced (28.5+/-7.9%, n=6). In two out of six Langendorff preparations, this QT(c) lengthening degenerated into torsade de pointes ventricular tachycardia. 5. Eliprodil significantly decreased the amplitude of rapid component of the delayed rectifier potassium current (I(Kr)), but slow component (I(Ks)), transient outward current (I(to)) and I(K1) were not considerably affected by the drug when measured in dog ventricular myocytes by applying the whole-cell configuration of the patch-clamp technique. 6. The results indicate that eliprodil, under normal conditions, moderately lengthens cardiac repolarisation by inhibition of I(Kr). However, after the attenuation of the normal 'repolarisation reserve', this drug can induce marked QT interval prolongation, which may result in proarrhythmic action.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Barium Compounds; Chlorides; Dogs; Electrocardiography; Electrophysiology; Female; Heart; In Vitro Techniques; Male; Membrane Potentials; Microelectrodes; Neuroprotective Agents; Papillary Muscles; Patch-Clamp Techniques; Piperidines; Potassium Channel Blockers; Potassium Channels, Inwardly Rectifying; Rabbits

To clarify mechanisms that the antiarrhythmic effects of matrine and berbamine are weaker than those of amiodarone and RP58866.. Experimental arrhythmic models were induced by aconitine, coronary artery ligation and electric stimulation in rats and rabbits. Whole-cell patch-clamp techniques were used to record IK1, IKr, IKs and Ito.. Matrine and berbamine significantly increased the dose of aconitine for induction of ventricular premature and ventricular tachycardia in rats, decreased the number of arrhythmias induced by coronary artery ligation in rats and increased ventricular fibrillation threshold (VFT) induced by electric stimulation in rabbits, but the anti-arrhythmic potency of matrine and berbamine was lower than that of amiodarone and RP58866. The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866. The IC50 of matrine for IK1, IKr, IKs, Ito were (46 +/- 3), (32.9 +/- 1.2), (37 +/- 8) and (7.6 +/- 0.5) mol x L(-1), respectively. The IC50 of amiodarone for IK1, IKr, IKs, Ito were (21 +/- 5) , (3.7 +/- 0.7), (5.9 +/- 0.9) and (5.9 +/- 0.6) mol x L(-1), respectively.. The inhibitory actions of matrine and berbamine on IK1, IKr, IKs, Ito were lower than those of amiodarone and RP58866, which might be the reason that the antiarrhythmic effects of matrine and berbamine were weaker than those of amiodarone and RP58866.

Topics: Aconitine; Alkaloids; Amiodarone; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzylisoquinolines; Chromans; Dogs; Female; Guinea Pigs; Male; Matrines; Piperidines; Potassium Channels; Quinolizines; Rabbits; Rats

We have found that intravenous administration of cannabinoid receptor (CB) agonist HU-210 (0.05 mg/kg), increases cardiac resistance against arrhythmogenic effect of epinephrine, aconitine, coronary artery occlusion and reperfusion in rats. Pretreatment with CB2-receptor antagonist, SR144528 (1 mg/kg), completely abolished the antiarrhythmic effect of HU-210. However this effect of HU-210 was not attenuated by pretreatment with CB1-receptor antagonist, SR141716A (3 mg/kg). We also found that HU-210 (0.05 mg/kg) decreased the relationship between infarction size and area of ischemia. It is concluded that CB2 receptor stimulation promotes an increase in the cardiac resistance against arrhythmogenic influences and probably increases myocardial tolerance of both ischemic and reperfusion damages in rats.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Arterial Occlusive Diseases; Camphanes; Cannabinoids; Coronary Artery Disease; Dronabinol; Epinephrine; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

The proarrhythmic activities of the selective I(Kr) blocker erythromycin and the less selective K(+) channel blockers, terikalant and clofilium, have been compared in an alpha(1)-adrenoceptor-stimulated, anaesthetized rabbit model. Terikalant (2.5, 7.5 and 25 nmol kg(-1) min(-1); n = 10), erythromycin (133, 400 and 1330 nmol kg(-1) min(-1); n = 8), clofilium (20, 60 and 200 nmol kg(-1) min(-1); n=10) or vehicle (n = 8) was infused intravenously over 19 min and there was a 15-min interval between each infusion [corrected]. QT and QTc intervals, and epicardial monophasic action potential duration were prolonged significantly (and to a similar extent) only by clofilium and terikalant. The total incidences of torsade de pointes were 60%*, 20%, 0% and 0% in clofilium-, terikalant-, erythromycin- and vehicle-treated animals, respectively (*P < 0.05 compared to vehicle control). In conclusion, terikalant exerted mild proarrhythmic activity though it prolonged repolarisation markedly. Despite being given in high doses, erythromycin neither prolonged repolarisation nor induced proarrhythmia.

Topics: Action Potentials; Adrenergic alpha-1 Receptor Agonists; Animals; Anti-Arrhythmia Agents; Anti-Bacterial Agents; Arrhythmias, Cardiac; Blood Gas Analysis; Blood Pressure; Body Temperature; Chromans; Electrocardiography; Erythromycin; Heart Rate; Male; Piperidines; Quaternary Ammonium Compounds; Rabbits; Torsades de Pointes

Intravenous injection of 10 mg/kg anandamide reduces the incidence and duration of epinephrine-induced arrhythmias in rats. SR141716A and SR144528, antagonists of cannabinoid receptor I and II did not abolish the antiarrhythmic effect of anandamide. These data suggest that the antiarrhythmic effect of anandamide is nonspecific or mediated via unknown cannabinoid receptors, but not associated with activation of cannabinoid receptors I and II.

Topics: Animals; Arachidonic Acids; Arrhythmias, Cardiac; Camphanes; Electrocardiography; Endocannabinoids; Epinephrine; Heart; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB2; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

The antiarrhythmic effects of a novel antiarrhythmic drug AP-792, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[4-cyclohexylbutyl]piperidine hydrochloride, were analyzed using the epinephrine-, digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmia models. Intravenous administration of AP-792 (0.3 or 1.0 mg/kg) effectively suppressed each of the ventricular arrhythmias, an action that resembles that of a typical cardioselective Ca2+ channel blocker, AH-1058. The antiarrhythmic action of AP-792 was slow in onset and longer-lasting than those in our previous studies using more than 50 antiarrhythmic drugs, including Na+ and Ca2+ channel blockers. These results suggest that AP-792 can become a unique long-acting antiarrhythmic drug.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Digitalis; Disease Models, Animal; Dogs; Electrocardiography; Epinephrine; Heart Ventricles; Injections, Intravenous; Ligation; Piperidines; Sodium Channel Blockers

We sought to determine whether potassium (K(+)) channel blockers (KBs) can activate extracellular signal-regulated kinase (ERK) and to characterize the upstream signals leading to ERK activation in cardiomyocytes.. Because KBs attenuate K(+) outward current, they may possibly prolong the duration of action potentials, leading to an increase in calcium (Ca(2+)) transient ([Ca(2+)](i)) in cardiomyocytes. Elevation of intracellular Ca(2+) levels can trigger various signaling events. Influx of Ca(2+) through L-type Ca(2+) channels after membrane depolarization induced activation of MEK and ERK through activation of Ras in neurons. Although KBs are frequently used to treat cardiac arrhythmias, their effect on signaling pathways remains unknown.. Primary cultured rat cardiomyocytes were stimulated with four different KBs-4-aminopyridine (4-AP), E-4031, tetra-ethylammonium and quinidine-and phosphorylation of ERK, proline-rich tyrosine kinase 2 (Pyk2) and epidermal growth factor receptor (EGFR) was detected. Action potentials were recorded by use of a conventional microelectrode. (Ca(2+))(i) was monitored by the fluorescent calcium indicator Fluo-4.. E-4031, 4-AP, tetra-ethylammonium and quinidine induced phosphorylation of ERK. 4-Aminopyridine prolonged the duration of action potentials by 37% and increased (Ca(2+))(i) by 52% at 1 mmol/l. Pre-incubation of ethyleneglycoltetraacetic acid, 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid tetrakis and diltiazem completely blocked this phosphorylation, whereas flufenamic acid and benzamil did not. 4-Aminopyridine induced tyrosine phosphorylation of Pyk2 and EGFR, which peaked at 5 and 10 min, respectively. Cytochalasin D, AG1478 and dominant-negative EGFR strongly inhibited the phosphorylation of ERK, whereas calphostin C, calmidazolium and KN62 did not.. These findings indicate that KBs induce ERK activation, which starts with Ca(2+) entry through the L-type Ca(2+) channel in cardiomyocytes, and that EGFR and Pyk2 are involved in this activation.

Topics: 4-Aminopyridine; Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channels, L-Type; Cells, Cultured; Cytochalasin D; Drug Evaluation, Preclinical; ErbB Receptors; Focal Adhesion Kinase 2; Mitogen-Activated Protein Kinases; Myocardium; Phosphorylation; Piperidines; Potassium Channel Blockers; Protein-Tyrosine Kinases; Pyridines; Quinazolines; Quinidine; Rats; Rats, Wistar; Tetraethylammonium; Time Factors; Tyrphostins

We sought to examine whether the antiarrhythmic effect of E4031 (E), or I(Kr) channel blocker, is affected by beta-adrenergic stimulation using isoproterenol (Iso) or by beta-adrenergic blockade (betaB) using, ONO1101, in a canine myocardial infarction model. Electrophysiologic studies were performed in 10 dogs with 7-day-old myocardial infarctions. Local QT intervals were measured at 47 sites on the infarcted myocardium using a mapping electrode. QT dispersion (QTd), as defined by the coefficient of variation of QT intervals, was obtained. Inducibility of ventricular arrhythmias was examined by programmed stimulation. These procedures were repeated during administration of E, E + Iso, and E + betaB. The effect of prolonging local QT intervals by E was counteracted by Iso, and was accentuated by betaB. The amount of prolongation was dependent on the baseline QT intervals, and QTd showed a tendency to decrease with E, to increase with E + Iso, and significantly decreased with E + betaB. Ventricular tachyarrhythmias were induced in a half of dogs with E + Iso, but were not induced with E + betaB. In the presence of adrenergic activation, I(Kr) blockers may exhibit a decreased antiarrhythmic effect. Beneficial synergism can be expected when an I(Kr) blocker is combined with a beta-blocker in the subacute phase of myocardial infarction.

Topics: Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; Dogs; Drug Therapy, Combination; Electrocardiography; Female; Heart; Heart Ventricles; Male; Morpholines; Myocardial Infarction; Piperidines; Potassium Channel Blockers; Pyridines; Urea

The antiarrhythmic profile and cardiohemodynamic effect of a novel Ca(2+) channel blocker, 4-(5H-Dibenzo[a, d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-p ropeny l]piperidine hydrochloride (AH-1058), were analyzed using the epinephrine-, digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmia models. Intravenous administration of AH-1058 (100 microg/kg) effectively suppressed each of the ventricular arrhythmias accompanied by weak hypotensive effects. The results contrast well with those of a typical Ca(2+) channel blocker, verapamil, which suppresses only the epinephrine-induced ventricular arrhythmia with severe hypotension. These results indicate that AH-1058 may possess a more selective inhibitory action on Ca(2+) channels in the heart than on those in the vessels. Furthermore, the antiarrhythmic actions of AH-1058 were slower in onset and longer-lasting, than those in our previous studies using other antiarrhythmic drugs, including Na(+) and Ca(2+) channel blockers. The antiarrhythmic effects of AH-1058 did not correlate with its plasma concentrations when administered either intravenously or orally. These results suggest that AH-1058 can become a long-acting Ca(2+) channel blocker with unique antiarrhythmic properties, and that AH-1058 may be used in certain pathological processes, for which selective inhibition of the cardiac Ca(2+) channels is essential.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bridged Bicyclo Compounds; Calcium Channel Blockers; Cardiovascular Agents; Coronary Vessels; Digitalis; Disease Models, Animal; Dogs; Epinephrine; Ligation; Piperidines; Plants, Medicinal; Plants, Toxic

This study sought to determine whether abnormal ventricular repolarization is implicated in cardiac arrhythmias of German shepherd dogs with inherited sudden death.. Moïse et al. (9) have identified German shepherd dogs that display pause-dependent lethal ventricular arrhythmias.. Ventricular repolarization was studied both in vivo using electrocardiogram recordings on conscious dogs and in vitro with a standard microelectrode technique performed on endomyocardial biopsies and Purkinje fibers. Pharmacological manipulation was used to evaluate the role of potassium channels.. In control conditions, electrocardiogram parameters were similar in both groups of dogs, except for the PR interval (18% longer in affected dogs, p < 0.05). Injection of d,l-sotalol (2 mg/kg) prolonged QT interval more in affected dogs (+14%, n = 9) than it did in unaffected dogs (+6%, n = 6, p < 0.05) and increased the severity of arrhythmias in affected dogs. In vitro, in control conditions, action potential duration (APD90) of endomyocardial biopsies and Purkinje fibers were significantly longer in affected dogs (respectively 209 +/- 3 ms, n = 30 and 352 +/- 15 ms, n = 17) than they were in unaffected dogs (197 +/- 4 ms, n = 25 and 300 +/- 9 ms, n = 30) at a pacing cycle length (PCL) of 1,000 ms. This difference increased with PCL. The kinetics of adaptation of APD90 to a change in PCL was faster in affected dogs. D,l-sotalol (10(-5) and 10(-4)M) increased APD90 in both groups of dogs, but this increase was greater in affected dogs, with the occurrence of triggered activity on Purkinje fibers. E-4031 (10(-7) and 10(-6) M), an I(Kr)-blocker, increased APD90 similarly in both groups of dogs. Chromanol 293B (10(-6) and 10(-5)M), an I(Ks)-blocker, increased significantly APD90 in unaffected dogs but had no effect in affected dogs.. These results support the hypothesis of an abnormal cardiac repolarization in affected dogs. The effects of 293B suggest that I(Ks) may be involved in this anomaly.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chromans; Death, Sudden, Cardiac; Dog Diseases; Dogs; Electrocardiography; Endocardium; Heart; In Vitro Techniques; Myocardium; Piperidines; Potassium Channel Blockers; Purkinje Fibers; Pyridines; Reference Values; Sotalol; Sulfonamides

1. The NHE1 isoform of the Na(+)/H(+) exchanger plays an important role in the regulation of intracellular pH and in cardiac cell injury caused by ischaemia and reperfusion. SL 59.1227 is a novel imidazolypiperidine Na(+)/H(+) antiport inhibitor which is structurally unrelated to previously described acylguanidine inhibitors such as cariporide. 2. Recovery of pH(i) following an intracellular acid load was measured in CCL39-derived PS120 variant cells, selectively expressing either NHE1 or NHE2 isoforms of the Na(+)/H(+) exchanger. pH(i) recovery was potently and selectively slowed by SL 59.1227 in NHE1-expressing cells (IC(50) 3.3+/-1.3 nM) versus NHE2-expressing cells (2.3+/-1.0 microM). The respective IC(50) values for cariporide were 103+/-28 nM (NHE1) and 73+/-46 microM (NHE2). 3. In anaesthetized rats following left coronary artery occlusion (7 min) and reperfusion (10 min) SL 59.1227 (10 - 100 microg kg(-1) min(-1) i.v.) inhibited ischaemia-mediated ventricular tachycardia (71 - 100%) and reperfusion-induced ventricular fibrillation (75 - 87%) and prevented mortality. Bolus i.v. administration of SL 59.1227 (1 mg kg(-1)) produced anti-arrhythmic effects when administered either before or during ischaemia. 4. Cardiac infarct size was determined in anaesthetized rabbits following left coronary artery occlusion (30 min) and reperfusion (120 min). Infarct size measured as a percentage of the area at risk was 36.2+/-3.4% (control group) versus 15.3+/-3.9% (SL 59.1227 0.6 mg kg(-1) i.v.). 5. SL 59.1227 is the first example of a potent and NHE1-selective non-acylguanidine Na(+)/H(+) exchanger inhibitor. It possesses marked cardioprotective properties.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzamides; Blood Pressure; Coronary Disease; Guanidines; Heart Rate; Heart Ventricles; Hydrogen-Ion Concentration; Imidazoles; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Piperidines; Rabbits; Rats; Rats, Sprague-Dawley; Sodium-Hydrogen Exchangers; Sulfones

Intravenous injection of the selective cannabinoid receptor agonist HU-210 in doses of 0.05 and 0.25 mg/kg increased heart resistance to arrhythmogenic effects of epinephrine, while intracerebroventricular infusion of this substance had no effect on the incidence of epinephrine-induced arrhythmia. The selective antagonist of type I cannabinoid receptors SR141716A in a dose of 3 mg/kg and ganglion blocker hexamethonium in a dose of 10 mg/kg did not modify the antiarrhythmic effect of HU-210. This effect of HU-210 is probably related to activation of type II peripheral cannabinoid receptors.

Topics: Animals; Arrhythmias, Cardiac; Cannabinoids; Disease Models, Animal; Dronabinol; Epinephrine; Ganglionic Blockers; Heart; Hexamethonium; Immunity, Innate; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Rimonabant

The synthesis of analogues of N,2-diphenyl-N-(4-piperidyl)acetamide endowed with antiarrhythmic activity is reported. Benzoyl, cinnamoyl, acetyl and propionyl groups replace the phenacyl group as N-acyl substituent, while pyridine replaces benzene as aromatic ring bound to the amide nitrogen. The title compounds were evaluated for antiarrhythmic activity on experimental arrhythmias induced by aconitine in rats. The presence of a n-propyl chain and an unsubstituted cinnamoyl moiety (1j) gives the highest protection against aconitine induced extrasystoles while the best efficacy against lethal effects is due to the presence of a n-propyl chain and an acetyl moiety (1m).

Topics: Aconitine; Aminopyridines; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chromatography, Thin Layer; Female; Gas Chromatography-Mass Spectrometry; Magnetic Resonance Spectroscopy; Male; Piperidines; Rats; Spectrophotometry, Infrared

We hypothesized that by limiting the Na+ and Ca2+ loading by a blocker/inhibitor of the Na+ channel (lidocaine), Na+ overload (R56865: N-[1-[4-(4-fluorophenoxy)butyl]-4-piperidinyl]-N-methyl-2-benzothiazo lamine), Ca2+ channel (verapamil), Na+ -H+ exchange (ethylisobutyl amiloride) or of Na+ -Ca2+ exchange (No. 7943: 2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate), it should be possible to reduce ischemia/reperfusion-induced arrhythmias. To test this hypothesis, we used anaesthetized rats subjected to 5 min of coronary artery occlusion followed by 10 min of reperfusion to study antiarrhythmic effects of above compounds on reperfusion-induced ventricular premature beats, ventricular tachycardia, and reversible and irreversible ventricular fibrillation. Compound or saline was administered as an intravenous bolus injection at 5 min before ischemia. Pretreatment with lidocaine (5 mg/kg), verapamil (0.63 mg/kg), R56865 (0.63 mg/kg) or ethylisobutyl amiloride (1.25 mg/kg) significantly reduced or abolished all types of ventricular arrhythmias. However, pretreatment with verapamil was associated with second or third degree heart block in 3 out of 12 animals. Pretreatment with No. 7943 did not significantly influence the ischemia/reperfusion-induced ventricular arrhythmias. The present results suggest that both intracellular Na+ -and Ca2+ -loading play important roles in reperfusion-induced ventricular arrhythmias and the inhibition of Na+ -Ca2+ exchange to limit Ca2+ loading probably does not play any important role in ischemia/reperfusion-induced arrhythmias in anaesthetized rats.

Topics: Amiloride; Anesthesia; Animals; Arrhythmias, Cardiac; Benzothiazoles; Blood Pressure; Calcium; Calcium Channel Blockers; Calcium Channels; Heart Rate; Lidocaine; Male; Myocardial Reperfusion Injury; Piperidines; Rats; Rats, Wistar; Sodium; Sodium Channel Blockers; Sodium Channels; Thiazoles; Verapamil

To determine the cardiocirculatory effects of total intravenous anesthesia (TIVA) using remifentanil and propofol in high-risk cardiac surgical patients.. Prospective study of 20 patients undergoing first-time implantation of a cardioverter-defibrillator (ICD).. Major, community, university-affiliated hospital.. In 20 patients with severely reduced left ventricular function (left ventricular ejection fraction <30%) undergoing first-time implantation of an ICD, TIVA using remifentanil and propofol was performed.. Extensive hemodynamic monitoring using a pulmonary artery catheter was performed: (T1) before induction of anesthesia, (T2) after intubation, (T3) after skin incision, (T4) after first defibrillation, and (T5) 10 minutes after extubation. Propofol, 3.0 +/- 0.6 mg/kg/h (range, 1.9 to 4.4 mg/kg/h), and remifentanil, 0.30 +/- 0.05 microg/kg/min (range, 0.21 to 0.40 microg/kg/min), were used. Total costs added up to US $44.60 per patient. Patients could be extubated within 12.5 +/- 4.2 minutes after stopping anesthesia. There were significant decreases in heart rate (HR; from 77 +/- 12 to 57 +/- 10 beats/min [T3]), mean arterial blood pressure (MAP; from 98 +/- 14 to 70 +/- 12 mmHg [T2]), and systemic vascular resistance (from 1,551 +/- 309 to 1,233 +/- 274 dyne x s x cm(-5) [T2]). Cardiac index (CI) slightly decreased only at T3 (from 2.46 +/- 0.42 to 1.92 +/- 0.29 L/min/m2; p = 0.04). The decrease in MAP could easily be treated by volume infusion in most patients (17 patients). Sixty-five percent of the patients needed dobutamine to increase CI to greater than 2.0 L/min/m2 (mean dose, 2.2 +/- 1.8 microg/kg/min). Dobutamine could be stopped before extubation in all patients. No patient needed sustained inotropic or ventilatory support and intensive care therapy could be avoided.. TIVA using remifentanil and propofol in patients with severely reduced left ventricular function is safe, well-controllable, and allows early extubation after implantation of an ICD. Because patients without complications did not need a postoperative intensive care stay, costs may be considerably reduced.

Topics: Aged; Anesthesia, Intravenous; Anesthetics, Combined; Anesthetics, Intravenous; Arrhythmias, Cardiac; Cardiotonic Agents; Defibrillators, Implantable; Dobutamine; Female; Hemodynamics; Humans; Male; Middle Aged; Monitoring, Intraoperative; Piperidines; Propofol; Remifentanil; Risk Factors; Ventricular Dysfunction, Left

The high incidence of sudden death in heart failure may reflect abnormalities of repolarization and heightened susceptibility to arrhythmogenic early afterdepolarizations (EADs). We hypothesized that overexpression of the human K+ channel HERG (human ether-a-go-go-related gene) could enhance repolarization and suppress EADs. Adult rabbit ventricular myocytes were maintained in primary culture, which suffices to prolong action potentials and predisposes to EADs. To achieve efficient gene transfer, we created AdHERG, a recombinant adenovirus containing the HERG gene driven by a Rous sarcoma virus (RSV) promoter. The virally expressed HERG current exhibited pharmacologic and kinetic properties like those of native IKr. Transient outward currents in AdHERG-infected myocytes were similar in magnitude to those in control cells, while stimulated action potentials (0.2 Hz, 37 degrees C) were abbreviated compared with controls. The occurrence of EADs during a train of action potentials was reduced by more than fourfold, and the relative refractory period was increased in AdHERG-infected myocytes compared with control cells. Gene transfer of delayed rectifier potassium channels represents a novel and effective strategy to suppress arrhythmias caused by unstable repolarization.

