Biomedical subjects

R H Levy

Publications and source records attributed to R H Levy.

At least 163 records · Page 9Linked to original sources

PubMed1976

Interactions of phenytoin and phenobarbital in terms of order and temporal spacing of administration in monkeys.

The present study investigated order and temporal spacing interactions of phenytoin and phenobarbital in terms of plasma levels during multiple dosing in monkeys. Phenytoin at a dose of 30 mg/kg and pehnobarbital at a dose of 3 mg/kg and phenobarbital at a dose of 3 mg/kg were administered separately to 4 animals (control group) by nasogastric intubation daily for 10 days. In four subsequent 10-day periods the drugs were administered together in 4 other animals (interaction group) at different times of the day (immediately following one another, 1/2 hr apart, and 6 hr apart) and in a different order of administration (either phenobarbital first and phenytoin later, or the reverse). Blood samples were obtained on the 5th, 8th, and 10th day of each 10-day period. The plasma data indicated: (a) phenytoin is capable of autoinduction, (b) phenobarbital lowers the levels of phenytoin under the four methods of administration studied here, and (c) phenytoin can affect the levels of phenobarbital. The latter interaction is a function of order and temporal spacing of drug administration.

Animals↗

PubMed1975

Pharmacokinetics of carbamazepine in normal man.

The bioavailability of commercial carbamazepine talbets with and without meals was compared to a propylene glycol solution respect to extent of absorption in 6 normal humans after a dose of 6 MG/KG. The presence of dose-dependent kinetics within a clinically sigificant range was also investigated. Serum and urine samples were assayed by gal-liquid chromatography (GLC). Carbamazepine is rapidly absorbed from the propylene glycol solution. Eight per cent of the dose was absorbed from the commercial tablet, resulting in therapeutic serum concentrations(30 to 6 mcg/ni). The data were consitent with disolution rate-limited absorption. Mean half-lives ranged from 31 to 35 hr. No dose-dependent kinetics were observed following administration of does of 3. 6. or 9 mg/kg. The fraction of dose abosrbed, the fraction excredted unchanged in urine, the time of maxium serum concentration, and absorption and elimination half-lives appear to be independent of dose. The time course of side effects could not be correlated with serum carbamazepine levels, suggesting that metabolities contributed to side effects.

Adult↗

PubMed1975

Pharmacokinetics of carbamazepine in monkeys following intravenous and oral administration.

The pharmacokinetics of carbamazepine were evaluated in four male rhesus monkeys. A 20-mg/kg dose was administered by intravenous (5-min) infusion and orally (nasal-gastric intubation) in a propylene glycol-ethanol-water solvent. Plasma and urine determinations were performed by GLC. All semilogarithmic intravenous curves exhibited an irregular decay behavior in the first 3-hr period, followed by a linear disappearance phase (T 1/2 equals 1.0-2.4 hr). Urinary excretion measurements confirmed the short elimination half-life and showed that less than 1% of the dose was excreted unchanged. Oral studies also yielded a short elimination half-life (1.0-1.60 hr), which was confirmed by urinary excretion measurements. The oral curves were analyzed pharmacokinetically. The fraction of the dose reaching the systemic circulation ranged between 58 and 87%. Measurable (but insignificant) amounts of drug were found in the feces after intravenous and oral administrations.

Administration, Oral↗

PubMed1975

GLC determination of procainamide in biological fluids.

A GLC method for the determination of procainamide in biological fluids is presented. By using a dipropyl analog of procainamide as an internal standard, both compounds can be chromatographed directly, yielding linear calibration curves and a sensitivity that allows quantitative determination of concentrations as low as 0.1 mug/ml. The extraction procedure was carefully modified to avoid hydrolysis of N-acetylprocainamide, a major metabolite of procainamide. The usefulness of the procedure is demonstrated by following the disappearance of procainamide from the plasma and urine of human subjects treated with the drug.

Chromatography, Gas↗

PubMed1975

Quinidine plasma concentration and exertional arrhythmia.

Quinidine gluconate was used to treat arrhythmia induced with maximal exercise testing. Twenty-nine subjects who had previously developed frequent premature contractions on testing were selected for further study. After a control maximal exercise test, quinidine (10 mg. per kilogram) in solution was given orally in a single dose, and two hours later the same test was repeated. Recurrence of premature contractions was completely prevented in five of the 19 subjects tested; suppression was better than the mean value in three others, and in 11 subjects it was below the mean value. The plasma concentration at two hours was 1.68 plus or minus 0.31 ug per milliliter, which is a therapeutic level. Raising the dose to 15 mg. per kilogram eliminated the premautre contractions in six subjects whose response to 10 mg. per kilogram had not been complete, but not in two others. Lowering the dose to 5mg. per kilogram lowered the plasma level to below the therapeutic level. No differences between the responses to the drug of the otherwise healthy subject and those with symptomatic heart disease could be found. Compared with the responses to the control tests, there were small but significant changes in the second test in heart rates, blood pressure, and duration of exercise. Aerobic working capacity estimated by Vo2max was unchanged. Mild toxic effects manifested by malaise and diarrhea were a common finding with both 10mg per kilogram and 15mg per kilogram of quinidine, but not with 5mg per kilogram.

