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Biomedical subjects

A J Atkinson

Publications and source records attributed to A J Atkinson.

At least 73 records · Page 4Linked to original sources
PubMed1979

N-Acetylprocainamide pharmacokinetics in functionally anephric patients before and after perturbation by hemodialysis.

NAPA pharmacokinetics were studied in 6 functionally anephric patients. Distribution and nonrenal elimination of this drug were found to be the same as in individuals with normal renal function but renal clearance was reduced, resulting in a mean elimination t 1/2 of 41.9 hr (6.2 hr in normal subjects). Renal clearance of NAPA correlated well with ClCr. Dialysis removed NAPA from both red blood cells and plasma and increased ClT approximately fourfold. Dialysis itself resulted in a 77% reduction in ClS that limited the total amount of NAPA removed by this procedure. This reduction in ClS was sustained for at least 3 hr after dialysis and attenuated rebound in plasma NAPA concentrations.

Acecainide↗
PubMed1978

Amphotericin B pharmacokinetics in humans.

The pharmacokinetics of amphotericin B were studied in two patients at the conclusion of long-term therapy for disseminated histoplasmosis. The distribution kinetics of this drug were adequately described by a three-compartment mamillary model with a total distribution volume averaging 4 liters/kg. The elimination phase half-life of amphotericin B was approximately 15 days, reflecting slow release of amphotericin B from a peripheral compartment. In accordance with previous reports, renal excretion accounted for only 3% of total amphotericin B elimination. The pharmacokinetic model for one of the patients also was used to compare the simulated amphotericin B serum levels that would be expected if initial therapy followed two recommended regimens.

Aged↗
PubMed1978

Hemoperfusion removal of digoxin from dogs.

Removal of digoxin by XAD-4 hemoperfusion columns was tested after four dogs were given 0.06 mg/kg of digoxin i.v. Dogs were perfused for 4 to 5 hr at a flow of 105 ml/min through a 100 gm XAD-4 column 16 hr after the dose. Pharmacokinetic analysis of digoxin levels was performed with a three-compartment model. The apparent postdistribution t1/2 was 16.0 +/- 2.9 (S.D.) hr and decreased to 7.1 +/- 2.1 hr during perfusion. Digoxin perfusion clearance was 46 ml/min. An average of 51 microgram of digoxin was recovered from used columns. CP of digoxin calculated from the total R was 127.5 +/- 13 ml/min or 2.3 times greater than plasma flow. With the use of 3H-digoxin, canine blood was found to contain 2.5 times as much digoxin as did plasma. After perfusion there was an increase in serum digoxin levels in all dogs. Computer analysis showed that the increase in plasma digoxin levels immediately after hemoperfusion occurred because the central compartment, which was depleted of digoxin during hemoperfusion, was refilled from peripheral compartments. This study demonstrated that (1) XAD-4 hemoperfusion doubles the rate of removal of digoxin from dogs, (2) dog whole blood contains more than twice as much digoxin than does plasma, so that hemoperfusion clearance exceeds plasma flow, and (3) a multicompartmental pharmacokinetic model explains the increase in serum digoxin concentrations observed at the completion of hemoperfusion.

Animals↗
PubMed1977

Dose-ranging trial of N-acetylprocainamide in patients with premature ventricular contractions.

Ten patients with chronic premature ventricular contractions (PVCs) received short-term oral therapy with N-acetylprocainamide (NAPA) to determine its antiarrhythmic efficacy and side effects under the conditions of a placebo-controlled, dose-ranging trial. NAPA was effective in suppressing PVCs in 8 patients but caused a paradoxical increase in PVC frequency in one. Results were equivocal in the remaining patient because PVCs did not recur when NAPA therapy was withdrawn. Mean NAPA plasma levels as high as 41.1 microng/ml did not have untoward hypotensive or myocardial depressant effects, as judged by electrocardiographic and systolic time intervals. There was, in fact, a consistent reduction in PEP/LVET ratio, indicating that NAPA increases the force of myocardial contraction. The mean NAPA elimination half-life of 10.9 hr was longer than the 6.2 hr half-life reported for normal subjects, but its prolongation was predictably correlated with reductions in creatinine clearance. Gastrointestinal side effects experienced by 3 patients and insomnia noted by 2 patients are similar to known adverse reactions to procainamide.

Aged↗
PubMed1977

Procainamide and N-acetylprocainamide kinetics investigated simultaneously with stable isotope methodology.

The pharmacokinetics of procainamide (PA) and N-acetylprocainamide (NAPA) were compared in 3 normal subjects after simultaneous intraveous injection of PA and NAPA-13C. The distribution kinetics of both compounds were modeled with a 3-compartment mamillary system, and it was found that their steady-state distribution volumes were not significantly different, averaging 1.41 L/kg for PA and 1.46 L/kg for NAPA. However, the intercompartmental clearances of NAPA were slower than those of PA. In these normal subjects, the average elimination t1/2 and total elimination clearance for PA were 2.5 hr and 589.8 ml/min, and for NAPA were 6.2 hr and 233.7 ml/min. Mean renal clearances of PA (346.7 ml/min) and of NAPA (199.5 ml/min) exceeded the usual rate of glomerular filtration, which suggests that both compounds are eliminated in part by renal tubular secretion. All subjects were phenotypic rapid acetylators of isoniazid and converted approximately one fourth of the administered PA dose to NAPA-12C. The fate of 15.4% of the administered PA and 14.5% of the administered NAPA-13C was not determined.