Topics: Action Potentials; Adenoviridae; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cation Transport Proteins; Cells, Cultured; DNA-Binding Proteins; Electric Conductivity; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Heart Ventricles; Humans; Piperidines; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines; Rabbits; Recombinant Proteins; Trans-Activators; Transcriptional Regulator ERG; Ventricular Function

The electrical alternans shown on an ST segment, ST alternans, is known as one of the most important predictors of ventricular fibrillation (VF). It has also been reported that sodium channel inhibition changes action potential configuration, especially on the repolarization phase. Thus, the sodium channel blocker may produce ST alternans and trigger reentrant arrhythmia.. A sodium channel blocker (disopyramide, lidocaine, or flecainide) was infused selectively into the left anterior descending coronary artery in anesthetized, open-chest dogs. Sixty unipolar electrograms were simultaneously recorded from the entire cardiac surface of the heart. The amplitude of ST alternans (STa) was determined as the difference in the ST-segment magnitude between 2 consecutive electrograms. We accepted the greatest STa among 60 leads for evaluation. High-dose flecainide (100 microg. kg-1. min-1) increased STa and evoked a spontaneous VF. The STa in high-dose flecainide loading (8.7+/-3.4 mV; mean+/-SEM) was significantly greater than that in disopyramide or lidocaine (0. 9+/-0.4 and 0.8+/-0.2 mV, P<0.05). Treatment of 4-aminopyridine (4-AP) suppressed the increase in STa and the occurrence of VF evoked by flecainide, while E4031 or verapamil did not inhibit those.. Flecainide caused the ST alternans that was closely correlated to the occurrence of VF. Because the ST alternans was suppressed by 4-AP treatment, a 4-AP-sensitive current such as Ito or Isus may play an important role on this phenomenon.

Topics: 4-Aminopyridine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Disopyramide; Dogs; Electrocardiography; Flecainide; Injections; Lidocaine; Piperidines; Pyridines; Sodium Channels; Ventricular Fibrillation; Verapamil

Topics: Age Factors; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Creatinine; Female; Humans; Male; Piperidines

Ebastine (EBS), a novel nonsedative antiallergic agent, is similar to terfenadine in its chemical structure. However, clinical arrhythmogenicity of EBS remains controversial. In this study, we evaluated the possible arrhythmogenic potency of EBS as assessed by QT prolongation from a pharmacokinetic-pharmacodynamic viewpoint in comparison with that of terfenadine. EBS was intravenously infused into anesthetized rats at a rate of 3.0 or 10 mg/kg/h for 60 min, and electrocardiographic effects were continuously monitored from lead II. The plasma concentrations of EBS and its major metabolite, carebastine, were also measured under the same conditions. When intravenously administered, EBS exhibited QT prolongation in an infusion rate-dependent manner, with a lag time. Pharmacokinetic-pharmacodynamic analysis of EBS based on the effect-compartment model revealed values of EC50, Emax and EC(10 ms), (where 10 ms of QT prolongation was evoked) of 0.73 microg/mL, 12.5 ms and 2.90 microg/mL, respectively. The EC(10 ms) value of EBS was five times higher than that of terfenadine reported previously (Ohtani et al., J. Pharm. Pharmacol., 49, 458-462 (1997)). In conclusion, EBS was suggested to be less arrhythmogenic than terfenadine.

Topics: Animals; Arrhythmias, Cardiac; Butyrophenones; Electrocardiography; Histamine H1 Antagonists; Male; Piperidines; Rats; Rats, Sprague-Dawley; Terfenadine

AH-1058 is a newly synthesized antiarrhythmic agent. We investigated the antiarrhythmic and electrophysiological effects of AH-1058 in experimental arrhythmia models and isolated cardiomyocytes. In the ouabain-induced arrhythmia model of the guinea pig, pretreatment with AH-1058 (0.1-0.3 mg/kg, i.v.) delayed the appearance of premature ventricular complex (PVC) and ventricular fibrillation (VF) induced by intravenous infusion of ouabain. However, disopyramide (10 mg/kg, i.v.) delayed only that of PVC, and verapamil (1 mg/kg, i.v.) failed to affect the ouabain-induced ventricular arrhythmias. In the reperfusion-induced arrhythmia model of the rat, in which 5-min coronary occlusion and 10-min reperfusion were produced, AH-1058 (0.1-0.3 mg/kg, i.v.) inhibited the incidence of both ventricular tachycardia (VT) and VF, whereas disopyramide (5 mg/kg, i.v.) inhibited only reperfusion-induced VF. On the other hand, a higher dose of AH-1058 (1 mg/kg, i.v.) did not affect the aconitine-induced arrhythmias in rats, which were inhibited by disopyramide (5 mg/kg, i.v.). We also confirmed oral activity of AH-1058 in the reperfusion-induced arrhythmia model of the rat. AH-1058, at doses of 2-4 mg/kg, dose-dependently inhibited VT and VF. Electrophysiological experiments with patch-clamp techniques revealed that AH-1058 potently suppressed the L-type Ca2+ currents in isolated cardiomyocytes of the guinea pig. These results suggest that AH-1058 is a potent antiarrhythmic drug having a Ca2+ channel-blocking action. The antiarrhythmic profile of AH-1058 is different from that of disopyramide and verapamil.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bridged Bicyclo Compounds; Electrophysiology; Female; Guinea Pigs; Male; Membrane Potentials; Ouabain; Perfusion; Piperidines; Rats; Rats, Sprague-Dawley

Effects of K+ channel modulators, cromakalim and E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulfonylaminobenzoyl) piperidine], on the relationship between the action potential duration (APD) and Ca2+ transients were examined in single myocytes isolated from guinea pig cardiac left ventricle. Application of cromakalim decreased APD at 90% repolarization (APD90) and Ca2+ transient elicited at 0.5 Hz (IC50s=0.6 and 3 microM, respectively). Application of 0.3 microM E4031 increased these parameters by 110% and 45%, respectively. Under voltage-clamp, the relation between the duration of depolarization to 0 mV and Ca2+ transients could be described by the sum of two exponential components; the time constants were approximately 5 and 280 msec, respectively. The first component was abolished by 10 microM ryanodine, suggesting the involvement of Ca2+-induced Ca2+ release (CICR). Neither cromakalim nor E4031 directly affected Ca2+ current and Ca2+ transients under voltage clamp. When APD was changed by K+ channel modulators, the relation between APD90 and Ca2+-transients was almost similar to that obtained by changing the depolarization duration under voltage-clamp. CICR was changed significantly only when APD90 was markedly shortened by cromakalim. The extensively prolonged AP and Ca2+ transient in the presence of E4031 were reduced by an addition of cromakalim. It is concluded that these two K+ channel modulators can significantly alter the AP-induced Ca2+ transient mainly by changing APD, which regulates both Ca2+ influx and extrusion.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Cromakalim; Glyburide; Guinea Pigs; Heart Ventricles; Hypoglycemic Agents; Male; Patch-Clamp Techniques; Piperidines; Potassium Channel Blockers; Pyridines; Time Factors; Vasodilator Agents; Ventricular Function

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Delayed Rectifier Potassium Channels; Dogs; Drugs, Investigational; Guinea Pigs; Humans; In Vitro Techniques; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Pyridines

We studied the effects of potassium channel openers (PCOs) on frequency dependent prolongations of action potential duration (APD), triggered activities and oscillatory action potentials (OSC) induced by E-4031 and dofetilide. The action potentials of canine Purkinje fibers were recorded by a glass microelectrode technique. The effects of E-4031 (10(-6)M) as well as that of additional nicorandil (2 x 10(-5) M) on the APD were examined. When abnormal automaticity was observed under perfusion of E-4031 (10(-5) M) or dofetilide (10(-5) M), action potentials were recorded continuously to estimate the sequential effects of additional perfusion of nicorandil (6 x 10(-5) M) or Y-26763 (10(-5) M) on triggered activities and OSC. APD prolongation by E-4031 at slower stimulation rates (cycle lengths > or = 1,000 msec) was suppressed by nicorandil in a dose dependent manner. Both nicorandil and Y-26763 abolished the train of early afterdepolarization (EAD) due to E-4031 or dofetilide with a shifting of the resting membrane potential to a more negative level. PCOs also normalized dofetilide induced abnormal automaticities (EAD, OSC). The antagonistic actions of PCOs on changes in action potential induced by class III antiarrhythmic agents may prevent the development of proarrhythmias produced by these agents.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Phenethylamines; Piperidines; Potassium Channel Blockers; Potassium Channels; Purkinje Fibers; Pyridines; Sulfonamides

Life-threatening arrhythmias and prolonged QT interval have been reported in adults and children using cisapride, a medication structurally similar to procainamide. Premature infants have reduced activity of cytochrome p-450, the system responsible for metabolism of cisapride, which could lead to QT prolongation. Therefore, we prospectively studied premature infants and children receiving cisapride to analyze the effect of prolonged cisapride therapy on QT interval.. Premature infants in a neonatal intensive care unit and children seen at a pediatric gastroenterology clinic in a tertiary care hospital had electrocardiography-analyzed and -corrected QT interval measured before cisapride (0.8/mg/kg per day) therapy, and again after 1 month of therapy. If baseline electrocardiography was not performed initially, it was obtained after cessation of therapy.. A total of 30 children participated in the study. Mean corrected QT interval was similar at baseline and at 1 month after therapy. Significant QT prolongation was not found, and no adverse effects were recorded.. Corrected QT interval during prolonged cisapride therapy at 0.8 mg/kg per day appears to be similar for premature infants and children. An inherent trend toward QT prolongation was not detected in either group. In the absence of other risk factors that alter cisapride metabolism or predispose to arrhythmia, cisapride may be safe for use in premature infants as well as in children. Additional studies are needed to confirm these data.

Topics: Arrhythmias, Cardiac; Child; Cisapride; Electrocardiography; Gastrointestinal Agents; Gastrointestinal Diseases; Heart; Humans; Infant, Newborn; Infant, Premature; Intensive Care Units, Neonatal; Piperidines; Prospective Studies; Safety

Subendocardial Purkinje myocytes from the 48-hour infarcted heart (IZPCs) have reduced resting potentials, possibly due to altered inwardly rectifying K+ currents IK1. Abnormal depolarization-activated outward K+ currents could contribute to long triangularly shaped action potentials of IZPCs.. We used whole cell patch recordings to compare cesium-sensitive IK1 and 4-aminopyridine (4-AP)-resistant, noninactivating sustained IK between normal Purkinje myocytes (NZPCs) and IZPCs. IZPCs showed decreased net membrane currents. Two IZPC groups were distinguished, based on 4-AP-resistant outward K+ currents. IZPC-I had isochronal IK1 current-voltage relations similar to NZPCs whereas IZPC-II showed significantly reduced IK1 and increased outward plateau currents. To study the sustained IK in the presence of the Class III antiarrhythmic agent E-4031, a two-pulse protocol was used to inactivate transient outward currents, followed by step depolarizations. E-4031-sensitive currents were significantly greater in IZPCs at depolarized potentials (> 0 mV). Similar to NZPCs, IZPC E-4031 currents showed time dependence during depolarization, lack of rectification at positive steps, and voltage-dependent recovery from block.. Decreased IK1 may account for reduced resting potentials in IZPCs. E-4031-sensitive currents in NZPCs, unlike those in canine ventricular myocytes, are sensitive to 4-AP and are larger in IZPCs.

Topics: 4-Aminopyridine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Cesium; Data Interpretation, Statistical; Dogs; In Vitro Techniques; Male; Membrane Potentials; Myocardial Infarction; Patch-Clamp Techniques; Piperidines; Potassium Channels; Purkinje Cells; Pyridines

1. CP-060S is a novel sodium and calcium overload inhibitor, and is also characterized as a calcium channel blocker. As these activities have each been shown independently to ameliorate ischaemia damage in the myocardium, the combination may synergistically exert cardioprotection. In this study, therefore, the protective effect of CP-060S against ischaemia- and reperfusion-induced arrhythmia was evaluated in anesthetized rats. 2. Rats were anaesthetized with pentobarbitone, and the left anterior descending coronary artery was occluded for either 5 min with subsequent reperfusion (a reperfusion-induced arrhythmia model) or 30 min without (an ischaemia-induced arrhythmia model). All drugs were intravenously administered 1 min before the onset of occlusion. 3. In the reperfusion-induced arrhythmia model, the animals in the vehicle-treated group exhibited ventricular tachycardia (VT) in 100%, ventricular fibrillation (VF) in 89%, and death caused by sustained VF in 56%. CP-060S (30-300 microg kg(-1)) dose-dependently suppressed the incidences of arrhythmias. Significant decreases occurred at 100 microg kg(-1) in VF (incidence: 42%) and mortality (8%), and at 300 microg kg(-1) in VT (50%), VF (33%) and mortality (8%). This protective effect of CP-060S was 10 times more potent than that of a pure calcium channel blocker, diltiazem (30-1000 microg kg(-1)) we tested, in terms of effective dose ranges. As both drugs decreased myocardial oxygen consumption estimated by rate-pressure product to a similar extent, the calcium channel blocking activity of CP-060S would not seem to be sufficient to explain its potency. 4. In the same model, co-administration of ineffective doses of diltiazem (300 microg kg(-1)) and a sodium and calcium overload inhibitor, R56865 (100 microg kg(-1)), produced significant suppression of VT (incidence: 62%), VF (46%) and mortality (8%). By contrast, co-administration of R56865 at the same dose with CP-060S (300 microg kg(-1)) did not add to the effect of a single treatment of CP-060S. 5. In the ischaemia-induced arrhythmia model, CP-060S (300 microg kg(-1)) significantly decreased the incidence of VF from 75% to 29%, whereas diltiazem (1 mg kg(-1)) was ineffective. 6. These results suggest that CP-060S inhibits both ischaemia- and reperfusion-induced arrhythmia. The combination of the calcium channel blocking effect and the calcium overload inhibition was hypothesized to contribute to these potently protective effects.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzothiazoles; Calcium Channel Blockers; Diltiazem; Hemodynamics; Male; Myocardial Ischemia; Myocardial Reperfusion; Piperidines; Rats; Rats, Sprague-Dawley; Thiazoles; Thiazolidines

Topics: Aged; Anti-Ulcer Agents; Arrhythmias, Cardiac; Cisapride; Humans; Male; Nervous System Diseases; Parasympathomimetics; Piperidines

The delayed outward rectifier K+ channel has a role in the increase in automaticity of myocytes under pathophysiological conditions. The purpose of the present study was to clarify the effect of blockade of outward rectifier K+ channels by a class III antiarrhythmic drug, E4031, on ischemia- and reperfusion-induced arrhythmias. Ion fluxes, energy metabolites and cardiac function were measured and the epicardial electrocardiograms of Langendorff-perfused rat hearts were recorded during initial perfusion, global or regional ischemia and reperfusion. 10(-7) M of E4031 administered during the initial perfusion did not prolong the QT interval, but slowed the heart rate (. 222, E4031: 183 bpm, p < 0.05), increased myocardial 45Ca2+ uptake (. 2.1, E4031: 2.9 mumol/g dwt, p < 0.05) and attenuated the loss of intracellular K+ during ischemia (. 238, E4031: 248 mumol/g dwt, p < 0.05). E4031 tended to reduce ischemia-induced ventricular tachyarrhythmias (. 60, E4031: 30%, n.s.), but reperfusion-induced ventricular tachyarrhythmias were sustained longer by the administration of E4031 (CONTROL: 255, E4031: 623 sec, p < 0.05). Prior exposure to E4031 decreased the depletion of high energy phosphates during ischemia, but suppressed their recovery during reperfusion. These results suggest that the attenuated loss of K+ from the ischemic myocardium and the decrease in heart rate by E4031 contributed to the reduction of ischemia-induced arrhythmias. However, the increase in myocardial Ca2+ uptake and altered energy metabolism may be responsible for the increase in reperfusion-induced arrhythmias.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Energy Metabolism; Heart; In Vitro Techniques; Male; Myocardial Reperfusion Injury; Myocardium; Piperidines; Potassium Channels; Pyridines; Rats; Rats, Sprague-Dawley; Ventricular Function, Left

Serious undesirable cardiac side effects have been reported with treatment with diphemanil methylsulfate (Prantal) in premature babies or neonates. To understand the origin of this problem, the authors undertook an electrophysiological study of the effects of this product in vitro on rabbit Purkinje fibres. In three separate series (N = 5 to N = 8), the effects of increasing concentrations (0.1 microM-30 microM) of diphemanil methylsulfate, different frequencies of stimulation (0.2 Hz, 1 Hz, 2 Hz) and duration of exposition (60 min followed by 120 min washout) were observed on the properties of the action potential. The results show a clearcut antiarrhythmic Class III type action characterised by a concentration-dependent prolongation of the action potential duration with an inverse frequency dependency without significant changes of the other parameters. During stimulation at 0.2 Hz, early post-depolarizations and induced activity were observed in 3/8 of the fibres exposed to 10 microM and 8/8 fibres exposed to 30 microM. The effect did not attain a steady state after 60 min of exposition. It was not reversed by 120 min of washout of the preparation. These results were compatible with the reported cardiac arrhythmic effects of prolongation of the QT interval and torsades de pointe.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Child; Drug Evaluation, Preclinical; Electric Stimulation; Electrocardiography; Humans; Long QT Syndrome; Piperidines; Purkinje Fibers; Rabbits

This study sought to 1) test the hypothesis that in the setting of bradycardia and drug-induced action potential prolongation, multiple foci of early afterdepolarizations (EADs) result in beat to beat changes in the origin and direction of the excitation wave front and are responsible for polymorphic arrhythmias; and 2) determine whether EADs may initiate nonstationary reentry, giving rise to the typical torsade de pointes (TDP) pattern.. In the past, it has been difficult to associate EADs or reentry with the undulating electrocardiographic (ECG) patterns of TDP.. A voltage-sensitive dye was used for high resolution video imaging of electrical waves on the epicardial and endocardial surface of the Langendorff-perfused rabbit heart. ECG and monophasic action potentials from the right septal region were also recorded. Bradycardia was induced by ablation of the atrioventricular node.. Perfusion of low potassium chloride Tyrode solution plus quinidine led to prolongation of the action potential and the QT interval. Eventually, EADs and triggered activity ensued, giving rise to intermittent episodes of polymorphic arrhythmia. In one experiment, triggered activity was followed by a long episode of vortex-like reentry with an ECG pattern characteristic of TDP. However, in most experiments, focal activity of varying origins and propagation patterns was observed. Triggered responses also showed varying degrees of local block. Similar results were obtained with E-4031. Burst pacing both at control conditions and in the presence of quinidine consistently led to vortex-like reentry whose ECG pattern resembled TDP. However, the cycle length of the arrhythmia with quinidine was longer than that for control ([mean +/- SEM] 194 +/- 12 vs. 132 +/- 8 ms, p < 0.03).. Drug-induced polymorphic ventricular arrhythmias may result from beat to beat changes in wave propagation patterns initiated by EADs or EAD-induced nonstationary reentrant activity. In contrast, burst pacing-induced polymorphic tachycardia in the presence or absence of drugs is the result of nonstationary reentrant activity.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Heart; Heart Conduction System; Image Processing, Computer-Assisted; Models, Cardiovascular; Organ Culture Techniques; Perfusion; Piperidines; Pyridines; Quinidine; Rabbits; Torsades de Pointes

Topics: Arrhythmias, Cardiac; Cardiac Surgical Procedures; Child; Cisapride; Gastrointestinal Agents; Gastrointestinal Motility; Humans; Piperidines

Topics: Antifungal Agents; Arrhythmias, Cardiac; Cisapride; Drug Interactions; Humans; Ketoconazole; Piperidines

In the present study the electrophysiological characteristics and the proarrhythmic potential of cisapride and a structurally related drug, mosapride, were compared. In the anesthetized guinea pig, cisapride and d-sotalol (0.01-10 micromol/kg i.v., n = 6) dose-dependently prolonged the duration of the monophasic action potential recorded from the left ventricle. The maximal lengthening was 18 +/- 3.2% at 1.0 micromol/kg (mean +/- S.E.M., P < .01 vs. base line) and 19 +/- 2.5% at 10 micromol/kg (P < .001) for cisapride and d-sotalol, respectively. In contrast, mosapride did not increase this variable. In a rabbit model of the acquired long QT syndrome, infusion of cisapride (0.3 micromol/kg/min for 10 min maximum, n = 6), but not mosapride or vehicle, was associated with a significant lengthening of the QTU interval (43 +/- 3.8 ms, P < .01). Furthermore, torsades de pointes appeared in two of the six rabbits given cisapride. In isolated rabbit Purkinje fibers (PF), cisapride increased the action potential duration (48 +/- 5.6% at 0.1 micromol/l, P < .01 vs. control, n = 4). Mosapride did not significantly influence the action potential duration (3 +/- 2.0% increase at 1.0 micromol/l, n = 6). However, after mosapride was washed out, the addition of cisapride (0.1 micromol/l) caused a 46 +/- 3.2% lengthening of the action potential duration (P < .01 vs. 1.0 micromol/l mosapride). Early afterdepolarizations and triggered activity appeared in four of eight cisapride-superfused PF stimulated at a very low frequency (0.1 Hz). In isolated rabbit cardiomyocytes, cisapride concentration-dependently blocked (IC50 = 9 nmol/l) the rapid component of the delayed rectifying K+ current (I(Kr)). Mosapride was approximately 1000-fold less potent in blocking I(Kr) (IC50 = 4 micromol/l). It is concluded that the electrophysiological characteristics of cisapride may explain the recently reported propensity to prolong the QT interval and to induce torsades de pointes in susceptible patients, although a structurally related benzamide, mosapride, did not appear to have electrophysiological features of relevance for induction of torsades de pointes in common with cisapride.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Benzamides; Cisapride; Guinea Pigs; Heart; In Vitro Techniques; Long QT Syndrome; Male; Morpholines; Piperidines; Purkinje Fibers; Rabbits; Structure-Activity Relationship

Cisapride (Propulsid) is a gastrointestinal prokinetic agent commonly used to treat nocturnal heartburn as well as a variety of other gastrointestinal disorders. The use of cisapride has been associated with acquired long QT syndrome and ventricular arrhythmias such as torsades de pointes which produces sudden cardiac death. These cardiotoxic effects can be due to blockade of one or more types of K+ channel currents in the human heart. For this reason we compared the effects of cisapride on two cloned human cardiac K+ channels, Kv1.5 and the human ether-a-go-go-related gene (HERG) stably transfected into mammalian cells. Using patch clamp electrophysiology, we found that cisapride was a potent inhibitor of HERG displaying an IC50 value of 44.5 nmol/l when tail currents at -40 mV were measured following a 2 s test depolarization to +20 mV. When HERG currents were measured at the end of prolonged (20 s) depolarizing steps to +20 mV, the apparent affinity of cisapride was increased and measured 6.70 nmol/l. The main effect of cisapride was to enhance the rate of HERG current decay thereby reducing current at the end of the voltage clamp pulse. Furthermore, the potency of cisapride for the HERG channel was similar to that observed for the class III antiarrhythmic agent dofetilide (IC50 = 15.3 nmol/l) and the nonsedating antihistamine terfenadine (IC50 = 56.0 nmol/l). In contrast to its effects on HERG, cisapride inhibited Kv1.5 channel currents weakly displaying an IC50 value of 21.2 micromol/l. It is concluded that cisapride displays specific, high affinity block of the human cardiac K+ channel HERG. It is likely that this interaction underlies the proarrhythmic effects of the drug observed under certain clinical settings.

