In vivo toxicity and antithrombotic profile of the oral formulation of the antileukemic agent, LFM-A13-F.
The specific inhibitor of the protein tyrosine kinase, Bruton's tyrosine kinase (BTK), alpha-cyano-beta-hydroxy-beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13, CAS 244240-24-2), is a chemosensitizing antileukemic agent with antithrombotic properties. Oral formulation of LFM-A13 (LFM-A13-F) did not cause acute, subacute or chronic toxicity in mice at dose levels up to 200 mg/kg. The in vivo antithrombotic activity of LFM-A13 was studied in a mouse model of collagen-induced fatal thromboembolism. Oral doses of LFM-A13-F dose dependently prevented collagen-induced thromboembolism in mice without causing bleeding. LFM-A13 could be combined with dipyridamole (CAS 58-32-2) without side effects. These results indicate that LFM-A13 may be particularly useful in the treatment of leukemia patients who are at risk for thromboembolic complications.
Paradigm Pharmaceuticals, LLC, Roseville, MN, USA.
Heather E
HE
Tibbles
Peter
P
Samuel
Doug
D
Erbeck
Sandeep
S
Mahajan
Fatih M
FM
Uckun
D000284:Administration, Oral; D000577:Amides / Q000494:pharmacology* / Q000633:toxicity*; D000818:Animals; D001760:Bleeding Time; D001772:Blood Cell Count; D001777:Blood Coagulation / Q000187:drug effects; D003094:Collagen; D004176:Dipyridamole / Q000494:pharmacology; D005260:Female; D005343:Fibrinolytic Agents; D051379:Mice; D008807:Mice, Inbred BALB C; D009570:Nitriles / Q000494:pharmacology* / Q000633:toxicity*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013923:Thromboembolism / Q000139:chemically induced
D000577:Amides; D005343:Fibrinolytic Agents; C118451:LFM A13; D009570:Nitriles; D010975:Platelet Aggregation Inhibitors; D004176:Dipyridamole; D003094:Collagen