Disease relevance of Licofelone

• In vivo dual inhibition of cyclooxygenase and lipoxygenase by ML-3000 reduces the progression of experimental osteoarthritis: suppression of collagenase 1 and interleukin-1beta synthesis [1].
• Furthermore, there is evidence from animal models to suggest that licofelone may stop disease progression [2].
• Preliminary data have also shown that licofelone coadministration with low-dose aspirin does not lead to increased GI toxicity [3].
• Using a mouse peritonitis model it was found that leukocyte accumulation was markedly reduced in licofelone treated animals (100mg/kg) compared to untreated mice [4].
• Licofelone reduced intima/media ratio in injured arteries, the macrophages infiltration in the neointimal area, monocyte chemoattractant protein-1 (MCP-1) gene expression, and the activation of nuclear factor-kappaB in rabbit atheroma [5].

High impact information on Licofelone

• Coincubation of licofelone with TGFbeta1 plus 1,25(OH)(2)D(3) did not affect FLAP or 5-LOX levels [6].
• In the presence of TGFbeta1 plus 1,25(OH)(2)D(3), naproxen, but not licofelone, induced MMP-1 production and both drugs decreased nitric oxide levels [6].
• Conversely, treatment with licofelone showed no effect on 5-LOX but significantly reduced FLAP expression levels [6].
• OBJECTIVE: To compare the effect of licofelone, NS-398 (an inhibitor of cyclooxygenase 2 [COX-2]), and BayX-1005 (an inhibitor of 5-lipoxygenase activating protein) on the production of leukotriene B(4) (LTB(4)) and prostaglandin E(2) (PGE(2)), and on cell biomarkers by human osteoarthritis (OA) subchondral osteoblasts [7].
• Because LTB(4) can modify cell biomarkers in OA and normal osteoblasts, our results suggest licofelone could modify abnormal bone remodeling in OA [7].

Chemical compound and disease context of Licofelone

• Preliminary results of clinical studies of licofelone in osteoarthritis indicate that the drug has a comparable or slightly better efficacy than that of naproxen but possesses a much better gastrointestinal safety [8].
• Zileuton (25-100 mg/kg, po), a 5-LOX inhibitor, indomethacin (1-30 mg/kg, po), a non-selective COX inhibitor, and licofelone (10-100 mg/kg, po) a dual inhibitor, significantly reversed the mechanical hyperalgesia and also caused an increase in cold allodynia threshold with different pharmacologic profile [9].

Biological context of Licofelone

• Treatment with therapeutic concentrations of licofelone (2.5 and 5.0 mg/kg/day) markedly reduced the level of chondrocyte apoptosis to the same extent in both therapeutic groups (p < 0.0001, p < 0.002, respectively) [10].
• Licofelone, an inhibitor of cyclooxygenase and 5-lipoxygenase, specifically inhibits cyclooxygenase-1-dependent platelet activation [11].
• 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 [12].
• No evidence of gastric damage or disturbance of peristalsis was observed following oral administration of ML 3000 [13].
• RESULTS: SCH28080-sensitive H,K-ATPase activity in highly-purified pig gastric microsomes was dose-dependently inhibited by ML 3000 (IC50 = 16.4 microM) [14].

Anatomical context of Licofelone

• Licofelone, at the maximal dose used, inhibited production of PGE(2) and LTB(4) by OA osteoblasts by a mean +/- SEM of 61.2 +/- 6.4% and 67.0 +/- 7.6%, respectively [7].
• Licofelone almost abolished 5-LOX activity by inhibiting leukotriene B4 generation in rabbit neutrophils and prevented platelet thromboxane B(2) production from whole blood [5].
• METHODS: Human osteoarthritis chondrocytes were stimulated by interleukin 1beta (IL1beta) and treated with or without: licofelone (0.3, 1, or 3 mug/ml); NS-398 (10 muM; a specific COX-2 inhibitor); or BayX-1005 (10 muM; a specific 5-LOX inhibitor) [15].
• The effect of licofelone on leukocyte recruitment was also evaluated in vivo [4].
• The gastric mucosa was normal in 93%, 89%, and 90% of volunteers who received licofelone 200 mg, licofelone 400 mg, or placebo, respectively, compared with 37% of volunteers receiving naproxen [16].

Associations of Licofelone with other chemical compounds

• For this purpose, 30 rabbits underwent injury of femoral arteries, and they were randomized to receive 10 mg/kg/day licofelone or 5 mg/kg/day rofecoxib or no treatment during 4 weeks with atherogenic diet in all cases [5].
• The present study extends the anti-lipoxygenase and anti-cyclooxygenase activities of licofelone to the production of arachidonic acid metabolites generated as a consequence of polymorphonuclear leukocyte-platelet transcellular metabolism and to polymorphonuclear leukocyte responses relevant to the pathogenesis of inflammation [17].
• Failure to prevent aggregation triggered by high concentrations of collagen/adrenalin in aspirin-treated platelets supports cyclooxygenase-1 as a specific target of licofelone [11].
• Homotypic polymorphonuclear leukocyte aggregation induced by fMLP, C5A and PAF was inhibited by licofelone with IC(50)s of 23.7 +/- 4.8, 15.6 +/- 3.4 and 15.4 +/- 4 microM, respectively [17].
• These results indicate that ML 3000 is clearly better tolerated by the gastrointestinal tract than indometacin after single and multiple administration up to 11 days in rats [18].

Gene context of Licofelone

• Licofelone is a competitive inhibitor of 5-LOX, COX-1 and COX-2 that is currently being developed for the treatment of osteoarthritis [2].
• Novel agents include the COX-inhibiting nitric oxide donors and the lipoxygenase (LOX)/COX inhibitor licofelone [19].
• Moreover, licofelone treatment (30 microM) attenuated expression of VCAM-1 and ICAM-1 on inflammatory EC [4].
• The regulation of human MMP-13 by licofelone, an inhibitor of cyclo-oxygenases and 5-lipoxygenase, in human osteoarthritic chondrocytes is mediated by the inhibition of the p38 MAP kinase signalling pathway [15].
• The aim of the present study was to investigate if there is a contribution of mechanisms other than the reduction of inflammatory prostaglandins and leukotrienes to the anti-inflammatory effect of the LOX/COX inhibitor licofelone [4].

Analytical, diagnostic and therapeutic context of Licofelone

• Initial endoscopy data in healthy volunteers have demonstrated that licofelone is well tolerated and has a GI safety profile similar to placebo and significantly better than naproxen [3].
• OBJECTIVES: To determine if treatment with licofelone, a combined 5-lipoxygenase and cyclo-oxygenase inhibitor, in vivo in experimental dog osteoarthritis can modify bone cell metabolism in long term in vitro subchondral osteoblast cell cultures (Ob) [20].
• Licofelone (60 mg/kg/5 days, p.os) prevented fMLP-induced ECG ischemic changes in all treated animals, reverted bradycardia and hypotension, and significantly reduced TxB(2) [21].
• The general pharmacological effects of ML 3000 following oral administration were investigated in experimental animals [13].
• Evidence is presented regarding action of licofelone, one COX/LOX inhibitor that is currently in advanced stages of clinical trials [22].

References