Topics: Arrhythmias, Cardiac; Cation Transport Proteins; Cell Line; Cisapride; DNA-Binding Proteins; Electrophysiology; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Heart; Humans; Kv1.5 Potassium Channel; Myocardium; Patch-Clamp Techniques; Phenethylamines; Piperidines; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Sulfonamides; Terfenadine; Trans-Activators; Transcriptional Regulator ERG; Transfection; Tumor Cells, Cultured

Class III activity has been proposed as a potential mechanism for the treatment of reentrant arrhythmias. The purpose of the present study was to assess the concordance in antiarrhythmic efficacy of MK-499, a selective blocker of IKr, the rapidly activating component of cardiac delayed rectifier K+ current, against programmed ventricular stimulation (PVS)-induced ventricular tachycardias and thrombotically induced lethal ischemic arrhythmias, and to characterize the electrophysiologic determinants of antiarrhythmic efficacy in the canine model of previous myocardial infarction. Single i.v. doses of 1.0, 3.0 and 10.0 micrograms/kg MK-499 were administered to anesthetized dogs with anterior myocardial infarctions. Protection (suppression + stabilization/slowing) vs. PVS-induced ventricular tachycardias occurred in 5/11 (45%) preparations at 1.0 microgram/kg, in 9/12 (75%) preparations at 3.0 micrograms/kg and in 10/11 (91%) preparations at 10.0 micrograms/kg i.v. MK-499. The incidences of lethal ventricular arrhythmias developing in response to thrombotically induced posterolateral myocardial ischemia were 34/40 (85%) in vehicle controls, 7/11 (64%) at 1.0 microgram/kg, 6/12 (50%, P < .05) at 3.0 micrograms/kg and 4/11 (36%, P < .01) at 10.0 micrograms/kg i.v. MK-499. Low-dose i.v. MK-499 prolonged ECG QT interval and increased noninfarct zone and infarct zone ventricular refractoriness. However, there was a poor concordance (56%) between response to PVS with MK-499 and response to thrombotically induced acute myocardial ischemia. Furthermore, different trends of association between site and magnitude of Class III effect and antiarrhythmic efficacy were observed for PVS- vs. ischemia-induced arrhythmias. Hence, although low-dose i.v. MK-499 provided significant protection against both electrically and ischemically triggered arrhythmias in the setting of previous myocardial infarction, protection against PVS-induced ventricular tachycardias was not highly predictive of protection against lethal ischemic arrhythmias in this preparation.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzopyrans; Dogs; Electrocardiography; Female; Heart; Male; Myocardial Infarction; Piperidines

Topics: Arrhythmias, Cardiac; Child; Cisapride; Extracorporeal Circulation; Female; Gastrointestinal Motility; Humans; Life Support Care; Piperidines; Sympathomimetics

Terfenadine and astemizole belong to the second generation histamine H1 antagonists and are widely prescribed for allergic and upper respiratory diseases. The popularity of the newer H1 antihistamines is due to their ability to provide relief from allergic symptoms without the undesirable side effect of sedation commonly associated with first generation H1 receptor antagonists such as diphenhydramine and promethazine. Recent clinical evidence that the second generation histamine H1 antagonists terfenadine and astemizole have the potential for inducing life threatening ventricular arrhythmias has raised questions as to whether other drugs in this class have similar cardiotoxic potential. The objective of this study was to evaluate and compare the arrhythmogenic potential of a series of second generation antihistamines in a quantitative experimental model predictive of adverse ECG effects in man. Antihistamines were given intravenously and electrocardiographic (ECG) and cardiovascular parameters (blood pressure and heart rate) were measured. The ECG wave form was analyzed to determine QTc interval, PR interval, QRS interval and heart rate. To determine the relative cardiotoxic potential of the antihistamines, the lowest dose producing significant prolongation of the QTc interval was compared with the dose required to inhibit by 50% the peripheral bronchospasm elicited by histamine at 10 micrograms/kg i.v. (antihistamine ED50). The second generation antihistamines studied were astemizole (CAS 68844-77-9), carebastine (CAS 90729-42-3), cetirizine hydrochloride (CAS 83881-52-1), ebastine (CAS 90729-43-4), norastemizole (CAS 75970-99-9), terfenadine (CAS 50679-08-8) and terfenadine carboxylate (CAS 83799-24-0). The second generation antihistamines astemizole, ebastine and terfenadine produced pronounced dose-dependent QTc interval prolongation effects. These arrhythmogenic effects occurred at doses that were between 1 and 4 times their respective peripheral antihistamine doses. These drugs produced significant disruption of the ECG wave form including large amplitude, morphologically aberrant T-waves and, in some cases, torsades de pointes-type arrhythmias. In contrast, terfenadine carboxylate (100 mg/kg i.v.), norastemizole (20 mg/kg, i.v.) and carebastine (50 mg/kg, i.v.), the major metabolites of terfenadine, astemizole and ebastine, were largely devoid of adverse ECG effects. Similarly, cetirizine (20 mg/kg, i.v.) was also found to not alter ECG or cardiova

Topics: Animals; Arrhythmias, Cardiac; Benzimidazoles; Blood Pressure; Electrocardiography; Guinea Pigs; Heart Diseases; Heart Rate; Hemodynamics; Histamine H1 Antagonists; Male; Models, Biological; Piperidines

Cisapride, a gastrointestinal prokinetic agent, has been associated with cases of Torsades de Pointes but its effects on the cardiac action potential have not been described. We investigated its electrophysiological effects on rabbit isolated Purkinje fibres. The results demonstrated that cisapride (0.01-10 microM) lengthened concentration-dependently the action potential duration without modifying other parameters and induced early after depolarizations and subsequent triggered activity. This typical class III antiarrhythmic effect, that showed "reverse" rate-dependence and was reduced by increasing external K concentration, can account for clinical arrhythmogenesis.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cisapride; Electrophysiology; Heart; Piperidines; Potassium; Purkinje Fibers; Rabbits; Torsades de Pointes

Arrhythmias induced by coronary artery ligation in cats, by CaCl2 and epinephrine in rats, and by ouabain in guinea-pigs were used as experimental models for studying the effects of a new calcium antagonist AR-1 ([1,2,5-trimethyl-4-phenyl-4-beta-(N-cyanoethyl-N-4'-methoxybenzyl) -ethylamino]piperidine, calcium channel blocker and calmodulin antagonist) on ventricular arrhythmias. Coronary ligation caused 90% lethality (ventricular fibrillation) with 12.5 min in untreated control cats, which was prevented by administration of AR-1 (4 mg/kg body weight (b.w.) before or after arrhythmia induction. Pretreatment with AR-1 afforded protection in a dose-related fashion. A dose of 1.5 mg/KG b.w. increased survival to 45%, and all cats dosed with 3 to 5 mg/Kg b.w. survived. CaCl2 (180 mg/Kg b.w., i.v.) induced ventricular fibrillation and 100% lethality. These effects were completely prevented by an anti-arrhythmic dose of AR-1 (3 mg/kg b.w.). Epinephrine-induced ventricular arrhythmias were also prevented by the same dose of AR-1. AR-1 (5 mg/kg b.w.) did not prevent ouabain (0.5 mg/kg b.w.)-induced arrhythmias that caused death within 17 +/- 3.7 min, but displayed protective effects during 67 +/- 7.7 min. The results from these animal studies, in conjunction with previously studies demonstrating coronarodilatory and anti-platelet efficacy of this compound, collectively suggest that AR-1 has a potential to become a useful antianginal and antiarrhythmic therapeutic agent.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium Channel Blockers; Calcium Chloride; Cardiovascular Agents; Coronary Vessels; Electrocardiography; Epinephrine; Male; Ouabain; Piperidines; Rats; Rats, Wistar; Tachycardia, Ventricular; Ventricular Fibrillation

We investigated the antiischemic and antiarrhythmic effects of R 56865 in pentobarbital-anesthetized, open-chest rabbits subjected to 10 min regional myocardial ischemia and 20 min reperfusion, using two experimental protocols. In the first, R 56865 (0.02-0.16 mg/kg) was administered as a bolus intravenous (i.v.) injection 5 min before ligation of a branch of the left circumflex coronary artery (LCX); in the second, the drug, at the highest dose studied (0.16 mg/kg), was injected by the same route during ischemia, 5 min after coronary artery ligation. Ischemia-induced ST segment increase and reperfusion-induced ventricular arrhythmias were determined in lead II of the four-limb ECG. Mean carotid arterial pressure and heart rate (HR) were also measured. When given before ischemia, R 56865 dose-dependently prevented ischemia-induced ST segment increase and reperfusion arrhythmias. The antiischemic and antiarrhythmic dose-response curves were superimposable, suggesting a common mechanism of action. R 56865 (0.16 mg/kg) fully attenuated ischemia-induced ST segment shift and ventricular arrhythmias on reperfusion. These protective effects were not associated with systemic hypotension or bradycardia. When high-dose R 56865 (0.16 mg/kg) was given during ischemia, ST segment shift and ventricular arrhythmias on reperfusion were not attenuated. The results strongly suggest that R 56865 affords protection against the deleterious effects of moderate ischemia by mechanisms not associated with an indirect reduction of cardiac work. R 56865 may elicit cardioprotection directly in ischemic tissue.

Topics: Analysis of Variance; Animals; Arrhythmias, Cardiac; Benzothiazoles; Calcium Channel Blockers; Disease Models, Animal; Dose-Response Relationship, Drug; Electrocardiography; Heart; Hemodynamics; Injections, Intravenous; Male; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Piperidines; Rabbits; Random Allocation; Thiazoles

We have investigated the ability of 5-hydroxytryptamine (5-HT) to elicit arrhythmic contractions in isolated human atrial strips as a function of pacing rate (0.1-2 Hz) using a method recently introduced by us (Kaumann and Sanders, this journal, 1993 b) and examined the nature of the 5-HT receptors involved. Right atrial appendage tissue was obtained from 14 patients undergoing cardiac surgery. None of the patients had advanced heart failure. 5-HT (0.6-20 mumol/l) induced arrhythmic contractions during pacing in 4/11 atrial strips from 3/4 patients who had not received beta blockers and in 21/27 atrial strips from 9/10 patients who had been chronically treated with beta blockers (primarily beta 1-selective). The incidence of arrhythmic contractions evoked by 5-HT did not reach statistical significance in the atrial tissue from the non-beta blocked patients but was highly significant in the atrial tissue from the chronically beta blocked patients. The arrhythmic contractions usually occurred more frequently at low than at high pacing rates and were observed at the physiological frequency of 1 Hz in 1/4 atrial strips from 1/4 of the non-beta blocked patients and 6/11 strips from 5/10 of the beta blocked patients. The 5-HT-evoked arrhythmic contractions were observed during blockade of beta 1-adrenoceptors, beta 2-adrenoceptors and 5-HT3 receptors, ruling out the participation of these receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adrenergic alpha-Antagonists; Aged; Arrhythmias, Cardiac; Drug Synergism; Female; Heart Atria; Heart Rate; Humans; In Vitro Techniques; Indoles; Male; Middle Aged; Myocardial Contraction; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Chromans; Dogs; Guinea Pigs; Humans; Piperidines; Potassium Channels; Rabbits; Rats; Species Specificity

Previous studies in guinea pig heart cells have shown pharmacologically and kinetically distinct components of the classical delayed rectifier current (IK), generally referred to as IKr (rapid IK) and IKs (slow IK). This study was designed to determine whether the human heart contains corresponding components.. The whole cell voltage clamp technique was used to study IK in single myocytes isolated from human right atrial appendages removed at the time of aortocoronary artery bypass surgery.. The activation of IK was best fitted by a biexponential relation, with time constants averaging 204(SEM 20) and 1080(197) ms at +10 mV. IK was inhibited by the specific IKr blocker E-4031 (5 microM), with the drug sensitive and drug resistant components having markedly different kinetic properties. The E-4031 sensitive current activated rapidly, while the drug resistant component activated more slowly, and the activation time courses of E-4031 sensitive and resistant currents paralleled the rapid and slow components of IK between -20 and +50 mV. The E-4031 sensitive component showed strong inward rectification, a half activation voltage (V 1/2) of -14.0(3.3) mV and a slope factor (k) of 6.5(1.5) mV, while the E-4031 resistant current had a linear current-voltage relationship, and values of +19.9(4.2) mV and 12.7(2.5) mV for V 1/2 and k respectively. The envelope of tails analysis showed a time dependent change in IKtail/IKstep under control conditions, and E-4031 strongly reduced the time dependent variation, suggesting that the E-4031 resistant current consisted of one dominant component.. (1) IK in human atrium shows kinetically distinguishable rapid and slow components. (2) These components correspond to E-4031 sensitive and resistant currents. (3) The kinetics and voltage dependence of the rapid (E-4031 sensitive) and slow (E-4031 resistant) components correspond to properties previously described in guinea pig myocytes. These findings have important potential implications for understanding the mechanisms of human atrial repolarisation and its regulation by the autonomic nervous system and antiarrhythmic drugs.

Topics: Arrhythmias, Cardiac; Cells, Cultured; Coronary Disease; Heart Atria; Humans; Membrane Potentials; Middle Aged; Patch-Clamp Techniques; Piperidines; Potassium Channels; Pyridines

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Chromans; Ion Channel Gating; Piperidines; Potassium Channels; Rats

We evaluated the antiarrhythmic efficacy of E-4031, a new class III drug, and compared it with that of conventional class I and II antiarrhythmic agents in terms of electrophysiological actions on refractoriness and conduction in a 7-day-old canine model of myocardial infarction. Sustained monomorphic VT was reproducibly induced in 26 dogs by a premature stimulation method from the right ventricle. Class I drugs (disopyramide, aprindine, flecainide) prevented VT induction in 5 of 13 dogs, and propranolol and E-4031 prevented it in 6 of 6 and 6 of 7 dogs, respectively. The effective refractory period (ERP) was determined at 47 epicardial sites overlying the infarct in each experiment by a S1S2 method. The standard deviation (SD) of the mean ERP of these sites was used as an index of ERP dispersion. The extent of ERP prolongation produced by class I drugs and E-4031 was significantly more marked than that produced by propranolol. However, the SD was increased by class I drugs and E-4031, but not by propranolol. Class I drugs increased the ERP dispersion mainly by an effect on the transmural infarct zone in which the control ERP was more prolonged than in the normal zone. E-4031 tended to prolong the ERP in both the normal and infarct zones, and had a minimal tendency to increase ERP dispersion. In contrast, propranolol decreased the ERP dispersion between zones. Conduction velocity calculated by epicardial mapping was significantly decreased by flecainide, but not by E-4031. We conclude that the antiarrhythmic effect of E-4031 depends largely on its ability to prolong refractoriness without suppressing conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Disease Models, Animal; Disopyramide; Dogs; Electrophysiology; Flecainide; Myocardial Infarction; Piperidines; Potassium Channel Blockers; Pyridines; Tachycardia, Ventricular

The effects of the Ito blocker, tedisamil (0.1, 1.0, and 3.0 mg/kg, IV), and the IK blocker, E-4031 (0.1, 1.0, and 3.0 mg/kg, IV), on the incidence and duration of reperfusion-induced arrhythmias were compared in the anesthetized rat (n = 12 per group). Reperfusion arrhythmias were evaluated after a 5 minute occlusion period of the left main coronary artery. In the absence of any pronounced effect on blood pressure, tedisamil and E-4031 reduced heart rate in a dose-dependent manner. During the preischemic period, QTc interval was increased by tedisamil but was not changed by E-4031. Both compounds increased the QTc interval during the ischemic period and also during the reperfusion. E-4031 was unable to reduce the incidence and duration of reperfusion-induced ventricular arrhythmias after 5 minutes of coronary artery occlusion. Tedisamil dose-dependently reduced the duration of reperfusion arrhythmias and their incidence. In a second set of experiments, the combination of tedisamil (1.0 mg/kg) with E-4031 (1.0 mg/kg) was administered. The electrocardiographic action of this combination was similar to that observed with tedisamil given alone. However, with the combination the incidence of fibrillation was reduced from 83% in the control group to 8% in the treated group (p < 0.001), and the mortality was reduced from 67% to 0% (p < 0.001), that is, to a greater extent than with tedisamil (1.0 mg/kg) alone. The results show that the blockade of Ito by tedisamil allows a reduction of reperfusion-induced mortality and that a specific IK blocker (E-4031) is devoid of antifibrillatory action in the anesthetized rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cyclopropanes; Disease Models, Animal; Drug Interactions; Drug Therapy, Combination; Electrocardiography; Heart Rate; Male; Piperidines; Pyridines; Rats; Rats, Wistar; Reperfusion Injury

Because the relative efficacy of antiarrhythmic agents on halothane-epinephrine arrhythmias has not been well characterized, this study was undertaken to comparatively evaluate the antiarrhythmic action of Na(+)-, K(+)- and Ca(2+)-channel blockers on epinephrine-induced ventricular arrhythmias during halothane anesthesia in rats.. Rats were anesthetized at random with either halothane (1.5%), isoflurane (2.0%), or pentobarbital (50 mg/kg intraperitoneally), and the lungs were mechanically ventilated with oxygen. The rats were studied in three consecutive protocols. Protocol I determined the arrhythmogenic thresholds of epinephrine during the three types of anesthesia in 33 rats. Protocol II determined the arrhythmogenic thresholds of epinephrine during halothane anesthesia in 64 rats receiving saline (control) or one of five antiarrhythmic agents. Protocol III measured the duration of epinephrine-induced arrhythmias during halothane anesthesia in 42 rats receiving saline (control) or one of five antiarrhythmic agents.. In protocol I, the arrhythmogenic doses of epinephrine during halothane, isoflurane, or pentobarbital anesthesia were 1.7 +/- 3.2, 11.1 +/- 0.6, and 39.0 +/- 3.9 micrograms/kg, respectively, and the corresponding plasma concentrations were 4.3 +/- 0.8, 103.7 +/- 9.2, and 246.7 +/- 28.9 ng/ml, respectively. In protocol II, the arrhythmogenic doses were similar in rats receiving saline and in those receiving lidocaine. The arrhythmogenic doses in rats receiving verapamil, flecainide (Na(+)- and K(+)-channel blocker), E-4031 (K(+)-channel blocker), or amiodarone(K(+)-channel blocker with Na(+)-, Ca(2+)-, and beta-blocking activity) increased significantly, i.e., 4.2, 4.2, 5.5, and 31.7 times control (P < 0.01). In protocol III, lidocaine had no effect on the duration of arrhythmias. Flecainide, E-4031, and verapamil markedly reduced the duration of arrhythmias induced by epinephrine, 8 micrograms/kg intravenously (P < 0.01), whereas only amiodarone markedly reduced the duration of arrhythmias induced by epinephrine, 16 micrograms/kg intravenously (P < 0.01).. It was concluded that agents with K(+)-channel blocking properties were the most effective in preventing halothane-epinephrine arrhythmias in rats.

Topics: Amiodarone; Anesthesia, Inhalation; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Epinephrine; Flecainide; Halothane; Isoflurane; Lidocaine; Male; Piperidines; Pyridines; Rats; Rats, Sprague-Dawley; Verapamil

We measured the QRS duration during a treadmill exercise test and the QT interval using a 24-hour Holter electrocardiogram at various heart rates to identify use-dependent QRS prolongation and reverse use-dependent QT prolongation of class I and III antiarrhythmic drugs. Use-dependent QRS prolongation was detected in 61%, 53%, and 64% of patients receiving disopyramide, mexiletine, and pilsicainide, respectively. Reverse use-dependent QT prolongation was found in 40% and 70% of patients receiving disopyramide and E4031. Drugs suppressed > or = 75% of the total premature ventricular contractions in all patients who had both use-dependent QRS prolongation and reverse use-dependent QT prolongation, in 79% of patients with use-dependent QRS prolongation alone, in 70% with reverse use-dependent QT prolongation alone, and in 11% with neither use-dependent QRS prolongation nor reverse use-dependent QT prolongation. Use-dependent QRS prolongation and reverse use-dependent QT prolongation were identified noninvasively and were useful in evaluating antiarrhythmic efficacy.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disopyramide; Drug Evaluation; Electrocardiography, Ambulatory; Exercise Test; Female; Heart Rate; Humans; Lidocaine; Male; Mexiletine; Middle Aged; Piperidines; Potassium Channels; Pyridines; Sodium Channels

The antiarrhythmic and direct cardiovascular effects of a new antiarrhythmic agent, bidisomide, alpha-(2-[acetyl(1-methylethyl)amino]ethyl)-alpha-(2- chlorophenyl)-1-piperidinebutanamide, were investigated. To determine the anti-arrhythmic effects, spontaneously occurring adrenaline-, digitalis- and two-stage coronary ligation-induced arrhythmias were used. Bidisomide suppressed these three arrhythmia models. The antiarrhythmic plasma concentration, IC50, of bidisomide for digitalis-induced arrhythmia was 22.1 micrograms/ml, and those calculated for intravenous bidisomide in 24 h and 48 h coronary ligation-arrhythmias were 15.1 and 11.6 micrograms/ml and that calculated for oral bidisomide in 24 h coronary ligation-arrhythmia was 5.4 micrograms/ml and that for adrenaline induced arrhythmia was 58.7 micrograms/ml. In the blood perfused sinoatrial node and papillary muscle preparations, bidisomide decreased the sinoatrial rate and contractile force and increased the intraventricular conduction time and coronary blood flow. These results indicate that bidisomide is similar to other class I antiarrhythmic agents such as pirmenol and KW-3401 in its antiarrhythmic profile and is expected to become a clinically useful antiarrhythmic drug.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Digitalis Glycosides; Dogs; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Epinephrine; Female; Myocardial Contraction; Piperidines; Sinoatrial Node

