Dosage-schedule independence of d-tubocurarine pharmacokinetics and pharmacodynamics, and recovery of neuromuscular function.
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Biomedical subjects
Publications and source records attributed to L B Sheiner.
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The percentage of mislabeled specimens detected (true-positive rate) and the percentage of correctly labeled specimens misidentified (false-positive rate) were computed for three previously proposed delta check methods and two linear discriminant functions. The true-positive rate was computed from a set of pairs of specimens, each having one member replaced by a member from another pair chosen at random. The relationship between true-positive and false-positive rates was similar among the delta check methods tested, indicating equal performance for all of them over the range of false-positive rate of interest. At a practical false-positive operating rate of about 5%, delta check methods detect only about 50% of mislabeled specimens; even if the actual mislabeling rate is moderate (e.g., 1%), only abot 10% of specimens flagged a by a delta check will actually have been mislabeled.
Apparent digoxin was measured in the serum of 21 patients receiving spironolactone and in 21 controls, by use of a sequential-saturation 3H-radioimmunoassay (RIA) and an equilibrium 125I-RIA. No patient had been given digoxin for at least four weeks. "Digoxin" values in the former group were significantly (p less than 0.05) higher than in the control group, and often were in or near the "therapeutic" range by the equilibrium 125I-RIA, but not by the sequential-saturation 3H-RIA. Canrenone (a major active metabolite of spironolactone) in the serum of the former group was measured by a newly developed liquid-chromatographic technique and correlated (r = 0.73) with "digoxin" concentrations by the 125I-RIA. However, external addition of canrenone to control serum in comparable concentrations did not cause appreciable "digoxin" values by the 125I-RIA. These findings suggest that other metabolites of spironolactone are responsible for the assay interference, the degree of which appears to depend on antibody specificity. Therefore, assay specificity should be established in clinical laboratories by using digoxin-free serum from patients ingesting spironolactone, and not by using spironolactone- or canrenone-fortified digoxin-free serum.
Three patients demonstrated twofold to threefold changes in total-body theophylline clearance during the course of a single hospitalization for an acute illness. These changes paralleled the changes in the patients' clinical status. Theophylline clearance decreased in one patient with worsening airway obstruction, whereas clearance increased in one patient with resolving pneumonia and in one patient with improving congestive heart failure. Total-body theophylline clearance may be unstable in acute, severe illness. Close monitoring of plasma theophylline concentration in such situations will allow appropriate dose adjustments to be made and is, therefore, indicated.
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To define conditions under which saliva lithium carbonate concentrations can be used as a guide in lithium therapy, serum (Cp) and saliva (Cs) concentrations were determined simultaneously under different circumstances in 12 patients receiving lithium, and the effect of seven variables for example, (sex, saliva flow rate) on the Cp:Cs ratio was examined. The average ratio was 0.57 if saliva was collected in the morning before breakfast and 0.45 otherwise. The Cp:Cs ratio was found to vary much more between individuals than within an individual. We propose a method that minimizes the effect of the interindividual variation on the error in the prediction of Cp from Cs by using one or two measured Cp:Cs ratios to adjust the individual ratio. Using this technique the Cs may be useful as a predictor of the Cp in monitoring lithium therapy.
Theophylline disposition (clearance, volume of distribution, and half-life) was measured in 31 normal volunteers and 26 acutely ill patients with airway obstruction within 24 hours of hospital admission and again when intravenous aminophylline was discontinued 2 to 10 days later. Sex, age, race, the diagnosis of asthma, and the diagnosis of chronic bronchitis were not significantly correlated with clearance. Clearance was significantly increased in smokers and significantly decreased in patients with congestive heart failure, pneumonia, and severe bronchial obstruction. The volume of distribution was not correlated with these variables. Within 24 hours of admission, the mean clearance in our patients without congestive heart failure or pneumonia was 44.5 ml per hour per kg of body weight, 40 per cent less than the value on which the widely used 0.9 mg per kg per hour dosage is based. The unexplained interindividual variability of clearance was significantly higher amont patients than control subjects, but intraindividual variability in clearance was not different in these 2 groups after correction for the effects of smoking, congestive heart failure, and so on. Large variability in clearance among patients makes the plasma theophylline concentration resulting from any dosage relatively uncertain. Based on the the results of this study, recommendations are made concerning theophylline dosage computation, and the clinical circumstances calling for determination of plasma theophylline concentrations.
