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PubMed1999

Electrophysiologic and blood-flow responses in the endocardium and epicardium to disopyramide and MS-551 during myocardial ischemia in the dog.

The aim of this study was to determine whether a quantitative relation exists between changes in regional myocardial blood flow (RMBF) and those in electrophysiologic determinants recorded via left ventricular endocardial and epicardial bipolar electrograms after administration of disopyramide (DP) and a class III antiarrhythmic drug, MS-551 (MS), during myocardial ischemia in the dog. Dogs were given DP (1 mg/kg, i.v., n = 14), MS (1 mg/kg, i.v., and 0.1 mg/kg/min, d.i.v., n = 13), or saline (n = 12). The effective refractory period (ERP) was determined by an S1-S2 extrastimulus method, and RMBF by a nonradioactive microsphere technique. The duration of regional electrograms (DRE) was measured as an indicator of conduction time in the myocardium. DP blunted ischemia-induced shortening of ERPs and lengthened DREs at the endocardial and epicardial sites, with a greater effect seen epicardially (p < 0.01 each). DP reduced RMBF, especially at the endocardial surfaces of the ischemic zone (p < 0.05). MS prolonged ERPs at the endocardial and epicardial sites in the ischemic and normal zones (p < 0.05-0.01), but there were no significant differences between the two sites. MS prolonged DREs (p < 0.05), but the magnitude of the prolongation of the DREs was similar to the values in the control group. MS had no effects on RMBF. DP treatment prolonged DREs at both sites in the ischemic zone more markedly than MS or saline treatment (p < 0.01 each). DP reduced RMBF at the endocardial site of the ischemic zone more markedly than MS or saline (p < 0.05 in each). Accordingly, MS prolonged ERPs, but did not increase disparities between endocardial and epicardial sites in the ischemic myocardium, whereas DP had a greater ERP-prolonging effect at the epicardial site than at the endocardial site. DP reduced endocardial RMBF more markedly than epicardial RMBF. These observations suggest that differences in ERPs between endocardial and epicardial ischemic myocardium caused by DP treatment are not due to the difference in RMBF reduction between the two tissue layers, and that DP and MS do not affect the same population of ion channel(s) when ERPs are prolonged.

Animals↗
PubMed1984

Determination of disopyramide phosphate in serum by high-performance liquid chromatography.

A method is described for the quantitation of disopyramide phosphate (Norpace) in serum by high-performance liquid chromatography. The analysis utilizes ultraviolet detection at 254 nm with a 5-micrometers reversed-phase column and a mobile phase consisting of acetonitrile, ammonium dihydrogen phosphate buffer, acetic acid, and water. The determination requires 100 microliters of serum sample and the analysis time (9 min) is rapid. Serum extraction is a two-step process using chloroform, sodium carbonate, and hydrochloric acid. Although acid is used, columns produced sharp peaks with consistent retention times for 6-8 months. This method provides selectivity and sensitivity with a precision of 3.8%, average recovery of 92.9% and no interference from 18 commonly administered drugs.

Chromatography, High Pressure Liquid↗
PubMed1987

Altered protein binding of disopyramide in plasma from patients with cancer and with inflammatory disease.

Protein binding of disopyramide (D) was studied in eight patients with cancer, seven with inflammatory diseases, and seven healthy subjects. Plasma samples containing concentrations of 0.2-12.0 micrograms/ml were ultrafiltered, and the free fractions were measured with fluorescence polarization immunoassay. The mean free fractions at D concentrations ranging from 1.0 to 6.0 micrograms/ml were significantly less in patients with cancer (p less than 0.01) and those with inflammatory diseases (p less than 0.05) than in healthy subjects. Patients with cancer had a greater (p less than 0.05) D binding than those with inflammatory diseases. A multiple regression analysis revealed a significant contribution of plasma alpha 1-acid glycoprotein (AAG) (r = -0.79, p less than 0.01), but not of albumin (r = -0.096), to the overall variability in D binding at 3.0 micrograms/ml. The mean capacity constant in the two patient groups was similar, but significantly (p less than 0.01) greater than in the healthy group. Nonspecific D binding was greater in cancer patients (p less than 0.01) compared to the other two groups. Our results suggest that (a) therapeutic range of D measured as total drug concentration in patients with cancer and with inflammatory diseases would be greater than previously thought, and (b) unidentified component(s) (other than AAG and albumin) might contribute to the greater D binding in cancer patients compared to other study groups.

