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PubMed2002

Analysis of moricizine block of sodium current in isolated guinea-pig atrial myocytes. Atrioventricular difference of moricizine block.

The effects of moricizine on Na+ channel currents (INa) were investigated in guinea-pig atrial myocytes and its effects on INa in ventricular myocytes and on cloned hH1 current were compared using the whole-cell, patch-clamp technique. Moricizine induced the tonic block of INa with the apparent dissociation constant (Kd,app) of 6.3 microM at -100 mV and 99.3 microM at -140 mV. Moricizine at 30 microM shifted the h infinity curve to the hyperpolarizing direction by 8.6 +/- 2.4 mV. Moricizine also produced the phasic block of INa, which was enhanced with the increase in the duration of train pulses, and was more prominent with a holding potential (HP) of -100 mV than with an HP of -140 mV. The onset block of INa induced by moricizine during depolarization to -20 mV was continuously increased with increasing the pulse duration, and was enhanced at the less negative HP. The slower component of recovery of the moricizine-induced INa block was relatively slow, with a time constant of 4.2 +/- 2.0 s at -100 mV and 3.0 +/- 1.2 s at -140 mV. Since moricizine induced the tonic block of ventricular INa with Kd,app of 3.1 +/- 0.8 microM at HP = -100 mV and 30.2 +/- 6.8 microM at HP = -140 mV, and cloned hH1 with Kd,app of 3.0 +/- 0.5 microM at HP = -100 mV and 22.0 +/- 3.2 microM at HP = -140 mV, respectively, either ventricular INa or cloned hH1 had significantly higher sensitivity to moricizine than atrial INa. The h infinity curve of ventricular INa was shifted by 10.5 +/- 3.5 mV by 3 microM moricizine and that of hH1 was shifted by 5.0 +/- 2.3 mV by 30 microM moricizine. From the modulated receptor theory, we have estimated the dissociation constants for the resting and inactivated state to be 99.3 and 1.2 microM in atrial myocytes, 30 and 0.17 microM in ventricular myocytes, and 22 and 0.2 microM in cloned hH1, respectively. We conclude that moricizine has a higher affinity for the inactivated Na+ channel than for the resting state channel in atrial myocytes, and moricizine showed the significant atrioventricular difference of moricizine block on INa. Moricizine would exert an antiarrhythmic action on atrial myocytes, as well as on ventricular myocytes, by blocking Na+ channels with a high affinity to the inactivated state and a slow dissociation kinetics.

Animals↗

PubMed1992

Defibrillation energy requirements during moricizine and moricizine-lidocaine therapy.

Defibrillation energy requirements may be altered by antiarrhythmic agents. We investigated the effects of moricizine on the defibrillation threshold (DFT) in 18 pentobarbital-anesthetized pigs. The animals were randomized, in a blinded fashion, to moricizine or control (0.9% saline) treatment groups. Each group underwent three treatment phases: baseline, drug infusion (moricizine or saline), and drug infusion combined with lidocaine. Moricizine (2 mg/kg loading dose, 1.5 mg/kg/h infusion) and lidocaine (5 mg/kg loading dose, 4 mg/kg/h infusion) were dosed to achieve therapeutic concentrations. After 5 s of induced ventricular fibrillation, defibrillation was performed using a cardiac defibrillator interfaced with two epicardial electrode patches. DFTs were determined at baseline, during the drug phase, and during the combination of lidocaine with moricizine or saline. DFT values in the animals randomized to the control group were 15.2 +/- 4.2, 14.0 +/- 3.3, and 17.8 +/- 8.7 J at baseline, saline infusion, and saline combined with lidocaine, respectively. No significant differences were observed among the treatment phases. DFT values in the animals randomized to moricizine group were 12.1 +/- 2.8, 13.8 +/- 5.2, and 22.9 +/- 7.1 J at baseline, moricizine infusion, and moricizine combined with lidocaine, respectively. The DFT values during the lidocaine-moricizine combination treatment phase were significantly greater than baseline and moricizine alone (p < 0.002). The mean change in the DFT from baseline to moricizine (14% increase) was significantly different than the mean change in the DFT from baseline to saline (8% decrease) (p = 0.03). Lidocaine added to moricizine increased the DFT by 84%, which was significantly different from the 27% increase in the DFT when lidocaine was added to saline (p = 0.02). We conclude that moricizine minimally increases the DFT, but the combination of moricizine with lidocaine results in a synergistic rise in the DFT that may have detrimental clinical implications.

