pyrimidinones and Arrhythmias--Cardiac

Topics: Amiodarone; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Bepridil; Drug Therapy, Combination; Humans; Pyrimidinones; Sotalol

The potential utility of nifekalant, a new Class III antiarrhythmic drug, to offer long-term protection against ventricular arrhythmia has been investigated in this case report. A 44-year-old male patient with dilated cardiomyopathy complicated with heart failure and persistent ventricular tachycardia was treated with nifekalant. The patient was treated with nifekalant for 31 days, which effectively terminated ventricular tachycardia and maintained sinus rhythm, with no clinical adverse reactions. After heart transplantation, postoperative follow-up showed good cardiac function and no arrhythmia. On the basis of nifekalant's working mechanism, there is a good chance that it can cure ventricular arrhythmia on a long-term basis.

Topics: Adult; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiomyopathy, Dilated; Humans; Male; Pyrimidinones; Tachycardia, Ventricular

The present study was conducted to clarify multiple cardiohemodynamic and electrophysiological properties including inotropic/lusitropic effects of nifekalant, a class III antiarrhythmic drug, in an isoflurane-anesthetized monkey. Nifekalant was administered intravenously at the therapeutic dose of 0.3 mg/kg over 10 min to male cynomolgus monkeys (n=4), followed by higher dose of 1 (n=3) or 3 mg/kg (n=1) that was limited due to arrythmogenicity. Left ventricular (LV) pressure-volume (PV) analysis revealed that the 0.3 mg/kg dose of nifekalant induced a negative lusitropic effect, recognized as a decrease in maximal rate of reduction in LV pressure and a prolonged isovolumic relaxation time. Nifekalant also decreased heart rate and increased LV end-diastolic pressure, but had no effects on the other cardiohemodynamic parameters examined. Electrophysiological analysis showed nifekalant at 0.3 mg/kg prolonged QT/QTc intervals with no evidence of arrhythmia. Higher doses of nifekalant induced ventricular arrhythmia in 3 out of 4 animals, in which both the short-term and long-term variability of the QT interval increased just before the occurrence of arrhythmia. In conclusion, a therapeutic dose of nifekalant had no effect on inotropic activity or cardiac compliance, whereas it showed negative lusitropic properties and QT/QTc prolongation in isoflurane-anesthetized monkeys. In addition, higher doses of nifekalant showed remarkable QT/QTc prolongation leading to arrhythmogenicity, which showed good accordance with clinical findings. Caution should be paid to negative lusitropic properties as well as arrhythmogenisity for the safe use of nifekalant.

Topics: Anesthesia; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Volume; Depression, Chemical; Diastole; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Hemodynamics; Infusions, Intravenous; Macaca fascicularis; Male; Myocardial Contraction; Pyrimidinones; Ventricular Function, Left; Ventricular Pressure

Topics: Adult; Antineoplastic Agents; Arrhythmias, Cardiac; Defibrillators, Implantable; Heart Neoplasms; Humans; Imidazoles; Male; Melanoma; Molecular Targeted Therapy; Oximes; Positron Emission Tomography Computed Tomography; Protein Kinase Inhibitors; Pyridones; Pyrimidinones; Skin Neoplasms

A 38-year-old woman with type 1 short-QT syndrome (SQTS) was referred to our hospital. Her ECG showed short QT/QTc interval and peaked T wave. Activation-recovery intervals (ARIs) were calculated from the intracardiac endocardial and epicardial electrode catheters placed in the left ventricle (LV). Intravenous administration of nifekalant prolonged effective refractory period at multiple ventricular sites as well as the QT/QTc interval (from 260/300 to 364/419 ms) on the surface ECG. Nifekalant also enlarged the transmural ARI dispersion of the ventricular repolarization, which was measured by the difference between the longest endocardial ARI and the shortest epicardial ARI during atrial pacing at 90 bpm, from 73 to 103-105 ms. These values corresponded to the intervals between the peak and end of the T wave on the surface ECG. Nifekalant-induced QT interval prolongation on the surface ECG may not indicate attenuation of the arrhythmogenic potential in the heart of SQTS patients.

