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Biomedical subjects

E Radwanski

Publications and source records attributed to E Radwanski.

At least 19 recordsLinked to original sources
PubMed1996

Pharmacokinetics and immunomodulatory properties of intravenously administered recombinant human interleukin-10 in healthy volunteers.

Normal volunteers received single doses of recombinant human interleukin-10 (rhIL-10; n = 6 per group) or placebo (n = 3 per group) by intravenous injection to characterize pharmacokinetics, tolerability, and immunomodulatory effects. Dosages were 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 25.0, 50.0, and 100.0 micrograms/kg. Dose-related adverse effects consisted of a mild-to-moderate flu-like syndrome characterized by fever with chills, headache, and myalgias at the highest dose. The mean terminal phase t1/2 ranged from 2.3 +/- 0.5 to 3.7 +/- 0.8 hours. Dose-related effects of rhIL-10 included transient increases of circulating neutrophils and monocytes and decreases of lymphocytes. rhIL-10 markedly suppressed, in a time- and dose-dependent manner, the synthesis of the inflammatory cytokines IL-1 beta and tumor necrosis factor alpha by whole blood stimulated ex vivo with bacterial lipopolysaccharide. Circulating numbers of CD14+/HLA-DR+ cells at 24 hours after the dose were increased in a dose-dependent manner. Effects on expression of HLA-DR by CD14+ cells were variable. There was no apparent effect on HLA-DR expression by CD20+ cells. The immunomodulatory effects of rhIL-10 merit further clinical investigation.

Adolescent↗
PubMed1996

Effect of felbamate on valproic acid disposition in healthy volunteers: inhibition of beta-oxidation.

We assessed the effects of felbamate (FBM) on the disposition of valpr oic acid (VPA) in healthy volunteer men. Eighteen subjects received sodium VPA, 400 mg/day for 21 days. Plasma and urine samples were taken on day 7 to document the steady-state disposition of VPA alone. From day 8 to day 21, subjects received placebo or FBM at the following doses (mg/day): 1,200, 2,400, 3,000, or 3,600 (n = 2-4 per group). Many adverse events (AE) occurred from about day 10; 2 subjects dropped out and 1 continued on a reduced FBM dose. Pharmacokinetic studies were repeated on day 21 for the 16 subjects who completed the study. FBM was measured in plasma and urine by high-performance liquid chromatography (HPLC). VPA and its 2-en, 4-en, and 3-oxo metabolites in plasma, and VPA (nonconjugated and total), and its 3-oxo and 4-hydroxy metabolites in urine were measured by gas chromatography/mass spectrometry (GC/MS). Mean plasma FBM trough concentrations on day 21 ranged from 26.9 mu g/ml (1,200 mg dose) to 76.8 mu g/ml (3,600-mg dose). Mean plasma VPA C max values were 32-42 mu g/ml in the various subgroups when VPA only was administered. Higher plasma VPA levels were observed when FBM was administered concurrently (55.4-63.8 mu g/ml). The excretion of 3-oxo-VPA in urine was significantly lower on day 21 than on day 7, whereas VPA-glucuronide was significantly increased. The effects of FBM on VPA disposition were dose dependent and were maximal at approximately 2400 mg/day. FBM has caused significant inhibition of the beta-oxidation pathway for VPA metabolic clearance, and this had been largely compensated by increased VPA glucuronidation.

Adult↗
PubMed1996

Pharmacokinetics and metabolism of genaconazole, a potent antifungal drug, in men.

The pharmacokinetics of genaconazole, a racemic triazole antifungal agent comprising 50% RR and 50% SS enantiomers, were studied in 12 healthy male volunteers after a single oral dose of 200 mg. The serum samples were analyzed for the two enantiomers by using a chiral high-pressure liquid chromatography assay. The concentrations of the RR and SS enantiomers in serum were virtually identical. The mean values for the maximum concentrations in serum (Cmax) (1.7 micrograms/ml), times to Cmax (4.0 to 4.2 h), half-lives (83 h), and areas under the concentration-time curve from 0 h to infinity (195 to 199 micrograms.h/ml) were similar for the two enantiomers. The results showed that the pharmacokinetic profiles of the two enantiomers were similar after a single oral dosing of the racemate. The pharmacokinetics of the RR enantiomer were also evaluated in 12 healthy male volunteers after a single oral dose of 100 or 200 mg. The ratios of the Cmaxs and of the areas under the concentration-time curves from 0 h to infinity for the two doses were about 2, indicating a dose proportionality. In a separate study, six healthy male volunteers received a single oral dose of 50 mg of 14C-labeled genaconazole. The Cmax values for total radioactivity (14C) and intact genaconazole were virtually identical (0.6 micrograms/ml). The mean half-lives in serum were about 73 h for both total radioactivity and genaconazole. The amounts of total radioactivity excreted in the 0 to 240-h interval (representing approximately three half-lives) in urine and feces were 66.6 and 9.3% of the dose, respectively; 64.4% of the dose was excreted in urine as parent drug. There were no detectable metabolites in either serum or urine. The data demonstrate that genaconazole (racemate) is well absorbed, undergoes negligible biotransformation, and is slowly excreted, primarily in the urine.

