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Related Experiment Videos

Modifying naloxone to reverse fentanyl-induced overdose.

Michael Voronkov1, Georgiy Nikonov1, Janna Ataiants2

  • 1Kappa-Pharma LLC, Alachua, FL 32615, United States.

International Journal of Pharmaceutics
|December 1, 2021
PubMed
Summary

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A novel bioreversible naloxone derivative, NX-90, effectively reverses fentanyl-induced overdose (OD) in rats. NX-90 demonstrates faster restoration of vital signs and reduced side effects compared to traditional naloxone, making it a promising antidote.

Area of Science:

  • Pharmacology
  • Toxicology
  • Drug Development

Background:

  • Fentanyl overdose reversal is a critical unmet medical need.
  • Existing antidotes like naloxone require rapid, effective delivery and sustained action.
  • A lipophilic antidote with fast onset is necessary for effective fentanyl overdose management.

Purpose of the Study:

  • To synthesize and evaluate a bioreversible naloxone derivative (NX-90) as a potential fentanyl antidote.
  • To compare the efficacy and pharmacodynamics of NX-90 against naloxone in a fentanyl-induced overdose model.
  • To assess the safety and metabolic profile of NX-90.

Main Methods:

  • In silico, in vitro, and in vivo evaluations of NX-90.
  • Intranasal and intravenous administration of NX-90 and naloxone in rats.
Keywords:
FentanylNaloxoneOverdose reversalPharmacology

Related Experiment Videos

  • Monitoring of physiological reflexes, heart rate (HR), and respiratory rate (RR).
  • Assessment of naloxone levels in circulation and brain matrix.
  • In vitro selectivity panels, Ames test, and CYP450 counter screens.

    • Main Results:

    • NX-90 demonstrated robust reversal of fentanyl-induced overdose in rats.
    • Intranasal NX-90 fully restored monitored reflexes, HR, and RR faster than equimolar naloxone.
    • NX-90 treatment resulted in significantly higher respiratory rate area under the curve (AUC) with no re-narcotization.
    • NX-90 exhibited lower circulating naloxone levels and a clean safety profile in various assays.
    • Demonstrated robust release of naloxone in the brain matrix after NX-90 administration.

    Conclusions:

    • NX-90 possesses a superior pharmacological profile for fentanyl overdose reversal compared to naloxone.
    • NX-90's enhanced pharmacodynamics and safety profile support its nomination for preclinical development.
    • NX-90 shows potential as an effective intranasal fentanyl antidote with improved efficacy and reduced side effects.