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At least 19 recordsLinked to original sources
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↗
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↗
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↗
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↗
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↗
PubMed1985

Pharmacokinetics of amiodarone, desethylamiodarone and other iodine-containing amiodarone metabolites.

In 23 patients treated with the iodine-containing antiarrhythmic drug amiodarone, the plasma concentrations of amiodarone, desethylamiodarone and iodine have been studied. Besides amiodarone and desethylamiodarone, a pool of iodine-containing substances, NANDAI (non-amiodarone-, non-desethylamiodarone-iodine), was present. At steady state the iodine content of NANDAI amounted to 64% and the iodine content of amiodarone plus desethylamiodarone to 36% of total serum iodine. At steady state 26% of the NANDAI fraction was made up of inorganic iodide, the average plasma concentration of which was at least 40 times above the upper limit of the normal range. The serum elimination half-life of NANDAI of 57-160 days exceeded that of amiodarone (35-68 days) and of desethylamiodarone (31-110 days). At steady state the serum concentration of desethylamiodarone appears to be related to the concentration of amiodarone by a Michaelis-Menten type function, yielding a Km of amiodarone of 2.45 mumol/l and a maximal desethylamiodarone concentration of 3.61 mumol/l.

Adolescent↗
PubMed1986

Interrelationships between serum levels of amiodarone, desethylamiodarone, reverse T3 and the QT interval during long-term amiodarone treatment.

The interrelationships between serum levels of amiodarone, desethylamiodarone, and reverse T3, and changes in the corrected QT interval (delta QTc) were examined in 22 patients during long-term treatment with amiodarone. At 1, 3, and 6 months of follow-up, the correlation coefficient between serum levels of amiodarone or desethylamiodarone and reverse T3 ranged from 0.01 to -0.2 (p greater than 0.4). At the same time intervals, the correlation coefficient between both amiodarone and desethylamiodarone levels and delta QTc ranged from 0.1 to -0.1 (p greater than 0.6), and the correlation coefficient between reverse T3 and delta QTc also ranged between 0.1 to -0.1 (p greater than 0.5). Substituting percent delta QTc for delta QTc also did not reveal a significant correlation. These data demonstrate that serum levels of reverse T3 cannot be used as a substitute for serum levels of amiodarone in monitoring patients being treated with amiodarone. The absence of a correlation between serum reverse T3 levels and delta QTc suggests that the delay in repolarization which occurs during amiodarone therapy is not secondary to an amiodarone-induced abnormality in thyroid hormone metabolism.

Adult↗
PubMed1987

Amiodarone induced phospholipidosis. Biochemical, morphological and functional changes in the lungs of rats chronically treated with amiodarone.

Amiodarone, an antiarrhythmic drug, causes pulmonary fibrosis in some patients during chronic treatment but the mechanism is unknown. We studied the effects of amiodarone on pulmonary biochemistry, morphology and function at doses of 25 and 50 mg/kg/12 hr given to rats by gavage for four weeks. Plasma and pulmonary phospholipids were significantly augmented, 13% and 88% respectively, in the group given amiodarone 50 mg/kg/12 hr compared to pair-fed controls. Typical phospholipidosis-like light and electron microscopic alterations were seen in the lung, their severity related to the extent of biochemical changes induced by amiodarone. Pulmonary function tests revealed mild but not significant changes in O2 and CO2 alveolar exchange efficiency and lung compliance (P-V curve) of treated animals in comparison to pair fed controls. Plasma average concentrations of amiodarone and its main metabolite, desethylamiodarone, after four weeks were 2.46 +/- 0.18 and 0.73 +/- 0.13 micrograms/ml, respectively, in the 50 mg/kg/12 hr group. In the same group amiodarone and desethylamiodarone concentrations in lung were 163 +/- 26 and 569 +/- 153 times higher than those in plasma. A highly significant correlation was found between amiodarone concentrations in plasma and lung and phospholipid content in the lung. A subgroup of animals received amiodarone 50 mg/kg/12 hr for 8 weeks. The pulmonary phospholipidosis-like lesions were similar to those observed after one month of treatment, no fibrosis was evident on light microscopic examination.

Amiodarone↗
PubMed1997

Randomised trial of effect of amiodarone on mortality in patients with left-ventricular dysfunction after recent myocardial infarction: EMIAT. European Myocardial Infarct Amiodarone Trial Investigators.

