The Experts below are selected from a list of 105 Experts worldwide ranked by ideXlab platform
Walter Flamenbaum - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic Interactions of Moricizine and Diltiazem in Healthy Volunteers
Journal of clinical pharmacology, 1996Co-Authors: Linyee Shum, Henry J. Pieniaszek, Cynthia A. Robinson, Anna F. Davidson, Paul J. Widner, Irma H. Benedek, Walter FlamenbaumAbstract:Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.
Leon H Greene - One of the best experts on this subject based on the ideXlab platform.
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circadian pattern of arrythmic death in patients receiving encainide flecainide or moricizine in the cardiac arrhythmia
Journal of the American College of Cardiology, 1994Co-Authors: Robert W Peters, Debra S Echt, Philip R Liebson, Allan H Barker, Robert J Capone, Brent Mitchell, Maria M Brooks, Leon H GreeneAbstract:Abstract Objectives. The purpose of this study was to assess the effect of antiarrhythmic drugs on the timing of arrhythmic death. Background. Sudden cardiac death remains a problem of epidemic proportions. Delineating its pathophysiology is an important step in devising preventive measures. Previous studies have shown a circadian pattern of onset of sudden cardiac death. The effect of antiarrhythmic drugs on this pattern has not been systematically studied. Methods. The Cardiac Arrhythmia Suppression Trial (CAST) was a multicenter double-blind, placebo-controlled study designed to determine whether suppression of ventricular ectopic activity by means of antiarrhythmic drugs (encainide, flecainide or moricizine) after acute myocardial infarction would reduce the incidence of arrhythmic death. Results. The trial was terminated prematurely because of an unexpectedly high mortality rate in the active treatment group. The onset of arrhythmic death in this group (in patients not receiving beta-adrenergic blocking agents) displayed a bimodal variation, with significant peaks in midmorning and late afternoon/early evening. More than half of the symptomatic events were accompanied by anginalike symptoms. Approximately 30% of all events occurred within 2 h of awakening. Conclusions. Our data suggest the possibility of a complex interaction among antiarrhythmic drags, sympathetic nervous system activation and acute myocardial ischemia. Planning of future antiarrhythmic drug trials will need to take this information into account.
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mortality and morbidity in patients receiving encainide flecainide or placebo the cardiac arrhythmia suppression trial
The New England Journal of Medicine, 1991Co-Authors: Debra S Echt, Philip R Liebson, Dulce Obiasmanno, Allan H Barker, Daniel Arensberg, Andrea Baker, Lawrence S Friedman, Brent L Mitchell, Robert W Peters, Leon H GreeneAbstract:Abstract Background and Methods. In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo. Results. Of 1498 patients, 857 were assigned to receive encainide or its placebo (432 to active drug and 425 to placebo) and 641 were assigned to receive flecainide or its placebo (323 to active drug and 318 to placebo). After a mean follow-up of 10 months, 89 patients had died: 59 of arrhythmia (43 receiving drug vs. 16 receiving placebo; P = 0.0004), 22 of nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving placebo; P = 0.0...
Linyee Shum - One of the best experts on this subject based on the ideXlab platform.
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Pharmacokinetic Interactions of Moricizine and Diltiazem in Healthy Volunteers
Journal of clinical pharmacology, 1996Co-Authors: Linyee Shum, Henry J. Pieniaszek, Cynthia A. Robinson, Anna F. Davidson, Paul J. Widner, Irma H. Benedek, Walter FlamenbaumAbstract:Sixteen healthy male volunteers completed a nonrandomized, sequential, three-phase study. The three phases were 1) moricizine at 250 mg every 8 hours for 7 days with 12 days washout; 2) diltiazem at 60 mg every 8 hours for 7 days; and 3) concomitant administration of moricizine at 250 mg and diltiazem at 60 mg every 8 hours for 7 days. The plasma concentration-time profiles were obtained at the end of each phase for moricizine, diltiazem (with its metabolites desacetyl-diltiazem and N-desmethyl-diltiazem), and both when administered together. Under steady-state conditions, there was a two-way (opposing) pharmacokinetic drug interaction when moricizine and diltiazem were coadministered in healthy volunteers. Both maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve from time 0 to the end of administration (AUC tau) of moricizine increased significantly by 88.9% and 121.1%, respectively. Oral clearance (Clo) decreased by 54%. The terminal half-life (t1/2) of moricizine was not affected, however (2.1 +/- 0.5 hours versus 2.4 +/- 0.7 hours). It is believed that these changes were due to the inhibition of hepatic metabolism by diltiazem, which resulted in an increased systemic availability of moricizine. Moricizine had opposite effects on the pharmacokinetics of diltiazem. Moricizine decreased the Cmax of diltiazem significantly (by 36%) and increased Clo by 52%. A small but statistically significant decrease in the t1/2 from 4.6 +/- 1.3 hours to 3.6 +/- 0.7 hours was observed. Despite this result, no remarkable changes (e.g., in Cmax, AUC, or t1/2) were found for the two major diltiazem metabolites desacetyl-diltiazem and N-desmethyl-diltiazem. It appears that the pharmacokinetic interaction of moricizine and diltiazem was metabolic. With the increase in moricizine concentrations and the decrease in diltiazem concentrations, adjustments in dose may be required to achieve optimal therapeutic response when coadministering both agents.
P E Carson - One of the best experts on this subject based on the ideXlab platform.
