Sympathoinhibitory effect of statins in chronic heart failure

Contains fulltext : 89087.pdf (publisher's version ) (Closed access)OBJECTIVES: Increased (central) sympathetic activity is a key feature of heart failure and associated with worse prognosis. Animal studies suggest that statin therapy can reduce central sympathetic outflow. This study assessed statin effects on (central) sympathetic activity in human chronic heart failure (CHF) patients. METHODS: Sympathetic activity was measured in eight patients with CHF patients during 8 weeks after discontinuation and 4 weeks after restart of statin therapy by microneurography for direct muscle sympathetic nerve recording (MSNA) and measurement of arterial plasma norepinephrine concentrations. RESULTS: During discontinuation of statin therapy, MSNA was significantly increased (73 +/- 4 vs. 56 +/- 5 and 52 +/- 6 bursts/100 beats, p = 0.01). Burst frequency was significantly higher after statin discontinuation (42 +/- 3 burst/min without statin vs. 32 +/- 3 and 28 +/- 3 burst/min during statin therapy, p = 0.004). Mean normalized burst amplitude and total normalized MSNA were significantly higher after statin discontinuation (mean normalized burst amplitude 0.36 +/- 0.04 without statin vs. 0.29 +/- 0.04 and 0.22 +/- 0.04 during statin, p < 0.05; total normalized MSNA 15.70 +/- 2.78 without statin, vs. 9.28 +/- 1.41 and 6.56 +/- 1.83 during statin, p = 0.009). Arterial plasma norepinephrine levels and blood pressure were unaffected. INTERPRETATION: Statin therapy inhibits central sympathetic outflow in CHF patients, as measured by MSNA.1 april 201

Développement de plateformes fluorescentes pour la conception d'agents multifonctionnels pour des applications d'imagerie in vitro et in vivo

