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Human pharmacokinetics and pharmacodynamics of MF 701 dermatan sulphate administered by continuous intravenous infusion
62
ABSTRACTS
Suppl.XIII, 1991
123
EFFECT
OF DEEMATAN SULFATE MF 701 (DS) ON THE HEMOSTATIC AND A RANDOMIZED, FIBRINOLYTIC PARAMETERS OF HEALTHY VOLUNTEERS: PLACEBO CONTROLLED CLINICAL STUDY Moia, B. Bottasso, P.M. Tenconi, M. Cugno, P.M. A. Tripodi,M. Mannucoi. A. Bianchi Bonomi Hemophilia and Thrombosis Center,
University ,of Milano, Milano, Italy. Eight healthy volunteers were randomized to receive 3 single subcutaneous (s.c.) doses of DS (100, 200 and 400 mg), a single S.C. dose of heparin (5,000 IU) and placebo. Wash out between treatments was two weeks. Blood samples were taken at 0; 1.5; 3; 6; 12 and 24 hours after treatment to measure PT, APTT, TT, thrombin generation, ATIII, HCII, fibrinolytic fibrinogen, tPA antigen and PA1 activity. A activity (fibrin plate), inhibition of thrombin generation significant, dose-dependent was obtained after DS and heparin. The extent of inhibition after 200 mg DS was comparable to that observed with heparin, prolonged after the but lasted longer. APTT was moderately largest DS dose and heparin, but it was not significantly different from that observed with placebo. The reduction of PA1 and the increase in the fibrinolytic activities were due to the seen in the other variation. No changes were circadian parameters. In conclusion we demonstrate that a single DS dose (200, or 400 mg) inhibits the ex vivo thrombin generation to an extent equal or superior to that of heparin and with a longer lasting effect. The effect on fibrinolysis is negligible.
124 HUMAN PHARMACOKINETICS AND PHARMACODYNAMICS OF MF 701 DERMATAN SULPHATE ADMINISTERED BY CONTINUOUS INTRAVENOUS INFUSION. G. Aanellj, B. Cosmi, C. Istituto di G.G. Nenci, G. Houin, F7- Gianese. Renga, F. Federici, Italy; CHU Purpan, Semeiotica Medica, University of Perugia, Toulouse, France; Mediolanum Farmaceutici, Milan, Italy. The pharmacokinetics and haemostatic effects of MF 701 dermatan CDS1 administered by i.v. infusion were studied in 11 healthy sulphate received 0.6 mg/kg/h MF 701 for volunteers. Each subject 10 hours. DS were measured by a chromogenic assay based on the plasma concentrations catalysis of thrombin inhibition by HC II. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28+0.46 h, a plasma clearance of 2.7SkO.46 l/h and a volume of distribution of 4.9221.36 1 (mean&SD). Steady-state was reached 3 to 6 hours after infusion started. The maximal DS plasma concentration was 16.4k5.7 pg/ml. Maximal APTT prolongation over pre-infusion values was 42+7X; TCT performed with bovine and human thrombin was prolonged by 1627% and 83+35X respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with that previously described after i-v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.
ABSTRACTS
Suppl.XIII, 1991
123
EFFECT
OF DEEMATAN SULFATE MF 701 (DS) ON THE HEMOSTATIC AND A RANDOMIZED, FIBRINOLYTIC PARAMETERS OF HEALTHY VOLUNTEERS: PLACEBO CONTROLLED CLINICAL STUDY Moia, B. Bottasso, P.M. Tenconi, M. Cugno, P.M. A. Tripodi,M. Mannucoi. A. Bianchi Bonomi Hemophilia and Thrombosis Center,
University ,of Milano, Milano, Italy. Eight healthy volunteers were randomized to receive 3 single subcutaneous (s.c.) doses of DS (100, 200 and 400 mg), a single S.C. dose of heparin (5,000 IU) and placebo. Wash out between treatments was two weeks. Blood samples were taken at 0; 1.5; 3; 6; 12 and 24 hours after treatment to measure PT, APTT, TT, thrombin generation, ATIII, HCII, fibrinolytic fibrinogen, tPA antigen and PA1 activity. A activity (fibrin plate), inhibition of thrombin generation significant, dose-dependent was obtained after DS and heparin. The extent of inhibition after 200 mg DS was comparable to that observed with heparin, prolonged after the but lasted longer. APTT was moderately largest DS dose and heparin, but it was not significantly different from that observed with placebo. The reduction of PA1 and the increase in the fibrinolytic activities were due to the seen in the other variation. No changes were circadian parameters. In conclusion we demonstrate that a single DS dose (200, or 400 mg) inhibits the ex vivo thrombin generation to an extent equal or superior to that of heparin and with a longer lasting effect. The effect on fibrinolysis is negligible.
124 HUMAN PHARMACOKINETICS AND PHARMACODYNAMICS OF MF 701 DERMATAN SULPHATE ADMINISTERED BY CONTINUOUS INTRAVENOUS INFUSION. G. Aanellj, B. Cosmi, C. Istituto di G.G. Nenci, G. Houin, F7- Gianese. Renga, F. Federici, Italy; CHU Purpan, Semeiotica Medica, University of Perugia, Toulouse, France; Mediolanum Farmaceutici, Milan, Italy. The pharmacokinetics and haemostatic effects of MF 701 dermatan CDS1 administered by i.v. infusion were studied in 11 healthy sulphate received 0.6 mg/kg/h MF 701 for volunteers. Each subject 10 hours. DS were measured by a chromogenic assay based on the plasma concentrations catalysis of thrombin inhibition by HC II. DS plasma levels followed a single compartment pharmacokinetic model, with a half-life of 1.28+0.46 h, a plasma clearance of 2.7SkO.46 l/h and a volume of distribution of 4.9221.36 1 (mean&SD). Steady-state was reached 3 to 6 hours after infusion started. The maximal DS plasma concentration was 16.4k5.7 pg/ml. Maximal APTT prolongation over pre-infusion values was 42+7X; TCT performed with bovine and human thrombin was prolonged by 1627% and 83+35X respectively. No anti-IIa or anti-Xa activities were detected by chromogenic tests. The treatment was well tolerated. The pharmacokinetics of MF 701 infusion are consistent with that previously described after i-v. bolus administration. The infusion of MF 701 allows fast achievement and steady maintenance of elevated DS plasma concentrations.