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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 -
British Journal of Clinical Pharmacology Apr 19901. The protein binding of disopyramide was measured in plasma obtained from nonpregnant women, pregnant women in the first, second, and third trimesters, matched pairs...
1. The protein binding of disopyramide was measured in plasma obtained from nonpregnant women, pregnant women in the first, second, and third trimesters, matched pairs of mothers and neonates (cord plasma), and 1 month postpartum women (n = 6 or 8 of each). 2. Plasma samples spiked with 0.2-12.0 micrograms ml-1 of the drug were ultrafiltered and the free fractions were measured with a fluorescent polarization immunoassay. 3. The mean (+/- s.d.) percentages of free drug at a total concentration of 3.0 micrograms ml-1 observed in the third trimester (46 +/- 9%) and neonate (79 +/- 5%) groups were greater (P less than 0.05 or 0.01) than that in the non-pregnant group (34 +/- 7%). In contrast, the corresponding value observed in the postpartum group (23 +/- 8%) was less (P less than 0.05) than that in the non-pregnant group. In addition, there was a significant (P less than 0.01) difference in the mean percentage of free drug at 3.0 micrograms ml-1 in plasma from mothers (43 +/- 9%) and neonates (79 +/- 5%). 4. A multiple regression analysis indicated that alpha 1-acid glycoprotein (r = -0.88, P less than 0.01), rather than albumin (r = -0.008), dominated the binding of disopyramide within the therapeutic range of drug concentration. An analysis of the binding parameters of disopyramide suggested that alterations in binding were attributable to changes in the capacity rather than the affinity of binding.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Adult; Blood Proteins; Disopyramide; Female; Fluorescence Polarization; Fluorescent Antibody Technique; Humans; Infant, Newborn; Models, Biological; Orosomucoid; Postpartum Period; Pregnancy; Protein Binding; Regression Analysis
PubMed: 2183867
DOI: 10.1111/j.1365-2125.1990.tb03660.x -
Journal of the American College of... Jun 1985Ten patients suffering from chronic premature ventricular complexes (greater than 60/h) were treated orally in a double-blind crossover study with encainide (50 mg three... (Clinical Trial)
Clinical Trial Comparative Study
Ten patients suffering from chronic premature ventricular complexes (greater than 60/h) were treated orally in a double-blind crossover study with encainide (50 mg three times a day) and disopyramide (200 mg three times a day), with five 7 day study periods: survey, placebo, encainide or disopyramide, washout placebo and disopyramide or encainide. At the end of each 7 day period, a 12 lead electrocardiogram, a 48 hour ambulatory electrocardiogram and a treadmill exercise test were performed. Blood levels of encainide and its metabolites and of disopyramide were measured at the end of each treatment (steady state). Drug efficacy was assessed by: 1) more than 80% reduction in the number of premature ventricular complexes per 24 hours, and 2) absence of ventricular tachycardia. Encainide was effective in four patients (complete suppression of premature ventricular complexes) and ineffective in five. One patient who showed a 92% reduction in the number of premature ventricular complexes developed sustained ventricular tachycardia after 24 hours of treatment. Disopyramide was effective in three patients (greater than 80% reduction in the number of premature ventricular complexes) and ineffective in seven patients. With encainide, the percent increase in PR, QRS and QT interval duration was, respectively: 32.7 (p less than 0.001), 30.8 (p less than 0.001) and 10.6% (p less than 0.01). With disopyramide this increase was not significant. Despite the variability of drug blood levels, a relation between blood levels and suppression of premature ventricular complexes on the 48 hour ambulatory electrocardiogram was found with encainide, but not with disopyramide.(ABSTRACT TRUNCATED AT 250 WORDS)
Topics: Administration, Oral; Adolescent; Adult; Aged; Anilides; Anti-Arrhythmia Agents; Arrhythmias, Cardiac; Cardiac Complexes, Premature; Clinical Trials as Topic; Disopyramide; Double-Blind Method; Electrocardiography; Encainide; Exercise Test; Female; Humans; Male; Middle Aged; Placebos
PubMed: 2582017
DOI: 10.1016/s0735-1097(85)80363-6 -
Circulation Journal : Official Journal... Sep 2002This study was designed to assess the effects of typical class I drugs on the terminal repolarization process of the in situ heart, which is a useful marker of the...
