Addition Of Amiodarone Research Articles

Polyunsaturated Fatty Acids (PUFA) Increases the Sensitivity of Saccharomyces cerevisiae to Ethanol by Impairing the Function of the Mitochondrial Unselective Channel (MUC)

Yeast cells uncouple its respiration by opening a mitochondrial unselective channel (MUC) that dissipates the membrane potential and accelerates oxygen consumption in order to avoid a deleterious buildup of ROS. Yeast incorporates polyunsaturated fatty acids (PUFA) into membranes when available in its environment, increasing the sensitivity of membranes to oxidative damage. One factor causing oxidative stress in yeast is ethanol accumulation during fermentation. The MUC is constituted by the voltage-dependent anionic channel (VDAC), the adenine nucleotide translocator and the cyclophilin D, being the VDAC a sensor for Ca2+ levels that promotes MUC closing under high Ca2+ concentrations. Moreover, MUC function is dependent on the phospholipid cardiolipin. In this work, we propose that yeast become more susceptible to ethanol stress when grow in the presence of PUFA by the impairment of MUC function due to enhanced lipid peroxidation. Yeast cells were grown in liquid YPD medium with (+C18:3) or without (-C18:3) 1mM linolenic acid and 10% ethanol. Ethanol decreased yeast growth by 20% and 90% in –C18:3 and +C18:3 cells, respectively. Ethanol also promoted lipid peroxidation only in +C18:3 cells. The addition of amiodarone, which increases cytosolic Ca2+ levels and promotes the closure of MUC, decreased 80% the growth in –C18:3 cells, while the +C18:3 cells showed the same levels of growth inhibition than without amiodarone. In – C18:3 cells respiring in uncoupled state (U), amiodarone decreased respiration by promoting MUC closing and coupling. Conversely, respiration was slightly inhibited by amiodarone in the +C18:3 cells. The role of MUC in the deleterious effects of ethanol in +C18:3 cells was confirmed in yeast mutants depleted in cardiolipin and VDAC, as these cells became insensitive to the effects of amiodarone. These results suggest that increased sensitivity to ethanol elicited by C18:3 may be due to impaired MUC function due to enhanced lipid peroxidation.

In Vitro Enhancement of Carvedilol Glucuronidation by Amiodarone-Mediated Altered Protein Binding in Incubation Mixture of Human Liver Microsomes with Bovine Serum Albumin.

Carvedilol is mainly metabolized in the liver to O-glucuronide (O-Glu). We previously found that the glucuronidation activity of racemic carvedilol in pooled human liver microsomes (HLM) was increased, R-selectively, in the presence of amiodarone. The aim of this study was to clarify the mechanisms for the enhancing effect of amiodarone on R- and S-carvedilol glucuronidation. We evaluated O-Glu formation of R- and S-carvedilol enantiomers in a reaction mixture of HLM including 0.2% bovine serum albumin (BSA). In the absence of amiodarone, glucuronidation activity of R- and S-carvedilol for 25 min was 0.026, and 0.51 pmol/min/mg protein, and that was increased by 6.15 and 1.60-fold in the presence of 50 µM amiodarone, respectively. On the other hand, in the absence of BSA, or when BSA was replaced with human serum albumin, no enhancing effect of amiodarone on glucuronidation activity was observed, suggesting that BSA played a role in the mechanisms for the enhancement of glucuronidation activity. Unbound fraction of S-carvedilol in the reaction mixture was greater than that of R-carvedilol in the absence of amiodarone. Also, the addition of amiodarone caused a greater increase of unbound fraction of R-carvedilol than that of S-carvedilol. These results suggest that the altered protein binding by amiodarone is a key mechanism for R-selective stimulation of carvedilol glucuronidation.

