[The cognitive effect of alprazolam in healthy volunteers]. / Az alprazolam kognitív funkciókra gyakorolt hatásának vizsgálata egészséges önkénteseken.

Randomised, double blind placebo controlled crossover study has been performed to evaluate the effect of single dose of anxiolytic alprazolam on the cognitive function in 18 healthy male volunteers. The subject received a single dose of 0.75 mg, 1.75 mg alprazolam or placebo in randomised order. Performances on cognitive tests (immediate and delayed word recall test, digit symbol substitution test, critical fusion frequency and multiple choice reaction test) and subjective rating of the drug effect have been evaluated before and at several occasions after the administration of alprazolam or placebo. According to the results of the statistical analysis alprazolam impaired the performance in cognitive tests dose dependently and induced subjective sedation. The applied test battery proved to be capable to measure the effect of the drugs on the cognitive function in pharmacodynamic studies.

Gas chromatography nitrogen phosphorous detection (GC-NPD) assay of tofisopam in human plasma for pharmacokinetic evaluation.

Tofisopam (1-(3,4-dimethoxyphenyl)-4-methyl-5-ethyl-7,8-dimethoxy-5H-2,3-benzodiazepine) has been shown to be an effective anxiolytic agent in the wide-ranging clinical practice. A high sensitive gas chromatography nitrogen phosphorous detection (GC-NPD) bioanalytical method was developed and validated for the purpose of pharmacokinetic study of tofisopam. A liquid-liquid extraction method was used for the sample preparation. The mean recovery for tofisopam was 69.8% and the inter- and intra-day precision values were well below the 15% limit established for bioanalytical methods. A similar compound, girizopam was used as internal standard. The assay was linear in the 5-500 ng/ml range corresponding to therapeutically relevant plasma levels. The concentrations of the compound were measured in the plasma samples of 12 healthy male volunteers and the pharmacokinetic parameters were determined from the plasma concentration-time data. A rapid absorption and distribution, relatively short biological half-life and considerable inter-individual variation in the plasma concentration levels of parent compound were the main characteristics of the pharmacokinetics of tofisopam. According to these results, the new (GC-NPD) bioanalytical method proved to be capable of measuring concentration of tofisopam in human plasma and was successfully applied in a single dose pharmacokinetic study.

[Effect of tofisopam on CYP3A4 enzyme activity on human recombinant 3A4 supersome]. / Tofisopam hatása a humán rekombináns CYP3A4 szuperszóma enzim aktivitására.

Tofisopam is an anxiolytic agent of the BZD group, chemically 1(3-4 dimethoxyphenyl)-4methyl-5-ethyl-7,8 dimethoxy-5H-2,3-benzodiazepine. TZP differs from the traditional 1,4-benzodiazepines regarding the positions of the nitrogen atoms. Three clinical cases were reported where tofisopam increased the blood level of immunosuppressive agent leading clinically relevant adverse drug reaction and necessitating reduction of the dose of the drugs or discontinuation of the administration of tofisopam. The administered immunosuppressive agent is a substrate of the CYP3A4 system, so the effect of tofisopam on the CYP3A4 enzyme was investigated in vitro using human recombinant CYP3A4 supersome. Benzyoxy-4-(trifluoromethyl)-coumarin (BFC) was used as substrate. Tofisopam in 0.1, 0.25, 0.5, 0.75, 1 and 5 micromol/l concentrations inhibited dose dependently the enzyme activity. Activity inhibition rates were 4%, 29%, 40%, 56%, 61% and 94%, respectively and the IC50 was 0.8 micromol/l. The IC50 of positive control substance ketoconazole was 0.03 micromol/l. In in vitro experiments the inhibitory effect of tofisopam was lower than that of ketoconazole (potent CYP3A4 inhibitor) with an order of magnitude. According to the in vitro results it could be concluded that tofisopam is an inhibitor of CYP3A4 but to clarify the clinical importance of this inhibition further human clinical data are needed.

Influence of food on the oral bioavailability of deramciclane from film-coated tablet in healthy male volunteers.

The effect of a high-fat meal on the oral bioavailability of deramciclane 30 mg tablet was evaluated in 18 healthy male volunteers in a randomised, single dose, two-way crossover study. The drug was administered following an overnight fast or a standardised high-fat breakfast. The plasma concentrations of deramciclane and N-desmethylderamciclane were determined by using a validated HPLC-MS -MS/MS method. An effect of food on the bioavailability was indicated if the 90% confidence interval (CI) for the ratio of geometric means of fed and fasted treatments was not contained in the equivalence limit of 0.8-1.25 for AUC and C(max). The ratios of the mean C(max) and AUC(0-infinity) values of deramciclane were 1.24 (90% CI 1.12-1.38) and 1.31 (90% CI 1.21-1.41) in fed versus fasted subjects, which overlapped but exceeded the equivalence limit. In contrast to the parent compound, the 90% CI of the mean ratios for AUC(0-infinity) and C(max) of N-desmethylderamciclane were within the predefined range. The 24 and 31% increase in C(max) and AUC(0-infinity) of deramciclane, respectively, under fed condition is modest and probably has no clinical significance since it is relatively small compared to the inter-individual variability of these parameters.

[Study of the acid buffering capacity of dietary components regarding food-drug interactions]. / Táplálék összetevók in vitro savtompító képességének vizsgálata a gyógyszer-ételinterakció összefüggésében.

Food intake is known to exert numerous effects on drug pharmacokinetics through a variety of mechanisms, and for some medicinal compounds, food-drug interaction could prove of crucial clinical importance. As for acid-labile drugs, bioavailability studies performed in both fasting and fed states are considered essential. A simple and fast in vitro procedure using the USP Dissolution Apparatus II (paddle method) was applied to study acid buffering capacity of food components under simulated in vivo environment. As expected, carbohydrates (starch, sugars) and fat (oil emulsions) failed to show considerable acid buffering capacities, while protein-containing components (milk powder, gelatine) showed significant acid buffering capacity. The results of an in vitro model applying the so-called "standard meal" were in correlation with data obtained from studies performed in healthy volunteers. Nevertheless, in vitro models simulating both the fed and the fasting states in the GIT help explore factors related to food effect on drug dissolution; and consequently, achieve better insight into postprandial drug behaviour.

In vitro simulation of food effect on dissolution of deramciclane film-coated tablets and correlation with in vivo data in healthy volunteers.

The in vitro dissolution profiles of deramciclane 30 mg film-coated tablets, an acid-labile new 5-HT receptor antagonist, were studied under simulated fasting and fed conditions. Artificial gastric juice with pH adjusted to that of fasting conditions was applied either alone or after adding different dietary components. The use of the USP dissolution apparatus II (paddle method) showed that the presence of dietary components has markedly affected the amount of unchanged drug dissolved. As a similar tendency had been observed in food-effect studies in healthy volunteers, cumulative area under the curve (AUC(cum)) for both fed and fasting conditions were compared and an in vitro--in vivo correlation (IVIVC) was evaluated. A linear relationship was established between logarithmic in vivo blood sampling time and in vitro dissolution time assigned to equal AUC(cum) ratios (AUC(cum, fed)/AUC(cum, fasting)). Despite its limitations, in vitro modelling of in vivo conditions might help provide a base for predicting in vivo drug behaviour.