Pfizer Inc, San Diego, CA, USA. Ocular hypotensive activity of BOL-303259-X

Exp Eye Res. 2011 Sep;93(3):250-5. Epub 2011 Mar 9.
Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical models.
Krauss AH, Impagnatiello F, Toris CB, Gale DC, Prasanna G, Borghi V, Chiroli V, Chong WK, Carreiro ST, Ongini E.
Source

Pfizer Inc, San Diego, CA, USA.
Abstract

The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 μg) and 0.12% (36 μg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 μg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.

NicOx dispose d’une option de co-promotion des produits comprenant le BOL-303259-X aux Etats-Unis.


Je vous avez dit que MG était un malin et qu'il bossait sur plusieurs dossiers

Un deux plus!!! NCX 125

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) NicOx Research Institute, Bresso, Milan, ITALIE
(2) University of Nebraska, Omaha, Nebraska, ETATS-UNIS
(3) Pfizer Global Research and Development-La Jolla, San Diego, California, ETATS-UNIS

Titre du document / Document title
A Novel Nitric Oxide Releasing Prostaglandin Analog, NCX 125, Reduces Intraocular Pressure in Rabbit, Dog, and Primate Models of Glaucoma
Auteur(s) / Author(s)
BORGHI Valentina (1) ; BASTIA Elena (1) ; GUZZETTA Massimiliano (1) ; CHIROLI Valerio (1) ; TORIS Carol B. (2) ; BATUGO Minerva R. (3) ; CARREIRO Samantha T. (3) ; CHONG Wesley K. M. (3) ; GALE David C. (3) ; KUCERA David J. (3) ; LIU JIA (3) ; PRASANNA Ganesh (3) ; ONGINI Ennio (1) ; KRAUSS Achim H. P. (3) ; IMPAGNATIELLO Francesco (1) ;
Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)
(1) NicOx Research Institute, Bresso, Milan, ITALIE
(2) University of Nebraska, Omaha, Nebraska, ETATS-UNIS
(3) Pfizer Global Research and Development-La Jolla, San Diego, California, ETATS-UNIS
Résumé / Abstract
Purpose: Nitric oxide (NO) is involved in a variety of physiological processes including ocular aqueous humor dynamics by targeting mechanisms that are complementary to those of prostaglandins. Here, we have characterized a newly synthesized compound, NCX 125, comprising latanoprost acid and NO-donating moieties. Methods: NCX 125 was synthesized and tested in vitro for its ability to release functionally active NO and then compared with core latanoprost for its intraocular pressure (IOP)-lowering effects in rabbit, dog, and nonhuman primate models of glaucoma. Results: NCX 125 elicited cGMP formation (EC50 = 3.8 ± 1.0 μM) in PC12 cells and exerted NO-dependent iNOS inhibition (IC50 = 55 ± 11 μM) in RAW 264.7 macrophages. NCX 125 lowered IOP to a greater extent compared with equimolar latanoprost in: (a) rabbit model of transient ocular hypertension (0.030% latanoprost, not effective; 0.039% NCX 125, Δmax = -10.6 ± 2.3 mm Hg), (b) ocular hypertensive glaucomatous dogs (0.030% latanoprost, Δmax = -6.7 ± 1.2 mm Hg; 0.039% NCX 125, Δmax = -9.1 ± 3.1 mm Hg), and (c) laser-induced ocular hypertensive non-human primates (0.10% latanoprost, Δmax = -11.9 ± 3.7 mm Hg, 0.13% NCX 125, Δmax = -16.7 ± 2.2 mm Hg). In pharmacokinetic studies, NCX 125 and latanoprost resulted in similar latanoprost-free acid exposure in anterior segment ocular tissues. Conclusions: NCX 125, a compound targeting 2 different mechanisms, is endowed with potent ocular hypotensive effects. This may lead to potential new perspectives in the treatment of patients at risk of glaucoma.

vous avez bien raison mais le cours reste super bas...?

Programmes disponibles pour des collaborations potentielles sur le site de Nicox
Le programme de recherche sur l’Œdème Maculaire Diabétique (OMD), incluant le composé tête-de-série NCX 434.
Le NCX 434 a t' il trouvé un collaborateur ?






17 Septembre 2011


NCX 434, a novel nitric oxide (NO)-donating triamcinolone acetonide analog shows long lasting activity in the VEGF-induced leakage model of diabetic macular edema in rabbits

Authors
F. Impagnatiello1,C. De Nardi1, S. Brambilla1, V. Chiroli1 , AH Krauss2, G. Prasanna2 and E. Ongini1

1NicOx Research Institute, Bresso, Milan, Italy
2Department of Ocular Biology, Pfizer Inc, San Diego, CA.

Abstract
Diabetic macular edema (DME) is mainly treated with anti-vascular endothelial growth factor (anti-VEGF) agents or intravitreal (IVT) glucocorticoids. Glucocorticoids and, in particular, triamcinolone acetonide (TA), are highly effective drugs but they require repeated monthly injections and significantly enhance the risk of hypertensive glaucoma in patients. To address these issues we synthesized a novel NO-donating TA analog which was later shown to enhance oxygen saturation in non-human primate optic nerve head when administered IVT and to be devoid of IOP raising effects.
Here we further explored the efficacy on macular edema of NCX 434 over time using the VEGF-induced leakage model in New Zealand white rabbits and monitored its residence time in the vitreous compared to TA.
The IVT injection of NCX 434 (6.0 mg/eye) inhibited VEGF-induced retinal leakage up to 90 days post dosing more effectively than reference TA administered at equimolar doses in rabbits. Consistent with that, significant amount (20% of the injected dose) of NCX 434 was still detectable in the vitreous of NCX 434-treated eyes 90 days post-dosing while TA was below the limit of quantification at the same time point.
The present data further indicate that NCX 434 is as effective as TA but its activity last longer than that of TA when tested in a rabbit model of diabetic macular edema. These and previous findings make this an important new therapeutic opportunity to be further explored for the treatment of macular edema.

Ce sont des publications de travaux menés avant 2009. Pfizer et Nicox ont annoncé en 2009 cesser leur collaboration en opthalmo.

Bonjour Sylvie,


Je ne comprends pas pourquoi Pfizer apparait sur un congrès en septembre 2011 sachant qu'il a vendu ses droits contre le glaucome à Nicox et en plus il a cessé leur collaboration comme tu l'as dit précédemment.

logique... Pfizer a réalisé une partie ou la totalité de ces travaux, logique qu'ils figurent sur la publi, y compris malgré la fin de leur collaboration

Bonsoir Raymond,


Pour la logique, je suis pas trop d'accord si tu lis le journal en dessous, Pfizer n'apparaît pas et pourquoi ?
J'ai pas souvenir d'avoir lu un article des études de Pfizer sur le NCX 434 mais je serai ravie de lire un article de celui- ci.
Pour finir le NCX 434 est une nouvelle entité moléculaire (NEM) donneuse d’oxyde nitrique.

En espérant te lire ou vous lire,

SEB

Journal of Ocular Pharmacology and Therapeutics
Enhanced Oxygen Saturation in Optic Nerve Head of Non-Human Primate Eyes Following the Intravitreal Injection of NCX 434, an Innovative Nitric Oxide-Donating Glucocorticoid
To cite this article:
Bahram Khoobehi, Valerio Chiroli, Daniela Ronchetti, Daniela Miglietta, Hillary Thompson, Ennio Ongini, and Francesco Impagnatiello. Journal of Ocular Pharmacology and Therapeutics. April 2011, 27(2): 115-121. doi:10.1089/jop.2010.0150.
Published in Volume: 27 Issue 2: April 18, 2011
Online Ahead of Print: March 17, 2011
Full Text: • HTML • PDF for printing (306 KB) • PDF w/ links (323.8 KB)


Bahram Khoobehi,1
Valerio Chiroli,2
Daniela Ronchetti,2
Daniela Miglietta,2
Hillary Thompson,1,3
Ennio Ongini,2 and
Francesco Impagnatiello2
1Department of Ophthalmology, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
2NicOx Research Institute, Bresso, Milan, Italy.
3Department of Biostatistics, School of Public Health, Louisiana State University Health Sciences Center, New Orleans, Louisiana.
Address correspondence to:
Dr. Francesco Impagnatiello
Nicox Research Institute
Via Ariosto 21
20091 Bresso, Milan
Italy
E-mail: impagnatiello@nicox.it
Received: October 15, 2010
Accepted: February 14, 2011

Abstract

Purpose: Hypoxia of the retina and optic nerve head (ONH) is believed to be pivotal in the development of ocular vascular disorders, including diabetic macular edema (DME). Glucocorticoids are among the most effective agents for the treatment of back of the eye diseases. However, this class of compounds is highly liable to increase intraocular pressure (IOP) and does not improve ocular perfusion or tissue oxygenation. Nitric oxide (NO) has vasodilating properties and lowers IOP in experimental models and humans, suggesting that its properties might complement those of glucocorticoids. NCX 434 is an NO-donating triamcinolone acetonide (TA) that is less likely to increase IOP while targeting both the vascular and inflammatory components of DME.

Methods: NCX 434 was studied in vitro with respect to its NO-releasing properties in isolated methoxamine-precontracted rabbit aortic rings and glucocorticoid-like activity in recombinant human glucocorticoid receptors. IOP and oxygen saturation in the ONH and overlaying arteries and veins were studied in the anesthetized cynomolgus monkey. Measurements were taken using, respectively, an applanation tonometer and a hyperspectral imaging system before and 7, 14, 21, 31 and 41 days after the intravitreal injection of NCX 434 (5.8 mg/eye) or TA equimolar doses (4.0 mg/eye).

Results: NCX 434 inhibited 3H-dexamethasone-specific binding (IC50=34±5 nM) on human glucocorticoid receptors and elicited NO-dependent aortic ring relaxation (EC50 of 0.5±0.1 μM, Emax 98.9%). In monkey eyes, NCX 434 enhanced, whereas TA did not, oxygen saturation in various ONH areas (*P<0.05 vs. basal), decreased it in veins, and did not affect it in the overlaying arteries. Neither NCX 434 nor TA altered IOP significantly at all time points. However, at 31 days post-treatment TA appeared to start increasing IOP (ΔIOP=+3.31±0.51 mmHg, 30.8%, over baseline, NS).

Conclusions: NCX 434 enhances ocular tissue oxygenation. This feature appears to depend on its NO-donating properties; thus, the compound deserves to be further investigated for the treatment of DME and other ocular disorders with impaired ocular perfusion.

Juste pour dire que Sylvie et Raymond avaient raison sur le NCX 434.
Il faisait partie du programme de recherche conjoint entre NicOx et Pfizer.