The Experts below are selected from a list of 294 Experts worldwide ranked by ideXlab platform
Gary A Thompson - One of the best experts on this subject based on the ideXlab platform.
-
the metabolic profile of Azimilide in man in vivo and in vitro evaluations
Journal of Pharmaceutical Sciences, 2005Co-Authors: P Riley, Gary A Thompson, P C Figary, J R Entwisle, A L Roe, R Ohashi, N Ohashi, T J MooreheadAbstract:The metabolic fate of Azimilide in man is unusual as it undergoes a cleavage in vivo resulting in the formation of two classes of structurally distinct metabolites. During a metabolite profiling study conducted in human volunteers to assess the contribution of all pathways to the clearance of (14)C-Azimilide, greater than 82% of radioactivity was recovered in urine (49%-58%) and feces (33%). Urine, feces, and plasma were profiled for metabolites. A cleaved metabolite, 4-chloro-2-phenyl furoic acid was present at high concentration in plasma (metabolite/parent AUC ratio approx. 4), while other plasma metabolites, Azimilide N-oxide (metabolite/parent AUC ratio 0.001), and a cleaved hydantoin metabolite (metabolite/parent AUC ratio = 0.3) were present at lower concentrations than Azimilide. In urine, the cleaved metabolites were the major metabolites, (> 35% of the dose) along with phenols (as conjugates, 7%-8%), Azimilide N-oxide (4%-10%), a butanoic acid metabolite (2%-3%), and desmethyl Azimilide (2%). A limited investigation of fecal metabolites indicated that Azimilide (3%-5%), desmethyl Azimilide (1%-3%), and the butanoic acid metabolite (< 1%) were present. Contributing pathways for metabolism of Azimilide, identified through in vitro and in-vivo studies, were CYPs 1A1 (est. 28%), 3A4/5 (est. 20%), 2D6 (< 1%), FMO (est. 14%), and cleavage (35%). Enzyme(s) involved in the cleavage of Azimilide were not identified.
-
influence of coadministration on the pharmacokinetics of Azimilide dihydrochloride and digoxin
The Journal of Clinical Pharmacology, 2005Co-Authors: Alfred E Corey, Nikhil Parekh, Suzanne N. Valentine, Roger D Toothaker, Jeff R Agnew, Werner Moehrke, Gary A ThompsonAbstract:The influence of coadministration on digoxin and Azimilide pharmacokinetics/pharmacodynamics was assessed in a randomized, 3-way crossover study in 18 healthy men. Serial blood and urine samples were obtained for Azimilide and digoxin quantitation. Treatment effects on pharmacokinetics were assessed using analysis of variance. The relationship between Azimilide blood concentrations and QT c prolongation was characterized by an E m a x model. Effects of coadministration on pharmacodynamics were assessed using a mechanistic-based inhibition model. Azimilide pharmacokinetics was unaffected by digoxin, except for a 36% increase in CL r [P = .0325), with no change in CL o . Digoxin pharmacokinetics was unaffected by Azimilide, except for a 21% increase in C m a x (P = .0176) and a 10% increase in AUC τ (P =.0121). Digoxin coadministration increased the apparent EC 5 0 with no effect on E m a x , consistent with competitive inhibition (K i = 0.899 ng/mL). The pharmacokinetic and pharmacodynamic changes observed upon coadministration were small and are not expected to be clinically important.
-
influence of ketoconazole on Azimilide pharmacokinetics in healthy subjects
British Journal of Clinical Pharmacology, 2004Co-Authors: Mohamed El Mouelhi, Dan Worley, Barbara Kuzmak, Anthony J Destefano, Gary A ThompsonAbstract:Aim To assess the influence of ketoconazole on Azimilide pharmacokinetics. Methods A two-period randomized crossover study was conducted in healthy male and female subjects (19–45 years). Placebo or 200 mg ketoconazole were administered orally every 24 h for 29 days. On day 8, a single oral dose of 125 mg Azimilide dihydrochloride was coadministered following an overnight fast. Blood samples were obtained prior to and for 22 days following Azimilide dihydrochloride administration. The plasma protein binding of Azimilide was also assessed at 6 h after dosing. Results Following ketoconazole administration, a 16% increase in Azimilide AUC (90% confidence interval (CI) 112%, 120%), a 12% increase in Cmax (95% CI 107%, 116%), a 13% increase in t1/2,z (95% CI 107%, 120%) and a 14% decrease in CLo (95% CI 82%, 90%) were observed. Conclusions The changes in Azimilide pharmacokinetics following ketoconazole treatment are not clinically important since the 90% CI for the AUC fell within the prespecified range of 80–125%. Thus, no clinically important drug interactions are expected when Azimilide dihydrochloride is coadministered with CYP3A4 inhibitors.
