[Effect of etmosin on biliary motility disorders in patients with ischemic heart disease]. / Vplyv etmozynu na porushennia motoryky zhovchovyvidnykh shliakhiv u khvorykh na ishemichnu khvorobu sertsia.

We have studied the influence of Etmosin medication on severity of IHD clinical presentations and comprised biliary motility in 162 patients aged 26 to 60. Dynamic echocholecystography (DECG) has been applied. The obtained data suggest using Etmosin in patients with ischemic heart disease and comprised biliary motility makes for normalizing tonus of the Odi sphincter and decreasing the rate of episodes of angina pectoris, although was not found any influence of Etmosin on gall-bladder motility. The use of Etmosin enables in patients with IHD and comprised biliary motility to decrease reflex angina pectoris.

Human moricizine metabolism. I. Isolation and identification of metabolites in human urine.

1. Using synthetic standards and/or spectral data, seven moricizine metabolites were structurally identified in human urine. Two novel metabolites were identified as phenothiazine-2-carbamic acid and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate. Two novel human moricizine metabolites, 2-amino-10-(3-morpholino-propionyl) phenothiazine, a previously identified dog metabolite, and 2-aminophenothiazine, a previously identified rat metabolite, were also identified. Three additional human metabolites, phenothiazine-2-carbamic acid ethyl ester sulphoxide (P2CAEES), moricizine sulphoxide, and ethyl ¿10-[N-(2'-hydroxyethyl)3-aminopropionyl] phenothiazin-2-yl¿ carbamate, all previously described in the literature, were observed. 2. Both 2-amino-10-(3-morpholinopropionyl) phenothiazine and ethyl [10-(3-aminopropionyl) phenothiazin-2-yl] carbamate, and possibly ethyl ¿10-[N-(2'-hydroxyethyl) 3-aminopropionyl]phenothiazin-2-yl¿ carbamate, possess the structural characteristics thought to be necessary for class 1 antiarrhythmic activity.

[Studies on ethmozine sustained-release tablet remaining-floating in stomach].

An oral sustained-release system of ethmozine (E-HBS) was developed. The in vitro release characteristics of E-HBS were shown primarily to be of the first order of kinetics (Kr = 0.2436 h-1). The gamma-scintiphotographic study showed that E-HBS remained in the human stomach for more than 6 hours after ingestion, much longer than the conventional tablet (1-1.5 h). The plasma concentration-time curve of E-HBS exhibited typical sustained-release characteristics. The percentage of drug released in vitro vs the percentage of drug release in vivo of E-HBS indicated excellent linearity.

Effect of chronic oral moricizine and intravenous epinephrine on ventricular fibrillation and defibrillation thresholds.

The purpose of this study was to determine the effects of chronic oral moricizine therapy and physiological doses of epinephrine on ventricular fibrillation and defibrillation thresholds using an implantable transvenous/subcutaneous defibrillation system in a pig model. Thirteen pigs completed the three phases of the study. After a baseline study on day 1, the animals were randomized to receive moricizine 10-15 mg/kg tid or placebo for seven doses, at which time the protocol was repeated on day 4. The same protocol was again repeated on the same day after infusion of physiological doses of epinephrine. Multiple ventricular fibrillation and defibrillation thresholds were measured during each study. Moricizine did not alter ventricular fibrillation nor defibrillation thresholds, whereas epinephrine increased the ventricular defibrillation threshold from 20.8 J to 23.7 J (P < 0.05). In addition, we observed an increase in both ventricular fibrillation (19.7 J vs 12.6 J; P < 0.05) and defibrillation (20.8 J vs 17.8 J; P 0.05) thresholds over the 4 days of the study. These findings suggest that moricizine may be a safe antiarrhythmic agent to use in patients with implantable cardioverter defibrillators, and that elevated endogenous epinephrine may render defibrillation more difficult.

[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.

Pharmacokinetics of moricizine in young patients.

Moricizine is a novel phenothiazine antiarrhythmic agent that depresses the activity of ectopic foci, has a low incidence of adverse effects relative to other agents, and is useful in treating pediatric atrial ectopic tachycardia. A study was conducted to determine the pharmacokinetics of moricizine in children after oral administration. Moricizine was isolated from frozen serum obtained from four male patients (ages 7, 8, 9, and 18 years) receiving the drug for supraventricular tachycardia and analyzed by high-performance liquid chromatography with ultraviolet detection according to an established protocol. Peak serum levels were between 400 and 2000 ng/mL. Elimination of moricizine did not follow simple single-compartment pharmacokinetics. In three patients we observed an increase or slower decline in blood level occurring after 4 hours. Because of the paroxysmal nature of the tachycardias, decreases in patient heart rate could not be correlated with moricizine blood level. These results suggest that the pediatric pharmacokinetics of moricizine excretion are complex and may differ from those seen in adults.

