Abstract
Ivacaftor–lumacaftor and ivacaftor are two new breakthrough cystic fibrosis transmembrane conductance modulators.
The interactions of ivacaftor and its two metabolites hydroxymethylivacaftor (iva-M1) and ivacaftorcarboxylate (iva-M6) with neurotransmitter receptors were investigated in radioligand binding assays.
Ivacaftor displayed significant affinity to the 5-hydroxytryptamine (5-HT; serotonin) 5-HT2C receptor (pKi=6.06±0.03), β3-adrenergic receptor (pKi=5.71±0.07), δ-opioid receptor (pKi=5.59±0.06) and the dopamine transporter (pKi=5.50±0.20); iva-M1 displayed significant affinity to the 5-HT2C receptor (pKi=5.81±0.04) and the muscarinic M3 receptor (pKi=5.70±0.10); iva-M6 displayed significant affinity to the 5-HT2A receptor (pKi=7.33±0.05). The in vivo central nervous system activity of ivacaftor (40 mg·kg−1 intraperitoneally for 21 days) was assessed in a chronic mouse model of depression. In the forced swim test, the ivacaftor-treated group displayed decreased immobility (52.8±7.6 s), similarly to fluoxetine (33.8±11.0 s), and increased climbing/swimming activity (181.5±9.2 s). In the open field test, ivacaftor produced higher locomotor activity than the fluoxetine group, measured both as mean number of paw touches (ivacaftor 81.1±9.6 versus fluoxetine 57.9±9.5) and total distance travelled (ivacaftor 120.6±16.8 cm versus fluoxetine 84.5±16.0 cm) in 600 s. Treatment of 23 cystic fibrosis patients with ivacaftor–lumacaftor resulted in significant improvements in quality of life (including anxiety) in all five domains of the AweScoreCF questionnaire (p=0.092–0.096).
Our findings suggest ivacaftor displays potential clinical anxiolytic and stimulating properties, and may have beneficial effects on mood.
Abstract
The novel CFTR potentiator ivacaftor displays potential pre-clinical and clinical anxiolytic and antidepressant properties, which may have beneficial effects on mood and well-being in CF patients receiving ivacaftor or ivacaftor–lumacaftor therapy http://ow.ly/thK430iaigr
Footnotes
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Conflict of interest: None declared.
Support statement: J. Li and T. Velkov are supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI111965). J. Li is an Australian National Health and Medical Research Council (NHMRC) Senior Research Fellow and T. Velkov is an Australian NHMRC Industry Career Development Level 2 Research Fellow. D. Hoyer is supported by the NHMRC. E.K. Schneider is an appointed Young Ambassador for the American Society of Microbiology and acknowledges support from the Australian Postgraduate Award. Funding information for this article has been deposited with the Crossref Funder Registry.
- Received October 11, 2017.
- Accepted January 29, 2018.
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