Topics: Action Potentials; Adolescent; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Pacing, Artificial; Electrocardiography; Electrophysiologic Techniques, Cardiac; Fatal Outcome; Female; Heart Conduction System; Heart Defects, Congenital; Heart Rate; Humans; Predictive Value of Tests; Pyrimidinones; Time Factors; Treatment Outcome

A 42-year-old Thai man was administered the combination drugs liponavir/ritonavir and abacavir/lamivudine. On day 3 he was admitted and his electrocardiogram demonstrated sinus arrest with junctional escape rhythm with a rate of 42 min(-1). Three days after stopping the medication he reverted to normal sinus rhythm. A 55-year-old Caucasian man was admitted to hospital with triple vessel disease. He had a permanent pacemaker inserted 4 years previously for Mobitz type II AV block detected on stress electrocardiogram, which developed 1 month after initiation of lopinavir/ritonavir. These two cases highlight the importance of considering lopinavir/ritonavir induced arrhythmias when dealing with HIV-positive individuals.

Topics: Adult; Anti-HIV Agents; Arrhythmias, Cardiac; Electrocardiography; HIV Infections; Humans; Lopinavir; Male; Middle Aged; Pyrimidinones; Ritonavir

To analyze the clinical features and risk factors of adverse reactions associated with telbivudine.. Clinical data were collected from cases that presented with serious adverse reactions to telbivudine. We analyzed general information and medicine status, clinical features, results of examination, and misdiagnosis.. Out of 105 patients who were treated with telbivudine for hepatitis B in an outpatient department from January, 2007 to January, 2008, five presented with serious adverse drug reactions. Most of these five patients had used other nucleoside analogues in the past. Four were treated with a combination of telbivudine and interferon or another nucleoside analogue, while the other received an increased dose of telbivudine. The main adverse reactions were myalgia and general weakness. This was accompanied by cardiac arrhythmia in one patient, and nervous symptoms in three. Serum creatine kinase was elevated. The rate of misdiagnosis was high.. The adverse reactions were related to telbivudine, but the biological mechanism of the reactions is not yet clear. Combination therapy with interferon or another nucleoside analogue and a high dose may increase the risk of adverse reactions.

Topics: Adult; Arrhythmias, Cardiac; Creatine Kinase; Drug Synergism; Hepatitis B, Chronic; Humans; Interferons; Male; Middle Aged; Muscle Weakness; Neuralgia; Nucleosides; Pyrimidinones; Retrospective Studies; Risk Factors; Telbivudine; Thymidine

The chronic atrioventricular block dog is a useful model for predicting the future onset of drug-induced long QT syndrome in clinical practice. To better understand the arrhythmogenic profile of this model, we recorded the action potentials of the isolated ventricular tissues in the presence and absence of the class III antiarrhythmic drug nifekalant. The action potential durations of the Purkinje fiber and free wall of the right ventricle were longer in the chronic atrioventricular block dogs than in the dogs with normal sinus rhythm. Nifekalant in concentrations of 1 and 10 microM prolonged the action potential durations of Purkinje fiber and the free wall in a concentration-dependent manner. The extent of prolongation was greater in the chronic atrioventricular block dogs than in the normal dogs. However, increase of temporal dispersion of ventricular repolarization including early afterdepolarization was not detected by nifekalant in either group of dogs, indicating lack of potential to trigger arrhythmias in vitro. These results suggest that the ventricular repolarization delay in the chronic atrioventricular block model by nifekalant may largely depend on the decreased myocardial repolarization reserve, whereas the trigger for lethal arrhythmia was not generated in the in vitro condition in contrast to the in vivo experiment.

Topics: Action Potentials; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Dogs; Dose-Response Relationship, Drug; Heart Block; Heart Ventricles; Microelectrodes; Purkinje Fibers; Pyrimidinones

Ventricular tachycardia (VT), ventricular fibrillation (VF), and atrial flutter (AFL) are potentially fatal or serious complications arising after cardiac surgery. Generally, we treat these complications with class I antiarrhythmic agents and/or direct counter shock (DC). However, sometimes these complications do not respond to antiarrhythmic agents and require frequent DC. Moreover, these class I agents induce heart failure due to their negative inotropic effect. Nifekalant hydrochloride (NIF) is a class III antiarrhythmic agent that prolongs the refractory period of the atrial and ventricular myocardium without any negative inotropic action. From July 2003 to September 2004, we treated 11 patients with NIF for perioperative arrhythmias (VT 5, VF 2, and AFL 4). NIF was administered by continuous intravenous infusion (0.3 to 0.4 mg/ kg/h) to prevent the recurrence of VT/VF and AFL. NIF prevented the recurrence of VT in 3 of the 5 cases. No recurrence was observed in 2 cases with VF. Furthermore, NIF prevented the recurrence of AFL in all the 4 patients. None of the patients exhibited changes in heart rate, cardiac output, and QTc interval. Additionally, no occurrence of Torsades de pointes was observed in any of the cases. In conclusion, NIF is an effective and safe antiarrhythmic agent for the treatment of perioperative arrhythmias under continuous monitoring of the QTc interval.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Flutter; Cardiac Surgical Procedures; Female; Humans; Male; Middle Aged; Postoperative Complications; Pyrimidinones; Tachycardia, Ventricular; Ventricular Fibrillation

