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At least 19 recordsLinked to original sources

PubMed1999

Amiodarone interaction with beta-blockers: analysis of the merged EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) databases. The EMIAT and CAMIAT Investigators.

BACKGROUND: Investigations with in vitro and animal models suggest an interaction between amiodarone and beta-blockers. The objective of this work was to explore if an interaction with beta-blocker treatment plays a role in the decrease of cardiac arrhythmic deaths with amiodarone in patients recovered from an acute myocardial infarction. METHODS AND RESULTS: A pooled database from 2 similar randomized clinical trials, the European Amiodarone Myocardial Infarction Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was used. Four groups of post-myocardial infarction patients were defined: beta-blockers and amiodarone used, beta-blockers used alone, amiodarone used alone, and neither used. All analyses were done on an intention-to-treat basis. Unadjusted and adjusted relative risks for all-cause mortality, cardiac death, arrhythmic cardiac death, nonarrhythmic cardiac death, arrhythmic death, or resuscitated cardiac arrest were lower for patients receiving beta-blockers and amiodarone than for those without beta-blockers, with or without amiodarone. The interaction was statistically significant for cardiac death and arrhythmic death or resuscitated cardiac arrest (P=0.05 and 0.03, respectively). Findings were consistent across subgroups. CONCLUSIONS: These findings are based on a post hoc analysis. However, they confirm prior results from in vitro and animal experiments suggesting an interaction between beta-blockers and amiodarone. In practice, not only is the adjunct of amiodarone to beta-blockers not hazardous, but beta-blocker therapy should be continued if possible in patients in whom amiodarone is indicated.

Adrenergic beta-Antagonists↗

PubMed2006

Prospective randomized study comparing amiodarone vs. amiodarone plus losartan vs. amiodarone plus perindopril for the prevention of atrial fibrillation recurrence in patients with lone paroxysmal atrial fibrillation.

AIMS: The purpose of this trial was to compare the long-term efficacy of low-dose amiodarone with losartan and perindopril (both combined with low-dose amiodarone) for the prevention of atrial fibrillation (AF) recurrence in patients with lone paroxysmal AF. METHODS AND RESULTS: One-hundred and seventy-seven patients with lone paroxysmal AF were randomly assigned to three treatment groups: group 1 received low-dose amiodarone alone, group 2 received low-dose amiodarone plus losartan, and group 3 received low-dose amiodarone plus perindopril. Left atrial diameter was measured with transthoracic echocardiogram at baseline and 6, 12, 18, and 24 months after randomization. The primary endpoint was the incidence of AF documented by 12-lead ECG or Holter after 14 days and within 24 months after randomization. The primary endpoint was reached in 24 patients (41%) in group 1, 11 (19%) in group 2, and 14 (24%) in group 3 (P = 0.02). The Kaplan-Meier survival analysis demonstrated a significant reduction in AF recurrence in group 2 (P = 0.006, log-rank test) as well as in group 3 (P = 0.04, log-rank test) when compared with group 1. No difference in the AF recurrence-free survival was found between group 2 and group 3. After 24 months follow-up, the left atrial diameter in group 2 and group 3 was significantly smaller than that in group 1 (36 +/- 2.3 and 35 +/- 2.4 vs. 38 +/- 2.4 mm, P < 0.001 for both comparisons). CONCLUSION: The results of this study suggest that the combination of perindopril or losartan with low-dose amiodarone is more effective than low-dose amiodarone alone for the prevention of AF recurrence in patients with lone paroxysmal AF. Adding losartan or perindopril to amiodarone can inhibit left atrial enlargement in this group of patients.

Amiodarone↗

PubMedDate not supplied

Role of antiarrhythmic agents after myocardial infarction with special reference to the EMIAT and CAMIAT trials of amiodarone. European Myocardial Infarct Amiodarone Trial. Canadian Amiodarone Myocardial Infarction Trial.

