{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T20:16:00Z","timestamp":1758399360800},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,6,24]],"date-time":"2020-06-24T00:00:00Z","timestamp":1592956800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Food and Drug Administration, Center for Drug Evaluation and Research Intramural"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,9,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In 2017, Opana ER was voluntarily removed from the U.S. market based on concerns that its risks outweighed its therapeutic benefits. The data that supported this conclusion were based on postmarketing evaluation that demonstrated increased intravenous abuse associated outbreaks of HIV, hepatitis C, and uniquely, a thrombotic thrombocytopenic purpura (TTP)-like syndrome. In 2017, the cause was mechanistically linked to intravenous exposure of the high-molecular weight polyethylene oxide (PEO), an excipient component of the drug product. However, it was unknown how differing PEO preparations might alter this response in vivo. Knowing the likelihood of a PEO driven atypical thrombotic microangiopathy with hemolytic uremic syndrome (TMA-HUS), this study was specifically designed with the primary objective focused on understanding the impact of PEO molecular weight on TMA-HUS in a guinea pig model of acute repeat PEO (1, 4, and 7 MDa) dosing. Results from this analysis suggest that repeated dosing with PEO 4 and 7 MDa, but not 1 MDa induced a marked intravascular hemolysis with schistocytes, mild anemia, thrombocytopenia, hemoglobinuria, and kidney injury, consistent with observations of a TMA-HUS-like syndrome. Nonetheless, observations of tissue microthrombi, complement or altered von Willebrand factor involvement were not observed, which would be consistent with a definitive TMA. Further, only 7 MDa PEO dosing was associated with marked renal hypoxia. Taken together, this study defines renal injury risk with PEO formulations &amp;gt;1 MDa that is driven by a robust intravascular hemolysis and potentially, tissue hypoxia.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaa099","type":"journal-article","created":{"date-parts":[[2020,6,16]],"date-time":"2020-06-16T19:11:44Z","timestamp":1592334704000},"page":"235-247","source":"Crossref","is-referenced-by-count":3,"title":["Polyethylene Oxide Molecular Size Determines the Severity of Atypical Thrombotic Microangiopathy in a Guinea Pig Model of Acute Intravenous Exposure"],"prefix":"10.1093","volume":"177","author":[{"given":"Jin Hyen","family":"Baek","sequence":"first","affiliation":[{"name":"Laboratory of Biochemistry and Vascular Biology, Division of Blood Components and Devices, Office of Blood Research and Review; Center for Drug Evaluation and Review, FDA, Silver Spring, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hye Kyung H","family":"Shin","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Vascular Biology, Division of Blood Components and Devices, Office of Blood Research and Review; Center for Drug Evaluation and Review, FDA, Silver Spring, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Soo Min","family":"Koo","sequence":"additional","affiliation":[{"name":"Laboratory of Biochemistry and Vascular Biology, Division of Blood Components and Devices, Office of Blood Research and Review; Center for Drug Evaluation and Review, FDA, Silver Spring, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yamei","family":"Gao","sequence":"additional","affiliation":[{"name":"Division of Viral Products, Office of Vaccines, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haiou","family":"Qu","sequence":"additional","affiliation":[{"name":"Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality; Center for Drug Evaluation and Review, FDA, Silver Spring, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Feng","sequence":"additional","affiliation":[{"name":"Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality; Center for Drug Evaluation and Review, FDA, Silver Spring, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoming","family":"Xu","sequence":"additional","affiliation":[{"name":"Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Quality; Center for Drug Evaluation and Review, FDA, Silver Spring, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julia","family":"Pinto","sequence":"additional","affiliation":[{"name":"Division of New Drug Product II, Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research (CDER), FDA, Silver Spring Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Upendra","family":"Katneni","sequence":"additional","affiliation":[{"name":"Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chava","family":"Kimchi-Sarfaty","sequence":"additional","affiliation":[{"name":"Division of Plasma Protein Therapeutics, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research (CBER), FDA, Silver Spring Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul W","family":"Buehler","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Maryland School of Medicine, Baltimore, Maryland"},{"name":"The Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, University of Maryland School of Medicine, Baltimore, Maryland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,6,24]]},"reference":[{"key":"2020101315044467500_kfaa099-B1","doi-asserted-by":"crossref","first-page":"1022","DOI":"10.1053\/j.ajkd.2014.01.015","article-title":"Thrombotic microangiopathy and acute kidney injury associated with intravenous abuse of an oral extended-release formulation of oxymorphone hydrochloride: Kidney biopsy findings and report of 3 cases","volume":"63","author":"Ambruzs","year":"2014","journal-title":"Am. 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