-
effect of mild and moderate hepatic impairment on Azimilide pharmacokinetics following single dose oral administration
Journal of Pharmaceutical Sciences, 2004Co-Authors: Alfred E Corey, Jeffrey R Agnew, Eileen C King, Nikhil Parekh, James H Powell, Gary A ThompsonAbstract:Abstract Azimilide dihydrochloride (75–125 mg/day) is currently being developed for use in prolonging the time to recurrence of atrial fibrillation/flutter and for reducing the frequency of shocks in patients with an implantable cardioverting defibrillator. This study investigated the influence of mild and moderate hepatic impairment on Azimilide pharmacokinetics. Six subjects each with mild and moderate hepatic impairment (Child–Pugh grades A and B, respectively) were age, weight, smoking status, and gender-matched to a healthy subject (total N = 24). Each subject was administered a single, oral dose of 100 mg Azimilide dihydrochloride following an overnight fast. Blood/plasma and urine samples were collected up to 28 days and over 9 days, respectively, and analyzed using HPLC with MS/MS or UV detection. For Azimilide, most parameters in subjects with mild to moderate hepatic impairment were within 25% of those observed in matched healthy subjects, with no statistically significant differences observed. For F-1292 (major metabolite in plasma), a significant decrease in AUC was observed in subjects with moderate hepatic impairment, secondary to an increase in renal clearance (CL r ). Based on these results, no a priori dosage adjustment is required in subjects with mild to moderate hepatic impairment. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1279–1286, 2004
-
influence of Azimilide on cyp2c19 mediated metabolism
The Journal of Clinical Pharmacology, 2004Co-Authors: Mohamed El Mouelhi, Dan Worley, Barbara Kuzmak, Anthony J Destefano, Gary A ThompsonAbstract:The purpose of this study was to assess the influence of multiple-dose oral administration of Azimilide dihydrochloride on CYP2C19-mediated metabolism. A two-period, randomized crossover study was conducted in 40 healthy male subjects who were phenotyped as extensive CYP2C19 metabolizers. Oral doses of placebo or 125 mg of Azimilide dihydrochloride were administered every 12 hours for 3 days, followed by every 24 hours for 5 days; 20 mg omeprazole was coadministered on Day 8. Blood or plasma samples were obtained over 24 hours and analyzed for Azimilide or omeprazole/5-hydroxyomeprazole using high-performance liquid chromatography with tandem mass spectrometry. Data were analyzed using "noncompartmental" analysis. Azimilide blood concentrations observed in this study were similar to those previously observed at steady state in patients. Based on AUC(m)/AUC(p) for omeprazole, Azimilide does not significantly inhibit CYP2C19-mediated metabolism (90% confidence interval [CI] = 104%-111%). For 5-hydroxyomeprazole, no significant changes in pharmacokinetics were observed. For omeprazole, a statistically significant decrease ( approximately 12%) was observed for AUC. However, this change was small and is not expected to be clinically important since the CI was contained within those used to establish bioequivalence. These results indicate that Azimilide does not inhibit CYP2C19-mediated metabolism. Since this isozyme had the lowest in vitro IC(50) values for the cytochrome P450s most commonly involved with the metabolism of drugs (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4), Azimilide-related drug interactions mediated via these isozymes are not anticipated.
Edward L.c. Pritchett - One of the best experts on this subject based on the ideXlab platform.
-
efficacy of Azimilide for the maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation in the presence and absence of structural heart disease
American Journal of Cardiology, 2006Co-Authors: Charles R Kerr, Edward L.c. Pritchett, Richard L. Page, Stuart J. Connolly, Peter R Kowey, Witold Ruzyllo, Mikhail Y Ruda, William E. WilkinsonAbstract:Azimilide hydrochloride (Azimilide), an investigational antiarrhythmic drug, has shown variable efficacy in preventing atrial fibrillation (AF). This study was designed to assess its efficacy in maintaining sinus rhythm in patients with paroxysmal AF and heart disease. Patients with symptomatic paroxysmal AF were screened for 1 month by transtelephonic monitoring. After recording 1 episode of AF in the screening period, they were randomized to receive Azimilide 125 mg or placebo once daily. Patients were stratified by the presence or absence of congestive heart failure or coronary heart disease (CHF/CHD). A maximum of 220 patients without CHF/CHD were randomized, with the remainder having CHF/CHD. Patients with CHF/CHD were monitored for 3 days during loading. The primary efficacy analysis was the time to the first symptomatic recurrence of AF in the CHF/CHD group. Secondary analyses were the time to the first recurrence in the entire population and the time to the first recurrence in those with significant structural heart disease. The median time to recurrence of AF in the CHF/CHD group was 10 days in the 2 treatment arms. Nonsignificant trends were seen toward efficacy of Azimilide in the CHF/CHD group (hazard ratio 1.28, 95% confidence interval 0.97 to 1.70, p=0.087), structural heart disease group (hazard ratio 1.22, 95% confidence interval 0.96 to 1.56, p=0.11), and overall group (hazard ratio 1.22, 95% confidence interval 1.00 to 1.49, p=0.053). No patient died. In conclusion, Azimilide showed a nonsignificant trend toward efficacy in maintaining sinus rhythm in patients with AF.
