Summary
We have previously characterized the new antiplatelet agent picotamide as a dual thromboxane
synthase inhibitor/thromboxane A2 receptor antagonist in human platelets. We have now studied the antithrombotic activity
of this drug in a simple animal model of lung platelet thromboembolism in the mouse.
Picotamide, given i. p. 1 hr before the thrombotic challenge, protected mice from
death caused by the i. v. injection of collagen plus epinephrine in a dose-dependent
way; the dose reducing mortality by 50% was 277 mg/kg while for aspirin it was 300
mg/ kg. Picotamide was also able to reduce the mortality provoked by the i. v. injection
of the stable TxA2 mimetic U46619; BM 13.505, a pure TxA2-receptor blocker, was also effective while aspirin was totally inactive. Picotamide,
finally, reduced the lethal consequences of the i. v. injection of a 12.5% suspension
of hardened rat red blood cells, a model in which platelets are not involved; aspirin
was totally ineffective in this model while nicardipine, a calcium channel blocker,
was active. Picotamide did not inhibit the formation of TxB2 in serum at any of the doses tested (100 to 750 mg/kg i.p.) while it did enhance
significantly PGI2-synthesis from mice aortae and, even more, from mice lungs. The i.v. administration
of picotamide (250 mg/kg 2 min before the thrombotic challenge) lead to a strong inhibition
of serum TxB2 (−84.6%) and was associated with a higher antithrombotic effect
Picotamide (375 mg/kg) reduced also significantly the drop in the number of circulating
platelets and the number of histologi-cally-detected lung thromboemboli provoked by
i. v. collagen plus epinephrine; however, aspirin (300 mg/kg), although less effective
against mortality, was more active than picotamide in this respect. Finally, the addition
of aspirin (100 and 300 mg/kg) to picotamide (250 and 375 mg/kg) led to a better antithrombotic
effect despite a strong inhibition of PGI2 synthesis. Our data show that picotamide
prevents sudden death provoked in mice by platelet lung thromboembolism through a
mechanism largely independent from eicosanoid synthesis and only partially dependent
on platelet inhibition. This drug reduces also the lethal consequences of mechanical
(platelet-independent) lung embolism. A direct vasodilatory action on pulmonary vessels
might explain the protective effects of picotamide in this model.
