A thromboxane A2/prostaglandin H2 receptor antagonist (S18886) shows high antithrombotic efficacy in an experimental model of stent-induced thrombosis.
Acute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A(2)/prostaglandin H(2) receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s. Antithrombotic effects were assessed as (111)In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD < or =48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated animals, respectively (P < 0.05), while ASA+CLOP showed a 58% reduction versus placebo (P < 0.01). After 3 hours, ASA+CLOP decreased PD by 55%, S18886 by 40%, CLOP alone by 28% (P < 0.05), and ASA showed no inhibition versus placebo. Similar effects were found in S18886- and ASA+CLOP-treated animals at both times. Fibrin(ogen) deposition followed the same pattern. Collagen-induced LTA was significantly reduced by ASA, ASA+CLOP, and S18886; S18886 abolished U46619-induced LTA; and, CLOP +/- ASA reduced ADP-induced LTA in a time-dependent manner. TPr blockade did not prolong BT, whereas CLOP +/- ASA significantly did (P < 0.0001). In conclusion, blockade of the TPr provided a fast and potent platelet inhibitory effect in a porcine model of in-stent thrombosis comparable to that of blocking both the ADP receptor and cyclooxygenase activation; in addition, TPr provided a more favorable bleeding risk profile.
Vilahur
Gemma
G
Cardiovascular Research Center, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau (UAB), Barcelona, Spain.
Casaní
Laura
L
Badimon
Lina
L
D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D001241:Aspirin / Q000494:pharmacology; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D000077144:Clopidogrel; D004195:Disease Models, Animal; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced; D009281:Naphthalenes / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011422:Propionates / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D011474:Prosthesis Design; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013193:Stainless Steel; D015607:Stents / Q000009:adverse effects*; D013552:Swine; D013927:Thrombosis / Q000097:blood / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D013988:Ticlopidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D005343:Fibrinolytic Agents; D009281:Naphthalenes; D010975:Platelet Aggregation Inhibitors; D011422:Propionates; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013193:Stainless Steel; D005337:Fibrin; D005340:Fibrinogen; C501362:terutroban; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin