Search

Abstract omitted due to copyright. [ABSTRACT FROM AUTHOR]

Objective: Mexazolam is an oxazolo-benzodiazepine demonstrating chemical similarities to oxazolam and cloxazolam. This trial aimed to assess the effect of mexazolam on psychomotor performance. Design: The study was a double-blind, single-dose, randomised, two-way crossover, placebo-controlled trial. Study participants: 33 healthy male and female adult volunteers. Main outcome measures: Psychomotor performance was evaluated through the Leeds Psychomotor Test Battery [critical flicker fusion (CFF) threshold and choice reaction time with its three components (recognition reaction time - RRT, motor reaction time - MRT, and total reaction time - TRT)] and, in an exploratory way, a car-driving simulation (CDS). After performing a baseline test set, each volunteer received, in a randomised fashion, either a single oral dose of mexazolam 1mg or placebo and, 3 hours later, the test set was repeated. After a washout of at least 10 days, the procedures were repeated in a crossover way. Tolerability was assessed through the reporting of adverse events. Results: A total of 33 healthy subjects were enrolled. In the Leeds Psychomotor Test Battery, no statistically significant differences were found between post- versus pre-placebo results, post- versus pre-mexazolam results, and placebo versus mexazolam results (post-administration: CFF: p = 0.480, RRT: p = 0.195, MRT: p = 0.470, TRT: p = 0.169). In the CDS, there were no statistical differences between placebo and mexazolam scores [pre-administration: total time score (TTS): p = 0.519, best lap time (BLT): p = 0.499; post-administration: TTS: p = 0.940, RRT: p = 0.995]. There was a statistically significant improvement between post- and pre-placebo scores (TTS: p = 0.032, BLT: p = 0.023) and between post- and pre-mexazolam scores (TTS: p = 0.016, BLT: p = 0.030), indicating a learning effect induced by the repetition of the tests. A total of three volunteers reported a total of three adverse events: somnolence, which occurred following mexazolam administration, and headache and flu-like syndrome, which occurred after placebo administration. Conclusions: Mexazolam does not have psychomotor performance-impairing effects at therapeutic doses. Reduced effects on psychomotor performance in anxious patients may lead to better compliance and to specific indications for this benzodiazepine. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate the relative bioavailability and bioequivalence of two omeprazole enteric-coated formulations following repeated doses (steady state) in healthy male and female adult volunteers. Design and Study Participants: The study formulation (Ompranyt 20mg capsules, Bial-Industrial Farmaceutica SA, Spain) was compared with an omeprazole reference formulation (Mopral 20mg capsules, Laboratório Astra, Spain). 24 participants were randomised using a two-way, crossover design to receive either one capsule/day of Ompranyt or one capsule/day of Mopral during two sequential periods of five consecutive days each. The participants were administered the drugs in the fasting state. Omeprazole concentrations in plasma samples were quantified by a validated method using a reversed-phase high performance liquid chromatography with UV detection (HPLC-UV). The validation method is described. Setting: The study was conducted at the Human Pharmacology Unit, Department of Research & Development, Laboratorios Bial (S. Mamede do Coronado, Portugal). Results: The arithmetic mean ± SD values of the area under the plasma concentration versus time curve from time zero to infinity (AUC) were 1474 ± 1417 µg/L·h for Ompranytand 1490 ± 1276 µg/L·h for Mopral. The geometric means ratio (Ompranyt/Mopral) was 0.99, with 90% confidence intervals (CI) of 0.97-1.03. The estimated maximum plasma concentration (C) was 630.1 ± 516.7 µg/L for Ompranytand 736.7 ± 443.3 µg/L for Mopral, with a geometric means ratio (Ompranyt/Mopral) of 0.96 (90% CI: 0.94-0.99). Bioequivalence of these two formulations was accepted based on the two one-sided ANOVA for AUCas well as for C. In both cases, the 90% CI lies within the acceptance range of 0.80-1.25. Conclusion: Bioequivalence of Ompranyt and Mopral was demonstrated after repeated drug administration in fasting conditions, and both products were similarly well tolerated. Therefore, both formulations are expected to be equivalent in a clinical setting. [ABSTRACT FROM AUTHOR]

