Comparison of nanosuspensions and hydroxypropyl-beta-cyclodextrin complex of melarsoprol: pharmacokinetics and tissue distribution in mice
| Autor: | Alain Astier, Marc Muchow, Siham Ben Zirar, Stéphane Gibaud |
|---|---|
| Přispěvatelé: | Cibles thérapeutiques, formulation et expertise pré-clinique du médicament (CITHEFOR), Université de Lorraine (UL) |
| Rok vydání: | 2007 |
| Předmět: |
Chemistry
Pharmaceutical Pharmaceutical Science Melarsoprol 02 engineering and technology Pharmacology MESH: Melarsoprol 030226 pharmacology & pharmacy Median lethal dose Mice 0302 clinical medicine MESH: Animals Tissue Distribution MESH: Trypanocidal Agents media_common beta-Cyclodextrins General Medicine U937 Cells [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences 021001 nanoscience & nanotechnology Trypanocidal Agents 3. Good health 2-Hydroxypropyl-beta-cyclodextrin Leukemia medicine.anatomical_structure Female 0210 nano-technology Biotechnology medicine.drug Drug MESH: beta-Cyclodextrins media_common.quotation_subject Antineoplastic Agents MESH: U937 Cells Lethal Dose 50 03 medical and health sciences MESH: Chemistry Pharmaceutical Pharmacokinetics Suspensions medicine Distribution (pharmacology) Animals Humans MESH: Tissue Distribution MESH: Mice MESH: K562 Cells MESH: Humans business.industry medicine.disease Acute toxicity MESH: Lethal Dose 50 MESH: Suspensions Immunology MESH: Antineoplastic Agents Nanoparticles Bone marrow business K562 Cells MESH: Female MESH: Nanoparticles |
| Zdroj: | European Journal of Pharmaceutics and Biopharmaceutics European Journal of Pharmaceutics and Biopharmaceutics, Elsevier, 2008, 70 (2), pp.649-56. ⟨10.1016/j.ejpb.2008.05.012⟩ |
| ISSN: | 0939-6411 |
| DOI: | 10.1016/j.ejpb.2008.05.012⟩ |
| Popis: | International audience; The aim of this work was to develop and compare two formulations of melarsoprol (nanosuspension and hydroxypropyl-beta-cyclodextrin inclusion complex). The arsenic concentrations in the organs have been assessed on a mouse model. Since this organoarsenical drug has been proposed for the treatment of cerebral trypanosomiasis and refractory leukaemias, special emphasis has been put on the bone marrow and on the brain. The organic solution of melarsoprol (Mel B, 0.039mmol/kg), injected intravenously as control formulation, was found to concentrate significantly in the bone marrow (C(max)=1.64mmol/g), though, not surprisingly, the brain concentration was quite high (C(max)=0. 093mmol/g) and the LD(50) was 0.12mmol/kg. The hydroxypropyl-beta-cyclodextrin inclusion complex was found to concentrate much more in the brain (C(max)=0.25mmol/g) leading to a higher acute toxicity (i.e., lower LD(50); 0.056mmol/kg). Nevertheless, even if the encephalopathy risk has to be taken in to account, this could be considered as a positive point for the treatment of the cerebral trypanosomiasis, which is the main indication for this drug. On the contrary, the use of nanosuspensions allowed us to reduce the cerebral concentration (C(max)=0.02micromol/g) and the acute toxicity (LD(50)=0.25mmol/kg). Moreover, nanosuspensions, especially those prepared with polxamer 407, preserved a good in vitro antileukemic activity (IC(50)=3.34+/-0.33 after 48h on K562) with high bone marrow concentrations (C(max)=1.85micromol/g). As a consequence this formulation could be proposed for the treatment of refractory leukaemias. |
| Databáze: | OpenAIRE |
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