Daunorubicin and daunorubicinol tissue concentrations in gastric cancer patients after local administration of a liposomal preparation.

BACKGROUND: In order to study a model that maximizes gastric cancer tissue and lymph node exposure to antineoplastic drugs while simultaneously reducing their systemic bioavailability, we implemented a preliminary investigation of the disposition of a daunorubicin liposomal preparation (D) in gastric cancer patients by means of gastric submucosa injection. METHOD: After a dose finding study, 12 patients (candidates for gastric resection because of gastric cancer) were studied by administering two doses of 50 mg of D (the highest tolerated dose) 1 week before surgery. RESULTS: Mean tissue concentrations at surgery were higher in cancer, normal non-injected peritumoral mucosa, and lymph node tissues than in serum or urine, in which there were only trace concentrations. While epigastric pain and histological modifications (inflammation and thickening of the gastric layers) were manifest in patients treated with 75 mg doses in the dose finding session, no clinical signs or symptoms of toxicity were recorded in those administered with 50 mg doses. CONCLUSIONS: Local administration of D may allow it to reach high concentrations in normal non-injected peritumoral mucosa, and lymph nodes, while simultaneously avoiding significant systemic exposure and toxicity. This procedure could merit further investigation, in view of a possible use of anthracyclines against metastatic diffusion through the lymphatic system in gastric cancer patients who are candidates for gastric resection.

Pharmacokinetics of two oral cyclosporin a formulations in clinically stable heart-transplant patients.

In order to evaluate the pharmacokinetics of cyclosporine A comparing the traditional (CsA-SCG) with the microemulsion formulation (CsA-ME), 20 clinically stable heart-transplant patients were enrolled in the study. All patients were on a thrice-daily dosage regimen (mean single dose 1.14 +/- 0.4 mgkg(-1)body weight) of CsA-SCG. The steady-state area under the concentration-time curve during a dosage interval was calculated during three sequential periods: (1) the first after the morning oral dose of CsA-SCG; (2) the second (8 days later) after 2 hours intravenous infusion of cyclosporine; (3) the third after the CsA-ME morning oral dose (30 days after the milligram-to-milligram dose conversion). After switching from standard formulation CsA-SCG to CsA-ME, significant changes were observed in C(max)(ss)( 732 +/- 178 vs 935 +/- 250 ng ml(-1), P< 0.001) and t(max)( 2.63 +/- 1.21 vs 1.36 +/- 0.49 h, P< 0.001). The CsA-ME mean bioavailability was higher than CsA-SCG ( 75 +/- 19 vs 66 +/- 16%;P< 0.001). The main CsA pharmacokinetic parameters of both formulations in clinically stable heart-transplant patients presented evident differences from data obtained in other transplant-patient populations.

Oral and intravenous disposition of cyclosporine in psoriatic patients.

After informed consent was obtained and with the approval of the Local Ethical Committee, cyclosporine A (CsA) kinetics was studied in 63 psoriatic patients by giving them 2.5 mg/kg CsA orally. In order to calculate oral bioavailability, F, 22 patients were given the same dose i.v. Values of the calculated kinetic parameters were oral F = 22-63%; half-life, t1/2 beta, = 11.05-13.70 h; volume of distribution, Vd, = 4.00-5.02/L/kg; total body clearance, Cl, = 4.25-4.14 ml/min/kg. The area under the blood concentration time curve was more closely related to the dose (r = 0.66) than were trough levels (r = 0.52). No significant relationship was observed between the kinetic parameters studied and the age of the patient.