Isolation and characterization of sulphoxidation metabolites of moricizine in rat and human biological fluids.

The sulphoxidation metabolites of moricizine, moricizine sulphoxide (M-sulphoxide) and moricizine sulphone (M-sulphone) were isolated and identified in the rat bile and urine and in human plasma and urine following administration of moricizine hydrochloride. The sulphoxide and sulphone were synthesized chemically by peroxidation of moricizine hydrochloride with hydrogen peroxide at 25 degree C and 60 degree C, respectively, and were characterized by melting point determination (MP), infrared spectroscopy (IR), mass spectroscopy (MS), thin layer chromatography (TLC) and high performance liquid chromatography (HPLC). In the rats (n=7), which were kept in metabolic cages and given intravenous moricizine (0.72 mg), the mean +/- SD percentages recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.11 +/- 0.09%, 0.74 +/- 0.45% and 5.16 +/- 4.24%, respectively. The corresponding recoveries in the bile were 0.13 +/- 0.04% as moricizine, 3.39 +/- 1.62% as M-sulphoxide and 2.16 +/- 1.07% as M-sulphone. After an oral dose of moricizine HCl (300 mg) the plasma concentrations of moricizine, M-sulphoxide and M-sulphone at 4 h in two healthy subjects were 0.43, 0.11 and 0.10 microg/ml and 0.32, 0.17 and 0.27 microg/ml, respectively for Subject 1 and Subject 2. The percentages of dose recovered in the urine as moricizine, M-sulphoxide and M-sulphone were 0.14 and 0.02%, 0.27 and 0.36%, and 0.30 and 0.24%, respectively for Subject 1 and Subject 2. It is suggested that an investigation of the disposition of moricizine and its sulphoxidation metabolites in patients will be valuable for elucidating the prolonged effects in the treatment of ventricular arrhythmias.

Relations between heart failure, ejection fraction, arrhythmia suppression and mortality: analysis of the Cardiac Arrhythmia Suppression Trial.

OBJECTIVES: We studied the relations between heart failure, ejection fraction, arrhythmia suppression and mortality. BACKGROUND: Both left ventricular ejection fraction and functional class of heart failure are strongly associated with mortality after acute myocardial infarction. Both are also related to the presence of ventricular arrhythmias and have been identified as factors related to the ability to suppress ventricular arrhythmias. Little has been reported about the relations between these two factors and arrhythmia suppression or mortality. METHODS: Baseline data from the Cardiac Arrhythmia Suppression Trial were used to define several categories of heart failure and to relate both the resulting categories and ejection fraction to arrhythmia suppression and mortality using logistic and survival regression analytic methodologies. RESULTS: Regardless of the prospective baseline definition of heart failure used, the data consistently showed that heart failure was a more powerful predictor of subsequent congestive heart failure events and arrhythmia suppression and was equally powerful in predicting death. However, each variable provided incremental information when included in the prediction model. Heart failure and ejection fraction appeared to be independent predictors of death. Interactions were observed: A low ejection fraction was more predictive of failure of arrhythmia suppression in patients with than without evidence of heart failure before or at baseline; a low ejection fraction was more predictive of subsequent congestive heart failure events in patients without than with evidence of heart failure before or at baseline. CONCLUSIONS: Although heart failure as a prognostic feature appears to be somewhat superior to ejection fraction, both are powerful predictors of arrhythmia suppression and cardiac events in patients with ventricular arrhythmia after myocardial infarction. Each provides incremental prediction.

Moricizine concentration to guide arrhythmia treatment: with attention to elderly patients.

