The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements.
We optically measured effects of orally available ivacaftor (Kalydeco®) on sweat rates of identified glands in 3 R117H subjects, each having a unique set of additional mutations, and compared them with 5 healthy control subjects tested contemporaneously. We injected β-adrenergic agonists intradermal...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5395152?pdf=render |
| _version_ | 1818623616652148736 |
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| author | Jessica E Char Colleen Dunn Zoe Davies Carlos Milla Richard B Moss Jeffrey J Wine |
| author_facet | Jessica E Char Colleen Dunn Zoe Davies Carlos Milla Richard B Moss Jeffrey J Wine |
| author_sort | Jessica E Char |
| collection | DOAJ |
| description | We optically measured effects of orally available ivacaftor (Kalydeco®) on sweat rates of identified glands in 3 R117H subjects, each having a unique set of additional mutations, and compared them with 5 healthy control subjects tested contemporaneously. We injected β-adrenergic agonists intradermally to stimulate CFTR-dependent 'C-sweat' and methacholine to stimulate 'M-sweat', which persists in CF subjects. We focused on an R117H-7T/F508del subject who produced quantifiable C-sweat off ivacaftor and was available for 1 blinded, 3 off ivacaftor, and 3 on ivacaftor tests, allowing us to estimate in vivo fold-increase in sweat rates produced by ivacaftor's effect on the open probability (PO) of R117H-CFTR. Measured sweat rates must be corrected for sweat losses. With estimated sweat losses of 0.023 to 0.08 nl·gland-1·min-1, ivacaftor increased the average C-sweat rates 3-7 fold, and estimated function as % of WT were 4.1-12% off ivacaftor and 21.9-32% on ivacaftor (larger values reflect increased loss estimates). Based on single tests, an R117H-7T/ R117H-7T subject showed 6-9% WT function off ivacaftor and 28-43% on ivacaftor. Repeat testing of an R117H-5T/F508del subject detected only trace responding to ivacaftor. We conclude that in vivo, R117H PO is strongly increased by ivacaftor, but channel number, mainly determined by variable deletion of exon 10, has a marked influence on outcomes. |
| first_indexed | 2024-12-16T18:43:54Z |
| format | Article |
| id | doaj.art-bab51c2ebaf049ac8b2c7e1cfb55db0e |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-16T18:43:54Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-bab51c2ebaf049ac8b2c7e1cfb55db0e2022-12-21T22:20:55ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01124e017548610.1371/journal.pone.0175486The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements.Jessica E CharColleen DunnZoe DaviesCarlos MillaRichard B MossJeffrey J WineWe optically measured effects of orally available ivacaftor (Kalydeco®) on sweat rates of identified glands in 3 R117H subjects, each having a unique set of additional mutations, and compared them with 5 healthy control subjects tested contemporaneously. We injected β-adrenergic agonists intradermally to stimulate CFTR-dependent 'C-sweat' and methacholine to stimulate 'M-sweat', which persists in CF subjects. We focused on an R117H-7T/F508del subject who produced quantifiable C-sweat off ivacaftor and was available for 1 blinded, 3 off ivacaftor, and 3 on ivacaftor tests, allowing us to estimate in vivo fold-increase in sweat rates produced by ivacaftor's effect on the open probability (PO) of R117H-CFTR. Measured sweat rates must be corrected for sweat losses. With estimated sweat losses of 0.023 to 0.08 nl·gland-1·min-1, ivacaftor increased the average C-sweat rates 3-7 fold, and estimated function as % of WT were 4.1-12% off ivacaftor and 21.9-32% on ivacaftor (larger values reflect increased loss estimates). Based on single tests, an R117H-7T/ R117H-7T subject showed 6-9% WT function off ivacaftor and 28-43% on ivacaftor. Repeat testing of an R117H-5T/F508del subject detected only trace responding to ivacaftor. We conclude that in vivo, R117H PO is strongly increased by ivacaftor, but channel number, mainly determined by variable deletion of exon 10, has a marked influence on outcomes.http://europepmc.org/articles/PMC5395152?pdf=render |
| spellingShingle | Jessica E Char Colleen Dunn Zoe Davies Carlos Milla Richard B Moss Jeffrey J Wine The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements. PLoS ONE |
| title | The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements. |
| title_full | The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements. |
| title_fullStr | The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements. |
| title_full_unstemmed | The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements. |
| title_short | The magnitude of ivacaftor effects on fluid secretion via R117H-CFTR channels: Human in vivo measurements. |
| title_sort | magnitude of ivacaftor effects on fluid secretion via r117h cftr channels human in vivo measurements |
| url | http://europepmc.org/articles/PMC5395152?pdf=render |
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