-
antiarrhythmic efficacy of Azimilide in patients with atrial fibrillation maintenance of sinus rhythm after conversion to sinus rhythm
American Heart Journal, 2006Co-Authors: Edward L.c. Pritchett, Richard L. Page, Stuart J. Connolly, Peter R Kowey, Charles R Kerr, William E. WilkinsonAbstract:Background Azimilide dihydrochloride (Azimilide) is an investigational antiarrhythmic drug that has been tested in patients with a variety of arrhythmias. In patients with atrial fibrillation, it has shown excellent efficacy in some previous trials and minimal efficacy in others. Methods Patients who had symptomatic atrial fibrillation for >48 hours but Results A total of 446 patients were randomized in the study; 314 were in the subgroup with structural heart disease. The median time to arrhythmia recurrence in both treatment groups with structural heart disease was 13 days, and the difference between treatments was not significant ( P = .4596, n=314). The relative risk for recurrence (placebo:Azimilide) was 1.104 (95% CI 0.849-1.436). There was 1 death in the placebo group and 3 in the Azimilide group. Conclusions Azimilide did not demonstrate clinically important or statistically significant efficacy in reducing the risk for arrhythmia recurrence in patients with structural heart disease who were in atrial fibrillation and converted to sinus rhythm.
-
symptoms at the time of arrhythmia recurrence in patients receiving Azimilide for control of atrial fibrillation or flutter results from randomized trials
American Heart Journal, 2003Co-Authors: Stuart J. Connolly, Stephen R. Marcello, Daniel J. Schnell, William E. Wilkinson, Richard L. Page, Edward L.c. PritchettAbstract:Abstract Background Azimilide is a new antiarrhythmic agent being developed for the management for atrial fibrillation and flutter (AF). Four randomized, placebo-controlled, double-blind trials have been performed that investigated the effect of Azimilide on time to first recurrence of symptomatic AF. This paper examines the data collected during those studies regarding the symptoms reported by patients at the time of AF recurrence Methods At the time that patients reported their first documented symptomatic recurrence of arrhythmia, they were systematically asked whether or not they were experiencing any of the following 6 symptoms: palpitation, fatigue, chest pain, shortness of breath, dizziness, or sweating. Patients were required to answer yes or no. A symptom score was created varying from 0 to 6, in increasing order of number of symptoms reported. This was compared for patients receiving either of 2 doses of Azimilide or placebo. The relationship between the number of symptoms, heart rate at time of arrhythmia recurrence and treatment was analyzed. Results In 2 separate studies, Azimilide at a dose of 125 mg/day significantly reduced the number of symptoms at the time of arrhythmia recurrence compared to placebo. On the other hand, in 2 studies, the dose of 100 mg/day did not significantly reduce symptom burden. The individual symptoms significantly reduced by Azimilide125 mg/day were fatigue, shortness of breath, chest pain and dizziness. Palpitations and sweating were not significantly reduced. Modeling of heart rate at the time of arrhythmia recurrence, symptoms and treatment indicated that a small reduction in heart rate with Azimilide accounted for only a small part of the symptom reduction. There was another effect of Azimilide: an average reduction of 0.38 symptoms ( P Conclusion Azimilide (125 mg/day) reduces the number of symptoms reported at the time of AF recurrence.
-
asymptomatic or silent atrial fibrillation frequency in untreated patients and patients receiving Azimilide
Circulation, 2003Co-Authors: Richard L. Page, Stephen R. Marcello, Daniel J. Schnell, William E. Wilkinson, Stuart J. Connolly, Thomas W Tilsch, Edward L.c. PritchettAbstract:Background— Asymptomatic, or “silent” atrial fibrillation could increase the risk of stroke. Little is known about the frequency of asymptomatic atrial fibrillation in patients who also have symptomatic atrial fibrillation; similarly, little is known about the effect of antiarrhythmic drug therapy on asymptomatic atrial fibrillation. Methods and Results— Patients in sinus rhythm with a history of symptomatic atrial fibrillation or atrial flutter received placebo or Azimilide (35 to 125 mg) once daily for 6 or 9 months in 4 similar double-blind trials. The end point was the first recurrence of a symptomatic ECG-documented supraventricular arrhythmia. Routine transtelephonic electrocardiograms, in the absence of symptoms, were recorded for 30 seconds every 2 weeks until patients completed follow-up or documented a symptomatic supraventricular arrhythmia. Of the 1380 patients, 489 received placebo. Among these patients receiving placebo, 303 transmitted at least one routine ECG while asymptomatic. Asymptomat...
-
Azimilide for atrial fibrillation: clinical trial results and implications.