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interaction of baseline characteristics with the hazard of encainide flecainide and moricizine therapy in patients with myocardial infarction a possible explanation for increased mortality in the cardiac arrhythmia suppression trial cast
Circulation, 1994Co-Authors: Jeffrey L Anderson, Edward V. Platia, Richard W Henthorn, T A Buckingham, M D Carlson, Alfred P Hallstrom, P E CarsonAbstract:BACKGROUNDThe Cardiac Arrhythmia Suppression Trial (CAST) was designed to test the hypothesis that suppression of ventricular ectopy with antiarrhythmic drugs after a myocardial infarction reduces the incidence of sudden arrhythmic death. Patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The encainide and flecainide arms of the study were discontinued in 1989 (CAST-I) and the moricizine arm in 1991 (CAST-II) because of excess mortality. To explore the mechanisms of these adverse outcomes, we examined the interaction of baseline characteristics with the hazard of therapy with encainide, flecainide, or moricizine compared with their respective placebos.METHODS AND RESULTSCAST-I comprised 755 patients assigned to flecainide or encainide and 743 patients assigned to placebo, whereas in CAST-II, 502 patients received moricizine and 491 patients received placebo. Clinical and laboratory baseline vari...
Philip R Liebson - One of the best experts on this subject based on the ideXlab platform.
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circadian pattern of arrythmic death in patients receiving encainide flecainide or moricizine in the cardiac arrhythmia
Journal of the American College of Cardiology, 1994Co-Authors: Robert W Peters, Debra S Echt, Philip R Liebson, Allan H Barker, Robert J Capone, Brent Mitchell, Maria M Brooks, Leon H GreeneAbstract:Abstract Objectives. The purpose of this study was to assess the effect of antiarrhythmic drugs on the timing of arrhythmic death. Background. Sudden cardiac death remains a problem of epidemic proportions. Delineating its pathophysiology is an important step in devising preventive measures. Previous studies have shown a circadian pattern of onset of sudden cardiac death. The effect of antiarrhythmic drugs on this pattern has not been systematically studied. Methods. The Cardiac Arrhythmia Suppression Trial (CAST) was a multicenter double-blind, placebo-controlled study designed to determine whether suppression of ventricular ectopic activity by means of antiarrhythmic drugs (encainide, flecainide or moricizine) after acute myocardial infarction would reduce the incidence of arrhythmic death. Results. The trial was terminated prematurely because of an unexpectedly high mortality rate in the active treatment group. The onset of arrhythmic death in this group (in patients not receiving beta-adrenergic blocking agents) displayed a bimodal variation, with significant peaks in midmorning and late afternoon/early evening. More than half of the symptomatic events were accompanied by anginalike symptoms. Approximately 30% of all events occurred within 2 h of awakening. Conclusions. Our data suggest the possibility of a complex interaction among antiarrhythmic drags, sympathetic nervous system activation and acute myocardial ischemia. Planning of future antiarrhythmic drug trials will need to take this information into account.
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mortality following ventricular arrhythmia suppression by encainide flecainide and moricizine after myocardial infarction the original design concept of the cardiac arrhythmia suppression trial cast
JAMA, 1993Co-Authors: Andrew E Epstein, Jeffrey L Anderson, Philip R Liebson, Al Hallstrom, William J Rogers, Allen A Seals, Jerome D Cohen, Robert J Capone, D G WyseAbstract:Objective. —To test the hypothesis that in survivors of myocardial infarction, the suppression of ventricular premature depolarizations improves survival free of cardiac arrest and arrhythmic death. Design. —International, prospective, multicenter, randomized, placebo-controlled trial. Setting. —University and community hospitals. Patients. —A total of 3549 patients with myocardial infarction and left ventricular dysfunction. Intervention. —Administration of encainide, flecainide, moricizine, or placebo to suppress ventricular premature depolarizations. Main Outcome Measures. —Overall survival and survival free of cardiac arrest or arrhythmic death were compared in patients randomized to long-term, active antiarrhythmic drug therapy vs corresponding placebo, using the stratified log rank statistic. Results. —At 1 year from the time of randomization to blinded therapy, 95% of placebo-treated patients vs 90% of active drug—treated patients remained alive ( P =.0006). Similarly, at 1 year, 96% of placebo-treated patients vs 93% of active drug—treated patients remained free of cardiac arrest or arrhythmic death ( P =.003). Conclusions. —The suppression of asymptomatic or mildly symptomatic ventricular arrhythmias after myocardial infarction does not improve survival and can increase mortality. Treatment strategies designed solely to suppress these arrhythmias should no longer be followed. ( JAMA . 1993;270:2451-2455)
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mortality and morbidity in patients receiving encainide flecainide or placebo the cardiac arrhythmia suppression trial
The New England Journal of Medicine, 1991Co-Authors: Debra S Echt, Philip R Liebson, Dulce Obiasmanno, Allan H Barker, Daniel Arensberg, Andrea Baker, Lawrence S Friedman, Brent L Mitchell, Robert W Peters, Leon H GreeneAbstract:Abstract Background and Methods. In the Cardiac Arrhythmia Suppression Trial, designed to test the hypothesis that suppression of ventricular ectopy after a myocardial infarction reduces the incidence of sudden death, patients in whom ventricular ectopy could be suppressed with encainide, flecainide, or moricizine were randomly assigned to receive either active drug or placebo. The use of encainide and flecainide was discontinued because of excess mortality. We examined the mortality and morbidity after randomization to encainide or flecainide or their respective placebo. Results. Of 1498 patients, 857 were assigned to receive encainide or its placebo (432 to active drug and 425 to placebo) and 641 were assigned to receive flecainide or its placebo (323 to active drug and 318 to placebo). After a mean follow-up of 10 months, 89 patients had died: 59 of arrhythmia (43 receiving drug vs. 16 receiving placebo; P = 0.0004), 22 of nonarrhythmic cardiac causes (17 receiving drug vs. 5 receiving placebo; P = 0.0...