The role of antiarrhythmic agents in the post-MI patients has been investigated for several years. Recently, clinical trials have assessed the effects of amiodarone in the post-MI population. The Basel Antiarrhythmic Study of Infarct Survival (BASIS) trial showed a reduction in total mortality, sudden death, and life-threatening ventricular arrhythmias with amiodarone therapy. The European Myocardial Infarct Amiodarone Trial (EMIAT) did not show a mortality benefit, but amiodarone was associated with fewer antiarrhythmic deaths. The Canadian Amiodarone Myocardial Infarction Trial (CAMIAT) showed no significant impact on mortality, but arrhythmia deaths and resuscitated cardiac deaths were reduced. Amiodarone therapy after MI should be reserved for the treatment of symptomatic or sustained ventricular arrhythmias. The current data do not support routine use of amiodarone in all patients after MI.

Amiodarone↗

PubMed2003

Combined amiodarone and silymarin treatment, but not amiodarone alone, prevents sustained atrial flutter in dogs.

UNLABELLED: Amiodarone/Silymarin Treatment for Sustained Atrial Flutter. INTRODUCTION: Because amiodarone generates free radicals that may mediate amiodarone's toxicity, simultaneous therapy with an antioxidant might be beneficial if the antioxidant did not impair amiodarone's antiarrhythmic action. We tested whether simultaneous administration of a flavonoid antioxidant, silymarin, altered the electrophysiologic (EP) actions of amiodarone in 62 open chest dogs with electrically induced atrial flutter created by a Y-shaped right atrial incision. METHODS AND RESULTS: Fifteen dogs received oral amiodarone (600 mg/day); 15 dogs received amiodarone (600 mg/day) and silymarin (70 mg bid); and 8 dogs received silymarin (70 mg bid) alone. All dosing was for 8 weeks; 24 control dogs received no drugs prior to induction of atrial flutter. Atrial flutter was induced by rapid right atrial pacing, and EP measurements were made before (presurgical) and after (postsurgical) creation of a Y-shaped right atrial incision. There was no difference in the frequency of induction of atrial flutter lasting >30 minutes among amiodarone-treated (8/15 [53%]), silymarin-treated (4/6 [67%]), and control (15/21 [71%]) groups, whereas the frequency of induction in the amiodarone+silymarin dogs (2/15 [13%]) was significantly reduced (P = 0.008) compared with the other three groups. Both amiodarone and amiodarone+silymarin treatment prolonged the presurgical and postsurgical right atrial effective refractory period (P = 0.012) compared with control; however, there was no significant difference in either parameter between the amiodarone+silymarin-treated and amiodarone-treated groups. The increase in atrial flutter mean cycle length (postsurgical minus presurgical) was significantly (P = 0.005) less in the amiodarone+silymarin-treated and control dogs compared with the amiodarone-treated dogs (16 +/- 11 msec for amiodarone+silymarin; 24 +/- 8 msec for control; and 42 +/- 14 msec for amiodarone treatment). Amiodarone+silymarin treatment resulted in a longer postsurgical right atrial refractory period (155 +/- 13 msec) than atrial flutter mean cycle length (154 +/- 19 msec), consistent with reduction and/or elimination of the excitable gap. Silymarin alone did not exert significant EP or antiarrhythmic action. CONCLUSION: Amiodarone exerted no preventative antiarrhythmic action in this atrial flutter model, probably because it could not reduce the excitable gap of atrial flutter. However, an antioxidant, silymarin, without a direct antiarrhythmic action, when administered together with amiodarone, potentiated amiodarone's antiarrhythmic actions and prevented sustained atrial flutter by reduction and/or elimination of the excitable gap.

Amiodarone↗

PubMed2000

Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with amiodarone: a substudy of EMIAT (The European Myocardial Infarct Amiodarone Trial).

