Antiarrhythmic Agent Amiodarone Research Articles

Disruption of Intracellular Calcium Homeostasis as a Therapeutic Target Against Trypanosoma cruzi.

There is no effective cure for Chagas disease, which is caused by infection with the arthropod-borne parasite, Trypanosoma cruzi. In the search for new drugs to treat Chagas disease, potential therapeutic targets have been identified by exploiting the differences between the mechanisms involved in intracellular Ca2+ homeostasis, both in humans and in trypanosomatids. In the trypanosomatid, intracellular Ca2+ regulation requires the concerted action of three intracellular organelles, the endoplasmic reticulum, the single unique mitochondrion, and the acidocalcisomes. The single unique mitochondrion and the acidocalcisomes also play central roles in parasite bioenergetics. At the parasite plasma membrane, a Ca2+-−ATPase (PMCA) with significant differences from its human counterpart is responsible for Ca2+ extrusion; a distinctive sphingosine-activated Ca2+ channel controls Ca2+ entrance to the parasite interior. Several potential anti-trypansosomatid drugs have been demonstrated to modulate one or more of these mechanisms for Ca2+ regulation. The antiarrhythmic agent amiodarone and its derivatives have been shown to exert trypanocidal effects through the disruption of parasite Ca2+ homeostasis. Similarly, the amiodarone-derivative dronedarone disrupts Ca2+ homeostasis in T. cruzi epimastigotes, collapsing the mitochondrial membrane potential (ΔΨm), and inducing a large increase in the intracellular Ca2+ concentration ([Ca2+]i) from this organelle and from the acidocalcisomes in the parasite cytoplasm. The same general mechanism has been demonstrated for SQ109, a new anti-tuberculosis drug with potent trypanocidal effect. Miltefosine similarly induces a large increase in the [Ca2+]i acting on the sphingosine-activated Ca2+ channel, the mitochondrion and acidocalcisomes. These examples, in conjunction with other evidence we review herein, strongly support targeting Ca2+ homeostasis as a strategy against Chagas disease.

Exacerbation of Toluene’s Neuro- and Hepato-Toxicity by Amiodarone or Chlorpropamide: Involvement of Oxidative Stress

Volatile solvent abuse is an important health problem and results in serious injury to the central nervous system. Neuroprotective effects were reported for the sulfonylurea group of drugs and for the anti-arrhythmic agent amiodarone, and these drugs have a K+ channel-blocking effect. The K+ channels are of interest for their ability to modulate brain damage. The aim of this study was to investigate the effect of amiodarone and chlorpropamide on the development of oxidative stress and brain and liver damage induced by toluene injection in rats. Toluene (900 mg/kg) was intraperitoneally (ip) administered alone or in combination with amiodarone or chlorpropamide (18 or 36 mg/kg, orally) once a day for 2 consecutive days. The brain and liver content of malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO), and the activity of paraoxonase-1 (PON-1) were determined. In addition, butyrylcholinesterase (BChE) and the concentration of the anti-apoptotic protein (Bcl-2) were determined in brain homogenates. Histopathological examination of brain and liver sections was also performed. Results showed that compared to controls, toluene resulted in increased oxidative stress in the brain and liver tissues. MDA and NO concentrations were markedly raised along with decreased levels of GSH and PON-1 activity. Toluene also inhibited BChE activity and decreased Bcl-2 level in the brain tissue. The biochemical changes induced by toluene were aggravated by the administration of either amiodarone or chlorpropamide. Rats treated with toluene exhibited dead neurons, perineuronal vacuolations, infiltrative cells, glial cells, and degeneration of some Purkinje cells. In the liver, massive hepatic inflammatory infiltrate, hemorrhage, vacuolar degeneration, apoptosis, and degeneration of hepatocytes were observed. The co-administration of either amiodarone or chlorpropamide caused dose-dependent exacerbation of the toluene-induced pathological changes. These findings suggest the involvement of oxidative stress in the neuro- and hepato-toxicity by toluene and imply a greater toxicity in toluene abusers treated with either amiodarone or chlorpropamide.

