Ketamine Infusions: Pharmacokinetics and Clinical Effects

Idvall, J.; Ahlgren, I.; Aronsen, K. F.; Stenberg, P.

doi:10.1093/bja/51.12.1167

Cited by 296 publications

(126 citation statements)

References 12 publications

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“…27 The common clinical dosages for ketamine in humans range from 0.5 to 10 mg·kg -1 iv, 28 with resultant plasma concentrations of 60-80 µM. 28,29 Therefore, the concentrations of ketamine used for the invitro and vivo portions of these experiments are similar to the concentrations used clinically.…”

Section: Discussionmentioning

confidence: 99%

Ketamine suppresses endotoxin-induced NF-κB expression

Sakai

Ichiyama

Whitten

et al. 2000

Can J Anesth/J Can Anesth

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Purpose: Ketamine reduces endotoxin-induced production of proinflammatory cytokines, including tumour necrosis factor-α (TNF), in several types of inflammatory cells, including monocytes and macrophages. Transcription of the genes that encode production of these proinflammatory cytokines is regulated by nuclear factor-kappa B (NF-6B). Cytoplasmic B protein is activated by endotoxin (LPS) as well as by TNF, allowing B protein to migrate into the cell nucleus to activate gene transcription for these inflammatory mediators. Because NF-6B is likely involved in brain injury and inflammatory neurodegenerative disease, such as multiple sclerosis, we examined whether ketamine inhibits LPS-induced activation of NF-6B in human glioma cells in vitro and intact mouse brain cells in vivo. Methods: Endotoxin-induced NF-6B expression in both the human glioma cells in vitro and the intact mouse brain cells in vivo was determined by electrophoretic mobility shift assays (EMSA) of nuclear extracts and measurement of NF-6B expression by densitometry. Endotoxin was injected intracerebroventricularly in vivo and intact brain was harvested. Klenow fragment labeling was used to identify NF-6B protein for both the in vivo and vitro experiments.Results: Endotoxin treatment increased NF-6B expression (P < 0.05) both in vivo and vitro compared with control (untreated) cells. Ketamine suppressed endotoxin-induced neuronal NF-6B activation in a dose-dependent manner (P < 0.05, except for the 10 -5 M concentration in vitro) both in vivo and vitro.Conclusion: Ketamine inhibits endotoxin-induced NF-6B expression in brain cells in vivo and vitro and it is suggested that this may have implications in the neuroprotective effects of ketamine reported by other investigators.Objectif : La kétamine réduit la production de cytokines pro-inflammatoires induite par endotoxine, y compris le facteur nécrosant des tumeurs (TNF), dans certains types de cellules inflammatoires comprenant les monocytes et les macrophages. La transcription des gènes qui encodent la production de ces cytokines pro-inflammatoires est réglée par le facteur-kappa B nucléaire (NF-6B).La protéine cytoplasmique 6B est activée par l'endotoxine (LPS) et par le TNF et peut ainsi migrer dans le noyau cellulaire et activer la transcription génique pour ces médi-ateurs de l'inflammation. Comme le NF-6B participe probablement aux lésions cérébrales et aux maladies inflammatoires neurodégénératives, dont la sclérose en plaques, notre but était de savoir si la kétamine inhibe l'activation de NF-6B induit par LPS dans des cellules de gliome humain in vitro et dans des cellules cérébrales intactes de souris in vivo. Méthode : L'expression du NF-6B induite par endotoxine dans les cellules humaines in vitro et dans les cellules de souris in vivo a été déterminée par une étude de retardement de la mobilité électrophorétique (ERME) d'extraits nucléaires et la mesure de l'expression du NF-6B a été faite par densitométrie. L'endotoxine a été injectée dans les ventricules cérébraux in vivo et du tissu...

