[Effect of the sympathetic nervous system activation on the antifibrillatory efficacy of various anti-arrhythmia agents]. / Vliianie aktivatsii simpaticheskoi nervnoi sistemy na antifibrilliatornoe deistvie protivoaritmicheskikh sredstv raznykh klassov.

Experiments with a 7-min occlusion followed by reperfusion of the left coronary artery in narcotized rats showed that antiarrhythmic drugs of various classes--ethacizin (class I), AL-275 (class III), and CM-345 (class V)--produce pronounced antifibrillatory and antiarrhythmic effects. AL-275 and CM-345, in contrast to ethacizin, retained their efficacy under the conditions of isoproterenol-induced stimulation of beta-adrenoceptors. This difference in behavior is probably explained by dissimilar effects of the antiarrhythmics on the ion channels of cardiomyocite membranes.

[Possibilities of correcting adverse effects of anti-arrhythmia agents]. / Vozmozhnosti korrektsiii neblagopriiatnykh éffektov antiaritmicheskikh preparatov.

A hundred and twenty two patients with premature ventricular contractions and paroxysmal tachycardias were comprehensively studied prior to and following treatment regimen with ethacizin, befol, sodium succinate and their combinations. Besides its significant antiarrhythmic activity, ethacizin displayed a number of adverse cardiac effects, such as excessive negative inotropic and dromotropic ones. Befol and sodium succinate in combination with ethacizin can reduce or even eliminate these side effects in rest and during simulated mental stress and graded exercise. The antiarrhythmic effect of the combined therapy preserved or even became stronger. This therapy may be long performed for arrhythmias even in patients with circulatory insufficiency and cardiac conduction disturbances caused or redoubled by ethacizin.

Simultaneous determination of moricizine and its sulphoxidation metabolites in biological fluids by high-performance liquid chromatography.

A simultaneous assay for moricizine, its two sulphoxidation metabolites, moricizine sulphoxide and moricizine sulphone, using high-performance liquid chromatography (HPLC) is described. The drug and metabolites and clozapine (internal standard) in biological fluids were extracted using pentanesulphonic acid into diethyl ether. The ethereal extract was evaporated to dryness and the residue was redissolved in the mobile phase (methanol-water-triethylamine, 65:35:0.5, v/v). The analyses were performed on a microBondapak reversed-phase C18 column housed in a Waters Z-module, linked to a C18 pre-column, with a run-time of 12 min. The retention times were 2.7, 3.5, 6.2 and 9.7 min for moricizine sulphone, moricizine sulphoxide, moricizine and clozapine, respectively. The recovery of the compounds from plasma ranged from 89.9% for the sulphoxide to 98.1% for clozapine. The limits of detection of the assay for moricizine, moricizine sulphoxide and moricizine sulphone were 20, 10 and 5 ng/ml, respectively.

Combination ethacizin and ethmozin treatment of resistant ventricular ectopy: theoretical, experimental, and clinical study.

Ethmozin (Moricizine HCl) and ethacizin are two class I antiarrhythmic drugs with different rate constants of interaction with the sodium channel. Computer simulation using the "guarded-receptor" model predicted that the combination of ethacizin and ethmozin should exert a greater decrease in excitability and conduction at short coupling intervals, but little effect at normal heart rates (HR). To test this prediction, we measured intraventricular conduction delay in canine hearts in vivo. In agreement with the model, the combination more potently prolonged the delay only at intervals < 600 ms as compared with ethacizin alone. Combination therapy was tested in 6 patients with idiopathic ventricular ectopic depolarizations (VEDs). Three patients were resistant to either ethmozin or ethacizin monotherapy, and three could not tolerate effective doses because of side effects. Quantitative continuous ECG monitoring showed that total VEDs in the resistant group decreased 0 and 17 +/- 13% for 400 and 800 mg/day ethmozin and 18 +/- 12 and 55 +/- 12% for 100 and 200 mg/day ethacizin, respectively. Combined therapy with ethmozin (400 mg/day) and ethacizin (100 mg/day) reduced the number of VEDs by 78 +/- 2% in these patients without side effects. In the "nonresistant" but intolerant group of patients, use of the combination allowed relief of symptomatic ectopy without side effects. A theoretical model correctly predicted an effective combination of class I antiarrhythmic drugs, one with "fast-off" and one with "slow-off" kinetics, which may provide a general rationale for choosing drug combinations.