OBJECTIVES: This substudy tested a prospective hypothesis that European Myocardial Infarct Amiodarone Trial (EMIAT) patients with depressed heart rate variability (HRV) benefit from amiodarone treatment. BACKGROUND: The EMIAT randomized 1,486 survivors of acute myocardial infarction (MI) aged < or =75 years with left ventricular ejection fraction (LVEF) < or =40% to amiodarone or placebo. Despite a reduction of arrhythmic mortality on amiodarone, all-cause mortality was not changed. METHODS: Heart rate variability was assessed from prerandomization 24-h Holter tapes in 1,216 patients (606 on amiodarone). Two definitions of depressed HRV were used: standard deviation of normal to normal intervals (SDNN) < or =50 ms and HRV index < or =20 units. The survival of patients with depressed HRV was compared in the placebo and amiodarone arms. A retrospective analysis investigated the prospective dichotomy limits. All tests were repeated in five subpopulations: patients with first MI, patients on beta-adrenergic blocking agents, patients with LVEF < or =30%, patients with Holter arrhythmia and patients with baseline heart rate > or =75 beats/min. RESULTS: Centralized Holter processing produced artificially high SDNN but accurate HRV index values. Heart rate variability index was < or =20 U in 363 (29.9%) patients (183 on amiodarone) with all-cause mortality 22.8% on placebo and 17.5% on amiodarone (23.2% reduction, p = 0.24) and cardiac arrhythmic mortality 12.8% on placebo and 4.4% on amiodarone (66% reduction, p = 0.0054). Among patients with prospectively defined depressed HRV, the largest reduction of all-cause mortality was in patients with first MI (placebo 17.9%, amiodarone 10.3%, 42.5% reduction, p = 0.079) and in patients with heart rate < or =75 beats/min (placebo 29.0%, amiodarone 19.3%, 33.7% reduction, p = 0.075). Among patients with first MI and depressed HRV, amiodarone treatment was an independent predictor of survival in a multivariate Cox analysis. The retrospective analysis found a larger reduction of mortality on amiodarone in 313 (25.7%) patients with HRV index < or =19 U: 23.9% on placebo and 17.1% on amiodarone (28.4% reduction, p = 0.15). This was more expressed in patients with first MI: 49.4% mortality reduction on amiodarone (p = 0.046), on beta-blockers: 69.0% reduction (p = 0.047) and with heart rate > or =75 beats/min: 37.9% reduction (p = 0.054). CONCLUSION: Measurement of HRV in a large set of centrally processed Holter recordings is feasible with robust methods of assessment. Patients with LVEF < or =40% and depressed HRV benefit from prophylactic antiarrhythmic treatment with amiodarone. However, this finding needs confirmation in an independent data set before clinical practice is changed.

Aged↗

PubMed1996

The efficacy of intravenous amiodarone for the conversion of chronic atrial fibrillation. Amiodarone vs quinidine for conversion of atrial fibrillation.

BACKGROUND: Chronic atrial fibrillation (CAF) is a serious condition with significant morbidity and mortality. The mainstay of drug therapy for the conversion of atrial fibrillation to sinus rhythm continues to be quinidine. The value and safety of intravenously (i.v.) administered amiodarone therapy vs quinidine sulfate therapy was compared in a cohort of patients with CAF of more than 3 weeks' duration. OBJECTIVES: To evaluate the efficacy of i.v. administered amiodarone and oral quinidine sulfate containing 300 mg of quinidine in the conversion of CAF and to assess the effect of oral amiodarone in the conversion of CAF in the patients in whom CAF did not convert with IV amiodarone. METHODS: Thirty-two patients with CAF of more than 3 weeks' duration were randomized to either i.v. amiodarone treatment or oral digoxin/quinidine treatment in a randomized unblinded single crossover study. The converters continued either oral amiodarone therapy or quinidine extended-action tablet (Quinidex) therapy. RESULTS: Seventeen patients were randomized to the quinidine group and 15 patients to the amiodarone group. Nonconverters from the quinidine group crossed over to the amiodarone group. Amiodarone and quinidine were equally effective at 24 hours in converting CAF (eight [47%] of 17 patients in the quinidine group vs 12 [44%] of 27 patients in the amiodarone group; P, not significant). At 2 and 9 months of oral therapy, amiodarone was superior to quinidine in maintaining sinus rhythm. Only two of eight patients in the quinidine group tolerated the medication. All patients in the amiodarone group tolerated the medication. One additional patient converted to sinus rhythm at 2 months (13 [48%] of 27), and five more patients converted at 9 months (18 [67%] of 27). Amiodarone therapy and digoxin/quinidine therapy were equally effective at 48 hours in controlling ventricular response at rest. CONCLUSIONS: During the first 48 hours of treatment, i.v. amiodarone and oral quinidine were equally effective in converting CAF to sinus rhythm. At 2 and 9 months of therapy, treatment with oral amiodarone was superior to that of quinidine in restoring sinus rhythm. Long-term treatment with oral amiodarone is better tolerated than with quinidine.