Cardiac Electrophysiology Review, 2003Co-Authors: Edward L.c. Pritchett, Stephen R. MarcelloAbstract:Azimilide dihydrochloride (or Azimilide) is a class III antiarrhythmic drug currently under investigation that has been tested in atrial fibrillation in four randomized, placebo-controlled clinical trials to assess efficacy and dose range. These investigational trials showed that doses of Azimilide 100 and 125 mg once daily prolonged the time to symptomatic arrhythmia recurrence in patients with a history of symptomatic atrial fibrillation, atrial flutter or both. Doses of 75 mg or less were not useful in this indication. Safety of Azimilide has been examined in several different types of studies. In a large randomized clinical trial of post-infarct patients, Azimilide neither increased nor decreased mortality risk. In patients with supraventricular arrhythmias, the most common adverse effects reported by patients on Azimilide were approximately equal in frequency with those on placebo: headache, asthenia, infection, diarrhea and dizziness. Infrequent cases of torsade de pointes and severe neutropenia were reported in patients taking Azimilide. Azimilide is an investigational antiarrhythmic drug that has shown efficacy in patients with atrial fibrillation.
William E. Wilkinson - One of the best experts on this subject based on the ideXlab platform.
-
Azimilide for the treatment of atrial fibrillation atrial flutter and paroxysmal supraventricular tachycardia results of a randomized trial and insights on the concordance of symptoms and recurrent arrhythmias
Journal of Cardiovascular Electrophysiology, 2008Co-Authors: L Richard M D Page, L Edward C M D Pritchett, M Stuart D Connolly, William E. WilkinsonAbstract:Azimilide Efficacy and Symptom Concordance. Introduction: Azimilide hydrochloride is an investigational antiarrhythmic medication that had shown evidence of efficacy in prolonging the time to recurrence of atrial fibrillation (AF) or atrial flutter (AFL) and paroxysmal supraventricular tachycardia (PSVT). This study was designed to confirm efficacy of 125 mg daily Azimilide. Methods and Results: The primary endpoint was ECG-documented recurrence of AF, AFL, or PSVT, followed for a maximum of 180 days. Four hundred eighty-two patients were enrolled in the United States and Canada (422 with AF or AFL and 60 with PSVT). The primary efficacy analysis included 402 patients with AF-AFL and 56 patients with PSVT. There was no significant difference in the time to first recurrence of symptomatic supraventricular arrhythmia in the AF-AFL stratum (median of 38 days for Azimilide versus 27 days for placebo; hazard ratio [HR] of 1.14, P = 0.29). Similarly, there was no difference in time to recurrence in the PSVT stratum (>180 days for Azimilide versus 135 days for placebo; HR = 1.28, P = 0.55). There were three deaths in the Azimilide group and one in the placebo group. Four patients had nonsustained ventricular tachycardia (one torsades de pointes), all in the Azimilide group. Asymptomatic recurrence was frequent in the AF-AFL group (8% with Azimilide and 11% with placebo), but was absent in the PSVT group. False recurrence was common in both groups. Conclusion: Azimilide 125 mg daily was not associated with significant prolongation of the time to recurrent symptomatic supraventricular arrhythmias. There was substantial discordance between symptoms and recurrence. (J Cardiovasc Electrophysiol, Vol. pp. 1-6) atrial fibrillation, Azimilide, silent atrial fibrillation, asymptomatic, false recurrence, antiarrhythmic medication
-
efficacy of Azimilide for the maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation in the presence and absence of structural heart disease
American Journal of Cardiology, 2006Co-Authors: Charles R Kerr, Edward L.c. Pritchett, Richard L. Page, Stuart J. Connolly, Peter R Kowey, Witold Ruzyllo, Mikhail Y Ruda, William E. WilkinsonAbstract:Azimilide hydrochloride (Azimilide), an investigational antiarrhythmic drug, has shown variable efficacy in preventing atrial fibrillation (AF). This study was designed to assess its efficacy in maintaining sinus rhythm in patients with paroxysmal AF and heart disease. Patients with symptomatic paroxysmal AF were screened for 1 month by transtelephonic monitoring. After recording 1 episode of AF in the screening period, they were randomized to receive Azimilide 125 mg or placebo once daily. Patients were stratified by the presence or absence of congestive heart failure or coronary heart disease (CHF/CHD). A maximum of 220 patients without CHF/CHD were randomized, with the remainder having CHF/CHD. Patients with CHF/CHD were monitored for 3 days during loading. The primary efficacy analysis was the time to the first symptomatic recurrence of AF in the CHF/CHD group. Secondary analyses were the time to the first recurrence in the entire population and the time to the first recurrence in those with significant structural heart disease. The median time to recurrence of AF in the CHF/CHD group was 10 days in the 2 treatment arms. Nonsignificant trends were seen toward efficacy of Azimilide in the CHF/CHD group (hazard ratio 1.28, 95% confidence interval 0.97 to 1.70, p=0.087), structural heart disease group (hazard ratio 1.22, 95% confidence interval 0.96 to 1.56, p=0.11), and overall group (hazard ratio 1.22, 95% confidence interval 1.00 to 1.49, p=0.053). No patient died. In conclusion, Azimilide showed a nonsignificant trend toward efficacy in maintaining sinus rhythm in patients with AF.
