Biomedical subjects
Publications and source records attributed to G Levy.
Intraduodenal administration of isoproterenol together with ascorbic acid caused a much greater increase in the heart rate and pulse pressure, and a greater decrease in the mean blood pressure of anesthetized dogs than was observed after intraduodenal administration of isoproterenol alone. No potentiating effect was observed when isoproterenol and the vitamin were injected intravenously.
The protein binding of warfarin was determined in the serum of 18 normal adult subjects (8 males and 10 females). A statistically significant negative correlation between free fraction of warfarin and albumin concentration was found. The free fraction of warfarin in the serum of women was significantly larger than that in the serum of men, apparently due to the lower albumin concentration in the serum of women.
The pharmacokinetics of theophylline following intravenous injection of aminophylline, 4 mg/kg of body weight, were determined in 30 children with asthma and in 6 normal adult volunteers. The average total clearance of theophylline was 87 ml/hr/kg in the children and 57 ml/hr/kg in the adults. The biologic half-life of theophylline in the children ranged from 1.42 to 7.85 hours, reflecting mainly pronounced interindividual differences in the elimination rate constant of the drug. There was no significant difference between the children and adults with respect to the distribution rate constants and apparent volumes of distribution of theophylline, but the elimination rate constant of the drug was considerably higher in children than in adults. Thus, children eliminate theophylline more rapidly on the average than do adults and also show pronounced interindividual differences in the elimination of the drug. Compared to adults, children tend to require relatively larger amounts of theophylline per day and the doses may have to be given at shorter intervals of time.
The effect of the non-steroidal anti-inflammatory agent naproxen on the protein binding of racemic warfarin in pooled human serum was determined by equilibrium dialysis. The free fraction of warfarin in serum increased practically linearly with increasing naproxen concentration. At the highest naproxen concentration tested (400 mcg/ml), the warfarin free fraction was 74% larger than the control free fraction value.
In the course of a restrospective study, some hemostatic parameters were studied in connection with 65 cases of septicaemia. From this study, it follows that coagulation troubles are more frequent in septicaemiae induced by negative Gram germs, but that this frequency is actually linked with circulatory troubles. Besides, as for the biological diagnosis of the disseminated intravascular coagulation syndrome in this instance, it is not possible to take strictly into account the fibrinogen values or the rate of thrombocytes.
In view of a previous report suggesting an increased metabolism of the beta-blocking agent pindolol with decreasing renal function in man, the relationship between renal function and the elimination kinetics of pindolol has been re-examined. There is a statistically significant positive correlation between the renal clearances of pindolol and creatinine but there is no correlation between the non-renal clearance of pindolol and the renal clearance of creatinine. Thus, there is no evidence of an increased metabolism (non-renal clearance) of pindolol with decreasing renal function.
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To determine if the common practice of giving antacids to patients on salicylate therapy has an effect on serum salicylate concentrations, we gave a widely used antacid, aluminum and magnesium hydroxide, and aspirin concomitantly to three children with rheumatic fever. Urinary pH increased appreciably, and serum salicylate concentrations decreased by 30 to 70 per cent. In five healthy adult volunteers concomitant administration of antacid had no effect on the bioavailability of aspirin. Pharmacokinetic analysis revealed that the antacid-induced decrease of serum salicylate concentrations was due to increased renal clearance of salicylate caused by the rise in urinalry pH.
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The purpose of this study was to determine the amount of salicylate acquired by a newborn infant from a mother who took 6.5 gm of aspirin a day during her entire pregnancy, and to characterize the kinetics of salicylate elimination by the infant. This healthy female infant was born with a salicylic acid concentration of 25 mg/100 ml plasma and 75 mg/kg body weight. The drug was eliminated during the first 5 days of life, primarily in the form of salicyluric acid. Salicylate elimination was relatively slower than in normal adults, but more rapid than in newborn infants of mothers who had taken only one small dose of aspirin shortly before delivery. The apparent in vivo KM and Vmax for salicylurate formation, on a body weight basis, were at the adult level. The slower elimination of salicylate (relative to adults) by the infant was due to immaturity of the glucuronidation and renal excretory pathways.
The post-distributive neonatal:maternal plasma salicylate concentration ratio following salicylate administration to the mother before delivery is appreciably higher than unity. The protein binding of salicylate and the albumin concentration in one such plasma pair were considerably higher in the neonatal than in the maternal plasma. Equilibrium dialysis of neonatal plasma or serum from 6 newborn infants against that of their mothers produced a neonatal: maternal salicylate concentration ratio above unity in all cases even if the albumin concentration in the neonatal serum did not exceed that in the maternal serum. However, there was a strong correlation between the neonatal:maternal concentration ratios of salicylate and albumin. These observations demonstrate that conclusions concerning the distribution of a drug across the placenta in relation to its plasma protein binding characteristics must be based on the results of binding studies with plasma or serum from neonates and their mothers, and not from other adult subjects.
The pharmacokinetics of acetaminophen elimination were determined in 4 anephric patients during hemodialysis and on an interdialysis day. The biologic half-life of acetaminophen ranged from 119 to 147 min on an interdialysis day and was decreased by 42% to 53% during hemodialysis. Individual mean dialyzer extraction ratios, based on assay of plasma samples from blood flowing into and out of the dialysis unit, were 0.46 to 0.78 for acetaminophen, 0.53 to 0.57 for acetaminophen glucuronide, 0.13 to 0.60 for acetaminophen sulfate, and 0.70 to 0.87 for urea nitrogen. There was a strong correlation between the extraction ratios of acetaminophen and urea nitrogen. Hemodialysis was the major or sole routine of elimination of acetaminophen glucuronide and sulfate in the anephric patients.
It is shown on the basis of pharmacokinetic simulations and experimental data that adequate evaluation of aspirin dosage forms with different absorption rates by urinary excretion measurements in man requires that such measurements be made during the first hour after drug administration. Measurements made only after 3 hours are totally inadequate for that purpose. An assessment of the completeness of absorption obviously does not require serial measurements but needs only a determination of the total amount excreted.
This study was carried out to determine if ethanol, which enhances theophylline absorption from the rat small intestine, has a similar effect when administered orally to human subjects. Seven normal adults received 200 mg of theophylline/m-2 of body surface area, in 50 ml of either aqueous solution or hydroalcoholic solution containing 20% ethanol. There was no significant difference in the average plasma concentrations of theophylline produced by these two solutions, but three subjects (all female) experienced nausea after taking the aqueous solution while none became nauseous after taking theophylline in the hydroalcoholic solution.
Previous studies in this laboratory demonstrated that the rate of intestinal absorption of theophylline in rats is increased significantly by ethanol in low concentrations and that this absorption enhancing effect is associated with an increased net water flux from the intestine. It is now shown that other alcohols, namely methanol, n-propanol, n-butanol, glycerin, propylene glycol, and, to a lesser extent, mannitol and sorbitol, can also increase net water flux from the small intestine of anesthetized rats. Polyethylene glycol 200 and 400 had no such effect, suggesting that these compounds do not penetrate to a site of action that elicits the increased net water flux. At initial concentrations of 0.1 and 1.0 M, glycerin and propylene glycol increase significantly the intestinal absorption rate of theophylline from the small intestine of anesthetized rats. The results show that the theophylline absorption enhancing effect of ethanol is not limited to that particular alcohol.
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