Administration, Oral↗

PubMed2003

Long-term amiodarone therapy and the risk of complications after cardiac surgery: results from the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT).

OBJECTIVE: This study was undertaken to determine the association between amiodarone therapy and risk of complications of cardiac surgery in patients in the randomized placebo-controlled, double-blind Canadian Amiodarone Myocardial Infarction Arrhythmia Trial. METHODS: Prospectively collected data regarding postoperative complications in 82 patients who underwent cardiac surgery during Canadian Amiodarone Myocardial Infarction Arrhythmia Trial participation were analyzed; 36 patients were randomly assigned to receive amiodarone and 46 were assigned to receive placebo. Of the patients randomly assigned to receive amiodarone, 24 patients continued amiodarone treatment to within 7 days of the operation (active amiodarone group) and 12 patients had the amiodarone discontinued at least 7 days before the operation (discontinued amiodarone group). RESULTS: The baseline characteristics of the three groups were similar. The risks of ventricular fibrillation, atrial fibrillation, and respiratory complications were similar. The risk of requiring an intra-aortic balloon pump was significantly increased by amiodarone (34.8% vs 16.7% vs 8.7% for active amiodarone, discontinued amiodarone, and placebo groups, respectively, P =.024). There was no significant difference in the use of temporary pacing. Neither the mean duration of stay in the intensive care unit nor the 7- and 30-days mortalities were affected by amiodarone. CONCLUSIONS: Patients receiving long-term amiodarone treatment after myocardial infarction had a higher rate of intra-aortic balloon use after cardiac surgery. There was no increased risk of pulmonary complications, need for pacing, or death.

Administration, Oral↗

PubMed1984

Clinical efficacy and electropharmacology of continuous intravenous amiodarone infusion and chronic oral amiodarone in refractory ventricular tachycardia.

The clinical efficacy and electropharmacologic effects of continuous intravenous (i.v.) amiodarone infusion (10 to 20 mg/kg/day for 4 to 7 days) followed by chronic oral amiodarone therapy (400 to 800 mg/day for 24 to 53 days) were evaluated in 17 patients with refractory sustained ventricular tachycardia (VT) or ventricular fibrillation. Intravenous amiodarone infusion prolonged the RR interval (from 754 +/- 85 to 860 +/- 157 ms, p less than 0.05), PR interval (from 192 +/- 53 to 212 +/- 54 ms, p less than 0.01) QRS duration (from 103 +/- 21 to 117 +/- 25 ms, p less than 0.001) and QTc interval (from 423 +/- 22 to 466 +/- 31 ms, p less than 0.001). Chronic oral amiodarone treatment had similar but more pronounced effects on electrocardiographic intervals. The ventricular effective refractory period tended to prolong after i.v. amiodarone infusion (p less than 0.1 to greater than 0.05) but prolonged significantly after chronic oral amiodarone (p = 0.025). Mean serum amiodarone concentration was 1.7 +/- 1.0 mg/liter with infusion and 1.5 +/- 0.6 mg/liter with oral therapy. Intravenous amiodarone infusion suppressed spontaneous VT in 5 of 9 patients with frequent VT recurrences, but had no effect on cycle length of spontaneous VT. Chronic amiodarone therapy either suppressed spontaneous VT recurrences or prolonged cycle length during VT recurrences. VT induction after i.v. amiodarone was not predictive of VT induction or spontaneous VT recurrences after chronic oral amiodarone treatment. Thus, i.v. amiodarone has limited value in acute control of VT and clinical or electrophysiologic response to it is not predictive of long term therapeutic results with amiodarone.

Administration, Oral↗

PubMed1991

Voltage- and use-dependent modulation of calcium channel current in guinea pig ventricular cells by amiodarone and des-oxo-amiodarone.

