-
Pharmaceutical Research Feb 1998The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
PURPOSE
The aim of this research was to determine the mechanism by which a co-administered meal decreases the oral absorption of bidisomide and does not influence the oral absorption of the chemically-related antiarrhythmic agent, disopyramide.
METHODS
Bidisomide plasma levels, following oral administration and intravenous infusion in the fasted state and with various meal treatments, were determined in human subjects. A dialysis technique was employed to examine the potential for drug binding to meal homogenates. Plasma levels, following drug administration through duodenal and jejunal intestinal access ports and following various meal treatments with oral drug co-administration, were compared for bidisomide and disopyramide in a canine model.
RESULTS
Bidisomide plasma AUC was significantly reduced following oral drug co-administration with breakfast compared to fasted-state controls in human subjects and in dogs independent of the composition of the solid cooked breakfast. While intravenous bidisomide infusion in human subjects showed a statistically significant reduction in AUC 15 minutes after oral administration of a high fat breakfast as compared to drug infusion in the fasted state, the reduction (-13%) was substantially smaller than the reduction (from -43% to -63%) observed with oral bidisomide meal co-administration. The percentages of bidisomide and disopyramide lost by binding to homogenates of cooked breakfast were 25.0 +/- 5.7% and 23.7 +/- 7.7%, respectively, as determined by dialysis at 4 hours. In dogs, the extent of absorption of disopyramide was comparable from oral, duodenal and mid-jejunal administration while the extent of bidisomide absorption from mid-jejunal administration was significantly lower than for oral or duodenal administration. Non-viscous liquid meals decreased Cmax but not AUC, while viscous homogenized solid meals decreased both Cmax and AUC for bidisomide with oral drug-meal co-administration. Oral non-caloric hydroxypropyl methylcellulose meals decreased bidisomide to the same extent as homogenized solid meals but did not lower disopyramide AUC.
CONCLUSIONS
The significant reduction in bidisomide plasma levels observed with meal co-administration in human subjects was predominantly mediated through a reduction in drug absorption and was independent of solid meal composition. The difference in meal effect on the absorption of the two drugs in humans did not appear to be a function of drug binding to cooked meal components over typical human upper gastrointestinal residence times. In dogs, the high-viscosity medium generated by oral co-administration of a solid meal reduced the upper intestinal absorption of bidisomide and disopyramide. Bidisomide AUC was decreased since it was well absorbed in the upper but not lower small intestine. Disopyramide AUC was not significantly affected since it was well absorbed from both regions. A similar mechanism may play a role in drug plasma level reductions following oral co-administration with solid meals for drugs showing similar regionally-dependent absorption profiles.
Topics: Animals; Anti-Arrhythmia Agents; Area Under Curve; Biological Availability; Dogs; Female; Food-Drug Interactions; Humans; Infusions, Intravenous; Intestinal Absorption; Male; Piperidines; Viscosity
PubMed: 9523307
DOI: 10.1023/a:1011958400362 -
Zhongguo Yao Li Xue Bao = Acta... Sep 1997To study influence of congestive heart failure (CHF) and acute myocardial infarction (AMI) on alpha 1-acid glycoprotein (AGP) and sialic acid (SA) concentration, and...
AIM
To study influence of congestive heart failure (CHF) and acute myocardial infarction (AMI) on alpha 1-acid glycoprotein (AGP) and sialic acid (SA) concentration, and binding of AGP to disopyramide (Dis).
METHODS
Sera from 85 healthy subjects, 6 patients with CHF, and 6 patients with AMI were determined by immunochemistry for AGP, by HPLC method for sialic acid (SA), and by ultrafiltration and HPLC for the free fraction of Dis.
RESULTS
Serum AGP concentrations (g.L-1) were 0.74 +/- 0.16 (healthy), 1.18 +/- 0.40 (d 1, CHF) and 0.90 +/- 0.24 (d 14, CHF), 1.53 +/- 0.26 (d 5, AMI) and 1.08 (d 14, AMI). The free Dis were 1.76 +/- 0.62 (d 1) and 2.14 +/- 0.48 (d 14), in CHF patients, 1.66 +/- 0.52 (d 5) and 1.77 (d 14) in AMI patients. The changes of serum SA and AGP concentrations showed the same tendency.
