Slow‐sustained delivery of naloxone reduces typical naloxone‐induced precipitated opioid withdrawal effects in male morphine‐dependent mice

Lewter, Lakeisha A.; Johnson, Marisa C.; Treat, Anny C.; Kassick, Andrew J.; Averick, Saadyah; Kolber, Benedict J.

doi:10.1002/jnr.24627

Cited by 17 publications

(15 citation statements)

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“…24 The subcutaneously administered covalent nanoparticles (cNPs) were based on a biodegradable poly(lactic acid) polymer scaffold and presented minimal indications of precipitated withdrawal in morphinedependent mice relative to free naloxone. 24,25 More recent advances in this area have also focused on the development of novel, long-acting naloxone formulations with minimal withdrawal symptoms including a first-in-class oral nanoparticle preparation derived from a functional PLA-PEG-HCDA polyester copolymer 26 as well as a slow-release, subcutaneous naloxone dosage form based on self-assembling peptide hydrogels. 27 While these disclosures speak to the efficacy of their corresponding drug delivery systems toward epoxymorphinan-based opioid structures like morphine, none of the previously described methodologies had been evaluated against synthetic opioids.…”

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confidence: 99%

“…Given the widely recognized need for therapeutics that more effectively counteract synthetic opioid toxicity, several research groups have recently taken steps to address this critical issue in the context of extended-release MOR antagonist delivery systems. − Our laboratory has demonstrated the utility of covalently loaded naloxone nanoparticle ( c NLX-NP) technology as an effective, long-lasting MOR antagonist formulation against high dose morphine (10 mg/kg) . The subcutaneously administered covalent nanoparticles ( c NPs) were based on a biodegradable poly(lactic acid) polymer scaffold and presented minimal indications of precipitated withdrawal in morphine-dependent mice relative to free naloxone. , More recent advances in this area have also focused on the development of novel, long-acting naloxone formulations with minimal withdrawal symptoms including a first-in-class oral nanoparticle preparation derived from a functional PLA-PEG-HCDA polyester copolymer as well as a slow-release, subcutaneous naloxone dosage form based on self-assembling peptide hydrogels . While these disclosures speak to the efficacy of their corresponding drug delivery systems toward epoxymorphinan-based opioid structures like morphine, none of the previously described methodologies had been evaluated against synthetic opioids …”

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confidence: 99%

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Covalently Loaded Naloxone Nanoparticles as a Long-Acting Medical Countermeasure to Opioid Poisoning

Kassick

Luengas

et al. 2021

ACS Pharmacol. Transl. Sci.

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The mu opioid receptor antagonist naloxone has been a vital, long-standing countermeasure in the ongoing battle against opioid use disorders (OUD) and toxicity. However, due to its distinctive short elimination half-life, naloxone has shown diminished efficacy in cases of synthetic opioid poisoning as larger or repeated doses of the antidote have been required to achieve adequate reversal of severe respiratory depression and prevent episodes of renarcotization. This report describes the synthesis, characterization, and in vivo evaluation of a novel, nanoparticle-based naloxone formulation that provides extended protection against the toxic effects of the powerful synthetic opioid fentanyl. The strategy was predicated on a modified two-step protocol involving the synthesis and subsequent nanoprecipitation of a poly(lactic-co-glycolic acid) polymer scaffold bearing a covalently linked naloxone chain end (drug loading ∼7% w/w). Pharmacokinetic evaluation of the resulting covalently loaded naloxone nanoparticles (cNLX-NP) revealed an elimination half-life that was 34 times longer than high dose free naloxone (10 mg/kg) in male Sprague–Dawley rats. This enhancement was further demonstrated by cNLX-NP in subsequent in vivo studies affording protection against fentanyl-induced respiratory depression and antinociception for up to 48 h following a single intramuscular injection. These discoveries support further investigation of cNLX-NP as a potential therapeutic to reverse overdose and prevent renarcotization from fentanyl and its potent analogs.

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confidence: 99%

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confidence: 99%

Covalently Loaded Naloxone Nanoparticles as a Long-Acting Medical Countermeasure to Opioid Poisoning

Kassick

Luengas

et al. 2021

ACS Pharmacol. Transl. Sci.

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“…Recently, cNP‐Nal was shown to produce significantly fewer withdrawal signs in opioid‐dependent mice, compared with withdrawal precipitated by free naloxone 46 . In morphine‐dependent mice, significant behavioral signs of withdrawal were observed after the administration of 8 mg/kg of free naloxone.…”

Section: Novel Treatments: Covalent Naloxone Nanoparticles As Long‐acmentioning

confidence: 99%

“…Recently, cNP-Nal was shown to produce significantly fewer withdrawal signs in opioid-dependent mice, compared with withdrawal precipitated by free naloxone. 46 In morphine-dependent mice, significant behavioral signs of withdrawal were observed after the administration of 8 mg/kg of free naloxone. In contrast, the behavior of morphine-dependent mice that received cNP-Nal (0.75 or 7.5 mg/kg) was not different from behavior of morphine-dependent mice that received control injections (saline or cNP-Empty).…”

Section: Novel Treatments: Covalent Naloxone Nanoparticles As Long-acmentioning

confidence: 99%

Countermeasures for Preventing and Treating Opioid Overdose

France

Ahern

Averick

et al. 2020

Clin Pharma and Therapeutics

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The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large‐scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans‐agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5‐HT)1A receptor agonists; (5) fentanyl‐binding cyclodextrin scaffolds; (6) detoxifying biomimetic “nanosponge” decoy receptors; and (7) antibody‐based strategies. These approaches could also be applied to treat opioid use disorder.

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“…Blomqvist et al (2020) report that peripheral antagonism of opioid receptors is not sufficient to prevent morphine tolerance, implicating central rather than peripheral mechanisms in opioid tolerance. Lewter et al (2020) then tackle the problem of opioid physical dependence by developing an innovative nanoparticle approach for sustained release of naloxone; they find that slow release reduces the severity of withdrawal in morphine-dependent mice. Some people with opioid physical dependence may also struggle with opioid use disorder.…”

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confidence: 99%