Acetylation↗
PubMed1977

Kinetics of procainamide and N-acetylprocainamide in renal failure.

Four normal subjects and four functionally anephric patients were given 6.5 mg/kg of body wt of procainamide hydrochloride i.v., and plasma concentrations of procainamide (PA) and its major active metabolite N-acetylprocainamide (NAPA) were measured. Two individuals in each group were fast isonicotinic acid hydrazide (INH) and PA acetylators. The pharmacokinetics of PA and NAPA were analyzed with a computer program (SAAM 23). Volume of distribution (Vdss) and renal clearance of PA were similar in normal subjects regardless of acetylator phenotype. Nonrenal clearance was faster (383 vs. 244 ml/min), and PA elimination half-life (t 1/2) was shorter (2.6 vs. 3.5 hr) in fast acetylators. In the functionally anephric patients, Vdss was similar to that of normal subjects. Nonrenal clearence was faster (117.5 vs. 93.5 ml/min) and PA t 1/2 shorter (10.8 vs. 17.0 hr) in fast than in slow acetylators. In these patients, acetylation accounted for 56% of PA elimination, and NAPA concentrations reached 0.8 microgram/ml or more. The t 1/2 of NAPA in renal failure was 41.5 hr, in accord with predictions from studies in normal subjects, assuming no impairment in nonrenal NAPA elimination. PA metabolism, however, is severely impaired by renal failure, so PA t 1/2 was prolonged to an unpredictably greater extent than would be expected from studies in normal subjects.

Adult↗
PubMed1976

Antiarrhythmic efficacy of N-acetylprocainamide in patients with premature ventricular contractions.

Oral administration of a 1.5-gm dose of N-acetylprocainamide (NAPA) to 9 patients with premature ventricular contractions (PVCs) confirmed previous indirect evidence that this metabolite of procainamide has antiarrhythmic efficacy and potency comparable to those of procainamide. Although the mechanism by which NAPA acts as an antiarrhythmic drug is not known, it was found that the 6 patients with coupled PVCs responded to NAPA therapy and that the 3 patients without coupled PVCs failed to respond. Coupling interval prolongation also occurred during NAPA therapy in 4 of the 6 responding patients. These observations suggest that NAPA may terminate coupled PVCs by slowing and then interrupting conduction of re-entrant impulses, as has been proposed for procainamide. NAPA plasma concentrations of 7.4-17.2 mug/ml were well tolerated by the patients and produced an average fall of 3 mm Hg in mean arterial pressure and a 7.6% mean increase in corrected QT interval.

Aged↗
PubMed1976

Hemodialysis for severe procainamide toxicity: clinical and pharmacokinetic observations.

A 67-yr-old woman who ingested approximately 7 gm procainamide developed severe hypotension, renal insufficiency, and life-threatening cardiac toxicity. Hemodialysis doubled the rate of procainamide elimination and increased fourfold the clearance of NAPA, the N-acetylated metabolite of procainamide. Observations of procainamide and N-acetylprocainamide (NAPA) plasma levels during the patient's recovery suggest that lethargy and profound hypotension can be expected when these levels total 60 mug/ml and that severe cardiac toxicity should be anticipated with levels totaling 42 mug/ml or more. Hemodialysis also permitted investigation of the effects of hypotension on the pharmacokinetics of these compounds. The apparent volume of procainamide distribution was reduced from a normal value of 2 L/kg to 0.76 L/kg, and that of NAPA from 1.4 L/kg to 0.63 L/kg. The elimination + 1/2 of procainamide was prolonged from the normal of 3 hr to 10.5 hr, and that of NAPA from 6 to 35.9 hr. Procainamide absorption was also slowed in this clinical setting, causing procainamide plasma levels to continue rising for some time after toxicity was first recognized.

Acetylation↗
PubMed1975

Antiarrhythmic potency of N-acetylprocainamide.

Compared to procainamide in an animal arrhythmic model, the antiarrhythmic potency of the N-acetylated metabolite of procainamide (NAPA) was 92% with respect to dose and 70% with respect to plasma level. The antiarrhythmic effects of combinations of the drugs were additive. Measurements of procainamide and NAPA plasma levels needed to suppress ventricular extrasystoles suggested that both compounds are nearly equipotent in patients as well. The average plasma level required for arrhythmia control in these patients was equivalent to 5.1 mcg/ml procainamide. Since patients on long-term procainamide therapy have plasma concentrations of NAPA that are usually comparable to, and occasionally greater than, their procainamide levels, dose regiments based on procainamide levels alone need revision to include consideration of the levels of this metabolite.

Animals↗
PubMed1975

Pharmacological activity, metabolism, and pharmacokinetics of glycinexylidide.

Glycinexylidide (GX) is a metabolite of lidocaine that is frequently present in mug/ml concentrations in the plasma of patients treated with lidocaine infusions for 24 hr or more. Plasma levels of GX have 26% the antiarrhythmic activity of lidocaine in an animal model, and GX adversely affects the mental performance of normal subjects at plasma concentrations comparable to those found in patients. The total volume of GX distribution in man is similar to that of lidocaine but the plasma clearance is less, so that the 10-hr elimination phase half-life of GX is much longer than the 1 1/2 hr half-life reported in normal subjects for lidocaine. About half of an administered dose of GX is excreted unchanged in urine, roughly 15% appears in urine as conjugates of xylidine and p-OH xylidine, and the fate of the rest is unknown.

Animals↗