An exploration of interactions between the antiarrhythmic drug dronedarone and hERG potassium channel pore

Dronedarone is a non-iodinated analogue of the Class III antiarrhythmic agent amiodarone. It exerts potent inhibition of “hERG” potassium channels that underpin the cardiac rapid delayed rectifier potassium current, IKr. This study aimed to extend understanding of interactions between dronedarone and the hERG channel. Whole-cell patch-clamp recordings were made at 37?C of hERG channel current (IhERG) from HEK-293 cells expressing wild-type (WT) hERG or alanine mutants of residues in the channel’s pore-helix/selectivity filter region (T623, S624, V625) or S6 helices (S649, Y652, F656, V659). Molecular docking simulations were performed using a cryo-EM structure of hERG and a MthK-based homology model. The half-maximal inhibitory (IC50) value for WT IhERG inhibition by dronedarone was 42.6 ± 3.9 nM (n= at least 5 cells for each of 6 concentrations). 600 nM dronedarone exerted reduced WT IhERG block when the direction of K+ flux was reversed, consistent with interactions between the drug and permeant ion. In contrast with recently reported data for amiodarone, the S624A mutation did not attenuate IhERG blockade, whilst T623A and V625A channels exhibited modestly attenuated block. The S649A mutation was without significant effect and the Y652A and F656A mutations exhibited modest reductions in block. The V659A mutation produced the most marked effect on dronedarone action. Docking simulations were generally consistent with modest interactions with canonical binding residues and suggested an indirect rather than direct effect of the V659A mutation on the drug’s action. These findings leave open the possibility that as yet unexplored residue(s) could act as key determinants of high affinity hERG channel block by dronedarone.

The Antiarrhythmic Drug, Amiodarone, Decreases AKT Activity and Sensitizes Human Acute Myeloid Leukemia Cells to Apoptosis by ABT-263

BackgroundSuccessful treatment of leukemia requires new medications to combat drug resistance, but the development of novel therapies is an arduous and risky endeavor. Repurposing currently approved drugs or those already in clinical development to treat other indications is a more practical approach. Moreover, combinatorial therapeutics are often more efficacious than single agent therapeutics because the former can simultaneously target multiple pathways that mitigate tumor aggressiveness and induce cancer cell death. Material and MethodsIn this study, we combined the class III antiarrhythmic agent amiodarone and the BH3 mimetic ABT-263 based on data from a prior drug screen to assess the degree of apoptotic induction in 2 human leukemia cell lines. ResultsThe combination yielded statistically significant increases in apoptosis in both cell lines by downregulating AKT activity and increasing cleaved caspase-3. ConclusionsOverall, our findings suggest that combining K+ channel blockers with prosurvival Bcl-2 family inhibitors is a promising therapeutic approach in treating leukemia.

Lung injury as a complication of treatment with amiodarone

This is a review of current literature on lung injury which is one of the most hazardous adverse effects of an antiarrhythmic agent amiodarone referred to as amiodarone-induced pulmonary toxicity (AIPT). Finding on AIPT prevalence, risk factors, dose dependence, therapy duration and probability of AIPT occurrence have been analyzed. Issues of clinical pharmacology and the most common adverse effects of amiodarone have been discussed. Pathophysiological and pathological features and clinical manifestations of AIPT including diffuse pneumonitis, bronchiolitis, respiratory failure and acute respiratory distress syndrome have been described. Diagnosis of AIPT is based on routine methods such as lung function tests, chest X-ray, high-resolution computed tomography, and lung tissue biopsy. Management approaches include dose reduction or drug withdrawal and administration of systemic steroids. Preventive measures include baseline spirometry, regular X-ray examination and information about symptoms of this complication provided to the patients.

Widely used pharmaceuticals present in the environment revealed as in vitro antagonists for human estrogen and androgen receptors

A considerable amount of scientific evidence indicates that a number of pharmaceuticals that could be detected in the environment can contribute towards the development of problems associated with human reproductive systems, as well as those of wildlife. We investigated the estrogenic and androgenic effects of select pharmaceuticals with high production volume and environmental relevance. We examined the receptor-binding activities of these pharmaceuticals in the T47D human cell line using altered secretion of cytokine CXCL12. Functional yeast-luciferase reporter gene assays were also employed to confirm the mechanism of receptor binding by estrogen and androgen. Non-steroidal anti-inflammatory drugs, namely ibuprofen, diclofenac and antiarrhythmic agent amiodarone showed strong anti-estrogenic effects in the T47D cell line.In the yeast-luciferase assay, these anti-inflammatory drugs also demonstrated anti-estrogenic potency and inhibited the E2 response in a concentration-dependent manner. Amiodarone did not exhibit any response in the yeast-luciferase assay; therefore, the endocrine disruption presumably occurred at a different level without directly involving the receptor. All the anti-inflammatory drugs considered in this study, including ketoprofen, naproxen and clofibrate, exhibited a dose-dependent antagonism towards the androgen receptor in the yeast-luciferase assays. Several other drugs, including the stimulant caffeine, did not show any response in the tests that were employed.A risk assessment analysis using ‘Hazard Quotient’ suggested a potential risk, especially in the cases of ibuprofen, ketoprofen, diclofenac and clofibrate.The results reveal the intrinsic endocrine disrupting nature of several pharmaceuticals and thus could contribute towards explaining a number of adverse health effects on humans and wildlife.

