Flurbinitroxybutylester: a novel anti-inflammatory drug has enhanced antithrombotic activity.
We have recently shown that the introduction of a nitroxybutylester moiety into flurbiprofen, to form Flurbi-NO, results in a compound with markedly reduced undesired effects in the gastrointestinal tract. This effect has been shown to be linked to nitric oxide release from the Flurbi-NO. Here we have investigated whether this is associated with a reduction in platelet aggregability in vivo, as assessed in a mouse model of thromboembolism and a rat model of platelet aggregation, and found in both models that Flurbi-NO is more potent than flurbiprofen at inhibiting collagen-induced platelet aggregation. Further in vitro studies using human washed platelets and cells in culture suggest that this is due to the release of NO from Flurbi-NO following the action of (possibly plasma) esterases. Together with our earlier data, these results strongly suggest that Flurbi-NO and other members of this class of drugs, have particular potential as anti-thrombotic agents devoid of gastrointestinal side effects.
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D004837:Epinephrine / Q000633:toxicity; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009569:Nitric Oxide / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013923:Thromboembolism / Q000139:chemically induced / Q000188:drug therapy*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; C095631:nitroflurbiprofen; D009569:Nitric Oxide; D005480:Flurbiprofen; D003094:Collagen; D004837:Epinephrine