CONCLUSION
The free Dis in serum was affected by the change of AGP binding in CHF and AMI patients.
Topics: Adult; Aged; Disopyramide; Female; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Orosomucoid; Protein Binding; Sialic Acids
PubMed: 10322928
DOI: No ID Found -
Journal of Clinical Medicine Jul 2022Obstructive hypertrophic cardiomyopathy (oHCM) has been studied primarily in comprehensive centers of excellence. Broadening the understanding of patients with oHCM in...
Clinical Characteristics and Healthcare Resource Utilization among Patients with Obstructive Hypertrophic Cardiomyopathy Treated in a Range of Settings in the United States.
Obstructive hypertrophic cardiomyopathy (oHCM) has been studied primarily in comprehensive centers of excellence. Broadening the understanding of patients with oHCM in the general population may improve identification and treatment in other settings. This retrospective cohort study identified adults with oHCM from a large electronic medical record database comprising data from 39 integrated delivery networks (IBM Explorys; observational period: January 2009-July 2019). Clinical characteristics, healthcare resource utilization (HCRU), and outcomes were reported. Of 8791 patients, 53.0% were female and the mean index age was 61.8 years. Cardiovascular drugs prescribed included beta-blockers (80.5%), calcium channel blockers (46.0%), and disopyramide (2.4%). Over time, heart failure, atrial fibrillation, and ventricular arrhythmias increased. Surgical procedures included septal myectomy (22.0%), alcohol septal ablation (0.6%), and heart transplantation (0.3%). Implantable cardioverter defibrillators were present in 11.2% of patients. After initial septal reduction therapy (SRT), HCRU increased and 550 patients (27.7%) required a reintervention. Of the overall group, 2.7% experienced sudden cardiac arrest by end of study. In conclusion, this cohort of patients with oHCM had guideline-recommended drug therapy and procedures. Despite this, heart failure, atrial fibrillation, and ventricular arrhythmias increased, and more than a quarter of patients undergoing SRT required reintervention. These unresolved issues emphasize the unmet need for new, effective therapies for patients with oHCM.
PubMed: 35807183
DOI: 10.3390/jcm11133898 -
Cellular Physiology and Biochemistry :... 2018Early repolarization syndrome (ERS) has been recently recognized as early repolarization pattern with idiopathic ventricular fibrillation. However, the genetic...
BACKGROUND/AIMS
Early repolarization syndrome (ERS) has been recently recognized as early repolarization pattern with idiopathic ventricular fibrillation. However, the genetic background of ERS has not been fully understood.
METHODS
A Chinese family with sudden cardiac death associated with ERS was investigated. Direct sequencing of ERS susceptibility genes was performed on the proband and family members. Whole-cell patch-clamp methods were used to characterize the mutant channel expressed in HEK 293 cells.
RESULTS
One missense mutation (p. K801T) was found in the hERG (KCNH2 gene) by the direct sequencing of candidate genes. Whole cell voltage clamp studies of the K801T mutation in HEK 293 cells demonstrated a 1.5-fold increase in maximum steady state current (37.2±7.3 vs 20.3±4.4 pA/pF) that occurred at a 20 mV more positive potential compared to the wild type channels. The voltage dependence of inactivation was significantly shifted in the positive voltage direction (WT -59.5±1.4 vs K801T -44.3±1.2 mV). Kinetic analysis revealed slower inactivation rates of K801T, but faster rates of activation and deactivation. The hERG channel blockers tested inhibited K801T-hERG channel in concentration response, and the potencies of these drugs can be rank-ordered as follows: quinidine> disopyramide> sotalol> flecainide.
CONCLUSION
Our study indicated that the K801T mutation caused the gain of function of hERG channels that may account for the clinical phenotype of ERS. Quinidine and disopyramide could improve the function of K801T-hERG mutant channel, and may be therapeutic options for patients with the K801T hERG mutation.
