Biomedical subjects

A Frydman

Publications and source records attributed to A Frydman.

At least 37 records · Page 2Linked to original sources

PubMed1991

A comparative pharmacokinetic and pharmacodynamic study of conventional and sustained-release preparations of acebutolol in healthy volunteers.

Pharmacokinetics and the degree of beta-blockade of sustained release (SR) acebutolol (500 mg/day) and conventional acebutolol (200 mg tid) were examined after the first oral dose and after 10 days of treatment in ten healthy volunteers. After the first dose, acebutolol Cmax did not significantly differ between the two formulations; however, on day 10 acebutolol Cmax was significantly higher after SR formulation. Cmax of diacetolol, the major metabolite, did not differ between SR and conventional acebutolol neither on day 1 nor on day 10. The dose-corrected relative bio-availability of acebutolol was not different from 100% on day 1 and day 10; however the dose-corrected diacetolol AUC, SR/conventional ratio, was significantly lower than 100% on days 1 and 10. Both acebutolol preparations exerted a significant reduction in exercise tachycardia over 24 h on day 1 and day 10; however, conventional acebutolol exhibited a greater reduction 24 h after the first dose. Exercise-induced increase in systolic blood pressure was similarly inhibited by both treatments except for 24 h after the first dose when systolic blood pressure was significantly higher with SR than with conventional acebutolol. The percent reduction in heart rate during exercise was linearly correlated with log acebutolol plasma concentrations for each treatment regimen. These results suggest that beta-blockade exerted by SR acebutolol in healthy volunteers is equivalent to that of conventional acebutolol.

Acebutolol↗

PubMed1991

Comparative bioavailability study of cefixime administered as tablets or aqueous solution.

The relative bioavailability of cefixime was studied in 24 healthy male volunteers, with each subject receiving a single 400mg dose of cefixime administered as an aqueous solution, a 400mg tablet and two 200mg tablets, in a randomised crossover sequence. Serum and urine samples were analysed using high-performance liquid chromatography. Peak cefixime levels were achieved 3 hours after administration of the solution vs 4 hours for the 2 tablet formulations; however, the extent of absorption was only slightly improved with the solution (by 14 and 7% compared with the 1 x 400 and 2 x 200mg tablets, respectively). The 400mg and 2 x 200mg tablets were found to be bioequivalent. The pharmacokinetic profile of the 400mg cefixime tablet (mean maximum plasma concentrations of 4.4 mg/L at 4 hours, area under the concentration-time curve of 34.4 mg/L.h, and apparent terminal elimination half-life of 3.7 hours) supports the clinical evaluation of a 400mg once-daily dosage regimen for cefixime.

Adult↗

PubMed1991

Pharmacokinetics of pyrimethamine in healthy young volunteers using a new solid phase extraction/HPLC method.

The single dose pharmacokinetics of pyrimethamine were determined in 12 healthy young volunteers using a newly developed fully automated analytical system which combines liquid solid extraction on disposable extraction columns and high performance liquid chromatography. This technique is highly sensitive (detection 1 ng/ml) and reproducible. Following a 50mg dose of the drug, the plasma concentration peaked at 0.48 0.13 g/ml (msd) and was attained 2.5 hours (median value) post dosing. Thereafter, the plasma level of pyrimethamine decreased slowly, the level at 336 hours after administration being still about 40 ng/ml. The area under the plasma concentration-time curve (AUC0-inf) was 56.8 18.4 h.mg/ml. The volume of distribution Vd was: 2.42 1.25 l/kg and the total clearance: 15.55 4.48 ml/h/kg. Urinary excretion represented about 20% to 40% of the dose after seven days of the administered dose.

Adult↗

PubMed1991

Evaluation of Bayesian estimation to discriminate subpopulations of patients with altered pharmacokinetics using fragmentary data: a pilot study with pefloxacin.