BACKGROUND: Ventricular arrhythmias are a major cause of death after myocardial infarction, especially in patients with poor left-ventricular function. Previous attempts to identify and suppress arrhythmias with various antiarrhythmic drugs failed to reduce or actually increase mortality. Amiodarone is a powerful antiarrhythmic drug with several potentially beneficial actions, and has shown benefit in several small-scale studies. We postulated that this drug might reduce mortality in patients at high risk of death after myocardial infarction because of impaired ventricular function, irrespective of whether they had ventricular arrhythmias. METHODS: The European Myocardial Infarct Amiodarone Trial (EMIAT) was a randomised double-blind placebo-controlled trial to assess whether amiodarone reduced all-cause mortality (primary endpoint) and cardiac mortality and arrhythmic death (secondary endpoints) in survivors of myocardial infarction with a left-ventricular ejection fraction (LVEF) of 40% or less. Intention-to-treat and on-treatment analyses were done. FINDINGS: EMIAT enrolled 1486 patients (743 in the amiodarone group, 743 in the placebo group). Median follow-up was 21 months. All-cause mortality (103 deaths in the amiodarone group, 102 in the placebo group) and cardiac mortality did not differ between the two groups. However, in the amiodarone group, there was a 35% risk reduction (95% CI 0-58, p = 0.05) in arrhythmic deaths. INTERPRETATION: Our findings do not support the systematic prophylactic use of amiodarone in all patients with depressed left-ventricular function after myocardial infarction. However, the lack of proarrhythmia and the reduction in arrhythmic death support the use of amiodarone in patients for whom antiarrhythmic therapy is indicated.

Aged↗
PubMed1995

Randomized, double-blind comparison of intravenous amiodarone and bretylium in the treatment of patients with recurrent, hemodynamically destabilizing ventricular tachycardia or fibrillation. The Intravenous Amiodarone Multicenter Investigators Group.

BACKGROUND: After several days of loading, oral amiodarone, a class III antiarrhythmic, is highly effective in controlling ventricular tachyarrhythmias; however, the delay in onset of activity is not acceptable in patients with immediately life-threatening arrhythmias. Therefore, an intravenous form of therapy is advantageous. This study was designed to compare the safety and efficacy of a high and a low dose of intravenous amiodarone with bretylium, the only approved class III antiarrhythmic agent. METHODS AND RESULTS: A total of 302 patients with refractory, hemodynamically destabilizing ventricular tachycardia or ventricular fibrillation were enrolled in this double-blind trial at 82 medical centers in the United States. They were randomly assigned to therapy with intravenous bretylium (4.7 g) or intravenous amiodarone administered in a high dose (1.8 g) or a low dose (0.2 g). The primary analysis, arrhythmia event rate during the first 48 hours of therapy, showed comparable efficacy between the bretylium group and the high-dose (1000 mg/24 h) amiodarone group that was greater than that of the low-dose (125 mg/24 h) amiodarone group. Similar results were obtained in the secondary analyses of time to first event and the proportion of patients requiring supplemental infusions. Overall mortality in the 48-hour double-blind period was 13.6% and was not significantly different among the three treatment groups. Significantly more patients treated with bretylium had hypotension compared with the two amiodarone groups. More patients remained on the 1000-mg amiodarone regimen than on the other regimens. CONCLUSIONS: Bretylium and amiodarone appear to have comparable efficacies for the treatment of highly malignant ventricular arrhythmias. Bretylium use, however, may be limited by a high incidence of hypotension.

Aged↗
PubMedDate not supplied

Amiodarone and desethylamiodarone concentrations in plasma and tissues of surgically treated patients on long-term oral amiodarone treatment.