Amiodarone is an effective antiarrhythmic drug handicapped by serious side effects. The mechanism of its antiarrhythmic activity is not known but is presumed to involve inhibition of current flowing through ion channels. Des-oxo-amiodarone, a close structural analogue of amiodarone, was synthesized based on the hypothesis that the toxic and therapeutic properties reside in different parts of the molecule and that chemical modification could result in a less toxic agent that yet preserved amiodarone's antiarrhythmic efficacy. We compared the effects of amiodarone and des-oxo-amiodarone on Ca current in enzymatically dispersed guinea pig ventricular myocytes using the whole-cell patch-clamp method. Amiodarone caused both a tonic and a phasic (use-dependent) reduction of the Ca current. The relationship between membrane potential and the availability for channel opening upon depolarization (inactivation curve) was shifted toward more negative membrane potentials by amiodarone (delta - 10.6 +/- 2.2 mV, n = 7). The use-dependent reduction of the Ca current was also dependent on the frequency of the voltage clamp steps (0.5 Hz, 40.2 +/- 7.9%; 1.0 Hz, 50.0 +/- 6.7%). Dex-oxo-amiodarone had a dual effect on the Ca current: After maintaining the membrane potential for several seconds at negative membrane potentials (less than -45 mV), the Ca current was increased by des-oxo-amiodarone. Des-oxo-amiodarone also shifted the Ca channel inactivation curve to more negative membrane potentials up to 16 mV. Consequently, Ca current could be increased or decreased depending on the experimental conditions. Enhancement of Ca current by des-oxo-amiodarone was transient and was supplanted entirely by the antagonistic effects of the drug after approximately 5 min. The antagonistic effects of des-oxo-amiodarone on Ca current were also use- and frequency-dependent.

Action Potentials↗

PubMed2006

Hepatocellular toxicity and pharmacological effect of amiodarone and amiodarone derivatives.

The aim of this work was to compare hepatocellular toxicity and pharmacological activity of amiodarone (2-n-butyl-3-[3,5 diiodo-4-diethylaminoethoxybenzoyl]-benzofuran; B2-O-Et-N-diethyl) and of eight amiodarone derivatives. Three amiodarone metabolites were studied, namely, mono-N-desethylamiodarone (B2-O-Et-NH-ethyl), di-N-desethylamiodarone (B2-O-Et-NH(2)), and (2-butyl-benzofuran-3-yl)-(4-hydroxy-3,5-diiodophenyl)-methanone (B2) carrying an ethanol side chain [(2-butylbenzofuran-3-yl)-[4-(2-hydroxyethoxy)-3,5-diiodophenyl]-methanone; B2-O-Et-OH]. In addition, five amiodarone analogs were investigated, namely, N-dimethylamiodarone (B2-O-Et-N-dimethyl), N-dipropylamiodarone (B2-O-Et-N-dipropyl), B2-O-carrying an acetate side chain [[4-(2-butyl-benzofuran-3-carbonyl)-2,6-diiodophenyl]-acetic acid; B2-O-acetate], B2-O-Et carrying an propionamide side chain (B2-O-Et-propionamide), and B2-O carrying an ethyl side chain [(2-butylbenzofuran-3-yl)-(4-ethoxy-3,5-diiodophenyl)-methanone; B2-O-Et]. A concentration-dependent increase in lactate dehydrogenase leakage from HepG2 cells and isolated rat hepatocytes was observed in the presence of amiodarone and of most analogs, confirming their hepatocellular toxicity. Using freshly isolated rat liver mitochondria, amiodarone and most analogs showed a dose-dependent toxicity on the respiratory chain and on beta-oxidation, significantly reducing the respiratory control ratio and oxidation of palmitate, respectively. The reactive oxygen species concentration in hepatocytes increased time-dependently, and apoptotic/necrotic cell populations were identified using flow cytometry and annexin V/propidium iodide staining. The effect of the three least toxic amiodarone analogs on the human ether-a-go-go-related gene (hERG) channel was compared with amiodarone. Amiodarone, B2-O-acetate, and B2-O-Et-N-dipropyl (each 10 microM) significantly reduced the hERG tail current amplitude, whereas 10 microM B2-O-Et displayed no detectable effect on hERG outward potassium currents. In conclusion, three amiodarone analogs (B2-O-Et-N-dipropyl, B2-O-acetate, and B2-O-Et) showed a lower hepatocellular toxicity profile than amiodarone, and two of these analogs (B2-O-Et-N-dipropyl and B2-O-acetate) retained hERG channel interaction capacity, suggesting that amiodarone analogs with class III antiarrhythmic activity and lower hepatic toxicity could be developed.

