Evaluation of novel formulations of D-β-hydroxybutyrate and melatonin in a rat model of hemorrhagic shock

Andrea Wolf, Seema Thakral, Kristine E. Mulier, Raj Suryanarayanan, Gregory J. Beilman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

D-β-hydroxybutyrate and melatonin (BHB/MLT) infusion improves survival in hemorrhagic shock models. The original BHB/MLT formulation contains dimethyl sulfoxide (DMSO) to increase melatonin solubility. We formulated BHB/MLT solutions wherein DMSO was replaced either with 10% polyvinylpyrrolidone (BHB/MLT/PVP) or with 5% hydroxypropyl-β-cyclodextrin/2.5% PVP/2.5% polyethylene glycol 400 (BHB/MLT/CD). Safety and efficacy of the new and the original BHB/MLT solution were tested in a lethal rat hemorrhagic shock model, with seven groups: 1) sham, 2) shock, untreated, 3) shock, lactated Ringer's solution (LR), 4) shock, 4 M BHB/MLT/DMSO, 5) shock, 2 M BHB/MLT/DMSO, 6) shock, BHB/MLT/PVP and 7) shock, BHB/MLT/CD. BHB/MLT/DMSO was given at full strength and 1:1 dilution to match the concentration of the novel formulations. Rats were anesthetized, instrumented, and 40% of the total blood volume was withdrawn in three steps, followed by four-hour long shock. Treatment boluses were infused half-way throughout hemorrhage. Survival was highest in BHB/MLT/CD-treated rats (8/10), followed by the BHB/MLT/PVP (6/10), 4 M BHB/MLT/DMSO (5/10) or 2 M BHB/MLT/DMSO (5/10), LR (3/10) and the untreated group (0/11). Survival did not differ significantly between BHB/MLT groups (p > 0.05), but was significantly higher in BHB/MLT/CD than in LR-treated animals (p = 0.018). BHB/MLT/PVP and BHB/MLT/CD constitute promising candidates for clinical hemorrhagic shock treatment.

Original languageEnglish (US)
Pages (from-to)104-112
Number of pages9
JournalInternational journal of pharmaceutics
Volume548
Issue number1
DOIs
StatePublished - Sep 5 2018

Bibliographical note

Funding 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 ).

Funding 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).

Publisher Copyright:
© 2018 Elsevier B.V.

Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.

Keywords

  • Antioxidant
  • Cyclodextrin
  • Hemorrhagic shock
  • Ketone body
  • Lyophilization
  • Resuscitation fluid

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