To test the relationship between plasma moricizine concentration and the electrocardiogram (ECG) and arrhythmia suppression, 17 symptomatic cardiac patients with 30 or more ventricular premature complexes per hour were studied. Seven patients were mature adults, less than 60 years of age; and ten were elderly adults, more than 60 years of age. During steady-state moricizine therapy, patients had plasma moricizine concentration determined over a dosing interval, and had standard 12-lead ECG and a 24-hour ambulatory ECG recorded. The mean moricizine dose was 215 +/- 29 mg every 8 hours; mean maximal moricizine concentration was 1.4 +/- 0.84 micrograms/ml; and mean t1/2 beta was 1.5 +/- 0.7 hours. Baseline age-related differences were found, including prolonged electrocardiographic intervals (PR and QRS) (P < .05), increased ventricular arrhythmias (P < .05), and reduction in creatinine clearance (P < .05) in the elderly. Compared with pretreatment values, PR (P < .05) and QRS (P < .05) prolongation was observed, and was more marked in elderly patients. Over a dosing interval, there were dynamic changes on the ECG that paralleled plasma moricizine concentration; that is, peak and nadir intact moricizine concentration occurred simultaneously with ECG changes: QRS and JTc prolonged (P < .05), and PR prolongation approached significance (P = 0.09). Suppression of ventricular premature complexes of 80% or more occurred in 15 patients, and ventricular tachycardia was abolished in 10 of 12 patients. Probit analysis revealed that the therapeutic antiarrhythmic concentration ranged from 0.20 to 3.6 micrograms/ml.(ABSTRACT TRUNCATED AT 250 WORDS)

Enzyme induction by moricizine: time course and extent in healthy subjects.

Moricizine.HCl, a novel phenothiazine derivative with oral antiarrhythmic activity, was examined for its potential to induce its own hepatic metabolism and to alter the pharmacokinetics of the test substrate, antipyrine, in 12 healthy male subjects. Antipyrine oral clearance increased from a starting value of .74 mL/minute/kg to .98 (+32%, P < .01) after 7 days of moricizine administration (250 mg every 8 hours) and to 1.15 mL/minute/kg after 14 days (+47%, P < .05); t1/2 was correspondingly reduced. Moricizine oral clearance increased from a baseline of 3.01 L/hour/kg to 3.62 (+20%, P < .05) after 6 days of oral moricizine and 4.66 (+51%, not significant) after 13 days. Moricizine t1/2 was marginally, but consistently, increased (+23%, P < .05) instead of decreased as one would expect because of enzyme induction, presumably due to a decrease in systemic bioavailability and its influence on the oral volume of distribution. In half of the subjects who discontinued moricizine after 7 days, antipyrine pharmacokinetic values returned to near baseline 7 days later. Although moricizine was able to induce its own hepatic metabolism and that of antipyrine after 6 or 7 days of continuous administration, the electrocardiographic properties of moricizine did not appear to be altered by continuous dosing.

Antifibrillatory and electrophysiologic actions of moricizine alone and in combination with lidocaine: a prospective, randomized trial.

OBJECTIVE: The Cardiac Arrhythmia Suppression Trial II showed that moricizine acutely increases the occurrence of sudden cardiac death. Thus the objective of this investigation was to evaluate the antifibrillatory properties of moricizine (a new antiarrhythmic agent) alone and in combination with lidocaine (an established antifibrillatory agent). DESIGN: Prospective, double-blind, randomized, placebo-controlled trial. SETTING: Laboratory at a large, university-affiliated medical center. SUBJECTS: Eighteen domestic farm swine with a mean weight of 39 +/- 5 kg. INTERVENTIONS: After pentobarbital anesthesia, the animals were instrumented. A bipolar pacing catheter was placed in the right ventricular apex and a pig-tail catheter was placed in the aortic arch for induction of ventricular fibrillation and aortic blood pressure monitoring. Subsequently, the pigs were randomized to moricizine or control (0.9% saline) groups. Each group underwent three treatment phases: baseline, drug (moricizine 2 mg/kg loading dose, 1.5 mg/kg/hr infusion, or saline bolus and infusion), and drug combined with lidocaine (5 mg/kg loading dose, 4 mg/kg/hr infusion). Ventricular fibrillation threshold was determined every 5 to 10 mins over a 1-hr period during each treatment phase. RESULTS: Ventricular fibrillation threshold values in the animals randomized to control were 16.8 +/- 7.6, 18.1 +/- 8.9, and 23.9 +/- 10.4 mA at baseline during saline infusion, and when saline was combined with lidocaine, respectively. The values during the saline-lidocaine combination treatment phase were significantly greater than the values at baseline and during saline treatment alone (p < .001). Ventricular fibrillation threshold values in the animals randomized to receive moricizine were 15.5 +/- 4.4, 18.1 +/- 5.1, and 21.1 +/- 8.4 mA at baseline, during moricizine infusion, and when moricizine was combined with lidocaine. The values during the lidocaine-moricizine combination treatment phase were significantly greater than values at baseline (p = .005), but not during moricizine treatment alone (p = .16). The increase in ventricular fibrillation threshold from baseline to moricizine (17%) was similar to the increase from baseline to saline (7%), p = .37. The increase in ventricular fibrillation threshold when lidocaine was added to moricizine (13%) was less than the increase with lidocaine alone (32%), p = .05. CONCLUSION: In this experimental model, moricizine, at the dose studied, lacked antifibrillatory properties. Moreover, moricizine did not contribute to the antifibrillatory effects of lidocaine.

