Ibudilast, a phosphodiesterase inhibitor, in combination with low-dose aspirin potently inhibits guinea pig carotid artery thrombosis without extending bleeding time and causing gastric mucosal injury

摘要

A combination of low-dose aspirin (ASA) and a phosphodiesterase inhibitor has been clinically tried for the secondary prevention of atherothrombotic diseases. The in vivo antithrombotic property of ibudilast (CAS 50847-11-5), a phosphodiesterase 4 (PDE4) inhibitor, was evaluated in a photochemically-induced guinea pig carotid artery thrombosis model in combination with low-dose ASA. The time required to decrease the carotid artery blood flow to the reading "zeroo" was defined as the time to occlusion (TTO) of the artery through thrombogenesis. Each independent use of ASA (300mg/kg, p.o.) and ibudilast (3 and 10mg/kg, p.o.) significantly prolonged the TTO, and ASA (300mg/kg) significantly increased bleeding time (BT) and gastric mucosal injury. A selective PDE4 inhibitor rolipram (1 and 5mg/kg, p.o.) tended to prolong the TTO without extending BT. ASA (100mg/kg) plus ibudilast (3mg/kg) and ASA (100mg/kg) plus rolipram (5mg/kg) markedly prolonged the TTO compared with each agent alone. Interestingly, ASA (100mg/kg) plus ibudilast (3mg/kg) caused a longer TTO than ASA (300mg/kg) alone, without significant extension of BT and gastric mucosal injury as observed in ASA (300mg/kg). These results indicate that the combination of low-dose ASA and ibudilast has a more potent antithrombotic effect than ASA alone without increasing bleeding tendency and gastric mucosal injury. The potent in vivo antithrombotic effect of this combination may be brought about by an action that is associated with PDE4 inhibition of ibudilast.