A brain-targeted ampakine compound protects against opioid-induced respiratory depression

Dai, Wei; Xiao, Dian; Gao, Xiang; Zhou, Xinbo; Fang, Tongyu; Zheng, Yongchang; Su, Rui‐Bin

doi:10.1016/j.ejphar.2017.05.025

Cited by 19 publications

(12 citation statements)

References 37 publications

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“…44 Given the results of both preclinical and experimental human studies, ampakines may represent a promising class of compounds for therapeutic use in opioid-induced respiratory depression without affecting opioid-induced analgesia. 45 CX1739 is a newer potent ampakine that reportedly readily crosses the blood-brain barrier, is metabolically stable, and has passed through phase I and II clinical trials in adults. 46 These researchers suggested a possible therapeutic use of this ampakine, that is, to treat apnea of prematurity in infants, because they showed that it improved respiratory drive in newborn rat pups that displayed slow breathing and marked apneas but was without effect if breathing of the newborn pups was faster with more stable rhythms and in older pups.…”

Section: Ampakinesmentioning

confidence: 99%

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

et al. 2018

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The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.

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Section: Ampakinesmentioning

confidence: 99%

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

et al. 2018

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“…A second approach involves the use of respiratory stimulants in combination with opioid medication as a compensatory strategy to protect against OIRD (Algera et al, 2019, Manzke et al, 2003, Imam et al, 2020. Such strategies have shown promise in animal models (Mosca et al, 2014, Kimura et al, 2015, Guenther et al, 2010, Sun et al, 2019, Haw et al, 2016, Dai et al, 2017 and in some human trials (Oertel et al, 2010, Persson et al, 1999 but not others (Lötsch et al, 2005, Oertel et al, 2007. Optimization of this approach will require a detailed mechanistic understanding of the physiological consequences of MOR activation in the respiratory network.…”

Section: Introductionmentioning

confidence: 99%

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

Baertsch

Bush

Burgraff

et al. 2021

eLife

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The analgesic utility of opioid-based drugs is limited by the life-threatening risk of respiratory depression. Opioid-induced respiratory depression (OIRD), mediated by the μ-opioid receptor (MOR), is characterized by a pronounced decrease in the frequency and regularity of the inspiratory rhythm, which originates from the medullary preBӧtzinger Complex (preBӧtC). To unravel the cellular- and network-level consequences of MOR activation in the preBӧtC, MOR- expressing neurons were optogenetically identified and manipulated in transgenic mice in vitro and in vivo. Based on these results, a model of OIRD was developed in silico. We conclude that hyperpolarization of MOR-expressing preBӧtC neurons alone does not phenocopy OIRD. Instead, the effects of MOR activation are twofold: 1) pre-inspiratory spiking is reduced and 2) excitatory synaptic transmission is suppressed, thereby disrupting network-driven rhythmogenesis. These dual mechanisms of opioid action act synergistically to make the normally robust inspiratory rhythm generating network particularly prone to collapse when challenged with exogenous opioids.

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“…Since 2016, four new studies on ampakines in animal models of respiratory depression were published aimed at the development of a respiratory stimulant for human or veterinary medicine (CD-8-17C, LCX001, CX1739, and CX1942). [37][38][39][40] All show promising results counteracting the effect of potent opioids such as Reversal of Opioid Toxicity van der Schrier et al…”

Section: Ampakinesmentioning

confidence: 99%

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

et al. 2021

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Opioids may produce life-threatening respiratory depression and death from their actions at the opioid receptors within the brainstem respiratory neuronal network. Since there is an increasing number of conditions where the administration of the opioid receptor antagonist naloxone is inadequate or undesired, there is an increased interest in the development of novel reversal and prevention strategies aimed at providing efficacy close to that of the opioid receptor antagonist naloxone but with fewer of its drawbacks such as its short duration of action and lesser ability to reverse high-affinity opioids, such as carfentanil, or drug combinations. To give an overview of this highly relevant topic, the authors systematically discuss predominantly experimental pharmacotherapies, published in the last 5 yr, aimed at reversal of opioid-induced respiratory depression as alternatives to naloxone. The respiratory stimulants are discussed based on their characteristics and mechanism of action: nonopioid controlled substances (e.g., amphetamine, cannabinoids, ketamine), hormones (thyrotropin releasing hormone, oxytocin), nicotinic acetylcholine receptor agonists, ampakines, serotonin receptor agonists, antioxidants, miscellaneous peptides, potassium channel blockers acting at the carotid bodies (doxapram, ENA001), sequestration techniques (scrubber molecules, immunopharmacotherapy), and opioids (partial agonists/antagonists). The authors argue that none of these often still experimental therapies are sufficiently tested with respect to efficacy and safety, and many of the agents presented have a lesser efficacy at deeper levels of respiratory depression, i.e., inability to overcome apnea, or have ample side effects. The authors suggest development of reversal strategies that combine respiratory stimulants with naloxone. Furthermore, they encourage collaborations between research groups to expedite development of viable reversal strategies of potent synthetic opioid-induced respiratory depression.

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A brain-targeted ampakine compound protects against opioid-induced respiratory depression

Cited by 19 publications

References 37 publications

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

Averting Opioid-induced Respiratory Depression without Affecting Analgesia

Dual mechanisms of opioid-induced respiratory depression in the inspiratory rhythm-generating network

Advances in Reversal Strategies of Opioid-induced Respiratory Toxicity

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