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The combination of antiarrhythmic agents, amiodarone or dronedarone, with the anticoagulant rivaroxaban is used clinically in the management of atrial fibrillation for rhythm control and secondary stroke prevention respectively. Renal drug-drug interactions (DDIs) between amiodarone or dronedarone and rivaroxaban were previously ascribed to inhibition of rivaroxaban secretion by P-glycoprotein at the apical membrane of renal proximal tubular epithelial cells. Benzbromarone, a known inhibitor of organic anion transporter 3 (OAT3), shares a benzofuran scaffold with amiodarone and dronedarone. However, inhibitory activity of amiodarone and dronedarone against OAT3 remains arcane. Here, we conducted in vitro transporter inhibition assays in OAT3-transfected HEK293 cells which revealed amiodarone, dronedarone and their respective major pharmacologically-active metabolites N-desethylamiodarone and N-desbutyldronedarone possess inhibitory activity against OAT3, with corrected K i values of 0.042, 0.019, 0.028 and 0.0046 μM respectively. Protein binding effects and probe substrate dependency were accounted for in our assays. Static modelling predicted 1.29-, 1.01-, 1.29- and 1.16-fold increase in rivaroxaban exposure, culminating in a predicted 1.29-, 1.01-, 1.28- and 1.15-fold increase in major bleeding risk respectively, suggesting potential OAT3-mediated DDI between amiodarone and rivaroxaban. Future work involving physiologically-based pharmacokinetic modelling is crucial in holistically predicting the complex DDIs between the benzofuran antiarrhythmic agents and rivaroxaban., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2021 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)

Leishmaniasis is a parasitic disease representing an important problem of public health. Visceral leishmaniasis, resulting from infection with Leishmania donovani, causes considerable mortality and morbidity in the poorest region of the word. At present there is no current effective treatment, since the approved, drugs are expensive and are not free of undesirable side effects. Therefore, there is a need for the identification of new drugs. In this context, the parasite Ca 2+ regulatory mechanisms in which mitochondria and acidocalcisomes are involved have been postulated as important targets for several trypanocidal drugs. Thus, amiodarone and dronedarone, common human antiarrythmics, exert its known action on these parasites through the disruption of the intracellular Ca 2+ homeostasis. AMIODER is a benzofuran derivate based on the structure of amiodarone that recently demonstrates a significant effect on Trypanosoma cruzi. We now report the effect of AMIODER on Leishmania donovani demonstrating that it inhibit the growth of promastigotes and also of amastigotes inside macrophages, the clinically relevant stage of the parasite, obtaining IC 50 values significantly lower than those reported for T. cruzi. We also show that this compound disrupted Ca 2+ homeostasis in L. donovani, through its action on two organelles involved in the intracellular Ca 2+ regulation and on the bioenergetics of the parasite. AMIODER totally collapsed the electrochemical membrane potential of the unique giant mitochondrion and simultaneously induced the alkalinization of acidocalcisomes, driving together to a large increase in the intracellular Ca 2+ concentration of the parasite as the main mechanism of action of this benzofurane derivative., (Copyright © 2019. Published by Elsevier B.V.)

Chagas disease is a neglected tropical affection caused by the protozoan parasite Trypanosoma cruzi. There is no current effective treatment since the only two available drugs have a limited efficacy and produce side effects. Thus, investigation efforts have been directed to the identification of new drug leads. In this context, Ca 2+ regulating mechanisms have been postulated as targets for antiparasitic compounds, since they present paramount differences when compared to host cells. Amiodarone is an antiarrhythmic with demonstrated trypanocidal activity acting through the disruption of the parasite intracellular Ca 2+ homeostasis. We now report the effect of a benzofuran derivative based on the structure of amiodarone on T. cruzi. This derivative was able to inhibit the growth of epimastigotes in culture and of amastigotes inside infected cells, the clinically relevant phase. We also show that this compound, similarly to amiodarone, disrupts Ca 2+ homeostasis in T. cruzi epimastigotes, via two organelles involved in the intracellular Ca 2+ regulation and the bioenergetics of the parasite. We demonstrate that the benzofuran derivative was able to totally collapse the membrane potential of the unique giant mitochondrion of the parasite and simultaneously produced the alkalinization of the acidocalcisomes. Both effects are evidenced by a large increase in the intracellular Ca 2+ concentration of T. cruzi., (Copyright © 2018 Elsevier Inc. All rights reserved.)

We found that amiodarone has potent antifungal activity against a broad range of fungi, potentially defining a new class of antimycotics. Investigations into its molecular mechanisms showed amiodarone mobilized intracellular Ca2+, which is thought to be an important antifungal characteristic of its fungicidal activity. Amiodarone is a synthetic drug based on the benzofuran ring system, which is contained in numerous compounds that are both synthetic and isolated from natural sources with antifungal activity. To define the structural components responsible for antifungal activity, we synthesized a series of benzofuran derivatives and tested them for the inhibition of growth of two pathogenic fungi, Cryptococcus neoformans and Aspergillus fumigatus, to find new compounds with antifungal activity. We found several derivatives that inhibited fungal growth, two of which had significant antifungal activity. We were surprised to find that calcium fluxes in cells treated with these derivatives did not correlate directly with their antifungal effects; however, the derivatives did augment the amiodarone-elicited calcium flux into the cytoplasm. We conclude that antifungal activity of these new compounds includes changes in cytoplasmic calcium concentration. Analyses of these benzofuran derivatives suggest that certain structural features are important for antifungal activity. Antifungal activity drastically increased on converting methyl 7-acetyl-6-hydroxy-3-methyl-2-benzofurancarboxylate (2b) into its dibromo derivative, methyl 7-acetyl-5-bromo-6-hydroxy-3-bromomethyl-2-benzofurancarboxylate (4).

