Nouvelle étude pré-clinique positive pour NCX-6560

NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties

European Journal of Pharmacology, In Press, Accepted Manuscript, Available online 5 June 2007,

Stefania Momi, Francesco Impagnatiello, Massimiliano Guzzetta, Roberta Caracchini, Giuseppe Guglielmini, Rossana Olivieri, Angela Monopoli and Paolo Gresele

Abstract
We compared the lipid-lowering, vasodilating, anti-thrombotic and anti-inflammatory properties of NCX 6560, a novel NO-releasing derivative of atorvastatin, with those of atorvastatin.
NCX 6560 and atorvastatin induced similar inhibition of cholesterol biosynthesis in rat smooth muscle cells (IC50 = 1.9+0.4 and 3.9+1.0 μM, respectively). However, in hyperlipidemic mice, a 5-week oral treatment with NCX 6560 (46.8 mg/kg/day, p.o.) was more effective than equivalent atorvastatin (40 mg/kg/day, p.o.) at lowering serum cholesterol (NCX 6560: -21% vs controls, P<0.05; atorvastatin -14% vs control, P=NS). In norepinephrine-pre contracted rabbit aortic rings, NCX 6560-induced vasodilation (EC50 = 53.5+8.3 μM) and in PC12 cells it stimulated cGMP formation (EC50 =1.8+0.7 μM), while atorvastatin was inactive. In lipopolysaccharide from Escherichia coli (LPS)-treated RAW 264.7 macrophages, NCX 6560 reduced iNOS expression and dimer assembly more efficiently than atorvastatin and inhibited nitrite accumulation (IC50 = 6.7+1.6 μM) and TNFa release.
U46619- or collagen plus epinephrine-induced platelet pulmonary thromboembolism in mice were reduced by NCX 6560 at 46.8 mg/kg p.o. (mortality -44% and -56% vs vehicle, respectively; P< 0.05 ), but not by atorvastatin 40 mg/kg, p.o. In the U46619-induced mortality model, isosorbide mononitrate (ISMN) (20 mg/kg, p.o.), a pure NO-donor, was also active (mortality -40%, P<0.05).
NCX 6560 significantly reduced ex vivo platelet adhesion to collagen at high shear (-31±1.3% vs vehicle), and so did ISMN (-33.3±1.7 % vs vehicle). Atorvastatin was ineffective. NCX 6560, but not atorvastatin, reduced blood pressure in eNOS-knockout mice (-16%, P<0.001 vs vehicle), an effect not observed in normal wild type mice. On the contrary, ISMN provoked a significant drop of blood pressure both in wild type (-20%, P<0.05 vs vehicle) and in eNOS-/- mice (-21%, P<0.05 vs vehicle).
In conclusion, NCX 6560 exerts greater lipid lowering, anti-thrombotic and anti-inflammatory effects than atorvastatin, due to a large extent to NO-release.
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