Deux nouvelles publications scientifiques sur le NCX 911

Voici une nouvelle contribution de Jacques Stéphane (pseudonyme) :

je vous avais déjà fait mention de mes soupçons sur l'accord pharmaceutique avec Pfizer et son Viagra (Sildanefil) en ce qui concerne le NCX 911 (voir ) .

Une étude vient juste d'être publiée sur Pubmed qui entérine ces suppositions. Une fois encore, les nouvelles doivent être lues dans la presse scientifique officielle et non dans les communiqués de Nicox qui concernent plus la seule gestion courante de l'entreprise.

Le domaine thérapeutique concerné est encore évidemment celui des fonctions érectiles. Je vous invite vivement à le lire si vous avez un abonnement chez ScienceDirect ou Pubmed.



Received 3 March 2005; revised 10 May 2005; accepted 19 May 2005. Available online 15 June 2005.

Effect of sildenafil citrate and a nitric oxide donating sildenafil derivative, NCX 911,next term on cavernosal relaxation and superoxide formation in hypercholesterolaemic rabbits

Abstract

Hypercholesterolaemia promotes erectile dysfunction through increased superoxide formation and negation of nitric oxide (NO) bioactivity in cavernosal tissue. The source of superoxide has not been clearly defined, however. Sildenafil (Viagra™), the standard therapy for erectile dysfunction, may also be rendered more effective by the presence of an NO donor. One drug that intrinsically fulfils this criterion is sildenafil nitrate (previous termNCX 911)next term, an NO donating derivative of sildenafil.
The objective of this study, therefore, was to determine the source of superoxide and its effect on erectile function in corpus cavernosum from hypercholesterolaemic rabbits and to determine whether previous termNCX 911next term confers an improvement over sildenafil citrate in this model. Hypercholesterolaemia elicited an increase in superoxide formation by rabbit cavernosal tissue and a reduction of carbachol-stimulated relaxation both of which were reversed by diphenylene iodonium chloride and apocynin (NADPH oxidase inhibitors). In response to sodium nitroprusside, hypercholesterolaemia also caused an attenuation of cavernosal relaxation which was not reversed with NADPH oxidase inhibitors.
Both sildenafil citrate and previous termNCX 911next term significantly reversed impaired carbachol-stimulated relaxation and inhibited superoxide formation by cavernosal tissue from hypercholesterolaemic rabbits, previous termNCX 911next term being more potent. previous termNCX 911next term also augmented cavernosal cGMP levels, an effect blocked by the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo {4,3-a}quinoxalin-1-one (ODQ).
These data demonstrate that hypercholesterolaemia promotes erectile dysfunction through an augmentation of superoxide derived from NADPH oxidase in cavernosal tissue. It also indicates that NO donating sildenafil may be therapeutically more beneficial than conventional sildenafil in treating erectile dysfunction with an oxidative stress-related aetiology.



Un deuxième article sur les dépressions respiratoires et problèmes d'irrigation cardiaque qui étaient à l'origine des recherches sur le Viagra :
Voici l'abstract de cet article publié ce 27 juin 2005 et disponible ce 30 juin. Par Sildenafil il faut entendre 'Viagra' (c'est son nom scientifique).



British Journal of Pharmacology advance online publication, 27 June 2005; doi:10.1038/sj.bjp.0706305.

Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91(phox) expression in porcine pulmonary artery endothelial cells.

Muzaffar S, Shukla N, Srivastava A, Angelini GD, Jeremy JY.

Department of Cardiac Surgery, Bristol Heart Institute, Bristol Royal Infirmary, University of Bristol, Bristol BS2 8HW.

Acute respiratory distress syndrome (ARDS) is associated with increased superoxide (O(2)(*-)) formation in the pulmonary vasculature and negation of the bioavailability of nitric oxide (NO). Since NO inhibits NADPH oxidase expression through a cyclic GMP-mediated mechanism, sildenafil, a type V phosphodiesterase inhibitor, may be therapeutically effective in ARDS through an augmentation of NO-mediated inhibition of NADPH oxidase.

