benzofurans and Bradycardia

Amiodarone, an investigational drug in the United States, has had considerable use in this country and worldwide in the treatment of cardiac arrhythmias. This article reviews the clinical pharmacology of this potentially useful antiarrhythmic agent.

Topics: Amiodarone; Animals; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Atrial Fibrillation; Autonomic Nervous System; Benzofurans; Bradycardia; Drug Interactions; Eye; Heart Conduction System; Heart Ventricles; Hemodynamics; Humans; Injections, Intravenous; Kinetics; Liver; Lung; Skin; Tachycardia; Thyroid Gland

Topics: Aged; Amiodarone; Benzofurans; Bradycardia; Clinical Trials as Topic; Female; Humans; Male; Middle Aged; Syndrome; Tachycardia

Topics: Aged; Benzofurans; Bradycardia; Clinical Trials as Topic; Drug Combinations; Electrocardiography; Female; Humans; Hypokalemia; Isoproterenol; Male; Monitoring, Physiologic; Oxazines; Pacemaker, Artificial; Potassium Chloride; Prenylamine; Prognosis; Quinidine; Syncope; Tachycardia; Ventricular Fibrillation

The aim of the current study was to determine the central cyclooxygenase (COX) pathway and central thromboxane signaling in the cardiovascular effects evoked by arachidonic acid (AA). As a main control for the study, different doses of AA (75, 150, or 300 µg) were administered intracerebroventricularly (i.c.v.). Centrally injected AA dose- and time-dependently increased mean arterial pressure and decreased heart rate in conscious normotensive Sprague-Dawley rats. The maximal cardiovascular effects of AA were observed at min 10 of the injection and lasted almost 30 min. To investigate the central mechanism of the AA-induced cardiovascular effect in conscious normotensive animals, pretreatment with nonselective COX inhibitor indomethacin (200 µg; i.c.v.), thromboxane A2 (TXA2) synthesis inhibitor furegrelate (250 or 500 µg; i.c.v.), or TXA2 receptor antagonist SQ-29548 (8 or 16 µg; i.c.v.) was carried out 15 min before AA (150 µg; i.c.v.) injection. While indomethacin completely prevented the pressor and bradycardic responses to AA, furegrelate and SQ-29548 attenuated these effects in part in awake normotensive rats. In conclusion, these findings suggest that the pressor and bradycardic cardiovascular effects of centrally injected AA are dependent on COX activity being totally central and the TXA2 signaling pathway being subsequently central, at least in part.

Topics: Animals; Arachidonic Acid; Benzofurans; Blood Pressure; Bradycardia; Bridged Bicyclo Compounds, Heterocyclic; Cardiovascular System; Fatty Acids, Unsaturated; Heart Rate; Hydrazines; Indomethacin; Infusions, Intraventricular; Male; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane A2, Prostaglandin H2; Signal Transduction; Thromboxane A2

The antimuscarinic profile of the experimental drug solifenacin/YM905 [(+)-(1 S,3' R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate] for the treatment of overactive bladder was compared with the commonly prescribed agent oxybutynin. In radioligand binding assays, p K(i) values of solifenacin for M(1), M(2), and M(3) receptors were 7.6, 6.9, and 8.0, respectively. These values for oxybutynin were 8.6 (M(1)), 7.7 (M(2)), and 8.9 (M(3)). Solifenacin and oxybutynin antagonized the contractile effect of carbachol (CCh) on isolated guinea pig urinary bladder smooth muscle (detrusor), displaying the negative logarithm of antagonist apparent affinity constant (p K(b) value) of 7.1 for solifenacin and 7.4 for oxybutynin. To study the tissue selectivity between bladders and salivary glands, guinea pig detrusor and mouse submandibular gland cells were stimulated with CCh and monitored for intracellular Ca2+, as determined by Fura 2 fluorescence. Ca2+ mobilization of detrusor cells was inhibited equipotently by solifenacin (p K(i)=8.4) and oxybutynin (p K(i)=8.6), whereas that of the gland cells was antagonized less potently by solifenacin (p K(b)=7.4) than by oxybutynin (p K(b)=8.8), although the M(3) subtype mediated both cell responses. In anesthetized rats, solifenacin (63-2100 nmol kg(-1) or 0.03-1 mg kg(-1)) dose-dependently inhibited CCh-stimulated increases in urinary bladder pressure, while its inhibitory effects on salivation and bradycardia were apparent only at a dose of 2100 nmol kg(-1). In contrast, oxybutynin within a dose range of 77-770 nmol kg(-1) (0.03-0.3 mg kg(-1)) inhibited responses of the bladder and salivary gland slightly more potently than that of the heart. In addition, inhibitory effects of darifenacin indicated a major role of M(3) receptors in the bladder and salivary gland. Therefore, M(3) receptor antagonism by solifenacin could be bladder-selective. This selectivity remains to be elucidated and may provide new approaches to the pharmacotherapy of overactive bladder.