[Pharmacokinetics of moracizine and moracizine sulfoxide in healthy volunteers].

The pharmacokinetics of moracizine (Mor) and moracizine sulfoxide (Mor-SO) determined by reversed phase HPLC was reported. The data in 6 volunteers after a single oral dose (600 mg) showed an one-compartment open model. The peak concentration in plasma (2.1 +/- 0.4 micrograms.ml-1) of Mor reached within 1-2 h. The Mor-SO concentration in plasma was much lower (0.19 +/- 0.06 micrograms.ml-1) than that of Mor, but its elimination T1/2 (2.3 +/- 1.0 h) was similar to that of Mor (1.5 +/- 1.0 h). The recoveries of Mor, Mor-SO, moracizine sulfone (Mor-SO2) in urine within 48 h were 0.07%, 0.25%, and 0.06% of the total dose, respectively. The Mor and Mor-SO concentration ranges in plasma for 9 arrhythmic patients after 2-wk therapeutic trial were 0.09 +/- 0.07 to 0.9 +/- 0.5 microgram.ml-1 and 0.040 +/- 0.023 to 0.15 +/- 0.06 micrograms.ml-1, respectively. These results suggested that cumulative doses would not result in accumulation of the drug and the anti-arrhythmic effect of Mor-SO might not be realized.

[Comparative analysis of antiarrhythmic action and electrophysiological effects of a new benzodiazepine derivative gidazepam and ethacizin in arrhythmias of various genesis]. / Sravnitel'nyi analiz antiaritmicheskogo deistviia i élektrofiziologicheskikh éffektov novogo proizvodnogo benzodiazepina gidazepama i étatsizina pri aritmiiakh serdtsa razlichnogo geneza.

The antiarrhythmic and electrophysiological effects of the new benzodiazepine tranquilizer gidazepam versus ethacizin were examined in patients with cardiac arrhythmias. The antiarrhythmic effect of the agent was found during 24-day monitoring and simulated psychoemotional stress in 81% of patients with neurocirculatory dystonia and in 61% of patients with coronary heart disease. The antiarrhythmic effects developed with gidazepam-induced changes in electrophysiological properties of the cardiac conduction system. The preventive antiarrhythmic effect of gidazepam was demonstrated to be higher than that of ethacizin during stress in patients with arrhythmias of extra-ischemic genesis.

[Clinical effectiveness of cordarone in combination with other anti-arrhythmia agents in refractory atrial fibrillation and adverse effects of the drugs]. / Klinicheskaia éffektivnost' kordarona v sochetanii s drugimi antiaritmicheskimi preparatami pri refrakternoi k terapii forme mertsaniia predserdii i pobochnye deistviia primeniaemykh lekarstv.

The study was undertaken to examine 105 patients with various circulatory diseases complicated by atrial fibrillation. Patients with refractory atrial fibrillation who had taken combined antiarrhythmic therapy were found to be more responsive to the combinations of cordarone + kinilentin (quinidine disulphate) and cordarone + ethacizin. The combinations of cordarone+digoxin and cordarone + finoptin were demonstrated to be less beneficial.

[Atherogenic properties of phenothiazine drugs manifesting in cultured cells of the human aortic intima]. / Aterogennye svoistva fenotiazinovykh preparatov, proiavliaemye v kul'ture kletok intimy aorty cheloveka.

The effects of phenothiazine drugs on the levels of cholesterol in smooth cells of the human aortic intima. Two antiarrhythmics (ethacizin and ethmozine) and two neuroleptics (trifluoperazine and chlorpromazine) were evaluated. The three agents ethacizin, trifluoperazine, and chlorpromazine given in concentrations of 10(-7) to 10(-5) M were ascertained to cause intracellular cholesterol accumulation, whereas ethmozine produced no effects on the intracellular levels of cholesterol. Ethacizin failed to cause cholesterol accumulation when the cells were incubated with ethacizin in the culture medium supplemented with lipid-deficient serum. Ethacizin in a concentration o 10(-5) M was shown to inhibit the synthesis of cholesterol esters and had no action on the intracellular synthesis of steroids.

Effects of multiple doses of moricizine hydrochloride on its pharmacokinetics and hepatic microsomal enzymes in rats.

We studied the influence of chronic moricizine hydrochloride (MRZ) treatment on the drug's pharmacokinetics and on drug metabolizing enzyme activities in rats. Separate groups of 8 rats (4 males and 4 females) were treated with 40 and 100 mg/kg oral MRZ once daily for 7 days and saline control for 7 days prior to the preparation of hepatic microsomal enzyme suspensions. Depending on the substrate, treatments with multiple oral MRZ increased or decreased hepatic microsomal enzyme activities. For the pharmacokinetic study, rats (4 males and 4 females) were treated with 40 mg/kg oral MRZ once daily for 7 days. A comparison of MRZ pharmacokinetics obtained on day 1 relative to day 7 revealed that both AUC0-t and AUC0-infinity increased about 7-fold in males and 2-fold in females. Cmax also increased about 5-fold from day 1 to day 7 in males. These increases in blood concentrations and AUC's are likely due to enzyme inhibition. Results obtained from female rats on days 1, 4 and 7 suggest that metabolic changes probably occur after the 4th day of dosing. Therefore, chronic MRZ treatment affected its pharmacokinetics and hepatic metabolizing enzyme activities in rats.

[Prospective course of therapy arresting attacks of atrial fibrillation in patients with preexcitation syndromes]. / Prospektivnaia évoliutsiia kupiruiushchei terapii pri pristupakh mertsiatel'noi aritmii u bol'nykh s sindromom prezhdevremennogo vozbuzhdeniia zheludochkov.

A comparative study of antiarrhythmic drugs was performed in 81 patients with atrial fibrillation attacks in the presence of preexcitation syndrome. The first intravenous administration of cordarone was effective in 84.06%, disopyramide--in 69%, ajmaline in 44.8, verapamil in 42.1, novocaine amide in 39.4 and ethacizin in 38.5% of the patients. The first oral administration of quinidine and kinilentin arrested 80.4% of arrhythmia attacks, disopyramide 66.7% propranolol and mexitil 37.5 and 33.3%, respectively. Prospective evolution of antiarrhythmic therapy manifested with decreased therapeutic efficacy of the drugs from 55.7 to 26.2% in the whole group during the period of 1-5 years.

Modulating intraventricular conduction through competition of two class 1 antiarrhythmic agents: experience with ethacizin and lidocaine in canine heart.

The frequency-dependent effects on the intraventricular conduction through the dog heart in situ produced by two class 1 antiarrhythmic drugs, ethacizin and lidocaine, with different kinetic properties were investigated. Conduction delay was measured using stimulation of the His-bundle after pharmacologically induced atrioventricular (AV) block. Electrical events were derived from local epicardial bipolar electrograms at the base of the right ventricle. The stimulation program consisted of several 50-pulse trains with progressively shorter interstimulus intervals (ISI) separated by a l-s pause. Ethacizin (1.5 mg/kg) increased conduction delay by 30% at ISI of 1000 ms, and the effect was enhanced when ISI was shortened to 200 ms; l-s pauses did not significantly increase conduction velocity. Addition of lidocaine (12 mg/kg) strongly potentiated the ethacizin effect at ISI shorter than 300 ms without any noticeable increase in conduction delay at longer intervals. The major result was dramatic acceleration of conduction during the l-s pauses while both drugs were infused. With this combination, conduction delay after pause was shorter than with ethacizin alone, which is consistent with the competition of the drugs for the same binding site inside the sodium channel. Combination of two class 1 compounds in clinical practice may enhance their antiarrhythmic effects without adversely inhibiting normal impulse conduction in the heart. Computer-predicted data were in reasonable agreement with experimental results. The "guarded receptor" model, thus, can provide a simple method for predicting local anesthetic drug interactions in man.

Ethacizin blockade of calcium channels: a test of the guarded receptor hypothesis.

