{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,11]],"date-time":"2026-10-11T06:23:52Z","timestamp":1791699832794,"version":"4.3.4"},"reference-count":93,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T00:00:00Z","timestamp":1629849600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006942","name":"Medical University of South Carolina","doi-asserted-by":"publisher","award":["Neuroscience Insitute Discovery Grant"],"award-info":[{"award-number":["Neuroscience Insitute Discovery Grant"]}],"id":[{"id":"10.13039\/100006942","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000065","name":"National Institute of Neurological Disorders and Stroke","doi-asserted-by":"publisher","award":["F31NS108623"],"award-info":[{"award-number":["F31NS108623"]}],"id":[{"id":"10.13039\/100000065","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Instituto Carlos III,","award":["FISPI14\/0433"],"award-info":[{"award-number":["FISPI14\/0433"]}]},{"name":"Spanish Ministry of Health","award":["EC11-246"],"award-info":[{"award-number":["EC11-246"]}]},{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["P60743"],"award-info":[{"award-number":["P60743"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>N-acetylcysteine (NAC) and vitamin D provide effective neuroprotection in animal models of severe or inflammation-sensitized hypoxic ischemic encephalopathy (HIE). To translate these FDA-approved drugs to HIE neonates, we conducted an early phase, open-label trial of 10 days of NAC (25, 40 mg\/kg q12h) + 1,25(OH)2D (calcitriol 0.05 mg\/kg q12h, 0.03 mg\/kg q24h), (NVD), for pharmacokinetic (PK) estimates during therapeutic hypothermia and normothermia. We paired PK samples with pharmacodynamic (PD) targets of plasma isoprostanoids, CNS glutathione (GSH) and total creatine (tCr) by serial MRS in basal ganglia (BG) before and after NVD infusion at five days. Infants had moderate (n = 14) or severe HIE (n = 16), funisitis (32%), and vitamin D deficiency (75%). NVD resulted in rapid, dose-responsive increases in CNS GSH and tCr that correlated positively with plasma [NAC], inversely with plasma isofurans, and was greater in infants with lower baseline [GSH] and [tCr], suggesting increases in these PD markers were titrated by neural demand. Hypothermia and normothermia altered NAC PK estimates. NVD was well tolerated. Excluding genetic syndromes (2), prolonged ECMO (2), lost-to-follow-up (1) and SIDS death (1), 24 NVD treated HIE infants have no evidence of cerebral palsy, autism or cognitive delay at 24\u201348 months. These data confirm that low, safe doses of NVD in HIE neonates decreased oxidative stress in plasma and CNS, improved CNS energetics, and are associated with favorable developmental outcomes at two to four years.<\/jats:p>","DOI":"10.3390\/antiox10091344","type":"journal-article","created":{"date-parts":[[2021,8,26]],"date-time":"2021-08-26T00:19:26Z","timestamp":1629937166000},"page":"1344","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["NAC and Vitamin D Improve CNS and Plasma Oxidative Stress in Neonatal HIE and Are Associated with Favorable Long-Term Outcomes"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4196-483X","authenticated-orcid":false,"given":"Dorothea D","family":"Jenkins","sequence":"first","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Medical University of South Carolina, 10 McClennan Banks Drive, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8262-804X","authenticated-orcid":false,"given":"Hunter G","family":"Moss","sequence":"additional","affiliation":[{"name":"Center for Biomedical Imaging, Department of Radiology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Truman R","family":"Brown","sequence":"additional","affiliation":[{"name":"Center for Biomedical Imaging, Department of Radiology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milad","family":"Yazdani","sequence":"additional","affiliation":[{"name":"Center for Biomedical Imaging, Department of Radiology, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sudhin","family":"Thayyil","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Imperial College London, London W12 0HS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6034-7976","authenticated-orcid":false,"given":"Paolo","family":"Montaldo","sequence":"additional","affiliation":[{"name":"Centre for Perinatal Neuroscience, Imperial College London, London W12 0HS, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0061-4742","authenticated-orcid":false,"given":"Maximo","family":"Vento","sequence":"additional","affiliation":[{"name":"Neonatal Research Group, Health Research Institute Hospital La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6979-2235","authenticated-orcid":false,"given":"Julia","family":"Kuligowski","sequence":"additional","affiliation":[{"name":"Neonatal Research Group, Health Research Institute Hospital La Fe, 46026 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2764-6533","authenticated-orcid":false,"given":"Carol","family":"Wagner","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Medical University of South Carolina, 10 McClennan Banks Drive, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce W","family":"Hollis","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, Medical University of South Carolina, 10 McClennan Banks Drive, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8664-803X","authenticated-orcid":false,"given":"Donald B","family":"Wiest","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacy and Outcomes Sciences, College of Pharmacy, Medical University of South Carolina, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1159\/000430860","article-title":"Hypothermia Does Not Reverse Cellular Responses Caused by Lipopolysaccharide in Neonatal Hypoxic-Ischaemic Brain Injury","volume":"37","author":"Osredkar","year":"2015","journal-title":"Dev. 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