Therefore, the effect of sildenafil citrate and NO-donating sildenafil (NCX 911) on O(2)(*-) formation and gp91(phox) (active catalytic subunit of NADPH oxidase) expression was investigated in cultured porcine pulmonary artery endothelial cells (PAECs).PAECs were incubated with 10 nM TXA(2) analogue, 9,11-dideoxy-9alpha,11alpha-methanoepoxy-prostaglandin F(2alpha) (U46619) (+/-sildenafil or NCX 911), for 16 h and O(2)(*-) formation measured spectrophometrically and gp91(phox) using Western blotting.

The role of the NO-cGMP axis was studied using morpholinosydnonimine hydrochloride (SIN-1), the diethylamine/NO complex (DETA-NONOate), the guanylyl cyclase inhibitor, 1H-{1,2,4}oxadiazolo{4,3-a}quinoxalin-1-one (ODQ), and the protein kinase G inhibitor, 8-bromoguanosine-3',5'-cyclic monophosphorothioate, Rp-isomer (Rp-8-Br-cGMPS). NO release was studied using a fluorescence assay and O(2)(*-)-NO interactions by measuring nitrites.After a 16-h incubation with 10 nM U46619, both NCX 911 and sildenafil elicited a concentration-dependent inhibition of O(2)(*-) formation and gp91(phox) expression, NCX 911 being more potent (IC(50); 0.26 nM) than sildenafil citrate (IC(50); 1.85 nM).

These inhibitory effects were reversed by 1 muM ODQ and 10 muM Rp-8-Br-cGMPS. NCX 911 stimulated the formation of cGMP in PAECs and generated NO in a cell-free system to a greater degree than sildenafil citrate. The inhibitory effect of sildenafil was augmented by 1 muM SIN-1 and blocked partially by the eNOS inhibitor 10 muM N(5)-(1-iminoethyl)-ornithine (L-NIO). Acutely, sildenafil and NCX 911 also inhibited O(2)(*-) formation, again blocked by 1 muM ODQ. NCX 911 reacted with O(2)(*-) generated by xanthine oxidase, an effect that was inhibited by superoxide dismutase (500 U ml(-1)).Since O(2)(*-) formation plays contributory role in ARDS, both sildenafil citrate and NCX 911 may be indicated for treating ARDS through suppression of NADPH oxidase expression and therefore of O(2)(*-) formation and preservation of NO bioavailability.



Une fois de plus, le NCX 911 rebondit dans l'actualité. Ce NO-Viagra semble décidemment bien au centre des préoccupations des chercheurs. Son potentiel et ses résultats positifs et significatifs en font un produit de choix pour Pfizer. Cette étude est un élément supplémentaire qui démontre deux choses essentielles:

1) Les bons résultats du NCX 911 dans le domaine thérapeutique qui le concerne: les fonctions érectiles
2) Les recherches actives et systématiques de comparaison du NCX 911 avec le Viagra pour ses propriété érectiles.

Le NCX 911 semble être donc effectivement au coeur de l'accord avec Pfizer et il semble se confirmer qu'il devient un nouvel acteur majeur dans le portefeuille de produits Nicox. Ce produit est à surveiller grâce à la littérature scientifique car, (et cela serait conforme à l'accord de confidentialité avec Pfizer) Nicox ne mentionne rien sur le NCX 911 dans ses communiqués de presse ni sur son site.

Jacques Stéphane (Pseudonyme)

SOURCES

Pubmed: 27 juin 2005
Sildenafil citrate and sildenafil nitrate (NCX 911) are potent inhibitors of superoxide formation and gp91(phox) expression in porcine pulmonary artery endothelial cells.
Muzaffar S, Shukla N, Srivastava A, Angelini GD, Jeremy JY.


Le Viagra
France Handicap Mag


a Contribution to the Outlook of nicoX: le NCX 911
Jacques Stéphane
http://members.lycos.co.uk/ncx/nonofficial.htm#911

[RECHERCHE] Les NCX cachés
Jacques Stéphane