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Comparison of recombinant hirudin (HBW 023) and standard heparin in preventing thrombus formation in a Wessler model
50 FIBRINOLYSIS 122 Comparison of recombinant hirudin (HBW 023) and standard heparin in preventing thrombus formation in a Wessier model BARA L, BLOCH MF, *CAMEZ A, SYM4MA MM Laboratoire de Thrombose Exp&imentale, Facultt! de Mkdecine, Park Vr, *Laboratoire Hoe&t, Park, France
Forty-eight (6 x 8) anaesthetized New Zealand male rabbits were randomized to receive HBW 023 (12.5,25,50,100,200, 400 ,@kg), standard heparin (90 pg/kg) or placebo. Five minutes after administration of the drug, the experimental thrombosis was induced by the injection of human serum into the ear marginal vein and ligation of the jugular vein (Wessler model). After 10 min. stasis, the jugular vein was cut off and examined by an experimentator unaware of the treatment administered. Four variables were used to determine the inhibitory effect of the drug on clot formation (score, fresh and retracted weight, and protein dosage of the
123 Pharmacokinetics and tissue distribution of 125i-iabeiied depoiymerised dermatan suiphate in the rat DAWES J The Heart Research Institute, Sydney Australia
Dermatan sulphate is potentially an alternative drug to heparin. Depolymerised dermatan sulphate (DDS; DESMIN 370, Alfa Wassermann-Opocrin, Bologna, Italy) may in addition possess some of the pharmacokinetic advantages displayed by low molecular weight heparins. DDS was radiolabelled with 125-I and 370 KBq were administered to male Sprague-Dawley rats together with 3 mg/kg carrier unlabeled DDS (i.v.) and 3, 4 or 12 mg/kg (i.m.). DDS was cleared by complex kinetics involving several phases, consisting of a rapid redistribution phase followed by clearance with a half-life of 100 min and a final phase with a half-life of 13.8 h. Thus low levels of DDS persisted in the circulation
124
Human pharmacokinetics and pharmacodynamics of MF 701 dermatan suiphate administered by continuous intravenous infusion AGNELLI G, COSMI B, RENGA C, FEDERICI I$ NENCI GG, *HOUIN G, **GIANESE F Istituto di Semeiotica Medica, Universityof Per&a, Italy, *Unit&de Pharmacocin&ique Clinique, CHU Purpan, Toulouse, France, **Medical Depattment, Mediolanum Farmaceutici, Milan, Italy
The pharmacokinetics and haemostatic effects of MF 701 dermatan sulphate (DS) administered by i.v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg/kg/h MF 701 for 10 hours. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HC II. DS plasma levels followed a single compartment pharmacokinetic model,
thrombus). Interestingly the plasma level of HBW 023 could be determined using a chromogenic thrombin substrate assay according to Griessbach. - ID50 was the dose of the drug that induced a more or less complete inhibition of thrombosis in 50% of the dose group test (score 5 1). A highly significant relation was found between the four parameters and both injected doses and HBW 023 plasma levels. The ID50 of HBW 023 is about 2OO&kg which corresponds to a plasma concentration of 920 ng/ml of the injected drug. The injected doses equipotent to 90 pg/kg of standard heparin range between 110 and 170 &kg according to the parameter used (score, thrombus weight or protein dosage of the thrombus). The plasma circulating rate of hirudin was in the range of 350 to 500 @ml.
for 96 h even though the maximum plasma concentration occurred within 30 min of i.m. administration. The pharmacokinetics were not affected by dose, and most of the injected radiolabel was excreted in the urine. About 40% of the radiolabel present in the blood was associated with the cellular elements, and it was also found in all tissues other than the brain. The tissues may act as reservoirs for slow release of DDS into the plasma, supplying the persistent low levels found in blood and urine. Gel filtration and affinity chromatography of ex vivo samples indicated that intact 125-I-DDS was the major component at all times, and the only labelled material present in urine.
with a half-life of 1.28k0.46 h, a plasma clearance of 2.7520.46 l/h and a volume of distribution of 49221.36 1 (means+SD). Steady-state was reached 3 to 6 hours after infusion started. The maximal DS plasma concentration was 16.425.7 &ml. Maximal AF’TT prolongation over pre-infusion values was 42&7%; TCT performed with bovine and human thrombin was prolonged by 1627% and 83235% 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.
Forty-eight (6 x 8) anaesthetized New Zealand male rabbits were randomized to receive HBW 023 (12.5,25,50,100,200, 400 ,@kg), standard heparin (90 pg/kg) or placebo. Five minutes after administration of the drug, the experimental thrombosis was induced by the injection of human serum into the ear marginal vein and ligation of the jugular vein (Wessler model). After 10 min. stasis, the jugular vein was cut off and examined by an experimentator unaware of the treatment administered. Four variables were used to determine the inhibitory effect of the drug on clot formation (score, fresh and retracted weight, and protein dosage of the
123 Pharmacokinetics and tissue distribution of 125i-iabeiied depoiymerised dermatan suiphate in the rat DAWES J The Heart Research Institute, Sydney Australia
Dermatan sulphate is potentially an alternative drug to heparin. Depolymerised dermatan sulphate (DDS; DESMIN 370, Alfa Wassermann-Opocrin, Bologna, Italy) may in addition possess some of the pharmacokinetic advantages displayed by low molecular weight heparins. DDS was radiolabelled with 125-I and 370 KBq were administered to male Sprague-Dawley rats together with 3 mg/kg carrier unlabeled DDS (i.v.) and 3, 4 or 12 mg/kg (i.m.). DDS was cleared by complex kinetics involving several phases, consisting of a rapid redistribution phase followed by clearance with a half-life of 100 min and a final phase with a half-life of 13.8 h. Thus low levels of DDS persisted in the circulation
124
Human pharmacokinetics and pharmacodynamics of MF 701 dermatan suiphate administered by continuous intravenous infusion AGNELLI G, COSMI B, RENGA C, FEDERICI I$ NENCI GG, *HOUIN G, **GIANESE F Istituto di Semeiotica Medica, Universityof Per&a, Italy, *Unit&de Pharmacocin&ique Clinique, CHU Purpan, Toulouse, France, **Medical Depattment, Mediolanum Farmaceutici, Milan, Italy
The pharmacokinetics and haemostatic effects of MF 701 dermatan sulphate (DS) administered by i.v. infusion were studied in 11 healthy volunteers. Each subject received 0.6 mg/kg/h MF 701 for 10 hours. DS plasma concentrations were measured by a chromogenic assay based on the catalysis of thrombin inhibition by HC II. DS plasma levels followed a single compartment pharmacokinetic model,
thrombus). Interestingly the plasma level of HBW 023 could be determined using a chromogenic thrombin substrate assay according to Griessbach. - ID50 was the dose of the drug that induced a more or less complete inhibition of thrombosis in 50% of the dose group test (score 5 1). A highly significant relation was found between the four parameters and both injected doses and HBW 023 plasma levels. The ID50 of HBW 023 is about 2OO&kg which corresponds to a plasma concentration of 920 ng/ml of the injected drug. The injected doses equipotent to 90 pg/kg of standard heparin range between 110 and 170 &kg according to the parameter used (score, thrombus weight or protein dosage of the thrombus). The plasma circulating rate of hirudin was in the range of 350 to 500 @ml.
for 96 h even though the maximum plasma concentration occurred within 30 min of i.m. administration. The pharmacokinetics were not affected by dose, and most of the injected radiolabel was excreted in the urine. About 40% of the radiolabel present in the blood was associated with the cellular elements, and it was also found in all tissues other than the brain. The tissues may act as reservoirs for slow release of DDS into the plasma, supplying the persistent low levels found in blood and urine. Gel filtration and affinity chromatography of ex vivo samples indicated that intact 125-I-DDS was the major component at all times, and the only labelled material present in urine.
with a half-life of 1.28k0.46 h, a plasma clearance of 2.7520.46 l/h and a volume of distribution of 49221.36 1 (means+SD). Steady-state was reached 3 to 6 hours after infusion started. The maximal DS plasma concentration was 16.425.7 &ml. Maximal AF’TT prolongation over pre-infusion values was 42&7%; TCT performed with bovine and human thrombin was prolonged by 1627% and 83235% 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.