In vivo antiarrhythmic effects of diltiazem hydrochloride and nifekalant hydrochloride, a pure class III antiarrhythmic drug (Vaughan Williams' classification), on adrenaline induced ventricular arrhythmias were examined in halothane anesthetized guinea pigs. Continuous adrenaline infusion (12.5 microg/kg per min) induced ventricular arrhythmias. Arrhythmogenicity was significantly increased with vagotomy and higher concentration of halothane. After injection of diltiazem at 0.5 mg/kg, the arrhythmic ratio (the number of ventricular ectopic beats divided by the total heart beats) was significantly reduced compared with the predrug control value (0.69 vs 0.04, P<0.05). No significant change of arrhythmic ratio was observed after injection of nifekalant (0.57 vs 0.61, ns). After administration of nifekalant, the mean minimum adrenaline infusion rate that induced ventricular arrhythmia decreased from 9.29 to 6.43 microg/kg per min. On the other hand, before administration of diltiazem, the mean arrhythmogenic rate of adrenaline was 8.50 microg/kg per min, but ventricular arrhythmias were no longer induced during continuous infusion of diltiazem at 0.5 mg/kg per min. These results were qualitatively consistent with previous experiments using the canine halothane-adrenaline model. In conclusion, the halothane-adrenaline arrhythmia model using the in vivo guinea pig is useful for screening drugs with potential anti- or pro-arrhythmic properties.

Topics: Adrenergic alpha-Agonists; Anesthetics, Inhalation; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Diltiazem; Electrocardiography; Epinephrine; Guinea Pigs; Halothane; Long QT Syndrome; Male; Pyrimidinones; Vagotomy

We investigated the proarrhythmic effects of MS-551 and KCB-328, class III antiarrhythmic drugs using adrenaline-induced arrhythmia models in halothane anaesthetized, closed-chest dogs. In the control period, adrenaline, starting from a low dose of 0.25 to up to 1.0 microg/kg/50 s i.v., was injected to determine the arrhythmia inducing dose and the non-inducing dose. After MS-551 or KCB-328 administration, the adrenaline injection was repeated and the interval between the injection and the occurrence of arrhythmia (latent interval), the changes in arrhythmic ratio (as calculated by dividing the number of ventricular premature contraction by the number of the total heart rate) and the severity of arrhythmia were observed. MS-551 infusion, 1 mg/kg/30 min, decreased the heart rate (HR) by 16% (P<0.01) and prolonged the QTc interval by 20% (P<0.01). During the 30 min of MS-551 infusion, arrhythmias occurred in three out of seven dogs (torsades de pointes (TdP) type VT in one dog). After these arrhythmias disappeared, MS-551 decreased the latent interval of the adrenaline arrhythmias produced by the inducing dose (30+/-2 s compared with 43+/-3 s of the control interval, P < 0.05), increased the arrhythmic ratio (P<0.05) and induced arrhythmias by non-inducing adrenaline doses (P<0.05). Effect of a new class III drug KCB-328 infusion, 0.3 mg/kg/30 min, was compared witih MS-551 using the same model. KCB-328 decreased the HR by 21% (P<0.01) and prolonged the QTc interval by 25% (P<0.01). During the 30 min of infusion, arrhythmias occurred in five out of seven dogs (TdP in two dogs). KCB-328 also decreased the latent interval of the adrenaline arrhythmias produced by the inducing doses (31+/-3 s compared with 49+/-7 s of the control period, P<0.05), but did not significantly alter the arrhythmic ratio. Adrenaline induced TdP only after MS-551 or KCB-328 was administered, i.e. after MS-551, 1 mg/kg/30 min, 3/7 versus 0/7 in the control; KCB, 0.3 mg/kg/30 min, 3/7 versus 0/7 in the control. To examine the direct arrhythmogenic effect of MS-551 and whether an adrenergic mechanism plays some role on this arrhythmogenesis, a bolus injection of MS-551, 3 mg/kg, was injected either without pre-treatment or after pre-treatment with propranolol 0.3 mg/kg. MS-551 induced arrhythmias in five out of seven dogs (TdP in one dog). Also in the propranolol pre-treated dogs, MS-551 induced arrhythmias in five out of seven dogs (TdP in 1 dog). In conclusion, these observations indi