The effect on calcium channels of the sodium channel antagonist, ethacizin, was studied in isolated frog ventricular cells using the whole cell voltage-clamp methodology. Ethacizin was found to block inward calcium current in a frequency-, voltage-, and concentration-dependent manner. The frequency-dependent blocking properties were modeled by considering the drug interaction with a voltage-dependent mixture of calcium channels harboring either an accessible or an inaccessible binding site. With repetitive stimulation, the pulse-to-pulse reduction in peak current is shown to be exponential, with a rate linearly related to the interstimulus interval and the drug concentration. Observed frequency- and concentration-dependent blocks were consistent with the predictions of the model, and mixture-specific rate constants were estimated from these data. The negligible shift in channel inactivation and the reduction of apparent binding and unbinding rates with more polarized membrane potentials imply the active moiety of ethacizin blocks open channels and is trapped within the channel at resting membrane potentials. The binding rate at 0 mV is similar to that observed in studies of interactions of other open channel blocking agents with voltage- and ligand-gated channels.

[Influence of ethacizin (the diethyl analog of ethmozine) on phase-dependent parasympathetic effects on the heart]. / Vliianie étatsizina (dietilovogo analoga étmozina) na fazozavisimye parasimpaticheskie éffekty na serdtse.

The influence of ethacizin (a diethylamine analog of ethmozine) (1.10(-7)-1.10(-6) g/ml) upon the phase-dependent chronotropic parasympathetic effects was studied on the perfused frog heart. The vagolytic influence of ethacizin (5.10(-7) and 1.10(-6) g/ml) was detected; the concentration of 1.10(-7) g/ml was found ineffective. The vagolytic effect consisted of a decreased maximum of phase-dependent effect, reduced latency and time required for the manifestation of the maximum increase. The period of inhibitory vagal stimulus effectiveness did not change significantly.

Ethacizin: a new efficacious Soviet antiarrhythmic drug of the phenothiazine group.

Ethacizin, a new Soviet antiarrhythmic agent of the phenothiazine group, was tested on 82 patients with ventricular rhythm disturbances. Antiarrhythmic effects of the drug were assessed by means of ambulatory ECG monitoring. The investigation protocol included acute drug testing with 50 mg, 100 mg, and 150 mg, and short-term maintenance therapy with 150 to 300 mg/24 hours of ethacizin (mean 183 +/- 46 mg/24 hours) for 3 to 14 days (mean 7 +/- 3 days). Ethacizin reduced the total number of ventricular premature beats (VPBs) from 17,263/24 hours (on placebo) to 3458/24 hours (p less than 0.001) and suppressed couplets and ventricular tachycardia (VT) runs by 90% in 94% and 96% of patients, respectively. Maximum blood plasma concentration of ethacizin was observed in 110 to 120 minutes and accounted for 300 to 447 ng/ml (mean 354 +/- 77 ng/ml), with a minimum therapeutic drug plasma concentration ranging from 29 to 101 ng/ml (mean 73 +/- 27 ng/ml). There was a significant increase in PQ and QRS intervals with ethacizin. Ethacizin was well tolerated. Thus ethacizin had high antiarrhythmic efficacy in patients with VPBs and no significant side effects.

[Clinical pharmacokinetics and hemodynamics of ethacizin in the acute period of myocardial infarct]. / Klinicheskaia farmakokinetika i gemodinamika étatsizina v ostrom periode infarkta miokarda.

Clinical pharmacokinetics of ethacizine and its effect on parameters of the central and peripheral hemodynamics in the acute period of myocardial infarction were studied. The appearance of an additional maximum or "concentration plateau" on the concentration-time curve following a single intravenous injection of the drug was noted in most cases. To describe experimental data, a three-compartment model with lag time was proposed. The pharmacokinetic parameters obtained indicate that ethacizine is characterized by a less value of clearance and greater period of half-elimination as compared to ethmozine. Ethacizine was shown to exert no considerable effect on hemodynamics that makes it possible to recommend its use in acute myocardial infarction when cardiac rhythm disorders occur.

[Possibility of the pharmacologic treatment of post-ischemic myocardial damage]. / Vozmozhnost' farmakologicheskogo vozdeistviia na postishemicheskoe povrezhdenie miokarda.

The influence of ethacizin and nonachlazin on the size of myocardial necrosis, caused by 1.5-hour partial occlusion of the coronary artery was studied in conscious rabbits. The drugs were administered for 3 days, after the blood supply in the ischemic zones had been recovered. Ethacizin had a more pronounced effect, as compared to nonachlazin. The data obtained suggest that in the case of isochemic heart disease pharmacotherapy can be used not only for the prevention and arrest of anginal attacks, but also for the treatment of postischemic cardiac lesions.