Deux communications orales par des membres de l'EA 3452 seront présentées au congrès APA à Wuhan en Chine
"Development of a HPLC-fluorescence assay to prove the in vivo sustained release of a fragile peptide from in situ formulations" par le Dr Ariane Boudier
L'article "In vivo and in silico evaluation of a new nitric oxide donor, S,S'-dinitrosobucillamine" vient de paraître dans le journal "Nitric Oxide".
Auteurs : Bouressam ML, Meyer B, Boudier A, Clarot I, Leroy P, Genoni A, Ruiz-Lopez M, Giummelly P, Liminana P, Salgues V, Kouach M, Perrin-Sarrado C, Lartaud I, Dupuis F.
Référence de l'article : Nitric Oxide. 71 (2017) 32-43 doi: 10.1016/j.niox.2017.10.004.
Abstract
Purpose: In a previous work, we have synthetized a new dinitrosothiol, i.e. S,S′-dinitrosobucillamine BUC(NO)2 combining S-nitroso-N-acetylpenicillamine (SNAP) and S-nitroso-N-acetylcysteine (NACNO) in its structure. When exposed to isolated aorta, we observed a 1.5-fold increase of •NO content and a more potent vasorelaxation (1 log higher pD2) compared to NACNO and SNAP alone or combined (Dahboul et al., 2014). In the present study, we analyzed the thermodynamics and kinetics for the release of •NO through computational modeling techniques and correlated it to plasma assays. Then BUC(NO)2 was administered in vivo to rats, assuming it will induce higher and/or longer hypotensive effects than its two constitutive S-mononitrosothiols.
Methods: Free energies for the release of •NO entities have been computed at the density functional theory level assuming an implicit model for the aqueous environment. Degradation products of BUC(NO)2 were evaluated in vitro under heating and oxidizing conditions using HPLC coupled with tandem mass spectrometry (MS/MS). Plasma from rats were spiked with RSNO and kinetics of RSNO degradation was measured using the classical Griess-Saville method. Blood pressure was measured in awake male Wistar rats using telemetry (n = 5, each as its own control, 48 h wash-out periods between subcutaneous injections under transient isoflurane anesthesia, random order: 7 mL/kg vehicle, 3.5, 7, 14 μmol/kg SNAP, NACNO, BUC(NO)2 and an equimolar mixture of SNAP + NACNO in order to mimic the number of •NO contained in BUC(NO)2). Variations of mean (ΔMAP, reflecting arterial dilation) and pulse arterial pressures (ΔPAP, indirectly reflecting venodilation, used to determine effect duration) vs. baseline were recorded for 4 h.
Results: Computational modeling highlights the fact that the release of the first •NO radical in BUC(NO)2 requires a free energy which is intermediate between the values obtained for SNAP and NACNO. However, the release of the second •NO radical is significantly favored by the concerted formation of an intramolecular disulfide bond. The corresponding oxidized compound was also characterized as related substance obtained under degradation conditions. The in vitro degradation rate of BUC(NO)2 was significantly greater than for the other RSNO. For equivalent low and medium •NO-load, BUC(NO)2 produced a hypotension identical to NACNO, SNAP and the equimolar mixture of SNAP + NACNO, but its effect was greater at higher doses (-62 ± 8 and -47 ± 14 mmHg, maximum ΔMAP for BUC(NO)2 and SNAP + NACNO, respectively). Its duration of effect on PAP (-50%) lasted from 35 to 95 min, i.e. shorter than for the other RSNO (from 90 to 135 min for the mixture SNAP + NACNO).
Conclusion: A faster metabolism explains the abilities of BUC(NO)2 to release higher amounts of •NO and to induce larger hypotension but shorter-lasting effects than those induced by the SNAP + NACNO mixture, despite an equivalent •NO-load.
Communication Orale au congrès de l'European Council for Cardiovascular Research:
S-nitrosation decreases AT1 receptor mediated vasoconstriction and myogenic tone on rat middle cerebral arteries
par M-L BOURESSAM, Doctorante
Nous avons le plaisir d'accueillir Justine Bonetti au sein de notre équipe en tant que Doctorante.
Nous lui souhaitons la bienvenue
Nous avons le plaisir d'accueillir Benjamin Creusot au sein de notre équipe sur le poste d'Adjoint Technique en analyses physico-chimiques.
Nous lui souhaitons la bienvenue
Conférences à la Faculté de Pharmacie
Jeudi 14 septembre à 15h30 - salle Cordebard
Amélioration du passage des barrières par les molécules biologiquement actives, Pr Gilles Ponchel, UMR CNRS 8612, Institut Galien Paris Sud
Intérêt de cibler NRP-1 dans les tumeurs cérébrales pour améliorer les thérapies par rayonnement, Dr Cédric Boura, CRAN UMR 7039, Université de Lorraine
Nous avons le plaisir d'accueillir Anita UMERSKA au sein de notre équipe sur le poste ATER en pharmacie galénique.
Nous lui souhaitons la bienvenue
Lors du concours de l'école doctorale BioSE, Mlle Justine Bonetti a obtenu une bourse de thèse en co-tutelle Université de Lorraine/Université de Sienne.
Son travail portera sur "Therapeutic potential of S-nitrosothiols in the prevention of atherosclerosis: modulation of monocytes and smooth muscle cells metaplasia into foam cells".
Ses directeurs seront Caroline Gaucher et Alfonso Pompella (co-encadrant Alessandro Corti).
Mr Arnaud Pallotta, doctorant de l'équipe, soutiendra sa thèse d'Etat de Docteur en Pharmacie le 13 juillet 2017 à 10h30 en salle Richard.
Elle s'intitule "Impact des nanotechnologies sur les dispositifs médicaux".
Le jury est composé de:
- Pr Igor Clarot (Président)
- Dr Ariane Boudier (Directrice de thèse)
- Dr Anthony Puzo (Pharmacien)
- Dr Juliana Tournebize (Pharmacienne)
- Dr Dominique Decolin (Maître de Conférences)