Adult↗
PubMed1992

Steady-state pharmacokinetics and bioavailability of total and unbound disopyramide in children with cardiac arrhythmias.

We studied the pharmacokinetics of the total (protein-bound plus -unbound and unbound forms of disopyramide (DP) at steady-state in six children (aged 5.2 to 12.2 years) with cardiac arrhythmias who had received repeated oral DP therapy. Maximum concentrations after the oral dose were reached at 2.5 +/- 1.1 h (mean +/- SD) for both total and unbound DP. The bioavailabilities calculated from total and unbound plasma concentration-time curves were 99 +/- 23 and 89 +/- 27% of the dose, respectively. These parameters seen in our children are similar to those reported from adult subjects. The mean elimination half-lives (t1/2), volumes of distribution, and total body clearances (CL) of total and unbound DP were 3.15 +/- 0.64 and 2.50 +/- 0.37 h, 1.02 +/- 0.25 and 2.60 +/- 0.38 L/kg, and 3.79 +/- 0.82 and 13.12 +/- 2.60 ml/min/kg, respectively. These mean CL and t1/2 values are considerably greater and shorter, respectively, than those reported from adult subjects. The findings indicate that the greater doses of DP per kg of body weight reportedly required for attaining a therapeutic plasma drug level in pediatric age patients should be due to a greater drug CL in children than in adults. A sustained-release preparation of DP may be required for pediatric patients to minimize a large fluctuation of plasma drug levels during the dosing intervals.

Arrhythmias, Cardiac↗
PubMed1995

Nomogram for estimating plasma unbound disopyramide concentrations in patients with varying plasma alpha 1-acid glycoprotein concentrations.

Since plasma protein binding of disopyramide (DP)--a class IA antiarrhythmic widely used in the prevention and treatment of various types of cardiac arrhythmias--is not only saturable within the therapeutic range but also altered under various pathophysiological conditions, the interpretation of total DP concentrations, Ctotal, measured during routine therapeutic drug monitoring (TDM) is often complicated. To circumvent this problem, we attempted to establish a comprehensive nomogram that allows estimation of unbound DP concentrations (Cu) based upon Ctotal of the drug and plasma concentration of alpha 1-acid glycoprotein (AAG), a major DP-binding protein. The nomogram was formulated with use of the in vitro binding data retrieved from 103 subjects categorized into 10 different groups each with a different mean concentration of AAG (range: 0.14-1.54 g/L). Data analysis, using a binding model assuming one specific binding site and nonspecific binding(s), revealed that alterations in plasma DP binding are attributable mainly to those in the capacity, Bmax, rather than affinity, ka, constant of the specific binding site. In addition, plasma AAG concentration correlated significantly (r = 0.90, p < 0.001) with the Bmax value over the range 0.09-2.28 g/L. For this reason, we substituted Bmax calculated by the regression equation as a function of AAG and the overall mean ka and nonspecific binding parameter values for the respective individual variables of the binding model, so that Cu of each plasma sample was estimated from the corresponding data on Ctotal and plasma AAG levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗
PubMed2005

Repolarization dynamics in patients with idiopathic ventricular fibrillation: pharmacological therapy with bepridil and disopyramide.

