Influence Of Amiodarone Research Articles

Amiodarone Enhances Anticonvulsive Effect of Oxcarbazepine and Pregabalin in the Mouse Maximal Electroshock Model.

Accumulating experimental studies show that antiarrhythmic and antiepileptic drugs share some molecular mechanisms of action and can interact with each other. In this study, the influence of amiodarone (a class III antiarrhythmic drug) on the antiseizure action of four second-generation antiepileptic drugs was evaluated in the maximal electroshock model in mice. Amiodarone, although ineffective in the electroconvulsive threshold test, significantly potentiated the antielectroshock activity of oxcarbazepine and pregabalin. Amiodarone, given alone or in combination with oxcarbazepine, lamotrigine, or topiramate, significantly disturbed long-term memory in the passive-avoidance task in mice. Brain concentrations of antiepileptic drugs were not affected by amiodarone. However, the brain concentration of amiodarone was significantly elevated by oxcarbazepine, topiramate, and pregabalin. Additionally, oxcarbazepine and pregabalin elevated the brain concentration of desethylamiodarone, the main metabolite of amiodarone. In conclusion, potentially beneficial action of amiodarone in epilepsy patients seems to be limited by neurotoxic effects of amiodarone. Although results of this study should still be confirmed in chronic protocols of treatment, special precautions are recommended in clinical conditions. Coadministration of amiodarone, even at low therapeutic doses, with antiepileptic drugs should be carefully monitored to exclude undesired effects related to accumulation of the antiarrhythmic drug and its main metabolite, desethylamiodarone.

Influence of amiodarone on spectral analysis of heart rate variability in patients with atrial fibrillation (clinical observation)

Spectral analysis of heart rate variability can be successfully used to evaluate the effectiveness of therapy. The use of this method gives an idea of the role of the autonomic nervous system in the regulation of chronotropic function of the heart. These data help to define conditions of manifestation of efficiency of antiarrhythmic drugs. In this study, spectral analysis were studied in patients with persistent atrial fibrillation. The effect of amiodarone class III antiarrhythmic drug were studied this study.

The influence of amiodarone on serum hs-CRP and QTd in patients with ventricular arrhythmia of coronary heart disease

Objective To observe the influence of amiodarone on serum high-sensitivity C-reactive protein (hs-CRP) and QT dispersion (QTd) in patients with ventricular arrhythmia of coronary heart disease.Methods 92 patients with ventricular arrhythmia of coronary heart disease were randomly divided into the observation group(n =50 cases) and the control group (n =42 cases).The patients in the observation group were treated through the conventional treatment plus amiodarone,while the patients in the control group were treated through the conventional treatment plus metoprolol.They were treated for two weeks.Serum hs-CRP and QTd were detected before and after treatment.Results The total effective rate of the observation group was 94％ and that was 83％ in the control group.There was significant difference between two groups (x2 =4.790,P ＜ 0.05).After treatment,the serum hs-CRP and QTd were decreased(t =2.009,2.019,11.020,4.975,P ＜ 0.05),those in the observation group were significandy lower than in the control group(t =2.018,5.102,P ＜ 0.05).Conclusion Amiodarone can decrease serum hs-CRP and QTd in patients with ventricular arrhythmia of coronary heart disease and improve patients' condition. Key words: Arrhythmia; Amiodarone; C-reactive protein; QT dispersion

Amiodarone Modulation of Intracellular Transport of Calcium Ions in Cardiomyocites

The influence of amiodarone on intracellular transport of calcium ion in cardiomyocytes of rat was investigated. The experiments were performed on isolated papillary muscles of Wistar rats. Force-frequency dependence (0.7, 1, 2, 3, 4 Hz), extrasystolic and postextrasystolic contractions and post-rest (4-60 s) reactions of rat myocardium after amiodarone treatment (1 μM) were investigated. Decay potentiation coefficient of contraction force was estimated. Results. The analyses of force-frequency dependence has shown that amiodarone prevent the decreasing of the force contraction at increasing of the stimulation frequency. Amiodarone promotes increase of the time constant t1(T50), that indicate the drug promotes acceleration of Са2+ transport inside the SR resulting increase of Са2+ in the places of its release from the sarcoplasmic reticulum (SR). Treatment of papillary muscle with amiodarone decreased amplitude of extrasystolic contractions. As known, postextrasystolic and post-rest reactions of myocardium characterize the SR function. We have found amiodarone increased potentiation of postextrasystolic and post-rest contractions. Preliminary caffeine perfusion of muscles preparations cancelled the amiodarone-induced increasing postextrasystolic and post-rest potentiation. However, potentiation decay coefficient before and after treatment with amiodarone didn’t have difference. Conclusions, amiodarone influences on intracellular calcium ions homeostasis by modulation SR functions related with most likely are stipulated either by activation of Са2+ transport from uptake sites to release sites or by prevent of Са2+ leakage from the SR.