Topics: Adult; Death, Sudden, Cardiac; ERG1 Potassium Channel; HEK293 Cells; Heterozygote; Humans; Male; Mutation, Missense; Pedigree; Ventricular Fibrillation
PubMed: 30481776
DOI: 10.1159/000495549 -
British Journal of Pharmacology and... Dec 1963An intermittent infusion of ouabain, 4 mug during 30 sec every 1.5 min, regularly caused ventricular fibrillation in guinea-pigs. The beta-receptor blocking drug,...
An intermittent infusion of ouabain, 4 mug during 30 sec every 1.5 min, regularly caused ventricular fibrillation in guinea-pigs. The beta-receptor blocking drug, pronethalol (5 mg/kg), increased the dose of ouabain required to produce extrasystoles, completely prevented fibrillation, and significantly raised the lethal dose of ouabain. Dichloroisoprenaline had similar effects, but a dose of 15 mg/kg was required. When fibrillation had already been produced by ouabain, pronethalol (3 to 4 mg) administered slowly restored a regular rhythm, but rapid injection sometimes produced cardiac arrest. As much as 20 to 25 mg/kg of pronethalol could be given to animals deeply anaesthetized with urethane or pentobarbitone, but with light chloroform or ether anaesthesia, 5 mg/kg of pronethalol caused a large fall in blood pressure and complete heart-block.
Topics: Anesthetics; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Blood Pressure; Brugada Syndrome; Cardiac Complexes, Premature; Cardiac Conduction System Disease; Disopyramide; Ethanolamines; Guinea Pigs; Heart; Heart Conduction System; Isoproterenol; Ouabain; Pharmacology; Research; Strophanthins; Sympatholytics; Toxicology
PubMed: 14110746
DOI: 10.1111/j.1476-5381.1963.tb02014.x -
British Journal of Clinical Pharmacology Dec 2003The F1S and A genetic variants of alpha1-acid glycoprotein (AAG) change under various physiological and pathological conditions. They also vary in their drug binding...
AIMS
The F1S and A genetic variants of alpha1-acid glycoprotein (AAG) change under various physiological and pathological conditions. They also vary in their drug binding abilities. We have studied the stereoselective binding ability of each of the AAG variants using enantiomers of disopyramide (DP) and warfarin (WR).
METHODS
The AAG variants were separated by hydroxyapatite chromatography. Binding of drug enantiomers to the AAG variants was studied by the Hummel-Dreyer method. The characteristics of the binding activities were examined by Scatchard plot analysis. The first five amino-terminal amino acids (residues 112-116) of the cyanogen bromide (CNBr) fragment (residues 112-181) of each of the separated AAG fractions were elucidated by Edman degradation.
RESULTS
Commercial AAG was separated into two main fractions. Residues 112-116 of fraction 2 were identical to the amino acid sequences predicted from the AAG A gene, LAFDV, and encode the F1S variant. In fraction 3, the deduced amino acid sequence of the AAG B gene, FGSYL, was established, and encodes the A variant. The binding affinities of both DP enantiomers in fraction 3 were significantly higher than those in fraction 2. The differences between dissociation constants (Kd) in fractions 2 and 3 were 5.2-fold for (S)-DP (P < 0.05) and 3.7-fold for (R)-DP (P < 0.001). The dissociation constant of (S)-DP (0.39 +/- 0.08 micro m) was lower than that of (R)-DP (0.53 +/- 0.10 micro m) in fraction 3 [95% confidence interval (CI) - 0.282, - 0.010; P < 0.05], although the binding activities of the DP enantiomers were almost the same in fraction 2. By contrast WR enantiomers had a higher binding affinity in fraction 2 than in fraction 3, the differences in dissociation constants between fractions 2 and 3 being 12.6-fold for (S)-WR (P < 0.001) and 8.3-fold for (R)-WR (P < 0.001). The dissociation constant of (S)-WR (0.28 +/- 0.10 microm) was significantly lower than that of (R)-WR (0.48 +/- 0.08 microm) in fraction 2 (95% CI - 0.369, - 0.028; P < 0.05), but there were no significant differences between the binding activities of WR enantiomers in fraction 3.
