benzofurans and Cardiomyopathies

Rayless goldenrod (Isocoma pluriflora) sporadically poisons horses and other livestock in the southwestern United States. Similar to livestock poisoning by white snakeroot (Ageratina altissima) in the midwestern United States, previous research suggests that benzofuran ketones (BFK: tremetone, dehydrotremetone, 6-hydroxytremetone, and 3-oxyangeloyl-tremetone) are responsible for the toxicity of rayless goldenrod. However, experimental reproduction of rayless goldenrod-induced disease and detailed descriptions of poisoning in horses with known concentrations of tremetone and other BFK has not been documented. In this study four horses were fed increasing amounts of rayless goldenrod to obtain doses of approximately 0, 10, 30, and 60 mg BFK/kg BW for 14 days. After seven days of dosing the horse dosed with 60 mg BFK/kg BW horse developed depression, reluctance to eat, dehydration, trembling, and muscle fatigue. Biochemical alterations including increases in the serum enzyme activities of CK, AST, ALT, and LDH, and increased cardiac troponin I concentration, were also identified. Physiologically the clinically poisoned horse had decreased endurance seen as reluctance to perform on the treadmill with increased resting heart rate and a prolonged recovery of heart rate following treadmill exercise. The condition of the horse continued to decline and it was euthanized and necropsied on day 10. At necropsy the myocardium was pale and soft and many of the appendicular and large apical muscles were pale and moist. Histologically, the myocardium had extensive myocardial degeneration and necrosis with extensive fibrosis and multifocal mineralization. Several of the large appendicular muscles in this horse also had small foci of skeletal muscle degeneration and necrosis. Less severe myocardial changes were also identified in the horse dosed with 30 mg BFK/kg BW after 14 days of dosing. No clinical, biochemical or histologic changes were identified in the control horse and the horse dosed with 10 mg BFK/kg BW. These results suggest that doses of 60 mg BFK/kg BW for seven days produce extensive myocardial lesions in horses. The horse dosed with 30 mg BFK/kg BW developed less severe, but similar myocardial lesions over a longer duration, this suggests that poisoning may be cumulative and lower doses of longer duration are also toxic. Horses seem to be uniquely sensitive to rayless goldenrod-induced myocardial disease, therefore cardiac troponin I may be a useful marker o

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Asteraceae; Benzofurans; Cardiomyopathies; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Histological Techniques; Horses; Ketones; Plant Poisoning; Southwestern United States; Troponin I

The human amyloid disorders, familial amyloid polyneuropathy, familial amyloid cardiomyopathy and senile systemic amyloidosis, are caused by insoluble transthyretin (TTR) fibrils, which deposit in the peripheral nerves and heart tissue. Several nonsteroidal anti-inflammatory drugs and structurally similar compounds have been found to strongly inhibit the formation of TTR amyloid fibrils in vitro. These include flufenamic acid, diclofenac, flurbiprofen, and resveratrol. Crystal structures of the protein-drug complexes have been determined to allow detailed analyses of the protein-drug interactions that stabilize the native tetrameric conformation of TTR and inhibit the formation of amyloidogenic TTR. Using a structure-based drug design approach ortho-trifluormethylphenyl anthranilic acid and N-(meta-trifluoromethylphenyl) phenoxazine 4, 6-dicarboxylic acid have been discovered to be very potent and specific TTR fibril formation inhibitors. This research provides a rationale for a chemotherapeutic approach for the treatment of TTR-associated amyloid diseases.

Topics: Amino Acid Sequence; Amyloid Neuropathies; Anti-Inflammatory Agents, Non-Steroidal; Benzofurans; Binding Sites; Cardiomyopathies; Crystallography, X-Ray; Dicarboxylic Acids; Diclofenac; Drug Design; Flurbiprofen; Humans; Hydrogen Bonding; Models, Molecular; Molecular Sequence Data; ortho-Aminobenzoates; Oxazines; Prealbumin; Protein Structure, Quaternary; Resveratrol; Stilbenes; Structure-Activity Relationship; Thermodynamics

Topics: Adult; Amiodarone; Arrhythmias, Cardiac; Benzofurans; Cardiomyopathies; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Child; Female; Humans; Male; Middle Aged

In this experimental work we evaluated the effect of preventively administered Cordarone on the myocardial damage of rats, caused by isoproterenol. Cordarone had prevented the early mortality of rats up to 1 h, however, after the administration of high doses of Cordarone the late mortality of experimental animals was increased. In the group of rats, which were treated by Cordarone there were almost no small necroses of myocardium, which were, however, contrary--very often found in the control animals. We guess that this effect of Cordarone is caused by its influence on the heart rate, which is slowing down, by its antiarrhythmic effect and by its efficiency to improve the perfusion of myocardium by its power to decrease the resistance of coronary vessels.