KB130015 [KB; 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran] is a novel amiodarone derivative designed to retain the antiarrhythmic effects without the side effects. Unlike amiodarone, KB slows Na(+) current inactivation and could, via an increase in [Na(+)](i), potentially lead to Ca(2+) overload. Therefore, we studied the effects of KB on Na(+) and Ca(2+) handling in single pig ventricular myocytes using the whole-cell ruptured patch-clamp technique and K(5)fluo-3 as [Ca(2+)](i) indicator. KB at 10 microM did not prolong action potential duration but slightly increased the early plateau; spontaneous afterdepolarizations were not observed. The amplitude of the [Ca(2+)](i) transient was larger (434.9 +/- 37.2 versus 326.8 +/- 39.8 nM at baseline, n = 13, P < 0.05), and the time to peak [Ca(2+)](i) was prolonged. During voltage-clamp pulses, [Ca(2+)](i) transient peak was also larger (578.1 +/- 98.9 versus 346.4 +/- 52.6 nM at baseline, P < 0.05). Although L-type Ca(2+) current was reduced (by 21.9% at +10 mV, n = 9, P < 0.05), sarcoplasmic reticulum Ca(2+) content was significantly enhanced with KB. Forward Na(+)/Ca(2+) exchange was significantly decreased after KB application, but reverse mode of the Na(+)/Ca(2+) exchanger was significantly larger, suggesting an increase in [Na(+)](i) with KB. This was confirmed by a 2-fold increase of the [Na(+)]-dependent current generated by the Na/K-ATPase (from 0.17 +/- 0.02 to 0.38 +/- 0.06 pA/pF, P < 0.05). In conclusion, as predicted from the slowing of I(Na) inactivation, KB130015 leads to an increase in [Na(+)](i) and consequently in cellular Ca(2+) load. This effect is partially offset by a decrease in I(CaL) resulting in a mild inotropic effect without the signs of Ca(2+) overload and related arrhythmias usually associated with Na(+) channel openers.

2-Methyl-3- (3,5-diiodo-4-carboxymethoxybenzyl) benzofuran (KB130015; KB), a novel compound derived from amiodarone, has been proposed to have antiarrhythmic properties. Its effect on the G protein-coupled inward rectifying K+ current [IK(ACh) or IK(Ado)], ATP-sensitive K+ current [IK(ATP)], and background inward rectifying current (I(K1)) were studied in guinea pig atrial and ventricular myocytes by the whole-cell voltage-clamp technique. Receptor-activated IK(ACh/Ado), induced in atrial myocytes by the stimulation of either muscarinic or Ado receptors was concentration dependently (IC50 value of approximately 0.6-0.8 microM) inhibited by KB. Receptor-independent guanosine 5'-O-(3-thio)triphosphate-induced and background IK(ACh), which contributes to the resting conductance of atrial myocytes, were equally sensitive to KB (IC50 value of approximately 0.9 microM). IK(ATP) induced in atrial myocytes during metabolic inhibition with 2,4-dinitrophenol (DNP) was also suppressed by KB, whereas IK1 measured in ventricular myocytes was insensitive to the drug (KB < or =50 microM). Although being effective when applied from the outside, intracellular application of KB via the patch pipette affected neither IK(ACh) nor IK(ATP). 3,3',5-triodo-L-thyronin, which shares structural groups with KB, did not have an effect on the K+ currents. Consistent with the effects on single myocytes, KB did not depolarize the resting potential but antagonized the shortening of action potential duration by carbamylcholine-chloride or by DNP in multicellular preparations and antagonized the shortening of action potential duration by acetylcholine in single myocytes. It is concluded that KB inhibits IK(ACh) and IK(ATP) by direct drug-channel interaction at a site more easily accessible from extracellular side of the membrane.

KB130015 (KB015), a new drug structurally related to amiodarone, has been proposed to have antiarrhythmic properties. In contrast to amiodarone, KB015 markedly slows the kinetics of inactivation of Na(+) channels by enhancing concentration-dependently (K(0.5) asymptotically equal to 2 microM) a slow-inactivating I(Na) component (tau(slow) asymptotically equal to 50 ms) at the expense of the normal, fast-inactivating component (tau(fast) asymptotically equal to 2 to 3 ms). However, like amiodarone, KB015 slows the recovery from inactivation and causes a shift (K(0.5) asymptotically equal to 6.9 microM) of the steady-state voltage-dependent inactivation to more negative potentials. Despite prolonging the opening of Na(+) channels KB015 does not lengthen but often shortens the action potential duration (APD) in pig myocytes or in multicellular preparations. Only short APDs in mouse are markedly prolonged by KB015, which frequently induces early afterdepolarizations. KB015 has also an effect on other ion channels. It decreases the amplitude of the L-type Ca(2+) current (I(Ca-L)) without changing its time course, and it inhibits G-protein gated and ATP-gated K(+) channels. Both the receptor-activated I(K(ACh)) (induced in atrial myocytes by either ACh, adenosine or sphingosylphosphorylcholine) and the receptor-independent (GTPgammaS-induced or background) I(K(ACh)) are concentration-dependently (K(0.5) asymptotically equal to 0.6 - 0.9 microM) inhibited by KB015. I(K(ATP)), induced in atrial myocytes during metabolic inhibition with 2,4-dinitrophenol (DNP), is equally suppressed. However, KB015 has no effect on I(K1) or on I(to). Consistent with the effects in K(+) currents, KB015 does not depolarize the resting potential but antagonizes the APD shortening by muscarinic receptor activation or by DNP. Intracellular cell dialysis with KB015 has marginal or no effect on Na(+) or K(+) channels and does not prevent the effect of extracellularly applied drug, suggesting that KB015 interacts directly with channels at sites more easily accessible from the extracellular than the intracellular side of the membrane. At high concentrations KB015 exerts a positive inotropic action. It also interacts with thyroid hormone nuclear receptors. Its toxic effects remain largely unexplored, but it is well tolerated during chronic administration.

