Intranasal antiplatelet/antithrombotic efficacy of a novel platelet GPIIB/IIIA receptor antagonist DMP755.
This article describes the equivalent antiplatelet/antithrombotic effects of DMP755 at comparable doses by intranasal and i.v. administration but required substantially higher doses with the oral administration route. Antiplatelet and antithrombotic efficacy of DMP755 or its free acid form XV459 were determined in dogs. Arterial thrombosis models were induced either electrolytically (200 microA anodal current) in the carotid artery or mechanically by external clamping of femoral artery along with stenosis, which result in either total occlusive thrombus formation or cyclic flow reduction (CFR), respectively. Either DMP755 or its free acid form, XV459 demonstrated maximal and comparable antiplatelet efficacy at 0.025-0.1 mg/kg, intravenous (i.v.) or intranasal but not oral (PO) in mongrel dogs. The antiplatelet efficacy of DMP755 at 0.1 mg/kg, intranasal, or i.v. was determined in a cross-over design (n=8 in each group). In this study, a comparable and maximal antiplatelet efficacy for DMP755 after intranasal or i.v. was demonstrated suggesting 100% intranasal bioavailability as compared with the modest antiplatelet efficacy at 0.1 mg/kg, p.o. DMP755 administered at 0.1 mg/kg, intranasally or i.v. or at 0.3 mg/kg, p.o. prevented the incidence of electrolytic injury-induced arterial thrombosis in the carotid artery thrombosis model and prevented the incidence of cyclic flow reduction in mechanically injured and stenosed femoral artery. In conclusion, DMP755 has a comparable intranasal and intravenous antiplatelet/antithrombotic profiles along with a significant improvement over its oral profiles. These data also suggest the potential utility of intranasal DMP755 in various acute and chronic thromboembolic disorders. This is the first report of intranasal bioavailability of a glycoprotein receptor antagonist.
Mousa
S A
SA
DuPont Pharmaceuticals Company, Wilmington, Delaware 19880-0400, USA. shaker.a.mousa@dupontpharma.com
Mu
D X
DX
Hussain
M A
MA
D000281:Administration, Intranasal; D000284:Administration, Oral; D000596:Amino Acids / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D002339:Carotid Arteries; D004285:Dogs; D005260:Female; D005263:Femoral Artery; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007275:Injections, Intravenous; D007555:Isoxazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000517:prevention & control
D000596:Amino Acids; C116275:DMP 755; D005343:Fibrinolytic Agents; D007555:Isoxazoles; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; C104284:XV 459