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https://read.qxmd.com/read/30573991/is-the-history-repeated-can-2-r-6-r-hydroxynorketamine-be-another-antidepressant
#1
COMMENT
Shigeyuki Chaki, Jun-Ichi Yamaguchi
Historically, identification of active metabolites has contributed to drug discovery for psychiatric disorders. It has led to the identification of new medications such as desipramine (a metabolite of imipramine) and paliperidone (a metabolite of risperidone). ( R,S )-Ketamine, which has been regarded as the greatest breakthrough in depression research, is rapidly and stereoselectively metabolized into a variety of metabolites. Therefore, identification of an active substance after administration of ( R,S )-ketamine is a critical issue, not only to delineate the underlying mechanisms but also to pave the way to develop a new antidepressant...
2018: Journal of Experimental Neuroscience
https://read.qxmd.com/read/30570761/perioperative-intravenous-ketamine-for-acute-postoperative-pain-in-adults
#2
REVIEW
Elina Cv Brinck, Elina Tiippana, Michael Heesen, Rae Frances Bell, Sebastian Straube, R Andrew Moore, Vesa Kontinen
BACKGROUND: Inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. Perioperative ketamine may enhance conventional analgesics in the acute postoperative setting. OBJECTIVES: To evaluate the efficacy and safety of perioperative intravenous ketamine in adult patients when used for the treatment or prevention of acute pain following general anaesthesia. SEARCH METHODS: We searched CENTRAL, MEDLINE and Embase to July 2018 and three trials registers (metaRegister of controlled trials, ClinicalTrials...
December 20, 2018: Cochrane Database of Systematic Reviews
https://read.qxmd.com/read/30526293/comparison-of-pre-emptive-butorphanol-or-metamizole-with-ketamine-medetomidine-and-s-ketamine-medetomidine-anaesthesia-in-improving-intraoperative-analgesia-in-mice
#3
C Bauer, U Schillinger, J Brandl, A Meyer-Lindenberg, A Ott, C Baumgartner
In accordance with the 'refinement' component of the 3Rs, the primary aim of this study was to investigate and compare ketamine + medetomidine (KM) and s-ketamine + medetomidine (SKM) anaesthetic protocols in C57BL/6J mice (both sexes). We sought to determine whether s-ketamine could provide adequate surgical tolerance at a 50% dose relative to that of ketamine racemate and whether antagonism of medetomidine could be initiated 15 min earlier. The second aim was to investigate the potential improvement in analgesia for both anaesthetic protocols by adding butorphanol or metamizole...
December 8, 2018: Laboratory Animals
https://read.qxmd.com/read/30513009/an-update-on-ketamine-and-its-two-enantiomers-as-rapid-acting-antidepressants
#4
Kai Zhang, Kenji Hashimoto
Depression is one of the most disabling diseases worldwide. Approximately one-third of depressed patients are treatment-resistant to the currently available antidepressants and there is a significant therapeutic time lag of weeks to months. There is a clear unmet need for rapid-acting and more efficacious treatments. (R,S)-ketamine, an old anesthetic drug, appears now to be going through a renaissance. Areas covered: This paper reviews recent literature describing the antidepressant effects of ketamine and its enantiomer (S)-ketamine in patients with major depressive disorder (MDD) and bipolar disorder (BD)...
December 4, 2018: Expert Review of Neurotherapeutics
https://read.qxmd.com/read/30502360/lack-of-rapid-antidepressant-effects-of-kir4-1-channel-inhibitors-in-a-chronic-social-defeat-stress-model-comparison-with-r-ketamine
#5
Zhongwei Xiong, Kai Zhang, Tamaki Ishima, Qian Ren, Min Ma, Yaoyu Pu, Lijia Chang, Jincao Chen, Kenji Hashimoto
A recent study demonstrated a key role of astroglial potassium channel Kir4.1 in the lateral habenula in depression. We investigated whether Kir4.1 protein is altered in the brain regions from susceptible mice after a chronic social defeat stress (CSDS). Furthermore, we compared the rapid and sustained antidepressant actions of Kir4.1 inhibitors (quinacrine and sertraline) and (R)-ketamine, (R)-enantiomer of rapid-acting antidepressant (R,S)-ketamine, in a CSDS model. Western blot analysis of Kir4.1 protein in the brain regions (prefrontal cortex, nucleus accumbens, hippocampus) from CSDS susceptible mice and control mice (no CSDS) was performed...