CONCLUSIONS
DP and WR enantiomers bind preferentially to fraction 3 and fraction 2, respectively. Fractions 2 and 3 are encoded by the AAG A and the AAG B genes, respectively.
Topics: Amino Acid Sequence; Disopyramide; Electrophoresis, Polyacrylamide Gel; Humans; Orosomucoid; Stereoisomerism; Warfarin
PubMed: 14616427
DOI: 10.1046/j.1365-2125.2003.01909.x -
British Heart Journal Jul 1985The efficacy of sotalol in treating acute atrial fibrillation and flutter after open heart surgery was compared with that of a digoxin/disopyramide combination. Forty... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The efficacy of sotalol in treating acute atrial fibrillation and flutter after open heart surgery was compared with that of a digoxin/disopyramide combination. Forty adult patients with postoperative atrial arrhythmias were randomised into either group 1 (sotalol 1 mg/kg bolus intravenously plus 0.2 mg/kg intravenously over 12 hours) or group 2 (digoxin 0.75 mg intravenously, then two hours later disopyramide 2 mg/kg intravenous bolus and 0.4 mg/kg/h intravenously for 10 hours). In each group, 17 out of 20 patients reverted to sinus or junctional rhythm within 12 hours. The time to reversion in group 1 was significantly shorter than in group 2. Systolic blood pressure fell by greater than or equal to 20 mm Hg or to less than or equal to 90 mm Hg during drug administration in 17 out of 20 patients in group 1 (sotalol withdrawn in two) and in none out of 20 in group 2. Two patients in group 1 developed transient bradycardia (sotalol withdrawn in one). None of 17 patients in group 1 and two of 17 in group 2 relapsed temporarily into atrial fibrillation during the 12 hours of intravenous treatment. On continued oral treatment, one late relapse occurred in group 1 and five in group 2, and five patients in group 2 had disopyramide withdrawn because of anticholinergic side effects (acute urinary retention in four). Sotalol was as effective as the digoxin/disopyramide combination and acted significantly faster. Sensitivity to beta blockade in these patients may be related to high plasma catecholamine concentrations known to occur after cardiopulmonary bypass.
Topics: Atrial Fibrillation; Atrial Flutter; Cardiopulmonary Bypass; Clinical Trials as Topic; Digoxin; Disopyramide; Female; Humans; Infusions, Parenteral; Injections, Intravenous; Male; Middle Aged; Postoperative Complications; Sotalol
PubMed: 3893488
DOI: 10.1136/hrt.54.1.86 -
British Journal of Clinical Pharmacology Nov 1984Five hundred and seventy one patients admitted to a coronary care unit with suspected acute myocardial infarction were considered for entry into a double-blind study.... (Clinical Trial)
Clinical Trial Comparative Study
Five hundred and seventy one patients admitted to a coronary care unit with suspected acute myocardial infarction were considered for entry into a double-blind study. Two hundred and eighty-three patients were excluded, mainly because of recent treatment with beta-adrenoceptor blocking agents, life threatening arrhythmias requiring specific treatment and left ventricular failure presenting with hypotension or pulmonary oedema. Two hundred and eighty-eight entered the trial of whom 202 were subsequently confirmed to have had myocardial infarction. The effects of tocainide and disopyramide on ventricular arrhythmias were compared with placebo over the first 48 h period. The three treatments were given by a combination of intravenous infusion and oral administration. The doses used were tocainide 500 mg intravenously over 30 min plus 2800 mg orally over 48 h and disopyramide 150 mg intravenously over 30 min plus 1050 mg orally over 48 h. As judged by counts of ventricular premature beats, tocainide and disopyramide exerted a similar and significant antiarrhythmic effect. The median number of ventricular premature beats over the first 24 h of treatment was 58 on placebo compared with 30 on tocainide (P less than 0.05) and 19 on disopyramide (P less than 0.05). The corresponding figures for the second 24 h were 9, 6 and 2, respectively. There were eight deaths and three episodes of ventricular fibrillation with no significant differences between the three treatment groups. Sustained ventricular tachycardia was observed in one patient in the tocainide group.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Disopyramide; Female; Humans; Lidocaine; Male; Middle Aged; Myocardial Infarction; Tocainide; Ventricular Fibrillation
PubMed: 6439233
DOI: 10.1111/j.1365-2125.1984.tb02535.x -
Biological & Pharmaceutical Bulletin Jan 2005The present study evaluated the effect of fluconazole on the heart, as well as and the toxic interactions between fluconazole and disopyramide in chick embryos. Chick...
