pyrimidinones and Tachycardia

Noonan syndrome (NS) is a multisystemic disorder caused by germline mutations in the Ras/MAPK cascade, causing a broad spectrum of phenotypical abnormalities, including abnormal facies, developmental delay, bleeding diathesis, congenital heart disease (mainly pulmonary stenosis and hypertrophic cardiomyopathy), lymphatic disorders, and uro-genital abnormalities. Multifocal atrial tachycardia has been associated with NS, where it may occur independently of hypertrophic cardiomyopathy. Trametinib, a highly selective MEK1/2 inhibitor currently approved for the treatment of cancer, has been shown to reverse left ventricular hypertrophy in two RIT1-mutated newborns with NS and severe hypertrophic cardiomyopathy. Severe lymphatic abnormalities may contribute to decreased pulmonary compliance in NS, and pulmonary lymphangiectasias should be included in the differential diagnosis of a newborn requiring prolonged oxygen administration. Herein we report the case of a pre-term newborn who was admitted to our unit for the occurrence of severe respiratory distress and subentrant MAT treated with trametinib.

Topics: Cardiomyopathy, Hypertrophic; Humans; Infant, Newborn; Mutation; Noonan Syndrome; Oxygen; Pyridones; Pyrimidinones; ras Proteins; Tachycardia

Topics: Female; Humans; Infant, Newborn; MAP Kinase Kinase 1; MAP Kinase Kinase 2; Noonan Syndrome; Point Mutation; Proto-Oncogene Proteins c-raf; Pyridones; Pyrimidinones; Tachycardia

Agents with α-2 adrenoreceptor (AR) agonistic action have reportedly suppressed tachyarrhythmias..  We hypothesized that α-2 AR agonists would have an inhibitory effect on abnormal repolarization-related ventricular tachyarrhythmias (VTs). To test this hypothesis, the effects of 2 clinically available α-2 AR agonists (dexmedetomidine and clonidine) on the occurrence of VTs were assessed in a methoxamine-sensitized rabbit model of acquired long QT syndrome (Study 1: n=45). In control rabbits, administration of methoxamine and nifekalant almost invariably caused VTs (14/15). In contrast, incidence of VT significantly decreased during the treatment with dexmedetomidine (1μg·kg(-1)·min(-1): 5/12 [P<0.01 vs. control]) or with clonidine (33.3μg·kg(-1)·min(-1): 10/18 [P<0.01]). To verify that VTs in this animal model are triggered by early afterdepolarization (EAD), the monophasic action potential on the left ventricular surface was recorded in 28 open-chest rabbits (Study 2). EAD-like hump was less frequently detected during treatment with clonidine or dexmedetomidine (2/14) than in saline-treated rabbits (9/10, P<0.005). Presence of a hump was significantly related to the advent of VTs (P<0.05)..  Agents with α-2 AR agonistic action have an inhibitory effect on VTs in a rabbit model of long QT syndrome. Alpha-2 AR agonists, especially dexmedetomidine, may be a therapeutic choice for abnormal repolarization-related VTs that are resistant to conventional treatment. 

Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic alpha-2 Receptor Agonists; Animals; Anti-Arrhythmia Agents; Clonidine; Dexmedetomidine; Disease Models, Animal; Heart Conduction System; Humans; Long QT Syndrome; Methoxamine; Pyrimidinones; Rabbits; Tachycardia

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Bradycardia; Drug Combinations; Dyspnea; Electrocardiography; Female; HIV Protease Inhibitors; Humans; Lopinavir; Middle Aged; Pyrimidinones; Ritonavir; Syndrome; Tachycardia

Nifekalant is a class III antiarrhythmic drug, which prolongs the refractory period of the atrial and ventricular myocardium, without negative inotropic action. Intravenous nifekalant was administered in four patients with atrial tachyarrhythmia and severe heart failure to terminate or prevent atrial tachyarrhythmia.. Two of three episodes of atrial tachyarrhythmia were terminated by intravenous nifekalant (0.22 to 0.30 mg/kg) administration. Continuous intravenous infusion of nifekalant (0.15 to 0.40 mg/kg/hr) during six episodes to maintain the sinus rhythm, prevented recurrence of atrial tachyarrhythmia in five episodes in which prolongation of the QTc interval was observed to more than 450 msec. None of the patients showed worsening of the hemodynamics during treatment. One patient developed polymorphic ventricular tachycardia, which deteriorated into ventricular fibrillation.. Nifekalant may be effective for treating atrial tachyarrhythmia in patients with severe heart failure. Further clinical studies are needed to confirm these findings.

