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L B Sheiner

Publications and source records attributed to L B Sheiner.

144 records · Page 8Linked to original sources
PubMed1976

Relationship between the pharmacokinetics and pharmacodynamics of procainamide.

The kinetics of a measure of pharmcologic effect (prolongation of the QT interval) of procainamide, as well as the kinetics of the plasma concentration, urine excretion, and saliva concentration of the drug were investigated in 14 trials in 4 subjects. A single 500-mg dose was given by rapid intravenous infusion, and frequent subsequent determinations of the above variables were made. A 2-compartment pharmacokinetic model with a third compartment for the saliva was used to fit the plasma, urine, and saliva data simultaneously. Analysis of the data reveals that the kinetics of the drug concentrations in saliva and of the pharmacologic effect are indistinguishable. They both must be considered to be different from those of the drug concentrations in plasma. Thus, in normal individuals under the conditions of this study, saliva concentrations more precisely indicate the time-course of drug at a cardiac site of action, although they do not parallel plasma drug concentrations until 6 hr or more after a rapid intravenous infusion. The following average pharmacokinetic parameters for plasma were found: terminal half-life, 2.9 hr; total clearance, 828 ml/min; renal clearance, 334 ml/min; and steady-state volume of distribution, 180 L. Average distribution pseudoequilbrium half-time (t1/2 alpha) was 5.2 min from an initial volume of distribution of 36.6 L.

Electrocardiography↗
PubMed1975

Determinants of the renal clearance of digoxin.

The renal clearances of digoxin, creatinine, and urea nitrogen were determined simultaneously in each of 41 patients receiving digoxin, in most of whom there was prerenal azotemia. Mean plus or minus SD values were: blood urea nitrogen (BUN), 26.1 plus or minus 12.8 mg per 100 ml; creatine, 1.1 + 0.41 mg per 100 ml; creatinine clearance, 78 plus or minus 42 ml/min/1.73 m2; digoxin clearance, 66.6 plus or minus 42.1 ml/min/1.73 m2; urea nitrogen clearance, 27.8 plus or minus 19.2 ml/min/1.73 m2. Correlation analysis revealed that urea clearance is superior to creatinine clearance, and BUN is superior to serum creatinine concentration in the degree of relationship to renal digoxin clearance. Moreover, using partial correlation techniques, it is apparent that in these patinets digoxin clearance was significantly related to urine flow rate. These findings are compatible with the hypothesis that digoxin undergoes some degree of tubular reabsorption as well as filtration and secretion.

Adult↗
PubMed1975

Improved computer-assisted digoxin therapy. A method using feedback of measured serum digoxin concentrations.

Automated feedback control methods were applied to a medical problem, in a computer program that used measured serum digoxin concentrations (as feedback) to predict future concentrations and to achieve desired concentrations. The system was validated by comparing its ability with the corresponding ability of physicians to regulate digoxin dosage. The prospective, randomized study included 51 patients. In the presence of varying amounts of feedback (serum digoxin concentration) information, the computer always predicted future digoxin concentrations as accurately as did physicians. For both computer and physician, the decrease in the prediction errors when two concentrations were known against that when no concentrations were known was significant: mean absolute error decreased from 0.40 to 0.25 ng/ml for the physicians and from 0.45 to 0.27 ng/ml for the computer. Thus the computer system is capable of simulating and reproducing a sophisticated aspect of physician behavior: "learning" about individual patient responses. The computer achieved desired concentrations more accurately than did physicians, especially when two or more previous digoxin concentrations were abailable (mean absolute achievement error for computer, 0.28 ng/ml; for physicians, 0.50 ng/ml).

Achievement↗
PubMed1973

Pharmacokinetics of digoxin: interpreting bioavailability.

Three subjects were first given a digoxin tablet in the fasting state and subsequently received the same formulation in the fed state, to simulate a spurious oral bioavailability difference. As expected, when measured by peak serum digoxin concentration as well as by area under the serum digoxin concentration-time curve the bioavailability of digoxin appeared to be higher in the fasting state than in the fed state. However, when measured by cumulative five-day urinary excretion of digoxin bioavailability was identical in both conditions.This simple experiment illustrates the fact that the estimation of bioavailability is subject to considerable methodological error, of which the clinician must be aware when evaluating reports on drug bioavailability in general and of digoxin in particular.

Administration, Oral↗
PubMedDate not supplied

Steady-state pharmacokinetics of phenytoin from routinely collected patient data.

Previously reported routine phenytoin clinical pharmacokinetic data from Japan, England, and Germany were analysed to estimate population pharmacokinetic parameters. There were 780 steady-state phenytoin concentrations and associated dosage rates (mg/day) from 322 patients. The patient group spanned paediatric and adult ages, mean age being 18.4 +/- 17.3 (SD) years; 53% were males. The data were analysed using NONMEM, a computer programme designed for population pharmacokinetic analysis. Estimates of the influence of age, gender, data source, height and weight on the maximum elimination rate (Vm) and Michaelis-Menten constant (Km) were obtained. The Vm and Km of a 70 kg adult male European were estimated to be 415 mg/day and 5.7 mg/L, respectively. Vm is not influenced by gender, age or data source. The parameters of a power function of height and weight were estimated to adjust Vm for body size. The best function adjusts Vm in proportion to weight to the 0.6 power; height contains no useful information. Km is not influenced by gender. The Km for patients less than 15 years old is 43% less than that of older patients. The Km of Japanese patients appears to be 23% less than that for European patients. Even after adjustments for age, etc., apparent Vm and Km vary unpredictably among individuals with a coefficient of variation between 10 to 20% and approximately 50% respectively.

Adolescent↗
PubMedDate not supplied

Population pharmacokinetics of procainamide from routine clinical data.

Routine clinical pharmacokinetic data collected from patients receiving procainamide were analysed to estimate population pharmacokinetic parameters. 116 plasma concentration determinations for procainamide and 14 timed urine collections for the drug and its major metabolite N-acetylprocainamide (NAPA) were obtained from 39 patients, mostly males. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data from many individuals. Estimates of the influence of weight, height, renal function, and the presence of congestive heart failure (CHF) on the renal clearance (CLR), acetylation clearance (CLA), miscellaneous metabolic clearance (CLO), and volume of distribution (Vd) of procainamide were obtained. The mean (SE) CLR, CLA, CLO and Vd for procainamide in a 70kg patient with normal renal function were estimated to be 14.4 (2.3) L/h, 10.1 (1.7) L/h, 1.2 (1.3) L/h, and 136.0 (20.0) L, respectively. These pharmacokinetic parameters vary linearly with bodyweight; height adds no information if weight is known. The presence of CHF has no significant effect on either CLO or Vd, but reduces CLA and CLR by 11% (p less than 0.01). Even after adjustments for CHF, renal function and weight, the total clearance and Vd of procainamide vary unpredictably among individuals, with a coefficient of variation between 30 and 40%, and less than 50%, respectively.

Arrhythmias, Cardiac↗