Single-Cell Analysis: Visualizing Pharmaceutical and Metabolite Uptake in Cells with Label-Free 3D Mass Spectrometry Imaging.

Detecting metabolites and parent compound within a cell type is now a priority for pharmaceutical development. In this context, three-dimensional secondary ion mass spectrometry (SIMS) imaging was used to investigate the cellular uptake of the antiarrhythmic agent amiodarone, a phospholipidosis-inducing pharmaceutical compound. The high lateral resolution and 3D imaging capabilities of SIMS combined with the multiplex capabilities of ToF mass spectrometric detection allows for the visualization of pharmaceutical compound and metabolites in single cells. The intact, unlabeled drug compound was successfully detected at therapeutic dosages in macrophages (cell line: NR8383). Chemical information from endogenous biomolecules was used to correlate drug distributions with morphological features. From this spatial analysis, amiodarone was detected throughout the cell, with the majority of the compound found in the membrane and subsurface regions and absent in the nuclear regions. Similar results were obtained when the macrophages were doped with amiodarone metabolite, desethylamiodarone. The fwhm lateral resolution measured across an intracellular interface in high lateral resolution ion images was approximately 550 nm. Overall, this approach provides the basis for studying cellular uptake of pharmaceutical compounds and their metabolites on the single cell level.

A role for the autophagy regulator Transcription Factor EB in amiodarone-induced phospholipidosis

The antiarrhythmic agent amiodarone, a cationic amphiphilic drug, is known to induce phospholipidosis, i.e. the accumulation of phospholipids within lysosomal structures to give multi-lamellar inclusion bodies. Despite the concerns raised about phospholipidosis in the recent years, the molecular mechanisms underlying amiodarone- or other cationic amphiphilic drug-induced phospholipidosis are still under investigation. Here we demonstrated that amiodarone doses able to induce phospholiposis according to NBD-PC uptake assay (1–12μM, 24h) activates Transcription Factor EB (TFEB), a pivotal regulator of the autophagic pathway, in human HepG2 cells. Further evidences confirmed the effect of amiodarone on the autophagic-lysosomal system in HepG2 and BEAS-2B cells: lysosomal β-hexosaminidase isoenzymes secretion, transcriptional up-regulation of the lysosomal β-hexosaminidase α-subunit, alteration of cathepsin B, D and L intracellular maturation in a cell- and protease-specific manner. Autophagy activation was also demonstrated by increased conversion of LC3-I into LC3-II and reduced phosphorylation of the mTORC1 target S6 kinase. Besides, we provided evidence that TFEB over-expression prevents amiodarone-induced phospholipid accumulation, suggesting that this transcription factor could be a possible target to develop strategies for phospholipidosis attenuation.

Rapid Stimulating Effect of the Antiarrhythmic Agent Amiodarone on Absorption of Organic Anion Compounds

In a clinical setting, changes in pharmacokinetics due to drug-drug interactions can often directly affect the therapeutic safety and efficacy of drugs. Recently, interest has been shown in drug-drug interactions in the intestine. It is now recognized that changes in the functions of drug transporters substantially influence the absorption of administered drugs from the intestine. Amiodarone (AMD) is a potent drug used in the treatment of serious supraventricular and ventricular tachyarrhythmias. Despite its potent pharmacological effects, its wide clinical use is precluded by drug-drug interactions. In this study, we characterized the transporter function between AMD and various compounds in human intestinal model Caco-2 cells. AMD significantly and rapidly increased the uptake of [(3)H]estrone-3-sulfate (E-3-S) for 5 min. The apical-to-basal transport of [(3)H]E-3-S was significantly increased by AMD. The AMD-stimulated [(3)H]E-3-S uptake was inhibited by organic anion transporting polypeptide (OATP) substrates. Caco-2 cells treated with AMD showed increased OATP2B1 expression on the cell surface. AMD also increased the absorption of sulfobromophthalein (BSP), which is a typical organic anion compound, and the expression level of Oatp2b1 at the membrane in in vivo experiments. The results indicate that AMD induces OATP2B1/Oatp2b1 expression at the membrane in the intestine and enhances absorption of organic anion compounds.