The electrocardiographic parameters relating occurrence of ventricular fibrillation (VF) episodes in patients with idiopathic VF (IVF) are still unknown. The aim of this study was to clarify efficacy of pharmacological therapy in patients with IVF with respect to repolarization dynamics. The study group consisted of 8 men (age 43.6 +/- 9.1 years) with IVF (Brugada type 5 patients, prominent J wave in the inferior leads 3 patients) who had documented spontaneous episodes of VF, 7 of whom had implantable cardioverter defibrillators. The relation between QT and RR interval was analyzed from 24-hour Holter ECG using an automatic analyzing system before and after pharmacological therapy (bepridil 5 and disopyramide 3). From QT-RR linear regression lines, QT intervals were determined at RR intervals of 0.6 second [QT(0.6)], 1.0 second [QT(1.0)], and 1.2 seconds [QT(1.2)]. Pharmacological therapy increased the slope of QT-RR regression line from 0.105 +/- 0.020 to 0.144 +/- 0.037 (P < 0.05). Accordingly, QT(1.0) and QT(1.2) became longer after drug therapy [QT(1.0), 0.382 +/- 0.016 seconds vs 0.414 +/- 0.016 seconds (P < 0.01); QT(1.2), 0.403 +/- 0.017 seconds vs 0.442 +/- 0.021 seconds (P < 0.01)]. However, QT(0.6) did not change after drug administration. Before drug therapy the average episodes of VF were 5.5 +/- 5.8 (range 1 to 17) during the observation period of 19.3 +/- 17.6 months (range 6 to 60 months). After drug therapy, 6 patients had no episode of VF for 24 to 120 months (66.0 +/- 38.5 months). Two patients had a single episode of VF for 12- and 96-month follow-ups. Pharmacological therapy decreased the frequency of VF episodes in association with prolongation of QT intervals at slower heart rates. Not only J wave and ST elevation but also shorter QT intervals at slower heart rates may represent an electrophysiological substrate for development of VF episodes in these specific IVF patients.

Adult↗
PubMed1976

Disopyramide in ventricular tachycardia.

Administration of disopyramide phosphate (DE) i.v. in two doses, 30 min apart, to a patient with ventricular tachycardia was accompanied by no, or only slight, changes in systemic arterial pressure (SAP), cardiac output (Q), stroke work (SW), and pulmonary artery diastolic pressure (PADP). Heart rate fell from 123 to 103/min. Following reversion to sinus rhythm, which occurred 60 min after the second dose of DE at a serum concentration greater than 4.3 mug/ml, Q ans SW showed significant increases above their control values. PADP fell from 20 to 6 mmHg whereas the mean SAP remained largely unchanged. There seemed to be no adverse effects of drug administration. In this patient, recurrent attacks of ventricular tachycardia not responding to conventional antiarrhythmic treatment could be prevented by oral DE in a dose of 800 mg/day.

Blood Pressure↗
PubMed1979

Disopyramide plasma levels in cardiac patients on maintenance therapy.

The antiarrhythmic agent disopyramide, in a dosage of 200 mg/8 h, was given to 7 cardiac patients. The drug was fairly rapidly absorbed, and the mean peak plasma concentration (3.5 microgram/ml) was measured 1 h after administration of the first dose. The mean biological half-life (7.8 h) was slightly prolonged compared to that reported in normal volunteer subjects. Mean steady state plasma concentrations within the therapeutic range were attained 24--32 h after the start of medication. The fluctuations in the plasma levels were in the order or 30 percent; however, a wide spread of the values was observed. The drug was well tolerated.

Adult↗
PubMed1979

Haemodynamic and electrocardiographic effects of intravenous disopyramide (rythmodan) following acute myocardial infarction.

1 The haemodynamic and electrocardiographic effects of intravenous disopyramide were studied in fifteen patients with acute myocardial infarction. 2 Five minutes after drug injection a rise in heart rate, aortic mean and diastolic pressures and systemic vascular resistence was noted which persisted for at least 30 min. A small increase in pulmonary arterial diastolic pressure (mean = 1.5 mm Hg) occurred at 5 min only and no significant change of cardiac output was found throughout the period of the study (1 h). 3 Surface electrocardiograms revealed transient prolongation of the P-R interval and a sustained increase in the QTc interval. 4 The haemodynamic changes suggest an anticholinergic effect of the drug. There was no definite evidence of a negative inotropic effect in this study, however, these peripheral haemodynamic measurements might not have revealed a modest negative inotropic effect. 5 The electrocardiographic changes are similar to those previously reported in normals and in patients without acute myocardial infarction.

Adult↗
PubMed1980

Disopyramide and lignocaine. A comparison of cardiac effects using echocardiography.