-
antiarrhythmic efficacy of Azimilide in patients with atrial fibrillation maintenance of sinus rhythm after conversion to sinus rhythm
American Heart Journal, 2006Co-Authors: Edward L.c. Pritchett, Richard L. Page, Stuart J. Connolly, Peter R Kowey, Charles R Kerr, William E. WilkinsonAbstract:Background Azimilide dihydrochloride (Azimilide) is an investigational antiarrhythmic drug that has been tested in patients with a variety of arrhythmias. In patients with atrial fibrillation, it has shown excellent efficacy in some previous trials and minimal efficacy in others. Methods Patients who had symptomatic atrial fibrillation for >48 hours but Results A total of 446 patients were randomized in the study; 314 were in the subgroup with structural heart disease. The median time to arrhythmia recurrence in both treatment groups with structural heart disease was 13 days, and the difference between treatments was not significant ( P = .4596, n=314). The relative risk for recurrence (placebo:Azimilide) was 1.104 (95% CI 0.849-1.436). There was 1 death in the placebo group and 3 in the Azimilide group. Conclusions Azimilide did not demonstrate clinically important or statistically significant efficacy in reducing the risk for arrhythmia recurrence in patients with structural heart disease who were in atrial fibrillation and converted to sinus rhythm.
-
symptoms at the time of arrhythmia recurrence in patients receiving Azimilide for control of atrial fibrillation or flutter results from randomized trials
American Heart Journal, 2003Co-Authors: Stuart J. Connolly, Stephen R. Marcello, Daniel J. Schnell, William E. Wilkinson, Richard L. Page, Edward L.c. PritchettAbstract:Abstract Background Azimilide is a new antiarrhythmic agent being developed for the management for atrial fibrillation and flutter (AF). Four randomized, placebo-controlled, double-blind trials have been performed that investigated the effect of Azimilide on time to first recurrence of symptomatic AF. This paper examines the data collected during those studies regarding the symptoms reported by patients at the time of AF recurrence Methods At the time that patients reported their first documented symptomatic recurrence of arrhythmia, they were systematically asked whether or not they were experiencing any of the following 6 symptoms: palpitation, fatigue, chest pain, shortness of breath, dizziness, or sweating. Patients were required to answer yes or no. A symptom score was created varying from 0 to 6, in increasing order of number of symptoms reported. This was compared for patients receiving either of 2 doses of Azimilide or placebo. The relationship between the number of symptoms, heart rate at time of arrhythmia recurrence and treatment was analyzed. Results In 2 separate studies, Azimilide at a dose of 125 mg/day significantly reduced the number of symptoms at the time of arrhythmia recurrence compared to placebo. On the other hand, in 2 studies, the dose of 100 mg/day did not significantly reduce symptom burden. The individual symptoms significantly reduced by Azimilide125 mg/day were fatigue, shortness of breath, chest pain and dizziness. Palpitations and sweating were not significantly reduced. Modeling of heart rate at the time of arrhythmia recurrence, symptoms and treatment indicated that a small reduction in heart rate with Azimilide accounted for only a small part of the symptom reduction. There was another effect of Azimilide: an average reduction of 0.38 symptoms ( P Conclusion Azimilide (125 mg/day) reduces the number of symptoms reported at the time of AF recurrence.
-
asymptomatic or silent atrial fibrillation frequency in untreated patients and patients receiving Azimilide
Circulation, 2003Co-Authors: Richard L. Page, Stephen R. Marcello, Daniel J. Schnell, William E. Wilkinson, Stuart J. Connolly, Thomas W Tilsch, Edward L.c. PritchettAbstract:Background— Asymptomatic, or “silent” atrial fibrillation could increase the risk of stroke. Little is known about the frequency of asymptomatic atrial fibrillation in patients who also have symptomatic atrial fibrillation; similarly, little is known about the effect of antiarrhythmic drug therapy on asymptomatic atrial fibrillation. Methods and Results— Patients in sinus rhythm with a history of symptomatic atrial fibrillation or atrial flutter received placebo or Azimilide (35 to 125 mg) once daily for 6 or 9 months in 4 similar double-blind trials. The end point was the first recurrence of a symptomatic ECG-documented supraventricular arrhythmia. Routine transtelephonic electrocardiograms, in the absence of symptoms, were recorded for 30 seconds every 2 weeks until patients completed follow-up or documented a symptomatic supraventricular arrhythmia. Of the 1380 patients, 489 received placebo. Among these patients receiving placebo, 303 transmitted at least one routine ECG while asymptomatic. Asymptomat...