The objective of this thesis was the development and evaluation of new molecular platformsfor optical fluorescence imaging applications. This work sought to develop new tools that caneasily be modified and adapted to the specific needs of the intended use. This is required asthe fluorophore will influence the final properties and should thus be incorporated beforestructural optimization of the selected agent rather than at the very end. Two main axes wereexplored; the use of BODIPYs for the development of trackable therapeutic agents that areprimarily intended for in vitro applications and the use of azaBODIPYs for the design of an invivo compatible fluorescent platform.In the first part two fluorophores on the basis of a 3,5-dichloro-BODIPY were identified aspromising platforms. These platform molecules were selectively functionalized using a gold(I)-phosphine moiety, a thiosugar and a phosphonium to explore their selective functionalizationand investigate the influence of each substitutents position on the final properties. Weshowed that a site-specific, selective functionalization with these fragile substituents ispossible and developed 12 gold(I)-bearing therapeutic agents. We evaluated thephotophysical properties of all obtained compounds which was followed by a characterizationof their biological properties (antiproliferative properties on 3 cancer cell lines, lipophilicbalance and cellular gold accumulation as well as fluorescence imaging on 3 cell lines for upto 24h). We succeeded in developing a panel of closely related trackable compounds thatdisplay mixed activity in cells and distinct cellular localization. This investigation permitted theselection of three to four hits that will be studied further.In the second part we developed an in vivo-compatible multifunctional platform following twostrategies: the first was the use of 1,7-di(phenol)-3,5-di(phenyl)-azaBODIPY and thefunctionalization of the hydroxy groups for the development of a bioconjugable NIR-I probe.Unfortunately the developed probe displayed very unfavourable optical properties; wetherefore developed a new strategy that is entirely based on the functionalization of the boronatom. Using this approach we successfully synthesized 2 watersoluble, strongly fluorescent(NIR-I) molecular platforms that were conjugated to an innovative antibody to image the PD-L1 ligand. The developed probes displayed excellent optical properties, are stable for at least48h in mice plasma and were validated in a preclinical study on mice. The developed probesdisplayed strong fluorescence in vivo and showed no acute toxicity.The developed methodology shows great potential for further investigations and futurestudies; it can be transposed onto other closely related fluorophores and permits versatilefunctionalization with a large variety of compounds of interest. Its use is thus not limited tobiological, biochemical and medical applications.Cette thèse s’inscrit dans le développement et l’évaluation de nouvelles plateformesmoléculaires pour une application en imagerie optique par fluorescence. Nous avons cherché àdévelopper de nouveaux outils multifonctionnels et modifiables à façon. Cette approche estnécessaire car l’introduction d’un fluorophore peut fortement influencer les propriétés ducomposé final. Cela signifie que l’introduction du fluorophore sur l’agent sélectionné doit avoirêtre réalisé dès le départ. Pour cela deux axes principaux ont été étudiés; le premier consiste àutiliser des BODIPY pour le développement d’agents thérapeutiques traçables pour uneapplication principalement in vitro; le deuxième cible sur la conception de plateformes à based’AzaBODIPY compatibles avec l’imagerie in vivo.Dans la première partie deux fluorophores à base de 3,5-dichloro-BODIPY ont été identifiéscomme plateformes prometteurs. Ils ont été fonctionnalisés sélectivement par un agent or(I)-phosphine, un thiosucre et un phosphonium afin de pouvoir étudier l’influence du positionnementde chaque substituant sur les propriétés finales. Nous avons pu démontrer qu’unefonctionnalisation sélective et spécifique est possible avec ces substituants fragiles ; cela nous apermis de développer 12 agents théranostiques à base d’or(I). Les propriétés photophysiques etbiologiques ont ensuite été évaluées; pour cela nous avons déterminé leurs propriétés antiprolifératives (3 lignés cellulaires), la balance hydrophile, l’accumulation d’or dans les cellules etla localisation des composés des composés par microscopie confocale. Cette stratégie deplateforme multifonctionnelle nous a permis de développer un panel de composés traçables ayantdes activités mixtes ainsi que des distributions cellulaires distinctes. Cette étude a permisl’identification et la sélection de trois ou quatre composés qui feront l’objet d’une étudeapprofondie.Dans la deuxième partie de cette thèse nous avons développé des plateformes multifonctionnellescompatibles avec l’imagerie in vivo; pour cela nous avons poursuivi deux approches différentes.La première était l’utilisation de 1,7-di(phenol)3,5-di(phenyl)-azaBODIPY, suivi par safonctionnalisation sur les groupements OH afin de développer un traceur bioconjugablefluorescent dans le proche infrarouge (NIR-I). Malheureusement ce traceur possède despropriétés optiques très défavorables. Nous avons alors développé une approche innovante baséesur la fonctionnalisation de l’atome de bore. En s’appuyant sur cette approche deux traceursfortement fluorescents dans le proche infrarouge et solubles dans l’eau ont été développés. Cesfluorophores ont été conjugués sur un anticorps innovateur afin de permettre l’imagerie optiquedu ligand PD-L1. Les traceurs se sont montrés stables pour au moins 48h dans le plasma murin etpossèdent de très bonnes propriétés optiques. Comme preuve de concept nous avons conduitune étude préclinique in vivo. Cette étude a montré que les traceurs sont fortement fluorescents(NIR-I) et ne possèdent pas de toxicité imminente.La méthodologie développée pendant cette thèse présente un grand potentiel pour des étudesallant plus loin et des futures applications ; il est possible d’appliquer les principes et outilsdéveloppés sur d’autre fluorophores ; la méthodologie permet une fonctionnalisation très richeavec une grande variété de substituants d’intérêt. Son utilisation n’est pas limitée aux applicationsbiologiques, biochimiques et médicinales

Aza-BODIPY Platform: Toward an Efficient Water-Soluble Bimodal Imaging Probe for MRI and Near-Infrared Fluorescence

International audienceIn this study, an original aza-BODIPY system comprising two Gd3+ complexes has been designed and synthesized for magnetic resonance imaging/optical imaging applications, by functionalization of the boron center. This strategy enabled the obtainment of a positively charged bimodal probe, which displays an increased water solubility, optimized photophysical properties in the near-infrared region, and very promising relaxometric properties. The absorption and emission wavelengths are 705 and 741 nm, respectively, with a quantum yield of around 10% in aqueous media. Moreover, the system does not produce singlet oxygen upon excitation, which would be toxic for tissues. The relaxivity obtained is high at intermediate fields (16.1 mM-1 s-1 at 20 MHz and 310 K) and competes with that of bigger or more rigid systems. A full relaxometric and 17O NMR study and fitting of the data using the Lipari-Szabo approach showed that this high relaxivity can be explained by the size of the system and the presence of some small aggregates. These optimized photophysical and relaxometric properties highlight the potential use of such systems for future bimodal imaging studies

