title: Effects of bumetanide on neurobehavioral function in children and adolescents with autism spectrum disorders.
abstract: In animal models of autism spectrum disorder (ASD), the NKCC1 chloride-importer inhibitor bumetanide restores physiological (Cl-)ilevels, enhances GABAergic inhibition and attenuates electrical and behavioral symptoms of ASD. In an earlier phase 2 trial; bumetanide reduced the severity of ASD in children and adolescents (3-11 years old). Here we report the results of a multicenter phase 2B study primarily to assess dose/response and safety effects of bumetanide. Efficacy outcome measures included the Childhood Autism Rating Scale (CARS), the Social Responsive Scale (SRS) and the Clinical Global Impressions (CGI) Improvement scale (CGI-I). Eighty-eight patients with ASD spanning across the entire pediatric population (2-18 years old) were subdivided in four age groups and randomized to receive bumetanide (0.5, 1.0 or 2.0 mg twice daily) or placebo for 3 months. The mean CARS value was significantly improved in the completers group (P: 0.015). Also, 23 treated children had more than a six-point improvement in the CARS compared with only one placebo-treated individual. Bumetanide significantly improved CGI (P: 0.0043) and the SRS score by more than 10 points (P: 0.02). The most frequent adverse events were hypokalemia, increased urine elimination, loss of appetite, dehydration and asthenia. Hypokalemia occurred mainly at the beginning of the treatment at 1.0 and 2.0 mg twice-daily doses and improved gradually with oral potassium supplements. The frequency and incidence of adverse event were directly correlated with the dose of bumetanide. Therefore, bumetanide improves the core symptoms of ASD and presents a favorable benefit/risk ratio particularly at 1.0 mg twice daily.
authors.affiliation: CHU hoputal Le Cluzeau, CHU Limoges, Limoges, France.
authors.forename: E
authors.initials: E
authors.lastname: Lemonnier
authors.affiliation: CHU hoputal Le Cluzeau, Hôpital Sainte Marguerite, Marseille, France.
authors.forename: N
authors.initials: N
authors.lastname: Villeneuve
authors.affiliation: CHU hoputal Le Cluzeau, CHU le Vinatier, Bron, France.
authors.forename: S
authors.initials: S
authors.lastname: Sonie
authors.affiliation: CHU hoputal Le Cluzeau, CHU Lenval, Nice, France.
authors.forename: S
authors.initials: S
authors.lastname: Serret
authors.affiliation: CHU hoputal Le Cluzeau, CHU Le Rouvray, Sotteville les Rouen, France.
authors.forename: A
authors.initials: A
authors.lastname: Rosier
authors.affiliation: CHU hoputal Le Cluzeau, CHRU Brest, Brest, France.
authors.forename: M
authors.initials: M
authors.lastname: Roue
authors.affiliation: CHU hoputal Le Cluzeau, CHU Limoges, Limoges, France.
authors.forename: P
authors.initials: P
authors.lastname: Brosset
authors.affiliation: CHU hoputal Le Cluzeau, Hôpital Sainte Marguerite, Marseille, France.
authors.forename: M
authors.initials: M
authors.lastname: Viellard
authors.affiliation: CHU hoputal Le Cluzeau, CHU le Vinatier, Bron, France.
authors.forename: D
authors.initials: D
authors.lastname: Bernoux
authors.affiliation: CHU hoputal Le Cluzeau, CHU Le Rouvray, Sotteville les Rouen, France.
authors.forename: S
authors.initials: S
authors.lastname: Rondeau
authors.affiliation: CHU hoputal Le Cluzeau, CHU Lenval, Nice, France.
authors.forename: S
authors.initials: S
authors.lastname: Thummler
authors.affiliation: CHU hoputal Le Cluzeau, Neurochlore Research Team, Marseille, France.
authors.forename: D
authors.initials: D
authors.lastname: Ravel
authors.affiliation: CHU hoputal Le Cluzeau, Neurochlore Research Team, Marseille, France.|CHU hoputal Le Cluzeau, Neurochlore Research Team, C/O INMED, INSERM Unité 901, Aix Marseille Université, Marseille, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Ben-Ari
mesh_terms: D000293:Adolescent; D000855:Anorexia / Q000139:chemically induced; D001247:Asthenia / Q000139:chemically induced; D000067877:Autism Spectrum Disorder / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D002034:Bumetanide / Q000008:administration & dosage* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D003681:Dehydration / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007008:Hypokalemia / Q000139:chemically induced; D008297:Male; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide