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Biomedical subjects

E Radwanski

Publications and source records attributed to E Radwanski.

At least 37 records · Page 2Linked to original sources
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↗
PubMed1994

Pharmacokinetics of the triazole antifungal agent genaconazole in healthy men after oral and intravenous administration.

The pharmacokinetics of genaconazole, a potent new difluorophenyl-triazole antifungal agent, was studied in 12 healthy male volunteers following a single oral or intravenous administration of the drug. In a randomized two-way crossover design, each volunteer received either two 50-mg genaconazole tablets orally or a parenteral preparation containing 100 mg of genaconazole given as a 30-min intravenous infusion. Both dosage regimens were well tolerated. Blood and urine samples were collected up to 10 days after drug administration. Concentrations of genaconazole in plasma and urine were determined by a specific high-performance liquid chromatography assay with a limit of quantitation of 0.1 microgram/ml. Pharmacokinetic evaluation following oral and intravenous doses indicated that mean values for the area under the concentration-time curve from 0 h to infinity (137 and 136 micrograms.h/ml), half-life (50 and 49 h), volume of distribution (52 and 52 liters), and clearance (12 and 12 ml/min) were independent of the route of drug administration. The oral and intravenous administrations of genaconazole yielded virtually superimposable plasma concentration-time curves, resulting in an absolute bioavailability of 100%. Amounts of unchanged genaconazole found in urine samples from 0 to 240 h after oral and intravenous doses were comparable, and urinary excretion accounted for 76 and 78% of the administered dose, respectively. Renal clearances for the two routes of administration were also similar, and renal clearance accounted for over 80% of the total body clearance. The 100% absolute bioavailability of genaconazole regardless of the route of administration provides greater dosing flexibility in various clinical settings than currently exists.

Administration, Oral↗
PubMed1992

Correlation of in vitro release rate and in vivo absorption characteristics of four chlorpheniramine maleate extended-release formulations.

An in vitro/in vivo correlation was established for four formulations of chlorpheniramine maleate (histamine, H1-blocker) extended-release tablets exhibiting different in vitro release rate characteristics. In vitro release rate data were obtained for 12 individual tablets of each formulation using the USP Apparatus 2, paddle stirrer at 50 rpm in 1000 ml of distilled water at 37.0 +/- 0.5 degrees C. Inspection of the individual and mean release rate data indicated that the in vitro release rate of chlorpheniramine maleate was consistent with the intended design of the four extended-release formulations. The in vivo bioavailability and pharmacokinetics of these formulations were evaluated in 24 healthy subjects under fasting conditions. Wagner Nelson analyses of the in vivo data revealed extended release absorption profiles for all four formulations. Linear regression analyses of the mean percentage of dose absorbed versus the mean in vitro release resulted in a statistically significant correlation (r2 greater than 0.98, P less than 0.001) for each formulation. Qualitative rank-order correlations were observed among all combinations of in vitro and in vivo parameters. These data support a Level A correlation between the in vitro release rate profiles and the in vivo absorption for chlorpheniramine maleate determined under fasting conditions.

Adult↗
PubMed1992

Differential plasma duration of antiplatelet-activating factor and antihistamine activities of oral Sch 37370 in humans.

Preclinical studies have established that Sch 37370 (1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta [1,2-b]pyridin-11-ylidene)piperidine) is an orally active antagonist of platelet-activating factor (PAF) and histamine H1-receptors with potential therapeutic use in the treatment of asthma. To evaluate the efficacy and duration of anti-PAF and antihistamine actions of oral Sch 37370 in humans, a single dose (5 mg/kg) of Sch 37370 was given orally to each of 10 male subjects in a placebo-controlled, double-blind crossover study. Blood samples were drawn before and at various times (2 to 48 hours) after Sch 37370 or placebo. Plasma samples were analyzed for Sch 37370 by a gas chromatographic method, for the anti-PAF activity by measuring the aggregation of platelets stimulated with PAF, and for the antihistamine activity by measuring displacement of [3H]pyrilamine from rat brain membrane binding sites. The plasma anti-PAF activity declined from high levels at 2 hours to barely detectable levels at 24 hours; however, significant activity was still present at 12 hours. The plasma levels of Sch 37370 closely paralleled the anti-PAF profile. The plasma antihistamine activity reached a maximum within 2 to 8 hours and declined thereafter. However, 48 hours after Sch 37370, the antihistamine activity was still present at a significant level in most subjects. It is concluded that, in humans, oral Sch 37370 antagonizes both PAF and histamine with plasma antihistamine activity lasting longer than plasma anti-PAF activity.

Administration, Oral↗
PubMed1990

The effect of antacid and cimetidine on the oral absorption of the antifungal agent SCH 39304.

The single-dose pharmacokinetics of the antifungal agent SCH 39304 (Schering-Plough Corp., Kenilworth, NJ) were assessed alone and in combination with antacid and cimetidine. On three separate occasions nine healthy men received a single oral 50 mg dose of SCH 39304 either alone, with 60 mL antacid, or with oral cimetidine 300 mg four times a day for 4 days. Concomitant antacid or cimetidine administration had no significant effect on any of the SCH 39304 pharmacokinetic parameters studied. The oral absorption of SCH 39304, as assessed by the area under the plasma concentration-time curve (AUC) and the amount of drug recovered unchanged in the urine, was not affected by either antacid or cimetidine. The AUC0-1 for the drug given alone was 80.5 +/- 15.8 micrograms.hr/mL, compared to 81.4 +/- 12.7 and 79.7 +/- 9.6 micrograms.hr/mL with concomitant antacid and cimetidine, respectively. The amount of drug excreted in the urine (Ae0-1) was 22.7 +/- 5.1, 24.2 +/- 9.2, and 23.6 +/- 7.6 mg when the drug was given alone, with antacid, and with cimetidine, respectively. Antacid coadministration delayed absorption as evidenced by an increase in the tmax in 7 out of 9 subjects, although this did not reach statistical significance (P = .082, Wilcoxon test). We conclude that concomitant antacid or cimetidine does not alter the oral absorption or pharmacokinetic disposition of single-dose SCH 39304.

