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Biomedical subjects

G Levy

Publications and source records attributed to G Levy.

At least 343 records · Page 19Linked to original sources
PubMed1982

Relationship between concentration and anticoagulant effect of heparin in plasma of hospitalized patients: magnitude and predictability of interindividual differences.

The anticoagulant effect of heparin as reflected by the slope (S) of the relationship between heparin concentration and natural log of activated partial thromboplastin time (APTT) was determined in citrated plasma of 31 hospitalized, 21- to 80-yr-old patients (including many typical candidates for heparin therapy). Also determined were level of factors II, V, VII to XII, albumin, individual globulins, calcium, antithrombin III, fibrinogen, alpha-1-acid glycoprotein, alpha-1-antitrypsin, and alpha-2-macroglobulin and prothrombin time and hematocrit. Baseline APTT was 24.1 to 60.3 sec and S was 1.80 to 4.27 ml/u. S correlated with baseline APTT, hematocrit, total protein, functional antithrombin III, prothrombin time, beta-globulin, and factors II, VII, X, XI, and XII. A multiple linear regression equation with baseline APTT, total protein concentration, and factor XI as independent variables was "best" for predicting the S of these patients (r = 0.807, P less than 0.0001). A multiple linear regression equation with baseline APTT and hematocrit as independent variables, obtained in a previous study on healthy subjects, overpredicted the patients' S values. An equation with baseline APTT and gamma-globulins as independent variables yielded the best correlation predicted and actual S values for the combined group of patients and normal subjects (r = 0.715, P less than 0.0001). Our observations indicate that it may be possible to predict the heparin concentration-anticoagulant effect (APTT) relationship for individual patients before institution of heparin therapy.

Adult↗
PubMed1982

Massive intoxication with acetaminophen and propoxyphene: unexpected survival and unusual pharmacokinetics of acetaminophen.

A 28-year-old woman ingested an estimated 58 g acetaminophen and 9 g propoxyphene 20 h before hospitalization. Her serum acetaminophen concentration at 22 h was 485 micrograms/mL and declined with an unusually long half-life of 14 h. Hemodialysis for 4 h (started at 36 h) reduced the acetaminophen concentration from 250 to 32 micrograms/mL. The patient's complete recovery was remarkable because of the large amounts of drugs ingested, the delayed treatment, and prior exposure to enzyme inducers (known to increase acetaminophen hepatotoxicity). Administration of N-acetylcysteine prevented inorganic sulfate depletion usually caused by acetaminophen and may have increased the formation of acetaminophen sulfate. Some patients eliminate large overdoses of acetaminophen very slowly. Measures to enhance the elimination of this drug and its toxic metabolite by these individuals may be useful even when diagnosis or hospitalization is delayed.

Acetaminophen↗
PubMed1982

Effect of experimental renal failure on sulfate retention and acetaminophen pharmacokinetics in rats.

The investigation was designed to determine the effect of experimental renal failure on the retention of free (inorganic) sulfate and on the pharmacokinetics of acetaminophen in rats. Adult male Sprague-Dawley rats with renal failure produced by uranyl nitrate treatment or ligation of ureters had much higher serum free sulfate concentrations (about 2 and 5 mM, respectively) than normal animals (about 1 mM). The time-averaged total clearance of a 100-mg/kg dose of acetaminophen was higher in animals with renal failure than in normal rats and was positively correlated with serum free sulfate concentration (r = 0.76, P less than .001). Renal failure had no effect on the total clearance of a 15-mg/kg dose of acetaminophen, apparently because free sulfate was not appreciably depleted by this small dose. A 6-hr infusion of acetaminophen, at 36 mg/kg/hr, produced steady-state plasma concentrations of about 20 micrograms/ml within 2 hr in renal failure (ureter-ligated) animals, whereas in normal animals the plasma concentrations increased continuously to about 100 micrograms/ml at 6 hr. Free sulfate concentrations in serum at the end of the infusion were about 0.2 mM in normal animals and generally greater than 1 mM in the renal failure animals. The rats with renal failure converted most of the administered dose to acetaminophen sulfate, whereas normal animals metabolized much of the drug to acetaminophen glucuronide. These observations demonstrate the important effect of the endogenous free sulfate level in the body on the elimination kinetics and metabolic fate of a drug that is subject to conjugation with sulfate.

Acetaminophen↗
PubMed1981

Comparative pharmacokinetics of aspirin and acetaminophen.

Aspirin is extensively hydrolyzed to salicylic acid during absorption after oral administration. This hydrolysis is completed systemically. Salicylic acid, an effective analgesic, antipyretic, and anti-inflammatory agent, is eliminated by renal excretion and by metabolic conversion to conjugates with glycine and glucuronic acid, respectively, and to gentisic acid. Two of these metabolic processes are easily saturable, causing systemic clearance of salicylate to decrease with increasing dose. Acetaminophen metabolism during absorption is minor, and the drug is eliminated primarily by conjugation with glucuronic acid and with sulfate to pharmacologically inactive products. These processes become saturated only in the supertherapeutic dose range, thereby causing an increase in the fraction in the dose converted to a minor but potentially hepatotoxic metabolite. In the usual therapeutic dose range, acetaminophen is much more rapidly eliminated from the body than is salicylic acid.

Acetaminophen↗
PubMed1981

Evaluation of methods for producing renal dysfunction in rats.

