The kinetics of oxiracetam after single intravenous and oral doses (2000 mg) were investigated in four healthy volunteers. Following intravenous administration, the decline in serum levels showed a prolonged, rapid phase followed by a delayed terminal phase. Mean residence times ranged from 3.9 to 6.5 h. Volumes of distribution ranged from 0.9 to 1.81 X kg-1, whereas clearance values ranged from 100 to 119 ml X h-1 X kg-1 More than 90% of the intravenous dose was recovered unchanged in the urine within 48 h. Oral administration resulted in peak levels within 1-2 h; thereafter, the decline in serum levels showed a pattern similar to that observed after the intravenous dose--almost 50% of the oral dose was excreted in the urine within 6 h. The absolute availability of oral oxiracetam was 75 +/- 7%.

Administration, Oral↗

PubMedDate not supplied

In vivo plasma protein binding interaction between valproic acid and naproxen.

The effect of naproxen on the kinetics of free and total plasma valproic acid (VPA) was investigated in 6 normal volunteers by using a recently developed simple ultrafiltration technique associated with an immuno-enzymatic assay (Free Level System I, Syva). Each subject received a single oral dose of sodium valproate on two occasions: a) on a control day and b) during concurrent treatment with naproxen (500 mg b.i.d. for 5 consecutive days). Naproxen caused a slight but significant decrease in total plasma VPA levels but left free VPA levels essentially unchanged. The free VPA fraction increased with increasing total VPA concentrations: at equivalent values of total VPA, however, the free fraction was higher in the presence of naproxen. It is concluded that naproxen exerts a moderate displacing effect on protein bound VPA, thereby increasing the clearance of total drug but leaving essentially unchanged the clearance of free drug.

Adult↗

PubMedDate not supplied

Comparative pharmacokinetics and pharmacodynamics of eterobarbital and phenobarbital in normal volunteers.

The comparative pharmacokinetics and pharmacodynamics of single oral doses of eterobarbital (N,N'-dimethoxymethylphenobarbital, DMMP, 400 mg) and phenobarbital (200 mg) were evaluated in a double-blind study in 8 normal volunteers. Following administration of DMMP, no unchanged drug could be detected in serum. The active monomethoxymethyl metabolite (MMP) appeared rapidly in the circulation but its concentration remained generally low and declined below the limit of detection (0.5 micrograms/ml) usually before 9.5 h. Serum levels of DMMP-derived PB increased slowly and reached a peak between 24 and 48 h in most cases. One subject showed an atypical pharmacokinetic profile, characterized by relatively high levels of MMP and a delayed appearance of low levels of PB. After administration of PB, serum drug levels peaked within 1.5 h and remained, at all sampling times, higher than those observed after intake of DMMP. Compared with DMMP, PB induced greater sedative effects as assessed by visual analogue rating scale, critical flicker fusion frequency and multiple sleep latency tests.

Administration, Oral↗

PubMedDate not supplied

Oxiracetam pharmacokinetics following single and multiple dose administration in the elderly.

The kinetics of the nootropic drug oxiracetam was studied in 6 elderly female patients (age range 69-96 years) in good physical condition. After a single oral dose (800 mg), serum oxiracetam levels reached a peak (25 +/- 6 micrograms/ml) within 1-3 h and declined thereafter with a half-life of 3 to 6 h. Eighty-four percent of the administered dose was recovered in urine as unchanged drug within 24 h. During a maintenance regimen (800 b.i.d. at 8 a.m. and 2 p.m.) for 7 days oxiracetam did not show any accumulation in serum, trough serum levels before the morning and afternoon doses being 4.6 +/- 2.3 and 17.0 +/- 8.2 micrograms/ml respectively on day 4 and 5.7 +/- 3.3 and 17.9 +/- 7.7 micrograms/ml respectively on day 7. Comparison with previous pharmacokinetic data obtained in young subjects suggests that the clearance of the drug is lower in the elderly, probably as a result of the physiological decrease in renal function in old age.

Age Factors↗

PubMedDate not supplied

Pharmacokinetics of flutoprazepam, a novel benzodiazepine drug, in normal subjects.

The single dose pharmacokinetics of flutoprazepam and its active N-desalkyl metabolite were determined in 8 normal subjects by using newly developed, highly sensitive, GC-MS and HPLC techniques. Following a 2 mg dose of the drug, the concentrations of unchanged flutoprazepam in serum were extremely low (below 5 ng/ml at 2 h) and declined rapidly to undetectable levels within 6-9 h after dosing. At all sampling times, the serum concentration of the N-dealkylated metabolite (N-desalkylflurazepam) was much greater than that of the parent compound. This metabolite appeared in serum rapidly (within 2 h), reached a peak between 2 and 12 h and declined slowly, with an elimination half-life of about 90 h on average. The serum concentration of two additional putative metabolites (3-hydroxy-flutoprazepam and N-desalkyl-3-hydroxy-flutoprazepam) was below the limit of detection (2 ng/ml) in all samples. Mild CNS effects (documented by prolonged choice reaction time) were present at 2 and 4 h but were no longer detectable at 9 h. It is suggested that unchanged flutoprazepam is unlikely to contribute significantly to clinical effects and that the drug exerts its therapeutic activity through conversion to the slowly eliminated N-desalkyl metabolite.

