EO-199, a specific antagonist of antiarrhythmic drugs: assessment by binding experiments and in vivo studies

EO-199, a demethylated analog of the novel class I antiarrhythmic drug EO-122 was found to antagonize the antiarrhythmic activity of EO-122 and that of procainamide (Class IA). EO-199 did not block significantly the activity of a class IB antiarrhythmic agent, lidocaine. EO-199 also displaced the specific binding of [3H]EO-122 to rat heart membranes similarly to procainamide whereas lidocaine did not. The correlation between binding experiments and pharmacological effects points to a possible subclassification of these drugs; the two chemical analogs EO-199 and EO-122, as well as procainamide (IA) but not lidocaine (IB), compete at the same site or the same state of the sodium channel. The availability of a specific antagonist might be useful for studying the mechanism of action of antiarrhythmic drugs as well as an antidote in cases of antiarrhythmics overdose intoxication.     

Antiarrhythmic and electrophysiological properties of etmozin and its diethylamine analog]

Effects of antiarrhythmic drug etmosin and its diethylamine analogue (etmosin DAA) were compared in dogs with the ventricular rhythm disturbances induced by coronary artery ligation according to Harris' method. As demonstrated, both drugs stopped ventricular rhythm disturbances, but etmosin DAA had a more rapid and prolonged effect. Electrophysiological properties of etmosin and etmosin DAA were studied by the method of potential fixation on trabeculae of frog atria. Both drugs proved to reduce rapid sodium inflow, etmosin DAA acting more intensively and longer. Taking into account the high antiarrhythmic activity of etmosin DAA it is believed that this drug had good prospects for further investigation.     

Antiarrhythmic drugs, patients, and the pharmaceutical industry: value for patients, physicians, pharmacists or shareholders?

Antiarrhythmic drugs no longer seem to be big business. After the unexpected CAST trial results (excess mortality in the class 1C antiarrhythmic drug treatment arms in patients with coronary artery disease (CAD) and abundant ventricular extrasystoles),1 antiarrhythmic drug treatment became less popular for CAD patients. Since this category of patients represents the majority of cardiology patients with chronic disease, these results impacted on the antiarrhythmic drug market. In the years that followed, the use of class 1C drugs was even further discouraged.     

Effects of amiodarone on triggered activity induced by overdrive stimulation in Ca2+ overloaded ventricular muscle from guinea pig

1. The acute effects of amiodarone, a powerful antiarrhythmic drug, on transient depolarizations (TDs) and/or triggered activity (TA) induced by an overdrive stimulation in the condition of low potassium (2.7 mM) and high calcium (5.4 mM) solution were evaluated on isolated ventricular papillary muscles from guinea pig, by means of conventional miocroeleetrode techniques.2. The amplitude of the induced TDs was enhanced by increase in stimulus number and frequency during overdrive stimulation, and the coupling interval of TDs was shortened.3. Amiodarone (4.4 × 10⁻⁵ M) significatly decreased the amplitude of TDs, and prolonged the coupling interval.4. On the other hand, superfusion with a higher concentration (4.4 × 10⁻⁴) of amiodarone tended to induce automatic activity.5. Possible implications with respect to the antiarrhythmic activity of amiodarone are discussed.     

Suppression of Ventricular Tachyarrhythmias by Transvenous Intracardiac Pacing after Acute Myocardial Infarction

Transvenous intracardiac pacing was carried out on nine patients with recurrent ventricular tachyarrhythmia after drug treatment had failed. In eight patients recurrent Ventricular ectopic activity was suppressed by pacing at a rate above the sinus rate. With this technique the need for D.C. shock and repeated antiarrhythmic drugs can be avoided.     

Prevention of chloroform-induced ventricular tachycardia in mice as an index of antiarrhythmic activity

Prevention of chloroform-induced ventricular fibrillation has been the basis of an antiarrhythmic screening technique in mice. However, data from this laboratory indicated that exposure of mice to chloroform evokes ventricular tachycardia rather than ventricular fibrillation. In view of these observations, the original screening technique was revised and new criteria for antiarrhythmic activity were established. Subsequent validation of those criteria was determined with various beta antagonists and Class I antiarrhythmic agents. Each group of agents evoked dose-dependent antiarrhythmic activity whereas most Class I agents also evoked ataxia which was presumed to be of CNS origin. The revised screening procedure appears to be a sensitive and reliable predictor of antiarrhythmic activity and also provides information regarding the potential for undesirable CNS side effects.     

