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Biomedical subjects

G Levy

Publications and source records attributed to G Levy.

At least 379 records · Page 21Linked to original sources
PubMed1980

Clinical pharmacokinetics of salicylates: a re-assessment.

1 Aspirin is partly hydrolyzed to salicylic acid during absorption. Absorbed aspirin is rapidly hydrolyzed systemically. Salicylic acid elimination kinetics are dependent on drug concentration due to the limited capacity of two major biotransformation pathways: formation of salicyluric acid and of salicylphenolic glucuronide. 2 The time courses of the various pharmacological effects of single doses of aspirin are not directly coincident with the plasma concentrations of either aspirin or salicylic acid but there is reasonably good evidence that the pharmacological effects are related to the concentration of aspirin, salicylic acid, or both. 3 Steady-state plasma salicylate concentrations increase more than proportionally with increasing daily dose; the time required to reach steady state increases with increasing daily dose. Dosage intervals of 8 or even 12 h are usually sufficient to maintain plasma salicylate concentrations in the anti-inflammatory concentration range. Monitoring of plasma salicylate concentrations in this range is facilitated by the relatively small drug concentration fluctuations during a dosing interval at steady-state. 4 Limited data suggest that the pharmacological activity of salicylate is produced by free (unbound) drug. As the plasma protein binding of salicylic acid is concentration-dependent and subject to pronounced interindividual differences, it is preferable, at least in principle, to monitor free rather than total concentrations of salicylate in plasma. Although salicylate concentration in saliva reflects the free rather than total salicylate concentration in plasma or serum, use of saliva for indirect monitoring of plasma salicylate concentrations seems to be impractical for technical reasons.

Analgesics↗
PubMed1980

Protein binding of bilirubin in plasma of anephric patients.

The protein binding of bilirubin was determined in the plasma of seven adult surgically anephric patients, eight adult physiologically anephric patients (creatinine clearance < 5 ml/min) and 13 adult normal volunteers. The determinations were carried out with undiluted plasma to which bilirubin, about 10 mg/100 ml, had been added. The free fraction of bilirubin in plasma (ratio of free to total concentration was (19.8 +/- 8.1) X 10(-5) in the surgically anephric, (10.4 +/- 4.0) X 10(-5) in the physiologically anephric, and (1.81 +/- 0.34) X 10(-5) in the normal subjects (mean +/- standard deviation). Based on this difference in plasma protein binding, patients in renal failure may be expected to have lower steady state plasma concentrations of total (free plus bound) bilirubin than do patients with normal renal function if the formation rate and intrinsic metabolic clearance of the pigment are the same as in normal subjects. This conclusion is consistent with available clinical evidence.

Adult↗
PubMed1980

[Quantitative study of the effect of occlusal hypofunction on periodontal ligament with and alveolar osteoclastic resorption in rats].

An occlusal hypofunction has been produced by unilateral extraction of the maxillary molars in the rat and its effect has been studied on the antagonistic lower molars during a period of 15 days to 3 months. The quantitative analysis showed that the alveolar width decreased very significantly as early as the fifteen day. This fact was due to a decrease of the periodontal membrane width from the fifteenth day. This decrease was observed until 1 month on the alveolar surface undergoing apposition. The decrease of the alveolar width was also related to a drop of the periodontal membrane width as soon as fifteen days on the surface in resorption. The radicular width remained constant, confirming that it was the bone apposition and not the cementum apposition which caused the narrowing of the periodontal membrane. The quantitative study of the osteoclastic resorption showed that this later decreased but in a non significant on the alveolar surface undergoing remodeling.

Alveolar Process↗
PubMed1980

Factors affecting the serum protein binding of salicylic acid in newborn infants and their mothers.

The protein binding of salicylic acid in serum of 49 full-term newborn infants and their mothers immediately after delivery was determined, and potential variables affecting the results obtained were examined. The free fraction of salicylic acid added in vitro at an initial drug concentration of 20 mg/100 ml ranged from 0.104 to 0.242 in the infants and from 0.180 to 0.406 in the mothers. The ratio of free fraction values, infant:mother, was 0.67 +/- 0.13 (mean +/- SD). The more extensive serum protein binding of salicylic acid in the newborns' serum explains why serum salicylate concentrations at the time of delivery are usually higher in newborn infants than in their mothers. A cascade of patient characteristics (induction of labor by oxytocin, serum albumin concentration, duration of labor, mother's age, type of anesthesia, use of analgesics, and nonalbumin protein concentration) explained 61% and 37% of the variability of the salicylic acid free fraction values in the serum of infants and their mothers, respectively.

