tfc-612 and Disease-Models--Animal

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.

Topics: Alprostadil; Animals; Arterial Occlusive Diseases; Blood Pressure; Disease Models, Animal; Lauric Acids; Male; Platelet Aggregation Inhibitors; Rats; Rats, Sprague-Dawley; Skin

TFC-612 inhibited thrombus formation on wire coils inserted into the lumen of the inferior vena cava of rats after 5 oral doses of 1.0 and 3.2 mg/kg and subcutaneous doses of 1.0 and 3.2 micrograms/rat/hr. This compound showed slight inhibition of platelet aggregation induced by collagen at 1.0 and 3.2 mg/kg (po) and significant inhibition at 10 mg/kg. TFC-612 had no effect on the plasma coagulation system at 3.2 mg/kg. Conversely, oral doses of 0.32-3.2 mg/kg dose- dependently enhanced fibrinolytic activity as measured by euglobulin clot lysis time and lysis area on fibrin plates by euglobulin fraction. TFC-612 did not enhance fibrinolytic activity in vitro. These results suggest that the enhancement of fibrinolytic activity by TFC-612, which may be due to an increase in tissue plasminogen activator release or reduction of plasminogen activator inhibitors release, contributes to its inhibition of thrombus formation.

Topics: Alprostadil; Animals; Blood Coagulation; Disease Models, Animal; Fibrinolytic Agents; Male; Platelet Aggregation Inhibitors; Rats; Rats, Inbred Strains; Thrombophlebitis