<b>Concurrent Use of Statins and Amiodarone</b>

To estimate the concurrent use between statins and amiodarone in context with published case reports of drug-interaction-induced rhabdomyolysis. Retrospective analysis of a longitudinal prescription claims database for concurrent prescriptions of statins and amiodarone dispensed during 2006. The study population includes an unprojected annual number of patients who filled a prescription for an HMG CoA reductase inhibitor or simvastatin-containing products or lovastatin-containing products or Lipitor (atorvastatin) or Caduet (amlodipine/atorvastatin) concurrently with brand and generic forms of amiodarone during 2006. The concurrency analysis was used to provide context for published case reports of rhabdomyolysis/myopathy related to simvastatin and amiodarone concurrent use. Episodes of concurrent use between statins and amiodarone. Findings from this analysis indicate noteworthy amiodarone and statin concurrency (44%) when based on amiodarone patient volume. Atorvastatin had the greatest level of concurrency (23.5%) with amiodarone followed by simvastatin (13.3%). Proportionality based on amiodarone patient volume shows a greater level of concurrency with 20 mg (6%) and 40 mg (5.5%) simvastatin strengths compared with other simvastatin strengths. Clinicians should be vigilant in monitoring the regimens of patients prescribed a statin with drugs that may increase the risk of myopathy. In particular, since nearly half of the patients prescribed amiodarone may also be prescribed a statin, then addition of amiodarone or changes in statin dose should trigger a drug regimen review and patient level monitoring. Clinicians should avoid simvastatin doses greater than 20 mg per day in patients taking amiodarone.

Mitochondrial matrix fragmentation as a protection mechanism of yeast Saccharomyces cerevisiae

It was shown that separate fragments of the inner mitochondrial compartment (mitoplasts) can exist under a single non-fragmented outer membrane. Here we asked whether fragmentation of the inner mitochondria could prevent rupturing of the outer membrane and release of pro-apoptotic molecules from the mitochondrial intermembrane space into the cytoplasm during mitochondrial swelling. First, we showed that in Saccharomyces cerevisiae yeast addition of amiodarone causes formation of electrically separate compartments within mitochondrial filaments. Moreover, amiodarone treatment of Deltaysp2 mutant produced a higher proportion of cells with electrically discontinuous mitochondria than in the wild type, which correlated with the survival of cells. We confirmed the existence of separated mitoplasts under a single outer membrane using electron microscopy. Mitochondria with fragmented matrixes were also detected in cells of the stationary phase. Our data suggest that such fragmentation acts as a cellular protective mechanism against stress.

Clinical factors influencing the sensitivity to warfarin when restarted after surgery

Resumption of oral anticoagulation after surgery may result in a different maintenance dose of warfarin than before the procedure. Knowledge of the clinical determinants of postoperative response could help avoid excessive anticoagulation in sensitive patients or avoid extended delays in achieving a therapeutic level in resistant patients. Retrospective review. Two hundred warfarin-treated patients who were managed by our clinic for surgery. Two independent adjudicators classified the postoperative response to warfarin as Resistant, Normal or Sensitive, based on previous maintenance dose, international normalized ratio (INR) on the day of resumption, number of days until INR of >1.9 and doses of warfarin given. A third adjudicator resolved disagreements. Clinical data were extracted from the patient records and correlated with the response. Interobserver agreement for classification of postoperative response was moderate (weighted kappa 0.46) with 37 (18.5%) considered resistant, 135 (67.5%) normal, 27 (13.5%) sensitive and one patient was not classifiable. The main type of surgery was cardiac. In univariable analysis only addition of amiodarone after surgery was associated with a sensitive response (P = 0.04). After adjustment for all other factors with an ordered categorical response, amiodarone remained as the sole independent risk factor (P = 0.02) for a sensitive response, odds ratio 0.41 (95% confidence interval 0.19-0.89) for Normal instead of Sensitive or for Resistant instead of Normal. Altered sensitivity to warfarin occurs in about one-third of patients after surgery and can be predicted by the introduction of concomitant amiodarone therapy but not by patient factors or the nature of the procedure. Changes in concomitant medications after surgery should alert doctors of the potential for increased sensitivity to warfarin.