Quinidine is a strong perturber of acidic phospholipid bilayer order and fluidity

The effect of an antiarrhythmic drug, quinidine, on the organization of model phospholipid membranes was studied by the spin-labeling technique. Quinidine strongly perturbs the molecular organization of lipid bilayers prepared from acidic phospholipids (phosphatidylserine, phosphatidic acid) and has only a slight effect on neutral phosphatidylcholine membranes. The interaction of the drug with acidic phospholipids manifests itself in a pronounced increase in the order parameter of the region close to the polar surface of the bilayer and in some decrease in its inner hydrocarbon core fluidity. It is suggested that the perturbation in the organization of membrane lipids may contribute to the mechanisms by which quinidine exerts its pharmacological effects.     

High-performance liquid chromatographic isolation and fast atom bombardment mass spectrometric identification of Di-N-desethylamiodarone, a new metabolite of amiodarone in the dog

Amiodarone is an antiarrhythmic drug which has received considerable attention in recent years. It has been suggested that the unusual pharmacodynamic characteristics of this drug may be due in part to the influence of active metabolites. Using fast atom bombardment (FAB) mass spectrometry we have identified a new metabolite of amiodarone, the di-N-desethyl analog (DDEA). This metabolite was present in the blood of dogs treated with the parent drug, and showed a greater affinity for myocardium than did the parent drug. The unique features of FAB mass spectrometry over electron impact mass spectrometry was an essential element in facilitating the identification of this new metabolite. Whether or not this metabolite has pharmacologic activity or is responsible for some of the side effects occurring during amiodarone administration is not known.     

Opposite change with ischaemia in the antifibrillatory effects of class I and class IV antiarrhythmic drugs resulting from the alteration in ion transmembrane exchanges related to depolarization

It is known that class I antiarrhythmic drugs lose their antifibrillatory activity with severe ischaemia, whereas class IV antiarrhythmic drugs acquire such activity. Tachycardia, which is also a depolarizing factor, has recently been shown to give rise to an alteration of ion transmembrane exchanges which is particularly marked in the case of calcium. This leads one to wonder if the change in antifibrillatory activity of antiarrhythmic drugs caused by ischaemia depends on the same process. The change in antifibrillatory activity was studied in normal conditions ranging to those of severe ischaemia with a class I antiarrhythmic drug, flecainide (1.00 mg x kg(-1) plus 0.04 mg x kg(-1)x min(-1), a sodium channel blocker, and a class IV antiarrhythmic drug, verapamil (50 microg x kg(-1) plus 2 microg x kg(-1) x min(-1)), a calcium channel blocker. The experiments were performed in anaesthetized, open-chest pigs. The resulting blockade of each of these channels was assessed at the end of ischaemic periods of increasing duration (30, 60, 120, 180, 300, and 420 s) by determining the ventricular fibrillation threshold (VFT). VFT was determined by means of trains of diastolic stimuli of 100 ms duration delivered by a subepicardial electrode introduced into the myocardium (heart rate 180 beats per min). Ischaemia was induced by completely occluding the left anterior descending coronary artery. The monophasic action potential was recorded concurrently for the measurement of ventricular conduction time (VCT). The monophasic action potential duration (MAPD) varied with membrane polarization of the fibres. The blockade of sodium channels by flecainide, which normally raises VFT (7.0 +/- 0.4 to 13.8 +/- 0.8 mA, p < 0.001) and lengthens VCT (28 +/- 3 to 44 +/- 5 ms, p < 0.001), lost its effects in the course of ischaemia. This resulted in decreased counteraction of the ischaemia-induced fall of VFT and decreased aggravation of the ischaemia-induced lengthening of VCT. The blockade of calcium channels, which normally does not alter VFT (between 7.2 +/- 0.6 and 8.4 +/- 0.7 mA, n.s.) or VCT (between 30 +/- 2 and 34 +/- 3 ms, n.s.), slowed the ischaemia-induced fall of VFT. VFT required more time to reach 0 mA, thus delaying the onset of fibrillation. Membrane depolarization itself was opposed as the shortening of MAPD and the lengthening of VCT were also delayed. Consequently there is a progressive decrease in the role played by sodium channels during ischaemia in the rhythmic systolic depolarization of the ventricular fibres. This reduces or suppresses the ability of sodium channel blockers to act on excitability or conduction, and increases the role of calcium channel blockers in attenuating ischaemia-induced disorders.     