Recent developments in antiarrhythmic therapy have indicated that the best approach to pharmacologically controlling supraventricular arrhythmias and life-threatening ventricular tachyarrhythmias is by prolonging cardiac repolarization rather than by blocking conduction. In this context, amiodarone has emerged as the most potent compound, but its universal use has been limited by its toxicity profile. There are data to suggest that an important component of amiodarones antiarrhythmic action might be mediated via inhibition of thyroid hormone action in the heart. Therefore, a new series of carboxymethoxybenzoyl and benzyl derivatives of benzofuran has been prepared and evaluated as thyroid hormone receptor antagonists. Within this series, 2-methyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)benzofuran KB130015 (7) was found to reveal the most promising in vitro data. It inhibits the binding of (125)I-T(3) to the human thyroid hormone receptors (hThR) alpha(1) and beta(1). T(3)-Antagonism was confirmed in reporter cell assays employing CHOK1 cells (Chinese hamster ovary cells) stably transfected with hThR alpha(1) or hThR beta(1) and an alkaline phosphatase reporter gene downstream a thyroid response element. The derived IC(50) values were 2.2 microM for hThR alpha(1) and 4.1 microM for hThR beta(1). Compound 7 was selected for further characterization of chronic effects on ventricular papillary muscle by transmembrane electrophysiology after daily intraperitoneal injection of the ligand (40 mg/kg body weight) in guinea pigs. Compound 7 was found to prolong the action potential duration at 90% (APD(90)) repolarization time (219 +/- 22 ms, control: 186 +/- 9 ms, p < 0.01) without exhibiting any reverse rate dependency of action in a manner similar to that of amiodarone. In general, preliminary tolerance experiments with 7 demonstrated an improved safety profile compared to that of amiodarone. In summary, 7 appears to be less toxic than amiodarone while maintaining its electrophysiologic properties consistent with antiarrhythmic activity. Its potential antiarrhythmic actions warrant further investigations.

We compared the ability of a new amiodarone-like agent, SR 33589, with that of amiodarone, D,L-sotalol, and lignocaine to reduce the incidence of ventricular fibrillation (VF) and associated arrhythmias caused by acute coronary artery occlusion in anesthetized pigs. Ischemia was induced by occlusion of the left coronary descending artery (LAD) for 30 min. Premature ventricular complexes (PVCs), ventricular tachycardia (VT), and ventricular fibrillation (VF) were recorded during coronary occlusion. SR 33589 (1.25, 2.50, and 5 mg/kg intravenously, i.v.) markedly reduced the occurrence of ventricular arrhythmias during ischemia. The incidence of VF was reduced from 90% in the control group to 30% (p < 0.05) with 1.25 mg/kg, to 10% (p < 0.001) with 2.50 mg/kg, and to 20% (p < 0.01) with 5 mg/kg. In addition, SR 33589, especially at the two higher doses, caused a sustained reduction in both the incidence of VT and the number of PVCs per minute. In comparison, amiodarone 10 and 20 mg/kg i.v. reduced the incidence of VF (40 and 50%, respectively), but these reductions never reached a level of statistical significance. The incidence of VT and the number of PVCs per minute were also decreased significantly by amiodarone. D,L-sotalol 3 mg/kg i.v. exerted significant anti-arrhythmic activity; the incidence of VF was reduced 20% (p < 0.01), and both the incidence of VT and number of PVC per minute were also reduced. In contrast, lignocaine given as a 2-mg/kg bolus followed by an infusion at 70 micrograms/kg/min had no antiarrhythmic or antifibrillatory activity in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effects of SR 33589 and amiodarone on the cardiac beta-adrenoceptor were studied in vitro and after chronic treatment by means of [125I]-(-)-iodocyanopindolol ([125I]-(-)-CYP) binding and measurement of adenylate cyclase activity. 2. Binding of [125I]-(-)-CYP was inhibited in a dose-dependent manner by SR 33589 (IC50=1.8 +/- 0.4 microM, nH=0.93 +/- 0.06) and amiodarone (IC50=8.7 +/- 2.0 microM, nH=9.2 +/- 0.03). Saturation binding experiments indicated a non-competitive interaction such that SR 33589 (1 and 3 microM) and amiodarone (5 and 10 microM) reduced the Bmax of [125I]-(-)-CYP binding without any effect on the KD. Kinetic studies showed that the rate of association of [125I]-(-)-CYP was unchanged while the rate of dissociation was increased both in the presence of SR 33589 (10 microM) and amiodarone (30 microM).3. Under the same conditions, the receptor stimulated adenylate cyclase activity was inhibited in a dose-dependent, but non-competitive manner, by SR 33589 (isoprenaline-, glucagon- and secretin-stimulated enzyme inhibited 50% at 6.8 +/- 0.6 microM, 31 +/- 10 microM and 12 +/- 3 microM, respectively) while the basal, GTP- and GPP(NH)p-stimulated enzyme was inhibited by 5-10% and the NaF and forskolin-stimulated enzyme by 50% at 500 microM. Amiodarone exhibited a similar pattern of inhibition. 4. After chronic oral treatment (50, 100, 150 mg kg(-1) per day, 14 days), both SR 33589 and amiodarone produced a dose-dependent decrease in Bmax without any effect on KD as determined from [125I]-(-)-CYP saturation experiments and a decrease of the isoprenaline- and glucagon-stimulated adenylate cyclase activity without any effect on basal enzyme activity or activity when stimulated by agents acting directly on regulatory catalytic units. 5. Unlike amiodarone, SR 33589 does not contain iodine substituents. Plasma levels of T3, T4, and rT3 were changed after SR 33589 treatment except a decrease in T4 level at the highest dose whilst the T4 T3 ratio and the level of rT3 were dose-dependently increased by amiodarone treatment. 6. In vitro, SR 33589 and amiodarone were characterized as non-competitive beta-adrenoceptor antagonists. Chronic treatment led to a down-regulation of the beta-adrenoceptor; the down-regulation cannot be attributed to an indirect effect mediated by the thyroid hormones. To reconcile these opposing observations, we propose that SR 33589 and amiodarone interact with the beta-adrenoceptor at a site close to the intracellular loops which are involved in the coupling with Gs and contain the phosphorylable sites.