Topics: Animals; Benzofurans; Bradycardia; Calcium; Carbachol; Cells, Cultured; Cytosol; Dose-Response Relationship, Drug; Female; Guinea Pigs; Humans; In Vitro Techniques; Isoquinolines; Kinetics; Male; Mandelic Acids; Mice; Mice, Inbred BALB C; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Pyrrolidines; Quinuclidines; Rats; Receptor, Muscarinic M3; Receptors, Muscarinic; Salivary Glands; Solifenacin Succinate; Tetrahydroisoquinolines; Urinary Bladder

Recently discovered serotonin3 (5-HT3) receptor antagonists are potent antiemetics in cytotoxic drug-induced vomiting. The specific site where 5-HT3 receptor antagonists act to abolish emesis is controversial. The major objective of this study was to determine whether the antiemetic effect of 5-HT3 receptor antagonists is exerted in the brain areas that reside inside or outside of the blood-brain barrier. Tropisetron, zatosetron (LY277359 maleate) and its quaternary analog zatosetron-QUAT were used in this study. Zatosetron and zatosetron-QUAT showed high affinity and selectivity for 5-HT3 receptors in radioligand binding studies. Both compounds antagonized 5-HT-induced bradycardia in rats with an approximate ID50 of 0.7 and 0.2 microgram/kg i.v., respectively. Zatosetron and tropisetron significantly inhibited cisplatin-evoked emesis in dogs (estimated ID50 values of 34.4 +/- 2.3 micrograms/kg and 108.3 +/- 4.8 micrograms/kg i.v., respectively). Zatosetron-QUAT (0.01-1.0 mg/kg i.v.) had no effect. [14C]-zatosetron-QUAT (100 micrograms/kg) was not detected in the brain after i.v. administration to rats, consistent with the inability of charged compounds to achieve significant brain concentrations. However, i.c.v. administration (100 ng/kg) of zatosetron-QUAT reduced emetic episodes significantly (11.6 +/- 1.6 vs. 2.8 +/- 1.2). These studies suggest that, in dogs, antagonism of 5-HT3 receptors located within the blood-brain barrier is important to block cisplatin-induced emesis.

Topics: Animals; Benzofurans; Binding Sites; Blood-Brain Barrier; Bradycardia; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex; Cisplatin; Dogs; In Vitro Techniques; Male; Rats; Rats, Sprague-Dawley; Serotonin Antagonists; Vomiting

The problem of a possible interaction between amiodarone and digoxin is still unsettled. We have recently treated two patients with digoxin intoxication who had received amiodarone for eight and 36 months respectively. Both developed extreme bradycardia requiring temporary pacemakers. The presence of hypothyroidism was confirmed in both cases by laboratory data. Judging by present knowledge concerning the interaction between amiodarone, thyroid function, and digoxin, it is suggested that digoxin intoxication was not the result of its direct interaction with amiodarone. The possibility that amiodarone-induced hypothyroidism precipitated digoxin intoxication seems to be more plausible. Prevention of digitalis toxicity in amiodarone-treated patients would therefore require monitoring of thyroid function every three to six months. Frequent monitoring of digitalis blood levels is also indicated in patients with amiodarone associated hypothyroidism. Early detection of hypothyroidism and digitalis intoxication is necessary in view of the severity of the course of the disease.