Atrial arrhythmias after lung and heart–lung transplant: Effects on short-term mortality and the influence of amiodarone

The incidence and effect of atrial fibrillation or flutter (AF) after lung transplant are variable. An effect of pharmacologic treatment on outcomes is undetermined. One hundred thirty-seven consecutive lung or heart-lung transplant patients were reviewed retrospectively. Uni- and multivariate analyses were performed to determine statistically significant risk factors for AF and short-term mortality. AF occurred in 45.0% of patients within 26 days. By univariate analysis, male gender was predictive of AF (hazard ratio [HR] = 2.25, 95% confidence interval [CI] 1.21 to 4.20, p = 0.011). Mortality within 200 days occurred in 36 of 137 (22.6%) patients. Those with AF had higher mortality than those without AF (27 of 62 [43.5%] vs 9 of 75 [12%]; p < 0.0001). Twenty-four of the 38 (63.1%) patients treated with amiodarone died, whereas 3 of 26 (11.5%) patients treated without amiodarone died (p < 0.0001). Mortality was similar among patients without AF, and those with AF not receiving amiodarone (9 of 75 [12%] vs 3 of 26 [11.5%], p = 1.00). By multivariate analysis, chronic obstructive pulmonary disease (HR = 0.395, CI 0.175 to 0.892, p = 0.025), primary pulmonary hypertension (HR = 7.245, CI 1.89 to 27.84, p = 0.0039), and use of amiodarone (HR = 2.967, CI 1.187 to 7.415, p = 0.020) were associated with death. Amiodarone was shown to be a significant statistical moderator (p < 0.0001) and mediator (p < 0.001) of mortality in AF patients. There was a high incidence of AF after lung or heart-lung transplant, and a significant increase in mortality in AF patients treated with amiodarone. In patients with severe lung pathology, amiodarone pulmonary toxicity may be more common than previously known, and may be a significant contributor to mortality. Amiodarone use should be restricted in the lung transplant patient population.

Optic neuropathy: amiodarone-induced or anterior ischemic optic neuropathy?

Optic neuropathy in patients taking amiodarone presents a diagnostic challenge. The changes at the optic discs and the optic nerve dysfunction could be induced directly by amiodarone, could be the result of a nonarteritic anterior ischemic optic neuropathy or could be a combination of these two factors. Various clinical criteria for the diagnosis of amiodarone-induced optic neuropathy have been described during the past 5 years. These include bilateral, usually insidious, visual loss and protracted optic disc edema over several months. Ophthalmological examinations should be carried out within the first 12 months (and particularly within 4 months) of initiating amiodarone and subsequently. Discontinuation of amiodarone should be considered in patients presenting with clinical features of amiodarone-induced optic neuropathy. However, in those patients in whom the mechanism of optic neuropathy is indeterminate or likely to be due to anterior ischemia, continuation with amiodarone therapy would be appropriate. Future studies aimed at understanding the effect of amiodarone on optic nerve axon biochemistry, physiology and structure leading to optic neuropathy, as well as identifying the influence of amiodarone in the perfusion of the anterior optic nerve by altering the blood flow in the short posterior ciliary arteries, will improve our understanding of the association between amiodarone intake and optic neuropathy.

