Moricizine
Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular c...
Ausführliche Beschreibung
Autor*in: |
Fitton, Andrew [verfasserIn] Buckley, Micaela M.-T. [verfasserIn] |
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E-Artikel |
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Sprache: |
Englisch |
Erschienen: |
1990 |
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Übergeordnetes Werk: |
Enthalten in: Drugs - Berlin [u.a.] : Springer, 1971, 40(1990), 1 vom: Juli, Seite 138-167 |
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Übergeordnetes Werk: |
volume:40 ; year:1990 ; number:1 ; month:07 ; pages:138-167 |
Links: |
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DOI / URN: |
10.2165/00003495-199040010-00007 |
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Katalog-ID: |
SPR033155836 |
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520 | |a Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... | ||
650 | 4 | |a Ventricular Tachycardia |7 (dpeaa)DE-He213 | |
650 | 4 | |a Disopyramide |7 (dpeaa)DE-He213 | |
650 | 4 | |a Encainide |7 (dpeaa)DE-He213 | |
650 | 4 | |a Sustained Ventricular Tachycardia |7 (dpeaa)DE-He213 | |
650 | 4 | |a Nonsustained Ventricular Tachycardia |7 (dpeaa)DE-He213 | |
700 | 1 | |a Buckley, Micaela M.-T. |e verfasserin |4 aut | |
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10.2165/00003495-199040010-00007 doi (DE-627)SPR033155836 (SPR)00003495-199040010-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Moricizine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... Ventricular Tachycardia (dpeaa)DE-He213 Disopyramide (dpeaa)DE-He213 Encainide (dpeaa)DE-He213 Sustained Ventricular Tachycardia (dpeaa)DE-He213 Nonsustained Ventricular Tachycardia (dpeaa)DE-He213 Buckley, Micaela M.-T. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 1 vom: Juli, Seite 138-167 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:1 month:07 pages:138-167 https://dx.doi.org/10.2165/00003495-199040010-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 1 07 138-167 |
spelling |
10.2165/00003495-199040010-00007 doi (DE-627)SPR033155836 (SPR)00003495-199040010-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Moricizine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... Ventricular Tachycardia (dpeaa)DE-He213 Disopyramide (dpeaa)DE-He213 Encainide (dpeaa)DE-He213 Sustained Ventricular Tachycardia (dpeaa)DE-He213 Nonsustained Ventricular Tachycardia (dpeaa)DE-He213 Buckley, Micaela M.-T. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 1 vom: Juli, Seite 138-167 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:1 month:07 pages:138-167 https://dx.doi.org/10.2165/00003495-199040010-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 1 07 138-167 |
allfields_unstemmed |
10.2165/00003495-199040010-00007 doi (DE-627)SPR033155836 (SPR)00003495-199040010-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Moricizine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... Ventricular Tachycardia (dpeaa)DE-He213 Disopyramide (dpeaa)DE-He213 Encainide (dpeaa)DE-He213 Sustained Ventricular Tachycardia (dpeaa)DE-He213 Nonsustained Ventricular Tachycardia (dpeaa)DE-He213 Buckley, Micaela M.-T. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 1 vom: Juli, Seite 138-167 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:1 month:07 pages:138-167 https://dx.doi.org/10.2165/00003495-199040010-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 1 07 138-167 |
allfieldsGer |
10.2165/00003495-199040010-00007 doi (DE-627)SPR033155836 (SPR)00003495-199040010-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Moricizine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... Ventricular Tachycardia (dpeaa)DE-He213 Disopyramide (dpeaa)DE-He213 Encainide (dpeaa)DE-He213 Sustained Ventricular Tachycardia (dpeaa)DE-He213 Nonsustained Ventricular Tachycardia (dpeaa)DE-He213 Buckley, Micaela M.-T. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 1 vom: Juli, Seite 138-167 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:1 month:07 pages:138-167 https://dx.doi.org/10.2165/00003495-199040010-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 1 07 138-167 |
allfieldsSound |
10.2165/00003495-199040010-00007 doi (DE-627)SPR033155836 (SPR)00003495-199040010-00007-e DE-627 ger DE-627 rakwb eng 610 ASE 44.40 bkl 44.38 bkl Fitton, Andrew verfasserin aut Moricizine 1990 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... Ventricular Tachycardia (dpeaa)DE-He213 Disopyramide (dpeaa)DE-He213 Encainide (dpeaa)DE-He213 Sustained Ventricular Tachycardia (dpeaa)DE-He213 Nonsustained Ventricular Tachycardia (dpeaa)DE-He213 Buckley, Micaela M.-T. verfasserin aut Enthalten in Drugs Berlin [u.a.] : Springer, 1971 40(1990), 1 vom: Juli, Seite 138-167 (DE-627)320609413 (DE-600)2021165-X 1179-1950 nnns volume:40 year:1990 number:1 month:07 pages:138-167 https://dx.doi.org/10.2165/00003495-199040010-00007 lizenzpflichtig Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA SSG-OPC-PHA SSG-OPC-ASE GBV_ILN_702 GBV_ILN_2190 44.40 ASE 44.38 ASE AR 40 1990 1 07 138-167 |
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Enthalten in Drugs 40(1990), 1 vom: Juli, Seite 138-167 volume:40 year:1990 number:1 month:07 pages:138-167 |
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Enthalten in Drugs 40(1990), 1 vom: Juli, Seite 138-167 volume:40 year:1990 number:1 month:07 pages:138-167 |