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Section: Discussionmentioning

confidence: 99%

Ketamine suppresses endotoxin-induced NF-κB expression

Sakai

Ichiyama

Whitten

et al. 2000

Can J Anesth/J Can Anesth

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“…Ketamine has been used extensively as an anesthetic agent and the plasma concentrations associated with subanesthetic psychosislike perceptual disturbances are in the range of 0.5-1 M, 28 and with anesthesia setting in at concentrations in the 10-100 M range. [29][30][31] Further, brain concentrations are known to be several fold higher than plasma concentrations, 32 suggesting that even the subanesthetic psychosis-like perceptual disturbances occur only at brain concentrations in the one to few micromolar range. Since the affinities of ketamine for the NMDA receptors as well as for the dopamine D 2 and serotonin 5-HT 2 are relevant in this M range, this would make a selective disruption of NMDA transmission by these agents unlikely.…”

Section: Discussionmentioning

confidence: 99%

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia

2002

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“…Ketamine produces an anaesthetic state at concentrations from 2.7 ± 4.7 mM (Little et al, 1972;Idvall et al, 1979). Whereas, analgesia occurs at lower ketamine concentrations (Grant & Lovinger, 1995).…”

Section: Discussionmentioning

confidence: 99%

Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

Coates

Flood

2001

British J Pharmacology

107

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1 Ketamine is a dissociative anaesthetic that is formulated as Ketalar, which contains the preservative benzethonium chloride (BCl). We have studied the e ects of pure racemic ketamine, the preservative BCl and the Ketalar mixture on human neuronal nicotinic acetylcholine receptors (nAChRs) composed of the a7 subunit or a4 and b2 subunits expressed in Xenopus laevis oocytes. 2 Ketamine inhibited responses to 1 mM acetylcholine (ACh) in both the human a7 and a4b2 nAChRs, with IC 50 values of 20 and 50 mM respectively. Inhibition of the a7 nAChRs occurred within a clinically relevant concentration range, while inhibition of the a4b2 nAChR was observed only at higher concentrations. The Ketalar formulation inhibited nAChR function more e ectively than was expected given its ketamine concentration. The surprising increased inhibitory potency of Ketalar compared with pure ketamine appeared to be due to the activity of BCl, which inhibited both a7 (IC 50 value of 122 nM) and a4b2 (IC 50 value of 49 nM) nAChRs at concentrations present in the clinical formulation of Ketalar. 3 Ketamine is a noncompetitive inhibitor at both the a7 and a4b2 nAChR. In contrast, BCl causes a parallel shift in the ACh dose-response curve at the a7 nAChR suggesting competitive inhibition. Ketamine causes both voltage-dependent and use-dependent inhibition, only in the a4b2 nAChR. 4 Since a7 nAChRs are likely to be inhibited during clinical use of Ketalar, the actions of ketamine and BCl on this receptor subtype may play a role in the profound analgesia, amnesia, immobility and/or autonomic modulation produced by this anaesthetic. British Journal of Pharmacology (2001) 134, 871 ± 879 Keywords: Neuronal nicotinic acetylcholine receptors; benzethonium chloride; ketamine; anaesthetic mechanism Abbreviations: BCl, benzethonium chloride; nAChRs, neuronal nicotinic acetylcholine receptors IntroductionKetamine is a dissociative anaesthetic, that is an e ective analgesic, amnestic and hypnotic, but causes hallucinations that limit its usefulness as a clinical anaesthetic agent. Due to its potency as an analgesic and its sympathomimetic properties, ketamine ®nds extensive use in the treatment of burn patients in intensive care settings. In the early 1980's Lodge described ketamine as a selective inhibitor of NMDA receptor activity and neuronal nicotinic receptors (nAChRs) on Renshaw cells of the cat spinal cord (Anis et al., 1983). Ketamine is also an antagonist of NMDA receptors in rat cortex (Harrison & Simmonds, 1985) and blocks these receptors at sub-clinical concentrations, by acting both as a use-dependent open channel blocker (Honey et al., 1985) and through allosteric inhibition (Orser et al., 1997). Ketamine inhibits the response to acetylcholine or nicotine in both muscle and neuronal type nAChRs (Sumikawa et al., 1983;Wachtel & Wegrzynowicz, 1992;Scheller et al., 1996;Durieux, 1995;Furuya et al., 1999;Flood & Krasowski, 2000;Friederich et al., 2000;Sasaki et al., 2000;Yamakura et al., 2000). In the case of nAChRs containing the a4 subunit, ...

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Ketamine Infusions: Pharmacokinetics and Clinical Effects

Cited by 296 publications

References 12 publications

Ketamine suppresses endotoxin-induced NF-κB expression

Ketamine suppresses endotoxin-induced NF-κB expression

NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D2 and serotonin 5-HT2 receptors—implications for models of schizophrenia

Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

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