Animals↗

PubMed1993

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.

Animals↗

PubMedDate not supplied

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.

Adult↗

PubMed1996

Pharmacokinetic interactions of moricizine and diltiazem in healthy volunteers.

Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.

Adolescent↗

PubMed1990

Moricizine: a new class I antiarrhythmic.

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of the Class I antiarrhythmic agent moricizine hydrochloride are reviewed. Moricizine is chemically similar to the phenothiazines but does not appear to block dopaminergic receptors. Its major electrophysiologic actions are a concentration-dependent decrease in maximum rate of phase 0 depolarization; increased rates of phase 2 and 3 repolarization, decreased action potential duration, and decreased effective refractory period. Moricizine causes a dose-related prolongation of the PR interval and of AV nodal, infranodal, and intraventricular conduction times but has little effect on ventricular repolarization. The antiarrhythmic and electrophysiologic effects are not correlated with plasma concentrations of the drug or its metabolites. Moricizine reduces the occurrence of ventricular premature contractions (VPCs), couplets, and nonsustained ventricular tachycardia. It appears to suppress symptomatic nonsustained ventricular tachycardia, sustained ventricular tachycardia, and ventricular fibrillation or flutter. Moricizine appears to be as effective as quinidine and more effective than disopyramide, propranolol, and imipramine but less effective than flecainide and encainide at reducing VPCs. Moricizine continues to be evaluated in the Cardiac Arrhythmia Suppression Trial, which was designed to assess the long-term benefit of arrhythmia suppression in patients with left ventricular dysfunction after myocardial infarction. Moricizine seems to be better tolerated than quinidine, disopyramide, and imipramine and to have less proarrhythmic potential than flecainide or encainide. Noncardiac adverse effects include dizziness, nausea, and headache. Cimetidine appears to decrease moricizine clearance, and decreased theophylline clearance has been reported in subjects given moricizine. The usual adult dosage of moricizine hydrochloride is 600-900 mg/day given in three divided doses; an every-12-hour regimen may be used in some patients. Because of the risk of proarrhythmic effects, indications are limited to treatment of documented life-threatening arrhythmias. Moricizine will compete with other agents as first-line therapy for life-threatening arrhythmias.

Arrhythmias, Cardiac↗

PubMed1995

Rate-dependent anisotropic conduction property in the epicardial border zone of canine myocardial infarcts and its modification by moricizine.

We evaluated anisotropic conduction properties, different conduction velocities depending on fiber orientation, in normal and infarcted myocardium and the effects of moricizine on anisotropic conduction. Various cycle lengths of stimulation were applied to 15 mongrel dogs, and epicardial mapping was performed using a 96-channel mapping electrode. Moricizine was then administered to seven dogs and the same procedure was performed. Conduction velocities were calculated from these maps. Programmed electrical stimulations were performed before and after moricizine administration to induce ventricular arrhythmias. Before moricizine administration, a rate-dependent decrease in longitudinal conduction velocity was observed in the infarcted zone. Moricizine suppressed longitudinal conduction in the normal zone significantly at 300 msec pacing, but not at slower rates. Moricizine at a dose of 4 mg/kg, on the other hand, suppressed longitudinal conduction in the infarcted zone significantly at all pacing cycle lengths. The effect of moricizine on transverse conduction was inconsistent. In three dogs, sustained ventricular tachycardia (VT) was induced either before or after moricizine administration. The mean cycle length of sustained VT was prolonged from 202 msec to 291 msec after 4 mg/kg of moricizine. Thus, the changes in cycle length of ventricular tachycardia observed were most likely the result of slowing of conduction velocity, especially in the longitudinal direction, in the infarcted myocardium. We conclude that the electrophysiologic nature of the subacute ischemic model was modified by moricizine, leading to depression of the conduction velocity of longitudinal conduction and the inducibility of ventricular arrhythmias.