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Ventricular Tachycardia Disopyramide Encainide Sustained Ventricular Tachycardia Nonsustained Ventricular Tachycardia |
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Fitton, Andrew @@aut@@ Buckley, Micaela M.-T. @@aut@@ |
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<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">SPR033155836</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230519202318.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">201007s1990 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.2165/00003495-199040010-00007</subfield><subfield code="2">doi</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)SPR033155836</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(SPR)00003495-199040010-00007-e</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">610</subfield><subfield code="q">ASE</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.40</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">44.38</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Fitton, Andrew</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Moricizine</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">1990</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">Text</subfield><subfield code="b">txt</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">Computermedien</subfield><subfield code="b">c</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">Online-Ressource</subfield><subfield code="b">cr</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. 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abstract |
Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... |
abstractGer |
Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... |
abstract_unstemmed |
Synopsis Moricizine (moracizine, ethmozine) is an orally active phenothiazine derivative with direct myocardial Class I antiarrhythmic activity and minimal CNS effects. Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. Proarrhythmic responses to therapeutic doses of moricizine were detected on noninvasiv... |
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Moricizine |
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Buckley, Micaela M.-T. |
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Placebo-controlled studies have confirmed its efficacy in suppressing nonmalignant ventricular arrhythmias (premature ventricular complexes, couplets and runs of nonsustained ventricular tachycardia), including those refractory to previous antiarrhythmic therapy. Preliminary findings have indicated that moricizine is also effective in suppressing atrial ectopic activity, atrioventricular nodal reentry tachycardia and Wolff-Parkinson-White tachycardias involving accessory pathways. As with other oral antiarrhythmics, malignant ventricular arrhythmias (sustained ventricular tachycardia and ventricular fibrillation) have been shown, both on noninvasive monitoring and programmed electrical stimulation, to be less susceptible to suppression by moricizine than nonmalignant ventricular arrhythmias. The therapeutic potential of moricizine is enhanced by its relatively low incidence of extracardiac adverse effects (predominantly gastrointestinal and neurological) and its lack of significant cardiodepressant activity in patients with normal or mildly to moderately depressed left ventricular function. Moricizine has proved to be more effective than disopyramide and propranolol in suppressing ventricular ectopic activity, of comparable efficacy to quinidine, but less effective than encainide and flecainide. The drug appears to be particularly suited to the suppression of ventricular ectopy in patients with preexisting left ventricular dysfunction. Further studies are required to confirm its long term efficacy and effects on mortality when used prophylactically in patients at increased risk of sudden cardiac death. Pharmacodynamic Studies The predominant cellular electrophysiological effect of moricizine is a frequency-dependent inhibition of the fast transmembrane sodium flux in cardiac tissue. In isolated cardiac tissues moricizine reduces the upstroke velocity (Phase 0) of the action potential and produces a relative prolongation of the effective refractory period, but has minimal effects on action potential amplitude, maximum diastolic potential and normal automaticity. Although a Class I antiarrhythmic, moricizine does not readily conform to any of the 3 subclasses (a, b or c). Abnormal automaticity, delayed after-depolarisations and triggered activity in isolated cardiac tissue are suppressed or abolished by moricizine. In vivo animal studies indicate that moricizine slows sinoatrial, atrioventricular and His-Purkinje conduction, but does not significantly alter sinus node automaticity, cardiac refractoriness or the QTc interval. Electrophysiological studies in humans with paroxysmal supraventricular tachycardia have indicated that moricizine has a dual action in increasing sinus node automaticity (cholinergic effect) and slowing sinoatrial, intra-atrial, atrioventricular nodal, His-Purkinje and ventricular conduction (membrane-stabilising effect), but that it does not alter cardiac refractoriness. In patients with supraventricular tachycardia associated with Wolff-Parkinson-White syndrome moricizine increased an-tero- and retrograde accessory pathway refractoriness and terminated induced re-entry tachycardia. In patients with atrioventricular nodal re-entry tachycardia, moricizine selectively suppressed retrograde conduction