Adenosine Triphosphate↗

PubMed1995

Measurement of serum amiodarone and desethylamiodarone by HPLC: its usefulness in the follow-up of arrhythmic patients treated with amiodarone.

Amiodarone is an antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias. Owing to its narrow therapeutical range, monitoring of drug concentration is mandatory. The circulating and tissue levels of amiodarone and of its main endogenous metabolite, N-desethyl-amiodarone, are currently measured by means of HPLC procedures, which are tedious and time-consuming, and often beset with problems and drawbacks. We have developed a new chromatographic assay for the simultaneous measurement of amiodarone and N-desethyl-amiodarone in serum samples, and tested its usefulness in the follow-up of 14 patients (8 men and 6 women, age range 40-65 years) with complex ventricular arrhythmias, treated with amiodarone for at least 5 weeks. This assay uses trifluoperazine dihydrochloride as internal standard and a preliminary extraction of serum samples with isopropyl ether. The assay procedure was the following: 350 microliter patient's serum, to which 1 microgram trifluoperazine was added, were extracted with 280 microliter isopropyl ether. After mixing and centrifugation, 50 microliter of the organic layer were filtered and then injected onto the HPLC system (15 cm x 3.9 mm Resolve 5-micrometer spherical silica column); the elution rate was 1.8 ml/min (mobile phase, 920 ml of methanol and 80 ml of ammonium sulfate buffer) in isocratic condition. The time for a complete assay of each serum sample was less than 20 min, and its working range was 0.1-5.0 microgram/ml of amiodarone. An excellent recovery of the drug from subtherapeutical values up to toxic amiodarone concentration was obtained. The intra-assay precision of amiodarone assay ranged form 5 to 11%, while the between-assay precision administered in all patients, without increasing the amiodarone concentration beyond the toxic threshold level. The plateau of the circulating levels of the drug was generally reached in about 5-12 days, at the acceptable therapeutical range, from 0.5 to 2 microgram/ml. In conclusion, this chromatographic method for the assay of serum amiodarone levels is sufficiently simple, rapid and reliable to be considered a useful tool in the follow-up of arrhythmic patients chronically treated with amiodarone.

Adult↗

PubMed1987

Amiodarone efficacy in a young population: relationship to serum amiodarone and desethylamiodarone levels.

Serum amiodarone and desethylamiodarone levels were measured in children and young adults receiving chronic amiodarone therapy. The study population consisted of 34 children and young adults with ventricular tachycardia (36%), atrial flutter (36%), and recurrent supraventricular tachycardia (27%). The mean age was 12.9 +/- 8.6 years (range 4 months to 23 years) and the mean daily dose of amiodarone was 6.6 +/- 3.7 mg/kg/day (range 2.5 to 25 mg). Serum amiodarone and desethylamiodarone levels after 10.1 months (range 1 to 40 months) were 0.85 +/- 0.63 microgram/ml and 0.67 +/- 0.42 microgram/ml, respectively. In three patients for whom amiodarone therapy was unsuccessful, serum amiodarone levels were 0.27, 0.85, and 1.18 micrograms/ml. There was no significant correlation between serum amiodarone or desethylamiodarone levels and dosage of amiodarone. Four patients, all 13 years or older, developed toxicity (skin rash [one patient], keratopathy [two patients], and hyperthyroidism [one patient]). There was no correlation between serum amiodarone and desethylamiodarone levels and toxicity; although there was a trend toward elevated reverse serum triiodothyronine levels in patients who developed toxicity, the values fell within the range of those patients without toxic side effects. Serum amiodarone levels do not appear to be of great value in predicting efficacy and toxicity of amiodarone in children and young adults receiving chronic drug therapy.

Adolescent↗

PubMed2005

[Thyroid dysfunction in long-term amiodarone administration. Correlation of the antiarrhythmic activity of amiodarone with its effect on thyroid function].