We have assessed the ability of amiodarone and the new amiodarone-like antiarrhythmic agent, SR 33589 (N,N-dibutyl-3-[4-((2-butyl-5-methylsulphonamido)benzofuran-3-yl-c arbonyl) phenoxy]propylamine), to inhibit the effects of adrenoceptor stimulation in anaesthetized and conscious dogs. In anaesthetized, atropinized dogs, adrenoceptor stimulation was achieved (i) by i.v. administration of adrenaline and measurement of increased blood pressure (ii) by i.v. administration of isoprenaline and measurement of increased heart rate and decreased blood pressure. In conscious dogs, adrenoceptor stimulation was achieved by i.v. administration of isoprenaline and measurement of increased heart rate. In anaesthetized, atropinized dogs, both amiodarone and SR 33589 inhibited to similar extents, alpha-adrenoceptor stimulation (as indicated by attenuation of adrenaline-induced increases in blood pressure). The beta 1-adrenoceptor inhibitory activity of SR 33589 (as demonstrated by blockade of isoprenaline-induced increases in heart rate) was significant, but less marked than amiodarone (heart rate elevation reduced by 39%, P < 0.001 with 10 mg/kg SR 33589 and by 52%, P < 0.01 with 10 mg/kg amiodarone). In contrast, its beta 2-adrenoceptor antagonistic activity (as demonstrated by blockade of isoprenaline-induced reduction in blood pressure) was more marked (mean blood pressure decrease reduced by 69%, P < 0.01 with 10 mg/kg SR 33589 and by 31%, P < 0.05 with 10 mg/kg amiodarone). In conscious dogs, both SR 33589 and amiodarone (12.5, 25 and 50 mg/kg p.o.) inhibited isoprenaline-induced increases in heart rate by approximately the same amount for varying durations depending on the dose.(ABSTRACT TRUNCATED AT 250 WORDS)

We compared the electrophysiological effects of a new amiodarone-like agent, SR 33589, with those of amiodarone. Mongrel dogs were anesthetized with chloralose, and electrodes were implanted in right atrium and ventricle for electrical stimulation and regional ECG measurement. Sinus cycle length (CL), AH interval, Wenckebach CL (WCL), atrial, atrioventricular node, and ventricular effective refractory periods (AERP, AVNERP, VERP), and parameters calculated from surface ECG were measured. SR 33589 was administered intravenously (i.v.) at 1, 2.5, or 5 mg/kg followed 60 min later by a second similar dose. The same protocol was followed with amiodarone 5 mg/kg, which reduced heart rate (HR) by 19% (p < 0.05), increased WCL by 31% (p < 0.01), AH interval by 14% (p < 0.05) and AERP, AVNERP, and VERP by 13% (p < 0.05), 19% (p < 0.05), and 11% (p < 0.01) respectively. No effect was observed on HV or PQ intervals. A second administration of 5 mg/kg changed these indexes further. SR 33589 (2.5 mg/kg) reduced HR by 21% (p < 0.001), increased WCL by 44% (p < 0.001), AH interval by 24% (p < 0.01), and AERP, AVNERP, and VERP by 17% (p < 0.001), 63% (p < 0.01), and 15% (p < 0.01) respectively, with an 18% increase in PQ interval (p < 0.05) but no significant effect on HV interval. Higher doses (5 mg/kg) and/or administration of a second dose both resulted in greater changes. Both amiodarone and SR 33589 prolonged VERP more at longer CL than at shorter CL, but the degree of reduction at shorter CL was less with SR 33589 than with amiodarone. Results suggest that acute administration of SR 33589 results in electrophysiological actions similar to those produced by amiodarone.

The effects of L 9394, a new compound closely related to amiodarone, were investigated in 44 patients by electrophysiological studies. Thirty two patients were given an intravenous injection of one of the following doses: 0.5, 1, 1.5 or 2 mg/kg. Conduction times of the A-V node (A-H interval) and of the His-Purkinje system (H-V interval) were measured by recording the His bundle potential. Refractory periods were determined by the extrastimulus technique. In the remaining 12 subjects, the action of L 9394 on sinus node was assessed. Sinus node recovery time was measured by rapid atrial stimulation and estimated atrial-sinoatrial conduction time deduced from the effects of atrial premature stimulation on sinus node activity. Results were as follows: (1) A-V nodal conduction was depressed after L9394. The A-H interval increased in direct proportion to the dose. Similarly, the effective and functional refractory periods of the A-V node were prolonged, more markedly after higher doses. (2) No change was shown in the His-Purkinje system. The H-V interval was unaltered. (3) L 9394 had no significant effects on the atrial or ventricular muscle. (4) Sinus cycle length as well as sinus node recovery time did not change significantly. In 7/12 patients, results of premature atrial stimulation suggested the formation of a sinoatrial block.

Administration of amiodarone hydrochloride (50-150 mg/kg i.p. daily) to rats, mice or hamsters resulted in the in vivo formation of a cytochrome P-450Fe(II)-amiodarone metabolite complex absorbing at 453 nm, unable to bind CO and biologically inactive. In rats, the amount of complex present in hepatic microsomes was small 24 hr after administration of a single dose of amiodarone (100 mg/kg i.p.) but was increased 2.5-times by pretreatment with phenobarbital and 8-times by pretreatment with dexamethasone phosphate. In addition, the complex increased linearly with time as the doses of amiodarone were repeated daily. When both enhancing factors were combined (treatment for 3 days with both dexamethasone and amiodarone), the amount of complex present in liver microsomes reached 0.78 nmol/mg protein or 40% of total cytochrome P-450 in rats. In these rats, in vitro disruption of the complex with potassium ferricyanide suppressed its Soret peak at 453 nm, increased by 70% the CO-binding spectrum of dithionite-reduced microsomes, and restored several monooxygenase activities. The 453 nm-absorbing complex was also formed in vitro upon incubation of amiodarone or N-desethylamiodarone with NADPH, EDTA and microsomes from dexamethasone-treated rats. The formation of the complex was smaller with microsomes from phenobarbital-treated rats and was not detected with microsomes from control rats. We conclude that amiodarone forms an inactive cytochrome P-450Fe(II)-metabolite complex in rats, mice and hamsters.