The effectiveness of blockade of the inwardly rectifying K+ current (IK1) in prevention of arrhythmias is unknown. We have examined the antiarrhythmic potential of a new selective IK1 blocker, RP58866, in rat, rabbit, and primate (marmoset) isolated hearts in the settings of acute ischemia and reperfusion.. In concentration-response studies (n = 12 per group), the drug reduced ischemia-induced ventricular fibrillation (VF) in rat from control incidence of 100 to 50%, 17% (p < 0.05), and 0% (p < 0.05) at 1, 3, and 10 mumol/L, respectively. RP58866 produced significant bradycardia at the 3- and 10-mumol/L concentrations and significant QT interval widening at all three concentrations (p < 0.05). When rat hearts (n = 12 per group) were paced (5 Hz) via the left atrium to prevent bradycardia, the antiarrhythmic effects of 10-mumol/L RP58866 were unmodified (ischemia-induced VF incidence was reduced by drug from 83% in control hearts to 8%; p < 0.05). Similarly, pacing did not prevent the drug's QT-widening activity at 90% repolarization (QT90 was 64 +/- 3 msec in control hearts versus 128 +/- 17 msec in the presence of 10 mumol/L of drug after 10 minutes of ischemia; p < 0.05). These values are similar to equivalent values in unpaced hearts (65 +/- 3 msec in control hearts versus 159 +/- 15 msec with 10 mumol/L of drug; p < 0.05). In separate groups of rat hearts (n = 10 per group) subjected to 10 minutes of ischemia, reperfusion-induced VF incidence was reduced from 90% in control hearts to 10% (p < 0.05), 0% (p < 0.05), and 0% (p < 0.05) by 1-, 3-, and 10-mumol/L RP58866. To examine whether drug actions were species-specific, we performed further studies in rabbit and primate using the middle concentration of RP58866 (3 mumol/L). Ischemia-induced VF incidence was too low in these species to assess the effects of the drug. However, RP58866 widened QT interval (p < 0.05), slowed heart rate (p < 0.05), and reduced the incidence of reperfusion-induced VF from 67% to 8% (p < 0.05) in rabbit. Furthermore, in the more clinically relevant primate species (marmoset; n = 9-12 per group), RP58866 (3 mumol/L) abolished ischemia-induced VT (36% incidence in control hearts; p < 0.05) and significantly reduced the incidence of ischemia-induced ventricular premature beats from 91% to 33% (p < 0.05). The drug was also effective against reperfusion VF in primates (incidence reduced from 64% in control hearts to 11%; p < 0.05). As in rat and rabbit, RP58866 significantly widened QT interval in primate and caused bradycardia before and during ischemia. RP58866 had no significant influence on coronary flow in any species. Finally, in further studies on rat, QT widening by RP58866 was found to persist relatively unmodified in nonischemic hearts perfused with solution containing K+. RP58866, a selective IK1 blocker, is a potent and efficacious new antiarrhythmic drug in ischemia and reperfusion in rat, rabbit, and primate. When tested in rat, pharmacological activity was undiminished by cardiac pacing or elevation of extracellular K+.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Callithrix; Cardiac Pacing, Artificial; Chromans; Electrocardiography; Heart; Male; Myocardial Reperfusion Injury; Piperidines; Potassium Channels; Rabbits; Rats; Rats, Wistar; Tachycardia, Ventricular; Ventricular Fibrillation

Several studies have suggested a central role for Na+/Ca2+ in the pathogenesis of ouabain-induced cardiac arrhythmias. To test this hypothesis, the effects on ouabain-induced arrhythmias of i.v. pretreatment with R 56,865, a Na+ and Ca2+ overload inhibitor, were compared with those of lidocaine, verapamil and tetrodotoxin in anesthetized guinea-pigs. Cardiac arrhythmias were induced by i.v. infusion of ouabain (10 micrograms/kg per min). All nine guinea-pigs pretreated with saline developed ventricular premature beats at an ouabain dose of 159 +/- 9 micrograms/kg (mean +/- S.E.M.), ventricular tachycardia at a dose of 190 +/- 10 micrograms/kg, ventricular fibrillation at a dose of 253 +/- 18 micrograms/kg and died at a dose of 269 +/- 16 micrograms/kg; none of the animals developed heart block or asystole. Pretreatment with R 56,865 (1.25 mg/kg, n = 6) significantly increased the ouabain doses required to induce ventricular premature beats, ventricular tachycardia, ventricular fibrillation and death relative to those for the saline group. Pretreatment with a Ca2+ entry blocker verapamil (0.32 mg/kg, n = 6) also significantly increased the ouabain doses required to provoke ventricular arrhythmias and death; this medication was associated with second or third degree heart block during ouabain infusion in four out of six animals. Pretreatment with lidocaine (10 mg/kg, n = 6) caused a significant increase in the dose of ouabain needed to initiate cardiac arrhythmias and to cause death. Pretreatment with a selective Na+ channel blocker tetrodotoxin (4 micrograms/kg, n = 6) also significantly increased the ouabain doses required to provoke ventricular premature beats, ventricular tachycardia, ventricular fibrillation, and death.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Arrhythmias, Cardiac; Benzothiazoles; Blood Pressure; Calcium; Electrocardiography; Guinea Pigs; Heart Rate; Lidocaine; Male; Ouabain; Piperidines; Sodium; Tetrodotoxin; Thiazoles; Verapamil

Triggered arrhythmias in rat right ventricular trabeculae are induced by triggered propagated contractions (TPCs) that start in damaged regions of the muscle and propagate along the preparation. We analyzed the effects of the Na+/Ca2+ overload inhibiting agents R 56865 on both TPCs and triggered arrhythmias. This compound has been shown to prevent ultrastructural signs of intracellular calcium overload and arrhythmias caused by exposure to toxic concentrations of cardiac glycosides. TPCs were induced by trains of 15 stimuli (2 Hz, 15 s intervals) at 19-21 degrees C and a [Ca2+]o of 1.0-2.5 mM in the superfusate. Force was measured with a silicon strain gauge; length and shortening of sarcomeres were measured at two sites of the muscle using laser diffraction techniques. Exposure to 1.14 x 10(-7) M R 56865 for 30 min decreased the force of the last stimulated twitch (twitch force) to 89.7 +/- 4.7% (mean +/- SEM) of control, the force produced by TPCs to 39.4 +/- 9.8%, and the velocity of propagation of TPCs to 52.8 +/- 6.3%, while TPC latency increased not significantly to 104.7 +/- 2.8% of control. R 56865 suppressed TPC force, for the same small decrease in twitch force (10%), significantly more than 100 nM D-600 did (29.5 +/- 2.0 vs. 12.4 +/- 3.1%). Eventually, TPCs disappeared in 8 of 14 muscles, in 2 of them without any decrease in twitch force. At 5.7 x 10(-7) M, R 56865 abolished TPCs in five additional trabeculae. An increase in [Ca2+]o reintroduced TPCs. During stimulation of 0.5 Hz, 1.14 x 10(-7) M R 56865 increased the stimulus threshold by 21 +/- 4% in 6 of 14 muscles and decreased the twitch force by 26 +/- 3% in 7 of 14 trabeculae. Triggered arrhythmias were induced in six muscles with the use of 0.5 mM caffeine or 5 nM Bay K 8644; R 56865 rapidly terminated these arrhythmias in all muscles. Although the mechanism of the antiarrhythmic effects of R 56865 remains to be determined, we speculate that the drug raises the threshold for both generation of triggered action potentials and calcium-induced calcium release from the sarcoplasmic reticulum.

Topics: Action Potentials; Animals; Arrhythmias, Cardiac; Benzothiazoles; Calcium; Calcium Channel Blockers; Electric Stimulation; Female; Gallopamil; Heart Ventricles; In Vitro Techniques; Male; Myocardial Contraction; Piperidines; Rats; Rats, Inbred Strains; Sarcoplasmic Reticulum; Thiazoles

The effects of cisapride on the gastrointestinal contractile activity and pharmacokinetics of disopyramide were determined in beagle dogs and patients with arrhythmia. In the animal experiments, the gastric motor index was significantly decreased by i.v. administration of disopyramide in a dose-dependent fashion. The peak decrease of the motor index was observed within 5 min after i.v. injection of disopyramide; the motor index then recovered gradually to the level present prior to drug administration. I.v. administration of cisapride (0.5 mg/kg) markedly increased gastrointestinal contractile activity following the decrease induced by disopyramide pretreatment (5 mg/kg, i.v.). In the clinical studies, the gastric emptying test was performed using the acetaminophen method. A significant correlation between plasma concentrations of disopyramide and gastric emptying time has been found (p < 0.001). The combination of disopyramide (100 mg t.i.d.) and cisapride (2.5 mg t.i.d.) significantly increased gastric emptying compared with that induced by disopyramide alone. The peak plasma concentration of disopyramide in association with cisapride oral administration was significantly higher, and the apparent absorption rate constant and lag time of disopyramide were about 2-fold higher and 2-fold shorter, respectively, than for disopyramide alone. Cisapride, acting as a cholinergic agonist, may counteract the anticholinergic effect of disopyramide on gastric motility. As a factor influencing drug absorption, gastric emptying is of importance, as it determines the rate of drug delivery to the small intestine. Therefore, the oral administration of disopyramide with cisapride may be useful for patients with delayed gastric emptying.

Topics: Administration, Oral; Animals; Arrhythmias, Cardiac; Cisapride; Disopyramide; Dogs; Drug Synergism; Female; Gastric Emptying; Gastrointestinal Motility; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines; Serotonin Antagonists

1. The effects of three class 1 antiarrhythmic drugs procainamide (class 1A) tocainide (class 1B) and lorcainide (class 1C) on microsomal Na(+)-K(+)-ATPase activity were compared with those of ouabain in guinea pig heart preparations. 2. All three antiarrhythmic drugs exhibited concentration-dependent inhibitory actions on the enzyme activity in a fashion similar to that of ouabain. 3. The rank order of their potencies showed the following tendency: lorcainide much greater than tocainide greater than procainamide. However, while the actions of lorcainide were comparable to those of cardiotonic steroids, those of procainamide became significant only at concentrations above 80 microM. 4. The IC50 values were 1.8 +/- 0.5 microM for ouabain, 14.6 +/- 3.4 microM for lorcainide, 2.8 +/- 0.7 mM for tocainide and 6.7 +/- 1.1 mM for procainamide. 5. The results demonstrate that these antiarrhythmic agents inhibit the ouabain-sensitive myocardial Na(+)-K(+)-ATPase activity in vitro with comparatively varying potencies. 6. These interactions may be pertinent to the proarrhythmic or arrhythmogenic effects of the class 1 type of antiarrhythmic drugs.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Guinea Pigs; Heart; In Vitro Techniques; Lidocaine; Male; Myocardium; Ouabain; Piperidines; Procainamide; Sodium-Potassium-Exchanging ATPase; Tocainide

Singlet oxygen and superoxide production by rose bengal photoactivation leads to rapid electrophysiological changes and arrhythmias. To investigate which intermediate is causative and to probe possible mechanisms, hearts (n = at least 6/group) were perfused aerobically for 10 min without rose bengal followed by 5 min with rose bengal before illumination for 20 min. In controls, all or most hearts exhibited ventricular premature beats, ventricular tachycardia, and complete atrioventricular block. Most antioxidants tested had no protective effect; histidine, however, significantly delayed the onset of electrocardiographic (ECG) changes. In further studies, two antiarrhythmic agents (quinidine and verapamil) had no little protective effect, whereas R56865 significantly delayed the onset of ECG changes and reduced the incidence of arrhythmias. However, spectrophotometric and laser pulse radiolysis studies showed that this apparent protective effect might have resulted from an interaction between R56865 and the rose bengal molecule, leading to a reduction in singlet oxygen production. In conclusion, the electrophysiological changes induced by rose bengal photoactivation are likely to be due to singlet oxygen; antiarrhythmic drugs appear to be unable to protect against the injury unless there is some interaction with the photoactivation process.

Topics: Animals; Antioxidants; Arrhythmias, Cardiac; Benzothiazoles; Coronary Circulation; Electrocardiography; Free Radicals; Heart Rate; Male; Oxygen; Photolysis; Piperidines; Rats; Rats, Inbred Strains; Rose Bengal; Superoxides; Thiazoles

The antiarrhythmic effects of R56865 were characterized both in vivo and in vitro. Four groups (n = 12 per group) of anesthetized rats, subjected to 5- or 30-min coronary artery ligation and reperfusion, were studied: saline, dimethyl sulfoxide (DMSO) carrier, and R56865 (0.5 or 2 mg/kg) were administered as an intravenous (i.v.) bolus before ligation. After 5 min of ischemia, the incidences of reperfusion-induced ventricular tachycardia (VT) and fibrillation (VF), which were high in the saline (100 and 75%, respectively) and DMSO (100 and 82%, respectively) control groups, were abolished with both doses of R56865. With 30 min of ischemia, R56865 (2 mg/kg) significantly reduced the incidences of ischemia-induced VT and VF (from 100 and greater than 50% to 25 and 8%, respectively). For in vitro studies, five groups (n = 12 per group) of isolated rat hearts subjected to 10- or 30-min coronary ligation and reperfusion were studied: unmodified buffer and buffer containing DMSO or R56865 (10(-7), 10(-8), 10(-9) M). After 10 min of ischemia, R56865 (10(-7) M) decreased reperfusion-induced VT and VF (from 100 and 75% in buffer controls to 42 and 8%, respectively) when administered throughout the experiment. With 30 min of ischemia, R5685 (10(-7) M) reduced the incidences of ischemia-induced VT and VF (from 75 and 67% in the buffer controls to 25 and 25%, respectively). Although reperfusion after 30 min of ischemia did not induce VF in any of the groups studied, VT and other arrhythmias did occur and their incidences were reduced significantly by R56865. To investigate whether calcium overload might mediate the effects of R56865, hearts were perfused aerobically with a high-calcium/low-sodium medium. VT and VF occurred in 80% of control hearts; R56865 (10(-7) M) did not prevent these arrhythmias. In conclusion, R56865 exerts a potent effect against ischemia- and reperfusion-induced arrhythmias through a mechanism which appears to operate during ischemia.

Topics: Analysis of Variance; Animals; Arrhythmias, Cardiac; Benzothiazoles; Calcium; Coronary Disease; Hemodynamics; In Vitro Techniques; Male; Myocardial Reperfusion; Piperidines; Potassium; Rats; Rats, Inbred Strains; Thiazoles

The electrophysiological and antiarrhythmic effects of pirmenol HCl were examined using the microelectrode technique applied to multicellular preparations and the suction-pipette whole-cell clamp method applied to ventricular myocytes from rabbit and guinea pig hearts. Pirmenol at 5 microM and higher doses suppressed the sinus node automaticity by depressing the slow diastolic depolarization without changing the maximum diastolic potential. Pirmenol at 1 microM and higher doses depressed the maximum upstroke velocity (Vmax) of action potentials and prolonged the action potential duration at 90% repolarization in atrial muscles and Purkinje fibers without affecting resting membrane potentials. Pirmenol at 5 microM depressed the early part of the plateau and lengthened the final repolarization of the action potentials in ventricular myocytes, of which effects were attributed to the depression of the calcium current and the delayed outward K+ current. Triggered tachyarrhythmias arising from delayed afterdepolarizations in papillary muscles and ventricular myocytes were markedly inhibited by 1-5 microM pirmenol. The drug changed the amplitude and appearance of the transient inward current in ventricular myocytes. These results suggest that pirmenol has electrophysiologic properties that could provide an antiarrhythmic action on various types of arrhythmias.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrophysiology; Guinea Pigs; Heart; In Vitro Techniques; Ion Channels; Microelectrodes; Myocardium; Papillary Muscles; Piperidines; Potassium Chloride; Purkinje Fibers; Rabbits; Sinoatrial Node; Species Specificity

Ventricular arrhythmias were induced by acute coronary artery ligation in anesthetized rats. 5-Hydroxytryptamine (5-HT) in doses of 100-200 micrograms kg-1, given i.v. 5 minutes before coronary artery ligation, enhanced the severity of ventricular arrhythmias as shown by a significant dose-dependent increase in the number of ventricular ectopic beats, duration of ventricular tachycardia (VT) and ventricular fibrillation (VF). This effect was antagonized by pretreatment with the selective 5-HT2-receptor antagonist ritanserin (1 mg kg-1, i.p.) given 15 minutes before 5-HT. Ritanserin when used alone was observed to produce a significant reduction in the number of ventricular ectopic beats and duration of VT and VF. 5-HT significantly lowered the heart rate and produced initial rise of the systolic blood pressure (SBP). These effects were antagonized by ritanserin. Ritanserin significantly lowered the heart rate but did not alter the SBP. It was postulated that 5-HT might be implicated in the genesis and determination of severity of ventricular arrhythmias induced by acute myocardial ischemia, and that this effect is mediated via 5-HT2-receptors. 5-HT2-receptor antagonists may provide potential useful therapeutic agents for the management of these arrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Coronary Vessels; Dose-Response Relationship, Drug; Heart Ventricles; Ligation; Male; Piperidines; Rats; Rats, Inbred Strains; Receptors, Serotonin; Ritanserin; Serotonin; Serotonin Antagonists

Semi-purified extracts of the skin of the Australian myobatrachid frog Pseudophryne coriacea (PS)displayed striking, reversible and, in part, dose-dependent effects on the systemic blood pressure of the rat and other experimental animals, as well as on the rat heart. The blood pressure response in the rat consisted typically in an abrupt, short-lasting fall, followed by a conspicuous, more persistent rise. The fall in pressure was abolished by atropine and potentiated by physostigmine, indicating a cholinergic mechanism; rise was abolished by prazosin and guanethidine, suggesting a release of catecholamines from adrenergic nerve terminals in the vasculature. Tachyphylaxis was the obvious result of exhaustion of stores of catecholamines. On the heart, as shown in the electrocardiographic tracings, PS produced a variety of rhythm disorders, attributable both to the release of aminergic transmitters and to a direct effect on the myocardium. Whereas the pressure and electrocardiographic responses were virtually unaffected by calcium channel antagonists and agonists, all the effects of PS were sharply reduced or completely abolished by the sodium channel blocker tetrodotoxin. This suggests that activation of sodium channels may play a role in the mechanism of action of PS. However, the exact nature of ionic flux(es)influenced by the extract of frog skin remains to be established.

Topics: Adrenalectomy; Alkaloids; Animals; Anura; Arrhythmias, Cardiac; Autonomic Agents; Blood Pressure; Calcium; Dogs; Electrocardiography; Guinea Pigs; Heart; In Vitro Techniques; Indolizines; Male; Oxygen Consumption; Piperidines; Rabbits; Rats; Rats, Inbred Strains; Salivation; Skin Physiological Phenomena; Sodium; Tissue Extracts

Using two-stage coronary ligation-, digitalis- and adrenaline-induced canine ventricular arrhythmias, antiarrhythmic effects of pirmenol were examined, and the minimum effective plasma concentration for each arrhythmia model was determined. Pirmenol suppressed all the arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by 24 hr coronary ligation, 48 hr coronary ligation, digitalis and adrenaline were 1.1 +/- 0.3 (by 3 mg/kg, i.v.), 1.1 +/- 0.3 (by 3 mg/kg, i.v.), 1.1 +/- 0.2 (by 3 mg/kg, i.v.) and 2.5 +/- 1.5 (by 3 mg/kg, i.v.) microgram/ml, respectively (mean +/- S.D.M., n = 6-7). The concentration for adrenaline-induced arrhythmia was significantly higher than those for the other types of arrhythmias. This pharmacological profile is similar to those of mexiletine, tocainide and cibenzoline. Since pirmenol had no deleterious effects on the blood pressure and sinus node activity, its clinical usefulness is expected.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Digitalis; Dogs; Epinephrine; Female; Ligation; Male; Piperidines; Plants, Medicinal; Plants, Toxic

In a single-blind study the multiple oral dose kinetics of pirmenol were related to its efficacy in eight patients with frequent (mean, 631; range, 167-1374 beats/hour) premature ventricular contractions (PVC). Oral pirmenol was started at 100 mg bid for 48 hours and increased to 150 mg bid in six patients to obtain more than 70% suppression of PVC counts. Efficacy was achieved without side effects. Pirmenol decreased heart rate but not PR interval, QRS duration, or QTc interval. Peak plasma levels after the first 100-mg dose occurred at 1 to 3 hours and ranged from 0.6 to 1.9 micrograms/mL. Plasma elimination half-life ranged from 9.7 to 31 hours (mean, 18.3). From 67.4 to 171.3 mg pirmenol (mean, 102.3 mg) were recovered in the urine in 48 hours after the last dose. Cumulative excretion in divided urine collections was consistent with a mean elimination half-life of 15 to 20 hours. The pharmacokinetics of pirmenol support oral twice-daily administration. The minimum PVC suppressing plasma level is between 0.5 and 1.5 micrograms/mL.

Topics: Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Half-Life; Humans; Male; Middle Aged; Piperidines

The effects of the 5-hydroxytryptamine2 (5-HT2) antagonists ketanserin and ritanserin on ischaemia- and reperfusion-induced arrhythmias were investigated in pentobarbitone-anaesthetised rats. Both ketanserin (3 mg kg-1) and ritanserin (1 mg kg-1) significantly reduced the incidence of ventricular fibrillation (from 60 to 25% and 88 to 12%, respectively) and the mortality induced by reperfusion after 5 min of myocardial ischaemia. Neither drug significantly altered the number of ventricular ectopic beats, the incidence of ventricular tachycardia, ventricular fibrillation, or mortality during the first 25 min of coronary artery occlusion. Significant dose-dependent reductions in heart rate and arterial blood pressure were observed with all doses of ketanserin (0.1-3 mg kg-1) and ritanserin (0.3 and 1 mg kg-1), but neither drug had any major effect on arterial blood gases or pH. In isolated guinea pig and rat atria and ventricular muscle preparations, ketanserin (10(-5) M) and ritanserin (3 X 10(-5) M) reduced the maximal driving frequency, whereas 5-HT itself was without effect. The results suggest that the antiarrhythmic activity of ketanserin and ritanserin observed in this study was probably not due to 5-HT2 receptor or alpha 1-adrenoceptor blockade, but may have been due to a direct action on cardiac muscle.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Female; Guinea Pigs; Ketanserin; Male; Piperidines; Rats; Rats, Inbred Strains; Ritanserin; Serotonin Antagonists

Topics: Arrhythmias, Cardiac; Benzeneacetamides; Drug Interactions; Humans; Male; Middle Aged; Piperidines; Rifampin

The effects of pirmenol in the treatment of ventricular arrhythmias were studied in 6 patients with heart disease and in 11 control subjects. In the patients with heart disease, ventricular arrhythmias were associated with myocardial infarction in 3, with mild aortic stenosis in 2 and with hypertrophic cardiomyopathy in 1. Pirmenol was administered in a 100 mg, 150 mg or 200 mg twice daily dosing schedule. Dosages were increased if necessary, until response, defined as greater than 70% suppression in the rate of premature ventricular contractions, occurred. Arrhythmia suppression was maintained in all 6 patients with heart disease at 52 weeks of follow-up.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Double-Blind Method; Female; Heart Diseases; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

Antiarrhythmic effects of a new antiarrhythmic drug, E-0747, were examined using four canine ventricular arrhythmia models: digitalis-, adrenaline- and two-stage coronary ligation-induced arrhythmias and a newly developed locally-induced digitalis arrhythmia. The minimum effective plasma concentration of E-0747 was determined for the first three arrhythmia models. E-0747 suppressed those arrhythmias, and the minimum effective plasma concentrations for arrhythmias induced by digitalis, adrenaline, 24 hr coronary ligation, and 48 hr coronary ligation were 1.4 +/- 0.6, 1.8 +/- 0.4, 1.6 +/- 0.4 and 2.2 +/- 0.2 micrograms/ml, respectively (mean +/- S.D., n = 5-10). The aforementioned minimum effective plasma concentrations of E-0747 for these arrhythmias were almost equal to the reported concentration in vitro to suppress the Na channels of isolated canine ventricular tissues. The class 1 property of E-0747 was also shown in a newly developed locally-induced digitalis arrhythmia. Thus E-0747 suppresses arrhythmia by inhibiting Na channels of cardiac cells and is expected to become a clinically useful antiarrhythmic drug.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Dogs; Epinephrine; Female; Ligation; Male; Ouabain; Piperidines

The efficacy, pharmacokinetics, and pharmacodynamics of pirmenol, a class Ia antiarrhythmic agent, were studied in patients with frequent symptomatic premature ventricular complexes (PVCs). Pirmenol was given every 12 hours to eight patients in a dose-ranging protocol, and median PVC suppression of 94% (range 72% to 100%) was achieved. The median effective pirmenol dose was 300 mg/day (range 200 to 500 mg/day), and mean (+/- SD) trough plasma pirmenol concentration at the effective dose was 0.98 +/- 0.29 micrograms/ml. The mean half-life of elimination was 10.5 +/- 2 hours. There was considerable overlap among patients with respect to plasma pirmenol concentration and times at which PVC frequency returned to 25%, 50%, and 75% of baseline during drug washout trials. Altering pirmenol's dose interval (while maintaining a constant daily dose) from 12 to 6 hours did not improve drug efficacy. Pirmenol was given to seven patients for long-term therapy (24 to 44 months). Median PVC suppression at 24 months was 70%. Pirmenol is safe and well tolerated, and it can be administered twice daily for PVC suppression.