Preliminary evaluation of pharmacological properties of some xanthone derivatives

A series of xanthone derivatives were synthesized and examined for electrocardiographic, antiarrhythmic, hypotensive and anticonvulsant activities as well as for α₁- and β₁-adrenergic binding affinities. Among the investigated compounds, some of them exhibited significant antiarrhythmic and/or hypotensive activity. The data obtained via receptor binding assay are in agreement with pharmacological results and could explain antiarrhythmic and/or hypotensive activity of the newly synthesized structures.     

Acetylcholinesterase: A probe for the study of antiarrhythmic drug-membrane interactions

Structural consequences of antiarrhythmic drug interaction with erythrocyte membranes were analyzed in terms of resulting changes in the activity of membrane-associated acetylcholinesterase. When enzyme inhibitory effects of drugs were compared at concentrations producing an equivalent degree of erythrocyte antihemolysis, a number of distinct groupings emerged, indicating that the molecular consequences of drug-membrane interaction are not identical for all agents examined. Differences in drug-induced acetylcholinesterase inhibition in intact erythrocytes, erythrocyte membranes and a brain synaptic membrane preparation emphasized the role of membrane structural organization in determining the functional consequences of antiarrhythmic interaction in any given system. While the inhibitory actions of lidocaine, D-600 and bretylium in intact red cells were not altered by an increased transmembrane chloride gradient, enhanced enzyme inhibition by quinidine and propranolol was observed under these conditions. The diverse perturbational actions of these membrane-stabilizing antiarrhythmics observed here may be indicative of a corresponding degree of complexity in the mechanisms whereby substances modify the potential-dependent properties of excitable tissues.     

Simulated Interactions between a Class III Antiarrhythmic Drug and a Figure 8 Reentry

Ventricular Fibrillation is responsible for a majority of sudden cardiac death, but little is known about how ventricular tachycardia (VT) degenerates into ventricular fibrillation. Several clinical studies focused only on preventing VT with a class III antiarrhythmic drug resulted in many deaths. Our simulations investigate the interactions between an antiarrhythmic drug likely to suppress a VT and a Figure 8 reentry. A parameter AAR is introduced to increase the action potential duration and therefore simulate various Class III drugs. Simulations are ran under several conditions (phases of the reentry, values of AAR, durations). They show that a VT can be suppressed whatever the phase of the reentry but it strongly depends on the duration of the effect. It confirms that a drug which can suppress a reentry can also worsen it. It also shows a great variety of activation patterns and thus the complexity of antiarrhythmic drugs effects. Simulations also demonstrate that suppressing VT is an increasing function of AAR.     

Antiarrhythmic activity of 4,6-di(het)aryl-5-nitro-3,4-dihydropyrimidin-(1H)-2-ones and its effects on arterial pressure in rats

The antiarrhythmic activity of 4,6-di(het)aryl-5-nitro-3,4-dihydropyrimidin-(1H)-2-ones toward two types of experimental rat arrhythmia has been studied. With CaCl(2) induced arrhythmia model, several agents have demonstrated high antiarrhythmic activity and the lack of influence on arterial pressure of rats.     

Synthesis and SAR studies of 1-substituted-n-(4-alkoxycarbonylpiperidin-1-yl)alkanes as potent antiarrhythmic agents.

Synthesis and SAR studies of the title compounds have resulted in the identification of structural and physicochemical parameter (Vw) contributing for antiarrhythmic activity. Among the two most promising compounds 3a & 3b, the 3a has shown antiarrhythmic activity comparable to quinidine.     

