{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:44:19Z","timestamp":1785422659207,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,19]]},"group-title":"Neuroscience","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,19]],"date-time":"2025-09-19T00:00:00Z","timestamp":1758240000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R21 HD103869"],"award-info":[{"award-number":["R21 HD103869"]}],"id":[{"id":"https:\/\/ror.org\/04byxyr05","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U2C DK135066"],"award-info":[{"award-number":["U2C DK135066"]}],"id":[{"id":"https:\/\/ror.org\/00adh9b73","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>A challenge in preclinical neonatal neuroprotection research is implementation of study designs that enable direct comparison of multiple potentially effective drugs. We used adaptive design to test four FDA approved drugs (azithromycin, erythropoietin, caffeine, melatonin) concurrently and determine which best combined safety and efficacy.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Seven-day-old (P7) rats underwent hypoxia-ischemia (HI; right carotid ligation + timed 8% O\n                    <jats:sub>2<\/jats:sub>\n                    exposure); some experiments included pre-treatment with agents that induced inflammation, and some included post-HI brief moderate hypothermia. Sensorimotor and neuropathology measures were incorporated into a Composite Score that also accounted for deaths. Outcome was initially evaluated at P21 and in confirmatory studies at P35. A pre-specified Bayesian algorithm with futility and efficacy stopping rules was devised to analyze emerging data and adjust subsequent animal allocation among drug groups.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In all models either azithromycin or erythropoietin (EPO) offered superior neuroprotection at P21 and the other was \u201crunner-up\u201d. Caffeine and melatonin conferred modest neuroprotection in pure HI but were quickly eliminated in hypothermia-treated HI. At P35 azithromycin and EPO outcomes were generally similar.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>These results support azithromycin or erythropoietin as candidate neuroprotective agents and warrant future studies in large animal neonatal cerebral hypoxia-ischemia models.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Impact<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Our preclinical comparative efficacy strategy using adaptive design tested four clinically available drugs (azithromycin, caffeine, erythropoietin and melatonin) in multiple preclinical rodent brain injury models and consistently identified differences in efficacy among drugs.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Three key factors differentiating our approach from existing reports were direct within-litter comparisons, evaluation in multiple injury models and inclusion of both function and neuropathology outcomes.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Either azithromycin or erythropoietin, even with a 2-hour initiation delay, was the most neuroprotective drug in all models, with the other a close \u201crunner-up\u201d.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Less effective drugs were recognized and eliminated early by the prespecified Bayesian algorithm.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>These results support azithromycin or erythropoietin as candidate neuroprotective agents and support future studies in large animal neonatal cerebral hypoxia-ischemia models.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.17.676833","type":"posted-content","created":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T00:05:18Z","timestamp":1758326718000},"source":"Crossref","is-referenced-by-count":1,"title":["Comparing Neuroprotective Drug Efficacy in Rodent Neonatal Brain Injury Models"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1320-905X","authenticated-orcid":false,"given":"John D.E.","family":"Barks","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiqing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Sturza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niko","family":"Kaciroti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William J.","family":"Meurer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faye S.","family":"Silverstein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092313250877000_2025.09.17.676833v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2010.05.010"},{"key":"2025092313250877000_2025.09.17.676833v1.2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1000389"},{"key":"2025092313250877000_2025.09.17.676833v1.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2119660"},{"key":"2025092313250877000_2025.09.17.676833v1.4","doi-asserted-by":"crossref","first-page":"22368","DOI":"10.3390\/ijms160922368","article-title":"Neuroprotective Strategies after Neonatal Hypoxic Ischemic Encephalopathy","volume":"16","year":"2015","journal-title":"Int. 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