A placebo-controlled study to determine the efficacy of oral disopyramide phosphate for the prophylaxis of ventricular dysrhythmias after acute myocardial infarction.

1 To evaluate oral disopyramide phosphate in the prophylaxis of dysrhythmias occurring in acute myocardial infarction (MI) patients (presenting within 12 h of symptoms, age 21-70 years), a placebo-controlled, randomized double-blind, in hospital trial was conducted. After prognostic stratification (anterior and non-anterior MI at each of 4 regional hospitals) patients were randomly assigned to receive oral disopyramide phosphate (loading dose 150, 200, or 300 mg followed 6 h later by 100, 150, or 200 mg every 6 h for patients assessed to weigh less than 55, 55-85, or greater than 85 kg, respectively or matching placebo. The primary exclusion criteria were overt heart failure, systolic BP less than 100 mmHg, significant heart block or history of urinary retention. Active drug or placebo was continued for 7 days or until (a) detection of "warning arrhythmias' requiring i.v. lignocaine intervention (greater than 5 for 7 days or until (a) detection of "warning arrhythmias' requiring i.v. lignocaine intervention (greater than 5 premature ventricular contractions (PVCs)/min, R on T PVCs, multifocal PVCs, bigeminal PVCs, ventricular tachycardia or ventricular fibrillation) or (b) onset of exclusion criteria. In addition, plasma drug concentrations were determined and 24 h electrocardiographic tapes were obtained on day 1, and on one of days 4-7 but these results are not presented here. 2 Out of 121 patients entering the trial, 101 had confirmatory ECG and enzyme changes. Of these, 9 of 47 patients receiving disopyramide phosphate required lignocaine compared to 20 of 54 receiving placebo (19% v 37%; P = 0.047). Corresponding numbers for patients discontinuing trial medication for other non-fatal complications of MI were 5 and 3, and for those dying, were 3 (2 infarct extensions and 1 massive infarction), and 0, respectively. Respective numbers discontinuing trial medication for possible drug side effects (viz. urinary retention requiring catheterization) were 6 and 1 (P = 0.031). 3 In circumstances where i.v. therapy is deemed impractical, use of oral disopyramide phosphate given prophylactically in patients with acute MI may reduce the incidence of "warning arrhythmias' by a clinically significant extent.     

The acute changes in serum binding of disopyramide and flecainide after myocardial infarction

Summary In the serum basic drugs are principally bound to alpha₁-acid glycoprotein (AAG). Following acute myocardial infarction it has been shown that the levels of AAG rise. The serum levels of total protein, albumin, AAG and the protein binding of 2 antiarrhythmic drugs which are bases, disopyramide and flecainide, was measured in vitro with blood samples from eleven patients taken over the first 5 days following myocardial infarction. Mean AAG levels significantly increased from 1.04 g/l on Day 1 to 1.80 g/l on Day 5. The binding of disopyramide, which is highly bound, rose from 80% to 87%, representing a 35% decrease in free drug concentration. In contrast the binding of flecainide fell from 61% to 53%, a 20% increase in free drug concentration. These data suggest that although the binding of strongly bound drugs responds appropriately to increases in binding protein after acute myocardial infarction, poorly bound drugs are displaced from binding sites possibly by endogenous substances. Since the pharmacological effects of a drug are related to its free (unbound) concentration, the changes in the proportions of free to bound drug after myocardial infarction may have important clinical implications.     

Prolonged variability in plasma protein binding of disopyramide after acute myocardial infarction.

1 Disopyramide plasma binding was determined in vitro in plasma from 20 patients with acute myocardial infarction (aged 35-79 years) and in 20 age and sex matched healthy subjects. Plasma samples were collected on days 1, 5 and 12 after infarction and when the patient returned to the outpatient clinic. 2 In healthy subjects there was a significant negative correlation between disopyramide free fraction and plasma alpha 1-acid glycoprotein (AAG) concentration. A similar correlation was observed in the patients with myocardial infarction, however this correlation was dependent on time elapsed after infarction. Disopyramide free fraction did not correlate with albumin concentration in either group. 3 Mean plasma AAG concentrations were increased by 63% within 5 days after infarction and had returned to initial levels some months later (73.5 +/- 7.8 days). On each of the four sampling days, a two to four fold individual variability in plasma AAG concentrations was observed. 4 Maximum increases in disopyramide plasma binding were shown on days 5 and 12 after infarction. These increases were dependent on both drug and AAG concentrations. Increases in fraction bound were greater at the higher drug concentrations. Within the usual therapeutic plasma range for disopyramide (2 to 5 mg/l), the mean increases in fraction bound, compared to day 1 data, varied from 22 to 45% respectively. 5 Sequential alteration in AAG concentration after infarction indicates that disopyramide plasma binding may not reach a steady state until some months after infarction. Prediction of the time to achieve this steady state would be difficult due to inter- and intra-patient variability in binding.     

