Journal article
Modifying naloxone to reverse fentanyl-induced overdose
International journal of pharmaceutics, v 611, 121326
05 Jan 2022
PMID: 34848365
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
[Display omitted]
Developing an effective antidote for fentanyl-induced overdose (OD) is an unmet medical need that requires both lipophilicity comparable to fentanyl and fast onset of overdose reversal. We synthesized and evaluated a bioreversible derivative of naloxone (NX-90) in silico, in vitro and in vivo to yield a robust reversal of fentanyl-induced OD in rats. All monitored reflexes along with the heart rate (HR) and respiratory rate (RR) were fully restored faster in the NX-90 groups than in naloxone groups on equimolar bases when given intranasally. In NX-90 treated rats RR over the time of observation (RR AUC) was significantly higher at all respective doses with no re-narcotization observed. Apart from the enhanced pharmacodynamics profile, NX-90 was found to have lower circulating levels of naloxone, clean profile in in vitro selectivity panels, as well as Ames and CYP450 counter screens. Finally, we demonstrated a robust release of the parent naloxone in brain matrix, as well as lower peripheral naloxone levels after NX-90 iv administration. With the demonstrated pharmacological profile superior yet congruent to naloxone we nominated NX-90 for preclinical development as an effective intranasal fentanyl antidote.
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Details
- Title
- Modifying naloxone to reverse fentanyl-induced overdose
- Creators
- Michael Voronkov - KappaGeorgiy Nikonov - KappaJanna Ataiants - Drexel UniversityLevon Isakulyan - KappaCristina Stefanut - University of Agricultural Sciences and Veterinary Medicine of Cluj-NapocaMihai Cernea - University of Agricultural Sciences and Veterinary Medicine of Cluj-NapocaJohn Abernethy - Io Therapeutics
- Publication Details
- International journal of pharmaceutics, v 611, 121326
- Publisher
- Elsevier
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Community Health and Prevention
- Web of Science ID
- WOS:000779306000005
- Scopus ID
- 2-s2.0-85120745593
- Other Identifier
- 991019168689604721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Pharmacology & Pharmacy