Topics: Adult; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Flutter; Female; Heart Failure; Humans; Infusions, Intravenous; Male; Middle Aged; Pyrimidinones; Tachycardia

Nifekalant hydrocholoride, a novel class III antiarrhythmic agent, was used as the treatment in 4 patients with extensive anterior infarction and severe ventricular dysfunction. The malignant ventricular tachyarrhythmia was effectively suppressed at a relatively low dose, without compromising the hemodynamics, indicating that this potent K+ channel blocker has therapeutic potential for acute myocardial infarction.

Topics: Aged; Anti-Arrhythmia Agents; Electrocardiography; Hemodynamics; Humans; Male; Middle Aged; Myocardial Infarction; Potassium Channel Blockers; Pyrimidinones; Tachycardia; Ventricular Dysfunction

To investigate the clinical effects of MS-551, a Class III antiarrhythmic agent, 11 patients underwent electrophysiological study. MS-551 was given intravenously as an initial dose of 0.2 or 0.3 mg/kg for 5 minutes followed by the continuous infusion at 0.2 or 0.3 mg/kg for 30 minutes, respectively, in all patients. The rate corrected QT interval increased significantly from 3 minutes after the beginning of MS-551 infusion. The sinus heart rate decreased significantly by 8% at 10 minutes after the drug administration (P < 0.025). Mean PR and QRS intervals, and blood pressure were not significantly affected by the drug. Mean PA, AH, and HV intervals during sinus rhythm were also not affected. The effective refractory periods (ERPs) of the atrium and ventricle were significantly prolonged by 13% from 202 +/- 24 ms to 231 +/- 26 ms (P < 0.0005), and by 7% from 238 +/- 11 ms to 257 +/- 13 ms (P < 0.002), respectively, by MS-551. The ERP of the atrioventricular node and sinoatrial nodal recovery time were not changed significantly by the drug. This is a report of the effects of MS-551 in humans. This agent could be useful for treatment of tachyarrhythmias by prolongation of ERPs of the atrium and ventricle without significant variations of blood pressure and intracardiac conduction times. It is noteworthy that MS-551 slightly but significantly decreased heart rate.

Topics: Aged; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrioventricular Node; Blood Pressure; Bundle of His; Electrocardiography; Electrophysiology; Female; Heart Atria; Heart Rate; Heart Ventricles; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Middle Aged; Pyrimidinones; Refractory Period, Electrophysiological; Sinoatrial Node; Tachycardia

The antiarrhythmic effects of MS-551, which prolongs cardiac action potential duration without affecting the maximum upstroke velocity of the action potential, were assessed in three different canine ventricular arrhythmia models: 1) ventricular tachycardia (VT) induced by electrical stimuli 3-5 days after myocardial infarction, 2) spontaneous ventricular tachyarrhythmias 24-48 hr after two-stage coronary ligation and 3) ventricular tachyarrhythmias induced by digitalis. Intravenous administration of MS-551 (0.1-1 mg/kg) decreased the susceptibility in 10 dogs out of 13 to VT or ventricular fibrillation evoked by programmed electrical stimulation (PES) delivered to the ventricular septum 3-5 days after myocardial infarction. Oral administration of MS-551 (3 mg/kg) also decreased the susceptibility to VT evoked by PES in 7 out of 10 conscious postinfarction dogs. Concurrently, intravenous (0.1-1 mg/kg) or oral (3 mg/kg) administration of MS-551 produced increases in the ventricular effective refractory periods (ERP) by 7 +/- 1% - 17 +/- 3% or 13 +/- 2%, respectively. Similarly, d-sotalol (0.3-3 mg/kg, i.v. and 10 mg/kg, p.o.) decreased the susceptibility to VT with increased ERP. However, MS-551 (1 and 10 mg/kg, i.v.) failed to inhibit both canine two-stage coronary ligation arrhythmia and digitalis arrhythmia. These results suggest that MS-551 is a pure class III antiarrhythmic drug which may be effective in the treatment of life-threatening reentrant tachyarrhythmias, but not in automaticity arrhythmias.

Topics: Administration, Oral; Animals; Anti-Arrhythmia Agents; Digitalis Glycosides; Disease Models, Animal; Dogs; Electric Stimulation; Electrocardiography; Female; Heart Rate; Injections, Intravenous; Male; Pyrimidinones; Tachycardia