Vectorisation de la ribavirine par les cyclodextrines : caractérisation physico-chimique des complexes et activité in vitro et in vivo sur le virus de la rougeole

Abstract : Despite vaccination, measles remains a burden with a mortality of about one million per year, mostly in the developing countries. Severe complications like acute encephalitis may necessitate an efficient therapy. Measles virus (MV) is susceptible to ribavirin (RBV) but the use of this drug is limited by its toxicity. In order to limit these drawbachs, we studied vectors able to carry antiviral molecules : the cyclodextrins (CDs). They are cyclic oligosaccharides with a hydrophobic central cavity. CDs can form complexes with numerous molecules, improving their biovailability and their biological properties. Firstly, our aim was to characterise interactions between RBV and native CDs (alpha, beta et gamma). The extent of complexation in solution has been evaluted by high performance liquid chromatography (HPLC) and nuclear magnetic resonance. Thermogravimetry, differential scanning calorimetry and infrared spectroscopy were used to characterise the solid state of all the binary systems. The 1 : 1 stoichiometry for the complexes was obtained by HPLC. The stability constants for RBV with alpha, beta et gamma CD were determined to be 1493 M-1, 2006 M-1, and 1179M-1, respectively. Secondly, we have evaluated in vitro the antiviral effects of complexes of RBV with alpha, beta or gamma CD against Edmonston and CAM/RB strains of MV grown on Vero cells. Complexation of RBV with alpha CD or beta CD has permitted a 5 fold decrease in the IC50, respectively with both strains. In contrast, gamma CD complexation showed no modification. Finally, to evaluate the benefit of such a complexation in vivo, a model of encephalitis to MV has been developed in CBA/ca mice, challenged intracranially with 1000 PFU. Preliminary results show a decrease of the viral load of MV in the brain of about 1 log eq. UFP/mL after 4 and 5 days after inoculation with the complex RBV/alpha CD at ratio 1 : 3 administered daily at 40[mu]/g by the intraperitoneal route.
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http://docnum.univ-lorraine.fr/prive/SCD_T_2005_0220_GRANCHER.pdf
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Submitted on : Thursday, March 29, 2018 - 10:48:53 AM
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Nicolas Grancher. Vectorisation de la ribavirine par les cyclodextrines : caractérisation physico-chimique des complexes et activité in vitro et in vivo sur le virus de la rougeole. Sciences agricoles. Université Henri Poincaré - Nancy 1, 2005. Français. ⟨NNT : 2005NAN11301⟩. ⟨tel-01746974⟩

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