Administration, Oral↗

PubMedDate not supplied

Pharmacokinetic studies on IdB 1016, a silybin- phosphatidylcholine complex, in healthy human subjects.

IdB 1016 is a complex of silybin (the main active component of silymarin) and phosphatidylcholine, which in animal models shows greater oral bioavailability and therefore greater pharmacological activity compared with pure silybin and silymarin. In order to assess its pharmacokinetic profile in man, plasma silybin levels were determined after administration of single oral doses of IdB 1016 and silymarin (equivalent to 360 mg silybin) to 9 healthy volunteers. Although absorption was rapid with both preparations, the bioavailability of IdB 1016 was much greater than that of silymarin, as indicated by higher plasma silybin levels at all sampling times after intake of the complex. Regardless of the preparation used, the terminal half-life was relatively short (generally less than 4 h). In a subsequent study, 9 healthy volunteers received IdB 1016 (120 mg b.i.d., expressed as silybin equivalents) for 8 consecutive days. The plasma silybin level profiles and kinetic parameters on day 1 were similar to those determined on day 8. Most of the silybin present in the systemic circulation was in conjugated form. Less than 3% of the administered dose was accounted for by urinary recovery of free plus conjugated silybin, a significant proportion of the dose probably being excreted in the bile. It is concluded that complexation with phosphatidylcholine in IdB 1016 greatly increases the oral bioavailability of silybin, probably by facilitating its passage across the gastrointestinal mucosa.

Administration, Oral↗

PubMedDate not supplied

Comparative pharmacokinetics and bioavailability of two oral formulations of thiocolchicoside, a GABA-mimetic muscle relaxant drug, in normal volunteers.

The comparative pharmacokinetic and bioavailability profile of two different formulations (tablets and capsules) of thiocolchicoside was investigated in 8 healthy male volunteers after administration of single oral 8 mg doses. Plasma samples were assayed by a capillary gas chromatography--mass spectrometry (GC-MS) method following enzymatic hydrolysis of thiocolchicoside to its aglycone (3-demethylthiocolchicine) and no attempt was made to account for the possible occurrence of hydrolysis in vivo. Irrespective of the formulation used, the drug was rapidly absorbed from the gastrointestinal tract, peak levels of about 17 ng/ml being detected within 1 h in most subjects. Elimination was rapid, with mean MRT values of 5-6 h. All kinetic parameters showed considerable interindividual variability but none differed significantly between the two formulations. Relative to the tablet formulation, the oral bioavailability of the capsule formulation was 1.06 +/- 0.39.

Administration, Oral↗

PubMedDate not supplied

The cost benefit ratio of enantiomeric drugs.

Several drugs possess a chiral structure, i.e. they contain one or more stereogenic centres in their molecule. While naturally occurring active principles usually contain a single enantiomer, most chiral drugs produced by chemical synthesis are used in the form of racemic mixtures of two or more diastereoisomers. These stereoisomers (including enantiomers) may interact in different ways with biological structures and, therefore, may exhibit widely different pharmacokinetic properties. In the pharmaceutical industry, partly in response to increasing demands raised by regulatory authorities, these considerations justify the current trend to develop the single enantiomer characterized by the most favourable profile of activity (eutomer). The availability of new chemical and analytical technologies facilitates stereoselective synthetic processes and separation of individual enantiomers from racemic mixtures. Any decision to develop a drug as a single enantiomer, however, should be made only after careful evaluation of the cost-benefit ratio, i.e. when the advantages of the eutomer in terms of efficacy and tolerability outweigh the associated increase in production and development costs with respect to the racemic drug. This article takes into consideration synthetic procedures and pharmacological profiles for a number of chiral drugs in therapeutic use (naproxen, labetalol, and warfarin) or selected for clinical development, such as the beta-blocker dilevalol or the mucokinetic agent 3'-hydroxyfarrerol. These examples demonstrate that the kinetic, pharmacological and toxicological properties of individual enantiomers need to be clearly characterized before any decision can be made concerning the development of a chiral drug. The choice of preferentially developing a single enantiomer should be based on careful consideration of production and development costs and actual therapeutic advantages especially in terms of improved safety.

Animals↗

PubMedDate not supplied

A double-blind, placebo-controlled clinical study on the effect of a standardized ginseng extract on psychomotor performance in healthy volunteers.

