Population pharmacokinetics of intravenous amiodarone in patients with refractory ventricular tachycardia/fibrillation.

A population approach was used to determine the pharmacokinetics of amiodarone in 245 patients receiving intravenous amiodarone for the short-term treatment of refractory, hemodynamically destabilizing, ventricular tachycardia and/or fibrillation. A two-compartment model employing proportional statistical models to estimate intersubject variability and an additive-proportional model to estimate residual error were found to best describe the data. The mean (% coefficient of variation, CV) value for clearance was 0.22 L/hr/kg (13%), central volume of distribution was 0.30 L/kg (11%), peripheral volume of distribution was 10.0 L/kg (9.5%), and intercompartmental clearance was 0.71 L/hr/kg (16%). The mean (%CV) intersubject variance estimates were 1.52 (31%) for clearance, 0.37 (46%) for central volume, 0.37 (67%) for peripheral volume, and 0.44 (39%) for intercompartmental clearance. The estimate of residual error (%CV) was 0.53 (13%). Age, gender, height, serum creatinine concentration, serum alkaline phosphatase activity, ejection fraction, and therapeutic response to treatment did not contribute to the variability in patient pharmacokinetics. It was concluded that the pharmacokinetic parameters of amiodarone in these patients were similar to those reported for healthy volunteers and were similarly variable. Estimates of pharmacokinetic parameters made during short periods of observation may not be entirely consistent with parameters estimated during prolonged periods of observation of healthy volunteers who receive single doses.

Antiarrhythmic and pharmacokinetic evaluation of intravenous recainam in patients with frequent ventricular premature complexes and unsustained ventricular tachycardia.

The pharmacokinetics, antiarrhythmic activity and safety of intravenously administered recainam were evaluated in 15 men and 3 women. All patients had frequent (> 30/hour) ventricular premature complexes (VPCs) and unsustained ventricular tachycardia. Recainam was administered at a loading dose of 4.5 mg/kg/hour over 40 minutes, followed by a maintenance infusion of 0.9 mg/kg/hour for 23 hours and 20 minutes. Sixteen patients had satisfactory efficacy data. The mean frequency of total VPCs decreased by 92.6% and the mean frequency of runs decreased by 99.9% during the maintenance infusion. Suppressions of > or = 70% of total VPCs and > or = 90% of runs were maintained over the 23-hour, 20-minute maintenance infusion period in 16 of the 18 patients. During the maintenance infusion, hourly group plasma recainam concentrations ranged from mean +/- SD 2.6 +/- 0.7 to 3.4 +/- 0.9 micrograms/ml. Patients were observed for 24 hours after termination of the infusion. Periodic blood samples were obtained during and after termination of the infusion to determine recainam concentration. Urine specimens were collected over scheduled intervals to determine urinary excretion of recainam. A 2-compartment pharmacokinetic model was used to analyze the data. The following pharmacokinetic parameters were obtained: terminal elimination half-life, 5.0 +/- 0.8 hours; systemic clearance, 0.27 +/- 0.08 liter/hour/kg; and central and steady-state volume of distribution, 0.32 +/- 0.11 and 1.4 +/- 0.4 liter/kg, respectively. Adverse experiences were reported in 4 of the 18 patients, possibly drug-related in 2; none was considered severe or required discontinuation of recainam.(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of isosorbide mononitrate in angina pectoris.

The rapid development of tolerance has limited the applicability of oral and transdermal nitrates in the long-term management of patients with chronic stable angina pectoris. Recent well-controlled trials have demonstrated that asymmetrical, or eccentric, dosing of oral isosorbide mononitrate, in which 20-mg doses are taken at 8 A.M. and 3 P.M., provides at least 12 hours of antianginal coverage. There is no evidence for the development of tolerance with this schedule, which allows for a 17-hour nitrate withdrawal period. Likewise, the asymmetrical 20-mg twice daily regimen has not been associated with the zero-hour effect that has been reported with higher oral doses of isosorbide mononitrate and with intermittent nitroglycerin patch therapy. This approach also avoids the development of a clinical rebound phenomenon, as measured by increased episodes of angina and nitroglycerin consumption, compared with the pretreatment period, during the nitrate-free interval at night and the early hours of the morning.

Effect of CGP 17/582, a selective beta-adrenoceptor antagonist, on the haemodynamic and hypokalaemic response to adrenaline.

1. CGP 17/582B is a new beta-adrenoceptor antagonist which on experimental studies appears to combine selective beta 1-adrenoceptor blockade with partial agonist activity (ISA). Assessing beta-adrenoceptor selectivity and the degree of partial agonist activity in vivo can be difficult. 2. In a double-blind placebo controlled crossover study we have compared the effect of oral pretreatment for 7 days with CGP (100 mg twice daily), with propranolol (non-selective beta-adrenoceptor blocker with no ISA) and metoprolol (selective beta-adrenoceptor blocker with no ISA) on resting heart rate and heart rate response to submaximal exercise on a bicycle ergometer to assess the degree of beta-adrenoceptor blockade and also the changes in blood pressure, heart rate and potassium during the intravenous infusion of (-)-adrenaline to determine the degree of beta 2-adrenoceptor blockade. 3. Subjects underwent submaximal exercise testing on the second and fifth day of each treatment period and on the seventh day received a 2 h infusion of (-)-adrenaline (0.06 microgram kg-1 min-1). Heart rate, blood pressure, plasma potassium and catecholamines were measured throughout the study period. 4. All three active treatments significantly reduced exercise induced tachycardia. The (-)-adrenaline infusion significantly reduced plasma noradrenaline levels following propranolol and metoprolol and to a lesser extent with placebo but were unaltered on CGP. Baseline heart rate was unaltered by CGP but was significantly reduced by metoprolol and propranolol. Adrenaline significantly reduced plasma potassium levels following placebo and CGP pretreatment but plasma potassium was unaltered by adrenaline with metoprolol and propranolol pretreatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in lignocaine disposition during long-term infusion in patients with acute ventricular arrhythmias.