Topics: Administration, Oral; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Follow-Up Studies; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines; Time Factors

The influence of cardiac function as measured by the left ventricular ejection fraction on the pharmacokinetic variables of a new antiarrhythmic drug, lorcainide, was investigated in 20 cardiac patients. Patients were divided into two groups: those with normal (ejection fraction greater than .40) or depressed (ejection fraction less than .40) left ventricular function. The elimination half-life, plasma clearance rates, or volume of distribution of lorcainide were not significantly different in patients with either normal or depressed cardiac function. A decrease in arrhythmia frequency could be correlated to plasma lorcainide concentration in the majority of patients, and it was noted that at least 0.1 mg/L of lorcainide was required for the presence of an antiarrhythmic effect. Three unusual cases are presented to illustrate the importance of measuring plasma drug concentrations and calculating the drug pharmacokinetics and to correlate these to the antiarrhythmic response in order to minimize the risk of plasma drug accumulation and side effects. A review of published data shows a three- to sixfold interpatient variation in the elimination half-life of lorcainide with practical implications in its use as an antiarrhythmic drug.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Heart Diseases; Hemodynamics; Humans; Male; Middle Aged; Piperidines

The effect of the new compound R 56865 on ouabain-induced intoxication (8 X 10(-7) mol/l) was studied in guinea-pig papillary muscle. The positive inotropism induced by ouabain was not impaired by R 56865. Mechanical signs of intoxication, e.g. extrasystoles and contracture, as well as the development of spike-like action potentials could be prevented by pretreatment with R 56865 (3 X 10(-10)-10(-6) mol/l). We speculate that this new compound prevents ouabain-induced Ca overload of cardiac muscle.

Topics: Animals; Arrhythmias, Cardiac; Benzothiazoles; Calcium; Electrophysiology; Guinea Pigs; Heart; In Vitro Techniques; Ouabain; Papillary Muscles; Piperidines; Thiazoles

The effect of flecainide in 24 patients with inducible sustained ventricular arrhythmia and a history of remote myocardial infarction was determined. Flecainide was administered in oral doses individually adjusted to suppress all spontaneous ventricular tachycardia and 80% of ventricular premature complexes on 24 hour ambulatory (Holter) electrocardiography. Antiarrhythmic therapy, as assessed by Holter monitoring, was adequate in 20 (83%) of the study patients at a mean dose of 144 +/- 28 mg every 12 hours; the mean plasma flecainide level was 583 +/- 329 ng/ml. In 18 patients, the mean sinus cycle length, sinus node recovery time and atrial, atrioventricular nodal and ventricular refractory periods were unchanged. The AH interval increased by 15 +/- 15%, the HV interval by 35 +/- 32% and the QRS duration by 24 +/- 21%. Toxicity or failure to suppress ventricular premature complexes and ventricular tachycardia by Holter monitoring precluded electrophysiologic study with flecainide in four patients; two patients refused electrophysiologic study with flecainide for nonmedical reasons. Ventricular tachycardia was not inducible in 4 (22%) of 18 patients receiving flecainide. Sustained arrhythmia remained inducible in 14 patients (78%) despite evidence of antiarrhythmic efficacy on Holter monitoring, but the rate of the induced ventricular tachycardia was slower and symptoms were alleviated during ventricular tachycardia in 10 (56%) of 18 patients. The 4 patients who had no inducible ventricular tachycardia with flecainide, and the 10 patients who had inducible ventricular tachycardia with a longer cycle length and alleviation of their symptoms, have been followed up as outpatients for 16 +/- 7 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Electrocardiography; Female; Flecainide; Follow-Up Studies; Heart Ventricles; Humans; Male; Middle Aged; Monitoring, Physiologic; Myocardial Infarction; Piperidines; Time Factors

Ninety-four patients with ventricular tachycardia (VT), 49 with sustained and 45 with nonsustained VT, who had been refractory to or intolerant of other antiarrhythmic agents were treated in a multicenter, open-label study with flecainide acetate. Most had serious cardiac disorders associated with their arrhythmia: 49 patients (52%) had 1 or more conduction disorders on electrocardiography; 43 (46%) had congestive heart failure; 30 (33%) had left ventricular ejection fractions of 30% or less. Patients were initially treated orally in the hospital with 100 mg twice daily; dosage was titrated upward as needed at 4-day intervals to a maximal dose of 200 mg twice daily. Flecainide plasma level monitoring was performed to ensure plasma levels remained in the therapeutic range of 0.2 to 1.0 micrograms/ml. Patients were discharged with flecainide therapy if investigators judged it to be safe and effective. Minimum efficacy requirements included elimination of sustained VT and reduction of other ventricular arrhythmias as determined by 1 or more of the following: 24-hour electrocardiographic monitoring, programmed electrical stimulation, exercise testing and in-hospital monitoring. Sixty-eight patients (72%) were discharged with flecainide therapy. After a mean follow-up of 8 months, 45 patients (48%) were still taking flecainide, including 22 of 49 (45%) with sustained and 23 of 45 (51%) with nonsustained VT. Nine patients with sustained VT and 1 patient with nonsustained VT had aggravation of arrhythmia. Two patients had third-degree heart block. Nine patients died after discharge from the hospital: 6 from out-of-hospital sudden death and 3 from acute myocardial infarctions.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Humans; Male; Middle Aged; Piperidines; Tachycardia

We compared side effects with flecainide trough levels and ECG intervals among 43 patients who received flecainide for up to 34 months. Flecainide plasma levels were higher when associated with cardiovascular side effects (mean 1063 ng/ml; range 296 to 2050 ng/ml) than when no side effects occurred (mean 609 ng/ml; range 89 to 1508 ng/ml; P less than 0.001). The PR interval (P less than 0.001), QRS interval (P less than 0.001), and the rate-corrected QT interval (P less than 0.001) were greater at the time of cardiovascular side effects, but the rate-corrected JT interval was not. The therapeutic-toxic window for flecainide plasma level was 381 ng/ml (at least 50% probability of efficacy) to 710 ng/ml (less than 10% probability of cardiovascular side effects). The risk of cardiovascular side effects increases at higher plasma levels of flecainide and is associated with greater increases in the PR and QRS intervals from baseline than are routinely observed during flecainide dosing.

Topics: Aged; Arrhythmias, Cardiac; Cardiovascular Diseases; Dose-Response Relationship, Drug; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

Topics: Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Flecainide; Humans; Kinetics; Mexiletine; Patient Education as Topic; Piperidines

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

Antiarrhythmic therapy is known to be associated with a significant risk of adverse cardiac reactions, including a proarrhythmic response. This study assessed in 1,330 patients followed up for 292 +/- 393 days the predictive value for cardiovascular safety of a system by which patients were classified according to ventricular arrhythmias on entry, presence or absence of organic heart disease and drug dose for flecainide acetate. Baseline arrhythmia subgroups included patients with premature ventricular complexes only, nonsustained ventricular tachycardia, and sustained ventricular tachycardia. Proarrhythmic events occurred in 6.8% of patients overall and were serious in 2.3% and lethal in 1.0%. However, proarrhythmia was highly dependent on arrhythmia class on entry: serious nonlethal proarrhythmic events occurred in 6.6% of patients with sustained ventricular tachycardia, only 0.9% with nonsustained ventricular tachycardia and 0% with premature ventricular complexes (p less than 0.01). Proarrhythmic death occurred in 3.1% of patients with sustained ventricular tachycardia, 0.2% with nonsustained ventricular tachycardia and 0% with premature ventricular complexes only (p less than 0.01). Proarrhythmia was also influenced by the presence of structural heart disease: serious nonlethal proarrhythmia occurred in 2.6% of patients with versus 0.4% of those without organic heart disease, and death occurred in 1.2 versus 0%, respectively. These adverse events were also dependent on dosing regimen. Flecainide caused premature discontinuation due to new or worsened heart failure in 1.4% of patients, all with underlying organic heart disease; however, heart failure was not clearly related to dose or type of arrhythmia. Symptomatic conduction disturbances occurred in 2.2%, and were predicted by preexistent sinus node disease but not by other baseline features.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Arrhythmias, Cardiac; Death, Sudden; Drug Administration Schedule; Flecainide; Heart Failure; Humans; Inpatients; Outpatients; Piperidines; Risk; Syncope

Pirmenol, a new class IA antiarrhythmic agent, has shown promise in short-term trials, but long-term efficacy has not been documented. We thus evaluated 11 patients with frequent (greater than or equal to 60/h) premature ventricular complexes (PVC) given oral pirmenol for 25-727 days. Ten of 11 patients entering the long-term open trial had shown greater than or equal to 70% (mean 83%) PVC suppression during in-hospital pirmenol dose ranging. Long-term pirmenol was given in divided doses of 100-600 mg/day. Mean PVC frequency during baseline was 13,078/24 h (range, 3,218-32,718); couplets averaged 481/24 h (1-2,829) and runs 45/24 h (0-334). Ambulatory monitoring was performed at 1, 3, 6, and 12 months, then semiannually. Mean absolute PVC suppression at 1 month averaged 75% (p less than or equal to 0.02). Median individual percentage PVC suppression was 94%. During the first 3 months, 8 patients (73%) continued to show a favorable response (greater than or equal to 70% suppression), and 3 had arrhythmia recurrence and were dropped. One responder was withdrawn after the onset of paroxysmal atrial fibrillation, and another early responder was withdrawn after 3 months because of arrhythmia relapse. Six patients have been treated for over 1 year, with 99% mean PVC suppression. Mean couplet and run frequencies at 1 month decreased by means of 76% (p less than or equal to 0.05) and 92% (p = 0.001) respectively. At 1 year, couplets were suppressed 99.8% and runs by 99.7% in the 6 patients remaining on pirmenol.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Heart Ventricles; Hemodynamics; Humans; Male; Middle Aged; Outpatients; Piperidines; Time Factors

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cats; Female; Guinea Pigs; In Vitro Techniques; Male; Piperidines; Rats

The cardiovascular effects of a new antiarrhythmic Class I agent, pirmenol, were assessed noninvasively in 10 patients without heart failure. Infusion of 100 mg pirmenol was given over 30 min following baseline M-mode echocardiography, cuff blood pressure and systolic time interval measurements. The measurements were repeated after the infusion, and 15 and 60 min later. Heart rate increased by 14.7% (P less than 0.01). Significant increases were also noted in afterload parameters, mean arterial pressure (+10.1%; P less than 0.001) and mid-systolic left ventricular wall stress (+8.0%; P less than 0.05). Concomitantly a slight increase was observed in preload, reflected in lengthening of left ventricular end-diastolic diameter (+4.8%; P less than 0.05). A decrease in fractional shortening (-6.5%; P less than 0.05) and an increase in pre-ejection period/left ventricular ejection time ratio (+16.2%; P less than 0.01) suggested a negative inotropic effect. The increased afterload and heart rate may have contributed to changes in these indices, and therefore myocardial depression may appear more pronounced than it actually was. The main effects of intravenous administration of pirmenol are elevations in heart rate and blood pressure. The induced decrease in myocardial contractility is slight.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Echocardiography; Female; Heart Rate; Hemodynamics; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Flecainide; Heart Ventricles; Humans; Piperidines

In an effort to assess the ability of procainamide to predict effectiveness of antiarrhythmic agents at programmed electrical stimulation (PES) testing, we compared the result of procainamide at PES testing with that of all of the other agents studied. One hundred fifty-three patients underwent PES studies because of either sustained or nonsustained ventricular tachycardia (VT). Procainamide prevented VT induction in 79 of 153 patients. Seventy-four of the remaining 153 were inducible for VT on procainamide, with 55 of these being protected by another antiarrhythmic agent (p less than 0.001). If procainamide failed to prevent VT induction, other conventional and experimental agents were equally as likely to be effective in preventing VT induction. Analysis of flecainide acetate as a predictor of efficacy was also evaluated. Fifty-five patients received flecainide and 29 of these were protected at PES testing; 26 of these patients were also protected with another agent. When VT was inducible in patients who received flecainide, 15 of these 26 patients were protected by another agent, either conventional or experimental (p less than 0.01). Thus, if procainamide or flecainide prevented VT induction they accurately predicted effectiveness of other drugs; however, when they did not prevent VT induction, they served as a poor predictor of the possible effectiveness of other drugs. Serial drug testing at PES studies with multiple conventional and experimental drugs increases the likelihood of finding an effective antiarrhythmic agent.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Exercise Test; Female; Flecainide; Heart Rate; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Procainamide; Prognosis

Thirty-eight patients with prior history of cardiac arrest underwent programmed electrical stimulation (PES) studies and serial drug testing. Lorcainide was tested acutely in all 38 patients and prevented ventricular tachycardia (VT) or ventricular fibrillation (VF) induction in 14 patients and failed in 24 (efficacy rate 37%). Procainamide had failed clinically (cardiac arrest or breakthrough VT) in 16 patients, seven patients had previously severe adverse side effects, and thus only 15 were tested on procainamide at PES testing with seven protected. Following initial studies, 14 patients were started on lorcainide oral therapy and 24 on other therapy determined effective at PES testing (N-acetylprocainamide-two, flecainide-nine, bethanidine-three, slow-release procainamide hydrochloride-three, quinidine-two, cibenzoline-one, amiodarone-four). After 29 +/- 7 months follow-up, three are alive on lorcainide therapy, five discontinued therapy due to side effects; six died--three sudden deaths (33%) and two cardiac deaths (both myocardial infarctions). Twenty out of 24 patients are alive who were started on PES predicted effective therapy other than lorcainide; four died--three sudden deaths (13%) and one cardiac nonsudden death. Antiarrhythmic therapy guided by PES studies gives overall encouraging results in a cardiac arrest group of patients. Lorcainide, however, is not tolerated well and affords less protection against a sudden death recurrence than is noted in a population on other antiarrhythmic therapy predicted effective at PES testing.

Topics: Arrhythmias, Cardiac; Benzeneacetamides; Blood Pressure; Cardiac Pacing, Artificial; Electrocardiography; Female; Heart Arrest; Humans; Male; Middle Aged; Piperidines; Procainamide; Recurrence

Oral amiodarone therapy was given to seven patients already taking oral flecainide regularly. In one additional patient, administration of flecainide was temporarily discontinued when amiodarone therapy was begun, and then resumed. Amiodarone produced a rise in mean dose-adjusted flecainide plasma level (trough plasma level at steady state/daily dose) from 2.3 +/- 0.8 to 3.4 +/- 0.9 (ng/ml)(mg/day) (p less than 0.01). Accordingly, the mean dose of flecainide required to maintain similar plasma levels of the drug was one-third lower during combined treatment than during therapy with flecainide alone. This drug interaction must be accounted for when amiodarone and flecainide are used concomitantly.

Topics: Adult; Aged; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Drug Interactions; Female; Flecainide; Humans; Male; Middle Aged; Piperidines

Flecainide acetate is a recently introduced, class 1 antiarrhythmic agent that is highly effective in the treatment of ventricular and atrioventricular/nodal reentrant tachycardias. Although both intravenous and orally administered flecainide are known to cause an increase in the pacing threshold, an abrupt and potentially lethal rise in threshold causing failure of a properly functioning, newly implanted pacing system has not to our knowledge been described. We report such a case to stress the need for caution when using this drug in elderly pacemaker patients.

Topics: Aged; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Flecainide; Humans; Male; Piperidines; Tachycardia, Paroxysmal

The electrophysiological and antiarrhythmic properties of two new drugs, propafenone and flecainide, are distinctly different from those of known products of the same therapeutic category. Compared with other class I (membrane-stabilising) antiarrhythmic agents, propafenone exerts a beta-adrenergic inhibitory effect which may be clinically useful, and flecainide has a stronger depressant effect on intraventricular conduction. There is no prolongation of Q-T nor any risk of wave burst arrhythmia with either of these drugs. Their antiarrhythmic activities are superior to those of class I compounds currently available and they can be combined with amiodarone, which considerably potentializes these activities. Their extracardiac side-effects are rarely limitating. However, their intracardiac side-effects on the sinus node an on distal conduction may result in disorders of conduction or severe drug induced arrhythmia in patients with fragile conduction system or cardiac failure.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Electrophysiology; Flecainide; Heart Conduction System; Humans; Piperidines; Propafenone; Propiophenones

The effectiveness and safety of intravenous lorcainide was evaluated in 14 patients with normal (QRS less than 110 ms) and in 9 patients with prolonged QRS duration (QRS greater than or equal to 110 ms) showing chronic high frequency premature ventricular complexes (mean value of PVCs 17 min-1). Lorcainide was infused intravenously by intermittent bolus at 10 mg every minute to a total dose of 160 mg with exception of 5 patients with a prolonged QRS duration who only received 100 mg. The overall reduction of PVCs 1 hour after administration of the drug was 86% (p less than 0.05) in the patients with normal QRS duration and 98.5% (p less than 0.05) in the patients with a prolonged QRS duration. The mean plasma drug level achieved 1 h after treatment was 280 +/- 60 ng/ml in the patients with QRS less than 110 ms and 170 +/- 40 ng/ml in the patients with a QRS greater than or equal to 110 ms. Heart rate and blood pressure did not change but a significant increase (p less than 0.05) in QRS duration (+37%) was observed 30 min after the infusion of 160 mg lorcainide in the patient group with normal QRS duration. Lorcainide was well tolerated. Mild adverse effects were observed in five patients including: warmth sensation, vomiting, paresthesias, transient hypotension and the development of a junctional escape rhythm. Therefore lorcainide appears to be a safe and effective drug, that can even be administered to patients with a prolonged QRS duration.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Blood Pressure; Electrocardiography; Female; Heart Rate; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines

Each antiarrhythmic agent can cause side effects, but most of these are easily recognised by the patient or physician. However, one potentially serious side effect common to all of these drugs is aggravation of ventricular arrhythmia. Often this is without symptoms and goes unrecognised by the patient. It occurs in 11 to 16% of drug tests depending upon the method of drug evaluation employed. There are no ECG changes which predict its occurrence and blood concentrations of drug are usually within a therapeutic range. There are no clinical patient features which are associated with this toxic reaction and it does not correlate with the presence or extent of underlying heart disease, the nature of the presenting arrhythmia or the known electrophysiological properties of the antiarrhythmic drug. Careful evaluation of these drugs is therefore essential.

Topics: Anilides; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Disopyramide; Drug Evaluation; Electrocardiography; Encainide; Flecainide; Humans; Mexiletine; Piperidines; Procainamide; Propafenone; Propiophenones; Quinidine

Thirty-eight patients with organic heart disease and history of sudden cardiac arrest or recurrent sustained ventricular tachycardia were treated with flecainide. Coronary artery disease was present in 33 patients. Previous antiarrhythmic therapy consisted of two to eight drugs (mean four). Fourteen patients were resuscitated from sudden cardiac death and 24 patients had chronic recurrent sustained ventricular tachycardia. Twenty-eight patients had electrophysiologic testing before and during flecainide treatment. Sustained ventricular tachycardia became noninducible in 5 patients, nonsustained in 5 patients and slowed in 13 patients (cycle length increased from 278 +/- 64 to 395 +/- 91 ms; p = 0.002). Three of the 14 patients with sudden cardiac death and 15 of the 24 patients with recurrent sustained ventricular tachycardia remained on long-term flecainide treatment. The mean left ventricular ejection fraction in 16 of these 18 patients was 37%. Nonlimiting side effects occurred in seven patients (18%). Proarrhythmic effects were seen in four patients (10%). At a mean follow-up time of 11 +/- 3 months, 15 patients (39%) had had no recurrence, including 5 who had inducible sustained ventricular tachycardia and 5 who did not on retesting during treatment. In the 18 patients who received long-term therapy, 3 late deaths occurred, 1 of which was of arrhythmic origin. These data suggest that flecainide is effective in about 40% of patients with severe refractory ventricular arrhythmias. Its value as a single drug in the treatment of sudden cardiac death remains to be defined.

