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Pharmacocinétique Et Optimisation Galénique De Dithiarsolanes À Visée Antileucémique : Exemple Des Nanosuspensions D’Arsthinol Imane Ajana

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Pharmacocinétique Et Optimisation Galénique De Dithiarsolanes À Visée Antileucémique : Exemple Des Nanosuspensions D’Arsthinol Imane Ajana Pharmacocinétique et optimisation galénique de dithiarsolanes à visée antileucémique : exemple des nanosuspensions d’arsthinol Imane Ajana To cite this version: Imane Ajana. Pharmacocinétique et optimisation galénique de dithiarsolanes à visée antileucémique : exemple des nanosuspensions d’arsthinol. Sciences pharmaceutiques. Université Henri Poincaré - Nancy 1, 2010. Français. NNT : 2010NAN10018. tel-01775835 HAL Id: tel-01775835 https://hal.univ-lorraine.fr/tel-01775835 Submitted on 24 Apr 2018 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D'autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact : [email protected] LIENS Code de la Propriété Intellectuelle. articles L 122. 4 Code de la Propriété Intellectuelle. articles L 335.2- L 335.10 http://www.cfcopies.com/V2/leg/leg_droi.php http://www.culture.gouv.fr/culture/infos-pratiques/droits/protection.htm UNIVERSITE HENRI POINCARE – NANCY I UFR de Pharmacie ECOLE DOCTORALE "BIOLOGIE SANTE ENVIRONNEMENT" THESE Présentée et soutenue publiquement Le 30 mars 2010 Pour obtenir le titre de DOCTEUR DE L’UNIVERSITE HENRI POINCARE – NANCY I Mention : Sciences de la Vie et de la Santé Par Imane AJANA Titre de la thèse : Pharmacocinétique et optimisation galénique de dithiarsolanes à visée antileucémique : exemple des nanosuspensions d’arsthinol MEMBRES DU JURY Rapporteurs : Professeur Pierre JEANNESSON (Faculté de Pharmacie, Reims) Docteur Fabrice PIROT (Faculté de Pharmacie, Lyon) Examinateurs : Docteur Fariba NEMATI (Institut Curie, Paris) Professeur Alain ASTIER (Faculté de Pharmacie, Nancy) Professeur Philippe MAINCENT (Faculté de Pharmacie, Nancy) Docteur Stéphane GIBAUD, directeur de thèse (Faculté de Pharmacie, Nancy) Laboratoire de Pharmacie Clinique EA 3452 "Cibles thérapeutiques, formulation et expertise préclinique du médicament" Faculté de Pharmacie 5, rue Albert Lebrun 54001 Nancy Cedex, France UNIVERSITE HENRI POINCARE – NANCY I UFR de Pharmacie ECOLE DOCTORALE "BIOLOGIE SANTE ENVIRONNEMENT" THESE Présentée et soutenue publiquement Le 30 mars 2010 Pour obtenir le titre de DOCTEUR DE L’UNIVERSITE HENRI POINCARE – NANCY I Mention : Sciences de la Vie et de la Santé Par Imane AJANA Titre de la thèse : Pharmacocinétique et optimisation galénique de dithiarsolanes à visée antileucémique : exemple des nanosuspensions d’arsthinol MEMBRES DU JURY Rapporteurs : Professeur Pierre JEANNESSON (Faculté de Pharmacie, Reims) Docteur Fabrice PIROT (Faculté de Pharmacie, Lyon) Examinateurs : Docteur Fariba NEMATI (Institut Curie, Paris) Professeur Alain ASTIER (Faculté de Pharmacie, Nancy) Professeur Philippe MAINCENT (Faculté de Pharmacie, Nancy) Docteur Stéphane GIBAUD, directeur de thèse (Faculté de Pharmacie, Nancy) Laboratoire de Pharmacie Clinique EA 3452 "Cibles thérapeutiques, formulation et expertise préclinique du médicament" Faculté de Pharmacie 5, rue Albert Lebrun 54001 Nancy Cedex, France A mes chers parents A ma famille A mes amies Remerciements Je tiens tout d’abord à remercier Monsieur le Docteur Stéphane GIBAUD de m’avoir proposé ce sujet de thèse, et de m’avoir aiguillé et conseillé dans la réalisation de mes travaux pour mener à bien ce projet. Je remercie vivement : Monsieur le Professeur Pierre JEANNESSON et Monsieur le Docteur Fabrice PIROT qui me font l’honneur d’avoir accepté de juger ce travail de thèse et d’en être les rapporteurs. Madame le Docteur Fariba NEMATI qui me fait l’honneur d’avoir accepté de participer au jury de cette thèse. Monsieur le Professeur Alain ASTIER de m’avoir initié dans la réalisation de ce projet. Il me fait l’honneur d’avoir accepté de participer au jury de cette thèse. Monsieur le Professeur Philippe MAINCENT ; le Directeur de l’équipe EA 3452 qui m’a accueillie dans son unité de recherche pendant toute la période de ma thèse et pour l’honneur qu’il me fait d’avoir accepté de participer au jury de cette thèse. Je remercie Monsieur François DUPIRE pour son aide précieuse dans la réalisation de l’analyse des échantillons par CLHP-SM. Je remercie Monsieur le Docteur Raphael DUVAL pour sa disponibilité et pour les connaissances qu’il m’a su apporter en biologie cellulaire. Enfin, je remercie Mme Pascale CARNET pour sa bienveillance, son efficacité ainsi que tout le personnel du laboratoire de Pharmacie Clinique pour leur encouragement. Table des matières Introduction générale ............................................................................ 