The effect of oil as a dietary component on in vitro dissolution of an acid-labile drug.

The non-benzodiazepine-like anxiolytic agent deramiclane fumarate (EGIA-3886) was used to demonstrate that the presence of high oil/fat content in dissolution media serves as a barrier against accelerated drug degradation in acidic media.

Pharmacokinetics of panomifene in healthy volunteers at phase I/a study.

Panomifene (PAN) /E/-1,2,-diphenyl-1-[4-[2-(2-hydroxyethylamino)-ethoxy]-phenyl]-3, 3,3-trifluoropropene is a new original Hungarian compound and is a tamoxifen (TMX) analog. In the phase I/a study presented here the human tolerance, pharmacokinetics and endocrine effects of a single oral dose of panomifene were evaluated in healthy, post-menopausal, female volunteers. As to the dose escalation, pharmacokinetic studies were carried out at doses of 24, 48 and 96 mg in two volunteers, and 120 mg in one volunteer. To find a suitable dose or dose range, for further evaluation of the drug detailed pharmacokinetics were performed at a selected dose level (24 mg) in 10 volunteers. The pharmacokinetic study showed considerable interindividual variability of the parameters, and only a medium correlation between dose and AUC (r=0.876). At the selected dose level (24 mg p.o.) the peak concentration of the plasma was 67.7 +/- 17.4 ng/ml (Cmax(meas)), the time to peak was 3.6 +/- 1.8 h (t[max(meas)]). The mean of the terminal half-life was 70.0 +/- 23.1 h (t(1/2beta)). The area under the plasma concentration time curve (AUC) calculated by the kinetic equation (AUCcalc) was 4814 +/- 1172 and by the trapezoidal rule (AUCtrap) was 4612 +/- 1357 (ng/ml) h.

Study of the bone marrow penetration of radioactivity after oral administration of radiolabelled girisopam (EGIS-5810) in mice.

Girisopam (EGIS-5810) is a potent anxiolytic compound. Recent in vitro studies with the substance, in Chinese hamster ovary cells, indicated dose-dependent mutagenic activity. At the same time, in ex vivo bone marrow micronucleus tests performed after treating CFLP mice with extreme oral doses (875, 1300 and 1750 mg/kg) no mutagenic activity could be observed at any of the dose-levels. On the basis of the above results, it seemed reasonable to study the absorption and distribution of radioactivity and particularly its bone marrow penetration after administering tritiated and 14C-labelled girisopam at the same doses as those applied in the micronucleus test. The animals were sacrificed 30 minutes, 2 and 24 hours after treatment and the radioactivity content of blood, plasma and bone marrow was determined. For whole body autoradiography studies, the animals were sacrificed at the same time points, however they were treated with tritium-labelled girisopam. The results indicated that the absorption of radioactivity from the gastro-intestinal tract of the animals started immediately. The samples collected had well measurable radioactivity even 30 minutes after treatment. At the same time, it was also evident, that, in spite of the high doses, the absolute amount of radioactivity was rather low. At both dose-levels, the radioactivity concentration was the highest in samples collected 24 hours after treatment. This results indicated extremely delayed absorption. The radioactivity level of bone marrow was practically the same as that measured in blood. The samples of animals treated with the high-dose had higher radioactivity content, however the increase was not linearly proportional to the dose. Disproportionality can probably be explained by delayed absorption. The whole body autoradiography was in good agreement with the results of quantitative determinations. This results confirmed the observations obtained by ex vivo micronucleus test. The radioactivity penetrated in the bone marrow resulting a long time exposure of the radioactivity without any mutagenic effect.