{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T02:55:56Z","timestamp":1777949756331,"version":"3.51.4"},"reference-count":51,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL133240"],"award-info":[{"award-number":["R01 HL133240"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01 HL157942"],"award-info":[{"award-number":["R01 HL157942"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["K23 HL163445"],"award-info":[{"award-number":["K23 HL163445"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["SALATH22G0"],"award-info":[{"award-number":["SALATH22G0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000897","name":"Cystic Fibrosis Foundation","doi-asserted-by":"publisher","award":["SALATH23P0"],"award-info":[{"award-number":["SALATH23P0"]}],"id":[{"id":"10.13039\/100000897","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Transforming growth factor-\u03b21 (TGF-\u03b21) contributes to more severe pulmonary disease in people with cystic fibrosis (pwCF). Our preclinical\n                      <jats:italic>in vitro<\/jats:italic>\n                      and\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies demonstrated that losartan could reverse TGF-\u03b21-mediated mucociliary dysfunction, albeit at doses difficult to achieve by oral administration. This study therefore examined airway losartan concentrations after oral and inhaled dosing to evaluate if oral losartan could be even expected to improve mucociliary clearance.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted comparative pharmacokinetics studies in sheep assessing airway surface liquid (ASL) concentrations of losartan and its metabolites, EXP3179 and EXP3174, after oral and inhaled administration. Another pharmacokinetic study used oral losartan to compare serum levels in pwCF on and off CFTR modulators and healthy volunteers. Finally, an open-label clinical trial evaluated effects of oral losartan (50\u00a0mg twice daily for 14 weeks) on mucociliary and cough clearance (MCC\/CC) in pwCF off CFTR modulators as they have a need for novel therapies (NCT03435939).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In sheep, oral losartan (50\u00a0mg twice daily for 4 days) did not achieve ASL levels expected to improve CF-associated mucociliary dysfunction based on our previous data. In humans, single dose pharmacokinetics of oral losartan showed differential results in pwCF and healthy volunteers, with pwCF off CFTR modulators achieving the lowest serum levels of losartan and EXP3174 with a complete absence of EXP3179, the anti-inflammatory metabolite of losartan. The open label study included seven participants. Serum concentrations of losartan and EXP3174 at week 14 matched levels observed in pwCF not on modulators in the pharmacokinetic study. As expected, no improvements in whole-lung or peripheral MCC\/CC were found in participants with complete datasets. PpFEV1 remained unchanged, but nasal TGF-\u03b21 levels significantly decreased with treatment, although systemic inflammatory markers were unaffected (C-reactive protein, calprotectin, and serum amyloid A).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Reduced drug exposure compared to healthy volunteers reflects altered pharmacokinetics in pwCF. Nevertheless, oral losartan at clinically approved doses does not achieve airway concentrations needed to restore mucociliary function in any individual, and especially not in pwCF off modulators. Future studies should consider inhaled drug delivery to achieve therapeutically meaningful airway exposure to losartan and its metabolites.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1807581","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T04:25:07Z","timestamp":1777868707000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Oral losartan yields subtherapeutic airway exposure compared to nebulized delivery and fails to improve mucociliary clearance in cystic fibrosis"],"prefix":"10.3389","volume":"17","author":[{"given":"Charles D.","family":"Bengtson","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary Critical Care and Sleep Medicine, University of Kansas Medical Center","place":["Kansas, KS, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas","family":"Schmid","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary Critical Care and Sleep Medicine, University of Kansas Medical Center","place":["Kansas, KS, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael D.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary Critical Care and Sleep Medicine, University of Kansas Medical Center","place":["Kansas, KS, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John S.","family":"Dennis","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Pulmonary Critical Care and Sleep Medicine, University of Kansas Medical Center","place":["Kansas, KS, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. Steven","family":"Leeder","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Children\u2019s Mercy Research Institute, Children\u2019s Mercy Hospital","place":["Kansas, MO, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirby L.","family":"Zeman","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of North Carolina at Chapel Hill","place":["Chapel Hill, NC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William D.","family":"Bennett","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of North Carolina at Chapel Hill","place":["Chapel Hill, NC, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan","family":"Sabater","sequence":"additional","affiliation":[{"name":"Department of Research, Mount Sinai Medical Center","place":["Miami Beach, FL, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathalie","family":"Baumlin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Kansas Medical Center","place":["Kansas, KS, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthias","family":"Salathe","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Kansas Medical Center","place":["Kansas, KS, United States"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1136\/thorax.55.6.459","article-title":"TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis","volume":"55","author":"Arkwright","year":"2000","journal-title":"Thorax"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00509-2020","article-title":"Hyperglycaemia in cystic fibrosis adversely affects BK channel function critical for mucus clearance","volume":"57","author":"Bengtson","year":"2021","journal-title":"Eur. 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