The Influence of Amiodarone and ACE-Inhibitors on Atrial Fibrillation Recurrence

Introduction: The purpose of this study was to evaluate the efficacy of a dualcoil, active-can implantable cardioverter-defibrillator (ICD) system, implanted for the treatment of ventricular arrhythmias, in cardioversion of spontaneous episodes of atrial fibrillation (AF). Methods: The population was derived from 360 patients with icds implanted between July 1997 and June 2001. The study patients were 69 ± 8.9 years old, 83% were male, coronary artery disease was present in 78%, and a prior history of non-permanent AF was present in 54%. Beta blockers were used in 72% of patients and amiodarone in 27% of patients. The mean left ventricular ejection fraction was 31 ± 9%. Echocardiographic evaluation demonstrated moderate to severe left atrial enlargement in 41% of patients. Patients with permanent AF were excluded. Results: Atrial fibrillation resulted in an ICD discharge in 23 patients. Successful cardioversion occurred in 79% of episodes of AF with defibrillation energy of 30.5 ± 4.4 joules. In multivariate analysis, no patient characteristics, including left atrial size, ejection fraction, or concurrent use of beta blockers or amiodarone predicted success of cardioversion. Multiple discharges were delivered in 17% of these patients. Conclusion: Standard dual-coil, active-can ICD systems are highly successful at converting spontaneous AF that occurs in the clinical setting. There were no specialized defibrillation coils or algorithms required. The use of discriminatory algorithms for prevention of multiple ICD discharges due to atrial arrhythmias needs to be balanced with the high success rate of cardioversion.

Impact of Amiodarone on Electrophysiologic Properties of Pulmonary Veins in Patients with Paroxysmal Atrial Fibrillation

Pulmonary veins (PVs) are the predominant location of triggers for atrial fibrillation (AF), but little is known about the electrophysiologic properties of PVs. In addition, the influence of amiodarone on the electrophysiologic properties of PVs has not been elucidated. Fifty-five patients with symptomatic and drug-resistant AF were divided into two groups: group 1 patients (n=29) without antiarrhythmic drug therapy at the time of electrophysiologic study (EPS), and group 2 patients (n=26) undergoing continuous long-term treatment with amiodarone. EPS including programmed stimulation of both atria and within the PVs was performed in both groups. In group 1, the effective refractory period (ERP) of all PVs (174 +/- 62 msec) was significantly shorter than the ERP of the left atrium ([LA] 254 +/- 30 msec, P=0.0001) and right atrium ([RA] 221 +/- 29 msec, P=0.0001). The same pattern was observed in group 2 (PV: 210 +/- 58 msec; LA: 259 +/- 35 msec, P=0.0001; RA: 246 +/- 37 msec, P=0.0255). The ERP of all stimulated PVs was significantly lower in group 1 (174 +/- 62 msec) than in group 2 (210 +/- 58 msec; P=0.0001). The ERP of the left superior and right superior PVs and RA but not the left inferior PV and LA were significantly increased in patients treated with amiodarone. Decremental conduction properties were observed in all stimulated PVs, and there were no significantly differences between the maximal decrement of both groups. The distinctive electrophysiologic properties of PVs are emphasized by amiodarone therapy. Long-term amiodarone treatment is responsible for heterogeneous alteration of the PV electrophysiology, which may account for the individual antiarrhythmic responses in a subset of patients with paroxysmal AF.

Influence of Amiodarone on Urinary Excretion of 6β-Hydroxycortisol in Humans

Influence of Amiodarone on Urinary Excretion of 6β-Hydroxycortisol in Humans

Effects of Amiodarone on Ouabain Binding to Microsomal Na +, K +-ATPase in Guinea-Pig Heart Preparations

1. The influence of amiodarone on [ 3H]ouabain (OUA) binding to myocardial Na +, K +-ATPase was studied at various KCl concentrations in guinea pig heart microsomal preparations to test the hypothesis that the drug acts on the same receptor sites as cardiac glycosides. 2. First, a series of assays for OUA binding to Na +, K +-ATPase were performed in the range of 64–800 nM at 2.5, 5.0 and 10.0 mM K + concentration. The drug exhibited increasing binding tendency with increasing concentrations and elevation in K + levels. 3. Competitive binding assays were then performed at 256, 512 and 800 nM OUA in the presence of 50, 100 and 200 μM amiodarone at 5.0 mM KCl, respectively. At each OUA concentration, a concentration-dependent left-to-right shift was observed in the binding affinity with increasing amiodarone concentration. Similar assays at 2.5 and 10.0 mM K + showed the same trends. These effects were significant for 200 mM amiodarone at all K + levels and OUA concentrations. 4. Furthermore, different OUA concentrations were also shown to displace amiodarone in a concentration-dependent fashion. 5. These results indicate that amiodarone competes with OUA for specific binding sites on myocardial microsomal Na +, K +-ATPase. They lead to the conclusion that myocardial Na +, K +-ATPase is a possible receptor for some of the cardiac actions of amiodarone, such as its proarrhythmic effects.