Topics: Adolescent; Adult; Aged; Arrhythmias, Cardiac; Electrophysiology; Female; Flecainide; Follow-Up Studies; Humans; Long-Term Care; Male; Middle Aged; Piperidines

The electrophysiologic properties of flecainide, a new potent antiarrhythmic drug, are poorly defined. In this study, they were investigated by standard microelectrode technique in isolated cardiac muscle from rabbit and dog hearts. The concentrations of flecainide used were between 0.1 and 10.0 micrograms/ml. Flecainide produced a concentration-dependent decrease in maximal rate of rise of phase 0 of the action potential (Vmax), action potential amplitude and overshoot potential with an increase in the effective refractory period in ventricular muscle. Vmax was reduced by 52.5% after 1 microgram/ml of flecainide (p less than 0.001) and by 79.8% after 10.0 micrograms/ml (p less than 0.001). The corresponding values for Purkinje fibers were 18.6% (p less than 0.01) and 70.8% (p less than 0.001), respectively, but in these fibers the effective refractory period was shortened at the lower concentration and restored to control value at the higher concentration. The depression of Vmax by flecainide was frequency-dependent. The action potential duration was lengthened by flecainide in ventricular muscle and shortened in Purkinje fibers. At high concentrations (10 micrograms/ml), flecainide depressed slow channel-dependent fibers. Purkinje fiber automaticity induced by isoproterenol was slowed by flecainide. The data indicate that the overall electrophysiologic effects of flecainide in isolated cardiac muscle are complex with a major depressant action on Vmax that may account for its dominant antiarrhythmic effects. It is also possible that the differential effects of the compound on the action potential duration and refractoriness in ventricular muscle and Purkinje fibers contribute to the known arrhythmogenic potential of the drug.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Calcium; Dogs; Electrophysiology; Female; Flecainide; Heart Conduction System; Heart Ventricles; In Vitro Techniques; Male; Piperidines; Purkinje Fibers; Rabbits; Time Factors; Ventricular Function

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Humans; Middle Aged; Piperidines; Syncope; Tachycardia

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Flecainide; Humans; Piperidines

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

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Female; Flecainide; Humans; Male; Middle Aged; Piperidines

Topics: Administration, Oral; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Flecainide; Humans; Piperidines; Tachycardia, Paroxysmal; Wolff-Parkinson-White Syndrome

Flecainide acetate, a new potent class I antiarrhythmic agent, was administered to 152 patients (orally to 46, intravenously to 106) over a period of 22 months. Seven patients developed proarrhythmic effects. The only conduction abnormalities induced were PR interval prolongation and QRS complex widening, and no patient developed significant sinus bradyarrhythmias; patients with known serious abnormalities of impulse generation or conduction were excluded from this study. Five patients, of whom only 3 had pre-existing ventricular arrhythmias, developed ventricular tachycardia or ventricular fibrillation. QT and QTc interval prolongation was observed, but was due to QRS complex widening rather than an increase in the JT interval. A patient with Wolff-Parkinson-White syndrome had an inducible orthodromic atrioventricular tachycardia before flecainide administration, but only an antidromic tachycardia was induced after taking the drug. In 1 patient, flecainide administration resulted in an increase of atrial flutter cycle length, which resulted in the development of 1:1 atrioventricular conduction rate, and, overall, a faster ventricular rate. Two patients who developed ventricular arrhythmias were taking other antiarrhythmic agents, and in this series proarrhythmic effects occurred with both normal and high flecainide concentrations. Other published series are also summarised.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Humans; Male; Middle Aged; Piperidines

The objective of this study was to evaluate the haemodynamic and antiarrhythmic effects of flecainide acetate in patients with heart failure. Flecainide acetate, a class Ic antiarrhythmic agent, was given intravenously to 9 patients with congestive heart failure and frequent ventricular arrhythmias with nonsustained ventricular tachycardia. The drug (2 mg/kg) was infused slowly over 60 minutes. The maximum plasma level achieved was 218 (range 142-350) ng/ml. Six of the 9 patients experienced a 90% suppression of their arrhythmias for an average of 6.5 (range 2-15) hours. Pre-ejection period control (PEPc, 148.8 +/- 3.6 msec) increased to 157 msec and pre-ejection period/ejection time (PEP/ET) [control 0.449 +/- 0.027] to 0.516 (p less than 0.005), while the ejection time index (ETI) did not change. Cardiac index (control 2.4 +/- 0.36 L/min/m2) decreased by 11% (p less than 0.02), and pulmonary wedge pressure (control 13.4 +/- 2.4mm Hg) increased by 23% (p less than 0.05). Stroke work index, arterial pressure and vascular resistance did not change significantly. The parameters returned to control values on completion of the infusion. Flecainide acetate can be safely administered at the usual dose of 2 mg/kg to patients with congestive heart failure, provided that the infusion time is doubled. Antiarrhythmic efficacy under these conditions is good even at lower plasma concentrations.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Electrocardiography; Flecainide; Heart Failure; Hemodynamics; Humans; Piperidines

Flecainide acetate depresses both the upstroke of the intracellular action potential and the rate of diastolic depolarisation in isolated tissue preparations of atrial myocardium. It produces no consistent effect on action potential duration. Predictably, in the human heart, studied by clinical cardiac electrophysiological techniques, conduction velocity through atrial myocardium, the atrioventricular (AV) node and anomalous tissue is depressed following flecainide administration. Refractoriness of normal atrial or AV nodal myocardium is not prolonged but the recovery time of anomalous or abnormal tissue is lengthened by the drug. In response to the intravenous injection of flecainide, atrial fibrillation (90%), atrial tachycardia (100%), intra-AV nodal tachycardia (89%) and atrioventricular re-entrant tachycardia (80%) are generally terminated, and although atrial flutter is slowed, only a small proportion (20%) is terminated. There is little experience of the long term treatment of supraventricular tachycardia with oral flecainide. However, preliminary results suggest that flecainide is equally effective in the treatment of both supraventricular and ventricular arrhythmias. Thus, flecainide acetate is a 'broad spectrum' antiarrhythmic agent.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Flecainide; Guinea Pigs; Heart Conduction System; Humans; Piperidines; Refractory Period, Electrophysiological; Tachycardia, Paroxysmal

In a prospective study of 10 patients with chronic ventricular arrhythmias, flecainide 50mg tid and propranolol 20mg tid were administered, alone and in combination, in a crossover design. Before and after each treatment phase, routine ECG and 24-hour ECG were recorded, morning plasma concentrations of the drugs were measured, and side effects recorded. Treatment with flecainide alone resulted in a 38% mean reduction (p less than 0.05) of ventricular premature complexes, a 75% (p less than 0.01) mean reduction of couplets, and elimination of ventricular tachycardia. At the dosage administered, propranolol alone had no antiarrhythmic effect. The combination of flecainide and propranolol showed no additional therapeutic benefit although there was a small, but not significant, increase in ventricular premature complexes and couplets. Use of flecainide resulted in a 12% widening of the QRS complex, with no significant change in PQ time, QTc and heart rate. Combined therapy with propranolol and flecainide resulted in a 12% decrease of average heart rate. The same effect was achieved when propranolol was given alone. The average plasma concentration of flecainide increased by 25% during combined therapy with propranolol. There were few side effects related to flecainide at the dosage administered and no additional side effects were recorded during the combined treatment.

Topics: Adult; Aged; Arrhythmias, Cardiac; Drug Therapy, Combination; Electrocardiography; Female; Flecainide; Humans; Male; Middle Aged; Piperidines; Propranolol

The efficacy of the new class Ic anti-arrhythmic (aa) drug, Flecainide, has been evaluated in patients (pts) affected by frequent and/or severe chronic ventricular arrhythmias (VA), as assessed by 24 hours Holter monitoring and maximal exercise stress testing. The protocol consisted in a preliminary screening with multiple aa drugs (average 6.0 per pt) using the acute oral drug testing. The most effective drug was then given for 72 hours and 24 hours Holter monitoring and exercise stress testing repeated; if the efficacy was confirmed, chronic treatment was initiated and control visits were repeated after 3, 6 and 12 months. The study population consisted of 27 pts; 22 (81%) were in Lown class 4A (18%) or 4B (63%). Eight pts (30%) had a previous (greater than 1 year) myocardial infarction, while in 14 (52%) no evidence of cardiac disease was found. During acute oral drug testing a positive response (reduction of PVC's greater than 90% and abolition of grades 4A and 4B) was obtained with Flecainide, 200 mg, in 20 pts (74%). In 6 pts (22%) no effect was observed, while a possible proarrhythmic effect was observed in 1 pt (4%). Eighteen pts entered the second phase of the study with an average dose of Flecainide of 175 mg b.i.d. In 83% of the pts there was a positive concordance between the acute oral testing and the 72 hours treatment, as in 15 out of 18 pts grades 4A and 4B were totally abolished and the mean frequency of PVC's was reduced by 99%. In 3 pts (17%) no response was observed. Flecainide increased significantly PR (37 msec), QRS (20 msec) and QTc (28 msec). The plasma levels attained with chronic therapy (846 ng/ml) were higher than those achieved with the acute oral testing (372 ng/ml). Mild side effects (dizziness, tremor and headache) were observed in 33% of the pts and were all eliminated by a 100 mg reduction in Flecainide dose. Fifteen pts entered the third phase (long term treatment): in this group there was a 93.3% correlation with phase two, as in 14 out of 15 pts there was a complete abolition of grade 4B arrhythmias, a 98.8% reduction of couplets and a reduction in the number of PVC's greater than 85%. This study shows that Flecainide is a quite powerful aa drug with modest side effects. Its efficacy against chronic VA is high, also when compared to the most effective and available aa drugs.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Chronic Disease; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Monitoring, Physiologic; Piperidines

Topics: Arrhythmias, Cardiac; Chronic Disease; Flecainide; Heart Ventricles; Humans; Piperidines

We evaluated the efficacy of flecainide acetate (given intravenously to a maximal dose of 2 mg kg-1 and then orally in a dose of 100 mg b.d. or 100 mg t.d.s.) in the conversion to sinus rhythm of 50 patients exhibiting supraventricular arrhythmias (39 with atrial fibrillation, 6 with atrial flutter, 4 with supraventricular tachycardia and one with supraventricular tachycardia in association with the Wolff-Parkinson-White syndrome). Conversion was achieved in 36 patients (72%) (29 cases with atrial fibrillation, 4 cases with supraventricular tachycardia, 2 cases with atrial flutter and one case with Wolff-Parkinson-White syndrome), over a mean period of 7.4 +/- 9 h. The patients in which conversion was achieved had arrhythmias which had been in existence for a shorter time (5.3 +/- 9.8 days) than those in which conversion was not achieved (16.7 +/- 26.2 days) (P less than 0.01). The mean dosage of flecainide used to achieve conversion was 2.5 +/- 2.36 mg kg-1. Flecainide appears to be an effective agent for the conversion to sinus rhythm of atrial fibrillation and supraventricular tachycardias. Its efficacy in cases of atrial flutter has not yet been demonstrated.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Female; Flecainide; Heart Rate; Humans; Male; Middle Aged; Piperidines

There is a need for effective, well-tolerated antiarrhythmic agents, particularly those effective by both intravenous and oral routes. Lorcainide, a new antiarrhythmic drug with such properties, was given long-term orally to 24 patients controlled initially with intravenous therapy--19 with frequent (greater than 1/min) complex premature ventricular complexes (PVCs) on a baseline 24-hour Holter monitor and five with ongoing sustained ventricular tachycardia (VT) or frequent paroxysmal sustained VT, for a mean of 13 months (range 0.03 to 39.4 months). Long-term lorcainide was given in divided doses of 200 to 800 mg/day (median 260, mean 269 +/- 90 mg/day). Response to long-term lorcainide therapy was assessed at a mean of both 26 days and 12.2 months. Frequency of PVCs on baseline averaged 13,490/24 hours (median 10,578, range 2,115 to 61,716); couplets averaged 309/24 hours (median 166, range 0 to 5,686), and runs averaged 33/24 hours (median 30, range 0 to 2,951). Median frequency of PVCs decreased by 94% (p much less than 0.001) and 97% (p less than 0.01) at the first and second lorcainide efficacy assessments, respectively. Couplets decreased by a median of 99% (p much less than 0.001) and 100% (p less than 0.005) at the first and second assessments, respectively. Runs were suppressed by a median of 100% at both evaluations (p much less than 0.001). Only three (16%) of the patients with complex PVCs failed to respond to therapy. No recurrence during lorcainide has been noted in the five patients with ongoing sustained VT or recurrent episodes of VT.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Dose-Response Relationship, Drug; Drug Tolerance; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Time Factors

New antiarrhythmic drugs are chiefly assigned to Class 1C and 1B: "procainamide analogues" (acecainide, lorcainide, flecainide, encainide) and propafenone for the former, and mexiletine, tocainide and aprindine for the latter. Pharmacokinetics vary widely among the different antiarrhythmic agents. These and other problems which regulate therapeutic interventions, such as patient compliance, drug interactions, efficacy/toxicity ratio, drug combinations, and drug monitoring with plasma concentrations of antiarrhythmic agents are briefly considered.

Topics: Acecainide; Amiodarone; Anilides; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Bretylium Compounds; Drug Interactions; Encainide; Flecainide; Heart Ventricles; Humans; Lidocaine; Mexiletine; Moricizine; Phenothiazines; Piperidines; Propafenone; Propiophenones; Tocainide

Lorcainide is an antiarrhythmic drug with unusual pharmacokinetics and an active metabolite, norlorcainide, which complicate oral drug loading. In order to characterize the accumulation of lorcainide and norlorcainide and to define the onset of antiarrhythmic action during lorcainide loading, 9 patients with frequent ventricular ectopic beats were studied. During lorcainide loading with 100 mg orally twice daily, frequent ambulatory electrocardiographic recordings were monitored and blood samples for drug concentrations were determined. There was a 10-fold range of intersubject variation in plasma concentrations. Despite a half-life of only 8.9 +/- 2.3 hours, lorcainide did not reach steady state until after 4.5 days of therapy. Norlorcainide had a half-life of 26.5 +/- 7.2 hours and was estimated to come to steady state after 7 to 10 days. There was considerable intersubject variation in time of onset of antiarrhythmic response (2 to more than 4.5 days) and a 4- to 5-fold range of intersubject variation in threshold therapeutic plasma concentration (lorcainide 40 to 200 ng/ml, norlorcainide 80 to 300 ng/ml). These observations suggest that lorcainide should be started at low doses and the dose should not be increased more frequently than once a week.

Topics: Administration, Oral; Adult; Aged; Ambulatory Care; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Complexes, Premature; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Kinetics; Male; Middle Aged; Piperidines; Sleep Wake Disorders; Time Factors

The efficacy and safety of flecainide, 200 mg twice daily, was compared with disopyramide, 150 mg 4 times daily, in a randomized, double-blind, crossover study in 25 patients (19 men and 6 women, aged 20 to 71 years, mean 52.5) with more than 1,000 ventricular premature complexes (VPCs) in a pretrial 24-hour Holter monitoring screen. Each 14-day active treatment period was preceded and followed by a 7-day placebo period. Ambulatory ECGs were recorded at the end of each study week and analyzed blindly. Average VPCs recorded during each of the 2 active periods were compared with average VPCs in the placebo periods. Twenty-two of 25 patients attained therapeutic plasma levels of both drugs. The occurrence of VPCs was significantly less during flecainide than during disopyramide treatment, 92 and 39%, respectively (p less than 0.01). Complex arrhythmic events were significantly more suppressed with flecainide than with disopyramide. No difference was observed between the 2 drugs in the incidence or severity of reported side effects. PQ, QRS and QT intervals increased beyond normal limits on both drugs in some patients, significantly more with flecainide than with disopyramide. The JT interval did not change or decrease; hence, all changes in the QT interval were attributable to a widening of the QRS complex. Neither drug showed any significant effect on blood pressure or heart rate. Flecainide may be a well-tolerated and valuable alternative to currently available antiarrhythmic agents.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Disopyramide; Double-Blind Method; Drug Evaluation; Electrocardiography; Female; Flecainide; Heart Conduction System; Heart Rate; Humans; Male; Middle Aged; Piperidines; Random Allocation

Topics: Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Atrioventricular Node; Benzeneacetamides; Encainide; Flecainide; Heart Atria; Humans; Lidocaine; Piperidines; Tachycardia; Tocainide; Wolff-Parkinson-White Syndrome

Topics: Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzofurans; Drug Therapy, Combination; Flecainide; Humans; Piperidines

The widespread use of antiarrhythmic agents to control severe life-threatening arrhythmias evidenced the possibility of a worsening of arrhythmias induced by the same drugs. We performed a retrospective analysis studying the worsening phenomenon in patients who underwent pharmacological invasive and non invasive antiarrhythmic tests to choose the drug to be administered in the chronic treatment. Particularly we reviewed: 101 acute pharmacologic non invasive tests for "stable" ventricular ectopic beats using computerized automatic continuous recording system which allows quantitative and qualitative evaluation of arrhythmias. The drugs tested were: Propafenone (25 patients), Disopiramide (25 patients), Tocainide (11 patients), Lorcainide (8 patients), Lorajmine (13 patients), Nadolol (9 patients). In accordance with Vallebit et al., we considered arrhythmias worsening criteria: the onset of non sustained or sustained ventricular tachycardia; an increase of four fold the number of ventricular ectopic beats and/or ten fold the repetitive forms. A worsening of arrhythmias was observed in 4/101 (3.9% patients); 1/9 treated with Nadolol, 1/25 with Propafenone, 1/35 with Disopiramide, 1/13 with Lorajmine. For one young patient the worsening phenomenon could be considered a toxic picture, because of the very high drug plasmatic levels (Lorajmine) observed for the whole duration of the sustained VT induced from the drug. For the remaining 3 patients the response resambles a paradox effect. 34 pharmacologic invasive tests in 30 patients with common recurrent ventricular tachycardia, during electrophysiologic endocavitary study. The drugs tested were: Propafenone (12 patients), Amiodarone (11 patients), Ajmaline (4 patients), Tocainide (3 patients), Lorcainide (2 patients), Lorajmine (1 patient), Disopiramide (1 patient).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Aged; Ajmaline; Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Child; Disopyramide; Female; Follow-Up Studies; Humans; Lidocaine; Male; Middle Aged; Nadolol; Piperidines; Propafenone; Propanolamines; Propiophenones; Tocainide

Sudden cardiac death continues to be a major health hazard. Control of the problem requires identification of those at risk and effective therapy for prevention. Studies have shown that in patients with coronary disease or cardiomyopathy, salvos of ventricular tachycardia are an independent risk factor for sudden death. Therefore, the objective of therapy is the suppression of these forms. A large number of antiarrhythmic drugs are available, but there are no guidelines for the selection of an effective and well-tolerated agent. We have developed a systematic approach to drug selection which includes 4 phases: phase 0 is a control period to establish the prevalence and density of the arrhythmia; phase 1, acute drug testing, is designed to screen a number of drugs for effectiveness; during phase 2 the drug is administered for a brief period to evaluate efficacy and tolerance; phase 3, once the drug is determined to be well tolerated and effective, it is continued as part of a long-term program. This approach was applied in 76 patients who underwent testing with lorcainide. This drug was continued long term in 15 patients. After 23 months of follow-up, only 1 patient died suddenly. Therefore, patients with life-threatening ventricular arrhythmia can be protected from a recurrence by individualized drug therapy.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Dose-Response Relationship, Drug; Drug Evaluation; Electrophysiology; Follow-Up Studies; Heart Ventricles; Humans; Monitoring, Physiologic; Piperidines

Topics: Arrhythmias, Cardiac; Child, Preschool; Follow-Up Studies; Humans; Infant; Infant, Newborn; Metaproterenol; Methods; Piperidines; Postoperative Complications; Prognosis; Transposition of Great Vessels

During a one-week short-term in-hospital period, 60 patients with chronic ventricular arrhythmias were treated with 200 mg flecainide twice a day. Flecainide reduced premature ventricular complexes (PVCs) by more than 85% without causing important side-effects in 47 patients, who entered a one-year follow-up period and were followed with bimonthly 24-h ECGs. Median PVC-frequency remained reduced by more than 99% during the follow-up period. Repetitive ventricular beats and ventricular tachycardia were present in 83% and 42% of patients, respectively, before flecainide. During follow-up, these arrhythmias were seen in less than 32% and less than 10% of patients, respectively, at each 24-h ECG. Furthermore, the mean number of hours with repetitive ventricular beats and ventricular tachycardia remained reduced by more than 76% and more than 79%, respectively, throughout the follow-up period. Ventricular arrhythmias remained suppressed despite a gradual reduction in flecainide dosages (to a median of 300 mg day-1) and flecainide plasma levels. In nine out of 47 patients, an increase in ventricular arrhythmias above baseline values on one or more occasions was observed. During a flecainide withdrawal period, a 65-fold increase in median PVC-frequency was observed and ventricular tachycardia reappeared in 18 patients. Subjective side-effects were acceptable except for two patients. During the follow-up period, one patient developed reversible heart failure and sinus node dysfunction. During the total study period, four patients, with either severe coronary artery disease (2) or cardiomyopathy (2) developed lethal arrhythmias (3) or ischaemic events (1). We conclude that prolonged flecainide treatment is effective in a high proportion of patients with chronic ventricular arrhythmias. In some patients an arrhythmogenic effect may occur.

Topics: Adult; Aged; Arrhythmias, Cardiac; Chronic Disease; Dizziness; Drug Evaluation; Electrocardiography; Female; Flecainide; Follow-Up Studies; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Time Factors

The effects of lorcainide, a new antiarrhythmic drug, on serum electrolytes and osmolality are described in a series of 33 patients with organic heart disease and complex ventricular arrhythmias treated with lorcainide. In eight patients, a mean decrease in serum Na+ of 8.25 +/- 3.2 mEq/L was observed after a single 200 mg intravenous dose of lorcainide. Sixteen of 33 patients developed significant hyponatremia and hypoosmolality during oral treatment with lorcainide. In all except two patients, serum Na+ returned to normal values within 3 to 12 months of continued lorcainide therapy. Low serum Na+ and hypoosmolality in the absence of volume depletion, clinically manifest edema, and unaltered renal, adrenal, cardiac, or thyroid function suggest that this antiarrhythmic drug produced the syndrome of inappropriate antidiuretic hormone secretion (SIADH). SIADH appeared to be transient and asymptomatic in our patients. One patient developed severe hyponatremia with serum Na+ of 108 mEq/L when hydrochlorothiazide was given to control hypertension. It is concluded that SIADH is an important side effect of lorcainide therapy. We recommend that serum Na+ be carefully monitored in patients started on lorcainide therapy, and extreme caution should be exercised in prescribing diuretics to patients with persistent hyponatremia.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Hyponatremia; Inappropriate ADH Syndrome; Male; Middle Aged; Piperidines; Potassium; Sodium; Vasopressins

Flecainide acetate, a new potent class I antiarrhythmic agent, was given to 152 patients (46 orally and 106 intravenously) over a period of 22 months. Seven patients developed proarrhythmic effects. The only conduction abnormalities induced were PR interval prolongation and QRS complex widening, and no patient developed significant sinus bradyarrhythmias; patients with known serious abnormalities of impulse generation or conduction were excluded from this study. Five patients developed ventricular tachycardia or ventricular fibrillation of whom only three had preexisting ventricular arrhythmias. QT and QTc interval prolongation was observed but was due to QRS complex widening rather than to an increase in the JT interval. A patient with the Wolff-Parkinson-White syndrome had an inducible orthodromic atrioventricular (AV) tachycardia prior to flecainide, but only an antidromic tachycardia was induced after the drug. In one patient flecainide administration resulted in an increase of atrial flutter cycle length which resulted in development of 1:1 AV conduction and overall faster ventricular rate. Two patients who developed ventricular arrhythmias were taking other antiarrhythmic agents, and in this series proarrhythmic effects occurred with both normal and high flecainide concentrations.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrioventricular Node; Dose-Response Relationship, Drug; Electrocardiography; Female; Flecainide; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Tachycardia

Topics: Aged; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Flecainide; Heart Ventricles; Humans; Male; Piperidines; Tachycardia

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Flecainide; Humans; Piperidines

The results of a well-controlled multicenter shortterm safety and efficacy study, supported by results from several long-term studies, indicate that therapeutic doses of flecainide are well tolerated by most patients. The most frequently reported extracardiac adverse experiences were dizziness (30%) and visual disturbances (28%), often occurring in tandem. Headache, nausea, dyspnea and chest pain occurred at incidences of 6 to 9%; other adverse experiences occurred at incidences of greater than or equal to 5%. Because of study design, it is likely that these figures are overestimates; they include all reports, whether or not they were caused by flecainide. Extracardiac adverse experiences were given as reasons contributing to discontinuation of therapy in 10% of patients in the short-term and 6% of patients in the long-term studies. In most cases the inability to tolerate flecainide became evident early in therapy. No new adverse experiences indicative of any chronic toxic effect of flecainide were reported during the long-term studies. Side effects tended to be intermittent and to decrease over time.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dizziness; Dyspnea; Flecainide; Headache; Humans; Nausea; Piperidines; Vision Disorders

The results of antiarrhythmic testing in a variety of animal models indicate that flecainide acetate has potent antiarrhythmic activity. In these models it is more potent than lidocaine, procainamide and quinidine, as well as a number of investigational agents, and is active against both ventricular and supraventricular arrhythmias from a number of causes. Studies of its effects on the action potential from various cardiac tissues indicate that its primary effect is to slow the rate of rise of the action potential, placing it among the group of drugs commonly referred to as class I agents. In the intact animal, in accordance with its effects on the action potential, flecainide slows conduction throughout the cardiac conduction system, with the most marked effects on His-Purkinje conduction and ventricular activation.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disease Models, Animal; Dogs; Electrophysiology; Flecainide; Heart Conduction System; In Vitro Techniques; Lidocaine; Piperidines; Procainamide; Quinidine; Rabbits