Efficacy of Magnesium-Amiodarone Step-Up Scheme in Critically Ill Patients With New-Onset Atrial Fibrillation: A Prospective Observational Study

Amiodarone is considered a first-choice antiarrhythmic drug in critically ill patients with new-onset atrial fibrillation (AF). However, evidence supporting the use of this potentially toxic drug in critically ill patients is scarce. Magnesium sulphate (MgSO4) has shown to be effective for both rate and rhythm control, to act synergistically with antiarrhythmic drugs, and to prevent proarrhythmia. Treatment with MgSO4 may reduce the need for antiarrhythmic drugs such as amiodarone in critically ill patients with new-onset atrial fibrillation. The efficacy of a new institutional protocol was evaluated. Patients were treated with a new institutional protocol for new-onset atrial fibrillation in critically ill patients. An MgSO4 bolus (0.037 g/kg body weight in 15 minutes) was followed by continuous infusion (0.025 g/kg body weight/h). Intravenous amiodarone (loading dose 300 mg, followed by continuous infusion of 1200 mg/24 h) was given to those not responding to MgSO4 within 1 hour. Clinical response was defined as conversion to sinus rhythm or decrease in heart rate <110 beats/min. Sixteen of the 29 patients responded to MgSO4 monotherapy, whereas the addition of amiodarone was needed in 13 patients. Median (range) time until conversion to sinus rhythm after MgSO4 was 2 (1-45) hours. Median (range) conversion time in patients requiring amiodarone was 4 (2-78) hours, and median (range) conversion time in all patients was 3 (1-78) hours. The 24-hour conversion rate was 90%. Relapse atrial fibrillation was seen in 7 patients. The magnesium-amiodarone step-up scheme reduces the need for amiodarone, effectively converts new-onset atrial fibrillation into a sinus rhythm within 24 hours, and seems to be safe in critically ill patients.

Suppression by propranolol and amiodarone of an electrical storm refractory to metoprolol and amiodarone

A 60-year-old male patient with ischemic cardiomyopathy experienced an electrical storm 1 month after implantation of an internal cardioverter-defibrillator. Recurrent life-threatening episodes of ventricular tachycardia persisted despite maximal antiarrhythmic theraphy with amiodarone, metoprolol and mexiletine. After a total of more than 500 cardioversions, all antiarrhythmic medications were withdrawn, and the nonselective beta-blocker propranolol was initiated. Electrical stability was achieved and the patient was discharged on propranolol 400 mg/day. Two months later, a second arrhythmia cluster occurred that was controlled by the addition of amiodarone. The patient remains free of arrhythmia 15 months after the event with the combination of propranolol and amiodarone.

Role of Amiodarone in Heart Failure

Amiodarone is a unique drug with potential benefits in heart failure. Unlike other antiarrhythmic drugs, amiodarone has properties of all four of the Vaughan-Williams classes. Amiodarone causes hemodynamic effects, as a result of its direct effect on smooth muscle and its calcium channel and alpha adrenergic blockade; it dilates coronary arteries and increases coronary blood flow. Amiodarone also causes peripheral arterial vasodilatation and decreases systemic blood pressure and afterload. There have been several clinical trials that demonstrated the beneficial effects of amiodarone therapy in heart failure involving small number of patients. The effect of amiodarone on survival in patients with CHF was recently examined in two large randomized, placebo-controlled trials. The Gruppo de Estudo de la Sobrevida en la Insufficiencia Cardiaca en Argentina (GESICA) was performed in Argentina, and the Survival Trial of Antiarrythmic Therapy In Congestive Heart Failure (CHF-STAT) was performed in Veterans' Administration hospitals in the United States. The results of the GESICA trial suggested that the addition of amiodarone improved survival, decreased hospital admissions for congestive heart failure, and improved functional class in patients with heart failure. The CHF-STAT study demonstrated that amiodarone therapy was associated with no survival benefit for sudden death, despite significant suppression of ventricular arrhythmias and improvement in left ventricular function. In conclusion amiodarone is an effective antiarrhythmic agent in patients with heart failure. It has been shown to suppress ventricular ectopy with an acceptable frequency of adverse effects when administered in lower doses. The role of amiodarone in patients with ischemic cardiomyopathy and heart failure needs further study.