Administration of amiodarone (600 to 1,600 mg/day) to 28 patients during long-term digoxin therapy (0.25 +/- 0.05 mg/day) increased serum digoxin level from 0.97 +/- 0.45 to 1.98 +/- 0.84 ng/ml (p less than 0.001). Gastrointestinal side effects occurred in nine patients, central nervous system reactions occurred in five and cardiovascular reactions occurred in four. Pharmacokinetic studies in six patients with a 1 mg intravenous digoxin dose before and during amiodarone therapy increased serum digoxin level at 30 minutes from 8.59 +/- 1.68 to 10.07 +/- 1.70 ng/ml (p less than 0.05). Amiodarone caused a 31% prolongation of digoxin elimination half-life from 49.5 +/- 8.8 to 65.0 +/- 28.8 hours, but the increase in half-life was not statistically significant. Total body clearance was reduced significantly (29%, p less than 0.05) from 2.05 +/- 0.76 to 1.46 +/- 0.64 ml/min per kg. Nonrenal clearance also showed a significant decrease (33%, p less than 0.05) from 1.20 +/- 0.46 to 0.80 +/- 0.30 ml/min per kg. The renal clearance decreased by 22% and the volume of distribution decreased by 11% after amiodarone therapy, but these changes were not significant. The data show that the mechanism of digoxin-amiodarone interaction is multifactorial and emphasize the need for close monitoring of serum digoxin levels and clinical features during concurrent digoxin-amiodarone therapy.

The author examined the influence of Amiodarone, Perexiline maliate (Pexid) and the preparation CERM-1978 (Bepiridil) on the sinus rhythm and atrioventriular conduction of trained dogs with preliminary implanted electrodes for electrostimulation of the right atrium under the conditions of chronic experiment. The three preparations in doses of 2,5 and 5 mg/kg of body weight prolonged the refractory period of the atrioventricular zone, estimated by the method of "the maximal atrioventricular frequency". The br dicaric effect was also present, more manifested in a dose of 2.5 mg/kg of body weight. The established negative chrono- and dromotropic action had their maximum 15 minutes after the administration and lasted more than 2 hours.

It has been reported that amiodarone may interact with digoxin in man. We investigated the effects of amiodarone pretreatment (35 mg kg-1 day-1) on the pharmacokinetics of a single dose of digoxin (50 micrograms kg-1) in 6 rabbits. Total body clearance of digoxin was 138.84 +/- 44.67 and 147.99 +/- 29.17 ml min-1, serum half life 187.9 +/- 60.9 and 181.34 +/- 25.57 min and volume of distribution 35.4 +/- 8.54 and 37.8 +/- 3.9 litres before and after amiodarone treatment, respectively. None of these changes were statistically significant. We conclude that the presence of an amiodarone-induced change in digoxin pharmacokinetics in the rabbit was not evident and that other animal models will be necessary for studying this interaction.

Previous studies have shown decreased T3 and increased T4 and rT3 serum levels in subjects treated with amiodarone. We studied the acute effect of amiodarone on the in vitro conversion of T4 to T3 in suspensions of isolated rat hepatocytes. Iodine and melperone, another class III antiarrhythmic drug, were included in the study as controls. Amiodarone (60 microM) totally blocked the formation of T3 from T4, whereas concentrations of 6 and 0.6 microM reduced T3 formation to 13.7 +/- 10.6% and 63.9 +/- 15.9% (+/- SD), respectively, compared with untreated controls. The drug solvent did not affect the conversion rate. Iodide (120 microM) had an inhibitory effect of approximately 10% compared with the controls, whereas melperone did not affect this in vitro conversion. Amiodarone (60 microM) caused a slight but significant reduction of the cellular uptake of [125I]T4 after 10 min of incubation, whereas the 60 min values were unaltered. Our study indicates that amiodarone inhibits the 5'-monodeiodination of T4 to T3 in a dose-related manner. It is suggested that the antiarrhythmic activity of the drug is related to its inhibitory effect on the conversion of T4 to T3.

The potentiation of the anticoagulant effect of sodium warfarin by amiodarone is reported in 10 patients. Amiodarone appears to augment the depression of vitamin K-dependent coagulation factors caused by warfarin by an uncertain mechanism, and may lead to serious bleeding. The maintenance dose of warfarin should be halved when amiodarone and warfarin are prescribed together.

The effects of amiodarone given by rapid intravenous injection at a dosage of 10 mg/kg have been studied in the dog. The peak activity is found between the fifth and the tenth minute. The rate of discharge of the sinus is lowered by 36%. At the atrial level, the duration of the monophasic action potential (MAP) is increased by 9% and its dv/dt is lowered slightly, the total refractory period is increased by 22%, the effective refractory period is increased by 27%, the functional refractory period is increased by 19%, the ratio of the length of the effective period/duration of the MAP becomes slightly greater than unity, conduction facilitation disappears, and the period of slow conduction increases. In the A/V node the AH interval increases by 44% under normal rhythm, while atrial stimulation at 200/min. results in conversion to total AV block in more than half of the cases. The potential of the bundle of His and the HV interval are not altered. At ventricular level the duration of the monophasic action potential increases by 25%, its dv/dt decreases slightly, the total refractory period is increased by 8%, and the effective refractory period is increased by 14%.

