{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:53:12Z","timestamp":1791175992526,"version":"4.1.0"},"reference-count":12,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T00:00:00Z","timestamp":1791072000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100002347","name":"Bundesministerium f\u00fcr Bildung und Forschung","doi-asserted-by":"publisher","award":["01KI20386"],"award-info":[{"award-number":["01KI20386"]}],"id":[{"id":"10.13039\/501100002347","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Aloxistatin (E64d) is a membrane\u2010permeable cysteine protease inhibitor prodrug that is converted by esterases to the active metabolite E64c (loxistatin). This first\u2010in\u2010human study evaluated the safety, tolerability and pharmacokinetics of single ascending doses of inhaled E64d in healthy volunteers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this randomized, double\u2010blind, placebo\u2010controlled phase 1 trial, 47 healthy male volunteers contributed 48 study participations across six dose cohorts. Thirty\u2010six treatment assignments were to E64d and 12 to placebo. Study medication was administered by inhalation using a breath\u2010triggered mesh nebulizer. Safety assessments included adverse events, pulmonary function, gas exchange, cardiovascular parameters, and laboratory variables. Plasma concentrations of E64d and E64c were characterized following inhalation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      No serious adverse events occurred, no adverse event was classified as severe and no participant discontinued because of an adverse event. Ten adverse events occurred following E64d and four following placebo; one mild event of mucosal dryness was considered treatment related. No clinically relevant changes were observed in pulmonary, cardiovascular, or laboratory safety assessments. E64d appeared rapidly and transiently in plasma, with a median T\n                      <jats:sub>max<\/jats:sub>\n                      of 3\u00a0min. E64c showed sustained systemic exposure, with median T\n                      <jats:sub>max<\/jats:sub>\n                      values of approximately 15\u201320\u2009min and an elimination half\u2010life of approximately 30\u201340\u2009min across evaluable dose levels. Dose proportionality was not formally assessed.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Single ascending doses of inhaled E64d were generally well tolerated in healthy male volunteers. Inhalation resulted in rapid, transient systemic exposure to E64d followed by measurable formation of E64c. These findings provide a safety and pharmacokinetic basis for further investigation of inhaled aloxistatin.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70858","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:35:18Z","timestamp":1791174918000},"source":"Crossref","is-referenced-by-count":0,"title":["Safety and pharmacokinetics of inhaled aloxistatin: A first\u2010in\u2010human phase 1 dose escalation trial"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9910-2063","authenticated-orcid":false,"given":"Sebastian","family":"F\u00e4hndrich","sequence":"first","affiliation":[{"name":"Clinic of Pneumology Medical Center \u2010 University of Freiburg, Faculty of Medicine, University of Freiburg  Freiburg Germany"},{"name":"Faculty of Medicine University of Freiburg  Freiburg 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Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f6rn C.","family":"Frye","sequence":"additional","affiliation":[{"name":"Clinic of Pneumology Medical Center \u2010 University of Freiburg, Faculty of Medicine, University of Freiburg  Freiburg Germany"},{"name":"Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuan Phuoc","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Clinic of Pneumology Medical Center \u2010 University of Freiburg, Faculty of Medicine, University of Freiburg  Freiburg Germany"},{"name":"Faculty of Medicine University of Freiburg  Freiburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Herbstritt","sequence":"additional","affiliation":[{"name":"Faculty of Medicine University of Freiburg  Freiburg Germany"},{"name":"Clinical Trials Unit Medical Center \u2013 University of Freiburg  Freiburg 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