Serum phosphate in acute myocardial infarction

The aim of this study is to measure phosphate levels in AMI, compare and analyse its relation with left ventricular (LV) dysfunction and mortality. Serum phosphate was measured by kinetic assay method in 40 patients with acute myocardial infarction (AMI). Echocardiographic LV function was assessed in all and the patients were followed up for 30 days. Hypophosphatemia (< 2.5 mg/dl) was observed in 27% of AMI patients (11/40). These patients formed group 1 of our study. The rest 73% patients (29/40) with normal phosphate levels formed group 2. Mean Phosphate level in group 1 was 1.96 mg/dl (range 1.2-2.37) and mean ejection fraction (EF) was .35 (range .25-.50, p value < .001). Mean phosphate in group 2 was 3.693 (range 2.6-6.00) and mean EF was .53 (range .38-.65, p value < .001). In hospital mortality of the group 1 was 28% (3/11) while in group 2 was 6.8% (2/29). We conclude hypophosphatemia in AMI is associated with LV dysfunction which results in increased 30 day mortality.     

Intravenous disopyramide in acute myocardial infarction: a haemodynamic and pharmacokinetic study

We studied the haemodynamic and pharmacokinetic effects of intravenous disopyramide phosphate in 12 patients (average age, 59 years) with proven transmural myocardial infarction, whose symptoms began less than 12 h prior to the study. The aim was to assess the effects of intravenous disopyramide (2 mg/kg given over 5 min) on cardiac index (CI), left ventricular filling pressure (LVFP), heart rate (HR), mean systemic arterial blood pressure (BP), and systemic vascular resistance (SVR) for 60 min after administration of the drug. Both total and free concentrations of disopyramide in the plasma were also measured. A significant elevation (p less than 0.01) of LVFP (estimated indirectly as pulmonary artery end-diastolic pressure) occurred and persisted through the 1-h evaluation period. There was a small but significant (p = 0.02) initial fall in CI and a rise in SVR (p = 0.05). No significant changes occurred in HR or BP. Serum concentrations of disopyramide reached recommended therapeutic concentrations. There was no significant correlation of the changes in cardiac variables from pretreatment values with total serum concentrations, but the free concentration of disopyramide in plasma correlated better with cardiac effect, and the relationships of the free concentration of disopyramide to the changes in LVFP and in SVR from pretreatment values were significant (p less than 0.05). In two patients studied in detail, there was evidence of dose-dependent protein binding of disopyramide.     

Absorption,half-life,and toxicity of oral aprindine in patients with acute myocardial infarction

Summary Plasma concentrations of aprindine were used to assess its absorption, toxicity and disappearance rate after oral administration to patients within 24 hours of admission to a coronary care unit. Despite high oral doses, absorption was so slow that in half the patients effective plasma levels (exceeding 0.70 µg/ml) were not found during the first 12 hours of treatment. Therefore the oral route should not be used to treat cases of acute myocardial infarction with severe ventricular dysrhythmias. Clinical tolerance was good; there was one episode of delirium tremens in a chronic alcoholic (aprindine plasma concentration: 3 µg/ml); no case of tremor or cerebellar syndrome was observed. Disappearance of aprindine from plasma was slow, by far exceeding the half-lives found in healthy volunteers, and ranging from 20 to over 100 h. The variability of biological half-life in individual patients makes plasma level determinations necessary whenever aprindine is to be administered for a long period.     

Kinetics of disopyramide after intravenous infusion to patients with myocardial infarction and heart failure

Total body clearance, half-life and volume of distribution of disopyramide (Norpace, Searle G.D.) was measured during a six to eight hour infusion to steady state in twenty four patients with either congestive heart failure or acute myocardial infarction and compared to eleven patients without these diseases. All patients were given a bolus injection of 150 mg disopyramide followed by a continuous infusion of 18-24 mg per hour. Serum concentration of disopyramide and its main dealkylated metabolite were determined by HPLC. The clearance in patients without myocardial infarction or congestive heart failure was 1.71 +/- 0.60 ml/min./kg (mean +/- S.D.), not significantly different from those who had either myocardial infarction, congestive heart failure or both. Half-life was 798 min. in patients without heart failure, not significantly different from the values in the other groups. The ratio between disopyramide and its metabolite varied between 3 to 10. Twenty-six % of the steady state serum concentrations of disopyramide were outside the recommended therapeutic range (2-5 micrograms/ml), but no adverse haemodynamic effects were observed in any of the patients. The suggested dosage regimen of disopyramide seems to result in a satisfactory response.     

