Emanuele Martin, Balasubramaniam Balu
Mast Therapeutics, 12390 El Camino Real, Suite 150, San Diego, CA, 92130, USA,
Drugs R D. 2014 Jun;14(2):73-83. doi: 10.1007/s40268-014-0041-0.
Poloxamer 188 (P188) is a non-ionic amphiphilic copolymer with hemorheologic, antithrombotic, anti-inflammatory, and cytoprotective properties. It potentially has clinical utility in diverse diseases, such as acute myocardial infarction, acute limb ischemia, shock, acute stroke, heart failure, and sickle cell crisis. P188 is available as an excipient-grade product, manufactured to National Formulary specifications, which we refer to as P188-NF. During synthesis of P188-NF, polymerization of its polyoxyethylene and polyoxypropylene components generates undesirable low molecular weight (LMW) substances, such as truncated polymers and glycols. In early clinical studies, P188-NF yielded unexpected renal dysfunction. Here, we explore the nature of the renal dysfunction associated with P188-NF and use a purified (more homogenous) form of P188-NF (P188-P) to show that removal of LMW substances is associated with substantially less renal dysfunction. In both a remnant-kidney animal model and in clinical studies, P188-P demonstrates a substantially improved renal safety profile.
泊洛沙姆188（P188）是一种具有血液流变学、抗血栓形成、抗炎和细胞保护特性的非离子两亲共聚物。它在多种疾病中可能具有临床应用价值，如急性心肌梗死、急性肢体缺血、休克、急性中风、心力衰竭和镰状细胞危象。P188有作为辅料级产品供应，按照国家处方集规范生产，我们将其称为P188-NF。在P188-NF的合成过程中，其聚氧乙烯和聚氧丙烯成分的聚合会产生不良的低分子量（LMW）物质，如截短的聚合物和二醇。在早期临床研究中，P188-NF导致了意外的肾功能障碍。在此，我们探究与P188-NF相关的肾功能障碍的本质，并使用纯化（更均匀）形式的P188-NF（P188-P）来表明去除LMW物质与显著减轻的肾功能障碍相关。在残余肾动物模型和临床研究中，P188-P都表现出显著改善的肾脏安全性。