November 28, 2018: Pharmacology, Biochemistry, and Behavior
https://read.qxmd.com/read/30488740/mouse-rat-and-dog-bioavailability-and-mouse-oral-antidepressant-efficacy-of-2r-6r-hydroxynorketamine
#6
Jaclyn N Highland, Patrick J Morris, Panos Zanos, Jacqueline Lovett, Soumita Ghosh, Amy Q Wang, Carlos A Zarate, Craig J Thomas, Ruin Moaddel, Todd D Gould
BACKGROUND: ( R,S)-ketamine has gained attention for its rapid-acting antidepressant actions in patients with treatment-resistant depression. However, widespread use of ketamine is limited by its side effects, abuse potential, and poor oral bioavailability. The ketamine metabolite, ( 2R,6R)-hydroxynorketamine, exerts rapid antidepressant effects, without ketamine's adverse effects and abuse potential, in rodents. METHODS: We evaluated the oral bioavailability of ( 2R,6R)-hydroxynorketamine in three species (mice, rats, and dogs) and also evaluated five candidate prodrug modifications for their capacity to enhance the oral bioavailability of ( 2R,6R)-hydroxynorketamine in mice...
November 29, 2018: Journal of Psychopharmacology
https://read.qxmd.com/read/30442251/effect-of-intravenous-s-ketamine-on-the-mac-of-sevoflurane-a-randomised-placebo-controlled-double-blinded-clinical-trial
#7
RANDOMIZED CONTROLLED TRIAL
T Hamp, J Baron-Stefaniak, M Krammel, B Reiter, A Langauer, T Stimpfl, W Plöchl
BACKGROUND: Ketamine is routinely used in operating theatres, emergency departments, ICUs, and even outpatient units. Despite the widespread use of ketamine, only basic aspects of its interactions with inhalation anaesthetic agents are known, and formal testing of interactions in humans is lacking. The minimum alveolar concentration (MAC) of inhalation anaesthetics is used to guide the depth of anaesthesia, and several drugs are known to influence the MAC. The aim of this study was to investigate whether intravenous application of ketamine influences the MAC of sevoflurane in humans...
December 2018: British Journal of Anaesthesia
https://read.qxmd.com/read/30423596/-pain-therapy-aspects-in-tumour-surgery
#8
Stefan Wirz, Michael Schenk, Kristin Kieselbach
Due to preexisting pain or surgically induced sensitization patients undergoing oncological surgery are predisposed for a postoperative high pain intensity with the risk of developing persistent pain. In oncological surgery, pain therapy should be adapted to the underlying pain mechanism. Different treatment principles should be applied in a graded concept of acute pain therapy. The rationale implies the "conventional" use of the WHO step scheme, the administration of opioids as PCA as well as regional analgesia and agents with anti-hypersensitizing properties...
October 2018: Anästhesiologie, Intensivmedizin, Notfallmedizin, Schmerztherapie: AINS
https://read.qxmd.com/read/30385254/s-ketamine-reduces-marble-burying-behaviour-involvement-of-ventromedial-orbitofrontal-cortex-and-ampa-receptors
#9
Cristina Luz Tosta, Gabriela Pandini Silote, Maria Paula Fracalossi, Ariandra Guerini Sartim, Roberto Andreatini, Sâmia Regiane Lourenço Joca, Vanessa Beijamini
Previous clinical and pre-clinical studies suggest the involvement of ventromedial orbitofrontal cortex (vmOFC) and glutamatergic neurotransmission in obsessive-compulsive disorder (OCD). Ketamine, an NMDA glutamatergic receptor antagonist, has shown a rapid and long-lasting antidepressant effect, but its anti-compulsive effect has been scarcely investigated. The antidepressant effect of ketamine involves NMDA receptor blockade, AMPA receptor activation, increased serotonin (5-HT) release and attenuation of nitric oxide (NO) synthesis...
