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- Title
Polyethylene Oxide Molecular Size Determines the Severity of Atypical Thrombotic Microangiopathy in a Guinea Pig Model of Acute Intravenous Exposure.
- Authors
Baek, Jin Hyen; Shin, Hye Kyung H; Koo, Soo Min; Gao, Yamei; Qu, Haiou; Feng, Xin; Xu, Xiaoming; Pinto, Julia; Katneni, Upendra; Kimchi-Sarfaty, Chava; Buehler, Paul W
- Abstract
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 >1 MDa that is driven by a robust intravascular hemolysis and potentially, tissue hypoxia.
- Subjects
POLYETHYLENE oxide; THROMBOTIC microangiopathies; HEMOLYTIC-uremic syndrome; GUINEA pigs; MOLECULAR size; ESCHERICHIA coli O157:H7
- Publication
Toxicological Sciences, 2020, Vol 177, Issue 1, p235
- ISSN
1096-6080
- Publication type
Article
- DOI
10.1093/toxsci/kfaa099