Aza-BODIPY Platform: Towards an Efficient Water-Soluble Bimodal Imaging Probe for MRI and Near-Infrared Fluorescence

In this study, an original aza-BODIPY system comprising two Gd3+ complexes has been designed and synthesized for magnetic resonance imaging/optical imaging application, by functionalization of the boron center. This strategy enabled to obtain a positively-charged bimodal probe, which displays an increased water-solubility, optimized photophysical properties in the near-infrared region, and very promising relaxometric properties. The absorption and emission wavelengths are 705 and 741 nm respectively, with a quantum yield of around 10 % in aqueous media. Moreover, the system does not produce singlet oxygen upon excitation, which would be toxic for tissues. The relaxivity obtained is high at intermediate fields (16.1 mM-1.s-1 at 20 MHz and 310 K) and competes with that of bigger or more rigid systems. A full relaxometric and 17O NMR study and fitting of the data using the Lipari-Szabo approach showed that this high relaxivity can be explained by the size of the system and the presence of some small aggregates. These optimized photophysical and relaxometric properties highlight the potential use of such systems for future bimodal imaging studies.</p

Near-infrared emitting fluorescent homobimetallic gold(I) complexes displaying promising in vitro and in vivo therapeutic properties

International audienceBoron neutron capture therapy (BNCT) has the potential to specifically destroy tumor cells without damaging the tissues infiltrated by the tumor. BNCT is a binary treatment method based on the combination of two agents that have no effect when applied individually: 10B and thermal neutrons. Exclusively, the combination of both produces an effect, whose extent depends on the amount of 10B in the tumor but also on the organs at risk. It is not yet possible to determine the 10B concentration in a specific tissue using non-invasive methods. At present, it is only possible to measure the 10B concentration in blood and to estimate the boron concentration in tissues based on the assumption that there is a fixed uptake of 10B from the blood into tissues. On this imprecise assumption, BNCT can hardly be developed further. A therapeutic approach, combining the boron carrier for therapeutic purposes with an imaging tool, might allow us to determine the 10B concentration in a specific tissue using a non-invasive method. This review provides an overview of the current clinical protocols and preclinical experiments and results on how innovative drug development for boron delivery systems can also incorporate concurrent imaging. The last section focuses on the importance of proteomics for further optimization of BNCT, a highly precise and personalized therapeutic approach

Water-Soluble Aza-BODIPYs: Biocompatible Organic Dyes for High Contrast In Vivo NIR-II Imaging

International audienceA simple NIR-II emitting water-soluble system has been developed and applied in vitro and in vivo. In vitro, the fluorophore quickly accumulated in 2D and 3D cell cultures and rapidly reached the tumor in rodents, showing high NIR-II contrast for up to 1 week. This very efficient probe possesses all the qualities necessary for translation to the clinic as well as for the development of NIR-II emitting materials

Aza-BODIPY: A New Vector for Enhanced Theranostic Boron Neutron Capture Therapy Applications

International audienceBoron neutron capture therapy (BNCT) is a radiotherapeutic modality based on the nuclear capture of slow neutrons by stable 10 B atoms followed by charged particle emission that inducing extensive damage on a very localized level (<10 µm). To be efficient, a sufficient amount of 10 B should accumulate in the tumor area while being almost cleared from the normal surroundings. A water-soluble aza-boron-dipyrromethene dyes (BODIPY) fluorophore was reported to strongly accumulate in the tumor area with high and BNCT compatible Tumor/Healthy Tissue ratios. The clinically used 10 B-BSH (sodium borocaptate) was coupled to the water-soluble aza-BODIPY platform for enhanced 10 B-BSH tumor vectorization. We demonstrated a strong uptake of the compound in tumor cells and determined its biodistribution in mice-bearing tumors. A model of chorioallantoic membrane-bearing glioblastoma xenograft was developed to evidence the BNCT potential of such compound, by subjecting it to slow neutrons. We demonstrated the tumor accumulation of the compound in real-time using optical imaging and ex vivo using elemental imaging based on laser-induced breakdown spectroscopy. The tumor growth was significantly reduced as compared to BNCT with 10 B-BSH. Altogether, the fluorescent aza-BODIPY/ 10 B-BSH compound is able to vectorize and image the 10 B-BSH in the tumor area, increasing its theranostic potential for efficient approach of BNCT