This study was designed to assess the effects of typical class I drugs on the terminal repolarization process of the in situ heart, which is a useful marker of the potential of drug-induced long QT syndrome. Disopyramide (0.3 and 3.0 mg/kg per 10 min, n = 6) or mexiletine (0.3 and 3.0 mg/kg per 30s, n = 6) was intravenously administered to halothane-anesthetized beagle dogs under the monitoring of multiple cardiovascular parameters. Antiarrhythmic concentrations were obtained with the high dose of each drug. The low dose of disopyramide or mexiletine hardly affected any of the electrophysiological parameters assessed. The high dose of disopyramide prolonged the monophasic action potential duration (MAP90) and effective refractory period (ERP) to a similar extent, thus displacing the terminal repolarization period backward, which might provide a potential proarrhythmic substrate, particularly at a slow heart rate. On the other hand, the high dose of mexiletine shortened the MAP90, but prolonged the ERP, resulting in the disappearance of the terminal repolarization period, which could prevent premature excitation with its associated conduction slowing. These electrophysiological effects of disopyramide and mexiletine on the terminal repolarization phase may at least in part explain their clinically described antiarrhythmic and proarrhythmic properties.
Topics: Action Potentials; Anesthetics, Inhalation; Animals; Anti-Arrhythmia Agents; Blood Pressure; Cardiac Output; Disease Models, Animal; Disopyramide; Dogs; Electrocardiography; Halothane; Heart Rate; Long QT Syndrome; Mexiletine; Ventricular Function, Left
PubMed: 12224826
DOI: 10.1253/circj.66.857 -
British Medical Journal Oct 1977
Topics: Disopyramide; Drug Interactions; Humans; Male; Middle Aged; Pyridines; Tachycardia; Warfarin
PubMed: 922330
DOI: 10.1136/bmj.2.6091.866-a -
British Heart Journal Mar 1985Syncopal attacks in patients with bifascicular block may be due to both ventricular tachyarrhythmias and intermittent atrioventricular block in addition to non-cardiac...
Disopyramide induced second and third degree atrioventricular block in patients with bifascicular block. An acute stress test to predict atrioventricular block progression.
Syncopal attacks in patients with bifascicular block may be due to both ventricular tachyarrhythmias and intermittent atrioventricular block in addition to non-cardiac causes and lead to antiarrhythmic treatment with drugs or pacemaker or both. The acute electrophysiological effect of intravenous disopyramide 2 mg/kg body weight given over five minutes on the His-Purkinje system was assessed in 27 patients with chronic bifascicular block undergoing evaluation for permanent pacemaker treatment. The predictive value of this pharmacological stress test as regards the development of atrioventricular block during follow up was analysed. The HV interval increased (mean 43%) and the QRS duration was prolonged (mean 24%). Intrahisian or infrahisian second or third degree atrioventricular block occurred in 14 patients after disopyramide administration, requiring temporary pacing in four of them. Before the electrophysiological study 15 of the 27 patients had had at least two syncopal attacks of suspected cardiac origin but no evidence of second or third degree atrioventricular block. Second or third degree atrioventricular block was subsequently recorded in five of these 15 patients during a mean of two years follow up. The sensitivity, specificity, and predictive value of second or third degree atrioventricular block produced by disopyramide administration including subsequent atrial pacing--a positive disopyramide test--as regards later development of atrioventricular block were 80%, 90%, and 80% respectively. Intravenous administration of disopyramide to patients with bifascicular block and syncopal attacks of suspected cardiac origin may provoke atrioventricular block and asystole requiring immediate temporary pacing. Furthermore, a positive disopyramide test seems to have a significant value in predicting the later development of atrioventricular block.
Topics: Adult; Aged; Bundle-Branch Block; Disopyramide; Electrocardiography; Female; Follow-Up Studies; Heart Block; Heart Conduction System; Humans; Male; Middle Aged; Prognosis
PubMed: 3970790
DOI: 10.1136/hrt.53.3.328 -
Annals of Medicine and Surgery (2012) Oct 2023Aluminum phosphide (ALP) is a commonly used suicidal agent in an agrarian country like Nepal. The unmasking of the Brugada pattern in the electrocardiogram (ECG)...
INTRODUCTION AND IMPORTANCE
Aluminum phosphide (ALP) is a commonly used suicidal agent in an agrarian country like Nepal. The unmasking of the Brugada pattern in the electrocardiogram (ECG) associated with ALP poisoning is a rare phenomenon, and studies pertaining to it are scarce in the medical literature.
CASE PRESENTATION
An 18-year-old female presented to the emergency department with multiple episodes of vomiting, headache, blurring of vision, and abdominal pain after 4 h of consumption of ALP with suicidal intent. A 12-lead ECG revealed a coved ST-segment elevation and T-wave inversion in leads V1-V3 with right bundle branch block suggestive of a type 1 Brugada pattern. Her past medical and family history was not significant. The patient made an uneventful recovery with the required supportive treatments.