Stephen R. Marcello - One of the best experts on this subject based on the ideXlab platform.
-
cumulative experience of Azimilide associated torsades de pointes ventricular tachycardia in the 19 clinical studies comprising the Azimilide database
Journal of the American College of Cardiology, 2006Co-Authors: Craig M Pratt, Paul Dorian, Stephen R. Marcello, Martin Borggrefe, Hussein R Alkhalidi, Jose Brum, Michael J Holroyde, Peter J Schwartz, John A CammAbstract:Objectives The purpose of this study was to assess the incidence, temporal characteristics, and risk factors associated with Azimilide-associated torsades de pointes (TdP) ventricular tachycardia. Background Azimilide dihydrochloride is a class III antiarrhythmic drug possessing Ikr and Iks channel-blocking properties. Methods Oral Azimilide (75 to 125 mg/day) was taken by 5,375 patients in 19 clinical trials conducted at 775 international centers. Of 3,964 patients in double-blind studies, 1,427 had a history of atrial fibrillation or other supraventricular arrhythmia, 510 had an implantable cardioverter-defibrillator, and 2,027 were post-myocardial infarction patients with a left ventricular ejection fraction ≤35%. Results The TdP occurred in 56 patients assigned to Azimilide, was dose-related, and tended to occur earlier with an Azimilide-loading regimen. Forty-three percent of TdP patients had a QT interval corrected by Bazett’s formula, for heart rate, (QTc) ≥500 ms at the time of or before the TdP occurrence. Significant risk factors using logistic regression were increasing age, female gender, diuretic use, and lack of aspirin use. Conclusions Azimilide-associated TdP has characteristics and risk factors similar to other Ikr blockers. However, there is a distinctive temporal profile. The TdP events are not concentrated in the first week. The Azimilide-associated TdP rate is 1% (95% confidence interval 0.78 to 1.35) and is not increased in patients with low left ventricular ejection fraction, even in women.
-
the efficacy of Azimilide in the treatment of atrial fibrillation in the presence of left ventricular systolic dysfunction results from the Azimilide postinfarct survival evaluation alive trial
Journal of the American College of Cardiology, 2004Co-Authors: Craig M Pratt, Stephen R. Marcello, Hussein R Alkhalidi, Jose Brum, Michael J Holroyde, Peter J Schwartz, John A Camm, Steven N Singh, Alive InvestigatorsAbstract:Abstract Objectives The purpose of this study was to assess the effect of oral Azimilide dihydrochloride (AZ) 100 mg versus placebo on the onset, termination, and prevalence of atrial fibrillation (AF) in a subpopulation of patients in the Azimilide Postinfarct Survival Evaluation (ALIVE) trial. Background Previous clinical trials have demonstrated the antiarrhythmic effects of AZ in patients with AF. Azimilide was investigated for its effects on mortality in patients with depressed left ventricular (LV) function after recent myocardial infarction (MI) and in a subpopulation of patients with AF. Methods A total of 3,381 post-MI patients with depressed LV function were enrolled in this randomized, placebo-controlled, double-blind study of AZ 100 mg on all-cause mortality. A total of 93 patients had AF on the baseline 12-lead electrocardiogram (ECG). An additional 27 patients developed AF after initially being in sinus rhythm at randomization. These patients were identified through 12-lead ECGs obtained during routine visits at week 2, months 1, 4, 8, and 12. Results Patients with AF at baseline had a higher mortality than those without AF (p = 0.0006). Among AF patients, there was no difference in mortality between AZ patients and placebo patients (p = 0.82). Fewer AZ patients developed AF than placebo patients (p = 0.04). More AZ patients than placebo patients converted to sinus rhythm, but this difference did not achieve statistical significance (p = 0.076). Over one-year follow-up, more AZ patients were in sinus rhythm than placebo patients (p = 0.04). Conclusions Azimilide was safe and effective AF therapy in patients with depressed LV function after an MI.
