Effects of DX-9065a, an inhibitor of factor Xa, on ellagic acid-induced plantar skin thrombosis assessed in tetrodotoxin- and N(omega)-nitro-L-arginine-treated rats.
Effects of DX-9065a ((+)-2S-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride pentahydrate), a dibasic propanoic acid and an inhibitor of factor Xa, were compared with those of argatroban, a low molecular weight thrombin inhibitor, on the ellagic acid-induced plantar skin thrombosis in the rats treated with tetrodotoxin and N(omega)-nitro-L-arginine. Plantar skin blood flow was measured with laser Doppler flow meters, and skin temperature of the hindlimb was monitored simultaneously. In order to induce thrombus in plantar skin vasculature, ellagic acid (300 microg, i.a.) was injected into a branch of femoral artery. The formation of thrombus in femoral and plantar vessels was assessed by light microscopy. Ellagic acid decreased plantar skin blood flow and skin temperature. Intravenous injections of DX-9065a (3 mg/kg) and argatroban (1-3 mg/kg) significantly inhibited the ellagic acid-induced disturbance of plantar skin blood flow and lowering skin temperature without affecting bleeding time. The oral administration of DX-9065a (30-100 mg/kg) significantly prevented the decrease in skin temperature induced by ellagic acid, but it partially inhibited the disturbance of plantar skin blood flow. DX-9065a and argatroban also prolonged prothrombin time in a dose-dependent manner. These results suggest that DX-9065a effectively prevented thrombosis produced by ellagic acid in the skin circulation without a risk of bleeding.
Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan.
Daisuke
D
Chino
Yukiyoshi
Y
Fujita
Kunio
K
Ishii
Koichi
K
Nakayama
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004610:Ellagic Acid / Q000633:toxicity*; D065427:Factor Xa Inhibitors; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use*; D019335:Nitroarginine / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012867:Skin / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology; D012871:Skin Diseases / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control; D013779:Tetrodotoxin / Q000494:pharmacology; D013927:Thrombosis / Q000473:pathology / Q000517:prevention & control*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D011422:Propionates; D004610:Ellagic Acid; D019335:Nitroarginine; D013779:Tetrodotoxin