Effect of TFC-612, a 7-thia prostaglandin E1 derivative, on a peripheral arterial occlusive disease model in rats.
TFC-612, methyl 6-[((1R,2S,3R)-3-hydroxy-2-[(1E,3S,5R)-3-hydroxy-5- methyl-1-nonenyl)-5-oxocyclopentyl]-thio]-hexanoate, inhibited the progression of the lesion in a lauric acid-induced peripheral arterial occlusive model at 1.0 mg/kg p.o. or 1.0 microgram/rat/h s.c. in rats. Aspirin (32 mg/kg, p.o.), an anti-platelet drug, did not suppress the lesion growth. On the other hand, ketanserin (10 mg/kg, p.o.), a 5-HT2 antagonist, also inhibited the progression of the lesion. In vitro, TFC-612 inhibited rat platelet aggregation induced by collagen and ADP with IC50 values of 5.4 ng/mL and 9.5 ng/mL, respectively. Aspirin also inhibited collagen-induced aggregation with an IC50 value of 6.3 micrograms/mL, but not ADP-induced aggregation at 180 micrograms/mL. Ketanserin had no effect on either aggregation at 40 micrograms/mL. In ex vivo experiments, aspirin inhibited platelet aggregation induced by collagen at 10 and 32 mg/kg in rats. However, TFC-612 showed significant inhibition only at 10 mg/kg. TFC-612 and ketanserin increased dermal blood flow in the rat paw at 1.0 microgram/kg i.v. and 100 micrograms/kg i.v., respectively. Aspirin had no effect on blood flow at 3.2 mg/kg i.v. These results suggest that the improvement of microcirculation, in addition to anti-platelet action by TFC-612, contributes to its inhibitory effect in a peripheral arterial occlusive model in rats.
Motoyama
Y
Y
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Sakata
Y
Y
Seki
J
J
Dohi
M
M
Yoshida
K
K
D000527:Alprostadil / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001157:Arterial Occlusive Diseases / Q000139:chemically induced / Q000188:drug therapy*; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D007850:Lauric Acids / Q000633:toxicity; D008297:Male; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000098:blood supply / Q000187:drug effects
D007850:Lauric Acids; D010975:Platelet Aggregation Inhibitors; C030358:lauric acid; C054546:TFC 612; D000527:Alprostadil