-
symptoms at the time of arrhythmia recurrence in patients receiving Azimilide for control of atrial fibrillation or flutter results from randomized trials
American Heart Journal, 2003Co-Authors: Stuart J. Connolly, Stephen R. Marcello, Daniel J. Schnell, William E. Wilkinson, Richard L. Page, Edward L.c. PritchettAbstract:Abstract Background Azimilide is a new antiarrhythmic agent being developed for the management for atrial fibrillation and flutter (AF). Four randomized, placebo-controlled, double-blind trials have been performed that investigated the effect of Azimilide on time to first recurrence of symptomatic AF. This paper examines the data collected during those studies regarding the symptoms reported by patients at the time of AF recurrence Methods At the time that patients reported their first documented symptomatic recurrence of arrhythmia, they were systematically asked whether or not they were experiencing any of the following 6 symptoms: palpitation, fatigue, chest pain, shortness of breath, dizziness, or sweating. Patients were required to answer yes or no. A symptom score was created varying from 0 to 6, in increasing order of number of symptoms reported. This was compared for patients receiving either of 2 doses of Azimilide or placebo. The relationship between the number of symptoms, heart rate at time of arrhythmia recurrence and treatment was analyzed. Results In 2 separate studies, Azimilide at a dose of 125 mg/day significantly reduced the number of symptoms at the time of arrhythmia recurrence compared to placebo. On the other hand, in 2 studies, the dose of 100 mg/day did not significantly reduce symptom burden. The individual symptoms significantly reduced by Azimilide125 mg/day were fatigue, shortness of breath, chest pain and dizziness. Palpitations and sweating were not significantly reduced. Modeling of heart rate at the time of arrhythmia recurrence, symptoms and treatment indicated that a small reduction in heart rate with Azimilide accounted for only a small part of the symptom reduction. There was another effect of Azimilide: an average reduction of 0.38 symptoms ( P Conclusion Azimilide (125 mg/day) reduces the number of symptoms reported at the time of AF recurrence.
-
asymptomatic or silent atrial fibrillation frequency in untreated patients and patients receiving Azimilide
Circulation, 2003Co-Authors: Richard L. Page, Stephen R. Marcello, Daniel J. Schnell, William E. Wilkinson, Stuart J. Connolly, Thomas W Tilsch, Edward L.c. PritchettAbstract:Background— Asymptomatic, or “silent” atrial fibrillation could increase the risk of stroke. Little is known about the frequency of asymptomatic atrial fibrillation in patients who also have symptomatic atrial fibrillation; similarly, little is known about the effect of antiarrhythmic drug therapy on asymptomatic atrial fibrillation. Methods and Results— Patients in sinus rhythm with a history of symptomatic atrial fibrillation or atrial flutter received placebo or Azimilide (35 to 125 mg) once daily for 6 or 9 months in 4 similar double-blind trials. The end point was the first recurrence of a symptomatic ECG-documented supraventricular arrhythmia. Routine transtelephonic electrocardiograms, in the absence of symptoms, were recorded for 30 seconds every 2 weeks until patients completed follow-up or documented a symptomatic supraventricular arrhythmia. Of the 1380 patients, 489 received placebo. Among these patients receiving placebo, 303 transmitted at least one routine ECG while asymptomatic. Asymptomat...
-
Azimilide for atrial fibrillation: clinical trial results and implications.
Cardiac Electrophysiology Review, 2003Co-Authors: Edward L.c. Pritchett, Stephen R. MarcelloAbstract:Azimilide dihydrochloride (or Azimilide) is a class III antiarrhythmic drug currently under investigation that has been tested in atrial fibrillation in four randomized, placebo-controlled clinical trials to assess efficacy and dose range. These investigational trials showed that doses of Azimilide 100 and 125 mg once daily prolonged the time to symptomatic arrhythmia recurrence in patients with a history of symptomatic atrial fibrillation, atrial flutter or both. Doses of 75 mg or less were not useful in this indication. Safety of Azimilide has been examined in several different types of studies. In a large randomized clinical trial of post-infarct patients, Azimilide neither increased nor decreased mortality risk. In patients with supraventricular arrhythmias, the most common adverse effects reported by patients on Azimilide were approximately equal in frequency with those on placebo: headache, asthenia, infection, diarrhea and dizziness. Infrequent cases of torsade de pointes and severe neutropenia were reported in patients taking Azimilide. Azimilide is an investigational antiarrhythmic drug that has shown efficacy in patients with atrial fibrillation.
Alfred E Corey - One of the best experts on this subject based on the ideXlab platform.
-
influence of coadministration on the pharmacokinetics of Azimilide dihydrochloride and digoxin
The Journal of Clinical Pharmacology, 2005Co-Authors: Alfred E Corey, Nikhil Parekh, Suzanne N. Valentine, Roger D Toothaker, Jeff R Agnew, Werner Moehrke, Gary A ThompsonAbstract:The influence of coadministration on digoxin and Azimilide pharmacokinetics/pharmacodynamics was assessed in a randomized, 3-way crossover study in 18 healthy men. Serial blood and urine samples were obtained for Azimilide and digoxin quantitation. Treatment effects on pharmacokinetics were assessed using analysis of variance. The relationship between Azimilide blood concentrations and QT c prolongation was characterized by an E m a x model. Effects of coadministration on pharmacodynamics were assessed using a mechanistic-based inhibition model. Azimilide pharmacokinetics was unaffected by digoxin, except for a 36% increase in CL r [P = .0325), with no change in CL o . Digoxin pharmacokinetics was unaffected by Azimilide, except for a 21% increase in C m a x (P = .0176) and a 10% increase in AUC τ (P =.0121). Digoxin coadministration increased the apparent EC 5 0 with no effect on E m a x , consistent with competitive inhibition (K i = 0.899 ng/mL). The pharmacokinetic and pharmacodynamic changes observed upon coadministration were small and are not expected to be clinically important.
