The Pharmacological Properties in Animals of Ct1341—a New Steroid Anaesthetic Agent

Child, Korean J; Currie, J.P.; Davis, Brian; Dodds, Michael; Pearce, D. R.; Twissell, D.J.

doi:10.1093/bja/43.1.2-a

Cited by 230 publications

(80 citation statements)

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“…Acute exposure to levels of NS found in pregnancy leads to sedation and anesthesia (Child et al, 1971; Carl et al, 1990; Rupprecht, 2003), hence during pregnancy the mammalian brain faces the challenge to maintain an overall functional network, despite large hormonal changes. Indeed many women experience mild to severe disturbances in their neurological performance, mostly during times of fast rise or drop in progesterone and its neuroactive metabolites (Poser et al, 1986).…”

Section: Discussionmentioning

confidence: 99%

Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABAA receptors on parvalbumin interneurons

Ferando¹,

Módy²

2013

Front. Neural Circuits

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Gamma (γ) oscillations (30–120 Hz), an emergent property of neuronal networks, correlate with memory, cognition and encoding. In the hippocampal CA3 region, locally generated γ oscillations emerge through feedback between inhibitory parvalbumin-positive basket cells (PV+BCs) and the principal (pyramidal) cells. PV+BCs express δ-subunit-containing GABAARs (δ-GABAARs) and NMDA receptors (NMDA-Rs) that balance the frequency of γ oscillations. Neuroactive steroids (NS), such as the progesterone-derived (3α,5α)-3-hydroxy-pregnan-20-one (allopregnanolone; ALLO), modulate the expression of δ-GABAARs and the tonic conductance they mediate. Pregnancy produces large increases in ALLO and brain-region-specific homeostatic changes in δ-GABAARs expression. Here we show that in CA3, where most PV+ interneurons (INs) express δ-GABAARs, expression of δ-GABAARs on INs diminishes during pregnancy, but reverts to control levels within 48 h postpartum. These anatomical findings were corroborated by a pregnancy-related increase in the frequency of kainate-induced CA3 γ oscillations in vitro that could be countered by the NMDA-R antagonists D-AP5 and PPDA. Mimicking the typical hormonal conditions during pregnancy by supplementing 100 nM ALLO lowered the γ frequencies to levels found in virgin or postpartum mice. Our findings show that states of altered NS levels (e.g., pregnancy) may provoke perturbations in γ oscillatory activity through direct effects on the GABAergic system, and underscore the importance of δ-GABAARs homeostatic plasticity in maintaining constant network output despite large hormonal changes. Inaccurate coupling of NS levels to δ-GABAAR expression may facilitate abnormal neurological and psychiatric conditions such as epilepsy, post-partum depression, and post-partum psychosis, thus providing insights into potential new treatments.

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Section: Discussionmentioning

confidence: 99%

Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABAA receptors on parvalbumin interneurons

Ferando¹,

Módy²

2013

Front. Neural Circuits

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“…Several years later, this led to the development of steroidal anesthetics (Child et al, 1971). Of particular interest are the 3α-reduced steroid compounds, such as alphaxalone, which display potent anesthetic properties.…”

Section: Introductionmentioning

confidence: 99%

Analgesic strategies aimed at stimulating the endogenous production of allopregnanolone

Poisbeau

Keller

Aouad

et al. 2014

Front. Cell. Neurosci.

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A growing number of studies indicate that 3-alpha reduced neurosteroids are remarkable analgesics in various pain states. This is the case for allopregnanolone (AP), one of the most potent endogenous positive allosteric modulators of GABAA receptor function. From the pioneering work of Hans Selye, who described the sedative properties of steroids, synthetic compounds resembling the progesterone metabolite AP have been developed. If some of them have been used as anesthetics, it seems difficult to propose them as a therapeutic option for pain since they display several adverse side effects such as sedation, amnesia and functional tolerance. An alternative strategy, chosen by few laboratories around the world, is aimed at stimulating the local production of 3-alpha reduced neurosteroids in order to limit these well-known side effects. This pharmacological approach has the advantage of targeting specific structures, fully equipped with the necessary biosynthetic enzymatic machinery, where neurosteroids already act as endogenous pain modulators. The various pharmacological trials which attempted to treat pain symptoms by stimulating the production of 3-alpha reduced neurosteroids are reviewed here, as well as novel neurotransmitter systems possibly regulating their endogenous production.

