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A pilot dose finding study of pioglitazone in autistic children / L. CAPANO in Molecular Autism, 9 (2018)
[article]
Titre : A pilot dose finding study of pioglitazone in autistic children Type de document : Texte imprimé et/ou numérique Auteurs : L. CAPANO, Auteur ; A. DUPUIS, Auteur ; Jessica BRIAN, Auteur ; D. MANKAD, Auteur ; L. GENORE, Auteur ; R. HASTIE ADAMS, Auteur ; S. SMILE, Auteur ; T. LUI, Auteur ; D. ODROBINA, Auteur ; J. A. FOSTER, Auteur ; Evdokia ANAGNOSTOU, Auteur Article en page(s) : 59p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder Clinical trial Cytokines Drug therapy Efficacy Inflammation Maximum tolerated dose (MTD) Physiological effects of drugs Pioglitazone Safety profile Treatment Index. décimale : PER Périodiques Résumé : Background: Pioglitazone is a promising compound for treatment of core autism spectrum disorder (ASD) symptoms as it targets multiple relevant pathways, including immune system alterations. Objective: This pilot study aimed to elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5-12 years old. Methods: We conducted a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone. Twenty-five participants completed treatment. A modified dose finding method was used to determine safety and dose response among three dose levels: 0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg once daily. Results: Maximum tolerated dose: there were no serious adverse events (SAEs) and as such the maximum tolerated dose within the range tested was 0.75 mg/Kg once daily.Safety: overall, pioglitazone was well tolerated. Two participants discontinued intervention due to perceived non-efficacy and one due to the inability to tolerate interim blood work. Three participants experienced mild neutropenia.Early evidence of efficacy: statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale-Revised (RBS-R). Forty-six percent of those enrolled were deemed to be global responders. Conclusions and relevance: Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors. Randomized controlled trials using the confirmed dose are warranted. Trial registration: ClinicalTrials.gov, NCT01205282. Registration date: September 20, 2010. En ligne : https://dx.doi.org/10.1186/s13229-018-0241-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371
in Molecular Autism > 9 (2018) . - 59p.[article] A pilot dose finding study of pioglitazone in autistic children [Texte imprimé et/ou numérique] / L. CAPANO, Auteur ; A. DUPUIS, Auteur ; Jessica BRIAN, Auteur ; D. MANKAD, Auteur ; L. GENORE, Auteur ; R. HASTIE ADAMS, Auteur ; S. SMILE, Auteur ; T. LUI, Auteur ; D. ODROBINA, Auteur ; J. A. FOSTER, Auteur ; Evdokia ANAGNOSTOU, Auteur . - 59p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 59p.
Mots-clés : Autism spectrum disorder Clinical trial Cytokines Drug therapy Efficacy Inflammation Maximum tolerated dose (MTD) Physiological effects of drugs Pioglitazone Safety profile Treatment Index. décimale : PER Périodiques Résumé : Background: Pioglitazone is a promising compound for treatment of core autism spectrum disorder (ASD) symptoms as it targets multiple relevant pathways, including immune system alterations. Objective: This pilot study aimed to elucidate the maximum tolerated dose, safety, preliminary evidence of efficacy, and appropriate outcome measures in autistic children ages 5-12 years old. Methods: We conducted a 16-week prospective cohort, single blind, single arm, 2-week placebo run-in, dose-finding study of pioglitazone. Twenty-five participants completed treatment. A modified dose finding method was used to determine safety and dose response among three dose levels: 0.25 mg/kg, 0.5 mg/kg, and 0.75 mg/kg once daily. Results: Maximum tolerated dose: there were no serious adverse events (SAEs) and as such the maximum tolerated dose within the range tested was 0.75 mg/Kg once daily.Safety: overall, pioglitazone was well tolerated. Two participants discontinued intervention due to perceived non-efficacy and one due to the inability to tolerate interim blood work. Three participants experienced mild neutropenia.Early evidence of efficacy: statistically significant improvement was observed in social withdrawal, repetitive