The electrophysiologic (EP) effects of chronically administered amiodarone (AM) is known, but the nature of its acute effects are unclear. Whether the delayed onset of AM action is due to its metabolite, desethylamiodarone (DAM), is also uncertain. By standard microelectrode techniques in isolated canine ventricular muscle (VM) and Purkinje fibers (PF) and in rabbit sinoatrial (SA) node and atrium, we therefore studied the comparative effects of AM and DAM, 10(-6) M (0.68 micrograms/ml), 10(-5) M (6.8 micrograms/ml), and 5 X 10(-5) M (34 micrograms/ml), dissolved in ethanol and homologous serum. In VM, PF, and atria stimulated at 1 Hz, AM and DAM had no effect on Vmax, action potential amplitude (APA), or resting membrane potential. At 2-4 Hz, AM exerted a marked use-dependent effect in VM and PF. In atria, 5 X 10(-5) M, AM and DAM increased (p less than 0.01) action potential duration at 90% repolarization (APD90); the effective refractory period (ERP) increased by 10.5% (p less than 0.05 for AM) and 21.6% (p less than 0.01 for DAM). In VM, AM increased APD90 by 9.6% (p less than 0.01) at 10(-6) M, 13.7% (p less than 0.01) at 10(-5) M, and 16.9% (p less than 0.01) at 5 X 10(-5) M. The corresponding values for DAM were 5.6% (NS), and 7.3% (p less than 0.01), respectively. The ERP in VM was increased significantly by AM but not by DAM at all 3 drug concentrations without a change in APD90/ERP ratio. In PF, AM and DAM decreased APD50 and APD90; the effects were greater than those produced by the superfusion medium, but the degree of shortening in ERP induced by AM and DAM was not. AM and DAM (10(-5) and 5 X 10(-5) M) increased spontaneous cycle length of rabbit SA node. AM significantly decreased slope of phase 4 depolarization (10.4% at 10(-6) M, p less than 0.05; 14.5% at 10(-5) M, p less than 0.01; 24.0% at 5 X 10(-5) M, p less than 0.01). At 5 X 10(-5) M, AM significantly decreased APA, maximum diastolic potential and threshold potential with an insignificant effect on APD100.(ABSTRACT TRUNCATED AT 400 WORDS)

Interest in amiodarone has increased because of its remarkable efficacy as an antiarrhythmic agent. The purpose of this report is to review what is known about the electrophysiologic actions, hemodynamic effects, pharmacokinetics, alterations of thyroid function, response to treatment of supraventricular and ventricular tachyarrhythmias and adverse effects of amiodarone. Understanding the actions of amiodarone and its metabolism will provide more intelligent use of the drug and minimize the development of side effects. The mechanism by which amiodarone suppresses cardiac arrhythmias is not known and may relate to prolongation of refractoriness in all cardiac tissues, suppression of automaticity in some fibers, minimal slowing of conduction in fast channel-dependent tissue, or to interactions with the autonomic nervous system, alterations in thyroid metabolism or other factors. Amiodarone exerts definite but fairly minor negative inotropic effects that may be offset by its vasodilator actions. Amiodarone has a reduced clearance rate, large volume of distribution, low bioavailability and a long half-life that may last 2 months in patients receiving short-term therapy. Therapeutic serum concentrations range between 1.0 and 3.5 micrograms/ml. The drug suppresses recurrences of cardiac tachyarrhythmias in a high percent of patients, in the range of 80% or more for most supraventricular tachycardias and in about 66% of patients with ventricular tachyarrhythmias, sometimes requiring addition of a second antiarrhythmic agent. Side effects, particularly when high doses are used, may limit amiodarone's usefulness and include skin, corneal, thyroid, pulmonary, neurologic, gastrointestinal and hepatic dysfunction. Aggravation of cardiac arrhythmias occurs but serious arrhythmias are caused in less than 5% of patients. Amiodarone affects the metabolism of many other drugs and care must be used to reduce doses of agents combined with amiodarone.

Previous studies have shown that amiodarone can depress certain aspects of hepatic drug metabolism in the rat. This effect was assessed in vivo by investigating the single dose intravenous pharmacokinetics of phenytoin (10 mg/kg), quinidine (25 mg/kg) and lidocaine (7.5 mg/kg) in rats pretreated for three days with a single daily 100 mg/kg intraperitoneal dose of amiodarone hydrochloride. Compared to vehicle treated controls, significant reductions of 61% and 35% in the respective total clearances of phenytoin and quinidine were observed in the presence of amiodarone. Likewise, the elimination half-lives of phenytoin and quinidine were also significantly prolonged after amiodarone pretreatment. Lidocaine pharmacokinetic parameters were unchanged in the presence of amiodarone. These results suggest that altered hepatic drug clearance may play a part in the recently described clinical drug interactions between amiodarone and either phenytoin or quinidine.

Amiodarone is an effective antiarrhythmic agent whose use is associated with several drug interactions one of which is potentiation of the action of warfarin. The mechanism of this interaction has hitherto been unclear. We examined possible mechanisms in eight patients. Total plasma warfarin clearance was found to be reduced by amiodarone. No change was detected in the binding of warfarin to plasma proteins. No relationship was found between plasma amiodarone concentrations and the change in warfarin clearance.

In an attempt to assess their respective values for purposes of drug monitoring, plasma, red blood cell, atrial, and ventricular concentrations of amiodarone and N-desethylamiodarone (NDA) were measured, in 50 surgical patients, after a single oral dose (30 mg/kg); hemodynamic changes were assessed also. Amiodarone concentration was lower in red blood cells than in plasma and in myocardium. A relationship was found between the red blood cell concentration and plasma or myocardial concentrations of amiodarone (r = 0.79 and r = 0.68, p less than 0.00001). Hemodynamic studies were available in 17 treated patients and 13 control subjects before and at the time of surgery. In control subjects, hemodynamics did not change with time and general anesthesia. Oral amiodarone decreased the cardiac index (p less than 0.05) and heart rate (p less than 0.001) without significant changes in arterial pressure, systemic vascular resistance, or stroke volume index. The increase in capillary wedge pressure was related to amiodarone or NDA plasma, myocardial, and red blood cell concentrations (for amiodarone: r = 0.61, p = 0.006; r = 0.69, p less than 0.001; and r = 0.53, p = 0.02, respectively). We concluded that oral amiodarone impairs hemodynamics and that measurement of the amiodarone plasma concentration rather than the red blood cell concentration is the easiest method of monitoring the drug. However, establishment of the clinical utility of drug monitoring during chronic administration of amiodarone needs further investigation.

