Effects on primary haemostasis of an anti-inflammatory agent with 5-lipoxygenase and cyclooxygenase inhibitory activity.
OBJECTIVE
Licofelone ([2,2-dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid) has been demonstrated to inhibit cyclooxygenase (COX)-1, COX-2, and 5-lipoxygenase. The aim of this study was to investigate the in-vitro effects of licofelone on platelet function. Effects observed were compared with those produced by the classic COX-1 inhibitor aspirin (ASA).


METHODS
Platelet aggregation was assessed by a turbidimetric method. Platelet haemostatic performance was studied with the platelet function analyser (PFA-100), using collagen epinephrine and collagen ADP cartridges. Interaction of platelets with thrombogenic surfaces was analysed by perfusion experiments performed under flow conditions using both parallel and annular chambers.


RESULTS
Licofelone prolonged the lag time of platelet aggregation induced by arachidonic acid and reduced maximal platelet aggregation induced by ADP or collagen. Studies using PFA-100 demonstrated that licofelone (0.1, 1 and 10 muM) significantly prolonged closure times (P < 0.05) with both types of cartridges. In studies with the parallel chamber exposing purified collagen, both licofelone and ASA significantly reduced (P < 0.05) overall platelet interaction with the thrombogenic surface. In studies performed in annular chamber exposing a highly thrombogenic vessel surface, licofelone reduced height and area of the platelet masses deposited (7.0 +/- 0.5 mum; P < 0.005 and 80.2 +/- 17.3 mum; P < 0.05 vs. control 10.6 +/- 0.9 mum and 194.8 +/- 44.7 mum, respectively). ASA also impaired thrombus formation but differences did not reach the levels of statistical significance.


CONCLUSIONS
Under our experimental in-vitro conditions, licofelone interfered with platelet function as demonstrated by a diminished platelet aggregation, being more powerful than ASA and reducing the interaction of platelets with thrombogenic surfaces.
Hernandez
Maria Rosa
MR
Division of Haemotherapy and Haemostasis, Department of Medicine, Hospital Clínic i Provincial IDIBAPS, University of Barcelona, Barcelona, Spain.
Tonda
Raul
R
Pedreño
Javier
J
Salas
Eduardo
E
Arderiu
Gemma
G
Pino
Marc
M
Serradell
Mireia
M
Escolar
Gines
G
D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D003094:Collagen / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D006801:Humans; D016859:Lipoxygenase Inhibitors; D010974:Platelet Aggregation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*; D011817:Rabbits
D000085:Acetates; D000893:Anti-Inflammatory Agents; D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D016859:Lipoxygenase Inhibitors; D011758:Pyrroles; D016718:Arachidonic Acid; D003094:Collagen; C088092:licofelone; D001241:Aspirin