Administration, Oral↗
PubMed1995

Effect of food on the oral bioavailability of isosorbide-5-mononitrate administered as an extended-release tablet.

We evaluated the effect of a high-fat breakfast and gastric emptying rate on the oral bioavailability of a isosoribide-5-mononitrate (5-ISMN) controlled-release tablet formulation (IMDUR 60-mg tablets, Astra Hässle AB, Mölndal, Sweden) relative to an oral solution in 18 healthy men. Gastric emptying was monitored by radiotelemetry using the Heidelberg capsule technique. After administration of the 5-ISMN 60-mg solution, absorption was rapid with mean peak plasma 5-ISMN concentrations of 1533 ng/mL achieved in less than 1 hour. In contrast, after administration of IMDUR 60-mg tablets, the drug was more slowly absorbed, reaching mean peak plasma concentrations of 541 ng/mL in 3 to 4 hours. The bioavailability of 5-ISMN from IMDUR tablets under fasted conditions was approximately 78% relative to the solution; and, in the presence of food, the bioavailability was slightly increased to 86% (P = .057). The mean gastric residence time of IMDUR tablets under fasted conditions was 68 minutes, and in the presence of food was increased to 478 minutes, with 9 of the 18 subjects having gastric emptying delayed for at least 600 minutes. We conclude that in the presence of food, gastric emptying time is considerably increased causing a delay in drug absorption and a slight increase in the bioavailability of 5-ISMN from this controlled-release tablet formulation, however this effect is not clinically relevant.

Administration, Oral↗
PubMed1995

Effects of felbamate on the pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine.

The effects of felbamate on the multiple dose pharmacokinetics of the monohydroxy and dihydroxy metabolites of oxcarbazepine were assessed in a placebo-controlled, randomized, double-blind crossover study in 18 healthy male volunteers. Oxcarbazepine, 1200 mg/day, was administered on an open basis in combination with double-blind placebo or 2400 mg/day felbamate for two 10-day treatment periods separated by a 14-day washout period. Pharmacokinetic parameters of monohydroxyoxcarbazepine and dihydroxyoxcarbazepine were determined from plasma and urine samples obtained on the tenth day of each treatment period. Felbamate had no effect on monohydroxyoxcarbazepine plasma or urine pharmacokinetics compared with placebo, but it significantly increased values for dihydroxyoxcarbazepine maximum concentration and area under the curve from 0 to 12 hours, as well as urinary excretion of free and total dihydroxyoxcarbazepine. The mechanism that may account for the observations is the induction of oxidative metabolism of monohydroxyoxcarbazepine. Despite these changes, the relative amount of dihydroxyoxcarbazepine is small in comparison to monohydroxyoxcarbazepine, and antiepileptic activity is associated with monohydroxyoxcarbazepine rather than dihydroxyoxcarbazepine. Therefore we conclude that felbamate has no clinically relevant effects on the pharmacokinetics of oxcarbazepine in humans.

Adolescent↗
PubMed1995

Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive.

The effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive containing 30 micrograms ethinyl estradiol and 75 micrograms gestodene were assessed in a randomized, double-blind, placebo-controlled parallel-group study in healthy premenopausal female volunteers established in a regimen of oral contraceptive use. They received either placebo or 2400 mg/day felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles (months 1 and 2). Pharmacokinetic assessments of ethinyl estradiol and gestodene were performed on day 14 of both cycles. To determine whether ovulation occurred, plasma progesterone and urinary luteinizing hormone levels were measured, and diaries recording vaginal bleeding were kept. Felbamate treatment resulted in a significant 42% decrease in gestodene area under the plasma concentration-time curve (0 to 24 hours) (p = 0.018) compared with baseline, whereas a minor but not clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. There were no changes in the pharmacokinetics of ethinyl estradiol or gestodene after placebo treatment. No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment. Because of the effect of felbamate on the pharmacokinetics of gestodene and the report of intermenstrual bleeding, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during felbamate treatment.

Adult↗
PubMed1995

Loratadine administered concomitantly with erythromycin: pharmacokinetic and electrocardiographic evaluations.