1 The cardiac effects of disopyramide (D) and lignocaine (L) were measured and compared in normal volunteers (D n=4; L n=3) following the establishment of a series of three steady-state drug plasma concentrations spanning the therapeutic range (1.5-5 micrograms base ml-1). 2 During control and steady-state periods multiple measurements were made of heart rate, blood pressure, drug concentrations and echocardiographic measurement of cardiac dimensions and estimated left ventricular function. 3 No change in heart size or estimated function occurred with L except for a small increase in estimated cardiac output (+0.5 1 min-1) secondary to a small rise in heart rate (maximum +7 beats min-1). Blood pressure rose slightly (maximum +11 mmHg). 4 D caused an increase in heart size, marked at end systole (+0.63 cm), and a decrease in echo indices of ventricular function (25-33%). These changes were related to plasma drug concentration but were not reflected in cardiac output estimation since heart rate rose (+15 beats min-1). Blood pressure also rose (+10 mmHg). 5 Significant differences were shown between D and L at similar plasma drug concentrations. The negative inotropic effect of D may be greater than previously suggested and clinically important.

Adult↗
PubMed1982

Plasma binding of disopyramide and mono-N-dealkyldisopyramide.

1 Measuring total plasma levels of disopyramide (DP) and the main metabolite mono-N-dealkyldisopyramide (MND) in patients on maintenance therapy with DP has shown concentrations of MND comparable with those of DP, with wide intersubject variations. 2 A method which permits simultaneous measurement of unbound fraction of DP and MND has been developed. 3 In healthy subjects the unbound fraction of both DP and MND was concentration dependent, i.e. increased with higher concentrations of DP or MND. 4 The plasma protein binding of DP is altered by varying concentrations of MND. Clinically relevant concentrations of MND may increase the unbound fraction of DP approximately twofold. 5 The plasma protein binding of MND is also altered by varying concentrations of DP. Variation in the concentration of DP from the lower to the upper part of the therapeutic range may cause a 1.5-fold increase in the unbound fraction of MND. 6 In the assumed therapeutic range of 6-15 mumol DP/L, the interpatient variance of unbound DP concentration might be ten-fold or even higher. The present findings indicate the need for monitoring unbound drug concentrations in any attempt to establish plasma concentration/effect relationship.

Adult↗
PubMed1984

Relationship between alpha 1-acid glycoprotein and plasma binding of disopyramide and mono-N-dealkyldisopyramide.

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.

Adolescent↗
PubMed1986

Relationship between alpha 1-acid glycoprotein and distribution of disopyramide and mono-N-dealkyldisopyramide in whole blood.

The binding of disopyramide (DP) and mono-N-dealkyldisopyramide (MND) was measured by equilibrium dialysis in spiked whole blood (10 mumol l-1 DP or MND) from 50 patients having a serum concentration of alpha 1-acid glycoprotein (AAG) ranging from 0.40 to 3.14 g l-1, as well as in whole blood from five healthy subjects, spiked with different concentrations of AAG ranging from 0.61 to 3.33 g l-1. The binding ratio (moles bound divided by moles unbound) in all samples increased from 1.0 to 8.0 for DP and 0.6 to 3.3 for MND with increasing AAG concentrations. The binding varied according to the AAG concentrations both in patients and healthy subjects. Similarly total and free plasma concentrations of DP and MND were also measured. With increasing AAG concentrations the total concentrations measured increased from 9.0 to 15.9 mumol l-1 for DP and from 6.8 to 11.8 mumol l-1 for MND whereas the free concentrations decreased from 3.8 to 0.5 mumol l-1 for DP and from 5.0 to 2.0 mumol l-1 for MND. With increasing AAG concentrations the whole blood/plasma concentration ratio decreased from 1.11 and 1.47 to 0.63 and 0.85 for DP and MND respectively. The ratio between their concentration in cells and the unbound concentration in plasma, however, was constant over the whole AAG concentration range. The mean ratios for all samples were 3.0 and 3.1 for DP and MND respectively, indicating that both compounds are bound or distributed to the blood cells. The distribution of the drugs in whole blood changed according to increasing AAG concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1982

The effects of postligation administration of ORG 6001 and disopyramide on early ischaemia-induced arrhythmias in the anaesthetized rat.