Bayesian estimation of individual pefloxacin pharmacokinetic parameters was evaluated in patients with renal (n = 34) or hepatic (n = 16) impairments who participated in experimental pharmacokinetic studies during pefloxacin development. The trials involved singly intravenous dosing (300 to 850 mg as 0.5 to 1h-infusion) and serial pefloxacin plasma level measurements (n = 10-18 over 72-96 h). Bayesian estimation used only 2 measured plasma levels (end of infusion and either 12 hour (BE 12h) or 48 hour (BE 48h) levels) and a priori information obtained in a reference population of healthy volunteers (n = 19). The performance of Bayesian estimation in predicting total plasma clearance (Cl), elimination half-life (t1/2) and steady state volume of distribution (Vss) was evaluated with respect to weighted nonlinear least-square estimates using all the data points and a two-compartment model. Pharmacokinetic parameters (and their inter-individual variability) in patients differed significantly from those of healthy volunteers (e.g. t1/2 of 22 +/- 14 h, range 6-81 h vs. 11 +/- 2 h, range 8-17, p less than 0.001). BE 12h provided biased estimates of Cl and t1/2 (24 and 28% respectively) and poor precision (30 and 53% respectively), Vss being well estimated. The BE 48h estimator had good performance with unsignificant bias (less than 1%) and good precision (extremes 13 and 27% for Cl and t1/2 respectively). Patients with hepatic impairment had the more pronounced pharmacokinetics modifications and could even be discriminated from healthy volunteers using the biased BE 12h estimates. These results suggest that Bayesian estimation is quite robust to the a priori information.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Interaction of suriclone with central type benzodiazepine receptors in living baboons.

The interaction of suriclone and two of its main metabolites with central type benzodiazepine receptors, which had been labeled in vivo with the radioligand [11C]RO 15-1788, was investigated in living baboons. The concentration of radioligand bound to the receptors, as measured in brain transverse sections by positron emission tomography, decreased rapidly after the i.v. administration of suriclone at doses known to induce pharmacological effects. The rate and extent to which [11C]RO 15-1788 binding was displaced increased with increasing doses of suriclone. The half-inhibitory dose (ID50) was determined to be 0.08 mg/kg in vivo. The rapid inhibitory effect of suriclone on the in vivo binding of [11C]RO 15-1788 in the brain seems to reflect its ability to act at the GABA-benzodiazepine receptor complex, at or near to the benzodiazepine binding site, to induce its pharmacological activity. The i.v. injection of the demethylated metabolite of suriclone, RP 35,489, only caused a slight displacement of [11C]RO 15-1788 binding even at a dose of 2 mg/kg. Thus, suriclone appears to be more potent than RP 35,489 to displace the benzodiazepine 11C antagonist in vivo. The sulfoxide metabolite, RP 46,166, did not significantly change the kinetics of [11C]RO 15-1788 binding in the brain. The slight effects produced by high doses of RP 35,489 and RP 46,166 on [11C]RO 15-1788 binding in the brain suggest that these metabolites are probably not responsible for the expression of biological activity of suriclone mediated by benzodiazepine receptors.

Animals↗

PubMed1990

Steady state pharmacokinetics of zopiclone during multiple oral dosing (7.5 mg nocte) in patients with severe chronic renal failure.

Zopiclone is a new hypnotic cyclopyrrolone with a short elimination half-life (5.3 h). The pharmacokinetic profile of this drug was studied in 7 chronic renal failure (CRF) patients given 7.5 mg nocte for 7 consecutive nights. The pharmacokinetic values obtained were compared with the corresponding values found in healthy young volunteers given the same repeated dosage regimen. C max and T max were not significantly different between the two groups but the C min of unchanged zopiclone (at 24 h) post-dosing was significantly (p less than 0.001) higher in CRF patients (8.16 +/- 5.34 ng/ml) than in healthy volunteers (1.90 +/- 0.82 ng/ml). The AUC values in CRF patients were also significantly increased during the seventh day (742 +/- 212 h ng/ml) compared to healthy subjects (408 +/- 66.5 h ng/ml) and the elimination half-life of zopiclone was also longer in CRF patients (about 8 h) than in the reference group (about 5 h). Nevertheless, the accumulation ratios remained similar in the two groups (1.09 +/- 0.18 in CRF patients and 1.02 +/- 0.2 in healthy subjects). Thus no evident accumulation of zopiclone appeared in the CRF patients. As in the healthy subjects, no metabolites were detected in the plasma of the CRF patients although at steady state the urinary excretion of zopiclone and its N-oxide and N-desmethyl derivatives (2.03% +/- 1.52% and 1.99 +/- 0.65% of the dose, respectively) was significantly decreased compared to healthy subjects (3.7% +/- 2.1% and 32.6% +/- 4.5%, respectively). Zopiclone thus represents a safe alternative to benzodiazepine hypnotic therapy in patients with renal impairment.

Administration, Oral↗

PubMed1989

[Pharmacokinetics of cefixime in healthy volunteers after a single oral administration of 200 mg].

The antibacterial activity of cefixime is identical with that of parenteral third generation cephalosporins. Its kinetics were studied in 24 healthy male volunteers who received one single 200 mg tablet. Cmax was 3.25 mg/l and Tmax was 4 h. After 12 hours, serum concentrations were still as high as 0.70 mg/l. Half-life was 3.3 h and urinary excretion was not predominant. Thus, cefixime was characterized by its relatively long serum half-life as compared with other cephalosporins. Despite some degree of individual variations, serum and urine concentrations of the antibiotic remained for 12 hours above the MIC of susceptible pathogens.

Administration, Oral↗

PubMed1987

Simultaneous determination of zopiclone and its two major metabolites (N-oxide and N-desmethyl) in human biological fluids by reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of zopiclone and its main metabolites (N-oxide and N-desmethyl derivatives) in biological fluids. After selective extraction (dichloromethane-2-propanol) these compounds are chromatographed on a column packed with Spherisorb ODS-2 (5 micron) using monobasic sodium phosphate-methanol (45:55, v/v). The eluted compounds are measured by fluorescence detection. The limit of detection of the method is 5 ng/ml for zopiclone in plasma and urine and 10 ng/ml for its two main metabolites (coefficient of variation less than 10%). This method has been successfully applied to pharmacokinetic studies of zopiclone and its two main metabolites in healthy subjects and patients with chronic renal failure.

Adolescent↗

PubMed1987

Total and free ketoprofen in serum and synovial fluid after intramuscular injection.

Free and total ketoprofen levels in serum and synovial fluid were determined in 37 patients after a single intramuscular injection of ketoprofen, 100 mg. Free drug was separated by equilibrium dialysis. Ketoprofen was assayed by HPLC. Ketoprofen penetrated into the joints rapidly and significant concentrations were found at 15 minutes. The equilibrium time was about 3 1/2 hours. The AUC for total ketoprofen was greater in serum than in synovial fluid. On the other hand, the free fraction AUC in the serum and synovial fluid were quite similar. The mean residence time in the joint was about three times that in the systemic circulation. Ketoprofen was strongly bound to proteins and the percentage of free ketoprofen was not significantly different between serum and synovial fluid. These results provide a possible explanation for duration of the therapeutic effect of ketoprofen despite the short elimination half-life from the serum.

Adolescent↗

PubMed1986

Acute and chronic 24-hour gastric pH and pharmacokinetic studies with a long acting antisecretory drug (40749 RP) in peptic ulcer.

The purpose of this work was to compare the effects of a long acting antisecretory drug on 24-h gastric acidity after acute and chronic administration and to correlate the results observed with modifications of pharmacokinetic parameters. 40749 RP is a carbothioamide derivative antisecretory drug with a non anti H2, non anticholinergic mechanism of action. Eleven patients with an endoscopically proven duodenal ulcer received 100 mg of 40749 RP at 8 PM for 3 wk and thereafter a placebo for an additional 3 wk study period. At the end of the active drug treatment period all patients but one had healed. Continuous 24-h gastric pH recordings performed after the first and the last dose of 40749 RP showed a strong and yet still increasing acid inhibition, nine patients being nearly achlorhydric (i. e. pH greater than 3) during night at the end of treatment. Variations of acid inhibition between the start and the end of treatment were significantly correlated with modifications of pharmacokinetic parameters. Eight days after discontinuation of 40749 RP, basal acid secretion remained strongly inhibited. However at the end of the placebo period, endoscopy showed ulcer relapse in 4 patients (previously resistant to H2-blockers). These results confirmed that 40749 RP is a powerful and very long-acting antisecretory drug. They showed that the antisecretory effects of a long-acting drug should be assessed in conditions of chronic administration when therapeutic dose and regimen are to be determined.