Analysis of Variance↗

PubMed1987

Drug interactions with Ethmozine (moricizine HCl).

Moricizine HCl, a phenothiazine derivative synthesized in the USSR in 1964, has been shown to be an orally effective antiarrhythmic drug. Moricizine HCl has demonstrated a low incidence of generally mild and transient side effects. Studies of possible drug interaction between it and other drugs most likely to be administered to cardiovascular patients are currently being conducted in US drug trials. Possible interactions between moricizine HCl and cimetidine, and between moricizine HCl and digoxin, are reviewed. The coadministration of moricizine HCl had no effect on the pharmacokinetics of cimetidine; in contrast, cimetidine administration slowed the elimination of moricizine HCl. The implications of greater therapeutic and/or toxic effects of moricizine HCl must be considered for patients receiving cimetidine and moricizine HCl concomitantly. No significant interactions were observed when monitoring serum levels of moricizine HCl and digoxin in patients with normal renal function receiving digoxin therapy for congestive heart failure or atrial fibrillation. Moricizine HCl in therapeutic dosages (10 mg/kg daily) demonstrated antiarrhythmic efficacy without significant alterations in serum digoxin levels.

Cimetidine↗

PubMed1987

Antiarrhythmic efficacy of Ethmozine (moricizine HCl) compared with disopyramide and propranolol.

In the investigation of new antiarrhythmic drugs, comparative trials with clinically available antiarrhythmic agents provide a perspective from which to judge the new investigational agent. Two clinical investigations of moricizine HCl, each using a placebo-controlled, double-blind, crossover design, are summarized. In the first study, 18 patients with greater than or equal to 30 ventricular premature complexes (VPCs) per hour (mean 369 +/- 95) were given propranolol (120 mg daily) compared with moricizine HCl (816 +/- 103 mg daily). Propranolol suppressed 38% of VPCs in the study group, moricizine HCl, 81% of VPCs, and the combination of both drugs, 87%. Moricizine HCl was more effective than propranolol in suppressing VPCs at all individual levels greater than 70% (p less than 0.05, McNemar's test). The combination of moricizine HCl and propranolol was well tolerated. The second investigation used a placebo-controlled, double-blind, crossover design to compare the efficacy of disopyramide (600 mg daily) and moricizine HCl (800 mg daily) in 27 patients. Patients had greater than or equal to 40 VPCs/hr on a 24-hour ambulatory electrocardiogram. During moricizine HCl administration, the mean VPC frequency decreased from 524 to 151 VPCs/hr (71.2% reduction). In contrast, disopyramide reduced VPC frequency from 535 to 253 VPCs/hr (52.8% reduction) and demonstrated significantly greater side effects (p less than 0.05). Moricizine HCl was more effective than disopyramide in suppressing VPCs at all individual percent reduction levels greater than 70% (p less than 0.05, McNemar's test). Moricizine HCl was more effective in suppressing VPCs than either disopyramide or propranolol, with significantly fewer side effects.

Adult↗

PubMed1995

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.

Animals↗

PubMed1989

Determination of unlabeled and 13C6-labeled moricizine in human plasma using thermospray liquid chromatography-mass spectrometry.

Moricizine hydrochloride is an orally effective antiarrhythmic agent currently marketed in the Soviet Union and undergoing clinical testing in the United States. To facilitate the simultaneous analysis of unlabeled and 13C6-labeled moricizine in human plasma, a specific and sensitive method employing liquid-liquid extraction followed by thermospray liquid chromatography-mass spectrometry (LC-MS) was developed. Plasma samples, after addition of [2H11]moricizine as an internal standard, were extracted into methylene chloride under alkaline conditions. Extracts were evaporated, reconstituted with mobile phase, and chromatographed on an ODS column. The LC mobile phase consisted of methanol-0.1 M ammonium acetate containing 0.2% triethylamine (65:35) and it was used at a flow-rate of 1.5 ml/min. Under these conditions, moricizine and [13C6]moricizine coeluted at 1.2 min, while [2H11]moricizine eluted slightly earlier. The MS system consisted of a Finnigan 4600 TSQ and a Vestec thermospray interface. Selected ions at m/z 428, 434, and 439 were scanned at 0.2 s per ion. Over a plasma concentration range of 10-800 ng/ml, intra-day precision (n = 3) ranged from 1.8 to 13.3% and intra-day accuracy ranged from 1.9 to 15.8%. This method was successfully used to assay human plasma samples from a pilot moricizine bioavailability study in which tablets and solution containing moricizine hydrochloride and [13C6]moricizine, respectively, were simultaneously administered.