Progress in the pharmacological treatment of atrial fibrillation and flutter has been achieved by the introduction of the class III antiarrhythmic drug amiodarone. In the present study we tested amiodarone and a new class III antiarrhythmic drug, melperone, in experimentally induced atrial fibrillation and flutter in pentobarbital-anesthetized dogs. By high-rate stimulation in the right atrium, atrial fibrillation was induced in 4, and atrial flutter in 10 out of 22 dogs. Atrial flutter rate was 496 +/- 13 min-1 (median +/- 95% confidence interval). Both drugs converted the arrhythmias at doses from 2.5 to 10 mg . kg-1 and reduced that atrial flutter rate before conversion. Average ventricular rate during arrhythmias (261 +/- 16 min-1) decreased after amiodarone, and was unchanged or, in three out of nine dogs, increased after melperone. The doses of amiodarone converting the arrhythmias increased atrial refractoriness, whereas the effects on AV nodal conduction and refractoriness were variable. The results support the concept that atrial flutter is due to circus movement where the flutter rate is dependent upon atrial refractoriness. The class III antiarrhythmic drugs amiodarone and melperone seem to be equally potent in converting atrial arrhythmias.

Out of 690 patients (337 males and 353 females) on long-term acenocoumarol therapy, 80 (35 males and 45 females) were taking amiodarone. Forty patients had started amiodarone treatment while being treated with acenocoumarol. Of these, nine patients had begun amiodarone treatment while taking acenocoumarol. The relation between the daily dose of acenocoumarol and the prothrombin ratio (AC dose/PR ratio) has been considered a useful indicator to study the interaction between amiodarone and acenocoumarol. Differences of acenocoumarol daily dose between takers and non-takers of amiodarone were statistically significant (t = 5.35; P less than 0.001) for the whole population, for all the age groups, and also among males (t = 2.43; P less than 0.01) as well as among females (t = 5.38; P less than 0.001). Out of 40 patients chronically treated with acenocoumarol in whom amiodarone was instituted, 32 showed a decrease of the AC dose/PR ratio, while in eight patients no change was recorded (paired t-test, t = 5.82; P less than 0.001). In 15 patients who were being concomitantly treated with acenocoumarol and amiodarone, amiodarone was discontinued. An increase of the AC dose/PR ratio was recorded (paired t-test, t = 4.01; P less than 0.001). Nine patients had started treatment with amiodarone while receiving acenocoumarol and a decrease of the AC dose/PR ratio was documented; amiodarone was discontinued some months later, and an increase of the AC dose/PR ratio was seen.

Inhibition of in vivo isoproterenol-induced tachycardia by i.v. amiodarone was studied in anesthetized dogs. Significant dose-response curves to isoproterenol could not be obtained in single animals because of the time-dependent lowering of the inhibitory effect of the drug. Single isoproterenol injections after amiodarone in 105 dogs allowed dose-response curves to be obtained. The slope of these curves decreased with increasing doses of amiodarone, and the maximal rate stimulation diminished also in a dose-dependent manner. These features are consistent with a non-competitive inhibition pattern. A mechanism of the beta-adrenergic antagonism developed by amiodarone is suggested.

Potentiation of the anticoagulant-effect of warfarin by amiodarone was studied in 30 patients. Thirteen received both drugs concurrently, and 17 received warfarin alone and the combination sequentially. Warfarin doses were adjusted to maintain the prothrombin time between 25-30% of control and its kinetics were compared to those in 20 control patients who received warfarin alone. Potentiation occurred in 28/30 patients, presenting as a 35%-65% reduction in the required dose of warfarin, and was correlated with the dose of amiodarone (r = 0.77, p less than 0.01). The free warfarin fraction was not affected by amiodarone (1.8% vs 1.6% in the controls). Warfarin clearance was lower in amiodarone-treated patients than in the controls (1.4 vs 3.1 ml/min, p less than 0.01) with similar plasma concentrations (1.5 vs 1.2 micrograms/ml) despite administration of lower doses (23.3 vs 39 mg/week respectively). The amiodarone concentration was significantly correlated with the warfarin concentrations independent of the effect of amiodarone on the dose of warfarin. Amiodarone hat no effect on prothrombin other than through its actions on the dose and plasma concentration of warfarin. The mechanism of the amiodarone-warfarin interaction is pharmacokinetic through dose - and concentration - dependent inhibition of warfarin elimination.

In rat-brain synaptic membranes at a fixed temperature (37 degrees C), amiodarone dose-dependently inhibits the Na+/K+ ATPase activity (IC50 approximately equal to 2.10(-5)M) and produces a linear increase in the degree of fluorescence depolarization (P) of 1,6-diphenylhexatriene embedded in the lipid matrix. Amiodarone has no effect on Mg++ ATPase and K+PNPase activity up to 3.10(-4)M. Studies carried out at different temperatures indicate that 10(-5)M amiodarone inhibits the Na+/K+ ATPase and decreases the lipid fluidity at all the temperatures studied (9 - 40 degrees C). The compound significantly displaces the temperature of transition observed around 20 degrees C in both Na+/K+ ATPase activity and lipid fluidity to 24 degrees C with no changes in slopes. The results suggest that part of the selective inhibition of Na+/K+ ATPase activity by amiodarone could be due to the effects of the drug on lipid dynamics.