Modifications in the evolution of the dominant frequency in ventricular fibrillation induced by amiodarone, diltiazem, and flecainide: An experimental study

In 22 anesthetized mongrel dogs, spectral methods were used to analyze the surface electrocardiogram (ECG) for the time course of the dominant frequency in ventricular fibrillation and its modifications under the influence of amiodarone, diltiazem, and flecainide. The ECG was recorded over 5 minutes after triggering ventricular fibrillation. Following A/D conversion and by applying the Fourier fast transform, the frequency spectrum of the signals was obtained. In group 1 (5 dogs), the ECGs were obtained without prior drug administration; group 2 (5 dogs) first received amiodarone, 5 mg/kg; group 3 (7 dogs) received diltiazem, 0.2 mg/kg; and group 4 (5 dogs) received flecainide, 2 mg/kg. All drugs were administered intravenously. An initial increase in the dominant frequency of ventricular fibrillation was found in the control group and also in the groups that received amiodarone, diltiazem, or flecainide. Diltiazem significantly increased the dominant frequency and diminished the arrhythmia-slowing process. Amiodarone and flecainide tended to diminish the dominant frequency.

Hemodynamic effects of amiodarone during acute and chronic treatment in patients with recurrent sustained ventricular tachycardia.

In 15 patients with recurrent ventricular tachycardia, the hemodynamic effects of amiodarone were evaluated under oral loading (1000 mg/day for 14-16 days) and during chronic treatment (600 mg/day for a further 10 weeks). In all patients, coronary artery disease was present with a mean ejection fraction of 37%+/- 10%. The cardiac output during the sinus rhythm, as determined by thermodilution, did not change significantly during loading with amiodarone. During ventricular tachycardia, the cardiac output increased from 3.7 +/- 1.3 to 4.5 +/- 1.6 1/min under the influence of amiodarone in 5 patients. Echocardiographic measurements of the left ventricle dimensions did not show a directed change of the enddiastolic and endsystolic diameters and the fraction shortening at the end of the loading period and after 3 months of maintenance therapy. No negative inotropic effect of amiodarone could be demonstrated in patients with recurrent ventricular tachycardia and impaired left ventricular function due to coronary artery disease.

Influence of amiodarone on genetically determined drug metabolism in humans

Amiodarone has been shown to interact with the nongenetically determined hepatic elimination of several drugs, including phenytoin and digoxin. Its influence on genetically determined metabolic pathways has not been studied in humans. We examined the effects of oral amiodarone therapy on the genetically determined metabolism of isoniazid (N-acetyltransferase), mephenytoin (cytochrome P450MEPH), and dextromethorphan (CYP2D6). Eight patients with arrhythmias were studied before and 76 +/- 16 days after amiodarone (loading dose of 1000 mg/day for 10 days followed by a maintenance dose of 200 to 400 mg/day). Genetically determined enzyme activity was assessed indirectly by calculating the metabolic ratio (parent drug/metabolite in 8-hour urine for CYP2D6 and P450MEPH and N-acetylisoniazid/isoniazid in plasma for N-acetyltransferase) after oral administration of the parent compounds. At the time of phenotyping, plasma concentrations of amiodarone and N-desethylamiodarone were 0.66 +/- 0.35 micrograms/ml and 0.65 +/- 0.26 micrograms/ml, respectively. Amiodarone increased the log(metabolic ratio) of dextromethorphan from a median of -2.5 (range, -2.9 to -2.0) to a median of -1.9 (range, -2.5 to -1.5; p less than 0.02) but did not alter the metabolic ratio of mephenytoin or isoniazid. The amount of dextromethorphan excreted in urine increased from a median of 0.084 mumol/8 hours (range, 0.041 to 0.161 mumol/8 hours) to a median of 0.205 mumol/8 hours (range, 0.064 to 0.288 mumol/8 hours; p less than 0.02) and the amount of its metabolite (dextrorphan) tended to decrease from a median of 26 mumol/8 hours (range, 15 to 37 mumol/8 hours) to a median of 20 mumol/8 hours (range, 7 to 27 mumol/8 hours; p less than 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Amiodarone on erythrocyte Shape and Membrane Properties

1. Amiodarone is a potent anti-arrhythmic drug with lipophilic properties. The intercalation of such a drug into the membrane of erythrocytes may alter their shape and have an impact on the flow properties of blood. We therefore studied the influence of amiodarone on erythrocyte shape and deformability in vitro and in vivo. 2. Incubation in vitro with increasing amiodarone concentrations led to a progressive stomatocytic shape transformation and a decreased deformability of the erythrocytes. 3. Amiodarone treatment in eight patients did not affect erythrocyte morphology and deformability. However, an increase in the membrane cholesterol/phospholipid ratio was found. 4. The stomatocytic shape transformation of erythrocytes in vitro indicates that amiodarone intercalates in the inner hemileaflet of the lipid bilayer leading to membrane internalization. These results shed light on the interaction of amiodarone with biomembranes.