Various tests of psychomotor performance were carried out in a group of 16 healthy male volunteers given a standardized preparation of Korean ginseng (G 115; 100 mg twice a day for 12 weeks) and in a similar group given identical placebo capsules under double-blind conditions. A favourable effect of G 115 relative to baseline performance was observed in attention (cancellation test), processing (mental arithmetic, logical deduction), integrated sensory-motor function (choice reaction time) and auditory reaction time. However, end performance of the G 115 group was superior statistically to the placebo group only in mental arithmetic. No difference between G 115 and placebo was found in tests of pure motor function (tapping test), recognition (digit symbol substitution) and visual reaction time. No adverse effects were reported. It is concluded that G 115 may be superior to placebo in improving certain psychomotor functions in healthy subjects.

Adult↗

PubMedDate not supplied

Effects of valpromide and viloxazine on the elimination of carbamazepine-10,11-epoxide, an active metabolite of carbamazepine.

Explore the source record for details and available documents.

Adolescent↗

PubMedDate not supplied

Free and total serum concentrations of carbamazepine and carbamazepine-10,11-epoxide in infancy and childhood.

Total and free serum concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) at steady state were determined in 10 infants (ages 4-13 months), 10 preschool children (ages 3-5 years), and 11 school children (ages 7-11 years) receiving equivalent doses of CBZ alone. Free and total CBZ levels tended to increase with increasing age, while CBZ-E levels did not show any significant age dependency. As a result, CBZ-E/CBZ ratios were higher in infants and preschool children than in the older age group. The degree of plasma protein binding of CBZ and CBZ-E did not show any important differences among the various groups. These data provide evidence that, within a pediatric population, CBZ shows age-related dispositional changes which may be clinically important.

Age Factors↗

PubMedDate not supplied

Sodium valproate and valpromide: differential interactions with carbamazepine in epileptic patients.

To evaluate the comparative effects of valproic acid (VPA) and valpromide (VPM) on plasma levels and protein binding of carbamazepine (CBZ) and CBZ-10,11-epoxide (CBZ-E), 12 adult epileptic patients stabilized on CBZ monotherapy were divided into two groups. One group (n = 6) received sodium valproate (1,100 mg/day) for 2 weeks, while the other group (n = 6) was given, for the same period, a dosage of VPM (1,200 mg/day) expected to produce VPA levels equivalent to those achieved with valproate. Plasma CBZ levels were not affected by either treatment. In the valproate-treated group, plasma CBZ-E levels increased by 101% (range, 29-238%) within 1 week of combined therapy (p less than 0.02) and returned to baseline values after VPA treatment was stopped. In the VPM-treated patients, the elevation of plasma CBZ-E levels was much greater. In this group, plasma CBZ-E increased by 330% (range, 110-864%), and this was associated in two patients with the appearance of adverse effects which subsided after reducing the VPM dosage. The plasma protein binding of CBZ and CBZ-E was not affected significantly by VPM or valproate therapy. Plasma VPA levels were similar in the two groups. It is concluded that VPM is not simply a prodrug of VPA. Although both VPA and VPM increase CBZ-E levels--probably by inhibiting the enzyme epoxide hydrolase--the interaction caused by VPM is of much greater magnitude and potential clinical significance.

Carbamazepine↗

PubMedDate not supplied

Vigabatrin in the treatment of epilepsy: a double-blind, placebo-controlled study.

The efficacy and tolerability of vigabatrin (gamma-vinyl GABA, GVG), given as add-on therapy to 23 adult outpatients with severe drug-resistant epilepsy (17 with partial seizures), were studied using a double-blind, placebo-controlled, crossover design. The study consisted of two 7-week periods during which vigabatrin and placebo were administered in random sequence. Dosage was 1.0 g twice daily for patients weighing less than or equal to 65 kg and 1.5 g twice daily for patients weighing greater than 65 kg. Three patients were dropped from the study, two for reasons unrelated to treatment and one because of the appearance of vertigo, headache, dysarthria, and ataxia, which subsided rapidly when vigabatrin was stopped (3 g daily). Sixteen of the 20 patients available for analysis showed a decrease in the total number of seizures as compared with the placebo period. Of these, 12 showed a greater than 50% reduction in seizure frequency and 4 of the 12 showed a greater than 75% reduction. Both the total number of seizures and the number of partial seizures were significantly reduced by vigabatrin (p less than 0.01). Only in the patient who dropped out were severe adverse effects seen. The most frequently reported unwanted effect was mild drowsiness, which developed in seven patients on vigabatrin and in one on placebo. Positive effects, however, were also seen with six patients who reported an improved sense of well-being while receiving vigabatrin as compared with only 1 during the placebo period. No consistent changes in electrocardiogram (ECG), electroencephalogram (EEG), and visual-, auditory-, and somatosensory-evoked potentials were seen during the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