Ampakine CX1942 attenuates opioid-induced respiratory depression and corrects the hypoxaemic effects of etorphine in immobilized goats (Capra hircus)

Abstract

Objectives: To determine whether CX1942 reverses respiratory depression in etorphineimmobilized goats, and to compare its effects with those of doxapram hydrochloride. Study design:A prospective, crossover experimental trial conducted at 1753 m.a.s.l. Animals:Eight adult female Boer goats (Capra hircus) with a mean ± standard deviation mass of 27.1 ± 1.6 kg. Methods:Following immobilization with 0.1 mg kg −1 etorphine, goats received one of doxapram, CX1942 or sterile water intravenously, in random order in three trials. Respiratory rate, ventilation and tidal volume were measured continuously. Arterial blood samples for the determination of PaO 2 , PaCO 2 , pH and SaO 2 were taken 2 minutes before and then at 5 minute intervals after drug administration for 25 minutes.Results: Doxapram corrected etorphine-induced respiratory depression but also led to arousal and hyperventilation at 2 minutes after its administration, as indicated by the low PaCO 2 (27.8 ± 4.5 mmHg) and ventilation of 5.32 ± 5.24 L minute −1 above pre-immobilization values. CX1942 improved respiratory parameters and corrected etorphine's hypoxaemic effects more gradually than did doxapram, with a more sustained improvement in PaO 2 and SaO 2 in comparison with the control trial.Conclusions: CX1942 attenuated opioid-induced respiratory depression and corrected the hypoxaemic effects of etorphine in immobilized goats.Clinical relevance: Ampakines potentially offer advantages over doxapram, a conventional treatment, in reversing etorphine-induced respiratory depression without causing unwanted side effects, particularly arousal, in immobilized animals.2

Countering opioid-induced respiratory depression by non-opioids that are respiratory stimulants

“…In goats, i.v. doxapram reduced etorphine-induced respiratory depression by rapid reversal of all respiratory parameters except tidal volume 12 . In adult humans, doxapram is used to reverse respiratory depression post-anesthesia by direct input on brainstem centers with differential effects on the pre-Botzinger complex and the downstream motor output (XII) 13 .…”

Activating α4β2 Nicotinic Acetylcholine Receptors Alleviates Fentanyl-induced Respiratory Depression in Rats

“…Preclinical work has started toward developing a water-soluble ampakine, and those data with CX1942 showed partial reversal of opioid-induced respiratory depression within several minutes after administration in a goat model. 56 Thus, the ampakine technology continues to warrant investigation but has not yet been demonstrated to adequately fulfill the unmet clinical need of rapidly and effectively countering opioid-induced respiratory depression without loss of analgesia.…”

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

“…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.…”