4 research outputs found
Zofenopril inhibits the expression of adhesion molecules on endothelial cells by reducing reactive oxygen species.
Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two phase I studies in adults with advanced solid tumours
The doxorubicin analogue MEN-10755 has been identified as a compound with promising antitumour activity based on structure-activity studies of a new series of anthracycline disaccharides. The high antitumour activity of MEN-10755 in human tumour xenografts, including doxorubicin-resistant xenografts, and its unique pharmacological and biological properties made this novel disaccharide analogue an interesting candidate for clinical evaluation. Two pharmacokinetic phase I studies with different dosing schedules were performed in adults with solid refractory malignancies. The pharmacokinetics of MEN-10755 were studied after a 15-min i.v. infusion given once every 3 weeks or once every week for 3 weeks followed by I week rest. Plasma and urine levels of MEN-10755 were measured by HPLC with fluorescent detection. It was possible to combine the pharmacokinetic results of the two studies because there was no accumulation of MEN-10755 before the next infusion of MEN-10755 in the weekly study with I week rest. The administered dose levels on day I in this study were all in the lower range from the 3-weekly study. The postinfusion plasma kinetics of MEN-10755 were best described by a triexponential model. The plasma peak levels (C-max) of MEN-10755 showed a linear relationship with the administered dose. Peak plasma MEN-10755 levels ranged between 474 and 21,587 mug/l. The mean elimination half-life (T-1/2 gamma) was 20.7 +/- 9.0 h. The AUC(0-infinity) was proportional to the administered dose. The mean plasma clearance of MEN-10755 was 6.0 +/- 2.2 1/h per m(2) with a mean volume of distribution (V-ss) of 95.6 +/- 43.4 1/m(2). The mean renal excretion of unchanged drug within 24 h was 4.3 +/- 1.8 %. Compared to epirubicin and doxorubicin, the pharmacokinetics of MEN-10755 were characterized by an approximately twofold shorter terminal half-life, a much lower total plasma clearance and a much smaller volume of distribution