Circumferential pulmonary vein ablation for atrial fibrillation: back to the future?

antrum within the encircling lesions, elimination of anchor points of high frequency drivers, atrial debulking, and possibly ablation of ganglionated plexi within the targeted encircling lesions. As the role of PV antrum in AF is better understood, antral PV isolation has been widely performed as an effective ablation strategy to eliminate AF. It is within this context that we should evaluate the contribution by Arya et al. 7 in the current issue of the Journal. The authors report their experience in 674 consecutive patients, 85% of whom had paroxysmal AF, undergoing CPVA using a steerable sheath during 2005‐2007. An irrigated-tip ablation catheter was used with a maximum power of 25 W near the oesophagus and 40‐50 W elsewhere in the left atrium. The sole procedural endpoint was voltage attenuation along the circumferential lines around each set of PVs in patients with paroxysmal AF. Pulmonary vein isolation was not an endpoint of the procedure, but was achieved in 38% of patients. In a minority of patients with persistent AF, linear ablation along the roof and mitral isthmus was performed without confirmation of conduction block. Antiarrhythmic agents (flecainide or amiodarone) were used in 45% and 21% of patients for the first 3 and 6 months, respectively, and were discontinued after 6 months in all patients. Clinical outcome was based on symptoms or the presence of AF or AT on serial 7-day Holter recordings performed at 3, 6, and 12 months after the ablation procedure. The procedure and fluoroscopic times were approximately, 3 h, and 24 min, respectively. After a single-ablation procedure using a steerable sheath, 76% of patients were free from atrial arrhythmias during a 7-day monitoring period at 12 months. Approximately 50% of patients experienced early recurrence, which was due solely due to AT in about one-third of the patients. Early recurrence and a LA diameter .5 cm were associated with arrhythmia recurrence during follow-up. The clinical efficacy was similar among patients with paroxysmal or persistent AF. Six patients experienced pericardial tamponade, one of whom required surgery.

Quantification of Electrochemically Generated Iodine-Containing Metabolites Using Inductively Coupled Plasma Mass Spectrometry

For the risk assessment of drug candidates, the identification and quantification of their metabolites is required. The majority of analytical techniques is based on calibration standards for quantification of the metabolites. As these often are not readily available, the use of inductively coupled plasma mass spectrometry (ICPMS) is an attractive alternative for drugs containing heteroatoms. In this work, the online coupling of electrochemistry (EC), liquid chromatography (LC), and ICPMS is presented. The antiarrhythmic agent amiodarone, which contains two iodine atoms, is oxidized in an electrochemical flow-through cell under N-dealkylation and deiodination. The metabolites that are generated at different EC potentials are identified by electrospray ionization (ESI) mass spectrometry, compared to those from rat liver microsomal incubations and quantified by ICPMS. Phase-optimized LC, a recent approach for high-performance isocratic separations, is used to avoid the ICPMS calibration problems known to occur with gradient separations. The potential of the complementary use of ESI-MS and ICPMS for the qualitative and quantitative analysis of drug metabolites becomes apparent in this work.

Multiple Rundherdbildungen in der Lunge während Amiodaron-Therapie

During treatment with the antiarrhythmic agent amiodarone pulmonary infiltrates may be observed occasionally. Such a side-effect was seen in a 67-year-old patient after several months of amiodarone therapy (200 mg/d during 5 days of the week). After withdrawal of the drug the infiltrates regressed over a period of two months. No other causes for the pulmonary opacities could be established. So far, 13 patients with pulmonary changes during amiodarone treatment have been reported in the literature.