OBJECTIVE: To evaluate the effects of coadministration of loratadine and erythromycin on the pharmacokinetics and electrocardiographic repolarization (QTc) pharmacodynamics of loratadine and its metabolite descarboethoxyloratadine in healthy volunteers. METHODS: Twenty-four healthy volunteers were studied in a prospective, double-blind crossover design while confined in a Clinical Research Center. The primary pharmacodynamic end point of the study was the difference between baseline and day 10 mean QTc intervals obtained from surface electrocardiograms. Plasma concentrations of loratadine, descarboethoxyloratadine, and erythromycin were measured on treatment day 10 for pharmacokinetic analysis. Subjects received in random sequence the following three treatments for 10 consecutive days during three separate study periods: 10 mg loratadine every morning plus 500 mg erythromycin stearate every 8 hours, or 10 mg loratadine every morning plus placebo every 8 hours, or placebo every morning plus 500 mg erythromycin stearate. RESULTS: Concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine (40% increase in area under the plasma concentration-time curve [AUC]) and descarboethoxyloratadine (46% increase in AUC) compared with loratadine alone. Analysis of variance showed no difference between the treatment groups in effect on QTc intervals compared with baseline, and no significant change from baseline was observed. No clinically relevant changes in the safety profile of loratadine were observed, and there were no reports of sedation nor syncope. CONCLUSION: Although concomitant administration of loratadine and erythromycin was associated with increased plasma concentrations of loratadine and descarboethoxyloratadine, no clinically relevant changes in the safety profile of loratadine were observed. In this study, 10 mg loratadine administered orally for 10 consecutive days was well tolerated when coadministered with therapeutic doses of erythromycin stearate.

Adult↗
PubMed1995

Effects of felbamate on the pharmacokinetics of phenobarbital.

The effects of felbamate on the pharmacokinetics of phenobarbital and one of its main metabolites, parahydroxyphenobarbital, were assessed in a parallel-group, placebo-controlled, double-blind study, in 24 healthy volunteers. Pharmacokinetic parameters of phenobarbital and parahydroxyphenobarbital were determined from plasma and urine samples obtained after 28 days of daily administration of 100 mg phenobarbital and after a further 9 days of phenobarbital plus 2400 mg/day felbamate or placebo. Felbamate increased phenobarbital values for area under the plasma concentration-time curve from 0 to 24 hours and maximum concentration by 22% and 24%, respectively, whereas placebo had no effect. This increase was caused by a reduction in parahydroxylation of phenobarbital and possibly through effects on other metabolic pathways. Because felbamate inhibits the S-mephenytoin hydroxylase (CYP2C19) isozyme in vitro, it appears that phenobarbital hydroxylation is mediated in part by this isozyme.

Adult↗
PubMed1995

Pharmacokinetic interaction studies between felbamate and vigabatrin.

To assess the possible occurrence of pharmacokinetic interactions between the antiepileptic agents felbamate and vigabatrin, two randomized, double-blind, placebo-controlled, crossover studies were conducted in healthy male volunteers. In Study I, 18 subjects received oral vigabatrin 1000 mg every 12 h for two 8 days periods with felbamate 1200 mg every 12 h or placebo. In Study II, 18 other volunteers were administered oral felbamate 1200 mg every 12 h for two 8 days periods with vigabatrin 1000 mg every 12 h or placebo. On the eighth day of each treatment period, blood and urine samples were collected over 12 h for determination of the active S(+)- and inactive R(-)-vigabatrin enantiomer concentrations (Study I) or felbamate concentrations (Study II). In Study I, the pharmacokinetic parameters of R(-)-vigabatrin were similar during co-administration with felbamate or placebo. Felbamate produced a 13% increase in AUC(0.12 h) and an 8% increase in urinary excretion of S(+)-vigabatrin. Although these changes were statistically significant, their magnitude was small. In Study II, the pharmacokinetic parameters of felbamate were similar during concurrent administration with vigabatrin or placebo. These data indicate that there are no clinically relevant pharmacokinetic interactions between felbamate and vigabatrin in man.

Administration, Oral↗
PubMed1995

Pharmacokinetics and metabolism of 14C-isepamicin in humans following intravenous administration.