The negative inotropic effects of amiodarone on isolated guinea pig heart: A possible role of Na +-Ca 2+ Exchange

1. The negative inotropic effects of amiodarone (AM) were studied in isolated, isometrically contracting ventricular papillary muscles from guinea pigs. 2. AM, 4.4 × 10 −5 M, significantly decreased ouabain 10 −6 M)-induced increase in the developed tension. 3. Manganese (10 −2 M), a partial blocker of Na +-Ca 2+ exchange, attenuated the AM's negative inotropy. 4. Theophylline (1.5 × 10 −2 M), an inhibitor of phosphodiesterase, produced a marked increase in the tension (about twice compared to the ouabain effect). 5. However, the magnitude of decrease by AM in the tension in the presence of theophylline was similar to that in the case of ouabain. 6. Tetrodotoxin (TTX) decreased the contraction by about a half, and then subsequent addition of AM in the presence of TTX led to a further decrease in the tension. 7. Eventually co-existence of TTX and AM led to a decrease in tension of same degree, compared to the decrease in tension by AM alone. 8. The results suggest that a large portion of negative inotropic action of AM may, at least, reflect interference with the Na +-Ca 2+ exchange mechanism. 9. This interference with the Na +-Ca 2+ exchange mechanism may exert a strong negative inotropic effect of the drug, in combination with a decrease in Ca 2+ influx via Ca 2+ channels and/or an impairment of Ca 2+-sequestration.

Clinical and pharmacologic study of fetal supraventricular tachyarrhythmias

The purpose of this study was to evaluate the efficacy of maternal digoxin administration in 16 cases of fetal supraventricular tachyarrhythmia diagnosed by fetal echocardiography; cardiac anatomy was normal in all cases. The retrospective analysis included nine mothers who received digoxin orally in most cases, with control of the arrhythmia in two fetuses. The addition of amiodarone (five cases) and propranolol (two cases) yielded two successes with amiodarone. The therapeutic regimen of digoxin was then modified on the basis of poor response to orally administered digoxin. In the prospective study, digoxin was administered intravenously to seven mothers according to a standard protocol; high doses (1 to 2 mg intravenously) were prescribed for the first 24 hours and intravenous digoxin therapy was maintained for at least 5 days, depending on the fetal response. Digoxin pharmacokinetic studies of four mothers showed an increased plasma clearance and reduced elimination half-life. Digoxin controlled the five supraventricular tachycardias (with hydrops in four cases). Maternal flecainide therapy restored sinus rhythm in two cases of atrial flutter. Our prospective study emphasizes the efficacy and safety for the fetus and the mother of intravenously administered digoxin as a first-choice drug in the treatment of supraventricular tachyarrhythmias. Flecainide may be a promising second-choice drug but requires further clinical investigation. Amiodarone and propranolol seem to be ineffective.

Effects of Amiodarone on Serum T3and T4Concentrations in Hyperthyroid Patients Treated with Propylthiouracil