Relationship between amiodarone-associated thyroid dysfunction and antiarrhythmic activity of amiodarone was studied in 27 patients (13 with hypothyroidism, 8 with hyperthyroidism, 6 with euthyroid hyperthyroxinemia). Amiodarone-associated hypothyroidism and euthyroid hyperthyroxinemia were not associated with loss of antiarrhythmic efficacy of amiodarone. Hypothyroidism did not require amiodarone withdrawal and therapy with L-thyroxin was conducted at the background of continued amiodarone intake. Achievement of euthyroid state was not followed by recurrence of heart rhythm disturbances. Development of amiodarone-associated thyrotoxicosis was accompanied with loss of antiarrhythmic efficacy of amiodarone in all cases. In 87.5% of patients with thyrotoxicosis correction of the thyroid status was conducted under conditions of continued amiodarone intake as this drug had been given because of life threatening arrhythmias or proven resistance to other antiarrhythmic therapy. In 12.5% of patients it was possible to substitute other drugs for amiodarone. Correction of thyroid status and achievement of euthyroidosis in these patients was associated with restoration of amiodarone antiarrhythmic activity.

Aged↗

PubMed1989

Correlation of amiodarone dosage, heart rate, QT interval and corneal microdeposits with serum amiodarone and desethylamiodarone concentrations.

Pharmacokinetic-dynamic relations for amiodarone have been difficult to define. Few studies have successfully correlated serum amiodarone concentration with either dose or pharmacodynamic effects. Reduction in heart rate, prolongation of corrected QT interval and accumulation of corneal microdeposits are 3 clinical effects well suited for making kinetic-dynamic comparisons because they occur in virtually all patients receiving amiodarone. Data on heart rate, corrected QT interval, corneal microdeposits, cumulative dose and serum concentrations of amiodarone and desethylamiodarone (DEA) were collected over the course of 1 year after initiation of therapy in 27 patients (mean age 55.4 +/- 2.35 years). Mean elimination half-lives in this study population were 56 days for amiodarone and 129 days for DEA, as estimated from cumulation kinetics without drug withdrawal. The extremely long half-lives of amiodarone and DEA make demonstration of steady-state concentration-response relations difficult. A new approach using analysis of sequential data before steady-state reveals general relations between dose, DEA concentration and 3 clinically observable effects of amiodarone. A linear relation was evident between DEA concentration and log mean cumulative amiodarone dose (mg/kg) for the population. The steep segments of the concentration-response curves for heart rate, microdeposits and corrected QT interval occurred at low, medium and high serum amiodarone and DEA concentrations, respectively. Patients not developing a decrease in heart rate or corneal microdeposits likely have very low serum drug concentrations and may not be adequately treated. The monitoring of heart rate, corrected QT interval and corneal microdeposits as an aid to assessing adequacy of amiodarone therapy requires further study.

Amiodarone↗

PubMed2001

Toxicity of amiodarone and amiodarone analogues on isolated rat liver mitochondria.

BACKGROUND: Amiodarone is a well-known mitochondrial toxin consisting of a benzofuran ring (ring A) coupled to a p-OH-benzene structure substituted with 2 iodines and a diethyl-ethanolamine side chain (ring B). AIM: To find out which part of amiodarone is responsible for mitochondrial toxicity. METHODS: Amiodarone, ring A and B without the ethanolamine side-chain and iodines (B0), ring A and B with iodines but no ethanolamine (B2), ring B with 1 iodine and no ethanolamine (C1) and ring B with ethanolamine and 2 iodines (D2) were studied. RESULTS: In freshly isolated rat liver mitochondria, amiodarone inhibited state 3 glutamate and palmitoyl-CoA oxidation and decreased the respiratory control ratios. B0 and B2 were more potent inhibitors than amiodarone and B2 more potent than B0. C1 and D2 showed no significant mitochondrial toxicity. After disruption, mitochondrial oxidases and complexes of the electron transport chain were inhibited by amiodarone, B0 and B2, whereas C1 and D2 revealed no inhibition. Beta-oxidation showed a strong inhibition by amiodarone, B0 and B2 but not by C1 or D2. Ketogenesis was almost unaffected. CONCLUSIONS: Amiodarone, B0 and B2 are uncouplers of oxidative phosphorylation, and inhibit complexes I, II and III, and beta-oxidation. The benzofuran structure is responsible for mitochondrial toxicity of amiodarone and the presence of iodine is not essential.

Amiodarone↗

PubMed1986

Amiodarone and desethylamiodarone distribution in the atrium and adipose tissue of patients undergoing short- and long-term treatment with amiodarone.