The haemodynamic action of I-V Cordarone have been studied in 20 subjects over a 15 minute period. Over the 15 minute period we studied variations in left pulmonary and ventricular pressures, in cardiac output, and in the paramaters of contraction VEC max, V max and Taylor's index. At a dose of 5 mg/kg there is a fall in peripheral resistance (1274 +/- 232 to 915 dynes/s/cm-5), and the measurements of contraction hardly vary. At a dose of 10 mg/kg, after an initial increase in output and a fall in peripheral resistance there occurs, after 4 minutes, an increase in left ventricular end-diastolic pressure (from 6 +/- 2 to 13 +/- 4 mmHg, P less than 0.01), and a lowering of contractility (VEC max reduced from 49.7 +/- 12.4 to 27.1 +/- 3.8, P less than 0.001). We have shown that the first phase of this response is due to the solvent (Tween 80), while the fall in contractility is due to the amiodarone. Doses above 10 mg/kg must be used with care, and only if there is no evidence of impaired cardiac function.

A systematic approach to the investigation of metabolic degradation of drugs is presented. Extraction of the biological sample is avoided by direct injection of bile or urine in a reversed-phase high-performance liquid chromatography system. Good separation of the various metabolites is obtained by changing the composition of the mobile phase so that all components become separated from the solvent front and are eluted from the column. The metabolites can be detected by measuring the amount of radioactivity in the column effluent, which also serves as a check on the overall recovery. Simultaneous registration of the UV absorbance permits certain conclusions to be drawn with regard to the nature of the metabolites. This approach is illustrated in the screening for metabolites of Butoprozine, a new anti-anginal drug, in rat bile. Essentially, all metabolites could be followed by suitable adaptations of the mobile phase, thus providing a metabolid profile with a recovery of 95% of the radioactivity.

We describe a patient with bronchial asthma whose respiratory symptoms worsened during treatment and rechallenge with amiodarone. Laboratory studies on cultured pulmonary cells demonstrated an anti-beta-adrenergic effect of amiodarone not due to inhibition of beta-adrenergic receptor binding. Amiodarone should be used with caution in patients with obstructive pulmonary disease.

Treatment with amiodarone, an iodinated anti-arrhythmic drug, is associated with increases in serum rT3 and serum L-T4 with a mild variable decrease in T3. We have examined the metabolic basis for these changes by studying the kinetics of metabolism of 125I-labeled iodothyronines in rabbits given amiodarone (20 mg/kg BW) for 3 weeks. The mean +/- SE MCR of rT3 was significantly (P less than 0.05) lower in amiodarone-treated rabbits (1.88 +/- 0.14 liters/day) than that in the control animals (2.72 +/- 0.25 liters/day), with no appreciable changes in the MCR of T3. The mean MCR of T4 was also significantly lower in amiodarone-treated animals than in controls (0.23 +/- 0.03 vs. 0.37 +/- 0.04 liters/day; P less than 0.05). Amiodarone had no significant effect on daily production rates (PRs) of rT3 or T3, but the PR of T4 showed an increase which was significant (P less than 0.05) when expressed per unit BW. The mean +/- SE molar ratio of daily PRs of T3 and T4 was reduced significantly (P less than 0.05) from 0.75 +/- 0.12 in controls to 0.35 +/- 0.06 in drug-treated rabbits. Amiodarone treatment was also associated with a moderate reduction in the ratio of the PRs of rT3 and T4, but the change was not statistically significant. The overall data suggest that amiodarone administration is associated with a reduction in the MCRs of rT3 and T4 and a reduction in monodeiodination of T4 in the outer ring; monodeiodination of T4 in the inner ring either remains unaffected or decreases moderately.

Although synthesized as a coronary dilator for use as an antianginal agent over 20 years ago, amiodarone hydrochloride has recently drawn much attention as a potent antiarrhythmic compound for the control of a variety of cardiac dysrhythmias. The rapidly expanding clinical and experimental data continue to emphasize the unusual electrophysiologic, pharmacologic, and especially pharmacokinetic properties of this benzofuran derivative. The compound is a potent coronary dilator and has minimal negative inotropic propensity of a direct nature while exhibiting a mild degree of noncompetitive sympathetic antagonism. Pharmacokinetically, it has a long elimination half-life with a correspondingly long and variable latency of onset of therapeutic effect. Electrophysiologically, the drug has the propensity to lengthen the action potential duration and hence the voltage-dependent effective refractory period in all cardiac tissues after long-term, rather than short-term, administration. It has little effect on depolarization, conduction velocity, or the slow response. The precise ionic mechanisms mediating its effects on repolarization are not known. Clinically, the electrophysiologic effects of the drug differ significantly when it is given by mouth over a longer period and when it is given intravenously, a difference that remains to be explained in terms of mechanism. These differences, however, account for the varying spectrum of the drug's action after single intravenous doses (when its antiarrhythmic effects are essentially explained by the drug's action on the atrioventricular node and possibly its antiadrenergic actions) in comparison to long-term oral administration, which predictably suppresses ectopic activity and lengthens the effective refractory period in all cardiac tissues. These features may account for the drug's remarkable efficacy in the control of supraventricular and ventricular tachyarrhythmias. The safe and rational therapeutic uses of amiodarone as an antiarrhythmic agent presuppose detailed understanding of its manifold pharmacodynamic and pharmacokinetic properties.

Amiodarone is a new antiarrhythmic drug, commonly coadministered with digoxin in various cardiac disorders. Amiodarone caused a 10-fold increase of serum digoxin in rats, when the two drugs were simultaneously administered. Amiodarone significantly reduced digoxin uptake by renal cortical slices in the rat, and failed to reduce digoxin uptake by either heart or diaphragmatic muscle. The inhibition of the renal tubular uptake of digoxin caused by amiodarone may explain in part the increased serum digoxin concentration observed in vivo. Close resemblance was found between the mechanisms involved in the amiodarone-digoxin interaction, and those of digoxin interaction with either quinidine or verapamil.