Glycoprotein IIb/IIIa receptor antagonist (2S)-2-[(2-Naphthyl-sulfonyl)amino]-3-[[2-([4-(4-piperidinyl)-2-[2-(4-piperidinyl)ethyl] butanoyl]amino)acetyl]amino]propanoic acid dihydrochloride (CRL42796), in combination with aspirin and/or enoxaparin, prevents coronary artery rethrombosis after successful thrombolytic treatment by recombinant tissue plasminogen activator.
The antithrombotic effect of the glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist (2S)-2-[(2-naphthyl-sulfonyl)amino]-3-[[2-([4-(4-piperidinyl)-2-[2-(4-piperidinyl)ethyl] butanoyl]amino)acetyl]amino] propanoic acid dihydrochloride (CRL42796), administered alone, or in combination with aspirin, and/or enoxaparin, was examined in a canine left circumflex (LCX) coronary artery rethrombosis model. The electrolytic induction of arterial thrombosis was followed by intracoronary recombinant tissue plasminogen activator administration to achieve thrombolysis, and the adjunctive therapy was initiated 15 min earlier and maintained for 4 h. Thirty-five purpose-bred beagle dogs were randomized to receive one of the following treatments: group 0 (n = 6, placebo); group 1 (n = 6, CRL42796 15 microg/kg i.v. loading dose followed by 0.31 microg/kg/min i.v. infusion), group 2 (n = 6, aspirin 7 mg/kg, administered orally, at -47, -23, -17 h before entry into the experimental protocol); group 3 (n = 6, aspirin + CRL42796); group 4 (n = 6, aspirin + enoxaparin 0.6 microg/kg i.v. loading dose followed by 6.0 microg/kg/min i.v. infusion); and group 5 (n = 5, aspirin + CRL42796 + enoxaparin). The incidence of LCX reocclusion was as follows: group 0, 6/6; group 1, 3/6; group 2, 5/6; group 3, 2/6; group 4, 2/6; and group 5, 0/5. Aspirin pretreatment increased the tongue-bleeding time, whereas the addition of CRL42796 or enoxaparin did not prolong bleeding time to a further degree. However, the combination of the three drugs did increase bleeding time significantly, from 173.9 +/- 19.8 to 620.0 +/- 98.7 s. In conclusion, low-dose CRL42796 together with aspirin and enoxaparin prevented coronary artery rethrombosis, although bleeding time was prolonged. The latter may be of concern in the clinical use of combination therapy.
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
Ting-Ting
TT
Hong
Edward M
EM
Driscoll
Andrew J
AJ
White
Ardaman
A
Sherigill
Thierry A
TA
Giboulot
Benedict R
BR
Lucchesi
D000818:Animals; D001241:Aspirin / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000517:prevention & control*; D004151:Dipeptides / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004285:Dogs; D004359:Drug Therapy, Combination; D017984:Enoxaparin / Q000627:therapeutic use; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000627:therapeutic use; D015424:Reperfusion; D013449:Sulfonamides / Q000627:therapeutic use*; D015912:Thrombolytic Therapy; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
C472490:CRL 42796; D004151:Dipeptides; D017984:Enoxaparin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011994:Recombinant Proteins; D013449:Sulfonamides; D010959:Tissue Plasminogen Activator; D001241:Aspirin