CLINICAL DISCUSSION
Cardiac arrhythmias are the major cause of death in ALP poisoning. Unmasking of the Brugada ECG pattern is a rare but potentially fatal complication implicated in various pharmacological toxicities, including tricyclic antidepressants, cocaine, procainamide, disopyramide, flecainide, and rarely with ALP.
CONCLUSIONS
ALP poisoning can unmask the Brugada ECG pattern, which can lead to ventricular fibrillation and/or sudden cardiac death.
PubMed: 37811028
DOI: 10.1097/MS9.0000000000001129 -
Journal of Neurology, Neurosurgery, and... May 1982Ten patients with myotonic dystrophy were allocated at random to treatment with disopyramide and procainamide in a cross-over trial. Disopyramide was found to be at... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Ten patients with myotonic dystrophy were allocated at random to treatment with disopyramide and procainamide in a cross-over trial. Disopyramide was found to be at least as effective as procainamide in the relief of myotonia; and two patients who could not tolerate procainamide both tolerated disopyramide.
Topics: Adolescent; Adult; Child; Child, Preschool; Clinical Trials as Topic; Disopyramide; Female; Humans; Male; Muscle Contraction; Myotonic Dystrophy; Procainamide; Pyridines; Random Allocation
PubMed: 7045292
DOI: 10.1136/jnnp.45.5.461 -
Drugs in R&D Sep 2017Human α1-acid glycoprotein has genetic variants, the F1, S, and A variants, which can be separated isoelectrophoretically. These variants show differences in their...
OBJECTIVE
Human α1-acid glycoprotein has genetic variants, the F1, S, and A variants, which can be separated isoelectrophoretically. These variants show differences in their affinity of binding to several drugs. In this study, we investigated the factors determining drug binding to these α1-acid glycoprotein genetic variants using disopyramide, warfarin, and tamsulosin as marker compounds.
METHODS
Binding of the marker drugs to human α1-acid glycoprotein was determined by ultra-filtration in the presence or absence of various other drugs. For screening of the α1-acid glycoprotein variants to which the marker drugs became bound, the effects of various other drugs on their binding were studied. The binding data were analyzed using a competitive inhibition model and the relationship between the estimated dissociation constants and physicochemical properties, such as log P, was also analyzed.
RESULTS
The binding of tamsulosin was significantly decreased by aprindine, carvedilol, erythromycin, thioridazine, and warfarin, but not by disopyramide. The dissociation constants of drugs bound to F1/S variants were significantly correlated with their lipophilicity, but those for the A variant were not.
CONCLUSIONS
We were able to develop a simple screening method for determining individual α1-acid glycoprotein variants to which drugs would bind. The binding of drugs to F1/S variants may be determined mainly by drug lipophilicity.
Topics: Disopyramide; Genetic Variation; Humans; Hydrophobic and Hydrophilic Interactions; Orosomucoid; Protein Binding; Sulfonamides; Tamsulosin; Ultrafiltration; Warfarin
PubMed: 28646384
DOI: 10.1007/s40268-017-0193-9 -
British Journal of Clinical Pharmacology Jan 19801. A combined pharmacokinetic-pharmacodynamic model has been used to analyse the relationship between QT prolongation and changes in plasma concentration which occurred... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
1. A combined pharmacokinetic-pharmacodynamic model has been used to analyse the relationship between QT prolongation and changes in plasma concentration which occurred after disopyramide was given intravenously and orally to eight healthy subjects. 2. The pharmacokinetic models appropriate to intravenous and oral disopyramide have been extended by an 'effect compartment' which has no influence on the predetermined mass of drug in the body. 3. The model incorporates an adjustment for lag of effect behind any rapid changes in plasma concentration such as occur in the early distributive phase following intravenous administration. This permits calculation of the proportionality constant relating plasma concentration to effect. 4. Irrespective of the route of administration the mean (+/- s.d.) prolongation of the QT interval was 14.5 +/- 6.5 ms/micrograms ml-1. 5. There was no evidence that metabolite produced during first pass after oral administration made any significant contribution to effect. 6. This modelling technique should be applicable to the study of the concentration-effect relationship of a number of other drugs, both in health and in disease.
Topics: Administration, Oral; Disopyramide; Dose-Response Relationship, Drug; Electrocardiography; Heart Rate; Humans; Injections, Intravenous; Kinetics; Male; Models, Biological; Pyridines
PubMed: 7356895
DOI: 10.1111/j.1365-2125.1980.tb04799.x