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.     

Comparative haemodynamic effects of intravenous lignocaine, disopyramide and flecainide in uncomplicated acute myocardial infarction.

A prospective study evaluated the comparative haemodynamic effects of three Class I antiarrhythmics (lignocaine Class 1B, disopyramide Class 1A and flecainide Class 1C) in 30 patients with uncomplicated acute myocardial infarction. Three groups, each of 10 patients, were allocated to lignocaine (Group I) 1.5 mg kg-1 i.v. loading dose over 10 min followed by infusion at 3 mg kg-1 h-1, disopyramide (Group II) or flecainide (Group III), both administered as a 1.0 mg kg-1 i.v. loading bolus over 10 min followed by a 1.6 mg kg-1 h-1 infusion for 120 min. The plasma levels of each drug were in the described therapeutic range. Lignocaine decreased cardiac index (-0.3 l min-1 m-2 (9%); P less than 0.05) and stroke volume index (-5 ml m-2 (11%); P less than 0.01). Systemic blood pressure, heart rate and systemic vascular resistance index were unchanged. There was a small increase (+3 mm Hg (30%); P less than 0.01) in pulmonary artery occluded pressure (PAOP). Both disopyramide and flecainide increased systemic blood pressure; the maximum increases for mean blood pressure were +10 mm Hg (11%) and +4 mm Hg (4%) respectively. Both drugs reduced cardiac index (-0.5 l min-1 m-2 (16%): -0.4 l min-1 m-2 (11%)) and stroke volume index (-11 ml m-2 (25%): -5 ml m-2 (11%)). There were increases in heart rate (+13: +5 beats min-1) pulmonary artery occluded pressure (+2: +3 mm Hg) and systemic vascular resistance index (+696: +275 dyn s cm-5 m2).(ABSTRACT TRUNCATED AT 250 WORDS)     

Prophylaxis against ventricular arrhythmias in suspected acute myocardial infarction: a comparison of tocainide and disopyramide.

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)     

A trial of intravenous and oral mexiletine in acute myocardial infarction

Summary Intravenous and oral mexiletine prophylaxis was compared with lignocaine supplemented placebo in a single blind trial in 240 high-risk patients with acute myocardial infarction. Although atrial fibrillation, supraventricular tachycardia and ventricular extrasystoles occurred less frequently in the mexiletine treated patients, ventricular tachycardia and primary ventricular fibrillation were not prevented. Mortality at 6 weeks was less in the mexiletine group (19%) than placebo (27%) but not significantly so (0.2>p>0.1). An 80% chance of showing a significant difference would require 860 high-risk patients. Low plasma mexiletine levels after 3 h treatment were due to diamorphine and may explain failure to prevent major arrhythmias. Pretreatment with intravenous metoclopramide tended to reverse this effect of diamorphine.     

索拉非尼致高血压并发急性心肌梗死死亡

1例72岁女性患者,既往有高血压史,经治疗血压控制在正常范围内。因肾癌肺转移,口服甲苯磺酸索拉非尼片0.4 g,每天2次。用药2 d后,患者出现头痛,BP 170/120 mm Hg。给予贝那普利及吲达帕胺治疗,血压恢复正常,继续使用索拉非尼治疗,4 d后患者突发下壁心肌梗死,出现心律不齐,室颤。给予升压、扩容、抗凝、气管插管辅助呼吸、除颤等综合抢救治疗,终因病情危重,抢救无效死亡。     

Pharmacokinetics of oral disopyramide phosphate in patients with renal impairment.

1 The pharmacokinetics of disopyramide were studied after the oral administration of a 300 mg dose to 11 patients with stable chronic renal impairment (creatinine clearance 2-53 ml min-1). 2 Absorption half-life and volume of distribution were similar to those seen in normal subjects. 3 Mean plasma elimination half-life in these patients was 12.7 h, which is substantially greater than that reported for normal subjects. Elimination half-life tended to increase as creatinine clearance fell, and renal clearance of disopyramide correlated significantly (r=0.814; P < 0.001) with creatinine clearance. 4 From these results, we have calculated that patients with renal impairment should be started on a dose of disopyramide 1.5 mg kg-1 thrice daily and the regimen subsequently altered according to plasma concentrations of the drug. However, further studies are needed to define the handling of the metabolites of disopyramide.