Lignocaine disposition was studied in 30 patients with acute ventricular arrhythmias. Serum concentrations of lignocaine, its metabolites Monoethylglycine xylidide (MEGX) and glycine xylidide (GX), and alpha 1-acid glycoprotein (AAG) were analyzed during and after a 48-h lignocaine infusion. AAG concentrations tended to rise in patients with acute myocardial infarction (AMI), leading to binding of the drug in plasma. Lignocaine clearance was estimated at various times during the infusion using a Bayesian parameter estimation program and was found to decline over the course of the infusion. There was a significant reduction in clearance based on estimates obtained at the end of the infusion compared with estimates obtained during the first 0-5 h. Clearance was reduced both in patients who had an AMI and those who did not. Multiple linear regression analysis of the clearance data revealed that these changes could be described by a linear function of time and AAG concentration. These findings suggest that other factors in addition to protein binding changes may influence lignocaine disposition during long-term infusion.

The prophylactic use of phenytoin during iopamidol contrast studies of the subarachnoid space.

Contrast examinations of the subarachnoid space are associated with side effects including convulsions. Attention has been given to the prophylactic use of anticonvulsants. We describe a simple oral regimen using the established anticonvulsant phenytoin that can be administered to short-stay patients and that achieves effective serum and CSF concentrations. A preliminary account of this work was presented to the British Pharmacological Society in January 1984 in London.

Electrophysiological effects of felodipine in combination with metoprolol.

The combined use of some beta-adrenoceptor blocking agents with calcium channel blockers may cause adverse pharmacodynamic drug interactions: hypotension, heart block or even asystole may be precipitated. The electrophysiological effects of combined administration of intravenous metoprolol 10mg and the vasodilating calcium antagonist felodipine (0.1 mg/kg/bodyweight) were assessed in an open study by invasive methods. Following metoprolol, the heart rate was reduced from 69 +/- 24 to 60 +/- 16 beats/min (mean +/- SD, p less than 0.05) with a minor prolongation of the sinus node recovery time. The A-H interval was increased from 94 +/- 25 to 109 +/- 16 msec (p less than 0.005) and the H-V interval was unchanged. The effective refractory period of the atrioventricular node was prolonged from 327 +/- 54 to 361 +/- 62 msec (p less than 0.01) with a minor prolongation of the effective refractory period of the ventricular Purkinje fibres. Systolic and diastolic blood pressures showed a mean reduction of 11 (p less than 0.001) and 6mm Hg (p less than 0.05), respectively. Following felodipine, the changes in heart rate and effective refractory periods of the atrioventricular node and ventricular Purkinje fibres returned towards control values. No further prolongation of the A-H interval resulted and further blood pressure changes were minor. The absence of adverse haemodynamic or electrophysiological effects suggests that this combination of agents may be safely used.

Is erythrocyte membrane phospholipid organisation abnormal in Duchenne muscular dystrophy?

Many of the abnormalities reported in erythrocytes from Duchenne muscular dystrophy (DMD) patients, including alterations in the physical state of the membrane as determined by electron spin resonance, could arise from changes in the lipid components. Although several investigators have shown there to be no compositional differences between normal and DMD erythrocytes, there still exists the hitherto unexplored possibility that the normal asymmetric organisation of the lipids may be deranged in the disease. This report is concerned with the probing of the asymmetric transbilayer distribution of the glycerophospholipids using phospholipase A2 from bee venom. Our results suggest that more phosphatidyl choline (PC) is available for attack by the enzyme in the outer leaflet of the bilayer in DMD erythrocytes than in normals. This may be due to a greater than normal proportion of the PC being present in the outer leaflet or to enhanced transbilayer movement of PC molecules from the inner leaflet. Whichever the explanation, these findings indicate an organisational abnormality in DMD erythrocyte membranes.

Superoxide dismutase, glutathione peroxidase and thiobarbituric acid-reactive compounds in erythrocytes in Duchenne muscular dystrophy.

The activities of erythrocyte superoxide dismutase and glutathione peroxidase in patients with Duchenne muscular dystrophy were normal compared with healthy male controls, as were the levels of thiobarbituric acid-reactive compounds produced during incubation of erythrocytes in the presence of 10 mmol.1-1 hydrogen peroxide. These results suggest that the chief mechanisms for protecting the erythrocyte membrane from peroxidative damage are unimpaired and do not support the idea that the reported erythrocyte abnormalities in this disease result from increased susceptibility to lipid peroxidation.