Effects of advancing age on the efficacy and side effects of antiarrhythmic drugs in post-myocardial infarction patients with ventricular arrhythmias. The CAST Investigators.

OBJECTIVE: To determine the effect of age on the response to anti-arrhythmic drugs. DESIGN: Randomized controlled trial comparing particular drugs. SETTING: Multi-institutional (The Cardiac Arrhythmia Suppression Trial, CAST). PARTICIPANTS: 2,371 patients, age less than 80, with ventricular arrhythmias after a recent myocardial infarction. Subjects classified by age as less than or equal to 55, 56-65, and 66-79 years. INTERVENTION: Upwardly titrated doses of encainide, flecainide or moricizine. After identification of a tolerated and effective dose of one of the drugs, participants were randomized to that drug and dose versus its placebo for up to 10 months. MAIN OUTCOME MEASURES: Efficacy of drug (suppression of ventricular premature depolarizations and/or non-sustained ventricular tachycardia), side effects and mortality. RESULTS: Older patients had more previous MIs, congestive heart failure (CHF), hypertension, NSVT, repolarization abnormalities, digitalis use, and diuretic use. They had less pathologic Q-waves or electrocardiographic injury pattern, and their left ventricular ejection fraction (LVEF) was lower. First dose VPD suppression with the first drug averaged 53% and is not associated with age (P = 0.29). Adverse events including death are more frequent in older patients taking study drugs (P less than 0.001). This trend is consistent in all three study drugs and at varying LVEFs. History of prior MI, low LVEF, VPD (in log scale), and digitalis therapy also correlates with adverse events (all P less than 0.05). Following adjustment for these factors, older age is an independent predictor of adverse events (relative risk 1.30 per decade of age, P less than 0.001). CONCLUSIONS: Older age increases the susceptibility to adverse cardiac events from a class of relatively toxic antiarrhythmic agents.

Effect of moricizine on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers.

Moricizine HCl, a new orally active antiarrhythmic agent, induces its own hepatic metabolism and consequently may interfere with the metabolism of warfarin, a drug used commonly by cardiac patients that also is subject to extensive hepatic metabolism. Both drugs are also highly protein bound in plasma. To assess the possibility of an interaction, single-dose sodium warfarin (25 mg oral Coumadin, Du Pont Pharmaceuticals, Wilmington, DE) pharmacokinetics, pharmacodynamics; and plasma protein binding were examined in 12 healthy male volunteers 14 days before and 14 days after starting chronic oral moricizine HCl administration (250 mg every 8 hours). The terminal elimination rate constant of warfarin was increased by about 10% when measured in the presence of chronic moricizine administration. However, oral plasma clearance, apparent volume of distribution, maximum peak plasma concentration, time to reach peak concentration, and protein binding were unaffected. More importantly, there was no evidence of a pharmacodynamic interaction based on the prothrombin time profile. It was concluded that no clinically significant interaction occurs under these conditions.

[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.

A proarrhythmic response to sodium channel blockade: modulation of the vulnerable period in guinea pig ventricular myocardium.