Topics: Adrenergic alpha-Agonists; Adrenergic beta-Antagonists; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Dogs; Electrocardiography; Epinephrine; Female; Heart Rate; Hemodynamics; In Vitro Techniques; Male; Phenethylamines; Propranolol; Pyrimidinones; Sulfonamides

The effects of the new inotropic agent, SDZ 218-135 [(+)-(S)-4-[3-(4-diphenyl-methyl-1-piperazinyl)-2-hydroxy-propyl]- 6-(2-hydroxyethyl)-5-methyl-1,2,4-triazolo-[1,5-a]pyrimidin-7(4H)-one], were investigated using in vitro and in vivo techniques. In isolated rat atria, SDZ 218-135 elicited a dose-dependent increase in contractile force (+50% at 10 microM), which was paralleled by an increase in functional refractory period. In anesthetized rats SDZ 218-135 enhanced left ventricular (+)dP/dtmax by 100% at 10 mg/kg without influencing heart rate, arterial blood pressure, and cardiac output. In contrast to its predecessor, DPI 201-106, cardiac relaxation remained essentially unimpaired. The positive inotropic action was also maintained in a rabbit model of depressed heart function after myocardial infarction, where SDZ 218-135 increased peak acceleration of blood in the aorta. The prolongation of the effective refractory period in rat atria suggested possible antiarrhythmic effects. Indeed, SDZ 218-135 showed a dose-dependent marked reduction in reperfusion arrhythmias after coronary artery occlusion in rats. This effect was most likely due to a Class III action, since SDZ 218-135 significantly increased action potential duration (+10% at 10 microM/l) of the isolated guinea pig papillary muscle. In conclusion, SDZ 218-135 is a novel positive inotropic agent with an interesting profile of action. It does not impair cardiac relaxation and shows antiarrhythmic effects in a model of reperfusion-induced arrhythmias. The in vivo and in vitro data are consistent with a mechanism of action via sodium channel agonism.

Topics: Adenosine Triphosphate; Anesthesia; Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Disease Models, Animal; Electrophysiology; Female; Guinea Pigs; Heart Atria; Hemodynamics; Isometric Contraction; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Ovum; Papillary Muscles; Phosphodiesterase Inhibitors; Piperazines; Potassium; Propranolol; Pyrimidinones; Rabbits; Rats; Rats, Wistar; Sodium-Potassium-Exchanging ATPase; Triazoles

The antiarrhythmic effectiveness of a new class I agent, SC-36602, was evaluated in two canine models of ventricular arrhythmia. In a Harris coronary ligation-induced arrhythmia model, SC-36602 significantly reduced ectopic rate at doses of 8 mg/kg i.v. and 15, 20 and 30 mg/kg per os. In a ouabain-induced arrhythmia model, a 9 mg/kg i.v. dose of SC-36602 had a sustained (greater than or equal to 60 min) antiarrhythmic effect. The approximate plasma concentration of SC-36602 necessary for measurable antiarrhythmic activity was estimated to be 2-7 micrograms/ml after either i.v. or oral administration. No adverse cardiovascular or central nervous system effects were observed in conscious or anesthetized dogs in response to SC-36602.

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Glucose; Dogs; Electrocardiography; Female; Injections, Intravenous; Male; Ouabain; Potassium; Pyrimidinones; Time Factors

A series of 4,4-disubstituted tetrahydro- and 4,4-disubstituted hexahydro-3H-pyrido[1,2-c]pyrimidin-3-ones (4 and 5, respectively) were prepared from 2-aryl-2-(2-piperidinyl)-4-[N,N-bis (1-methylethyl)amino] butanamides (2). Individual racemates of the piperidinyl amides 2 were converted to pure racemic diaza bicyclic compounds that were evaluated for antiarrhythmic activity in the Harris dog model and anticholinergic activity in a muscarinic receptor binding assay. Selected compounds were subsequently evaluated for hemodynamic effects in anesthetized dogs where blood pressure depression and negative inotropic activity were assessed. Of this group, 4a (R = CH3) and 5a (R = CH3) showed the most favorable pharmacological profiles; the former compound was chosen for toxicity testing over the latter due to its lack of noncompetitive inhibition of acetylcholine-induced contractions of guinea pig ileum segments. Clinical evaluation is now under way.

Topics: Animals; Arrhythmias, Cardiac; Blood Pressure; Brain; Chemical Phenomena; Chemistry; Depression, Chemical; Disease Models, Animal; Dogs; Female; Guinea Pigs; Heart; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Pyridines; Pyrimidinones; Quinuclidinyl Benzilate; Rats; Receptors, Muscarinic; X-Ray Diffraction