Amiodarone (Cordarone) has been proven to be useful in the management of atrial fibrillation. However, because of a large iodine content, this drug is not used in this complication of thyrotoxicosis. We previously have observed a greater fall in serum T3 and T4 concentrations in hyperthyroid patients treated with amiodarone and methimazole than with methimazole alone. In the present study, we determined whether the addition of amiodarone to propylthiouracil (PTU) could improve the levels of circulating thyroid hormones in hyperthyroid patients, and we assessed the release of iodide from amiodarone by measuring the 24 h urinary iodine excretion. Twelve hyperthyroid patients were treated either with PTU, 600 mg daily for 10 days (group PTU), or with amiodarone (A), 1200 mg daily for 3 days in addition to PTU (group A-PTU). Basal serum T4, T3, and rT3 concentrations (mean +/- SEM) were respectively 206 +/- 13 nmol/L, 5.13 +/- 0.8 nmol/L, and 81 +/- 7 ng/dL for group PTU and 238 +/- 39 nmol/L, 4.73 +/- 1.06 nmol/L, and 84 +/- 12 ng/dL for group A-PTU (NS). In group A-PTU, plasma amiodarone peaked on day 3 (mean +/- SEM: 0.48 +/- 0.11 mg/L), and urinary iodine reached 5.27 +/- 1.28 mg/day on day 5. The fall in serum T3 and the increase in serum rT3 concentrations were significantly greater in group A-PTU than in group PTU (ANOVA, p less than 0.05). In group A-PTU, the minimal serum T3 concentration was observed on day 5 of treatment (28 +/- 6% of the pretreatment values).(ABSTRACT TRUNCATED AT 250 WORDS)

Interaction of amiodarone and desethylamiodarone with the cardiac muscarinic receptor in vitro

We studied the interaction of amiodarone hydrochloride (Cordarone) and its major metabolite desethylamiodarone with the muscarinic receptor in purified canine cardiac sarcolemmal vesicles by measuring equilibrium binding of the muscarinic antagonist [ 3H]quinuclidinyl benzilate (QNB) ∗ ∗ Abbreviations used are: [ 3H]-QNB, tritiated quinuclidinyl benzilate; HEPES, N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid; PLA 2, phospholipase A 2; DMSO, dimethylsulfoxide and carbachol displacement of [ 3H]-QNB. At a [ 3H]-QNB concentration of 0.02 n m, equilibrium binding was inhibited by amiodarone and desethylamiodarone with an IC 50 of 6.86 × 10 −6 m and 2.25 × 10 −6 m, respectively. The presence of increasing concentrations of [ 3H]-QNB in the incubation medium was able to reverse the inhibition seen with 1 × 10 −6 m amiodarone. Scatchard analysis of [ 3H]-QNB saturation isotherms (37°C, pH 7.4) in the presence of 1 × 10 −6 m amiodarone showed an apparent increase in equilibrium dissociation constant ( K d) over control from 0.045 ± 0.002 n m to 0.084 ± 0.001 n m while maximal binding capacity ( B max) was unaffected: 10.8 ± 1.14 and 10.5 ± 1.48 pmol/mg (means ± s.e.m., n = 3), respectively. The inhibitory effect of amiodarone on equilibrium binding was highly dependent on the drug:membrane phospholipid mole ratio with effects beginning at a ratio of less than 0.1:1. Hill plot analysis was consistent with the interaction of [ 3H]-QNB at a single site in the presence or absence of amiodarone. Amiodarone (3 × 10 −6 m) decreased the pseudo-first order forward rate constant of [ 3H]-QNB (0.02 n m) with the muscarinic receptor ( k obs = 4.05 ± 0.61 × 10 −4/s under control conditions and 2.36 ± 0.15 × 10 −4/s in the presence of amiodarone). The presence of 3 × 10 −6 m amiodarone from the start of the binding reaction had no observable effect on the rate of dissociation of [ 3H]-QNB (0.02 n m) as measured by the addition of 100 n m atropine at equilibrium. The addition of amiodarone (3 × 10 −6 m) increased the estimated K d values obtained from carbachol displacement curves of [ 3H]-QNB most noticeably at the low affinity binding site. Amiodarone had no effect on the relative abundance of each receptor subclass. The results therefore suggest that amiodarone and desethylamiodarone modulate agonist and antagonist binding to the muscarinic receptor in a competitive manner and may exert their effect at least in part, by influencing lipid-protein interactions.

Effects of amiodarone on the kinetics of antipyrine

An increased plasma half-life of antipyrine (phenazone) has been reported in a small number of patients with ventricular tachycardia following commencement of amiodarone therapy. 1 Interactions with other drugs such as warfarin 2 and digoxin 3 are common following the addition of amiodarone. This may be due, at least in part, 4 to impaired hepatic drug metabolism. This study evaluates the kinetics of antipyrine before and during long-term amiodarone therapy.