Follow-up tests ordered on 258 consecutively examined inpatients with low hemoglobin values on admission were analyzed. The appropriateness of the follow-up tests was evaluated by chart review after preselection by an algorithm. When the cause of the anemia was known or was irrelevant in view of the patient's clinical status, the laboratory use was judged to be adequate. Seventy-one percent of patients studied had an adequate follow-up, though 11% had nonindicated tests performed, scored as laboratory overuse. Twenty-four percent had no follow-up, scored as laboratory underuse. Five percent did not have all indicated tests done and had nonindicated tests done, scored as a mixture of underuse and overuse. Potential remedies to correct misuse are discussed.
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Electrocardiogram (ECG) electrodes and carotid arterial and superior vena caval (SVC) catheters were placed in eight nonpregnant ewes and 11 fetuses (109-129 days gestation) to measure heart rate, arterial presssure, P-R interval, left ventricular pre-ejection period (PEP), and left ventricular ejection time (LVET), before and after digoxin infusion into the SVC. After the ewes were killed, the steady state concentration of digoxin in plasma was related to the concentration in midbrain and left ventricular free wall. Although concentrations of digoxin in tissue differed between fetuses and ewes, tissue-plasma ratios were similar; the myocardial-plasma ratio was 87 for fetuses and 90 for ewes and the midbrain-plasma ratios were 6.4 and 5.3, respectively. In spite of these similarities, physiological and toxic effects differed at comparable plasma concentrations. Reduction in PEP/LVET ratio was greater in ewes than fetuses, and P-R interval prolongation was linearly related to digoxin concentration in fetuses but uncommon at plasma concentrations below 2 ng/ml in ewes. Arrhythmias occurred in six ewes, but in only one fetus, even though the mean steady state concentration of digoxin in plasma was 4.5 ng/ml in the fetuses and 2.3 ng/ml in the ewes. Atropine had little effect on digoxin-induced P-R interrval prolongation, and isoproterenol produced no tachyarrhythmias in the fetuses. Age-related differences in inotropic and arrhythmogenic effects of digoxin exist exist and are related to differences in drug response rather than drug kinetics; this provides experimental support for the different dosage responses.
To provide a data base for the establishment of a method to detect potentially incorrect SMA 6 test results, we analyzed 2970 pairs of SMA 6 results. For each test result, as well as for the urea nitrogen/creatinine ratio and the anion gap, we estimated to probability density function of the amount of change since the most recent test of the same type. We made separate estimates for each of three ranges of the current test result and two ranges of time-spacing between the tests. Tables of nonparametric estimates of selected points from each of the six distributions for each test result and calculated quantity were developed. These tables could be used to identify unlikely test results, either manually or with a laboratory computer.
The question of pH or flow dependence for the renal elimination of procainamide (PCA) was studied under 4 conditions in each of 4 subjects. Each subject received 500 mg of PCA intravenously at weekly intervals while in a state of (1) acid load (NH4Cl) and water deprivation, (2) acid load and water excess, (3) alkali load (NaHCO3) and water deprivation, and (4) alkali load and water excess. Plasma and urine were collected at frequent intervals for PCA and N-acetyl PCA (NAPA) analysis. Urine flow rates varied markedly between the water deprivation and water excess states (approximately 1.2 vs 5 ml/min, respectively), and urine pH varied markedly between the acid and alkali load states (pH = ca 5 vs 8, respectively). Despite this marked variation, there were no significant changes in PCA renal clearance or 24-hr PCA or NAPA excretion. If passive diffusion of PCA were taking place, such flow and pH changes would have caused marked changes in PCA clearance were the pH partition hypothesis true. We therefore conclude that passive diffusion is not an important mechanism in the renal elimination of PCA in man and that there must be tubular secretion. The implication for the clinical use of the drug is that dose adjustments need not be made in response to variations in urine flow and pH.