Twelve healthy adult male volunteers received 1 g (base equivalent) of 14C-isepamicin (131 microCi) as an intravenous bolus over 5 min. The areas under the plasma concentration-time curves at infinity for isepamicin (196 micrograms*h/ml) and total radioactivity (164 micrograms*h/ml) were similar, indicating no biotransformation of isepamicin. The disappearance of isepamicin from plasma followed a triexponential decline, with half-lives of 0.17, 2.12, and 34 h for the alpha, beta, and gamma phases, respectively. However, the contribution of the gamma phase to the total area under the concentration-time curve was only 2.6%. There were no detectable metabolites in plasma and urine, confirming that isepamicin was not biotransformed. The cumulative levels of isepamicin and total radioactivity excretion in urine from 0 to 120 h were 97.3 and 92.1% of the dose, respectively, indicating that the drug was excreted mainly as unchanged isepamicin in urine.

Adult↗
PubMed1995

Pharmacokinetics of intravenously administered isepamicin in men.

The pharmacokinetics of isepamicin, a broad-spectrum aminoglycoside antibiotic, were studied in men after intravenous administration. Three groups of six volunteers received isepamicin for 10 consecutive days by 0.5-h intravenous infusions at respective dosages of 7.5 mg/kg of body weight once daily, 7.5 mg/kg twice daily, and 15 mg/kg once daily. Levels of isepamicin in plasma and urine were determined by a specific high-performance liquid chromatography method. For all three groups, steady-state concentrations of the drug in plasma were attained with the first dose. The area under the concentration-time curve for plasma and urinary drug excretion were dose proportional. A half-life ranging from 2.0 to 2.5 h was independent of the dosage regimen. Isepamicin excreted in urine over 24 h accounted for about 100% of the dose. The results show that the pharmacokinetics of isepamicin are linear with these dosage regimens. The drug does not accumulate upon multiple dosing, undergoes no detectable biotransformation, and is cleared solely by urinary excretion.

Adult↗
PubMed1995

Multiple-dose pharmacokinetics of ceftibuten in healthy volunteers.

The pharmacokinetics of ceftibuten, a new cephalosporin antibiotic, and its conversion product, ceftibutentrans, were studied in healthy male volunteers following daily oral administration of a 400-mg capsule for 7 days. Mean concentrations of ceftibuten in plasma obtained on day 5 were similar to those obtained on day 7. Analysis of variance indicated that the concentrations in plasma on days 5 and 7 were at steady state. The mean accumulation factor was 1.14 for day 5 and 1.13 for day 7. The half-life (2.4 h) was independent of the duration of drug administration, and the mean maximum concentration of drug in plasma was 18 to 19 micrograms/ml. Urinary excretion was the major elimination route for ceftibuten, by which 57 to 59% of the drug was excreted unchanged over a 24-h period. The amounts of ceftibuten-trans in plasma and urine were low.

Adult↗
PubMed1995

Pharmacokinetics and dose proportionality of ceftibuten in men.

The pharmacokinetics and dose proportionality of ceftibuten were evaluated in healthy male volunteers receiving single oral doses of 200, 400, and 800 mg of ceftibuten. The drug was absorbed with similar times to the maximum concentration of drug in plasma for all three doses. Concentrations of ceftibuten in plasma increased with increasing dose. Analysis of variance was carried out on the dose-adjusted values for the maximum concentration of drug in plasma and the area under the plasma concentration-time curve; the results indicated that the concentrations in plasma after the 200- and 400-mg doses were dose proportional, and after the 800-mg of dose they were less than dose proportional. The elimination half-life from plasma ranged from 2.0 to 2.3 h and was independent of dose. The total excretion of unchanged ceftibuten in urine accounted for 53 to 68% of the dose, and the renal clearance was estimated to be 53 to 61 ml/min after all doses. The amount of ceftibuten-trans, the major in vitro and in vivo conversion product of ceftibuten, was low in both plasma and urine.

Adult↗
PubMed1995

Biopharmaceutic characteristics of a new extended-release theophylline formulation (Uni-Dur).

