KEA-1010, a ketamine ester analogue, retains analgesic and sedative potency but is devoid of Psychomimetic effects.

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Show simple item record Harvey, Martyn en Sleigh, James en Voss, Logan en Bickerdike, Mike en Dimitrov, Ivaylo en Denny, William en 2020-02-07T00:58:50Z en 2019-12-19 en
dc.identifier.citation BMC pharmacology & toxicology 20(1):85 19 Dec 2019 en
dc.identifier.issn 2050-6511 en
dc.identifier.uri en
dc.description.abstract BACKGROUND:Ketamine, a widely used anaesthetic and analgesic agent, is known to improve the analgesic efficacy of opioids and to attenuate central sensitisation and opioid-induced hyperalgesia. Clinical use is, however, curtailed by unwanted psychomimetic effects thought to be mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. KEA-1010, a ketamine ester-analogue designed for rapid offset of hypnosis through hydrolysis mediated break-down, has been shown to result in short duration sedation yet prolonged attenuation of nociceptive responses in animal models. Here we report on behavioural effects following KEA-1010 administration to rodents. METHODS:KEA-1010 was compared with racemic ketamine in its ability to produce loss of righting reflex following intravenous injection in rats. Analgesic activity was assessed in thermal tail flick latency (TFL) and paw incision models when injected acutely and when co-administered with fentanyl. Tail flick analgesic assessment was further undertaken in morphine tolerant rats. Behavioural aberration was assessed following intravenous injection in rats undergoing TFL assessment and in auditory pre-pulse inhibition models. RESULTS:KEA-1010 demonstrated an ED50 similar to ketamine for loss of righting reflex following bolus intravenous injection (KEA-1010 11.4 mg/kg [95% CI 10.6 to 12.3]; ketamine (racemic) 9.6 mg/kg [95% CI 8.5-10.9]). Duration of hypnosis was four-fold shorter in KEA-1010 treated animals. KEA-1010 prolonged thermal tail flick responses comparably with ketamine when administered de novo, and augmented morphine-induced prolongation of tail flick when administered acutely. The analgesic effect of KEA-1010 on thermal tail flick was preserved in opioid tolerant rats. KEA-1010 resulted in increased paw-withdrawal thresholds in a rat paw incision model, similar in magnitude yet more persistent than that seen with fentanyl injection, and additive when co-administered with fentanyl. In contrast to ketamine, behavioural aberration following KEA-1010 injection was largely absent and no pre-pulse inhibition to acoustic startle was observed following KEA-1010 administration in rats. CONCLUSIONS:KEA-1010 provides antinociceptive efficacy in acute thermal and mechanical pain models that augments standard opioid analgesia and is preserved in opioid tolerant rodents. The NMDA channel affinity and psychomimetic signature of the parent compound ketamine is largely absent for KEA-1010. en
dc.format.medium Electronic en
dc.language eng en
dc.relation.ispartofseries BMC pharmacology & toxicology en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.rights.uri en
dc.title KEA-1010, a ketamine ester analogue, retains analgesic and sedative potency but is devoid of Psychomimetic effects. en
dc.type Journal Article en
dc.identifier.doi 10.1186/s40360-019-0374-y en
pubs.issue 1 en
pubs.begin-page 85 en
pubs.volume 20 en
dc.rights.holder Copyright: The authors en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype Research Support, Non-U.S. Gov't en
pubs.subtype research-article en
pubs.subtype Journal Article en
pubs.elements-id 790427 en Medical and Health Sciences en Medical Sciences en Auckland Cancer Research en School of Medicine en Anaesthesiology en Science en Science Research en Maurice Wilkins Centre (2010-2014) en
dc.identifier.eissn 2050-6511 en
pubs.record-created-at-source-date 2019-12-21 en
pubs.dimensions-id 31856925 en

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