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Titolo:
THE USE OF ACTIVE-CENTER ACYLATION TO CONTROL THE PHARMACOKINETIC PROFILE OF A RECOMBINANT CHIMERIC PLASMINOGEN-ACTIVATOR
Autore:
WILSON S; CRONK DW; DODD I; ESMAIL AF; KALINDJIAN SB; MCMURDO L; BROWNE MJ; SMITH RAG; ROBINSON JH;
Indirizzi:
SMITHKLINE BEECHAM PHARMACEUT,DEPT BIOTECHNOL,YEW TREE BOTTOM RD EPSOM KT18 5XQ SURREY ENGLAND
Titolo Testata:
Thrombosis and haemostasis
fascicolo: 6, volume: 70, anno: 1993,
pagine: 984 - 988
SICI:
0340-6245(1993)70:6<984:TUOAAT>2.0.ZU;2-5
Fonte:
ISI
Lingua:
ENG
Soggetto:
THROMBOLYTIC AGENTS; VENOUS THROMBOSIS; ACYL-ENZYMES; B-CHAIN; COMPLEX; MECHANISM; TRYPSIN; FIBRINOLYSIS; PROTEINS; THERAPY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
29
Recensione:
Indirizzi per estratti:
Citazione:
S. Wilson et al., "THE USE OF ACTIVE-CENTER ACYLATION TO CONTROL THE PHARMACOKINETIC PROFILE OF A RECOMBINANT CHIMERIC PLASMINOGEN-ACTIVATOR", Thrombosis and haemostasis, 70(6), 1993, pp. 984-988

Abstract

Recombinant hybrid plasminogen activators consisting of the ''A'' chain of plasminogen linked to the ''B'' chain of t-PA that are inhibitedrapidly by plasma protease inhibitors have recently been described (Robinson et al. Circulation 1992; 86: 548-552). We have now shown that following bolus administration of native hybrid to guinea pigs, fibrinolytic activity was cleared rapidly from the circulation. Active centre acylation appeared to protect the hybrid from inhibition and allowedmaterial to circulate as potentially active species for prolonged periods. Clearance rates of a range of acyl derivatives of the hybrid were 7-35-fold slower than for native hybrid and 20-100-fold slower than for t-PA. Clearance rates were influenced markedly by deacylation rate, such that clearance half-life correlated well with deacylation half-life. We have thus shown that it is feasible to control the pharmacokinetic profile of a recombinant hybrid plasminogen activator over a wide range by selection of an appropriate acyl group for attachment to the active site. Such control is not possible with plasminogen activators that are cleared predominantly by mechanisms other than inhibition.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 26/11/20 alle ore 07:13:03