The present study evaluated the effect of fluconazole on the heart, as well as and the toxic interactions between fluconazole and disopyramide in chick embryos. Chick embryos have been widely used in pharmacologic and toxicologic experiments for evaluating drug action. Fertilized eggs of White Leghorns were incubated and investigated. Fluconazole 0.4 mg/egg, 0.8 mg/egg, 1.2 mg/egg alone or disopyramide 0.3 mg/egg alone was injected into the air sac of each fertilized egg. And fluconazole 0.4 mg/egg with disopyramide 0.3 mg/egg was injected into the air sac of each fertilized egg. Electrocardiograms (ECGs) were recorded 0 to 60 min after the drug injection, and heart rate was determined from ECG wave cycles. Changes in heart rate were expressed as mean-percent changes of the drug-treated groups to the matched control. After the administration of fluconazole 0.4 mg/egg alone, the heart rate did not differ compared with that of the controls. However, the heart rate was significantly decreased with the administration of fluconazole 0.8 mg/egg and 1.2 mg/egg. The heart rate was also significantly decreased by the administration of fluconazole 0.4 mg/egg together with disopyramide 0.3 mg/egg. In addition, an arrhythmia was produced by fluconazole and disopyramide. These findings indicate that the interaction between fluconazole and disopyramide has a marked influence on the heart rate in chick embryos.
Topics: Animals; Chick Embryo; Disopyramide; Drug Interactions; Electrocardiography; Fluconazole; Heart Rate
PubMed: 15635181
DOI: 10.1248/bpb.28.151 -
British Journal of Clinical Pharmacology Nov 1984Highly purified serum albumin did not bind either disopyramide (DP) or mono-N-dealkyldisopyramide (MND). The unbound fraction of DP and MND in highly purified serum...
Highly purified serum albumin did not bind either disopyramide (DP) or mono-N-dealkyldisopyramide (MND). The unbound fraction of DP and MND in highly purified serum alpha 1-acid glycoprotein (AAG) at 0.5 g/l was 57 and 62 and at 2.0 g/l 19 and 30% respectively. Unbound DP and MND were measured in spiked plasma (10 mumol/l of DP or MND), from 60 patients, having AAG concentrations varying from 0.4 to 3.0 g/l. Unbound drug varied from 13 to 58 and from 24 to 62% for DP and MND, respectively, and was inversely related to the plasma concentration of AAG (r = -0.9016, r = -0.9157). A linear relationship was found between the binding ratio (moles bound divided by moles unbound) and the plasma concentration of AAG for both DP (r = 0.9199) and MND (r = 0.9270), whereas no relationship was found between the binding ratios of DP or MND and the plasma concentrations of total protein, albumin, haptoglobin, alpha 1-antitrypsin or the immunoglobulins IgG, IgA or IgM. In patients on DP maintenance therapy, a linear relationship was found between percent unbound DP and the plasma concentration of DP in samples with similar AAG concentrations. Furthermore, a linear relationship was found between the binding ratio of DP and the plasma concentration of AAG in samples with similar DP concentrations. The present findings support the concept that AAG is the major serum protein responsible for the binding of DP and MND.
Topics: Adolescent; Adult; Aged; Disopyramide; Female; Humans; Male; Middle Aged; Orosomucoid; Protein Binding; Serum Albumin
PubMed: 6508986
DOI: 10.1111/j.1365-2125.1984.tb02542.x