Effects of aspirin and NO-aspirin (NCX 4016) on platelet function and coagulation in human endotoxemia.
Acetylsalicylic acid (ASA) prevents thromboembolic events by inhibiting platelet function through blocking of cyclooxygenase type 1 (COX-1). A nitroderivate of ASA, 2-(acetyloxy)benzoic acid 3-(nitrooxymethyl)-phenyl ester (NCX 4016) was synthesized, which additionally acts through nitric oxide release. In various in vitro and animal studies NCX 4016 exhibited antithrombotic and anti-platelet properties. We used the standardized model of endotoxin infusion into human volunteers to compare the effects of NCX 4016 and ASA on platelet function and TF-induced coagulation activation. The trial consisted of two parts. In the first part, 10 healthy male volunteers were included in a randomized, open cross-over trial to find a NCX formulation with optimal tolerability and pharmacokinetic data were obtained. The second part was a randomized, double blind placebo controlled clinical trial consisting of 30 healthy male volunteers in three parallel groups (n = 10 per group). Volunteers received either NCX 4016 (800 mg b.i.d.), ASA (425 mg b.i.d.) or placebo for 7 days, before infusion of 2 ng/kg endotoxin on day 8. ASA attenuated the endotoxin-induced platelet plug formation (measured by PFA-100) significantly better than NCX 4016 and placebo (p < 0.004), while there was no difference in soluble P-selectin or VWF-levels. Urine 11-dehydro-thromboxane B(2) levels were significantly lower in the ASA and NCX 4016 groups as compared to placebo (p < 0.05). Neither ASA nor NCX 4016 significantly changed prothrombin fragment(1 + 2), D-Dimer or tissue factor (TF)-mRNA levels. In summary, NCX 4016 had no effect on VWF release, platelet activation as measured by soluble P-selectin or TF gene expression. NCX 4016, at the dose tested, unlike ASA, had no effect on platelet collagen/epinephrine induced plug formation under high shear rates.
Derhaschnig
Ulla
U
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Schweeger-Exeli
Ingrid
I
Marsik
Claudia
C
Cardona
Francesco
F
Minuz
Pietro
P
Jilma
Bernd
B
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001241:Aspirin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D004311:Double-Blind Method; D019446:Endotoxemia / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy* / Q000652:urine; D004731:Endotoxins / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D006801:Humans; D008297:Male; D015539:Platelet Activation / Q000187:drug effects; D013929:Thromboxane B2 / Q000494:pharmacology / Q000652:urine; D055815:Young Adult
D000894:Anti-Inflammatory Agents, Non-Steroidal; D004731:Endotoxins; D013929:Thromboxane B2; C102148:nitroaspirin; D001241:Aspirin