behaviors, and externalizing behaviors as measured by the Aberrant Behavior Checklist (ABC), Child Yale-Brown Obsessive Compulsive Scale (CY-BOCS), and Repetitive Behavior Scale-Revised (RBS-R). Forty-six percent of those enrolled were deemed to be global responders. Conclusions and relevance: Pioglitazone is well-tolerated and shows a potential signal in measures of social withdrawal, repetitive, and externalizing behaviors. Randomized controlled trials using the confirmed dose are warranted. Trial registration: ClinicalTrials.gov, NCT01205282. Registration date: September 20, 2010. En ligne : https://dx.doi.org/10.1186/s13229-018-0241-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=371 Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism / F. S. LO in Molecular Autism, 9 (2018)
[article]
Titre : Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism Type de document : Texte imprimé et/ou numérique Auteurs : F. S. LO, Auteur ; R. S. ERZURUMLU, Auteur Article en page(s) : 13p. Langues : Anglais (eng) Mots-clés : Barrel cortex GABAA receptors Homeostatic plasticity Met receptor tyrosine kinase Pioglitazone Thalamocortical circuitry Index. décimale : PER Périodiques Résumé : Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1(cre)/Met(flox) mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1(cre)/Met(flox) mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor-mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment. En ligne : http://dx.doi.org/10.1186/s13229-018-0196-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354
in Molecular Autism > 9 (2018) . - 13p.[article] Insulin receptor sensitization restores neocortical excitation/inhibition balance in a mouse model of autism [Texte imprimé et/ou numérique] / F. S. LO, Auteur ; R. S. ERZURUMLU, Auteur . - 13p.
Langues : Anglais (eng)
in Molecular Autism > 9 (2018) . - 13p.
Mots-clés : Barrel cortex GABAA receptors Homeostatic plasticity Met receptor tyrosine kinase Pioglitazone Thalamocortical circuitry Index. décimale : PER Périodiques Résumé : Background: Met receptor tyrosine kinase regulates neurogenesis, differentiation, migration, connectivity, and synaptic plasticity. The human Met gene has been identified as a prominent risk factor for autism spectrum disorder (ASD). Met gene-altered mice serve as useful models for mechanistic studies of ASD. Inactivation of Met in excitatory cortical neurons in mice (Emx1(cre)/Met(flox) mice) yields a phenotype in which significantly decreased GABAA receptor-mediated inhibition shifts the excitation/inhibition (E/I) balance toward excitation in the somatosensory cortex. Further, unlike that seen in wild-type mice, insulin does not increase inhibition in the mutant cortex, suggesting that one of the consequences of kinase inactive Met gene could be desensitization of insulin receptors. To test this hypothesis, we investigated the effects of insulin receptor sensitizer, pioglitazone, on inhibition in the somatosensory thalamocortical circuitry. Methods: We used whole-cell patch clamp electrophysiology and analyzed excitatory and inhibitory responses of cortical layer IV excitatory cells following stimulation of their thalamic input in thalamocortical pathway intact brain slices. We applied insulin alone and insulin + a thiazolidinedione, pioglitazone (PIO), to test the effects of sensitizing insulin receptors on inhibitory responses mediated by GABAA receptors in the somatosensory cortex of Emx1(cre)/Met(flox) mice. Results: In WT brain slices, application of insulin together with PIO did not enhance the effect of insulin alone. In contrast, PIO application induced a much larger inhibition than that of insulin alone in Met-defective cortex. Thus, insulin resistance of GABAA receptor-mediated response in Met mutant mice may result from desensitized insulin receptors. Conclusions: Sporadic clinical studies reported improved behavioral symptoms in children with autism following PIO treatment. We show that PIO can aid in normalization of the E/I balance in the primary somatosensory cortex, a potential physiological mechanism underlying the positive effects of PIO treatment. En ligne : http://dx.doi.org/10.1186/s13229-018-0196-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354