Anti-thrombotic activity of RG13965, a novel platelet fibrinogen receptor antagonist

被引:7
作者
Bostwick, JS [1 ]
Kasiewski, CJ [1 ]
Chu, V [1 ]
Klein, SI [1 ]
Sabatino, RD [1 ]
Perrone, MH [1 ]
Dunwiddie, CT [1 ]
Cook, JJ [1 ]
Leadley, RJ [1 ]
机构
[1] RHONE POULENC RORER CENT RES,CARDIOVASC DRUG DISCOVERY,COLLEGEVILLE,PA 19426
关键词
platelet; glycoprotein; GPIIb/IIIa; fibrinogen; antagonist;
D O I
10.1016/0049-3848(96)00100-4
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
RG13965, a pseudotetrapeptide analogue of Arg-Gly-Asp (RGD), inhibited collagen-induced dog, monkey, human, hamster, mouse, and pig platelet aggregation in vitro with IC50 values of 3.7. 4.6, 6.3, 126, 136 and 1600 mu M, respectively. RG13965 (3, 10, and 30 mg/kg, i.v.) decreased the incidence of collagen/epinephrine-induced thrombosis in mice from 90% in untreated animals to 63, 37, and 0%, respectively. In hamsters, RG13965 (10 and 30 mg/kg, i.v.) prolonged the time required for formation of a hemostatic plug in severed mesenteric arteries by 1.6- and 3.6-fold, respectively. In a canine model of repetitive platelet thrombus formation in the coronary artery, RG13965 (0.1, 0.3, and 1 mg/kg, i.v.) reversibly inhibited cyclic flow reductions (CFRs) and inhibited ADP-induced ex vivo platelet aggregation by 29, 57. and 77%, respectively. RG13965 (1 mg/kg) completely inhibited CFRs for at least 40 min. Platelet count was not altered at any dose and template bleeding time was prolonged modestly (1.8-fold) at only the highest dose. RG13965 dose-dependently and reversibly inhibited thrombus formation at doses which did not completely inhibit ex vivo platelet aggregation and only modestly prolonged template bleeding time.
引用
收藏
页码:495 / 507
页数:13
相关论文
共 31 条
  • [1] LACK OF USEFULNESS OF PROLONGED BLEEDING TIMES IN PREDICTING HEMORRHAGIC EVENTS IN PATIENTS RECEIVING THE 7E3 GLYCOPROTEIN IIB/IIIA PLATELET ANTIBODY
    BERNARDI, MM
    CALIFF, RM
    KLEIMAN, N
    ELLIS, SG
    TOPOL, EJ
    [J]. AMERICAN JOURNAL OF CARDIOLOGY, 1993, 72 (15) : 1121 - 1125
  • [2] COLLEN D, 1994, THROMB HAEMOSTASIS, V71, P95
  • [3] INHIBITION OF PLATELET HEMOSTATIC PLUG FORMATION BY TRIGRAMIN, A NOVEL RGD-PEPTIDE
    COOK, JJ
    HUANG, TF
    RUCINSKI, B
    STRZYZEWSKI, M
    TUMA, RF
    WILLIAMS, JA
    NIEWIAROWSKI, S
    [J]. AMERICAN JOURNAL OF PHYSIOLOGY, 1989, 256 (04): : H1038 - H1043
  • [4] COOK NS, 1993, THROMB HAEMOSTASIS, V70, P531
  • [5] COOK NS, 1993, THROMB HAEMOSTASIS, V70, P838
  • [6] COX D, 1992, THROMB HAEMOSTASIS, V68, P731
  • [7] DIMINNO G, 1983, J PHARMACOL EXP THER, V225, P57
  • [8] FOLTS J, 1991, CIRCULATION, V83, P3
  • [9] MECHANISMS OF DISEASE - THE PATHOGENESIS OF CORONARY-ARTERY DISEASE AND THE ACUTE CORONARY SYNDROMES .1.
    FUSTER, V
    BADIMON, L
    BADIMON, JJ
    CHESEBRO, JH
    [J]. NEW ENGLAND JOURNAL OF MEDICINE, 1992, 326 (04) : 242 - 250
  • [10] RAPID AND SUSTAINED CORONARY-ARTERY RECANALIZATION WITH COMBINED BOLUS INJECTION OF RECOMBINANT TISSUE-TYPE PLASMINOGEN-ACTIVATOR AND MONOCLONAL ANTIPLATELET GPIIB/IIIA ANTIBODY IN A CANINE PREPARATION
    GOLD, HK
    COLLER, BS
    YASUDA, T
    SAITO, T
    FALLON, JT
    GUERRERO, JL
    LEINBACH, RC
    ZISKIND, AA
    COLLEN, D
    [J]. CIRCULATION, 1988, 77 (03) : 670 - 677