Amiodarone Pretreatment Effects on Ischemic Isovolumic Rat Hearts

Effects of amiodarone injected intravenously (i.v.) at two doses (10 and 20 mg/kg) on perfused isovolumic rat hearts were assessed by P-31 nuclear magnetic resonance (NMR). P-31 NMR is used to measure intracellular myocardial pH, phosphocreatine (PCr), and ATP contents time evolutions. Myocardial mechanical function is estimated by heart rate (HR), left ventricular developed pressure (LVP), and coronary flow (CF). In experimental procedure A (2-h retrograde perfusion), drug injection induced a dose-dependent bradycardia (10-20%) and a slight decrease in LVP but did not affect CF, pH, PCr, or ATP contents. Experimental procedure B consisted of 30-min stabilization, 18-min ischemia, and 72-min reperfusion. During ischemia, amiodarone did not preserve ATP and PCr pools and did not alleviate acidosis. ATP decreased to 30% of its control values, whereas the PCr peak was hardly detectable after 12 min of ischemia. After 24 min of reflow, HR, PCr, and pH of treated hearts recovered. LVP recovered after 36 min, whereas for control hearts, HR, PCr, and pH recovered after 42 min and LVP did not reach its control values at the end of reperfusion time. Faster pH recovery is explained by a preservation of Na+/K+ ATPase due to the influence of amiodarone on membrane lipid dynamics.

Mechanisms of digoxin-amiodarone interaction in the rat.

Amiodarone and digoxin are often used in combination and clinical experience suggests that amiodarone may increase serum digoxin levels and toxicity. We have investigated the influence of amiodarone on digoxin pharmacokinetics and tissue distribution in the rat. Forty-nine rats were injected with 10 mg/kg amiodarone sc three times a day for 7 days, while 49 others were injected with saline only. On the eighth day, all the rats received 0.5 mg/kg digoxin ip; 4, 5, 6, 7, 8, 10, and 12 hr later, groups of 7 amiodarone-pretreated and control animals were sacrificed, and plasma, heart, liver, muscle, brain, and kidney digoxin concentrations measured by radioimmunoassay. Data were analyzed by two-way ANOVA, with group comparisons using the Waller-Duncan multiple comparison procedure. Digoxin levels were significantly higher in the plasma, heart, muscle, and kidney of the amiodarone-pretreated rats at most points of measurement (P less than 0.05) whereas liver digoxin levels were elevated at 8, 10, and 12 hr. Kidney/plasma, heart/plasma, muscle/plasma, and especially liver/plasma ratios in the control groups significantly exceeded the values found in the amiodarone-pretreated group at most time points. Concentrations of digoxin in brain were not changed. This suggests that the volume of distribution is significantly altered in the amiodarone-pretreated group. Amiodarone increases plasma digoxin levels in rats as it does in humans, but the mechanism is unclear.

Hypothyroid-like effect of amiodarone in the ventricular myocardium of the rat.

Due to the similar electrophysiological effects of amiodarone and hypothyroidism in the myocardium, the induction of a local hypothyroid state has been proposed as the mechanism of action of amiodarone. To examine this hypothesis we have studied the influence of amiodarone on the distribution of ventricular isomyosins--a sensitive parameter of the thyroid state in the rat heart--and the effects of amiodarone on 3,5,3'-triiodothyronine (T3) myocardial nuclear receptor binding in vivo. Amiodarone induced a dosage-dependent redistribution of isomyosins similar to hypothyroidism, while simultaneously inducing a low T3 syndrome at the higher dose level. In hypothyroid rats, which were pretreated with amiodarone, substitution of T3 (2 micrograms/100 g) led to a complete reversal of the myosin pattern not differing from control hypothyroid rats which were only given T3; the effect of T3 (0.5 microgram/100 g) was however partially inhibited by amiodarone. Nuclear receptor binding of T3 determined in hypothyroid rats in vivo was unaffected by amiodarone. We conclude that amiodarone induces a hypothyroid-like state in the ventricular myocardium of rats by inhibiting the action of T3--an effect which cannot be attributed to an antagonism at the T3 nuclear receptor level.