Inhibition by aurintricarboxylic acid of von Willebrand factor binding to platelet GPIb, platelet retention, and thrombus formation in vivo.
Commercial aurintricarboxylic acid (ATA) was separated into molecular-weight (MW) fractions of < 210 to > 25,000, using gel permeation chromatography. Fractions with MW > 1,300 effectively inhibited both botrocetin-induced vWF and bovine vWF binding to fixed human platelets. These activities decreased with a MW > 17,000. Platelet retention for a human in vitro was reduced by ATA at 150 microM, as was that for rats ex vivo at 3 mg/kg. ATA prolonged tail transection bleeding time in rats but had only a weak effect on buccal mucosal bleeding time in dogs. ATA had no effect on platelet count but markedly prolonged PTT. ATA at 10 mg/kg exhibited antithrombotic activity and caused a marked improvement in patency status following successful thrombolysis by t-PA in electrically and copper coil-induced thrombosis models. These results suggest that specific inhibitors of the vWF-GPIb interaction such as ATA may prove useful as antithrombotic agents.
Kawasaki
T
T
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd., Ibaraki, Japan.
Kaku
S
S
Kohinata
T
T
Sakai
Y
Y
Taniuchi
Y
Y
Kawamura
K
K
Yano
S
S
Takenaka
T
T
Fujimura
Y
Y
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D001792:Blood Platelets / Q000166:cytology / Q000378:metabolism*; D002341:Carotid Artery Thrombosis / Q000209:etiology / Q000517:prevention & control; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D003435:Crotalid Venoms / Q000494:pharmacology; D004285:Dogs; D055590:Electromagnetic Phenomena; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005898:Glass; D006801:Humans; D008297:Male; D008863:Microspheres; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013927:Thrombosis / Q000209:etiology*; D014841:von Willebrand Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D003435:Crotalid Venoms; D005343:Fibrinolytic Agents; D010980:Platelet Membrane Glycoproteins; D014841:von Willebrand Factor; D001312:Aurintricarboxylic Acid; C030961:botrocetin