Background-The antiplatelet effect of clopidogrel may be attenuated by short-term coadministration of lipophilic statins.We investigated whether the coadministration of atorvastatin for 5 weeks in patients with acute coronary syndromes (ACS) could affect the antiplatelet potency of clopidogrel. Methods and Results-Forty-five hypercholesterolemic patients with the first episode of an ACS were included in the study. Patients were randomized to receive daily either 10 mg of atorvastatin (nϭ21) or 40 mg of pravastatin (nϭ24). Thirty patients who underwent percutaneous coronary intervention (PCI) received a loading dose of 375 mg of clopidogrel, followed by 75 mg/d for at least 3 months. In the remaining 15 patients who refused to undergo PCI, clopidogrel therapy was not administered. Eight normolipidemic patients with the first episode of an ACS were also included and received only clopidogrel. The serum levels of soluble CD40L and the adenosine 5Ј-diphosphate-or thrombin receptor activating peptide-14 -induced platelet aggregation, as well as P-selectin and CD40L surface expression, were studied at baseline (within 30 minutes after admission) and 5 weeks later. Neither atorvastatin nor pravastatin significantly influenced the clopidogrel-induced inhibition of platelet activation, nor did clopidogrel influence the therapeutic efficacy of atorvastatin. Conclusions-Atorvastatin does not affect the antiplatelet potency of clopidogrel when coadministered for 5 weeks in ACS patients.

The platelet integrin receptor alphaIIbbeta3 plays a critical role in thrombosis and haemostasis by mediating interactions between platelets and several ligands, primarily fibrinogen. We have previously shown that the synthetic peptide YMESRADRKLAEVGRVYLFL corresponding to residues 313-332 of alphaIIb, is a potent inhibitor of platelet aggregation and fibrinogen binding to alphaIIbbeta3, interacting with fibrinogen rather than the receptor. Furthermore, we have demonstrated that the biological activities of the above peptide are due to the sequence YMESRADR, which corresponds to residues 313-320. By using new synthetic peptide analogues we investigated the structural characteristics responsible for the biological activity of YMESRADR as well the possible influence of the adjacent amino acids on the peptide's biological potency. According to our results, the synthetic octapeptide YMESRADR, is a potent inhibitor of platelet aggregation and P-selectin expression. Furthermore, YMESRADR inhibits fibrinogen binding but it does not significantly influence the binding of PAC-1 to ADP-activated platelets. The inhibitory potency of YMESRADR was gradually diminished by deleting the YMES sequence from the amino terminus and prolonging the carboxyl terminus of this peptide with the KLAE sequence. Extension of YMESRADR towards the amino terminus with the GAPL sequence (GAPLYMESRADR) does not modify the biological activity of YMESRADR. Furthermore, extension of GAPLYMESRADR at its carboxy terminus with the KLAE sequence (GAPLYMESRADRKLAE) significantly diminished its biological potency. Substitution of E315 with D significantly enhances antiaggregatory potency and completely abolishes the inhibitory effect on P-selectin expression. Importantly, the D315-containing peptides inhibit to a similar extent both fibrinogen and PAC-1 binding to activated alphaIIbbeta3 in contrast to the E315-containing peptide which only inhibits fibrinogen binding. In conclusion, the present study suggests that the YMESRADR sequence 313-320 of alphaIIb, is an important functional region of the insert connecting the beta2 and beta3 antiparallel beta-strands of the W5 blade of the alphaIIb subunit. Structural changes significantly modify the biological properties of this region.

The alphaIIbbeta3 receptor, which is the most abundant receptor on the surface of platelets, can interact with a variety of adhesive proteins including fibrinogen, fibronectin and the von Willebrand factor. Fibrinogen binding on alphaIIbbeta3 is an event essential for platelet aggregation and thrombus formation. Mapping of the fibrinogen-binding domains on alphaIIb subunit suggested the sequence 313-332 as a possible binding site. This region was restricted to sequence alphaIIb 313-320 (Y313MESRADR320) using synthetic octapeptides overlapping by six residues. The YMESRADR octapeptide inhibits ADP-stimulated human platelets aggregation and binds to immobilized fibrinogen. In this study, we used the Ala scanning methodology within the sequence 313-320 aiming to evaluate the contribution of each amino acid in inhibiting platelet aggregation. It was found that the substitution of Y313, M314, E315 or S316 by A does not affect the activity of the parent octapeptide. The-RADR-motif seems to be the most essential for the biological activity of the alphaIIb 313-320 site. The conformational analysis of the YAESRADR, YMESAADR and YMESRAAR analogs by using NMR spectroscopy and distance geometry calculations revealed significant differences in their conformational states in DMSO-d6.

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