Adult↗

PubMed1985

Automated high-performance liquid chromatographic determination of spiramycin by direct injection of plasma, using column-switching for sample clean-up.

A fully automated high-performance liquid chromatographic method is described for the determination of spiramycin 1 in plasma. First, 1 ml of plasma is diluted with 1.5 ml of 4% acetonitrile containing spiramycin 2 as internal standard, and 1 ml is then injected via an automatic sampling unit. A pneumatic valve, which is remote-controlled by the programmable timer of an integrator, switches the sample, initially injected onto a precolumn for sample clean-up, to an analytical column for sample separation. This method was compared with a microbiological assay and has been successfully applied to pharmacokinetic studies on spiramycin in humans.

Chromatography, High Pressure Liquid↗

PubMed1982

[Pharmacokinetics of isosorbide dinitrate administered by intravenous infusion to hypertensive patients (author's transl)].

The pharmacokinetics of intravenous isosorbide dinitrate was investigated in 11 patients with labile hypertension and with normal renal and hepatic functions. The mode of administration (constant rate infusion without loading dose) was chosen in order to minimize side-effects and to approximate clinical conditions. Isosorbide dinitrate levels were measured by electron-capture gas chromatography. The volume of distribution during steady state (Vd beta = 318 +/- 117 I) and the elimination half-life (t1/2 beta = 64.8 +/- 30.5 min) were similar to those found after perlingual and oral administration. Systemic clearance (Cls = 3.80 +/- 1.48 I/min) was high for a drug given intravenously, presumably because of active hepatic extraction, intensive pre-systemic degradation and very active extra-hepatic metabolism. These findings should be compared with the considerable inter-individual variations observed in theoretical plasma concentrations during steady state and with the presence of two pharmacokinetic models (one -- and two -- compartments) in the patients under study. Comparison of the results obtained by the intravenous route with previously published results after perlingual and oral administration indicates the following bioavailability ratios: perlingual/i.v. = 31%, oral/i.v. = 20%, and oral/perlingual = 63%.

Female↗

PubMed1978

New electron-capture gas-liquid chromatographic method for the determination of mexiletine plasma levels in man.

A method for the determination of mexiletine in human plasma by gas-liquid chromatography with electron-capture detection is described. Plasma samples are extracted at pH 12 with dichloromethane after addition of the internal standard, the 2,4-methyl analogue of mexiletine. A derivative is obtained using heptafluorobutyric anhydride; according to gas chromatography-mass spectrometry it is a monoheptafluorobutyryl compound. The minimum detectable amount of mexiletine is 5 pg. Accurate determinations of human plasma levels were performed after oral or intravenous treatment.

Administration, Oral↗

PubMed1976

Comparison of the pharmacokinetics of intravenous dl-propranolol in borderline and permanent hypertension.

In borderline and permanent hypertensives after rapid i.v. injection of dl-propranolol 0.2 mg/kg plasma levels were measured and were fitted to a two-compartment open-model. In borderline patients, characterized by a high basal cardiac output (CO), plasma levels were always lower than in permanent hypertensives. The biological half-life was reduced and the central volume of distribution, volume of distribution at pseudo-equilibrium and total clearance (TC) were markedly increased. In the overall population, there was a significant positive correlation between CO and TC. Rapid achievement of a predetermined plateau in each group constituted experimental proof of the validity of the two-compartment open-model for kinetic analysis of propranolol i.v. If kinetic parameters from permanent hypertensive were applied to borderline hypertensives a lower plateau was obtained. Thus, in so far as beta-blockade is related to plasma level of propranolol, an increased intravenous dose may be required in patients with high CO.

Cardiac Output↗

PubMed1976