Comparative effects of heparin and the sulfatoid GM1474 on coagulation parameters in plasma and blood from various species.
1. The discovery and development of novel carbohydrate molecules based on heparin biology and pharmacology requires consideration of coagulation effects in evaluating the therapeutic potential of these agents. A novel sulfatoid compound, GM1474, possessing potent antiproliferative and antiangiogenic properties similar to those of heparin, was evaluated for comparative coagulation effects. 2. In vitro and in vivo effects of GM1474 on plasma-activated partial prothromboplastin time (aPTT) and whole-blood clotting time (WBCT) were monitored in plasma and blood from various species and compared with those of heparin. GM1474 possessed approximately 21.7% of the in vitro aPTT and 4.3% of the in vitro WBCT effects relative to heparin, utilizing human plasma and blood. 3. Similar differences between GM1474 and heparin were observed in plasma and blood from mice, rats, dogs and nonhuman primates. The concentrations of GM1474 producing a two-fold increase in aPTT and WBCT in vitro in the various species ranged from 2.95 to 11.4 times the concentrations of heparin producing similar effects. 4. In in vivo evaluations in mice, the intravenous doses of GM1474 producing 50% of the maximal elevation in plasma aPTT and bleeding time (IC50s) were 2.1 and 12.0 mg/kg, respectively. These doses represented approximately 6.4- and 27.9-fold the in vivo IC50, doses of heparin causing elevations in aPTT and bleeding times, respectively. 5. The results of this study demonstrate that GM1474 possesses significantly reduced effects on coagulation relative to heparin, as determined by in vitro and in vivo testing. 6. Species differences in sensitivity to GM1474 and heparin were also observed in in vitro profiling. The order of species sensitivity to GM1474 and heparin was similar (mice>human beings>rats>non-human primates>dogs) and indicates that the mouse may be the most predictive species with respect to coagulation effects in human beings.
Williams
P D
PD
Glycomed Inc., Alameda, CA 94501, USA.
Ye
H
H
Cheng
F C
FC
Fugedi
P
P
Tressler
R
R
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004285:Dogs; D006493:Heparin / Q000494:pharmacology*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010314:Partial Thromboplastin Time; D051381:Rats; D017207:Rats, Sprague-Dawley; D013431:Sulfates / Q000494:pharmacology*
D000925:Anticoagulants; D013431:Sulfates; D006493:Heparin