Carbon Isotopes↗

PubMed1993

Effect of moricizine on the pharmacokinetics of single-dose theophylline in healthy subjects.

We studied the effect of multiple oral doses of moricizine on the pharmacokinetics of theophylline in healthy male subjects. Twelve subjects initially received two single oral doses of theophylline, one in the form of immediate-release Aminophyllin on day 1 and the other in the form of controlled-release Theo-Dur on day 3. Multiple oral doses of moricizine (Ethmozine, 250 mg every 8 h) began on day 5 and continued for 18 days. While receiving moricizine, the subjects were again given the two formulations of theophylline in the same order on days 19 and 21. Theophylline pharmacokinetic profiles were obtained over 36 h after all theophylline administrations. Multiple-dose moricizine administration significantly decreased (p < 0.0005) theophylline area under the curve by 32 and 36% after Aminophyllin and Theo-Dur, respectively. Theophylline t1/2 was also significantly decreased (p < 0.02) by concomitant moricizine dosing. Moricizine had no apparent effect on theophylline absorption after Aminophyllin, based on the lack of changes in the maximum plasma concentration (Cmax) and the time to reach Cmax; however, moricizine administration did decrease (p < 0.0005) the Cmax of theophylline after Theo-Dur. We conclude that these pharmacokinetic changes are most likely due to enzyme induction mediated by moricizine. Consequently, concomitant use of moricizine and theophylline may necessitate the administration of more frequent and higher doses of theophylline.

Administration, Oral↗

PubMed1994

Mechanism of interruption of atrial flutter by moricizine. Electrophysiological and multiplexing studies in the canine sterile pericarditis model of atrial flutter.

BACKGROUND: Moricizine is said to have potent effects on cardiac conduction but little or no effect on cardiac refractoriness. METHODS AND RESULTS: The effects of moricizine (2 mg/kg IV) on induced atrial flutter were studied 2 to 4 days after the creation of sterile pericarditis in 11 dogs. Ten episodes of stable atrial flutter before and after the administration of moricizine were studied in 9 dogs in the conscious, nonsedated state, and 7 episodes were studied in 6 dogs in the anesthetized, open chest state. In the conscious state, the effects of moricizine on atrial excitability, atrial effective refractory period, and intra-atrial conduction times were studied by recording during overdrive pacing of sinus rhythm from epicardial electrodes placed at selected atrial sites. Moricizine prolonged the atrial flutter cycle length in all the episodes, from a mean of 133 +/- 9 to 172 +/- 27 milliseconds (P < .001), and then terminated 7 of the 10 episodes. Moricizine increased the atrial threshold of excitability from a mean of 2.3 +/- 1.4 to 3.3 +/- 2.2 mA (P < .01) and prolonged intra-atrial conduction times (measured from the sulcus terminalis to the posteroinferior left atrium) from a mean of 58 +/- 6 to 64 +/- 5 milliseconds (P < .005). Prolongation of the atrial effective refractory period from 166 +/- 20 to 174 +/- 24 milliseconds (P < .05) was observed only at the sulcus terminalis site. In the open chest studies, administration of moricizine prolonged the atrial flutter cycle length from a mean of 150 +/- 15 to 216 +/- 30 milliseconds (P < .001) and then terminated the atrial flutter in all 7 episodes. As demonstrated by simultaneous multisite mapping from 95 bipolar sites on the right atrial free wall, the atrial flutter cycle length prolongation was either due to further slowing of conduction in an area of slow conduction in the reentrant circuit of the atrial flutter (5 episodes) or further slowing of conduction in an area of slow conduction plus the development of a second area of slow conduction (2 episodes). The change in conduction times in the rest of the reentrant circuit was negligible (10.9 +/- 8.7% of the total change). In all 7 episodes, the last circulating reentrant wave front blocked in an area of slow conduction. CONCLUSIONS: Moricizine (1) prolongs the atrial flutter cycle length, primarily by slowing conduction in an area of slow conduction in the reentrant circuit, (2) terminates atrial flutter by causing block of the circulating reentrant wave front in an area of slow conduction of the reentrant circuit, and (3) effectively interrupts otherwise stable atrial flutter in this canine model. The reason for these effects of moricizine are not readily explained by its effects on global atrial conduction times and refractoriness studied during sinus rhythm. Local changes in conduction in an area(s) of slow conduction are responsible for both cycle length prolongation and atrial flutter termination rather than the traditional wavelength concept of head-tail interaction.