Topics: Aged; Amiodarone; Benzofurans; Bradycardia; Digoxin; Drug Interactions; Electrocardiography; Female; Heart Block; Humans; Hypothyroidism; Male

In 23 patients with symptomatic severe supraventricular and ventricular tachyarrhythmias the effectiveness and the side effects of a long-term therapy with the class III antiarrhythmic drug Amiodarone (Cordarone) in a dosage of 100-800 mg/die in monotherapy and combination therapy were investigated. In these cases it proved to be an excellently effecting antiarrhythmic drug in tachycardiac dysrhythmias at atrial and ventricular level with an altogether good tolerance. In 16 patients side effects appeared and above all concerned corneal micro-deposition without any clinical symptoms (10 patients). In 3 patients nuclear-medically insignificant changes of the function of the thyroid gland were found--also without clinical relevance. Three times a photosensitisation was conspicuous, only in one patient the therapy was finished on account of epigastric trouble after three months. Av-blockings of higher degree, particularly with bundle-branch block and severe sinus bradycardias as well as disturbances of the thyroid function are regarded as contraindications without preceding pacemaker implantation.

Topics: Adult; Amiodarone; Anti-Arrhythmia Agents; Benzofurans; Bradycardia; Drug Therapy, Combination; Electrocardiography; Female; Humans; Male; Middle Aged; Tachycardia; Thyroid Gland; Thyroxine; Triiodothyronine

Two recent reports support and one report disputes the existence of dangerous interactions between the new benzofuran antiarrhythmic amiodarone and the anaesthetic state. We have reviewed our experience with 17 anaesthetics administered to 16 patients taking amiodarone. Haemodynamics and serum amiodarone levels were evaluated where available. Twelve cases involved cardio-pulmonary bypass; of these, three patients died. There were no deaths in the non-cardio-pulmonary bypass group. The charts of 30 patients with poor left ventricular function, who were not receiving amiodarone but who were undergoing coronary artery bypass surgery, were reviewed to establish a comparison group. Interactions were manifested in three forms: nodal rhythm and/or complete heart block developed in ten of 15 patients (one patient had a preoperative pacemaker inserted for the sick sinus syndrome), poor cardiac output requiring intra-aortic balloon pump augmentation developed in six of 12 cardio-pulmonary bypass patients, or, a state of alpha adrenergic blockade leading to a low systemic vascular resistance despite alpha agonist therapy developed in two of 16 patients. We conclude that dangerous, fatal interactions may occur in patients taking amiodarone who undergo general anaesthesia with cardio-pulmonary bypass. Anaesthesia for non-cardiac surgery may be associated with haemodynamically significant bradyarrhythmias. We recommend aggressive invasive monitoring, including pulmonary artery catheterization and consideration of an atrio-ventricular pacemaker in high risk patients.

Topics: Adult; Aged; Amiodarone; Anesthesia, General; Anesthetics; Atropine; Benzofurans; Bradycardia; Cardiac Output; Drug Interactions; Female; Heart Block; Humans; Male; Middle Aged; Retrospective Studies

Topics: Aged; Amiodarone; Anesthesia, General; Benzofurans; Bradycardia; Coronary Artery Bypass; Heart Block; Humans; Male

Recurrent atypical ventricular tachycardia, with a long QT interval, was documented in a 56-year-old patient 16 days after discontinuing amiodarone 200 mg and 400 mg on alternate days. Tachycardia and variable prolongation of myocardial repolarization were abolished by temporary cardiac pacing and correction of mild hypokalaemia.