Topics: Amiodarone; Animals; Benzofurans; Cardiomyopathies; Isoproterenol; Male; Necrosis; Rats; Rats, Inbred Strains

We observed sinoatrial block due to chronic amiodarone administration in a 5-year-old boy with primary cardiomyopathy, Wolff-Parkinson-White syndrome and supraventricular tachycardia. Reduction in the dosage of amiodarone resulted in the disappearance of the sinoatrial block and the persistence of asymptomatic sinus bradycardia.

Topics: Amiodarone; Benzofurans; Cardiomyopathies; Child, Preschool; Dose-Response Relationship, Drug; Electrocardiography; Heart Block; Humans; Male; Sinoatrial Block

Previous studies have shown that amiodarone prevents sustained ventricular arrhythmias in 77% to 93% of patients. To date, a study using statistical analysis to verify the drug's effectiveness has not been reported. Amiodarone was given to 17 patients with drug refractory sustained ventricular arrhythmias. All patients had serious underlying heart disease including coronary artery disease (15 patients) or cardiomyopathy (two patients). Ten patients had angiographic evidence of a left ventricular aneurysm. All patients had left ventricular dysfunction. The mean left ventricular ejection fraction was 33%. In the 5.5 +/- 8.3 months prior to amiodarone, these 17 patients had documented sustained ventricular arrhythmias requiring countershock (41 episodes), overdrive pacing (four episodes), or intravenous drugs (three episodes). Amiodarone was given as a loading dose (1 gm/day for 10 days) and a maintenance dose (200 to 600 mg/day). During a follow-up period of 8.9 +/- 5.7 months, only eight episodes occurred requiring countershock (5) or overdrive pacing (2); one patient died suddenly. A statistical test constructed for this problem showed a significant (p greater than 0.001) reduced risk of experiencing a sustained ventricular arrhythmia after amiodarone. This statistical model confirms previous studies showing that amiodarone prevents sustained ventricular arrhythmias and prevents sudden cardiac death.

Topics: Aged; Amiodarone; Anti-Arrhythmia Agents; Benzofurans; Cardiomyopathies; Coronary Disease; Drug Resistance; Female; Follow-Up Studies; Heart Aneurysm; Heart Ventricles; Humans; Male; Middle Aged; Myocardial Infarction; Tachycardia; Ventricular Fibrillation

This paper is concerned with the effects of Lorcainide (LCN) and Amiodarone (AMD) on stress-induced myocardial lesions in rats. Forty rats were used. The first group (G-1) was used as a control (n = 10) and animals were injected with saline. Animals in group 2 (G-2) (n = 15) received AMD 10 mg per kilogram, and animals in group 3 (G-3) (n = 15) received LCN 3 mg per kilogram. During five minutes before the injections, the rats were submitted to a stress, consisting of intermittent cold water jets (6 degrees C). Animals were sacrificed one hour after injection, and the hearts were histologically studied. The relative areas of necrotic myocardium were assessed by Bertazzoli's modified method. In G-1, myocytolysis in the subendocardium of left ventricle (score: 2.2 +/- 0.79), contraction bands (1.2 +/- 1.03) and subendocardial myocardial damage (0.8) were common findings. In groups G-2 and G-3, the lesions described were found, but to a lesser degree; subendocardial myocytolysis: 1.6 +/- 0.63 and 1.07 +/- 0.4; contraction bands: 0.67 +/- 0.82 and 0.07 +/- 0.26; and subendocardial damage: 0.77 and 0.40. LCN and AMD markedly decreased stress-induced myocytolysis (p less than 0.01) (graph 1), but LCN was more effective than AMD (p less than 0.05). Comparison of severity and extension of contraction bands showed that only LCN had a significant effect (p less than 0.01) (graph 2); the same was observed as regards the decrease of damaged zones (p less than 0.05). From our data, LCN and AMD appears to have the capacity of reversing some of the stress-induced myocardial damage in rats.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Benzeneacetamides; Benzofurans; Cardiomyopathies; Female; Male; Myocardium; Necrosis; Piperidines; Rats; Rats, Inbred Strains; Stress, Physiological

Topics: Adult; Amiodarone; Arrhythmias, Cardiac; Atrial Fibrillation; Benzofurans; Cardiomyopathies; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Mitral Valve; Quinidine

Topics: Benzofurans; Cardiomyopathies; Disease; Electrocardiography; Furans; Heart Diseases; Hypoxia; Myocardium; Vasodilator Agents