nouvelle confirmation que NCX-6560 est une no-atorvastatine

A sa demande, je reprends ici un post de Mwoffen qu'il a publié sur le forum de boursier.com :

Articles/résumés sur la présentation du NCX6560 (qui confirme le NO-Atorvastatin) et du NCX4016. Compétences médicales requises. Il s'agit de la conférence du SISET qui s'est tenue cette année en Italie du 14 au 17 septembre. Bizarrement, cette conférence n'a jamais été reprise sur le site de Nicox ou dans son agenda. Encore une fois, pourquoi faire autant de mystère sur la nitro-atorvastatin qui est un secret de polichinelle ?

Si un toubib pourrait nous décortiquer cela, ce serait le top!

source : http://www.haematologica.it/free/siset2006.pdf

C055
NCX-4016, BUT NOT ASPIRIN, PREVENTS THE ACUTE HYPERGLYCEMIA-INDUCED
ENHANCEMENT OF SHEAR STRESS-INDUCED PLATELET ACTIVATION IN TYPE
2 DIABETES MELLITUS (TD2M)
Gresele P *, Marzotti S‚+ Guglielmini G *, Falcinelli E*, Giannini S*,
Minuz P§, Ballabio M#, Bolli GB+
Division of Internal and Cardiovascular Medicine# and Division of Endocrinological
Sciencesa+, Department of Internal Medicine, University of Perugia#;
Department of Biomedical and Surgical Sciences, University of Verona§, NicOx
SA, Milan; Italy#
T2DM is associated with a 2 to 4-fold increased risk of ischemic cardiovascular
disease and platelet hyperreactivity has been suggested as a
potential mechanism of enhanced arterial thrombosis. We have previously
shown that acute, short-term, hyperglycemia enhances shear
stress-induced platelet activation in T2DM (Gresele et al., J Am Coll
Cardiol 2003, 41: 1013). High shear stress-induced platelet activation is
known to be resistant to aspirin inhibition. NCX-4016 (NCX), a nitric
oxide-donating aspirin, is a novel antiplatelet and vascular anti-inflammatory
agent with wider activity than aspirin. We have evaluated comparatively
the effects of aspirin and NCX-4016 on the acute hyperglycemia-
induced platelet activation in patients with TD2M. In a
prospective randomized double-blind parallel group study, 40 diabetic
patients underwent 4hrs of acute hyperglycemia (13.9 mmol/l, 250
mg/dL) after a 14-day treatment with placebo or NCX (800 mg bid) or
aspirin (100 mg od) or the combination of the two. Primary endpoint
was the enhanced shear stress-induced platelet activation (O'Brien filter
test) provoked by a hyperglycemic clamp (4hrs, blood glucose 250
mg/dL) Platelet adhesion to collagen under high-shear conditions (3000
sec-1), expression of P-selectin on platelets recovered in the blood from
a sking wound (bleeding time-blood) and circulating platelet/leukocytes
aggregates were also measured. NCX was significantly better than
aspirin (p=0.043) and than placebo (p=0.039) in preventing hyperglycemia-
induced enhancement of shear stress-induced platelet activation
(post minus pre-clamp filter closure time: placebo -13.5±21.9 sec,
aspirin -12.7±22.9, NCX +10.6±24.9, NCX+ASA +12.0±34.0). Secondary
endpoints were consistent, showing a significant inhibitory effect of
NCX vs placebo, and not of aspirin, for adhesion under high shear conditions
(placebo +7.1±18.8 plts/μ m2, NCX -26.8±30.2; p=0.008), and
for the formation of circulating platelet/leukocyte aggregates (placebo
+1.2±2.4%, NCX -0.5±1.2%; p<0.05). The increased expression of Pselectin
on platelets in bleeding-time blood induced by hyperglycemia
was significantly reduced by both NCX and aspirin. All active treatments
significantly inhibited serum TxB2 and urinary 11-dh-TxB2.
These results suggest that NCX-4016 possesses antiplatelet effects additional
to those exerted by aspirin in diabetics, and therefore deserves further
clinical testing for cardiovascular prevention in T2DM.