The digoxin-amiodarone interaction

To assess the cause of the digoxin-amiodarone interaction, the systemic availability and renal excretion of digoxin were examined in 10 patients. Patients were studied before and after 1 week and 6 weeks of concurrent amiodarone therapy, and four were also studied after 4-8 months. Mean (+/- SD) peak plasma digoxin concentration rose from 1.55 +/- 0.6 microgram /1 prior to amiodarone therapy to 2.85 +/- 1.3 micrograms/1 after 1 week of combined therapy (p less than 0.01). Mean AUC also rose from 7.2 +/- 2.1 micrograms/1.h to 12.1 +/- 6.4 micrograms/1.h (p less than 0.01) during this period. Mean peak plasma digoxin concentration and AUC remained elevated after 6 weeks and, in the patients studied, at 4-8 months. Mean urinary digoxin clearance remained unchanged. Plasma amiodarone and desethylamiodarone concentrations were consistent with the prescribed doses. This study confirmed previous findings of raised plasma digoxin concentrations following the addition of amiodarone. It has also shown that this interaction is sustained for at least several months. The cause has not been fully elucidated but does not appear to be due to a change in the renal clearance of digoxin.

Effects of Amiodarone and Desethylamiodarone on Pituitary Deiodinase Activity and Thyrotropin Secretion in the Rat

The effect of acute administration of amiodarone, its major metabolite desethylamiodarone and iodine in an amount equal to that contained in amiodarone on serum thyroid hormone and thyrotropin (TSH) concentrations and hepatic and pituitary 5' deiodination of thyroxine (T4) in the euthyroid and hypothyroid rat was evaluated. Amiodarone, desethylamiodarone and iodine all caused a decrease in serum T4 and triiodothyronine (T3) concentrations in euthyroid rats, while serum TSH concentrations and pituitary and hepatic 5' deiodinase activities were decreased only in the amiodarone and desethylamiodarone-treated animals. Serum TSH was increased in the iodine treated rats. Amiodarone, but not iodine, decreased serum T3 and TSH concentrations and pituitary and hepatic 5' deiodinase activities in hypothyroid rats. Inhibition of hepatic 5' deiodinase activity was also observed by the addition of amiodarone in vitro in the absence of dithiothreitol (DTT) but not in the presence of DTT. The decrease in the serum T4 concentration observed with amiodarone and desethylamiodarone administration is probably secondary to the inhibitory effect of iodine released from the drugs on thyroidal T4 synthesis and secretion. Iodine inhibition of thyroidal T3 synthesis and secretion, decreased T4 substrate for a peripheral generation of T3 and inhibition of T4 to T3 conversion all contribute to the decrease in serum T3 observed. The decrease in the serum TSH concentration, despite low serum T4 and T3 concentrations and inhibition of pituitary 5' deiodinase, suggest that amiodarone may function as a thyroid hormone agonist in the pituitary.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone and thyroid hormone action.

In clinically euthyroid subjects on long-term amiodarone therapy free thyroxine (T4) concentrations were increased and free triiodothyronine (T3) levels reduced. There was also a marked increase in reverse T3 in the treated group. These changes are consistent with inhibition of peripheral deiodination of T4 and reverse T3. Despite the rise in T4 serum thyrotrophin (TSH) levels were increased, suggesting an effect of amiodarone on the anterior pituitary. To investigate the interaction of amiodarone with the cellular actions of thyroid hormones we examined the influence of the drug in vitro on the binding of T3 to isolated nuclei prepared from rat anterior pituitary tissue. Amiodarone inhibited the nuclear binding of T3 in a dose dependent fashion. Addition of amiodarone in vitro also stimulated TSH release from cultured rat anterior pituitary cells, consistent with a T3 antagonistic effect. These studies provide evidence for a direct influence of amiodarone on the thyrotroph, mediated via nuclear T3 receptor binding.