The time to onset of action of amiodarone is often long in patients treated for arrhythmias; one reason might be a slow entry of the drug into the target organ, the heart. Amiodarone and desethylamiodarone, its active metabolite, were measured in the plasma, atrial tissue and pericardial fat of patients undergoing cardiac surgery. Two groups were studied: patients treated with amiodarone for less than 28 days (short-term group) and those treated for 28 days or more (long-term group). Plasma levels of amiodarone in the two groups were not different, whereas levels of desethylamiodarone were significantly higher in the long-term group. Average concentrations of amiodarone in the atrium were higher with longer treatment periods (30.2 +/- 5.6 versus 13.2 +/- 2.5 micrograms/g wet weight of tissue); the same was true for desethylamiodarone (40.3 +/- 7.7 versus 15.7 +/- 3.7 micrograms/g). Amiodarone concentrations in fat were also significantly higher in the long-term than in the short-term group. Atrium/plasma concentration ratios of desethylamiodarone were higher than those of amiodarone, whereas fat plasma concentration ratios of desethylamiodarone were lower. In conclusion, the equilibration of amiodarone and desethylamiodarone concentrations between myocardium and plasma appears to occur slowly in patients undergoing long-term treatment with amiodarone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗

PubMed1996

Lack of effect of amiodarone on survival after extensive infarction. Polish Amiodarone Trial.

BACKGROUND: The purpose of this study was to elucidate whether the reduction of mortality with amiodarone after myocardial infarction depended on ejection fraction. METHODS: The data from the Polish Amiodarone Trial were analysed retrospectively. Patients with acute myocardial infarction and contraindications to beta-blockers were randomized on days 5-7 after admission to receive amiodarone (n = 305) or placebo (n = 308). Short and long-term (46 months) mortality were analysed comparing the groups with impaired (ejection fraction < 40%) and preserved (ejection fraction > or = 40%) left ventricular function. A subset of patients (n = 523) with available echocardiograms were subjected to this analysis. RESULTS: Long-term and sudden cardiac mortality were significantly reduced with amiodarone in the group of patients with ejection fraction > or = 40% (amiodarone versus placebo, respectively: 9.1 versus 16.5%, P < 0.05; 3.4 versus 8.2, P < 0.05). No beneficial effect of amiodarone was observed in the group with low ejection fraction (cardiac and sudden cardiac mortality: amiodarone versus placebo, 20.8 versus 19.3% and 7.8 versus 5.7% respectively). One-year mortality also revealed a favourable trend only in amiodarone-allocated patients with ejection fraction > or = 40%. CONCLUSION: Amiodarone decreased long-term and sudden cardiac mortality after myocardial infarction only in patients with preserved left ventricular function. No benefit was observed in patients with decreased ejection fraction.

Amiodarone↗

PubMed1987

Changes in cardiac muscle function and biochemistry produced by long-term amiodarone and amiodarone + triiodothyronine administration in the rabbit.

Cardiac muscle function and biochemistry were examined after long-term amiodarone administration in the rabbit (20 mg/kg/day for 28 days). Isolated cardiac muscle preparations were obtained from control and amiodarone-treated rabbits, and were studied in vitro. Amiodarone treatment did not alter the magnitude of force development in isolated atrial and papillary muscle preparations, but depressed the rate of force development (dF/dt). The muscle preparations responded similarly to inotropic and chronotropic stimulation with isoproterenol, histamine, and tyramine, although the intrinsic rate of right atrial preparations from the drug-treated animals was reduced. Na+-K+ ATPase activity in crude ventricular homogenates was increased in the amiodarone-treated group. Mitochondrial respiratory function in amiodarone-treated left ventricular tissue was depressed for glutamate, malate, and glutamate + malate. The reduction in respiratory function occurred without uncoupling oxidative phosphorylation or altering respiratory function for succinate. The pharmacologic effects of amiodarone observed in the present study were not observed with the simultaneous administration of triiodothyronine (5 micrograms/day). No difference in ATP-dependent calcium uptake or in calcium-dependent ATPase activity were observed in sarcoplasmic reticulum preparations from control, amiodarone, and amiodarone + T3 groups. The pharmacologic effects of amiodarone in rabbit hearts resemble those previously reported with hypothyroidism and are not observed after triiodothyronine administration.

Adenosine Triphosphatases↗