benzofurans and Heart-Defects--Congenital

The majority of sudden cardiac deaths in children occur in patients with prior arrhythmias and an abnormal heart. Amiodarone was given to 39 young patients (35 with an abnormal heart) with arrhythmias unresponsive to conventional treatment. Their age ranged from 6 weeks to 30 years with nine patients younger than 2 years of age. Atrial flutter was present in 16 patients, ventricular tachycardia in 14 patients and supraventricular tachycardia in 9 patients. The most common diagnosis (14 patients) was postoperative repair of congenital heart disease. The dose ranged from 2.5 to 21.6 mg/kg per day (mean 8.2). Elimination of arrhythmia (on 24 hour electrocardiography) occurred in 15 of 16 patients with atrial flutter, 11 of 14 with ventricular tachycardia and 5 of 9 with supraventricular tachycardia. Symptomatic side effects were: rash (three patients), headache (two patients), nausea (one patient) and peripheral neuropathy (one patient); seven patients had asymptomatic corneal microdeposits which normalized in all after the drug was discontinued. No side effects occurred in patients younger than 10 years of age. The following changed with treatment (p less than 0.05): heart rate decreased (three patients with atrial flutter and sick sinus syndrome required pacemaker implantation for bradycardia) and QTc increased; thyroxine (T4) and serum reverse triiodothyronine (T3) increased. During follow-up study (range 6 months to 3 years), 21 of the 39 patients continued to take amiodarone with complete control of arrhythmias, 9 were no longer taking the drug and 9 died (7 nonsudden and 2 sudden deaths). Amiodarone is an extremely effective treatment for infants and children with tachyarrhythmias resistant to conventional treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adolescent; Adult; Amiodarone; Atrial Flutter; Benzofurans; Child; Child, Preschool; Clinical Trials as Topic; Echocardiography; Electrocardiography; Heart Defects, Congenital; Humans; Infant; Tachycardia; Thyroid Gland

In mammals, the toxicity of halogenated aromatic hydrocarbons (HAH) correlates with their ability to activate the aryl hydrocarbon receptor (AHR). To test this correlation in an avian model, we selected six HAHs based on their affinity for the mammalian AHR, including: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD); 1,2,3,7,8-pentachlorodibenzo-p-dioxin (PCDD); 2,3,7,8-tetrachlorodibenzofuran (TCDF); 2,3,4,7,8-pentachlorodibenzofuran (PCDF); 3,3',4,4'-tetrachlorobiphenyl (PCB 77); and 2,2',4,4',5,5'-hexachlorobiphenyl (PCB 153). We determined the ability of these compounds to induce cardiotoxicity, as measured by an increase in heart wet weight on incubation day 10 in the chick embryo (Gallus gallus) and formation of the avian AHR/ARNT/DNA binding complex in chicken hepatoma cells. Relative potency values (RPs) were calculated by dividing the TCDD EC(50) (AHR/ARNT/DNA binding) or ED(50) (15% increase in day-10 heart wet weight) by the HAH congeners EC(50) or ED(50), respectively. The rank order of potencies for inducing cardiotoxicity were TCDD > PCDD = PCDF = TCDF > PCDF > PCB77, PCB 153, no effect. The RP values for inducing AHR/ARNT DNA binding were then correlated with those for inducing cardiotoxicity (the RP values of PCDD were determined to be statistical outliers). This correlation was found to be highly significant (r = 0.94, p = 0.017). The ability of PCDD to act as an AHR agonist was verified using luciferase reporter assays and analysis of cytochrome P4501A1 protein levels. These results indicate that the ability of HAHs to activate the avian AHR signaling pathway, in general, correlates with their ability to mediate cardiotoxicity in the chick embryo.

Topics: Animals; Benzofurans; Binding Sites; Blotting, Western; Cell Line; Chick Embryo; Cytochrome P-450 CYP1A1; Cytochrome P-450 Enzyme System; DNA; Dose-Response Relationship, Drug; Gene Expression Regulation; Heart; Heart Defects, Congenital; Humans; Immunoenzyme Techniques; Liver; Liver Neoplasms; Luciferases; Morphogenesis; Myocardium; Organ Size; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Receptors, Aryl Hydrocarbon; Statistics as Topic; Transcription Factors; Tumor Cells, Cultured

Topics: Amiodarone; Benzofurans; Child, Preschool; Electrocardiography; Heart Defects, Congenital; Heart Failure; Humans; Male; Tachycardia

The addition of amiodarone to digoxin therapy in nine children caused a sharp increase in digoxin serum concentrations (68% to 800%) in the presence of preserved serum creatinine and BUN concentrations. Digoxin half-life was prolonged. Digoxin accumulation could be attributed in part to the decrease in the renal clearance of digoxin resulting from inhibited tubular secretion of the drug and to the reduction in the distribution volume of digoxin caused by amiodarone. Creatinine clearance was not affected by amiodarone. This interaction appears to be more acute in children than in adults, presumably because of the more important role of the renal tubular secretion of digoxin in children. Whenever digoxin and amiodarone therapy are combined, the digoxin serum concentration should be monitored carefully, with appropriate reduction of the digoxin dose.

Topics: Adolescent; Amiodarone; Benzofurans; Cardiomyopathy, Dilated; Child; Child, Preschool; Creatinine; Digoxin; Drug Interactions; Heart Defects, Congenital; Heart Diseases; Humans; Infant; Male; Prospective Studies

Our use of amiodarone in 200 patients during an 8-year period confirms our previous experience which indicated that the drug was close to being the ideal antiarrhythmic agent in children's arrhythmias. Its absence of cardiac toxicity, its powerful antiarrhythmic properties, its depressive effect on the AV nodal conduction, combined with its beta-inhibitory effect makes it effective and harmless in practically all forms of atrial, junctional and ventricular arrhythmias, whatever the reentrant or automatic mechanism of the arrhythmia. The metabolism is much faster in children than in adults, making the drug active in a few hours, with a lesser prolonged duration of action. Though there is practically no limitation for its use on a short- or mean-term basis, the long-term use must be limited to truly refractory arrhythmias, a situation which is rarely encountered. In such cases, combining amiodarone with conventional therapy allows a decrease in the maintenance dosage and a lower incidence of extracardiac side effects.

Topics: Amiodarone; Arrhythmias, Cardiac; Atrial Fibrillation; Atrial Flutter; Benzofurans; Bundle-Branch Block; Child; Electrocardiography; Heart Conduction System; Heart Defects, Congenital; Heart Valve Diseases; Heart Ventricles; Humans; Infant; Tachycardia