Assessment of naloxone as a therapeutic for inhaled carfentanil in the ferret

McCranor, Bryan J.; Jennings, Laura; Tressler, Justin; Tuet, Wing Y.; Cox, V.; Racine, Michelle; Stone, Shannon; Pierce, Samuel A.; Pueblo, Erin; Dukes, Aliyah; Litvin, Samantha R.; Vignola, Justin N; Pennington, M. Ross; Wong, Benjamin

doi:10.1016/j.toxrep.2020.08.019

Cited by 6 publications

(3 citation statements)

References 38 publications

(52 reference statements)

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“… 16 Given that control and actively vaccinated rats were resilient to fentanyl-induced fatal overdose particularly in the first 1–2 h after exposure, it is possible that rodents are not suitable species to test for the efficacy of medications against opioid-induced overdose because very high doses of opioids are required for lethality, which may translate into higher drug plasma concentrations than those found in humans. It is indeed possible that other species, for example, ferrets 33 or large animals (e.g., pigs 34 , 35 ) may be required to study clinically relevant overdose scenarios. Overall, these results highlight the importance of evaluating the applicability of antifentanyl vaccines in vivo both for broad efficacy against a variety of fentanyl analogues of clinical interest, and for efficacy of fentanyl vaccines against high doses of fentanyl relevant for use as a strategy for overdose prevention.…”

Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy and Selectivity of Vaccines Targeting Fentanyl, Alfentanil, Sufentanil, and Acetylfentanyl in Rats

et al. 2022

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The ongoing public health emergency of opioid use disorders (OUD) and overdose in the United States is largely driven by fentanyl and its related analogues and has resulted in over 75 673 deaths in 2021. Immunotherapeutics such as vaccines have been investigated as a potential interventional strategy complementary to current pharmacotherapies to reduce the incidence of OUD and opioid-related overdose. Given the importance of targeting structurally distinct fentanyl analogues, this study compared a previously established lead conjugate vaccine (F 1 –CRM) to a series of novel vaccines incorporating haptens derived from alfentanil and acetylfentanyl (F 8, 9a, 9b, 10 ), and evaluated their efficacy against drug-induced pharmacological effects in rats. While no vaccine tested provided significant protection against alfentanil, lead formulations were effective in reducing antinociception, respiratory depression, and bradycardia elicited by fentanyl, sufentanil, and acetylfentanyl. Compared with control, vaccination with F 1 –CRM also reduced drug levels in the brain of rats challenged with lethal doses of fentanyl. These data further support investigation of F 1 –CRM as a candidate vaccine against fentanyl and selected analogues.

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Section: Discussionmentioning

confidence: 99%

Preclinical Efficacy and Selectivity of Vaccines Targeting Fentanyl, Alfentanil, Sufentanil, and Acetylfentanyl in Rats

et al. 2022

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“… 15 , 16 , 17 , 18 Renarcotization, wherein opioid‐ induced effects reappear following countermeasure administration and apparent recovery, represents an ongoing concern, particularly for more potent opioids, as current approved antagonists are often characterized by relatively short durations of action. 19 , 20 Notably, episodes of renarcotization have been reported for NTX, even though it is inherently longer‐acting and more potent than NX. 21 This possibility of renarcotization necessitates a more comprehensive understanding of the metabolic stability of opioids and opioid antagonists, especially in relation to each other.…”

Section: Introductionmentioning

confidence: 99%

“…However, the therapeutic potential of current antagonists against more potent synthetic opioids remains largely unknown 15–18 . Renarcotization, wherein opioid‐ induced effects reappear following countermeasure administration and apparent recovery, represents an ongoing concern, particularly for more potent opioids, as current approved antagonists are often characterized by relatively short durations of action 19,20 . Notably, episodes of renarcotization have been reported for NTX, even though it is inherently longer‐acting and more potent than NX 21 .…”

Section: Introductionmentioning

confidence: 99%

Metabolic clearance of select opioids and opioid antagonists using hepatic spheroids and recombinant cytochrome P450 enzymes

Tuet¹,

Pierce²,

Conroy³

et al. 2022

Pharmacology Res & Perspec

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The opioid crisis is a pressing public health issue, exacerbated by the emergence of more potent synthetic opioids, particularly fentanyl and its analogs. While competitive antagonists exist, their efficacy against synthetic opioids is largely unknown. Furthermore, due to the short durations of action of current antagonists, renarcotization remains a concern. In this study, metabolic activity was characterized for fentanyl‐class opioids and common opioid antagonists using multiple in vitro systems, namely, cytochrome P450 (CYP) enzymes and hepatic spheroids, after which an in vitro ‐ in vivo correlation was applied to convert in vitro metabolic activity to predictive in vivo intrinsic clearance. For all substrates, intrinsic hepatic metabolism was higher than the composite of CYP activities, due to fundamental differences between whole cells and single enzymatic reactions. Of the CYP isozymes investigated, 3A4 yielded the highest absolute and relative metabolism across all substrates, with largely negligible contributions from 2D6 and 2C19. Comparative analysis highlighted elevated lipophilicity and diminished CYP3A4 activity as potential considerations for the development of more efficacious opioid antagonists. Finally, antagonists with a high degree of molecular similarity exhibited comparable clearance, providing a basis for structure‐metabolism relationships. Together, these results provide multiple screening criteria for early stage drug discovery involving opioid countermeasures.

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