Adolescent↗
PubMed1980

Serum protein binding of drugs during and after pregnancy in rats.

The serum protein binding of salicylic acid (SA), sulfisoxazole (SUL), phenytoin (P), dexamethasone (D), diazepam (DI) and bilirubin (B) was determined in Long-Evans rats during pregnancy and after parturition. Serum free fraction (f) values were obtained by equilibrium dialysis (drugs) and by a reaction rate method (B). Concurrent control experiments were carried out on nonpregnant animals. Values of f were not significantly different from controls during the first 10 to 15 days of pregnancy. Pronounced increases in f of SA, SUL, P and D were observed on the 20th and 21st day of pregnancy; the f of DI was increased only on the 21st day and the f of B was not significantly changed at any time. The f values for SA, SUL and P returned almost to control levels 2 days after parturition (D, DI and B were not studied at that time). Additional studies with SUL, P and D on the 20th day of pregnancy showed that the increase in f occurred over a wide concentration range. Total serum protein and albumin concentrations were significantly decreased only on the 21st day of pregnancy. Pretreatment with activated charcoal decreased f of SA, SUL, P and D (the other compounds were not studied) in serum of 20-day pregnant (but not control) animals. The decreased protein binding of drugs in serum of pregnant rats appears to be due, at least in part, to accumulation of endogenous displacing agents.

Animals↗
PubMed1979

[Determination of proteins in cerebrospinal fluid of adults using two immunochemical methods (author's transl)].

A study of CSF proteins by electrophoretical and immunological techniques suggests the Laser immunonephelemetrical method is suitable as a "Standard method". The average levels of albumin, IgG, IgM, IgA and alpha-2-macroglobulin have been determined and the correlations between these levels have been calculated. The values of albumin and IgG allow a classification of neurologic diseases according to a diagram. The variations of IgM, IgA and alpha-2-macroglobulin levels are not yet explained.

Adult↗
PubMed1979

Pharmacokinetic monitoring of salicylate therapy in children with juvenile rheumatoid arthritis.

Free and total (sum of free and protein bound) salicylate concentrations in serum were determined in 17 children (age: 4-17 years) with definite juvenile rheumatoid arthritis. These measurements were carried out immediately before and 2, 4, and 8 hours after the morning dose during a strict 8 hourly aspirin treatment regimen (regular tablets) started 5 days earlier. The ratio of the 0 to 8 hour total salicylate concentrations was 0.95 +/- 0.10 (mean +/- SD), indicating that steady state had been attained. The ratio of the maximum to minimum concentrations during the dosing interval ranged from 1.05 to 2.26 and decreased with increasing average concentration. The concentration ratio was less than 1.3 at average salicylate concentrations above 20 mg/100 ml. It is concluded that the timing of a blood sample is not critical for monitoring steady state serum salicylate concentrations in the usual therapeutic range if the dosing interval is 8 hours or less. Free salicylate concentrations increased more than proportionately with increasing total concentrations due to the concentration dependent protein binding of the drug in serum.

Adolescent↗
PubMed1979

Effect of naproxen on the kinetics of elimination and anticoagulant activity of a single dose or warfarin.

The purpose of this investigation was to determine the effect of the nonsteroidal anti-inflammatory drug naproxen on the elimination kinetics and anticoagulant activity of warfarin. Ten healthy men received one oral dose of 50 mg racemic warfarin alone and with naproxen, 375 mg twice daily for 17 days beginning 10 days before warfarin. Naproxen administration caused a small but statistically significant increase in the free fraction of warfarin in serum but had no significant effect on the total clearance, volume of distribution, half-life, and anticoagulant activity of warfarin. Warfarin, on the other hand, apparently enhances the serum protein binding of haproxen. There was substantial intersubject variation but very little intrasubject variation in the anticoagulant effect of warfarin. The intersubject variation of the anticoagulant effect was not related to the elimination kinetics of warfarin.

Adult↗
PubMed1979

Effect of naproxen on the steady-state serum concentration and anticoagulant activity of warfarin.