Release of H-noradrenaline and formation of H-metabolites were studied in the saphenous vein of newborn (mean age, 18 h) and adult dogs. Vein strips were incubated with 0.23 μmol/l of H-noradrenaline during 1 h and washed out for 110 min; thereafter, the perifusion fluid was collected in 5-min samples. Electrical stimulation was applied at 120 min (1 Hz, 2 ms, 100 V, for 5 min). In some experiments the tissues were preincubated with 1 mmol/l pargyline (to inhibit monoamine oxidase). In these experiments, 12 μmol/l cocaine (to inhibit uptake), 41 μmol/l hydrocortisone (to reduce uptake) and 50 μmol/l U-0521 (to inhibit COMT) were present during the perifusion. H-noradrenaline, H-DOPEG, H-NMN, H-DOMA and H-OMDA were separated by column chromatography. The noradrenaline content of the tissue was estimated by HPLC followed by electrochemical detection. A morphological study was also carried out by light and electron microscopy. The endogenous noradrenaline content of the saphenous vein was 4.3 times higher in adults than in neonates. The number of varicosities was similar in adults and newborns but the number of vesicles per varicosity profile was 5 times higher in adults. Hence, the endogenous noradrenaline content per vesicle was about the same in adults and newborns. The accumulation of H-noradrenaline per vesicle was about 5 times higher in newborns than in adults. On the other hand, the vein wall media of neonates was about 3 times thinner than that of adults. The evoked fractional release of tritium was about 10 times higher in neonates than in adults, whether the inactivation pathways were blocked or not. This difference in the evoked fractional release therefore cannot be ascribed to any difference in the efficacy of the inactivation pathways between neonates and adults. On the other hand, the difference also cannot be ascribed to a different alpha-adrenoceptor-mediated inhibition of H-noradrenaline release since, as previously shown, this mechanism is as effective in newborns as in adults. It is concluded that the evoked fractional release of H-noradrenaline is higher in neonates than in adults because in neonates the majority of varicosities (and vesicles) is situated closer to the surface of the tissue such that both uptake from the surrounding media into the stores and release from the stores into the surrounding media become easier in the neonates. [ABSTRACT FROM AUTHOR]

BACKGROUND: Nebicapone is a reversible catechol-O-methyltransferase (COMT) inhibitor. Coadministration of a COMT inhibitor with levodopa and a dopa-decarboxylase inhibitor (carbidopa or benserazide) increases levodopa exposure and its therapeutic effect. OBJECTIVES: The primary objective of this study was to investigate the effect of nebicapone (50, 100, and 200 mg), compared with placebo, on levodopa pharmacokinetics when coadministered with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg. The secondary objectives were to investigate the effect of nebicapone on the erythrocyte-soluble COMT (S-COMT) activity and on the plasma levels of the levodopa 3-O-methylated metabolite (3-O-methyldopa [3-OMD]). Nebicapone's tolerability was also assessed. METHODS: This was a single-center, Phase I, doubleblind, randomized, placebo-controlled, 4-way crossover study conducted in healthy adult volunteers. Each of the 4 single-dose treatment periods was separated by a washout period of > or = 5 days. During the different treatment periods, subjects received a single dose of controlled-release levodopa 100 mg/benserazide 25 mg concomitantly with nebicapone 50, 100, and 200 mg or placebo. Plasma concentrations of nebicapone, levodopa, and 3-OMD were determined by HPLC. Blood samples (7 mL) for determination of plasma concentrations of levodopa, 3-OMD, and 2258 nebicapone, as well as for the assay of S-COMT activity, were collected in potassium EDTA test tubes at the following times: predose and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, and 24 hours postdose. S-COMT activity was assessed as the amount of metanephrine formed by the action of S-COMT on an epinephrine substrate. Spontaneously reported clinical adverse events (AEs) were recorded throughout the study. RESULTS: Sixteen subjects (8 females, 8 males; mean [SD] age, 26.13 [6.29] years; weight, 69.4 [12.4] kg; body mass index, 24.0 [3.0] kg/m2) completed the 4 treatment periods and had data available for pharmacokinetic and pharmacodynamic analyses. Compared with placebo, levodopa C(max) increased 25%, 30%, and 34%, and AUC increased 14%, 37%, and 42% after administration of nebicapone 50, 100, and 200 mg, respectively. After administration of nebicapone 50, 100, and 200 mg, 3-OMD C(max) decreased 44%, 57%, and 58%, and 3-OMD AUC(0-infinity) decreased 33%, 37%, and 45%, respectively, compared with placebo. Extent of exposure to levodopa, as assessed by using AUC(0-t), increased with all doses of nebicapone in relationship to placebo, but the difference did not reach statistical significance. This may be related to a relatively high inter-subject variability: %CVs ranged from 48.0% with nebicapone 100 mg to 66.8% with placebo. Maximum S-COMT inhibition by nebicapone occurred at approximately 1.5 hours postdose and ranged from 57% with nebicapone 50 mg to 74% with nebicapone 200 mg. There was an inverse correlation between plasma concentrations of nebicapone and S-COMT activity; T(max) of nebicapone plasma concentrations and time to occurrence of the maximum inhibition of S-COMT activity appeared to correlate. Nineteen AEs were reported; 8 were assessed by the investigator as possibly related to treatment. All AEs were mild in severity. There were no serious AEs or discontinuations due to AEs. No abnormalities in liver enzyme levels were found. CONCLUSIONS: When administered concomitantly with a single dose of controlled-release levodopa 100 mg/benserazide 25 mg, single doses of nebicapone 50, 100, and 200 mg were well tolerated in these healthy adult volunteers, and dose dependently inhibited S-COMT activity and reduced 3-OMD formation compared with placebo. However, there was no significant difference in levodopa bioavailability. [ABSTRACT FROM AUTHOR]