Kinetic analysis of myocardial uptake and negative inotropic effect of amiodarone in rat heart

The distribution kinetics of the highly lipophilic antiarrhythmic agent amiodarone is not well understood. The purpose of the present investigation was to develop a pharmacokinetic–pharmacodynamic (PK/PD) model to describe cardiac uptake and the negative inotropic effect of amiodarone in the isolated perfused rat heart. Amiodarone (10 μM) was infused for 15 min to 6 hearts. The time course of outflow concentration and left ventricular developed pressure were measured and analyzed by the model. The uptake of amiodarone by the heart was flow limited and characterized by an extremely high partition coefficient with a predicted tissue washout half-live of 17 h. Only 36.8% of input amount to heart recovered within 45 min after start of the 15 min infusion. The negative inotropic effect was delayed with a time constant of 11 min and the maximal decrease in left ventricular developed pressure was described by a sigmoid E max model with an E max of 37.7% and an EC 50 of 0.53 μM. Our results suggest a rapid tissue uptake and a moderate negative inotropic effect of amiodarone after intravenous injection.

Analyse der Todesursachen von ICD-Patienten in der Langzeitbeobachtung

Implantable cardioverter defibrillators represent an effective therapy to prevent sudden cardiac death in patients with ventricular arrhythmias. This implies a change in the spectrum of causes of death. There exist no large studies providing an exact differentiation of these causes of death. During a mean observation period of 41+/-29 months (3 d-12 yrs), we analyzed the outcome of 429 ICD patients (CAD n=274, dilative CMP n=97, others n=23, no structural heart disease n=35), mean age 62+/-12 years (23-87 yrs). The overall survival rate was 79.7% whereby 3.5% of these patients underwent successful heart transplantation and 2.1% died suddenly. 60.9% of all deaths showed a non-sudden cardiac cause (heart failure 56.3%, myocardial infarction 4.6%). In 28.7% a non-cardiac fatal event was present (cancer 11.5%, septicemia 6.9%, stroke 4.6%). The deceased showed significantly more often structural heart disease (100 vs 92%, p<0.02) and a lower left ventricular ejection fraction (37+/-14 vs 44+/-18%, p<0.02). Significant higher survival rates were associated with medication with beta blockers (88 vs 75%, p<0.02) and the class III antiarrhythmic agents sotalol und amiodarone (85 vs 77%, p<0.03). Mortality due to sudden death was reduced to 2.1% in ICD patients associated with a shift of causes of death towards severe heart failure. Therefore, special attention should be paid to the signs of heart failure in these patients to enable early initiation of appropriate therapeutic strategies.

Poster 74: Amiodarone as a Cause of Polyneuropathy: A Case Report

Setting: Regional care Veterans Administration hospital. Patient: A 50-year-old man with history of coronary artery disease and ventricular tachycardia who presents with 5 months of progressive bilateral extremity weakness, with loss of sensation, reflexes, and bowel incontinence. Case Description: The patient has a history of ventricular tachycardia and was placed on the class III antiarrhythmic agent amiodarone 2 years prior to symptom onset. Initially, the patient’s symptoms of weakness were described as difficulty rising from a chair and trouble swallowing.

Liver cirrhosis induced by long-term administration of a daily low dose of amiodarone: A case report

The anti-arrhythmic agent amiodarone (AD) is associated with numerous adverse effects, but serious liver disease is rare. The improved safety of administration of daily low doses of AD has already been established and this regimen is used for long-term medication. Nevertheless, asymptomatic continuous liver injury by AD may increase the risk of step-wise progression of non-alcoholic fatty liver disease. We present an autopsy case of AD-induced liver cirrhosis in a patient who had been treated with a low dose of AD (200 mg/d) daily for 84 mo. The patient was a 85-year-old male with a history of ischemic heart disease. Seven years after initiation of treatment with AD, he was admitted with cardiac congestion. The total dose of AD was 528 g. Mild elevation of serum aminotransferase and hepatomegaly were present. Liver biopsy specimens revealed cirrhosis, and under electron microscopy numerous lysosomes with electron-dense, whorled, lamellar inclusions characteristic of a secondary phospholipidosis were observed. Initially, withdrawal of AD led to a slight improvement of serum aminotransferase levels, but unfortunately his general condition deteriorated and he died from complications of pneumonia and renal failure. Long-term administration of daily low doses of AD carries the risk of progression to irreversible liver injury. Therefore, periodic examination of liver function and/or liver biopsy is required for the management of patients receiving long-term treatment with AD.