1 Etude bibliographique .......................................................................... 6 I. Dérivés arsenicaux dans le traitement des leucémies ......................................... 7 1. Trioxyde d’arsenic .......................................................................................................... 7 1.1. Historique ............................................................................................................................ 7 1.2. Propriétés physico-chimiques .............................................................................................. 8 1.3. Propriétés pharmacocinétiques ............................................................................................ 8 1.4. Intérêt thérapeutique du trioxyde d’arsenic sur les leucémies ............................................. 9 1.4.1. Leucémie de type LAM3 .............................................................................................. 9 1.4.2. Etudes cliniques ......................................................................................................... 10 1.5. Mécanisme d’action .......................................................................................................... 10 1.5.1. Induction de l’apoptose .............................................................................................. 11 1.5.2. Effet sur le système enzymatique ............................................................................... 12 1.6. Métabolisme ...................................................................................................................... 13 2. Mélarsoprol................................................................................................................... 15 2.1. Historique .......................................................................................................................... 15 2.2. Propriétés physico-chimiques ............................................................................................ 16 2.3. Propriétés pharmacocinétiques .......................................................................................... 16 2.4. Mécanisme d’action sur les cellules leucémiques ............................................................. 17 2.5. Etudes cliniques ................................................................................................................. 18 2.6. Voie d’élimination ............................................................................................................. 18 3. Arsthinol ....................................................................................................................... 20 3.1. Historique .......................................................................................................................... 20 3.2. Synthèse et préparation ..................................................................................................... 20 3.3. Propriétés physico-chimiques ............................................................................................ 21 3.4. Intérêt thérapeutique .......................................................................................................... 22 3.5. Voie d’élimination ............................................................................................................. 23 II. Neurotoxicité des dérivés arsenicaux ............................................................... 25 1. Arsenic inorganique...................................................................................................... 25 2. Arsenic organique ......................................................................................................... 25 Table des matières III. Particules colloïdales et passage des barrières biologiques .......................... 27 1. Nanosuspensions de principes actifs peu solubles ....................................................... 27 1.1. Introduction ....................................................................................................................... 27 1.2. Nanosuspensions ............................................................................................................... 29 1.2.1. Production à l’échelle d’un laboratoire
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