The effects of intravenous doses of Org 6001 and disopyramide (10 mg/kg) known to confer protection against early postligation-induced arrhythmias in the anaesthetized rat when given prophylactically, were assessed following postligation administration. When given 1 min after ligation both drugs greatly reduced the incidence of ventricular fibrilloflutter and completely prevented electrical deaths (45% in the controls). Protection was also seen when the drugs were given just before the expected onset of arrhythmias (4.5 min postligation).

Androstanols↗
PubMed1982

Electrophysiological effects of intravenous disopyramide phosphate on the Wolff-Parkinson-White syndrome.

The effects of a single intravenous infusion of 2mg/kg body weight disopyramide phosphate (DP) on the mode of initiation of reentrant supraventricular tachycardia were assessed in seven patients with Wolff-Parkinson-White (WPW) syndrome using bundle of His electrograms and the ventricular extrastimulus method. The delta wave disappeared in three patients after DP. However, retrograde conduction via the accessory pathway persisted even after DP administration in all patients. These effects contributed to the induction of reciprocating tachycardia after DP. The retrograde functional refractory period of the His-Purkinje system (HPS) and the effective refractory period of the accessory pathway were increased in all cases and contributed to the development of reentry HPS. After DP, the zone of reentry HPS widened in four cases (including a newly developed case) and remained unchanged in three cases. Reentrant supraventricular tachycardia zones widened in three cases; these widened reentrant supraventricular tachycardia zones were induced by the widened reentry HPS, that is, reentry HPS was followed by the reentrant supraventricular tachycardia. This study demonstrates that persistence of retrograde accessory pathway conduction and widened reentry HPS which might be dose-related after DP could be the retrograde determinants affecting the reentrant supraventricular tachycardia zone.

Adult↗
PubMed2000

Single oral administration of pilsicainide versus infusion of disopyramide for termination of paroxysmal atrial fibrillation: a multicenter trial.

A single oral dose of pilsicainide (PLS) is effective in terminating acute-onset atrial fibrillation (AF). However, the effectiveness of this single oral treatment has not been compared with the infusion of other antiarrhythmic drugs. The effects of a single oral dose of PLS on the termination of AF were compared with an infusion of disopyramide (DISO) in a multicenter trial. Seventy-two patients with electrocardiographically confirmed, symptomatic, paroxysmal AF (< 48-hour duration) were randomized to receive either a single 100- to 150-mg dose of PLS versus a 2 mg/kg (maximum dose = 100 mg) infusion of DISO. Successful defibrillation was defined as termination of AF within 2 hours of drug administration. Conversion of AF to sinus rhythm was achieved within 2 hours in 29 of 40 patients (73%) treated with PLS, and in 18 of 32 patients (56%) treated with DISO (NS). The mean time to return of sinus rhythm was 60 +/- 30 minutes in the PLS group versus 23 +/- 18 minutes in the DISO group (P < 0.001). DISO was particularly effective in terminating nocturnal AF, whereas PLS had a stable circadian effect. PLS was significantly more effective than DISO between 6 AM and 12 PM (64% vs 17%, P < 0.05). No adverse effect was observed in either group. In conclusion, a single oral dose of PLS was as effective as an infusion of DISO to restore sinus rhythm in patients with recent-onset AF. PLS consistently terminated AF regardless of its time of onset.

Administration, Oral↗
PubMed1976

Polymorphism of disopyramide.

Two crystal forms of disopyramide have been characterized using X-ray diffraction, differential scanning calorimetry and infrared spectroscopy. The kinetics of the solid state transformation of Form I to Form II has been analysed using the Prout-Tompkins theory. An activation energy of 144 kJ mol-1 is calculated for the system. Dissolution and plasma concentrations show no significant differences in bioavailability between the two polymorphs.

Biological Availability↗
PubMed1985

Influence of serum protein binding on hepatic clearance of S-disopyramide in the rabbit.

The effect of changing the protein binding of S-disopyramide, a compound that is highly extracted by the liver on its hepatic clearance in rabbits is described. Using indocyanine green clearance as a means of measuring hepatic blood flow, qualitative changes were observed which are in agreement with the results predicted by both the 'parallel tube' and the 'well-stirred' models. However, neither model alone could explain the quantitative changes. Suggestions are put forward to explain these results.

Animals↗