Hemorrhagic shock, caused by trauma, is a leading cause of preventable death. A combination treatment of D-β-hydroxybutyrate (BHB) and melatonin (MLT), in dimethyl sulfoxide - water, increased survival. A freeze-dried BHB–MLT formulation, with a short reconstitution time, has been developed. This intravenous formulation, prepared with an aqueous vehicle, completely eliminated dimethyl sulfoxide, thereby avoiding the potential problems associated with this solvent. The poor aqueous solubility of MLT necessitated the use of polyvinylpyrrolidine (PVP) as a complexing agent. Thus the prelyophilization solution contained BHB (2 M), MLT (21.5 mM) and PVP (40 mM). Using a combination of low-temperature X-ray diffractometry and thermal analysis, the lyophilization process parameters were optimized. Infra-red spectra revealed hydrogen bonding interaction between PVP and MLT, while BHB crystallized as BHB.0.25 H2O in the final lyophile. The formulation improved survival in a rat model of hemorrhagic shock. Based on the increase in rate of survival and longer survival time compared to untreated animals, we conclude that this formulation can serve as a promising first line of treatment for hemorrhagic shock.
Bibliographical noteFunding Information:
Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health Award Number UL1TR000114. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ST was partially supported by the William and Mildred Peters Endowment fund . Parts of this work were carried out in the Characterization Facility, University of Minnesota, a member of the NSF-funded Materials Research Facilities Network ( www.mrfn.org ).
© 2017 Elsevier B.V.
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- Beta hydroxybutyrate
- Hemorrhagic shock
- Resuscitation fluid