The acute electrophysiologic effects of i.v. flecainide acetate (2 mg/kg body weight) were assessed in 71 patients undergoing electrophysiologic study. Ten patients underwent investigation for sinus node dysfunction. Sinus cycle length shortened slightly, from 980 +/- 292 to 931 +/- 276 ms (p less than 0.01). Uncorrected or corrected sinus node recovery times or sinoatrial conduction time (according to the methods of Strauss and Narula) did not change in 6 patients with normal sinus node function and in 3 of 4 patients with abnormal sinus node function at rest. In the remaining patient maximal sinus node recovery time increased from a value at rest of 5,185 ms to 23,460 ms after flecainide. In the same patient sinoatrial conduction times at rest increased from 159 ms (Strauss method) and 143 ms (Narula method) to 1,398 and 1,455 ms, respectively, after flecainide. Thirty-three patients underwent electrophysiologic evaluation of anomalous atrioventricular (AV) pathways and reentrant tachycardias. Flecainide significantly prolonged accessory AV pathway anterograde and retrograde refractoriness. Anterograde accessory pathway block occurred in 33% of patients and retrograde accessory pathway block in 44%. Flecainide was successful in the acute termination of 86% of orthodromic atrioventricular reentrant tachycardias. In 15 patients with dual AV nodal pathways, only retrograde "fast" AH pathway refractoriness was significantly increased by flecainide, which was successful in the acute termination of 88% of intra-AV nodal reentrant tachycardias. In 28 patients who underwent endocardial pacing threshold assessment before and after i.v. flecainide, the acute threshold rose by a maximum of 117%, whereas the chronic threshold rose by a maximum of 83%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrioventricular Node; Cardiac Pacing, Artificial; Electrocardiography; Electrophysiology; Female; Flecainide; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Sinoatrial Node

Flecainide acetate was evaluated in a placebo-controlled, dose-ranging study performed in patients with stable, high-frequency ventricular arrhythmias. Three centers studied 35 patients in a 3-stage protocol. After a placebo baseline, increasing oral dosages from 100 to 300 mg twice daily were evaluated. Placebo was then reinstituted and after arrhythmia had recurred, the patients were discharged on the effective dosage to return to the clinic for evaluation 7 and 14 days later. Thirty of 35 patients had more than 80% suppression (mean 96%) of ventricular premature complexes (VPCs) and more than 95% reduction in complex VPCs. Arrhythmia suppression was seen at dosages of 100 to 200 mg twice daily in 73% of the patients. Twenty-three percent of patients required 500 to 600 mg/day. Mild side effects were seen in 46% of patients. These resolved or became tolerable at lower dosages in most patients. Effective therapy continued for 2 years in 24 of 29 patients, without any evidence of chronic toxicity. Pharmacokinetic studies indicate that many patients require 5 to 7 days of constant dosing before reaching steady state. Flecainide acetate is an effective antiarrhythmic with a narrow range of effective dosages.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Drug Evaluation; Electrocardiography; Female; Flecainide; Hemodynamics; Humans; Kinetics; Male; Middle Aged; Piperidines

The proarrhythmic potential and electrophysiologic effect of flecainide acetate, a potent class IC anti-arrhythmic agent, are considered in this report. Although the definition of a proarrhythmic effect is arbitrary, several such definitions are discussed and applied to data on flecainide. In patients with chronic ventricular arrhythmias, an increase in VPC frequency developed in 0 to 4% of patients, compared with 1 to 8% of patients who received quinidine and 2% who received encainide, another class IC agent. In patients with acute hemodynamically significant ventricular arrhythmias, the proarrhythmic effects were noted in 5 to 12%. Proarrhythmic effects appear to be more common in patients with left ventricular dysfunction and life-threatening ventricular arrhythmias. The depression of atrioventricular conduction produced by flecainide is similar to that seen with other class IC agents. Increases in PR and QRS intervals are related to dose and plasma concentration and are approximately 25% at therapeutic levels. These changes in the electrocardiographic intervals do not appear to carry important clinical implications and do not require discontinuation of flecainide. QT prolongation is absent or minimal with flecainide. Guidelines for management of patients with flecainide are suggested.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Flecainide; Hemodynamics; Humans; Piperidines

The efficacy and safety of oral flecainide for treatment of ventricular arrhythmias were assessed during a 3-day period in patients with various cardiac diseases. Of 11 patients who received a low dose of flecainide (median daily dose 240 mg), only 4 responded with 90% or greater reduction in premature ventricular complex frequency. Ventricular tachycardia could not be suppressed. During treatment no electrocardiographic changes occurred. 14 of the 19 patients who received a high dose of flecainide (median daily dose 480 mg), demonstrated a 90% or greater reduction in premature ventricular complexes, and ventricular tachycardia did not recur during treatment in 7 out of 9 patients. However, PQ, QRS, and QTc intervals were significantly increased. In general, flecainide was well tolerated and drug administration did not have to be discontinued because of side effects. Flecainide acetate treatment, with a median dose of 480 mg daily, appears to be highly effective for suppressing complex ventricular arrhythmias.

Topics: Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Drug Evaluation; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines; Tachycardia

The antiarrhythmic efficacy and safety of oral flecainide were assessed during a controlled 2-week and a subsequent 48-week long-term trial. Fifteen patients with frequent (more than 30 per hour) and complex ventricular arrhythmias (Lown grade IVA or IVB) who had been resistant or intolerant to 2 or more antiarrhythmic agents, were included in the study. Antiarrhythmic efficacy was controlled by 24-hour Holter monitoring at 2, 12, 24 and 48 weeks. The administration of 100 to 200 mg flecainide twice daily resulted in more than 90% suppression of VPCs and of complex ventricular arrhythmias in 14 of 15 patients. The minimum effective therapeutic dose could be titrated in 9 of 14 patients to 100 mg twice daily, in 3 of 14 patients to 150 mg twice daily and in 2 of 14 patients to 200 mg twice daily. During this therapy and a mean plasma concentration of 886 +/- 103 ng/ml, PQ and QRS duration, as well as QTc time and JTc interval were not significantly changed. Side effects (gastrointestinal complaints, nausea, obstipation, dizziness, visual disturbances, headache and impaired potency) were seen in 5 of 14 patients after 12 weeks, in 3 of 4 patients after 24 weeks and in only 2 of 14 patients after 48 weeks. Side effects were described as mild and tolerable and did not limit flecainide therapy except in 1 patient, who had discontinued therapy with flecainide after 3 days because of intense gastrointestinal symptoms. In conclusion, flecainide is highly effective and well tolerated in the long-term treatment of serious ventricular arrhythmias.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Drug Evaluation; Female; Flecainide; Humans; Male; Middle Aged; Piperidines

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Heart Rate; Humans; Kinetics; Piperidines

Topics: Amiodarone; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Complexes, Premature; Coronary Disease; Disopyramide; Electrocardiography; Humans; Lidocaine; Mexiletine; Piperidines; Propafenone; Propiophenones; Tachycardia; Tocainide

The effect of flécaïnide (new class I antiarrhythmic) on ventricular rhythm troubles was studied in 24 patients using Holter's method. The following results were obtained. For ventricular tachycardia, two cases of suppression, three cases of distinct reduction in the number and duration of attack and one failure were recorded. For single ventricular extrasystoles, doublets and triplets, nine very good results (80 to 100 per cent reduction of arrhythmia) and four 50 to 80 per cent reductions in ventricular prematurity were obtained. Results were uncertain in two patients as the disappearance of extra-systoles was not followed by relapse after termination of treatment. There were three failures. A twenty-fifth patient was treated with flécaïnide IV followed by oral administration with uncertain results. Undesirable effects are infrequent and are often characterized by sinusal bradycardia. Blurred vision and paraesthesia were encountered. The principal biological parameters remained unchanged.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Female; Flecainide; Humans; Male; Middle Aged; Piperidines; Tachycardia; Ventricular Fibrillation

To determine the effect of flecainide acetate, a Class IC antiarrhythmic drug, The medication was given to 28 patients with ventricular pacing electrodes. Eleven patients with temporary pacing electrodes (Group I) received intravenous flecainide (2 mg/kg over 10 minutes). Ten patients with chronic permanent electrodes (Group II) were given the same dose at the time of elective pulse generator change. Seven, with implanted multiprogrammable pacemakers capable of threshold analysis (Group III), were given intravenous flecainide and 5 of these were then given the drug orally for up to 3 weeks (100 mg/day increasing to 400 mg/day). In Group I the threshold measured at a pulse width of 0.5 ms rose from a control value of 0.66 to 1.44 volts after 10 minutes (p less than 0.01). In Group II the threshold rose from 1.73 to 2.13 volts (p less than 0.01) and 2 patients had total suppression of their ventricular escape rhythm for approximately one hour. In Group III patients, intravenous flecainide resulted in a rise escape rhythm for approximately one hour. In Group III patients, intravenous flecainide resulted in a rise of the pulse width threshold measured at 2.7 volts from 0.14 to 0.22 ms (p less than 0.02) and at 4.9 volts from 0.06 to 0.11 ms (p less than 0.05) after 10 minutes. After 3 weeks of oral therapy the threshold at 2.7 volts had risen to 0.11 ms /ms (p less than 0.05 after 10 minutes. After 3 weeks of oral therapy the threshold at 2.7 volts had risen from 0.09 to 0.28 ms (p less than 0.02) and at 4.9 volts from 0.06 to 0.16 ms (p less than 0.05) Flecainide significantly increased both acute and chronic thresholds and the most marked rise (greater than 200%) occurred during chronic oral therapy. Both intravenous and oral flecainide should be used with care in patients with either temporary or permanent pacing systems.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Dose-Response Relationship, Drug; Electrocardiography; Female; Flecainide; Heart Block; Humans; Male; Middle Aged; Pacemaker, Artificial; Piperidines; Tachycardia

Topics: Acute Disease; Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Heart Conduction System; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Drug Evaluation; Female; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines

Flecainide acetate, a new benzamide antiarrhythmic agent, was studied after single-dose intravenous administration to 35 male and female patients with nonlife-threatening premature ventricular contractions (PVCs). Prior Holter monitoring established that each patient had "stable" PVCs of at least 600/12 hr. PCV in 80% of the patients was attributed to underlying coronary heart disease and/or Chagas' disease. After bolus injections of flecainide acetate, cardiac rhythm was again monitored by Holter ECG recording for 24 hours. All patients had 100% suppression of PVCs, ranging from 60 to 1440 minutes in duration. The average duration of suppression for all patients was more than 8 hours (498 minutes). Follow-up at 6, 12, 18, and 24 hours showed statistically significant PVC reductions (p less than 0.01) when compared with control rates. Side effects were trivial. The extended half-life of this new agent (about 20 hours in cardiac patients) may allow a convenient twice-daily dosage schedule.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

Lorcainide disposition kinetics were studied after intravenous and oral administration to patients with ventricular arrhythmias. After intravenous doses ranging from 100 to 200 mg, blood samples were drawn and plasma was analyzed for lorcainide concentration by high-pressure liquid chromatography. A three-compartment model was used to fit the data. The model-independent calculated values for clearance, steady-state volume of distribution, and terminal half-life were 14.4 +/- 3.28 ml/min/kg, 6.33 +/- 2.23 l/kg, and 7.8 +/- 2.2 hr. After nine doses of oral lorcainide (100 mg every 12 hr) blood samples were drawn and analyzed for lorcainide and its active metabolite, norlorcainide. The lorcainide and norlorcainide half-lifes were 9.6 +/- 2.8 and 26.8 +/- 8.2 hr. Mean steady-state level of norlorcainide was 2.2 +/- 0.9 times the level of lorcainide. The data suggest that the clearance of lorcainide decreases with time during long-term dosing.

Topics: Administration, Oral; Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Female; Half-Life; Humans; Injections, Intravenous; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Topics: Adult; Aged; Ajmaline; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Female; Humans; Male; Middle Aged; Piperidines; Syncope; Time Factors

Antiarrhythmic actions of lorcainide were compared with those of disopyramide on different types of arrhythmias in animal models. It was shown in dogs that lorcainide and disopyramide were approximately equipotent against the arrhythmias following coronary occlusion. In guinea pigs, lorcainide was less effective than disopyramide against the ouabain-induced arrhythmia. Both drugs showed a weak protective action against the aconitine-induced ventricular arrhythmias, but had no effect on the cardiac arrest. In the arrhythmias induced by the application of acetylcholine on the right auricle of guinea pigs, the disappearance of P-waves and the disturbance of R-R intervals were inhibited by disopyramide, but lorcainide had no influence on these events; both prevented the atrial fibrillation induced by acetylcholine application. Both drugs by themselves induced ventricular arrhythmias in guinea pigs.

Topics: Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Coronary Vessels; Disopyramide; Dogs; Female; Guinea Pigs; Ligation; Male; Ouabain; Piperidines

After an initial pilot study in five patients, the effect of flecainide on chronic ventricular arrhythmias was tested during 48-hour oral administration of 250 mg twice a day in nine further patients with previously drug-resistant chronic, stable ventricular arrhythmias. Mean age was 45.9 +/- 14.9 years; seven patients were male. Three patients had coronary artery disease, whereas the diagnoses in the remaining patients were congestive cardiomyopathy, aortic stenosis or no apparent heart disease. Continuous Holter monitoring with quantitative evaluation was performed in all patients for 24 hours before and during a two days' period of treatment. The mean number of ventricular ectopic beats decreased from 20.3 +/- 6.4 beats/min during hour six of treatment and further to 3.1 +/- 7.7 beats/min during hour 25 to 48 after onset of treatment. In either of nine patients, the mean decrease in ventricular ectopic rate was 97.5%. In only one patient, therapy was ineffective, Ventricular couplets were completely suppressed in six of eight cases. Looking at the spontaneous variability of ventricular ectopic beats during the control period, eight of nine patients showed a decrease which considerably exceeded the statistically necessary one. Headache of moderate degree was reported in one case in the pilot study. Therapy had to be stopped after the first dose because of QRS widening in another patient. In conclusion, this short-term study suggests that flecainide may be an effective drug for the management of ventricular arrhythmias.

Topics: Adult; Anti-Arrhythmia Agents; Aortic Valve Stenosis; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Chronic Disease; Coronary Disease; Electrocardiography; Female; Flecainide; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

Pirmenol (CI-845), a new antiarrhythmic drug, was studied for the first time in humans to establish a minimum effective i.v. dose in 10 patients with chronic, stable premature ventricular complexes (PVCs) and to evaluate toxicity and pharmacokinetics. Infusions of 70-150 mg were associated with a 90% or greater reduction in PVCs nine of the 12 times they were administered to six patients. Peak plasma concentrations were 1.0-3.8 micrograms/ml at the end of these infusions. At the same time, small but significant increases in diastolic blood pressure (4 mm Hg) and QTc interval (0.01 second) were seen, but both values were within the normal range. Pirmenol was associated with no change in heart rate, systolic blood pressure, PR interval or QRS duration, renal, hepatic or hematologic function, or symptoms. Blood, plasma and free drug concentrations declined biexponentially after cessation of a 150-mg infusion (n = 4), with a terminal half-life of 7-9.4 hours. The therapeutic response, lack of toxicity, and relatively long half-life indicate that pirmenol is a promising antiarrhythmic agent.

Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Female; Half-Life; Heart; Humans; Kinetics; Male; Middle Aged; Piperidines

The electrophysiological effects of flecainide acetate (2 mg/kg as an intravenous infusion over five minutes) were assessed in 47 patients undergoing electrophysiological study. Seven patients had normal electrophysiology, 16 had a direct accessory atrioventricular pathway, 12 had dual atrioventricular nodal (AH) pathways, five had paroxysmal ventricular tachycardia, six had conduction system disease, and one patient had a left atrial tachycardia. No significant change occurred in sinus cycle length. The PA interval, AH interval, and HV interval were all significantly prolonged. The QRS complex duration increased significantly. The QT interval showed slight prolongation due entirely to the increase in QRS duration. Refractoriness of the atrial and ventricular myocardium was slightly prolonged, but was significant only at ventricular level. No significant change occurred in refractoriness of the normal atrioventricular node. Pronounced prolongation of retrograde "fast" AH pathway refractoriness was observed in those patients with dual AH pathways. Anterograde and retrograde accessory pathway refractoriness were both greatly increased. These electrophysiological properties strongly suggest that flecainide will be useful in the management of a wide variety of cardiac arrhythmias. It should be administered, however, with caution to patients with pre-existing conduction system disease. Because repolarization is not delayed flecainide is unlikely to induce ventricular arrhythmias related to prolongation of the QT interval.

Topics: Adolescent; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrophysiology; Female; Flecainide; Heart Conduction System; Humans; Male; Middle Aged; Piperidines

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Flecainide; Heart Ventricles; Myocardial Infarction; Piperidines

The coronary artery-ligated rat was investigated as an experimental model for studying the effects of pirmenol hydrochloride and reference for studying the effects of pirmenol hydrochloride and reference agents on early ventricular arrhythmias. Coronary artery ligation caused 89% lethality (ventricular fibrillation) within 10 min in untreated control rats. Vagal stimulation applied during periods of high-rate ventricular tachycardia reduced sinus, atrioventricular nodal and ventricular ectopic beats, with no uncoupled ectopic beats seen during stimulation. Rats studied with composite epicardial electrodes showed continuous electrical activity throughout diastole. These factors indicate that a reentry mechanism is likely involved. Pretreatment with pirmenol afforded protection in a dose-related fashion. A dose of 1.25 mg/kg increased survival to 58%, and all rats dosed with 2.5 to 10 mg/kg survived. Suppression of ventricular fibrillation was dose related and was complete at 5 mg/kg. The pirmenol plasma levels of 1.2 +/- 0.1 microgram/ml seen after the 5 mg/kg dose are similar to plasma levels seen at clinically effective doses, as well as at doses effective in other experimental arrhythmias. The reference agent quinidine was also highly effective in this model, all rats pretreated with 5 mg/kg survived with reduced premature ventricular beats and without a single episode of ventricular fibrillation or death. Fibrillation and/or death were also reduced by the reference agents, bretylium, lidocaine, propranolol and verapamil. The high efficacy of pirmenol against early ventricular arrhythmias in this study further defines its spectrum of activity, and suggests that pirmenol may be effective in a clinical setting where a reentrant mechanism is operative.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Vessels; Electric Stimulation; Heart Conduction System; Heart Ventricles; Male; Piperidines; Rats; Rats, Inbred Strains; Vagus Nerve

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Pacing, Artificial; Drug Evaluation; Female; Humans; Male; Middle Aged; Piperidines; Time Factors

Clinical and experimental studies indicate that ventricular arrhythmias, especially ventricular fibrillation, are in almost all cases the mechanism for sudden death occurring during the first 24 hours after the onset of an ischaemic myocardial event. Therefore a higher survival rate seems to depend on advances in antiarrhythmic therapy. The present study investigates the efficacy of the new local anaesthetic compound Flecainide in reducing or preventing ventricular arrhythmias and primary ventricular fibrillation, using a standardized experimental canine preparation. Our findings demonstrate that ventricular arrhythmias due to severe transmural myocardial infarction are reduced by 80-90% following the application of Flecainide. In some cases a complete abolition of the arrhythmias can be observed. The striking reduction in ventricular ectopics includes decreases in ventricular salves and R-on-T phenomena, which may lead to sudden death by precipitating ventricular fibrillation. The beneficial antiarrhythmic and antifibrillatory actions of Flecainide affect only the arrhythmias resulting from transmural necrosis of the myocardium ("in-hospital arrhythmias", 2nd-phase arrhythmias"), whereas the incidence of early ventricular arrhythmias, especially ventricular fibrillation occurring in the very inception of myocardial ischaemia ("pre-hospital arrhythmias", "1st-phase arrhythmias") is not prevented. Changes in hemodynamics and contractility due to Flecainide are not severe, even in myocardial infarction. Thus, our results indicate that the application of Flecainide in acute myocardial infarction in man may be successful in reducing therapy-resistant ventricular dysrhythmias.

Topics: Animals; Arrhythmias, Cardiac; Dogs; Flecainide; Heart Rate; Hemodynamics; Myocardial Infarction; Oxygen Consumption; Piperidines

Verapamil, nifedipine, perhexiline and SKF 525-A (2-diethylaminoethyl-2,2-diphenylvalerate . HCL) were evaluated for cardiac antiarrhythmic activity by assessing their effectiveness in increasing left ventricular fibrillation threshold (FT) and antagonizing ouabain-induced arrhythmias (OA), 24 h post infarction arrhythmias (CLA) and aconitine-induced atrial arrhythmias. Calcium antagonistic doses (ID50) of each agent were approximated by intravenous titration of the amount of drug required to reduce the left ventricular contractile force by 50% in dogs pretreated with hexamethonium (10 mg/kg) to block autonomic reflexes. ID50 doses of calcium antagonists were found not to be universally effective in any single arrhythmia model while causing significant changes in heart rate, blood pressure and frequently producing death or convulsion. It is suggested that local anesthetic or 'class 1' action probably accounts for the antiarrhythmic effectiveness of SKF 525-A (7-20 mg/kg i.v.) in all four arrhythmia models and for perhexiline-induced increased FT and antagonism of CLA (15-20 mg/kg). Antiarrhythmic effectiveness of verapamil against OA may be due to calcium antagonism action.

Topics: Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Calcium; Dogs; Female; Heart Rate; Lidocaine; Male; Myocardial Contraction; Nifedipine; Perhexiline; Piperidines; Proadifen; Pyridines; Verapamil

Lorcainide, a new class I antiarrhythmic drug, was administered intravenously to 10 patients with a documented history of ventricular arrhythmias. Three patients had arrhythmias resistant to all conventional antiarrhythmic drugs; in all other patients except one, previous antiarrhythmic drug therapy had to be discontinued because of poor efficacy or unacceptable adverse effects. Lorcainide was injected in incremental doses of 25 mg every 15 minutes and a dose of 182.4 +/- 26.5 mg (mean +/- standard deviation) of the drug was given. Lorcainide reduced the frequency of premature ventricular complexes in a dose-dependent manner. Plasma samples were analyzed for the drug concentrations which ranged from 0.31 to 1.14 mg/liter during the loading phase. Distribution and elimination of lorcainide follow a biexponential pattern and a fourfold intersubject variability in the pharmacokinetics of the drug was observed in these patients. The plasma half-life ranged from 6.2 to 23.1 hours (mean 13.1 +/- 5.0). Three patients are currently being treated orally with lorcainide. These data suggest that lorcainide is an effective antiarrhythmic drug with desirable pharmacokinetic properties, and long-term definitive studies are recommended.