Animals↗

PubMed1994

The effect of hepatic disease on the disposition of moricizine in humans.

The pharmacokinetics of moricizine and two of its metabolites, moricizine sulfoxide and phenothiazine-2-carbamic acid ethyl ester sulfoxide, were studied in healthy control subjects and in patients with chronic liver disease (cirrhosis). Moricizine disposition was significantly altered by hepatic cirrhosis. Compared to healthy subjects, the hepatic disease patients had an increased Cmax (59%), an increased t1/2 (141%), and a reduced plasma clearance (71%). Additionally, small but statistically significant increases were observed for tmax and the fraction of moricizine not bound to plasma proteins in patients with hepatic disease. The elimination of both moricizine metabolites was also altered by hepatic dysfunction as indicated by significantly prolonged terminal half-lives. Furthermore, there was a reduction in the conversion of moricizine to moricizine sulfoxide. Both hepatic blood flow and hepatic metabolizing capacity were assessed in all subjects and patients by administration of indocyanine green and antipyrine, respectively. Indocyanine green and antipyrine plasma clearances were decreased by 38 and 51%, respectively, indicating that both functions were diminished by hepatic cirrhosis. We conclude that the moricizine dose required for arrhythmia patients with hepatic disease should be lower, and perhaps, the dosing frequency should be less than in patients with normal liver function.

Administration, Oral↗

PubMed1987

Pharmacokinetics of moricizine HCl.

Moricizine HCl is a phenothiazine derivative with antiarrhythmic properties. It was developed in the USSR and is now undergoing clinical evaluation. Although preliminary work has shown moricizine HCl to be effective in treating both atrial and ventricular arrhythmias, little is known of its pharmacokinetics. There is a 4-fold variability in range for its elimination half-life and in volumes of distribution and clearance. There is a linear relation for peak plasma levels and area under the plasma concentration/time curve with regard to single-dose administration of moricizine HCl. The bioavailability of moricizine HCl connotes extensive first-pass effect, or presystemic metabolism. Very little of moricizine is excreted unchanged; it is extensively metabolized to certain compounds that are present in plasma for extended periods. Moricizine is extensively (92% to 95%) bound to plasma protein. Its coadministration with cimetidine leads to additive systemic effects; however, there is no evidence of alterations in steady-state levels when moricizine HCl is coadministered with digoxin. Because moricizine is a drug with active metabolites, its concentration/effect profile is complex; this poses a challenge for accurate dose titration. This may, however, be a helpful challenge in that the metabolites may one day prove useful in therapy. This surmise warrants further study.

Anti-Arrhythmia Agents↗

PubMed1987

Clinical, electrophysiologic and antiarrhythmic efficacy of moricizine HCl.