over the atrioventricular node. Moricizine is active in various experimental animal arrhythmia models, suppressing ouabain-induced arrhythmias and ventricular arrhythmias induced 24 hours after coronary artery occlusion in the dog. In patients with normal or impaired left ventricular function, moricizine was devoid of significant cardiodepressant activity during long term (≤ 6 months) administration. Baseline left ventricular ejection fraction was, generally, a minor determinant of clinical outcome in patients receiving moricizine for ventricular arrhythmias, being of importance only in those with severely depressed left ventricular function. Although a phenothiazine derivative, moricizine displays low affinity for striatal $ DA_{1} $-dopamine receptors in vitro, and correspondingly lacks significant psychotropic effects in humans. Pharmacokinetic Studies Although rapidly and almost completely absorbed from the gastrointestinal tract, moricizine is subject to extensive first-pass hepatic metabolism, resulting in an estimated bioavailability of 34 to 38% with oral doses of 300 to 500mg. The pharmacokinetics of moricizine are linear within the dose range 150 to 600mg, with peak plasma concentrations (0.5 to 1.5 mg/L) being achieved within 2 hours of oral administration of a 500mg dose. Moricizine is highly bound (≈95%) to plasma proteins. Information regarding the tissue distribution of moricizine and its metabolites is sparse, but the drug does appear to cross the blood-brain barrier. After oral administration the volume of distribution of moricizine in healthy volunteers is 8.3 to 11.1 L/kg. In humans, moricizine undergoes extensive hepatic biotransformation, with less than 1% of the parent drug being excreted unchanged in the urine and faeces following oral administration. Nine metabolites of moricizine have been identified in humans, but it is unclear whether any possess intrinsic antiarrhythmic activity. The moricizine plasma concentration-time relationship is biexponential and compatible with a 2-compartment elimination model. The plasma elimination half-life of moricizine following single-dose oral administration to healthy volunteers and patients with arrhythmias was 2 to 4 hours; this figure was extended to approximately 9 hours in arrhythmia patients on chronic oral administration. Multiple-dose studies have failed to demonstrate a consistent correlation between moricizine dose and plasma concentration in patients with arrhythmias. Discrepancies between the time of peak plasma moricizine concentrations (≈2 hours) and that of onset of antiarrhythmic response (16 to 20 hours) following initiation of oral therapy suggest that the therapeutic effect may be influenced by a metabolite(s). Therapeutic Trials Placebo-controlled trials have demonstrated the efficacy of oral moricizine in patients with nonmalignant ventricular arrhythmias, including some refractory to previous antiarrhythmic therapy. Moricizine 8 to 16 mg/kg/day (600 to 1500 mg/day) produced significant suppression of premature ventricular complexes and ventricular couplets in 50 to 80% and 68 to 100% of patients, respectively, and abolished runs of nonsustained ventricular tachycardia in 67 to 74% of patients. Antiarrhythmic efficacy was essentially maintained during long term (≤ 56 months) therapy, with a loss of responsiveness to moricizine occurring in approximately 15% of patients. The efficacy of moricizine in suppressing single and complex forms of ventricular ectopy appeared unrelated to the intensity of baseline ventricular ectopic activity or to the presence of underlying structural heart disease. On noninvasive monitoring, moricizine 600 to 1200 mg/day was significantly less effective in patients with spontaneous sustained ventricular tachycardia and/ or ventricular fibrillation (19 to 33% response rate) than in those with nonsustained ventricular tachycardia (62%). Induction of sustained ventricular tachycardia and/or ventricular fibrillation was prevented by moricizine in approximately 25% of patients during programmed electrical stimulation. During short term (≤ 2 weeks) therapy in small numbers of patients, moricizine 2.4 to 15 mg/kg/day (225 to 1200 mg/day) was effective in suppressing atrial ectopy and re-entry tachycardias. Double-blind, placebo-controlled trials indicated that moricizine 600 to 900 mg/day was of superior efficacy to disopyramide 600 mg/day and propranolol 120 mg/day in suppressing premature ventricular complexes and ventricular couplets, and of comparable efficacy to quinidine 1200 to 1600 mg/day in reducing couplets and runs of nonsustained ventricular tachycardia. The Cardiac Arrhythmia Pilot Study indicated that the efficacy of moricizine against ventricular ectopy and nonsustained ventricular tachycardia was comparable to that of encainide and flecainide in patients with moderately depressed left ventricular function (ejection fraction < 0.45). Adverse Effects The predominant noncardiac adverse effects associated with moricizine administration involve the gastrointestinal tract (nausea, abdominal discomfort) and central nervous system (dizziness, headache, perioral paraesthesia), and are generally mild, transient and resolve on dosage reduction. The overall incidence of noncardiac adverse effects, which variously ranged from 0 to 33% of patients, was significantly lower than that reported with disopyramide and quinidine, and similar to that seen with placebo. 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