Administration, Oral↗

PubMed1975

Pharmacokinetic properties of ethosuximide in monkeys. I. Single-dose intravenous and oral administration.

The pharmacokinetic profile of ethosuximide was studied in 6 chronically catheterized male rhesus monkeys at three dose levels (30, 60, and 90 mg/kg), intravenously and orally. Plasma and urine levels were assayed by GLC. The intravenous and oral kinetics of ethosuximide were described in terms of a one-compartment open model with first-order elimination (and first-order absorption for oral kinetics). Volume of distribution (overall mean +/- SD=0.80 +/- 0.09 liters/kg), total body clearance (overall mean +/- SD= 19.2 +/- 2.70 ml/hr/kg) and elimination half-life (overall mean +/- SD=28.98+/-3.35 hr and 28.10+/-3.17 hr following intravenous and oral administration, respectively) remained constant over the dosage range Appendix) was selected to describe the disposition of ethosuximide in monkeys. Accordingly, plasma concentrations of individual animals and the average concentrations of Fig. 1 were fitted to a monoexponential equation [Eq. (A1)]. A close agreement between experimental datum points and least-squares fit lines was observed at all three dose levels. Plots of C0 and area under the plasma concentration-time curve [AUC, measured by trapezoidal rule, Eq. (A3)] vs dose (Fig. 4) were linear as predicted by Model I. It may be concluded, therefore, that a one-compartment open model with first-order elimination is appropriate to describe the intravenous kinetic behavior of ethosuximide in monkeys. The volume of distribution (overall mean +/- SD = 0.80 +/- 0.09 liters/kg) observed in the present study is higher than total body water and therefore suggests accumulation of ethosuximide in body tissues. Tissue distribution studies have not been performed in monkeys. However, data on tissue/plasma ratios in rats (Dill et al., 1965; Chang et al., 1972) indicate that ethosuximide can partition outside the total body water compartment. This behavior is compatible with the high pKa value and negligible protein-binding characteristics of ethosuximide (Chang et al., 1972). As discussed by several workers (Levy, 1968; DiSanto and Wagner, 1972; Lockard et al., 1974), the establishment of dose independency in elimination processes (kinetic linearity) requires that single-dose studies be performed at several dose levels. In the dose range examined in the present study (30 to 90 mg/kg), there was no evidence of dose-dependent elimination kinetics after intravenous or oral administration. The overall mean (+/- SD) elimination half-life (28.5 +/- 3.24 hr) obtained in the present study is somewhat longer than the value (22.0 hr) observed by Chang et al. (1972) following a single-dose (100 mg/kg) oral administration of ethosuximide in 4 rhesus monkeys. In view of the agreement between the predictions of Model I and experimental intravenous data, a one-compartment open model with first-order absorption and elimination processes (Model II, Appendix) was studied. The bioavailability of the syrup formulation used in the oral studies was essentially complete (overall mean +/- SD=96% +/- 12.0) and dose-independent...

Administration, Oral↗

PubMed1975

Pharmacokinetic properties of ethosuximide in monkeys. II. Chronic intravenous and oral administration.

Three types of chronic-dosing experiments were implemented in a group of chronically catheterized male rhesus monkeys: Study I, constant rate infusion; Study II, infusion at three consecutive rates with priming doses; and Study III, oral multiple dosing at two consecutive levels with priming doses. Zero-order infusion rates and priming and maintenance doses were calculated for each animal using individual single-dose pharmacokinetic parameters. Ethosuximide was measured in plasma and urine by GLC. Experimental and predicted plasma and urine levels were in good agreement for all three studies. Total body clearance (Studies I and II) and elimination half-life (Studies I, II, and III) were not significantly different from their respective single-dose values. Excretion rate was proportional to infusion rate (Study II) and maintenance dose (Study III). It was established that in the case of ethosuximide in monkey, pharmacokinetic parameters derived from single-dose studies can be used to predict multiple-dosing schedules.

Administration, Oral↗

PubMed1975

The pharmacokinetics of procainamide in normal subjects using a specific gas chromatographic assay.

Previous procainamide pharmacokinetic studies have involved the use of colorimetric and fluorimetric methods for the determination of drug concentrations in plasma and urine. However, recent evidence shows that N-acetyl procainamide, the major metabolite in humans, is hydrolyzed during these assay procedures. As a result, a specific gas chromatographic method has been developed for the determination of procainamide in biological fluids. Using this assay procedure, the pharmacokinetics of procainamide were studied in 7 normal subjects following intravenous administration of the drug. The values of half-life (2.08 +/- 0.52 hr), volume of distribution (4.3 +/- 0.6 1/Kg) and total body clearance (1344 +/- 238 ml/min) found in this study differed from those previously reported. These discrepancies could be understood in terms of differences in assay specificity.

Blood Pressure↗

PubMed1974