Topics: Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Female; Humans; Kinetics; Male; Middle Aged; Piperidines; Time Factors

Topics: Acute Disease; Animals; Arrhythmias, Cardiac; Dogs; Flecainide; Lidocaine; Myocardial Infarction; Piperidines

The electrophysiological effects of the new antiarrhythmic drug Flecainide (R 818) was tested in altogether 27 patients with and without disturbances of sinus node function and intraventricular conduction. Flecainide was given intravenously in a dose of 1 mg/kg and 2 mg/kg. Constant "therapeutic" plasma levels were reached by application of 1 mg/kg as a bolus and an additional infusion of 1 mg/kg during the test period of 20 min. The drug had no significant effects on sinus node function even in patients with sinus node dysfunction tested so far. Intracardiac conduction time was prolonged within all compartments of the heart in a dose-dependent manner. After bolus injection of 1 mg/kg, the HRA-A interval lengthened by 10.4%, the A-H interval by 13.5%, the H-V time by 15.7% and the V-RVA interval by 29.1% of the control value. In addition, the QRS complex widened by 8.1%. After 2 mg/kg Flecainide the HRA-A interval was prolonged by 9.0%, the A-H interval by 24.4%, the H-V time by 40.2%, and the V-RVA interval by 16.5% of the control value. The QRS complex widened by 24.2%. In contrast, there was only a small and often insignificant increase in the refractoriness of the different compartments of the heart (5-15% increase of the control value). In two patients with bundle branch block, a higher degree A-V block distal the H potential occurred after 2 mg/kg Flecainide. These electrophysiological effects may explain some antiarrhythmic actions of Flecainide. In addition, possible side effects of the drug can be assessed. In patients with intraventricular conduction defects the drug should be used with caution especially when given iv in higher doses.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Electrocardiography; Female; Flecainide; Heart Conduction System; Humans; Male; Middle Aged; Piperidines

Topics: Action Potentials; Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiac Pacing, Artificial; Drug Evaluation; Electrocardiography; Female; Flecainide; Heart Conduction System; Humans; Male; Middle Aged; Piperidines

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dose-Response Relationship, Drug; Drug Resistance; Echocardiography; Electrocardiography; Exercise Test; Female; Flecainide; Humans; Kinetics; Male; Middle Aged; Myocardial Contraction; Piperidines; Stroke Volume

The electrophysiological effects of the intravenous administration of a new antiarrhythmic drug, lorcainide, were evaluated by programmed electrical stimulation of the heart in 23 patients with atrioventricular conduction disturbances (four patients), ventricular tachycardia (five patients), and accessory atrioventricular pathway (14 patients). Lorcainide did not affect the refractory period of the atrium, ventricle, atrioventricular node, or the AH interval. It lengthened the duration of the HV interval, the refractory period of the accessory pathway, and the width of the QRS complex. The drug terminated ventricular tachycardia in four of five patients. It is concluded that the drug may be of potential benefit in patients with ventricular tachycardia or accessory atrioventricular pathways (especially those with a short refractory period). Lorcainide is contraindicated in patients with bundle-branch block and prolonged HV interval.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cardiac Pacing, Artificial; Electrocardiography; Female; Heart Block; Heart Conduction System; Humans; Male; Middle Aged; Piperidines; Tachycardia

Topics: Angina Pectoris; Aniline Compounds; Arrhythmias, Cardiac; Calcium; Cardiomegaly; Diuretics; Heart Diseases; Heart Failure; Humans; Hypertension; Indapamide; Nifedipine; Perhexiline; Piperidines; Pyridines; Verapamil

The effect of oral N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzene acetamide (lorcainide) was studied in 12 patients with frequent and stable ventricular arrhythmias resistant to a number of other antiarrhythmic agents. Ambulatory electrocardiograms were obtained before and during treatment with lorcainide and in some patients after discontinuation of the drug. Lorcainide suppressed ventricular premature contractions by more than 90% in all but one patient. The daily doses were 200 mg (N = 8), 300 mg (N = 1), 400 mg (N = 1)and 600 mg (N = 2). Plasma concentrations of lorcainide and of the dealkylated metabolite ranged from 0.13 to 0.27 microgram/ml and 0.25 to 0.95 microgram/ml, respectively. Side effects such as insomnia and excessive perspiration were seen in 7 and 3 patients, respectively. Lorcainide is an effective antiarrhythmic agent against ventricular arrhythmias otherwise difficult to treat.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Drug Resistance; Electrocardiography; Female; Heart Ventricles; Humans; Male; Middle Aged; Piperidines

A new class I antiarrhythmic, flecainide, was investigated in 10 patients to assess short-term efficacy and safety. All patients were hospitalized for 3 days; no antiarrhythmics were given on days 1 and 3. On day 2 flecainide 1 mg/kg was given intravenously over 5 min. If the predrug arrhythmia(s) was not completely suppressed, additional boluses of 0.5 mg/kg were injected at 30- to 60-min intervals to a maximum of 5 mg/kg. Seven patients received 2 mg/kg, and 3 patients received 1 mg/kg. Before drug 5 patients had premature ventricular contractions (PVCs) (more than 4 per min); 2 patients had atrial fibrillation (AF) with PVCs; 1 patient had both PVCs and premature atrial contractions (PACs); and 2 patients had only PACs. One patient with PVCs failed to respond to flecainide; he was unresponsive to all available antiarrhythmic drugs. In the other 7 patients PVCs were suppressed for an average of 13 hr (range 6 to 24 hr), AF was not affected, and PACs were suppressed. Flecainide did not induce significant changes in P-R, QRS, or Q-T intervals. Side effects were negligible and included a tingling sensation and feeling of skin warmth for 15 min after drug in one patient.

Topics: Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Electrocardiography; Female; Flecainide; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines

A first series of personal results in the treatment of arrhythmia with lorcainide is presented. Findings were obtained by recording for 24 hr with Holter and compared with those observed in patients treated with quinidine. An ECG study was also made of the atrial and nodal refractory periods. The conclusion is drawn that lorcainaide possesses an undoubted and protracted anti-arrhythmic effect, and does not exert a significant influence on refractory period values.

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Drug Evaluation; Female; Humans; Male; Middle Aged; Piperidines

Topics: Aconitine; Action Potentials; Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Coronary Disease; Dogs; Dose-Response Relationship, Drug; Electrocardiography; Epinephrine; Female; Heart Conduction System; Hemodynamics; Male; Ouabain; Piperidines; Time Factors; Ventricular Fibrillation

The long-term anti-arrhythmic efficacy of lorcainide (R15 889) was studied in 20 ambulatory postmyocardial infarction patients. Lorcainide reduced the frequency of ventricular ectopic beats by more than 70% and 90% in 17 and 11 of the patients respectively. The anti-arrhythmic response improved with long-term administration of the drug. Fourteen patients complained of insomnia during the early stages of the study, but this side-effect waned later on. On electrocardiographic examination, the P-R interval, QTc interval and QRS duration were prolonged, and T-wave changes were noted while the patients were receiving lorcainide. Lorcainide seems to be a useful addition to the available anti-arrhythmic agents, and should form part of the armamentarium against ventricular ectopic activity.

Topics: Adult; Aged; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Humans; Male; Middle Aged; Myocardial Infarction; Piperidines; Ventricular Fibrillation

A 68-year-old patient developed increasingly frequent episodes of ventricular and supraventricular arrhythmias over the past five years. During the last 12 months, he was admitted to the hospital on several occasions with complex arrhythmias including multifocal PVCs, bigeminy, trigeminy, ventricular tachycardia, and atrial flutter and fibrillation. Large and frequent doses of quinidine, procainamide, disopyramide, propranolol, and digoxin failed to suppress his arrhythmias. He had no previous history of myocardial infarction or other heart diseases. Coronary arteriography revealed no obstruction of any major arteries or their branches. A new antiarrhythmic drug, lorcainide, was given intravenously and it suppressed all PVCs, including bigeminy and ventricular tachycardia. All his arrhythmias have been completely suppressed by oral regimens of lorcainide, 100 mg four times daily, for the past four months. This is the first case of oral treatment of ventricular arrhythmias with lorcainide in this country.

Topics: Administration, Oral; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Drug Resistance; Humans; Male; Piperidines

Topics: Acetanilides; Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Aorta; Aorta, Abdominal; Arrhythmias, Cardiac; Benzeneacetamides; Blood; Blood Proteins; Female; Hepatic Veins; Humans; In Vitro Techniques; Injections, Intravenous; Male; Middle Aged; Piperidines; Protein Binding; Pulmonary Artery

Topics: Acetanilides; Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Female; Humans; In Vitro Techniques; Infusions, Parenteral; Injections, Intravenous; Male; Middle Aged; Piperidines

Topics: Acetanilides; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Female; Heart Ventricles; Humans; Infusions, Parenteral; Male; Middle Aged; Piperidines; Time Factors

The neuroleptic butyrophenone, melperone, has been compared with antiarrhythmics, neuroleptics, alpha-blockers and beta-blockers in various experimental arrhythmias. Melperone 0.01--1 mg/kg intravenously antagonized ouabain-induced arrhythmias in conscious rabbits to the same degree as propranolol 2 mg/kg and quinidine 10 mg/kg intravenously probably mainly via s CNS depressive effect. It was found to be considerably weaker than propranolol 2 mg/kg, when anaesthetized guinea pigs were used. Melperone 0.1--10 mg/kg was inactive against aconitine-induced arrhythmias. Melperone 1--5 mg/kg antagonized adrenaline-induced arrhythmias in halothane-sensitized guinea pigs like phentolamine 1--5 mg/kg intravenously and was more potent than chlorpromazine, propranolol and quinidine. This study and an electrophysiological study suggest that melperone might be a type III anti-arrhythmic drug, which at the same time depresses CNS and reduces afterload.

Topics: Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Butyrophenones; Droperidol; Epinephrine; Guinea Pigs; Lidocaine; Male; Ouabain; Piperidines; Procainamide; Propranolol; Quinidine; Rabbits; Rats

Lorcainide hydrochloride or N-(4-chlorophenyl)-N-[1-(1-methyl-ethyl)-4-piperidinyl]benzeneacetamide mono-hydrochloride (R 15889) is a new anti-arrhythmic drug. Studies in dogs show that lorcainide is effective against post-infarction and ouabain-induced ventricular arrhythmias, and abolishes acetylcholine and aconitine-induced atrial fibrillation; it elevates the threshold of electrically induced ventricular fibrillation. In isolated dog and cow Purkinje fibers, in dog ventricular and in guinea-pig auricular muscle preparations, lorcainide decreases the rate of rise of the transmembrane action potential, the conduction velocity and spontaneous activity. It prolongs the refractory period of isolated Purkpinje and ventricular muscle preparations, and the functional refractory period of the AV node in the guinea-pig heart. It has no effect on Ca mediated electrical activity. Isometric force measurements in isolated cat papillary muscles and hemodynamic studies in anaesthetized and unanaesthetized dogs indicate that lorcainide moderately decreases myocardial contractility. Side effects observed at large doses are of central origin and include salivation, tremor and vomiting. Intravenous injection induces transient peripheral vasodilatation. Lorcainide is an antiarrhythmic of the local anaesthetic type. It is characterized by a good oral absorption, a long duration of action and a large safety factor.

Topics: Acetamides; Acetylcholine; Aconitine; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Cats; Cattle; Coronary Vessels; Dogs; Electrocardiography; Female; Guinea Pigs; Heart; Hemodynamics; In Vitro Techniques; Ligation; Male; Membrane Potentials; Myocardial Contraction; Ouabain; Piperidines; Refractory Period, Electrophysiological

In rats, the intravenous injection of 1 mg/kg A.D.P. (adenosine-5'-diphosphate) results in transient thrombocytopenia, bradycardia and arrhythmias. Pre-treatment of the animals with the antiarrhythmic compounds lorcainide, aprindine, procaine (1.25, 2.5, 5 mg/kg i.v.) and xylocaine (5, 10, 20 mg/kg i.v.) before A.D.P. injection results in a reduction of bradycardia and a faster normalization of heart rate. All 4 compounds were equipotent in this respect, but the higher dose of xylocaine used should be stressed. The duration of irregular heart rhythm after A.D.P. injection was significantly shortened by all 4 compounds. Peak thrombocytopenia after A.D.P. administration is reduced only by lorcainide and the highest dose of aprindine, with two dose levels of xylocaine, but is not reduced by procaine. Suloctidyl (50 mg/kg orally) had no effect on any of the parameters registered. From this study we conclude that the normalization by the compounds of cardiac rate and rhythm disturbances after A.D.P. is due to their direct antiarrhythmic effect rather than to inhibition of platelet aggregation.

Topics: Acetamides; Adenosine Diphosphate; Animals; Anti-Arrhythmia Agents; Aprindine; Arrhythmias, Cardiac; Benzeneacetamides; Drug Interactions; Heart Rate; Lidocaine; Male; Piperidines; Procaine; Propanolamines; Rats; Thrombocytopenia; Time Factors

The electrophysiologic properties of Lorcainide (1.25 and 2.5 mg/kg) were studied on 21 patients by intracardiac electrograms and atrial stimulation. A prolongation of the H-V interval, widening of QRS duration but only minor changes in A-H interval were found. The effective refractory period of the atria increased, the effective and functional refractory periods of the A-V node changed variable following Lorcainide. There was a slight increase in heart rate and the sinus node recovery time was longer after 2.5 mg/kg of the drug. The major site of action of Lorcainide in man appears to be the His-Purkinje system. In electrophysiologic terms the new antiarrhythmic agent closely resembles Aprindine.

Topics: Acetanilides; Anti-Arrhythmia Agents; Arrhythmia, Sinus; Arrhythmias, Cardiac; Bundle of His; Bundle-Branch Block; Cardiac Pacing, Artificial; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Humans; Piperidines; Sinoatrial Node

A novel benzanilide derivative, MJ 9067, has been shown to abolish experimental atrial and ventricular arrhythmiase effectively and promote the return of normal sinus rhythm in a variety of animal models. At intravenous dose levels ranging from 0.5 to 3.2 mg/kg, MJ 9067 successfully converted atrial fibrillation induced by either local application of aconitine or electrical stimulation, and ventricular tachycardia elicited by intravenous injection of ouabain or digoxin. The compound was equally effective in vagotomized or nonvagotomized dogs, and in intact cats and monkeys. The ventricular ectopic rate in conscious dogs 18 to 20 hours after two-stage ligation of a coronary artery was also markedly reduced by the drug at 2 mg/kg i.v. At antiarrhythmic dose levels, there were no undesirable effects noted on peripheral blood pressure, heart rate or the configuration of the electrocardiogram.

Topics: Aconitine; Anilides; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Blood Pressure; Cats; Digoxin; Dogs; Electric Stimulation; Electrocardiography; Female; Haplorhini; Heart Rate; Male; Ouabain; Piperidines; Saimiri; Tachycardia

The anti-arrhythmic properties of a new drug, lorcainide, have been evaluated. Lorcainide is highly efficient for the treatment of ventricular arrhythmias, especially ventricular extrasystoles and recurrent ventricular tachycardia. It is also efficient in the treatment of supraventricular extrasystoles and repetitive auricular tachycardia. It is ineffective in cases of auricular fibrillation and flutter. The drug also has effective anti-arrhythmic properties when administered orally. It has a small negative inotropic effect which was not clinically relevant in the patient group studied. Side effects were within acceptable limits and essentially consist of dizziness, tremor and blurring of vision, occurring only during rapid i.v. injection and depending upon the speed of injection.

Topics: Acetamides; Administration, Oral; Adult; Aged; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzeneacetamides; Electrocardiography; Humans; Injections, Intravenous; Male; Middle Aged; Piperidines

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Chronic Disease; Coronary Disease; Drug Evaluation; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines; Placebos

The effects of perhexiline on survival time and infarct size were studied in three animal models. Dogs pretreated orally with perhexiline, 200 mg/day/14 days, and monitored under anesthesia for 30 hours after ligation of the left anterior descending coronary artery (LAD) had infarct weights of 9.1+/-1.9 g as compared to 15.2+/-1.0 g in paired untreated controls (P less than .02). Twelve of 15 perhexiline-pretreated dogs survived the duration of these studies while only 5 of 15 control animals survived for the same period of time (P less than .05). Serum creatine phosphokinase activity was significantly lower in the treated dogs at 9, 12 and 15 hours after ligation (P less than .05). Conscious dogs, pretreated orally with perhexiline 200 mg/day/7 days or 400 mg/day/7 days and monitored without anesthesia or analgesia for 72 hours after coronary ligation had smaller infarcts (P200=26+/-5; P400=26+/-4; C=39+/-5 g; P less than .05) lower plasma peak creatine phosphokinase activity (P less than .05) and reduced heart rate (P400=198+/-8; C=226+/-8 beats/min; P less than .05) and reduced incidence of ventricular ectopic beats (P less than .05). In pentobarbital anesthetized open-chest dogs, perhexiline (3 mg/kg i.v.) reduced the sum of S-T segment elevation after left anterior descending coronary artery occlusion from 32+/-3 to 14+/-1 mV (P less than .001); this effect was associated with and/or preceded by a reduction in arterial pressure (101+/-4 to 78+/-5 mm Hg; P less than .001) and heart rate (151+/-8 to 138+/-7 beats/min P less than .025; Circumflex flow increased from 38+/-4 to 83+/-8 ml/min (P less than .01). In noninfarcted open-chest dogs, perhexiline administration (3 mg/kg i.v.) resulted in increases in coronary blood flow, narrowing of arterial-coronary sinus O2 difference and a 14% reduction in myocardial O2 consumption. The protective effects of perhexiline on the ischemic myocardium appear to result from reductions in heart rate and associated decrease in myocardial O2 demand as well as an antiarrhythmic effect.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Coronary Vessels; Creatine Kinase; Dogs; Electrocardiography; Female; Heart; Heart Rate; Male; Myocardial Infarction; Myocardium; Oxygen Consumption; Perhexiline; Piperidines; Time Factors

Topics: Adult; Aged; Angina Pectoris; Arrhythmias, Cardiac; Drug Evaluation; Female; Humans; Male; Middle Aged; Perhexiline; Piperidines

Topics: Anesthetics, Local; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Female; Guinea Pigs; Humans; Lidocaine; Male; Ouabain; Piperidines

In a preliminary study which lasted 14 weeks, an anti-anginal preparation, perhexiline maleate (Pexid), was prescribed in a dosage of 200 mg twice a day to 7 patients who were suffering from cardiac arrhythmias associated with ischaemic heart disease. There was a significant reduction in ventricular extrasystoles during the 4th and 8th weeks of the study in 6 of the patients who had multiple ventricular ectopic beats. In 4 of these patients, an effective anti-arrhythmic response was maintained until the end of the study. These findings confirm other studies regarding the efficacy of the preparation in reducing ventricular extrasystoles in patients with cardiac ischaemia.

Topics: Arrhythmias, Cardiac; Atrial Fibrillation; Cardiac Complexes, Premature; Coronary Disease; Female; Heart Ventricles; Humans; Male; Middle Aged; Perhexiline; Piperidines

Perhexiline maleate (Pexid), a promising clinical antiarrhythmic and antianginal drug, was evaluated for its electrophysiologic effects on the entire conduction system of the intact canine heart throughout a wide range of therapeutic and potentially toxic doses. Intracardiac conduction times were measured by bipolar intramyocardial and transvenous endocardial electrodes before and following the intravenous administration of each dose of perhexiline maleate, 3 mg/kg every 30 min for a total of 4 doses in 7 open-chest anesthetized dogs. Eight animals served as controls in which similar operative technique and electrophysiologic variables were recorded after infusion of the maleate diluent. In addition, the effects of perhexiline on atrial and ventricular thresholds to electrical stimulation were recorded, as well as the QRS and QT intervals, sinus rate, and rhythm disorders. It was observed that perhexiline did not significantly (p greater than .05) alter sinus rate, QT interval, QRS duration, PR interval, intra-atrial conduction time, atrioventricular nodal conduction time, and His-Purkinje conduction velocity. The drug did not affect the cardiac threshold to electrical stimulation of less than 0.1 ma. No ectopic atrial or ventricular activity emerged during the accumulated influence of the agent. From this study, it is concluded that perhexiline does not exert deleterious actions on the conduction system of the intact canine heart. In view of the negligible toxic effects and its efficacy in treating ventricular tachyarrhythmias in patients, the drug deserves further clinical evaluation.

Topics: Animals; Arrhythmias, Cardiac; Bundle of His; Dogs; Electric Stimulation; Electrocardiography; Heart; Heart Conduction System; Heart Rate; Perhexiline; Piperidines

Topics: Alkylation; Amides; Animals; Arrhythmias, Cardiac; Diethylamines; Dimethylamines; Disopyramide; Heterocyclic Compounds; Hydantoins; Isomerism; Mice; Piperidines; Quinidine; Structure-Activity Relationship; Urea; Ventricular Fibrillation

Topics: Adrenergic alpha-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Benzamides; Blood Pressure; Cats; Cell Membrane; Electric Stimulation; Electrocardiography; Female; Hypothermia, Induced; Indoles; Male; Piperidines; Ventricular Fibrillation

Topics: Adult; Antihypertensive Agents; Arrhythmias, Cardiac; Blood Pressure; Cardiomegaly; Diuretics; Electrocardiography; Female; Heart; Humans; Hypertension; Hypertension, Malignant; Hypertension, Renal; Male; Middle Aged; Minoxidil; Nephrectomy; Piperidines; Posture; Propranolol; Pyrimidines; Vasodilator Agents

Topics: Action Potentials; Animals; Antiemetics; Arrhythmias, Cardiac; Butanols; Digitalis Glycosides; Dogs; Epinephrine; Heart; Heart Atria; Heart Conduction System; In Vitro Techniques; Kinetics; Membranes; Piperidines; Rabbits; Refractory Period, Electrophysiological; Synaptic Transmission

Topics: Androstanes; Anesthesia, General; Arrhythmias, Cardiac; Blood Pressure; Cardiac Output; Electrocardiography; Halothane; Heart Rate; Hemodynamics; Humans; Neuromuscular Nondepolarizing Agents; Nitrous Oxide; Piperidines; Toxiferine; Venous Pressure

Topics: Animals; Antiemetics; Arrhythmias, Cardiac; Benzene Derivatives; Blood Flow Velocity; Blood Pressure; Butanols; Cardiac Output; Cats; Digoxin; Dogs; Electric Conductivity; Electrocardiography; Female; Heart Rate; Hemodynamics; In Vitro Techniques; Male; Ouabain; Papillary Muscles; Piperidines; Propranolol; Sinoatrial Node; Vascular Resistance

Topics: Androstanes; Arrhythmias, Cardiac; Female; Humans; Intubation, Intratracheal; Male; Neuromuscular Nondepolarizing Agents; Piperidines; Succinylcholine; Thiopental

Topics: Amides; Anesthetics, Local; Animals; Arrhythmia, Sinus; Arrhythmias, Cardiac; Blood Pressure; Cats; Epinephrine; Female; Guinea Pigs; Halothane; Ileum; In Vitro Techniques; Indoles; Lidocaine; Male; Muscle Contraction; Nicotine; Ouabain; Piperidines; Procaine; Propranolol; Quinidine; Tachycardia; Ventricular Fibrillation

Topics: Anesthesia, General; Anesthetics; Arrhythmias, Cardiac; Diazepam; Electric Countershock; Humans; Methods; Nitrous Oxide; Piperidines; Preanesthetic Medication; Thiopental

Topics: Anesthetics, Local; Anilides; Arrhythmias, Cardiac; Humans; Piperidines; Xylenes

Topics: Anesthetics, Local; Anilides; Animals; Arrhythmias, Cardiac; Female; Lidocaine; Male; Mepivacaine; Ouabain; Piperidines; Prilocaine; Rabbits; Xylenes

Topics: Anesthetics, Local; Anilides; Animals; Arrhythmias, Cardiac; Epinephrine; Female; Lidocaine; Male; Mepivacaine; Piperidines; Prilocaine; Rabbits; Xylenes

Topics: Adult; Aged; Anesthesia, General; Anesthesia, Intravenous; Anilides; Arrhythmias, Cardiac; Arteries; Blood Pressure; Diuresis; Electrocardiography; Female; Humans; Male; Middle Aged; Neoplasms; Palliative Care; Piperidines; Xylenes