The electrophysiologic effects and antiarrhythmic efficacy of moricizine HCl (1.5 to 2.0 mg/kg intravenously, and 600 to 800 mg orally/24 hours) were studied using electrophysiologic testing, ambulatory electrocardiographic monitoring, exercise stress testing and transesophageal stimulation of the left atrium. Moricizine HCl had no significant effects on the sinus node in patients with normal nodal function and did not depress sinoatrial conduction time even in patients with serious node dysfunction. Moricizine HCl significantly lengthened the following intervals: PA (32 +/- 5 to 40 +/- 5 ms), AH (82 +/- 13 to 92 +/- 12 ms), HV (45 +/- 12 to 50 +/- 12 ms), paced cycle length 1:1 atrioventricular node conduction (340 +/- 14 to 352 +/- 14 ms) and paced cycle length 1:1 ventriculoatrial conduction (300 +/- 14 to 400 +/- 13 ms). The refractory periods of atrium, atrioventricular node and ventricular myocardium did not change significantly, and there was no alteration of the QRS or QT intervals. The drug abolished anterograde and retrograde conduction over the accessory pathway and increased the refractory period of accessory pathway in all patients. Intravenous moricizine HCl terminated and prevented tachycardia in 72% and 68% of the patients, respectively. Oral moricizine HCl (600 to 800 mg/24 hours) prevented tachycardia in 40% of patients with a preexcitation syndrome. Intravenous moricizine HCl terminated atrioventricular nodal reentrant paroxysmal tachycardia in 66% of patients, whereas 40% responded to the oral drug. Moricizine HCl 600 to 800 mg/24 hours suppressed ventricular premature beats in 60% of patients. A similar drug, Ethacizine, had the same electrophysiologic effects as moricizine HCl but was more potent.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Arrhythmia Agents↗

PubMed1994

Block of Na+ channel by moricizine hydrochloride in isolated feline ventricular myocytes.

The effect of moricizine hydrochloride, a potent class I antiarrhythmic agent, on Na+ current (INa) of single feline ventricular myocytes were studied using whole cell patch clamp techniques. Moricizine inhibited INa in a concentration-dependent manner without altering the current-voltage relationship for INa. INa inhibition was expressed by the Hill equation with a Hill coefficient of 1.3 and dissociation constant of 105 microM in the resting state (holding potential = -140 mV). Moricizine 30 microM shifted the steady state inactivation curve for INa toward more negative potentials by 7.3 +/- 2.4 mV without causing significant changes in the slope factor. Recovery of INa from inactivation was retarded (time constant = 8 s) at a holding potential of -140 mV in the presence of 30 microM moricizine. When the start of INa block was studied in experiments using a double pulse protocol, moricizine reduced INa by only 4% after a 4-ms prepulse, but strongly inhibited it after prepulses longer than 200 ms. Intracellular application of 100 microM moricizine did not produce significant resting or use-dependent INa block. These results suggest that (1) moricizine blocks INa by binding to the Na+ channel with a 1:1 stoichiometry, (2) the drug has a higher affinity to the inactivated state than to the activated and resting states of the Na+ channel, (3) recovery kinetics of moricizine from Na+ channel inactivation, or drug dissociation observed during the transition from inactivated to resting state was relatively slow, (4) the drug binding site appeared to be located on the external side of the membrane.

Animals↗

PubMed1992

Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction.

BACKGROUND: The Cardiac Arrhythmia Suppression Trial (CAST) tested the hypothesis that the suppression of asymptomatic or mildly symptomatic ventricular premature depolarizations in survivors of myocardial infarction would decrease the number of deaths from ventricular arrhythmias and improve overall survival. The second CAST study (CAST-II) tested this hypothesis with a comparison of moricizine and placebo. METHODS: CAST-II was divided into two blinded, randomized phases: an early, 14-day exposure phase that evaluated the risk of starting treatment with moricizine after myocardial infarction (1325 patients), and a long-term phase that evaluated the effect of moricizine on survival after myocardial infarction in patients whose ventricular premature depolarizations were either adequately suppressed by moricizine (1155 patients) or only partially suppressed (219 patients). RESULTS: CAST-II was stopped early because the first 14-day period of treatment with moricizine after a myocardial infarction was associated with excess mortality (17 of 665 patients died or had cardiac arrests), as compared with no treatment or placebo (3 of 660 patients died or had cardiac arrests); and estimates of conditional power indicated that it was highly unlikely (less than 8 percent chance) that a survival benefit from moricizine could be observed if the trial were completed. At the completion of the long-term phase, there were 49 deaths or cardiac arrests due to arrhythmias in patients assigned to moricizine, and 42 in patients assigned to placebo (adjusted P = 0.40). CONCLUSIONS: As with the antiarrhythmic agents used in CAST-I (flecainide and encainide), the use of moricizine in CAST-II to suppress asymptomatic or mildly symptomatic ventricular premature depolarizations to try to reduce mortality after myocardial infarction is not only ineffective but also harmful.

Arrhythmias, Cardiac↗