BACKGROUND: There is a close relationship between improvement in airway function and the plasma concentration of theophylline, as well as between rapidly rising plasma theophylline concentrations and increased frequency of undesired effects. Development of pharmaceutical formulations and prescribed dosage intervals for theophylline dosage forms should therefore be directed toward providing the most stable plasma concentrations attainable. OBJECTIVE: To characterize the steady-state biopharmaceutic profile of Uni-Dur following once-daily or twice-daily administration. METHODS: Twenty-four adult male volunteers with average theophylline clearance (3.0 and 5.5 L.h-1) received three treatments on separate occasions: Uni-Dur 800 mg once-daily, Uni-Dur 400 mg twice-daily, and Uniphyl 800 mg once-daily. Treatments were taken after a meal for five days with at least 1 week washout between treatment periods. Trough blood samples were collected prior to the AM dose on days 3, 4, and 5, and at specified intervals up to 48 hours after the AM dose on day 5 for subsequent determination of theophylline concentrations in plasma. RESULTS: The area under the plasma concentration-time curve (AUC; microgram.mL-1.h) for theophylline over 24 hours on day 5 was 187 for Uni-Dur 800 mg once-daily, 187 for Uni-Dur 400 mg twice-daily, and 172 for Uniphyl 800 mg once-daily; the peak plasma concentrations were 10.4, 9.4, and 11.0 micrograms.mL-1 and the trough concentrations were 5.5, 7.2, and 3.5 micrograms.mL-1, respectively; fluctuation index (peak minus trough divided by trough) was 78%, 16%, and 231%, respectively. No further accumulation of theophylline occurred after day 3. No serious nor severe adverse events were reported during any treatment. CONCLUSIONS: Uni-Dur is an extended-release formulation that provides stable plasma concentrations of theophylline over a 24-hour period with less fluctuation than observed with a once-daily reference formulation. In subjects with normal theophylline clearance, Uni-Dur administered twice-daily provided remarkably stable theophylline plasma concentrations over a 24-hour period. Absorption of theophylline from Uni-Dur was not affected by food, and no evidence of dose-dumping was observed. Uni-Dur should provide efficacious theophylline therapy with minimal adverse events in patients with symptoms of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema.

Adult↗
PubMed1995

Pharmacokinetics of isepamicin.

Isepamicin is a new aminoglycoside that has activity against many bacteria resistant to other aminoglycosides. The pharmacokinetics of isepamicin have been characterized in neonatal, pediatric, adult, elderly and renally impaired human populations as well as in clinical trials using the techniques of population pharmacokinetics. The pharmacokinetics of isepamicin are uncomplicated and generally similar to those of other aminoglycosides, although there is some evidence that it may have less tissue accumulation. The drug is completely absorbed following intramuscular administration. The drug is not metabolized and unchanged isepamicin accounts for all of the drug substance in plasma and urine. It is completely eliminated via the renal route; consequently dosing in patients with renal insufficiency has to be adjusted according to the degree of renal impairment. The pharmacokinetics of isepamicin are generally linear. Thus peak plasma concentrations and area under the plasma concentration curve (AUC) values are proportional to the administered dose while clearance (1.1-1.3 mL/min/kg), volume of distribution at steady state (0.23-0.29 L/kg) and half-life (2-2.5 h) are independent of dose. There is no significant accumulation of drug in the plasma with once- or twice-daily dosing. The isepamicin plasma concentration curve following a 1 g intravenous dose to healthy volunteers can be best characterized by a tri-exponential curve corresponding to a t1/2 alpha of 0.17 h, a t1/2 beta of 2.1 h, and a gamma-phase of 34 h. The t1/2 beta represents the elimination phase and changes with age and renal functions, while the gamma-phase represents the return of drug to plasma from a deep compartment including binding in renal tissue. The gamma-phase represents less than 3% of the total AUC and does not change with age. Isepamicin readily distributes to extracellular fluid and pulmonary tissue. In conclusion, isepamicin demonstrates predictable linear kinetics and is similar pharmacokinetically to other aminoglycosides. Preliminary indications of decreased tissue accumulation implied from pharmacokinetic and pharmacodynamic characteristics of isepamicin favour once-daily dosing.

Adolescent↗
PubMed1995

Pharmacokinetics of isepamicin in paediatric patients.

The pharmacokinetics of isepamicin were evaluated in 50 paediatric patients ranging from newborn to 13 years old. Children with subdivided according to age: Group I (6-13 years); Group II (4 months to 6 years); Group III (16 days to 4 months); and Group IV (newborn to 16 days). All patients received isepamicin 7.5 mg/kg every 12 hours except those in Group IV who received 7.5 mg/kg once daily. Isepamicin was administered initially as an intravenous 30-minute infusion and then either intravenously or intramuscularly for between 4 and 12 days. Plasma samples were obtained after the first or second dose on day 1 at 0, 0.5, 1, 4, 6, 8 and 12 hours after the initiation of dosing and at 0.5 and 12 hours on other dosing days. Additional samples were collected in the Group IV patients at 18, 20 and 24 hours. Isepamicin showed a similar plasma concentration-time profile in Groups I, II and III (children from 16 days to 13 years), and in these groups the profile was generally similar to that observed in adults. Neonates up to the age of 16 days (Group IV) showed a distinctly different pharmacokinetic profile: a significantly larger AUC, longer half-life, lower Cmax and lower total body clearance. Isepamicin 7.5 mg/kg administered once daily to children less than 16 days old and twice daily to children aged 16 days to 13 years appears to be pharmacokinetically appropriate. The drug was very well tolerated by children of all age groups.

Adolescent↗