The purpose of this investigation was to determine whether the anti-inflammatory drug naproxen interacts with warfarin during prolonged administration of both drugs. Healthy adults received oral doses of warfarin daily for 26 days. Naproxen, 375 mg twice daily, was given from the eleventh through the twentieth days. Naproxen administration had no apparent effect on the steady-state concentrations of free and total (free and protein-bound) warfarin in serum, despite a small but statistically significant increase of the warfarin-free fraction in serum. There was no apparent difference between the prothrombin times (at a constant daily dose of warfarin) observed before, during, and after administration of naproxen.

Adult↗
PubMed1979

Acetaminophen kinetics in acutely poisoned patients.

A kinetic model of acetaminophen elimination over a wide dose range has been developed on the basis of (1) kinetic data from normal adults who received a usual dose (up to 2 gm) of the drug and (2) the composition of urinary metabolites of acetaminophen excreted within 24 hr by 29 patients who had ingested up to 26 gm of acetaminophen in suicide attempts (including 2 that were fatal and 5 with evidence of severe intoxication). The model consists of the following parallel pathways: conjugation with glucuronide by Michaelis-Menten kinetics, conjugation with sulfate by Michaelis-Menten kinetics, renal excretion of acetaminophen by apparent first-order kinetics, and formation of an oxidative metabolite (which is responsible for the hepatotoxicity of acetaminophen) by apparent first-order kinetics. There is good agreement between the model-predicted and actual urinary excretion of individual acetaminophen metabolites for doses of 0.8 to 26 gm and between model-predicted and actual plasma acetaminophen concentrations in both the low (normal subjects) and high (intoxicated subjects) concentration ranges. Computer simulations indicate that unsaturation of acetaminophen sulfate formation, previously shown to be feasible in vivo, should decrease the formation of the hepatotoxic metabolite. This prediction is consistent with experimental data obtained in preliminary studies on mice.

Acetaminophen↗
PubMed1979

Effect of sulfisoxazole on pharmacokinetics of free and plasma protein-bound bilirubin in experimental unconjugated hyperbilirubinemia.

The effect of sulfisoxazole on the time course of free (unbound) bilirubin concentrations in plasma was studied. Normal adult rats were made hyperbilirubinemic by continuous intravenous infusion of bilirubin. Sulfisoxazole was administered by either rapid intravenous injection or slow intravenous infusion, and the plasma concentrations of free and total (free plus bound) unconjugated bilirubin were determined as a function of time. Rapid injection of sulfisoxazole caused a rapid and pronounced decrease of total bilirubin concentrations in plasma but had only a transient effect on the concentration of free bilirubin. Slow infusion of sulfisoxazole caused a gradual and eventually pronounced decrease of total bilirubin concentrations in plasma but had no apparent effect on the concentration of free bilirubin at any time. These results are consistent with recently developed pharmacokinetic theory according to which the plasma clearance of total bilirubin should increase upon administration of a displacing agent while the plasma clearance of free bilirubin should remain unchanged. Bilirubin-induced encephalopathy caused by sulfisoxazole or other displacing agents may be due to very transient elevations of free bilirubin concentrations in plasma of infants with elevated plasma concentrations of total bilirubin and the consequent redistribution of the pigment to extravascular sites, including the brain.

Animals↗
PubMed1979

Effect of serum protein binding on sulfisoxazole distribution, metabolism, and excretion in rats.

This investigation determined the effect of serum protein binding on the kinetics of sulfisoxazole distribution, metabolism, and excretion. Adult rats, whose serum free fraction of sulfisoxazole (at a total concentration of 81 +/- 6 micrograms/ml) was 0.05-0.24, received a rapid intravenous injection of 20 mg/kg. Sulfisoxazole concentrations in plasma declined biexponentially with time. There were pronounced and reproducible interindividual differences in the total, metabolic, and renal sulfisoxazole clearances, each positively correlated with the serum free fraction of sulfisoxazole. The renal sulfisoxazole clearance had a component unaffected by serum protein binding. The apparent central compartment volume increased with an increasing serum free sulfisoxazole fraction, but the latter had not apparent effect on the first exponential term of the biexponential equation describing sulfisoxazole elimination kinetics in rats. Serum protein binding was a major determinant of intersubject differences in sulfisoxazole excretion and biotransformation kinetics.

Animals↗