title: Arsthinol nanosuspensions: pharmacokinetics and anti-leukaemic activity on NB4 promyelocytic leukaemia cells.
abstract: OBJECTIVE
  The organoarsenical arsthinol was used in the 1950s in the treatment of amoebiasis and yaws and was considered as 'highly tolerated'. The aim of this work was to study its anti-leukaemic activity and to develop nanosuspensions of the drug, thereby limiting brain concentrations and the risk of encephalopathy.
  
  
  METHODS
  Arsthinol nanosuspensions were produced by high-pressure homogenization. The anti-leukaemic activity was assessed on NB4 acute promyelocytic leukaemia cells (vs solutions of arsthinol, As(2)O(3) and melarsoprol). In addition, a pharmacokinetics study was performed to compare the nanosuspensions and the solution of arsthinol.
  
  
  RESULTS
  Arsthinol induced growth inhibition of NB4 cells at lower concentration (IC50 (concentration inhibiting growth by 50%) = 0.78 +/- 0.08 micromol/l after 24 h) than As(2)O(3) (IC50 = 1.60 +/- 0.23 micromol/l after 24 h) or melarsoprol (IC50 = 1.44 +/- 0.08 micromol/l after 24 h). When formulated as nanosuspension, arsthinol remained cytotoxic (IC50 = 1.33 +/- 0.30 micromol/l after 24 h). This formulation also reduced the drug's access to the brain (C(max) = 0.03 micromol/g) whereas bone marrow concentrations remained very high (C(max) = 2 micromol/g).
  
  
  CONCLUSIONS
  Nanosuspensions of arsthinol could be proposed for further studies in the treatment of acute promyelocytic leukaemia.
authors.affiliation: EA 3452 Cibles thérapeutiques formulation et expertise préclinique du médicament, Nancy Université, Nancy, France.
authors.forename: Imane
authors.initials: I
authors.lastname: Ajana
authors.forename: Alain
authors.initials: A
authors.lastname: Astier
authors.forename: Stéphane
authors.initials: S
authors.lastname: Gibaud
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001853:Bone Marrow / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008549:Melarsoprol / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D036103:Nanotechnology / Q000379:methods*; D010087:Oxides / Q000494:pharmacology; D013535:Suspensions / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D013535:Suspensions; C546471:arsthinol; D000077237:Arsenic Trioxide; D008549:Melarsoprol