The following methods for producing renal dysfunction in rats were compared: single-step 5/6th nephrectomy, two-step 5/6th nephrectomy, bilateral ureteral ligation, and uranyl nitrate injection. Control groups consisted of single- and two-step sham-operated animals and animals that received an injection of normal saline solution. The methods were evaluated on the basis of the following criteria, which were assessed daily for 6 days: survival, body weight, hematocrit, serum creatinine concentration, serum urea nitrogen concentration, serum glutamic pyruvic transaminase activity, serum albumin concentration, and serum protein binding of salicylate (determined every other day). Animals with bilateral ureteral ligation survived only 2 days, single-step 5/6th nephrectomy caused a high incidence of fatalities. Some of the methods were associated with the development of hypoalbuminemia, but no significant elevation of transaminase activity occurred. Serum protein binding of salicylate was reduced in rats with renal dysfunction. A strong positive correlation between the creatinine and urea nitrogen concentrations in the serum of animals with renal dysfunction (r = 0.91, p less than 0.001) and a negative correlation between the serum albumin concentration and salicylate free fraction (r = -0.71, p less than 0.001) were found. Uranyl nitrate injection has the advantages of technical simplicity, a high survival rate (no deaths in this study), and relatively consistent and sustained diminution of renal function (as reflected by serum creatinine and urea nitrogen concentrations).

Animals↗
PubMed1981

Absorption of orally administered sodium sulfate in humans.

Sodium sulfate can be used to enhance the conjugation of phenolic drugs with sulfate and to treat hypercalcemia. It is thought that sulfate in is absorbed slowly and incompletely from the digestive tract. The purposes of this investigation were to determine the absorption of large amount of sodium sulfate (18.1 g as the decahydrate, equivalent to 8.0 g of the anhydrous salt) and to compare the bioavailability when this amount is administered orally to normal subjects as a single dose and as four equally divided hourly doses. The 72-hr urinary recovery of free sulfate following single and divided doses was 53.4 +/- 15.8 and 61.8 +/- 7.8%, respectively (mean +/- SD, n=5, p greater than 0.2). The single dose produced severe diarrhea while the divided doses caused only mild or no diarrhea. Thus, a large amount of sodium sulfate, when administered orally in divided doses over 3 hr, is well tolerated and is absorbed to a significant extent. Orally administered sodium sulfate may be useful for the early treatment of acetaminophen overdose.

Administration, Oral↗
PubMed1981

Acetaminophen pharmacokinetics after overdose.

Concentrations of acetaminophen in serum and urinary excretion rates of acetaminophen glucuronide and acetaminophen sulfate were determined in a 15-year-old female who had ingested an overdose which resulted in the absorption of an estimated 9.92 g of acetaminophen. The results obtained are in reasonably good agreement with predictions of acetaminophen disposition based upon a previously developed pharmacokinetic model of capacity-limited acetaminophen elimination, but additional studies are needed to refine that model.

Acetaminophen↗
PubMed1981

Effect of heparin or salicylate infusion on serum protein binding and on concentrations of phenytoin in serum, brain and cerebrospinal fluid of rats.

The purpose of this investigation was to determine if administration of heparin causes displacement of an acidic drug from serum protein binding sites in vivo as has been suggested by several groups of investigators. Rats were injected and infused with phenytoin to produce steady-state serum concentrations of about 25 micrograms/ml. After 2 hr, some of the animals also received injections and infusions of either heparin or salicylic acid. Salicylic acid (about 300 micrograms/ml), a classical inhibitor of phenytoin protein binding, reduced the steady-state serum concentration of total (free plus bound) phenytoin but had no significant effect on the steady-state serum concentration of free phenytoin or on the concentrations of phenytoin in cerebrospinal fluid and brain. The concentrations of phenytoin in cerebrospinal fluid were almost identical to the free phenytoin concentrations in serum. Similar effects were observed with respect to 5-(p-hydroxyphenyl)-5-phenylhydantoin and were found to be due to displacement of this major metabolite of phenytoin from serum protein binding sites by salicylate. Heparin administration caused an apparent increase of the steady-state plasma concentration of free phenytoin when determined as the product of the concentration of total phenytoin and the free fraction measured by in vitro equilibrium dialysis. Since heparin treatment had no significant effect on the total concentrations of phenytoin in plasma, cerebrospinal fluid and brain, it is concluded that the apparent displacement of phenytoin from plasma proteins occurs in vitro, after collection of blood samples from heparinized animals.

Animals↗
PubMed1981

Acute effect of ethanol on hepatic first-pass elimination of propoxyphene in rats.

The purpose of this investigation was to determine if ethanol enhances the acute toxicity of propoxyphene not only by its central nervous system depressant effect but also by inhibiting the otherwise pronounced presystemic biotransformation of the analgesic. Administration of propoxyphene to adult male rats by injection into either the systemic (jugular vein) or hepatic portal circulation (pyloric vein) revealed that 40 +/- 12% (mean +/- S.D.) of a 12 mg/kg dose reached the systemic circulation intact after injection of the drug into the portal circulation. This estimate, based on the area under the plasma concentration time curve, was confirmed by the relative amounts of propoxyphene excreted unchanged in the urine. Acute infusions of ethanol, 1.5 ml/kg/hr from -3 to 0 hr and 0.5 ml/kg/hr from 0 to +3 hr into the portal circulation, increased the total systemic clearance of propoxyphene from 64 to 95 ml/min/kg on the average (P less than .02), probably due to increased hepatic blood perfusion rate. The same rate and route of ethanol administration caused an increase in the average systemic availability of propoxyphene from 28 to 56% (P less than .001) after injection of 8 mg/kg into the portal circulation. Since orally administered propoxyphene is ordinarily subject to extensive presystemic biotransformation in humans, the frequent association of ethanol intake with fatal propoxyphene intoxication may be due, at least in part, to an increased systemic availability of propoxyphene when taken with ethanol.

Animals↗