title: Efficacy of intranasal administration of artesunate in experimental cerebral malaria.
abstract: BACKGROUND
  Improving management of patients suffering from cerebral malaria is needed to reduce the devastating mortality and morbidity of the disease in endemic areas. Intravenous artesunate is currently the first-line treatment, but the lack of material and skills in the field make it difficult to implement in endemic areas. Intranasal route provides a very easy and direct gateway to blood and brain to deliver medications, by-passing the brain blood barrier. Therefore, it could be helpful and suitable to administer artesunate in the context of cerebral malaria, especially in young children. In this study, intranasal administration of artesunate to rescue from cerebral malaria using a murine model was tested.
  
  
  METHODS
  CBA/J mice infected with Plasmodium berghei ANKA strain received artesunate (20 mg/kg) or a placebo solution intranasally, either on day 5, 6 or 7 post-infection, during a controlled, blinded, randomized trial. Primary endpoint was mortality on day 12 post-infection. Secondary endpoints were parasitaemia and clinical stage. Pharmacokinetics data following administration were collected in blood and brains of treated mice. Local toxicity was evaluated by histopathologic examination of brain and nasal sections in blinded manner.
  
  
  RESULTS
  Intranasal administration of artesunate dramatically reduced the mortality rate (p < 0.001), preventing death in most cases. Parasitaemia loads decreased by 88.7% (61.8-100%) within 24 hours after administration. Symptoms of cerebral malaria were prevented or reversed. Dihydroartemisinin was detected in mice blood and brain within 15 minutes of intranasal administration. No direct nasal or brain toxicity was detected.
  
  
  CONCLUSIONS
  Intranasal delivery is an efficient route to timely and efficiently administer artesunate and therefore may contribute to decreasing malaria-related mortality.
authors.forename: Anne
authors.initials: A
authors.lastname: Marijon
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bonnot
authors.forename: Anthony
authors.initials: A
authors.lastname: Fourier
authors.forename: Coralie
authors.initials: C
authors.lastname: Bringer
authors.forename: Adeline
authors.initials: A
authors.lastname: Lavoignat
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Gagnieu
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Bienvenu
authors.affiliation: Université Claude Bernard Lyon 1, Malaria Research Unit, SMITH, ICBMS, UMR 5246 CNRS-INSA-CPE-UCBL1, 8 avenue Rockefeller, 69373 Lyon cedex 08, France. stephane.picot@univ-lyon1.fr.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Picot
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D037621:Artemisinins / Q000008:administration & dosage* / Q000032:analysis / Q000493:pharmacokinetics; D000077332:Artesunate; D001774:Blood Chemical Analysis; D001923:Brain Chemistry; D004195:Disease Models, Animal; D005260:Female; D016779:Malaria, Cerebral / Q000188:drug therapy*; D008808:Mice, Inbred CBA; D018512:Parasitemia / Q000175:diagnosis; D010919:Placebos / Q000008:administration & dosage; D011897:Random Allocation; D016037:Single-Blind Method; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000962:Antimalarials; D037621:Artemisinins; D010919:Placebos; D000077332:Artesunate