-
effect of mild and moderate hepatic impairment on Azimilide pharmacokinetics following single dose oral administration
Journal of Pharmaceutical Sciences, 2004Co-Authors: Alfred E Corey, Jeffrey R Agnew, Eileen C King, Nikhil Parekh, James H Powell, Gary A ThompsonAbstract:Abstract Azimilide dihydrochloride (75–125 mg/day) is currently being developed for use in prolonging the time to recurrence of atrial fibrillation/flutter and for reducing the frequency of shocks in patients with an implantable cardioverting defibrillator. This study investigated the influence of mild and moderate hepatic impairment on Azimilide pharmacokinetics. Six subjects each with mild and moderate hepatic impairment (Child–Pugh grades A and B, respectively) were age, weight, smoking status, and gender-matched to a healthy subject (total N = 24). Each subject was administered a single, oral dose of 100 mg Azimilide dihydrochloride following an overnight fast. Blood/plasma and urine samples were collected up to 28 days and over 9 days, respectively, and analyzed using HPLC with MS/MS or UV detection. For Azimilide, most parameters in subjects with mild to moderate hepatic impairment were within 25% of those observed in matched healthy subjects, with no statistically significant differences observed. For F-1292 (major metabolite in plasma), a significant decrease in AUC was observed in subjects with moderate hepatic impairment, secondary to an increase in renal clearance (CL r ). Based on these results, no a priori dosage adjustment is required in subjects with mild to moderate hepatic impairment. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:1279–1286, 2004
-
Effect of severe renal impairment on the pharmacokinetics of Azimilide following single dose oral administration.
British journal of clinical pharmacology, 2002Co-Authors: Alfred E Corey, Jeffrey R Agnew, Nikhil Parekh, James H Powell, Suzanne N. Valentine, Gary A ThompsonAbstract:Aims To assess the influence of severe renal impairment on Azimilide pharmacokinetics. Methods A single oral dose of 125 mg Azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22–28 and 10 days, respectively. Results Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h−1 kg−1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h−1 kg−1, 95% confidence interval on the ratio 0.67, 1.36) was observed. Conclusions Since Azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.
-
comparative oral bioavailability of Azimilide dihydrochloride in the fed and fasted states
British Journal of Clinical Pharmacology, 2000Co-Authors: Alfred E Corey, Jeffrey R Agnew, James H Powell, Suzanne N. Valentine, John D Nesbitt, Dan L Wagner, Gary A ThompsonAbstract:Aims This study investigated the relative oral bioavailability of Azimilide dihydrochloride following administration in the fed (high-fat meal) and fasted states. Methods This was a single-dose, randomized, two-way crossover study in 30 healthy, Caucasian, male subjects. Following oral administration, blood samples were collected over 27 days and analysed for Azimilide using h.p.l.c. with u.v. detection. Pharmacokinetic parameters were determined using ‘noncompartmental’ analysis and compared using an ANOVA and 90% or 95% confidence intervals. Results The extent of absorption was equivalent in the fed and fasted states (ratio = 96.2%; 90% CI=90.5%−102.4%). However, Cmax was decreased 19% following a high-fat meal (ratio=81.4%; 90% CI= 76.2%−87.0%). No difference in tmax or t½,z was observed. Conclusions Azimilide dihydrochloride may be orally administered to patients without regard to the prandial state.
-
pharmacokinetics and pharmacodynamics following intravenous doses of Azimilide dihydrochloride
The Journal of Clinical Pharmacology, 1999Co-Authors: Alfred E Corey, Jeffrey R Agnew, Nikhil Parekh, Suzanne N. Valentine, Jose Brum, Melanie WilliamsAbstract:Azimilide pharmacokinetics and pharmacodynamics were characterized in a safety and tolerance study of intravenously administered Azimilide dihydrochloride. This was a parallel-group design (seven treatments), and 68 healthy volunteers received the drug. Single intravenous infusion doses (4.5 to 9 mg/kg) were administered over 60 minutes, and single 4.5 mg/kg intravenous infusion doses were also given over 15 or 30 minutes. Blood and urine specimens were collected and analyzed for Azimilide and metabolites. QT c was measured as a marker of class III antiarrhythmic activity. Azimilide pharmacokinetics were dose proportional and did not differ among infusion rates. Azimilide pharmacodynamics did not differ among treatments. Mean E max ranged from 23 to 28%ΔQT c , with mean EC 50 of 509 to 566 ng/mL. Peak circadian variation in QT c was equivalent to 14% of E max . Rapid equilibration occurred between blood and the biophase. Unconfounded pharmacodynamic estimates required inclusion of circadian QT c variation in the pharmacodynamic model.