C056
NITRO-ATORVASTATIN (NCX-6560) INHIBITS CHOLESTEROL BIOSYNTHESIS AND SHOWS
ANTI-THROMBOTIC PROPERTIES SUPERIOR TO THOSE OF ATORVASTATIN
Momi S, Guglielmini G, Caracchini R, Monopoli A,1 Gresele P
Dept. of Internal Medicine, Sect. of Internal and Cardiovascualr Medicine, University
of Perugia, Perugia, Italy; 1NicOx Research Institute, Milan, Italy
Recently, a new class of compounds, incorporating a statin and a nitric
oxide (NO)-releasing moiety, have been reported to display enhanced
antiproliferative, antinflammatory and antithrombotic activities. Aim
of the present study was to evaluate a novel Nitro-atorvastatin deriva-tive (NCX6560), in comparison with its parent compound atrovastatin
(Ato) for its effectson cholesterol levels and on platelet dependent thrombosis.
In vitro, NCX6560 and Ato induced comparable inhibition of cholesterol
biosynthesis by rat smooth muscle cells (IC50 = 1.9+0.4 and
3.9+1.0 μM, respectively). However, a 5-week daily oral treatment with
NCX6560 (46.8 mg/kg/day) was more effective than an equivalent Ato
dose (40 mg/kg/day) at lowering serum cholesterol in CD1 mice on a
hyperlipidemic diet (NCX6560: -21% vs controls, p<0.05; Ato: -14% vs
control, p=NS). In vitro, NCX6560-induced vasodilation of rabbit aortic
rings (EC50 = 53.5+8.3 μM)while Ato was ineffective. The vasorelaxant
effect was confirmed in vivo by the reduction of blood pressure of
NCX6560, but not of Ato, in NOS-3 knockout mice (NCX=119.2±2.9*,
Ato=134.9±3.6, vehicle=140±2.1 mmHg, n=12, p<0.001* vs vehicle);
the blood pressure lowering effect was not observed in normal wild type
mice. Platelet pulmonary thromboembolism in mice, induced by the i.v.
injection of U46619 or collagen plus epinephrine, was reduced by a single
oral dosing of NCX6560 (46.8 mg/kg) (mortality -44% and -56% vs
vehicle, respectively; p<0.05), but not by Ato (40 mg/kg). Similarly,
NCX6560, but not Ato, inhibited mortality induced by mechanical pulmonary
microembolism by exerting a vasodilatory effect on the pulmonary
microcirculation. Finally, administration of NCX6560 (46.8
mg/kg, po) to CD1 mice on a high fat diet, but not of equimolar Ato, significantly
reduced ex vivo platelet adhesion to collagen at high shear
rate (C=56±1.6% surface coverage; Ato=5‚±1.6%; NCX6560=
40±1.25%, p<0.001 vs control and Ato). In conclusion NCX6560 exerts
greater lipid lowering, anti-thrombotic and anti-inflammatory effects
than Ato both in vitro and in vivo.


Pour rappel, atorvastatin = lipitor, médoc le plus vendu au monde. De ce que j'en tire:

La NO-Atorvastatin inhibe la biosynthèse du cholestérol et montre des propriétés anti-thrombotiques supérieure à la mol de base.

Pour résumer, l’adjonction de NO améliore l’activité antiproliférative, anti-inflammatoire et anti-thrombotique.
NCX6560 et Ato sont comparables sur les cellules molles de rats in vitro au niveau de la biosynthèse du cholestérol et de la thrombose des « platelets » (plaquettes ?) mais sur une période de 5 semaines de traitement orla, le NCX6560 est supérieur à la mol de base sur une souris CD1 avec diète hyper-lipidemique pour réduire le cholestérol (-21% contre -14%). Elle aussi des effets vaso-relaxants que ne produit pas la mol de base (cette fois sur un lapin en plus des souris) et il y a aussi une inhibition de la mortalité au niveau des micro-embolies pulmonaires. Bref, in vitro et in vivo, de la souris sauvage au rat, en passant par le lapin, le NCX6560 est supérieur au Lipitor de Pfizer. Voilà, petit résumé personnel mais un toubib pourrait expliquer les réelles implications et avancées…

On peut ajouter à tout ceci un commentaire fait par Querian sur le forum Boursorama :

Resume de la conférence
secrete de Nicox
Source; Boursier.com
1ère étude experimental de la division de medecine Cardiologique de Milan Italie Pr Guglielmi

NCX-4016 NO-aspirine: Cette étude montre la superiorité du NO-aspirine versus aspirine seule en ce qui concerne l'activité antiplaquettaire et antithrombotique déclenché par une hyperglycémie provquée. La conclusion c'est que le NO-aspirine possède un effet antiplaquettaire supérieure à l'aspirine chez les diabétiques.
Etude NCX-6560 : NO-Atorvastatin:Etude réalisée par la même équipe de Milan
Cette étude réalisée chez des animaux in vivo soumis à des régimes hyperlipidiques montre;1)diminution de l'adhésion plaquettaire sur du collagène,2)une diminution sensible de la biosynthèse du Cholésterol,3)une actiité antiinflammatoire,4) un effet anthithrombotique avec diminution du risque d'embolie pulmonaire après injection d'épinéphrine resposable de vasoconstrictionet de thrombose dans la circulation pulmonaire avec une baisse significative de la mortalité 44-56%.5) une action vasodilatatrice de la circulation pulmonaire 6° une vasodilatation de l'aorte chez le lapin et par coséquent une diminution de la pression arterielle. Bravo NICOX

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