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.4 - METABOLISM AND KINETICS242 - ENOX1235Brieger D; Dawes JProduction method affects the pharmacokinetic and ex vivo biological properties of lowmolecular weight heparins (ENG)THROMB HAEMOST, (1997) 77 (2) 317-322, 27REFLow molecular weight (LMW) heparins have prolonged circulating half-lives relative tounfractionated heparin.but the rates of plasma clearance differ between different LMWpreparations.To determine the impact of method of production on their pharmacokinetic andex vivo biological properties.two LMW heparins of similar molecular weight distribution,Logiparin and Fragmin, were radiolabelled with 125I, administered intravenollsly with 4mg/kg of carrier drug into rabbits, and the circulating radiolabelled material and anti-Xaactivity were analysed by size exclusion chromatography and affinity for antithrombin andPolybrene.Following administration of Logiparin, the anti-Xa amidolytic activity waseliminated-with the same half-life as the antithrombin-binding radiolabel and was notneutralised by antibody against tissue factor pathway inhibitor(TFPI).Larger moleculeswere cleared preferentially and were no longer detectable 8 h post injection.Thesefindings resemble those the authors have previously described for enoxaparin.AfterFragmin administration the antithrombin binding radiolabel was cleared more rapidly thanthe anti-Xa activity, and at late times after injection a significant amount of thisactivity was neutralised by antibody against TFP1.Sulphated radiolabel was eliminatedwith a similar half-life to the anti-Xa activity and sulphated molecules > 6000 Daremained in the circulation 8 h after administration.Fragmin, unlike Logiparin andenoxaparin, has no negatively charged sulphamino group at the reducing end of themolecule.The authors suggest that this minimises cellular interaction and protects thelarger molecules from elimination.They remain in the circulation, contributing to anti-Xaactivity by binding TFPI.Thus the method of production of LMW heparins may significantlyinfluence their pharmacokinetic properties and circulating anticoagulant activities.243 - ENOX1134Brieger D; Dawes JLong term persistence of biological activity following administration of enoxaparin sodium(Clexane) is due to sequestration of antithrombin-binding low molecular weight fragments -Comparison with unfractionated heparin (ENG)THROMB HAEMOST, (1996) 75 (5) 740-746, 24REFThe authors have previously reported (Brieger D, Dawes J.Thromb Haemost 1994, 72, 275-80)that the prolonged anti-Xa amidolytic activity following intravenous administration of thelow molecular weight heparin, enoxaparin sodium is mediated by small molecules derivedfrom the injected drug and an antithrombin binding penta/hexasaccharide can be detected inthe circulation as late as 1 week after administration.To investigate the mechanismunderlying this persistence, the authors administered 125I-labelled fractions ofenoxaparin sodium and unfractionated 125I-heparin to rabbits.Both 125I-heparin and theradiolabel high molecular weight (> 6000Da) enoxaparin sodium were more effectivelycleared from the circulation than the smaller components of LMW heparin.However, the datasuggest that the circulating biologically active penta/hexasaccharide was not anunmodified component of the injected drug but was derived from a subpopulation ofmolecules of intermediate molecular weight (1800-6000 Da) which was retained in thetissues.Significant quantities of both enoxaparin sodium and untractionated heparin wereretained in the internal organs.The authors propose that the sequestered subpopulationsofenoxaparin sodium and unfractionated heparin follow different catabolic routes.Afteradministration of both unfractionated and LMW heparin additional antithrombin bindingmaterial was released into the circulation by a bolus dose of heparin.This material wasnot contained on circulating blood cells and was probably sequestered on the endothelium.244 - ENOX0834Brieger DB; Dawes JCharacterisation of persistent anti-Xa activity following administration of the lowmolecular weight heparin enoxaparinsodium (Clexane) (ENG)THROMB HAEMOST, (1994) 72 (2) 275-280, 26REFIt is widely reported that persistent anti-Xa activity follows administration of lowmolecular weight heparins.To identify the effectors of this activity the authors haveinjected 125I-labelled enoxaparin sodium into rabbits and subsequently analysed thecirculating radiolabelled material and anti-Xa activity by affinity and size exclusionchromatography.Antithrombin III-binding material derived from the injected drug wasresponsible for all the anti-Xa amidolytic activity.At early times after injectionadditional anticoagulant activity which was largely attributable to tissue factor pathwayinhibitor was measured by the Heptest clotting assay after removal of glycosaminoglycansfrom plasma samples.Small radiolabelled fragments.including penta/hexasaccharide withaffinity for antithrombin III, were detectable in the circulation I week later, andsulphated oligosaccharides persisted for 3-4 weeks.Significant quantities of radiolabelremained in the liver and kidney several weeks post-injection, these organs may sequestersome of the injected drug and give rise to circulating biologically active material bydegradation and secretion of catabolic products into the plasma.245 - ENOX0737Iqbal O; Jeske W; Bacher P; Hoppensteadt DA; Walenga JM; Fareed JA comparison of the pharmacokinetic and pharmacodynamic profiles of Clexane andLovenoxindogs (ENG)SEMIN THROMB HEMOST, (1993) 19 (SUPPL 1) 199-209, 15REFComparison of the pharmacokinetic, phannacodynamic and biological activities of twopreparations of enoxaparin Clexane which contains sodium metabisulfite and Lovenox (USA)without sodium metabisulfite.These studies have been made using a dog model.246 - ENOX0387Dawes J99mtechnecium is not an appropriate radiolabel for in vivo studies of heparins (ENG)THROMB HAEMOST, (1991) 65 (6) 1295 AB: 2174The pharmacokinetics of enoxaparin labelled with 99mTc and 125I were compared.Enoxaparinwas administered at a dose of 1 mg/kg to rabbits.Plasma clearance of 125I-enoxaparinoccurred, after
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