The tissue disposition of amiodarone and its metabolite desethylamiodarone was studied in 12 surgical patients with various types of arrhythmias after chronic oral treatment with amiodarone. Amiodarone and desethylamiodarone concentrations in plasma and tissues were determined using a simple and sensitive high performance liquid chromatographic method. The mean plasma level of amiodarone and desethylamiodarone was found to increase from 0.55 microgram/ml to 1.40 microgram/ml and 0.68 microgram/ml to 1.80 microgram/ml for the respective components following the increase of the daily oral dose from 200 mg to 600 mg of amiodarone and indicates a linear relationship between plasma concentrations and dose. The mean levels of both drugs in different parts of the heart varied for amiodarone from 15 to 48 micrograms/g and for desethylamiodarone from 48 to 71 micrograms/g, with the highest values present in the epicardially resected ventricular myocardium. The mean cardiac tissue/plasma ratios ranged for amiodarone from 12 to 35 and for desethylamiodarone from 35 to 61 and show an extensive tissue uptake in the different parts of the heart for both drugs, with the metabolite accumulation 2 to 5 times higher than the parent compound. Relatively low levels, ranging for amiodarone from 2 to 15 micrograms/g and for desethylamiodarone from 5 to 25 micrograms/g, were observed in skeletal muscle, epidermis, skin and femoral artery. By far the largest content of the drugs was found in adipose tissue with mean concentrations of 207 +/- 98 micrograms/g and 82 +/- 43 g/g respectively for the parent compound and its metabolite, which suggests that fat constitutes the main depot of the drugs.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1985

Tissue distribution of amiodarone and desethylamiodarone in rats after multiple intraperitoneal administration of various amiodarone dosages.

Tissue distribution of amiodarone (Cordarone) and desethylamiodarone in the rat was studied after repeated intraperitoneal administration of the drug. Tissue and serum concentrations of amiodarone and desethylamiodarone were determined by high-performance liquid chromatography. The levels of amiodarone and desethylamiodarone in serum and tissues obtained after repeated intraperitoneal application of doses varying from 25 mg to 200 mg/kg show that the accumulation of amiodarone and desethylamiodarone in the rat is dose-dependent and both drugs are preferentially distributed in decreasing order in adipose tissue, lung, liver, kidney and thyroid gland. The penetration of the drug and its metabolite into brain was poor and with all the applied dosages brain levels were considerably lower than the corresponding serum levels. Desethylamiodarone serum and tissue concentrations were substantially lower than the corresponding amiodarone concentrations and varied from 1 to 48% (mean 15%) depending on the dosage used and the kind of tissue. The amiodarone tissue/serum concentration ratios were exceptionally high in adipose tissue (1,000-4,000) and moderate to high in the other tissues except brain (5-90), and indicate an extensive distribution of the drug with fat as a reservoir with a large storage capacity. The levels of amiodarone and desethylamiodarone, obtained with 50 mg/kg and 100 mg/kg dosages, showed in function of time clearly an increase in serum and tissues. The observed amiodarone tissue/serum ratios in function of time revealed no further significant increase (p less than or equal to 0.05) after 3 injections over a 6-day period, indicating the attainment of "steady-state".(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone↗
PubMed1987

Amiodarone--an inhibitor of phospholipase activity: a comparative study of the inhibitory effects of amiodarone, chloroquine and chlorpromazine.

Amiodarone, an antiarrhythmic drug, like chloroquine and chlorpromazine, is a tertiary amine with amphiphilic properties. Chloroquine and chlorpromazine are known inhibitors of phospholipases. All three drugs produce characteristic microcorneal deposits consistent with lysosomal accumulations of phospholipid. Similar lysosomal bodies were found in leukocytes of 15 patients on chronic amiodarone treatment as well as 3 patients each on chloroquine and chlorpromazine, suggestive of widespread systemic inhibition of lysosomal phospholipases. These lysosomal inclusions were similar in morphology, irrespective of the drug given, and were of four types: multilamellar, amorphous dense, amorphous light, or a combination of 2 or more of the preceding types. There was no simple relationship between the number of inclusion bodies per cell and the cumulative dose of amiodarone (r = 0.02) or amiodarone serum levels (r = 0.11). An in vitro assay was used to compare the effects of the three drugs on Ca2+-dependent phospholipase A2 and C activities. Phospholipase A2 activity was inhibited in a dose-dependent fashion (1-8 mg/assay) by all three drugs in the order: chlorpromazine greater than amiodarone greater than chloroquine. The inhibitory effect on phospholipase C was more pronounced with all three drugs, producing almost total inhibition at 8 mg/assay. In a Ca2+-independent lysosomal phospholipase A system, amiodarone had a greater effect, producing 85% inhibition at 1.2 mg/assay. These observations suggest that amiodarone, like other cationic amphiphiles, induces a generalized phospholipidosis by inhibiting phospholipid catabolism. Its therapeutic and toxic effects may be due to its ability to modulate both Ca2+-dependent membrane phospholipases and Ca2+-independent acid phospholipases.

Amiodarone↗