Preservation of TSPO by chronic intermittent hypobaric hypoxia confers antiarrhythmic activity

Abnormal activation of mitochondrial translocator protein (TSPO) contributes to arrhythmogenesis during cardiac metabolic compromise; however, its role in the antiarrhythmic activities of chronic hypoxia adaptation remains unclear. Our results demonstrated that 80% of normoxic rats developed ischaemic VF, whereas this condition was seldom observed in rats with 14 days of chronic intermittent hypobaric hypoxia (CIHH). TSPO stimulation or inhibition affected the arrhythmias incidence in normoxic rats, but did not change the CIHH‐mediated antiarrhythmic effects. Abrupt and excessive elevation of TSPO activity was positively linked to ischaemic VF, and CIHH preserved TSPO activity during ischaemia. The preservation of TSPO activity by CIHH also contributed to the maintenance of intracellular Ca homeostasis. These results suggest that the blunt sensitivity of TSPO to ischaemic stress may be responsible for the antiarrhythmic effects by CIHH.     

Correction of disorders of electric stability of the heart and arrhythmia by using a synthetic analog of acetylcholine

It was shown in experiments on Wistar male rats that ethyl, 3/2, ethyl, 2/2, dimethylhydrazine propionate iodate (EDIHYP), a synthetic acetylcholine analogue, eliminates in situ the fall of the ventricular fibrillation threshold and the extrasystole observed on the background of vagal bradycardia in experimental myocardial infarction and postinfarction cardiosclerosis. The elimination of disturbed heart electric stability was not accompanied by cholinergic, negative chronotropic effect of the drug. In isolated heart, high concentrations of EDIHYP (10(-4) M) had negative chronotropic effect but lacked antiarrhythmic effect in local ischemia and reperfusion. The bradycardia induced by EDIHYP was absent and the antiarrhythmic effect was strikingly pronounced on the background of muscarinic receptors blockade with atropine. Thus EDIHYP realizes its antiarrhythmic effect not via muscarinic receptors but by some other way which requires studying by methods of molecular pharmacology.     

Stobadine inhibits lysosomal enzyme release in vivo and in vitro

This study investigated the ability of stobadine, an effective cardioprotective drug with antiarrhythmic, antihypoxic and oxygen free radical scavenging properties, to protect cells against cyclophosphamide-induced toxic and cytotoxic damage in vivo and in vitro. Cyclophosphamide-induced toxic damage in female ICR mice was accompanied by marked increase in the activity of lysosomal enzymes in the spleen and kidney. Administration of stobadine prior to cyclophosphamide inhibited these biochemical changes. The in vivo protective effect of stobadine was comparable with its in vitro effect established in HeLa cells.     

Evidence for an inhibition of thyroid hormone effects during chronic treatment with amiodarone

The effects of chronic amiodarone treatment on several thyroid and cardiac function parameters were studied in 50 euthyroid patients with refractory ventricular arrhythmias, divided in responders and nonresponders according to their sensitivity to the antiarrhythmic action of the drug. No differences in the severity of cardiac disease and blood amiodarone concentrations were found in the two groups. Amiodarone induced a significant inhibition of peripheral T4 monodeiodination, more pronounced in responders compared to nonresponders. On the contrary, only in responsive patients, elevated basal and TRH-stimulated TSH levels were observed (despite serum T3 levels were not different from those in nonresponders) and the indirect indices of cardiac performance, particularly the systolic time intervals, fell in a range usually observed in the hypothyroid states. These findings suggest that amiodarone, besides the well-known inhibition of T4 to T3 conversion, also induces a partial resistance to the thyroid hormones, which is probably involved in the therapeutical effectiveness of the drug.     

An extralimital population in a warm climatic outpost: the case of the mothIdaea dilutaria in Scandinavia

The mothIdaea dilutaria Hübn. (Geometridae) has an isolated population on the Kullaberg peninsula in southern Sweden. Investigations of the local and micro-climate on the peninsula showed that the local distribution range of the moth coincided with the areas of warmest climate, supporting the hypothesis that the Kullaberg poppulation is dependent for its survival on the warm climate of this area and that the species here is a thermal relict from a previously warmer climatic period.