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The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites

Elena K. Schneider, Rachel M. McQuade, Vincenzo C. Carbone, Felisa Reyes-Ortega, John W. Wilson, Brenda Button, Ayame Saito, Daniel P. Poole, Daniel Hoyer, Jian Li, Tony Velkov
ERJ Open Research 2018 4: 00127-2017; DOI: 10.1183/23120541.00127-2017
Elena K. Schneider
1Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
2Dept of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia
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  • ORCID record for Elena K. Schneider
Rachel M. McQuade
3Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
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Vincenzo C. Carbone
4Animal Science, AgResearch Limited, Palmerston North, New Zealand
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Felisa Reyes-Ortega
5Dept of Applied Physics, Sciences Faculty, University of Granada, Granada, Spain
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John W. Wilson
6Dept of Medicine, Monash University, The Alfred Hospital, Melbourne, Australia
7Cystic Fibrosis Service, The Alfred Hospital, Melbourne, Australia
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Brenda Button
6Dept of Medicine, Monash University, The Alfred Hospital, Melbourne, Australia
7Cystic Fibrosis Service, The Alfred Hospital, Melbourne, Australia
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Ayame Saito
3Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
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Daniel P. Poole
3Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
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Daniel Hoyer
2Dept of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia
8The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia
9Dept of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA
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Jian Li
10Monash Biomedicine Discovery Institute, Dept of Microbiology, Monash University, Clayton, Australia
11These two authors contributed equally to this work
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Tony Velkov
1Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia
2Dept of Pharmacology and Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Australia
11These two authors contributed equally to this work
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  • For correspondence: tony.velkov@unimelb.edu.au
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  • FIGURE 1
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    FIGURE 1

    a) Secondary binding data for ivacaftor. [3H]mesulergine displacement data (Ki=866 nM) binding to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2C receptor. The reference compound is ritanserin (Ki=0.57 nM). b) Secondary binding data for ivacaftorcarboxylate (iva-M6). [3H]ketanserin displacement data (Ki=147 nM) binding to the 5-HT2A receptor. The reference compound is clozapine (Ki=2.4 nM). CPM: counts per minute.

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    FIGURE 2

    Molecular docking models of a) ivacaftor bound to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2C receptor and b) ivacaftorcarboxylate (iva-M6) bound to the 5-HT2A receptor. Ivacaftor, iva-M6 and residues within the receptor cavity are shown in ball-and-stick representation. The 5-HT2C and 5-HT2A receptors are shown in cartoon ribbon representation. The labelled side chains within the binding cavity represent contacts within 4 Å of the docked molecules.

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    FIGURE 3

    Results of the murine forced swim test and spontaneous locomotor activity tests for ivacaftor, fluoxetine and ketamine. a) Schematic diagram depicting the forced swim test. b) Effect of ivacaftor treatment (40 mg·kg−1 i.p. for 21 days) on swimming and climbing in the forced swim test (n=10). Fluoxetine (10.2 mg·kg−1 i.p. for 21 days) and ketamine (10 mg·kg−1 s.c.) were used as the comparators. c) Effect of ivacaftor, fluoxetine and ketamine on immobility in the forced swim test (n=10). *: p<0.05. d) Effect of ivacaftor and fluoxetine on spontaneous locomotor activity in the open field test measuring the distance (cm) travelled for 10 min (n=10). e) Effect of ivacaftor, fluoxetine and ketamine on spontaneous locomotor activity in the open field test measuring the number of touches for 10 min (n=10).

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    FIGURE 4

    Results of the AweScoreCF questionnaire completed by 23 adult cystic fibrosis (CF) patients 1 month before and 3 months after initiating ivacaftor–lumacaftor therapy: a) clinical parameters, b) general well-being, c) physical fitness, d) physique, e) psychological parameters and f) total score. Data are presented as mean±sem of a paired t-test. *: p<0.05. In eight out of 10 subdomains changes resulted in statistically significant improvement of quality of life and well-being of the 23 adult CF patients; a positive trend was observed in the subdomains sputum and mood.

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The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites
Elena K. Schneider, Rachel M. McQuade, Vincenzo C. Carbone, Felisa Reyes-Ortega, John W. Wilson, Brenda Button, Ayame Saito, Daniel P. Poole, Daniel Hoyer, Jian Li, Tony Velkov
ERJ Open Research Jan 2018, 4 (1) 00127-2017; DOI: 10.1183/23120541.00127-2017

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The potentially beneficial central nervous system activity profile of ivacaftor and its metabolites
Elena K. Schneider, Rachel M. McQuade, Vincenzo C. Carbone, Felisa Reyes-Ortega, John W. Wilson, Brenda Button, Ayame Saito, Daniel P. Poole, Daniel Hoyer, Jian Li, Tony Velkov
ERJ Open Research Jan 2018, 4 (1) 00127-2017; DOI: 10.1183/23120541.00127-2017
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