Absorption↗
PubMed1990

Pharmacokinetics of loratadine in patients with renal insufficiency.

The disposition of loratadine, a new orally active histamine H1 receptor antagonist and its primary metabolite descarboethoxyloratadine were characterized in adult volunteers with normal renal function (group I), patients with chronic renal failure, i.e., creatinine clearance less than 30 mL/min (group II), as well as chronic hemodialysis patients (group III). The effect of hemodialysis on the disposition of loratadine and descarboethoxyloratadine was also assessed. Subjects in groups I and II were given a single oral 40 mg dose of loratadine while the patients in Group III received two single 40 mg doses of loratadine (during an interdialytic period and just prior to hemodialysis). Loratadine was rapidly absorbed and the decline of plasma concentrations after attainment of the Cmax was biexponential in all subjects. No significant differences in t1/2 beta were observed between the three groups (8.7 +/- 5.9, 7.6 +/- 6.9, 8.6 +/- 1.6 hrs: in groups I, II, and III, respectively). The apparent total body clearance and apparent volume of distribution of loratadine also did not differ significantly among the three groups. No significant differences in the Cmax or tmax of the metabolite were observed. The metabolite AUC infinity 0 however was significantly greater in group II subjects: (212.4 +/- 37.8, 469.5 +/- 95.4, 325.2 +/- 114.6 ng.hr/mL; groups I, II, and III, respectively). No significant relationship was observed between the terminal elimination half-life of loratadine or descarboethoxyloratadine and creatinine clearance. Hemodialysis augmented endogenous clearance by less than 1%. The disposition of loratadine is not significantly altered in patients with severe renal insufficiency nor is hemodialysis an effective means of removing loratadine or descarboethoxyloratadine from the body.

Adult↗
PubMed1989

Single and multiple dose pharmacokinetic evaluation of flutamide in normal geriatric volunteers.

Single dose and steady-state pharmacokinetics of flutamide (F) and its active plasma metabolite, hydroxyflutamide (HF) were studied in twelve healthy geriatric volunteers administered 250 mg flutamide capsules on day 1 and 250 mg flutamide capsules three times a day on days 2 through 9. After oral administration, F was rapidly absorbed and metabolized. It was present in the plasma in small and variable concentrations, which precluded quantitative assessment of pharmacokinetic parameters for individual subjects. Steady-state plasma concentrations were reached on or before Day 6. The mean steady state Cmax (Day 9), 112.7 ng/ml, occurred at 1.3 hr. Pharmacokinetic analysis of mean data at steady-state gave a distribution and elimination half-life of 0.8 hr and 7.8 hours, respectively. The plasma levels for HF were much higher and less variable than F. The mean Cmax for HF averaged 894 ng/ml at 2.7 hours after a single dose and 1719 ng/ml (Day 9) at 1.9 hr after multiple doses. The distribution and elimination half-lives of HF at steady-state were 1.9 and 9.6 hours, respectively. The steady-state HF plasma concentrations were also achieved on or before Day 6 and were approximately twice those obtained after a single dose. From this study, it has been demonstrated that the pharmacokinetics of F and HF do not change appreciably upon multiple dosing of 250 mg F capsule given three times a day.

Administration, Oral↗
PubMed1988

Excretion of loratadine in human breast milk.

The excretion of loratadine, a new nonsedating antihistamine, into human breast milk was studied in six lactating nonpregnant volunteers. Each volunteer received one 40-mg loratadine capsule. Milk and blood were collected before and at specified times (to 48 hours) after dosing. Plasma and milk loratadine concentrations were determined by a specific radioimmunoassay, and those of an active but minor metabolite, descarboethoxyloratadine, by high performance liquid chromatography (HPLC). Breast milk concentration-time curves of both loratadine and descarboethoxyloratadine paralleled the plasma concentration-time curves. For loratadine, the plasma Cmax was 30.5 ng/mL at 1.0 hour after dosing and the milk Cmax was 29.2 ng/mL in the 0 to 2 hour collection interval. Through 48 hours, the loratadine milk-plasma AUC ratio was 1.2 and 4.2 micrograms of loratadine was excreted in breast milk, which was 0.010% of the administered dose. For descarboethoxyloratadine, the plasma Cmax was 18.6 ng/mL at 2.2 hours after dosing, whereas the milk Cmax was 16.0 ng/mL, which was in the 4 to 8-hour collection interval. Through 48 hours, the mean milk-plasma descarboethoxyloratadine AUC ratio was 0.8 and a mean of 6.0 micrograms of descarboethoxyloratadine (7.5 micrograms loratadine equivalents) were excreted in the breast milk, or 0.019% of the administered loratadine dose. Thus, a total of 11.7 micrograms loratadine equivalents or 0.029% of the administered dose were excreted as loratadine and its active metabolite. A 4-kg infant ingesting the loratadine and descarboethoxyloratadine excreted would receive a dose equivalent to 0.46% of the loratadine dose received by the mother on a mg/kg basis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