The vulnerable period (VP) is an interval of time during the cardiac cycle within which premature stimulation may lead to trains of responses (one: many stimulus-response coupling). Although the VP parallels the recovery of sodium channel availability, modulators of its boundaries remain unclear. Numerical studies of a uniform cable demonstrated that reduction in sodium channel availability increased the range of premature stimuli, resulting in unidirectional block, a precursor of reentrant activation. Consequently, we hypothesized that the kinetics of use-dependent sodium channel blockade could reflect one dimension of a drug's proarrhythmic potential. In strips from guinea pig right ventricle, we probed the boundaries of the VP in the presence of use-dependent sodium channel antagonists utilizing a train of stimuli followed by a premature stimulus. Under drug-free conditions when the sites of drive and premature stimulation were the same, the VP was less than 4 ms in duration. When the drive and premature sites were different, the drug-free VP was greater than 5 ms in 22 of 24 preparations and 0 in the other two, with an average VP duration of 16 +/- 10 ms (mean +/- SD). In the presence of 1 microM moricizine, VP = 17 +/- 4 ms; 12 microM moricizine, VP = 35 +/- 4 ms; 3 microM flecainide, VP = 50 +/- 17 ms; and 4 microM quinidine, VP = 2 +/- 1 ms. These results suggest that residual unsuppressed premature ventricular contractions (PVCs) in the presence of some class 1 drugs have a greater potential for initiating a proarrhythmic response than PVCs in the absence of a class 1 drug.

[Use of an anti-arrhythmia drug mexicord in the treatment of ventricular extrasystole]. / Primenenie antiaritmicheskogo preparata meksikorda v lechenii zheludochkovoi ekstrasistolii.

The antiarrhythmic agent mexicord (Polfa, Poland) versus ethmozine underwent a clinical trial. Meticord was found to have a marked antiarrhythmic effect and be useful in the long-term management of patients with ventricular tachyarrhythmias.

Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the Cardiac Arrhythmia Suppression Trial. CAST Investigators.

This report examines whether in the Cardiac Arrhythmia Suppression Trial death and cardiac arrest from encainide, flecainide and moricizine during the titration phase and from encainide and flecainide during the follow-up phase were related to presence (Q-wave acute myocardial infarction [Q-AMI]) or absence (non-Q-AMI) of pathologic Q waves. In all, 2,371 patients (70% with Q-AMI, 26% with non-Q-AMI, and 4% unknown) entered the titration phase, starting 117 +/- 163 days after index AMI and lasting for an average of 21 days. For the titration phase, no significant differences existed between Q-AMI and non-Q-AMI patients for death and cardiac arrest rate, ventricular premature complex suppression rate, and nonrandomization rate. A total of 1,498 patients entered the follow-up phase of an average of 10 months (starting 129 +/- 158 days after the index AMI), and were randomized to encainide or flecainide, or their matching placebos. In the placebo group, non-Q-AMI patients had a significantly lower rate of death and cardiac arrest than Q-AMI patients (1.0 and 4.6%, respectively; p = 0.04). Encainide and flecainide significantly elevated death and cardiac arrest rate in both non-Q-AMI patients (8.7%, p less than 0.01) and Q-AMI patients (7.8%, p = 0.04). The relative risk for encainide or flecainide over placebo in the non-Q-AMI patients was 8.7, which was significantly higher than 1.7 observed for the Q-AMI patients (p = 0.03). None of the baseline characteristics had any significant interaction with encainide or flecainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of food on the oral absorption and bioavailability of moricizine.

Moricizine, a unique Class I antiarrhythmic agent, was orally administered with and without a meal to 24 healthy male subjects to determine the effect of food on moricizine absorption and bioavailability. Relative to the fasting state, a standardized breakfast delayed the time to peak plasma moricizine concentration (1.2 vs. 0.9 hr; P less than .03) and lowered peak plasma moricizine concentration by 24% (0.55 vs. 0.72 microgram/mL; P less than .03). Bioavailability, as measured by area under the plasma moricizine concentration versus time curve, was not significantly altered by the meal.

Dose proportionality of moricizine after escalating multiple doses in healthy volunteers.

This study was designed to determine the dose linearity and proportionality of moricizine after multiple-dose administrations of 450 to 900 mg/day. The study design was an open-label, four-treatment, four-period sequentials escalating dose. Twelve subjects each received multiple doses of 150, 200, 250, and 300 mg of moricizine every 8 hours during 7 days of treatment. Blood samples for pharmacokinetic determinations were obtained on day 7 of each treatment period during an 8-hour time interval. Cmin determinations were also made on specific days of each treatment period. The AUC tau (area under the curve from time 0 to 8 hours), Cmax, and Cmin parameters were all normalized to the 250-mg (750 mg/day) dose. No statistically significant differences were seen in these parameters at the four treatment levels. It was concluded that moricizine follows first-order or linear pharmacokinetics after multiple dosing and exhibits dose proportional pharmacokinetics in the dosage-range studies. This range corresponds to the clinically useful dosage range.