Antithrombotic and platelet function inhibiting effects of ML3000, a new antiinflammatory drug with Cox/5-LOX inhibitory activity.
METHODS
The studies reported were designed to evaluate the effects of ML3000 on platelet aggregation and platelet-induced thrombin generation in human platelet rich plasma and its antithrombotic effect in a rat thrombosis model. ML3000 is a potent inhibitor of both COX-1/2 and 5-LOX with demonstrated antiinflammatory activity and a low incidence of GI mucosal injury in animal and human studies.


RESULTS
The antithrombotic activity of ML3000 (10, 30 and 100 mg/kg) and aspirin (30 and 100 mg/kg) was measured in the mesenteric venules of rats using the laser-induced thrombus model. Both ML3000 and aspirin, at all doses tested, showed significant antithrombotic activity. The mean number of laser injuries necessary to induce a thrombus that blocked the vessel was 1.93 +/- 0.28 in the control group, 3.3 +/- 0.53, 3.6 +/- 0.14 or 4.07 +/- 0.37 in the groups treated with ML3000 at 10, 30 or 100 mg/kg p.o. and 3.4 +/- 0.55 or 3.9 +/- 0.3 in the groups treated with Aspirin at 30 or 100 mg/kg p.o. The antithrombotic activity in this model was significant up to 12 h post-administration of 100 mg/kg ML3000 or Aspirin. The aggregation inhibiting activity of ML3000 (1-100 microg/ml) and indomethacin (1 microg/ml) was studied using the following inducing agents: ADP (1 and 2 microM), epinephrine (25 and 50 microM), collagen (0.5 and 1 microg/ml), and the thromboxane mimetic U46619 (0.8 and 1.6 microM). Aggregation inhibitory activity was observed with ML3000 in all assays except with the higher concentration of U46619 at 1.6 microM. Indomethacin (1 microg/ml) inhibited aggregation in all assays.


CONCLUSIONS
ML3000 has significant antithrombotic activity and a marked platelet aggregation inhibiting effect. Given its demonstrated antiinflammatory activity, platelet function inhibition, and antithrombotic effects along with a lack of effect on the GI mucosa, ML3000 may offer an alternative to the combination of a COX-2 inhibitor and aspirin in arthritis patients at risk for cardiovascular disease.
Tries
S
S
R&D-Division, Merckle GmbH, Blaubeuren, Germany. susatrie@merckle.de
Laufer
S
S
Radziwon
P
P
Breddin
H K
HK
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000085:Acetates; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D005343:Fibrinolytic Agents; D016859:Lipoxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D011758:Pyrroles; C088092:licofelone