In contrast, larger, more relatively hydrophilic poloxamer molecules, such as the species contained in the main peak of poloxamer 188, have the opposite effect and act as membrane sealants . Accordingly, we believe that certain LMW
components of the poloxamer 188 polymeric distribution may act more like Triton detergents to initiate or propagate membrane injury and, through this mechanism, may contribute to adverse renal effects. 5 Conclusions 1. The renal dysfunction associated with P188-NF (commercially available, excipient-grade material) is dose dependent www.selleckchem.com/products/azd1390.html and is characterized histologically by coarse vacuolization in the proximal tubule epithelium, with no evidence of necrosis or irreversible cellular damage. 2. The renal dysfunction observed with P188-NF is associated with LMW substances present in P188-NF. These substances can be reduced via supercritical fluid extraction. 3. Compared with P188-NF, P188-P with reduced
LMW selleck substances was better find more tolerated in a remnant-kidney animal model. In this model, P188-P resulted in less pronounced vacuolization, with more rapid recovery, less effect on serum creatinine, and significantly improved tolerability. Any effects of P188-P on renal function are predicted to be fully reversible. 4. In studies investigating P188-P, the pattern of dose-dependent changes in serum creatinine previously observed with P188-NF was not observed, even with significantly higher levels of exposure.
This suggests that the benefits of P188-P observed in animal studies translate to humans. Acknowledgments The authors wish to acknowledge the technical assistance of Abdul Al-Khalidi, Himanshu Shah, Pingping Wang, CYTH4 and Hal Lee in the preparation and characterization of purified poloxamer; Carlos Rivera-Marrero and Medea Mshvildadze for assistance with the nephrectomized rat studies; Melvin Schwartz for assistance with the histopathologic studies, and Doug McKenzie for assistance in the preparation of the manuscript. The studies were funded by CytRx Corporation, with additional support from an FDA Orphan Drug Product Grant. Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. References 1. Moloughney JG, Weisleder N. Poloxamer 188 (p188) as a membrane resealing reagent in biomedical applications. Recent Pat Biotechnol. 2012;6(3):200–11.PubMedCentralPubMedCrossRef 2. Maskaarinec S, Wu G, Lee K. Membrane sealing by poloxamers. Ann N.Y. Acad Sci. 1066;2005:310–20. 3. Marks JD, Pan CY, Bushell T, Cromie W, Lee RC. Amphiphilic, tri-block copolymers provide potent membrane-targeted neuroprotection. FASEB J. 2001;15(6):1107–9.PubMed 4. Manno S, Takakuwa Y, et al.