High affinity HERG K + channel blockade by the antiarrhythmic agent dronedarone: resistance to mutations of the S6 residues Y652 and F656

Pharmacological inhibition of human-ether-a-go-go-related gene (HERG) K + channels by structurally and therapeutically diverse drugs is associated with the ‘acquired’ form of long QT syndrome and with potentially lethal cardiac arrhythmias. Two aromatic amino-acid residues (Y652 and F656) on the inner (S6) helices are considered to be key constituents of a high affinity drug binding site within the HERG channel pore cavity. Using wild-type (WT) and mutant HERG channels expressed in mammalian cell lines, we have investigated HERG channel current ( I HERG) blockade at 37 ± 1 °C by dronedarone (DRONED), a non-iodinated analogue of the Class III antiarrhythmic agent amiodarone (AMIOD). Under our conditions WT I HERG tails, measured at −40 mV following activating pulses to +30 mV, were blocked with IC 50 values of ∼59 and 70 nM for DRONED and AMIOD, respectively. I HERG inhibition by DRONED was contingent upon channel gating, with block developing rapidly on membrane depolarization, but with no preference for activated over inactivated channels. High external [K +] (94 mM) reduced the potency of I HERG inhibition by both DRONED and AMIOD. Strikingly, mutagenesis to alanine of the S6 residue F656 (F656A) failed to eliminate blockade by both DRONED and AMIOD, whilst Y652A had comparatively little effect on DRONED but some effect on AMIOD. These findings demonstrate that high affinity drug blockade of I HERG can occur without a strong dependence on the Y652 and F656 aromatic amino-acid residues.

875-5 Randomized trial of two antiarrhythmic agents (amiodarone and sotalol) in patients with atrial fibrillation for whom direct current cardioversion is planned

875-5 Randomized trial of two antiarrhythmic agents (amiodarone and sotalol) in patients with atrial fibrillation for whom direct current cardioversion is planned

Ventricular instability and sudden death in patients with heart failure: lessons from clinical trials

Various trials using non-antiarrhythmic drugs, antiarrhythmic agents and implantable-cardioverter defibrillators (ICDs) have been performed in order to decrease the incidence of sudden death and to improve survival in chronic heart failure (CHF). The present review addresses some of the key findings of those trials. First, it addresses the importance of considering the potential electrophysiological effects of non-antiarrhythmic drugs and of using angiotensin-converting enzyme inhibitors, beta-blockers and antialdosterone agents in the optimal management of patients with CHF. Second, it reviews the effects of the antiarrhythmic agent amiodarone on mortality and arrhythmic deaths in patients with depressed left ventricular function. Third, it assesses the evidence that patients with CHF and a history of sustained ventricular arrhythmias or resuscitation may benefit from ICD implantation. Finally, it outlines the growing role of ICD therapy in patients with CHF as a primary indication.

The effect of amiodarone and/or antioxidant treatment on splenocyte blast transformation

Previous studies have shown that free radical reactions may play an important role in the pathogenesis of the adverse effects of the antiarrhythmic agent amiodarone. The aim of this study was to investigate the role of free radical reactions in amiodarone-induced changes in the cell-mediated immune response. Therefore, we investigated the effects of amiodarone alone and in combination with either vitamin E or silymarin on (a) spontaneous blast transformation of splenocytes, (b) concanavalin A (con A)-induced proliferation of splenocytes at three different lectin concentrations, and (c) the content of conjugated dienes in liver homogenate. Forty-eight male Fischer 344 rats were randomized to one of the following groups: 1, control; 2, amiodarone; 3, vitamin E; 4, amiodarone+vitamin E; 5, silymarin; 6, amiodarone+silymarin. The con A-induced splenocyte proliferation was significantly decreased in amiodarone-treated rats at all three lectin concentrations. In the amiodarone-treated group, the change of spontaneous blast transformation was not significantly different from the control. In groups treated with amiodarone plus either antioxidant, both the spontaneous and con A-induced splenocyte proliferation were significantly increased compared with the amiodarone-treated group, and were similar to those in the control group. Amiodarone treatment significantly increased, and both silymarin and vitamin E combined with amiodarone significantly decreased, the conjugated diene content of liver homogenate compared with amiodarone treatment alone. In conclusion, free radicals generated by amiodarone may be implicated in the adverse effects of amiodarone on cell-mediated immune response, and antioxidants applied together with amiodarone may protect against or reduce both the unfavorable immunological effects of amiodarone and amiodarone toxicity.