Topics: Amiodarone; Benzofurans; Bradycardia; Cardiac Pacing, Artificial; Electrocardiography; Female; Humans; Hypokalemia; Middle Aged; Substance Withdrawal Syndrome; Tachycardia

The efficacy of amiodarone in the prevention of atrial tachycardia is well recognised. However, there remains some controversy over its use in patients with a basal sinus bradycardia because of the risk of further depression of sinus node function. We studied the effects of acute and chronic amiodarone therapy in 13 patients with paroxysmal supraventricular tachycardia and intercritical sinus bradycardias of between 40 and 50/min. All patients underwent electrophysiological investigation under basal conditions and after 5 mg/kg IV amiodarone. Five patients were excluded from chronic oral amiodarone therapy after IV amiodarone for the following reasons : sinus bradycardia of less than 30/min; sinus node recovery times greater than 2 s; 2nd or 3rd degree sino-atrial block. The other 8 patients were administered oral amiodarone on a long term basis. They were followed up clinically with dynamic ECGs every three months over a period of 1 to 3 years. All symptoms regressed in 6 patients. In one patient, the daily attacks of palpitations decreased to one a week. One patient did not improve. No cases of sino-atrial standstill were observed, although the sinus rate remained unchanged. The results of our study show that amiodarone may be administered for long periods in patients with sinus bradycardia and attacks of paroxysmal supraventricular tachycardia if the dynamic ECG during the waking hours shows a heart rate of no less than 40/min, and if electrophysiological investigations do not show significant depression of sinus node function after acute intravenous administration of the drug.

Topics: Adult; Aged; Amiodarone; Benzofurans; Bradycardia; Female; Humans; Male; Middle Aged; Tachycardia, Paroxysmal

Topics: Aged; Amiodarone; Benzofurans; Bradycardia; Female; Humans; Hypotension; Intraoperative Complications

Topics: Adult; Aged; Amiodarone; Benzofurans; Bradycardia; Female; Follow-Up Studies; Humans; Male; Middle Aged; Sinoatrial Node; Syndrome; Tachycardia

Amiodarone, 600 mg orally daily, was used in an attempt to control supraventricular tachyarrhythmias in a patient with the sick sinus syndrome. Twenty days from the onset of therapy the Q-T interval lengthened. Episodes of ventricular flutter, ventricular fibrillation and self-terminating ventricular tachyarrhythmia (torsade de pointes) developed on the 28th day of amiodarone therapy. Temporary cardiac pacing prevented further episodes of ventricular fibrillation. Despite the suggestion that this drug may be given in large doses for long periods of time since it has a wide safety margin, we feel that the risk of lethal arrhythmias is such that caution is required in its use.

Topics: Amiodarone; Benzofurans; Bradycardia; Cardiac Pacing, Artificial; Electric Countershock; Electrocardiography; Female; Humans; Middle Aged; Sick Sinus Syndrome; Tachycardia; Ventricular Fibrillation

Topics: Aged; Amiodarone; Benzofurans; Bradycardia; Female; Heart Rate; Humans; Tachycardia, Paroxysmal; Wolff-Parkinson-White Syndrome

Topics: Amiodarone; Benzofurans; Bradycardia; Humans; Tachycardia

Five patients with the bradycardia-tachycardia syndrome have been treated successfully with the antiarrhythmic agent amiodarone. Three patients were treated for over nine months and one of these patients had corneal micro deposits. One patient had to be taken off the drug because of side effects. Amiodarone should be tried in patients suffering from the bradycardia-tachycardia syndrome before resorting to cardiac pacing.

Topics: Aged; Amiodarone; Benzofurans; Bradycardia; Corneal Diseases; Female; Humans; Male; Middle Aged; Syndrome; Tachycardia

Topics: Aged; Amiodarone; Benzofurans; Bradycardia; Electrocardiography; Exercise Test; Humans; Male; Middle Aged; Tachycardia

Topics: Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Bradycardia; Depression, Chemical; Heart Rate; Iodine Isotopes; Male; Rabbits; Rats; Thyroid Gland; Thyroidectomy