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“…Despite the relatively large injection volume, no muscle damage was observed [5]. Alphaxalone-alphadolone was solubilised with Cremophor®-EL, which resulted in adverse effects in dogs, cats, and humans [11,12] and consequently it was withdrawn from the market. Recently, a new formulation of alphaxalone without alphadalone and solubilised with the aid of cyclodextrin rather than Cremophor®-EL became available (Alfaxan®).…”

Section: Introductionmentioning

confidence: 99%

Comparison of three different sedative-anaesthetic protocols (ketamine, ketamine-medetomidine and alphaxalone) in common marmosets (Callithrix jacchus)

et al. 2013

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BackgroundHandling of common marmoset (Callithrix jacchus) usually requires chemical restraint. Ketamine has been associated with muscle damage in primates, while common marmosets, compared to other primates, additionally display an exceptional high sensitivity to ketamine-associated side-effects. Notably, muscle twitching movements of limbs and hands, and a marked increase in salivation are observed. We investigated two alternative intramuscular (i.m.) immobilisation protocols against ketamine (50 mg/kg; protocol 1) in a double-blind randomised crossover study in ten healthy adult common marmosets for use as a safe reliable, short-term immobilisation and sedation. These protocols comprised: alphaxalone (12 mg/kg; protocol 2) and 25 mg/kg ketamine combined with 0.50 mg/kg medetomidine (reversal with 2.5 mg/kg atipamezole; protocol 3A). Following completion and unblinding, the project was extended with an additional protocol (3B), comprising 25 mg/kg ketamine combined with 0.05 mg/kg medetomidine (reversal with 0.25 mg/kg atipamezole, twice with 35 min interval).ResultsAll protocols in this study provided rapid onset (induction times <5 min) of immobilisation and sedation. Duration of immobilisation was 31.23 ± 22.39 min, 53.72 ± 13.08 min, 19.73 ± 5.74 min, and 22.78 ± 22.37 min for protocol 1, 2, 3A, and 3B, respectively. Recovery times were 135.84 ± 39.19 min, 55.79 ± 11.02 min, 405.46 ± 29.81 min, and 291.91 ± 80.34 min, respectively. Regarding the quality, and reliability (judged by pedal withdrawal reflex, palpebral reflex and muscle tension) of all protocols, protocol 2 was the most optimal. Monitored vital parameters were within clinically acceptable limits during all protocols and there were no fatalities. Indication of muscle damage as assessed by AST, LDH and CK values was most prominent elevated in protocol 1, 3A, and 3B.ConclusionsWe conclude that intramuscular administration of 12 mg/kg alphaxalone to common marmosets is preferred over other protocols studied. Protocol 2 resulted in at least comparable immobilisation quality with acceptable and less frequent side effects and superior recovery quality. In all protocols, supportive therapy, such as external heat support, remains mandatory. Notably, an unacceptable long recovery period in both ketamine/medetomidine protocols (subsequently reversed with atipamezole) was observed, showing that α-2 adrenoreceptor agonists in the used dose and dosing regime is not the first choice for sedation in common marmosets in a standard research setting.

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The Pharmacological Properties in Animals of Ct1341—a New Steroid Anaesthetic Agent

Cited by 230 publications

References 0 publications

Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABAA receptors on parvalbumin interneurons

Altered gamma oscillations during pregnancy through loss of δ subunit-containing GABAA receptors on parvalbumin interneurons

Analgesic strategies aimed at stimulating the endogenous production of allopregnanolone

Comparison of three different sedative-anaesthetic protocols (ketamine, ketamine-medetomidine and alphaxalone) in common marmosets (Callithrix jacchus)

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