October 29, 2018: Neuropharmacology
https://read.qxmd.com/read/30296896/molecular-pharmacology-and-neurobiology-of-rapid-acting-antidepressants
#10
Todd D Gould, Carlos A Zarate, Scott M Thompson
For decades, symptoms of depression have been treated primarily with medications that directly target the monoaminergic brain systems, which typically take weeks to exert measurable effects and months to exert remission of symptoms. Low, subanesthetic doses of ( R,S)-ketamine (ketamine) result in the rapid improvement of core depressive symptoms, including mood, anhedonia, and suicidal ideation, occurring within hours following a single administration, with relief from symptoms typically lasting up to a week...
January 6, 2019: Annual Review of Pharmacology and Toxicology
https://read.qxmd.com/read/30246357/intraoperative-s-ketamine-for-the-reduction-of-opioid-consumption-and-pain-one-year-after-spine-surgery-a-randomized-clinical-trial-of-opioid-dependent-patients
#11
R V Nielsen, J S Fomsgaard, L Nikolajsen, J B Dahl, O Mathiesen
BACKGROUND: We aimed to explore the effect of intraoperative S-ketamine on analgesic consumption and pain one year after spine surgery in chronic opioid dependent patients undergoing spinal fusion surgery. METHODS: Single center, randomized, blinded trial of 147 patients. INTERVENTION: Perioperative S-ketamine bolus 0.5 mg/kg followed by S-ketamine 0.25 mg·kg-1 ·h-1 infusion or placebo. MAIN OUTCOMES: Analgesic use, pain (visual analogue scale 0-100 mm (VAS)) and labor market attachment one year after surgery assessed by written questionnaires...
September 23, 2018: European Journal of Pain: EJP
https://read.qxmd.com/read/30215218/lack-of-deuterium-isotope-effects-in-the-antidepressant-effects-of-r-ketamine-in-a-chronic-social-defeat-stress-model
#12
Kai Zhang, Hidetoh Toki, Yuko Fujita, Min Ma, Lijia Chang, Youge Qu, Shingo Harada, Tetsuhiro Nemoto, Akiko Mizuno-Yasuhira, Jun-Ichi Yamaguchi, Shigeyuki Chaki, Kenji Hashimoto
RATIONALE: (R,S)-ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, exhibits rapid and long-lasting antidepressant effects and anti-suicidal ideation in treatment-resistant patients with depression. However, the precise mechanisms underlying the antidepressant actions of (R,S)-ketamine are unknown. Although the previous report demonstrated the deuterium isotope effects in the antidepressant actions of (R,S)-ketamine, the deuterium isotope effects in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown...
November 2018: Psychopharmacology
https://read.qxmd.com/read/30174603/effects-of-ketamine-on-postoperative-pain-after-remifentanil-based-anesthesia-for-major-and-minor-surgery-in-adults-a-systematic-review-and-meta-analysis
#13
Juan F García-Henares, Jose A Moral-Munoz, Alejandro Salazar, Esperanza Del Pozo
Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been postulated as an adjuvant analgesic for preventing remifentanil-induced hyperalgesia after surgery. This systematic review and meta-analysis aims to assess the effectiveness of ketamine [racemic mixture and S -(+)-ketamine] in reducing morphine consumption and pain intensity scores after remifentanil-based general anesthesia. We performed a literature search of the PubMed, Web of Science, Scopus, Cochrane, and EMBASE databases in June 2017 and selected randomized controlled trials using predefined inclusion and exclusion criteria...
2018: Frontiers in Pharmacology
https://read.qxmd.com/read/30158438/ketamine-and-ceftriaxone-induced-alterations-in-glutamate-levels-do-not-impact-the-specific-binding-of-metabotropic-glutamate-receptor-subtype-5-radioligand-18-f-pss232-in-the-rat-brain
#14
Adrienne Müller Herde, Silvan D Boss, Yingfang He, Roger Schibli, Linjing Mu, Simon M Ametamey
Several studies showed that [11 C]ABP688 binding is altered following drug-induced perturbation of glutamate levels in brains of humans, non-human primates and rats. We evaluated whether the fluorinated derivative [18 F]PSS232 can be used to assess metabotropic glutamate receptor 5 (mGluR5) availability in rats after pharmacological challenge with ketamine, known to increase glutamate, or ceftriaxone, known to decrease glutamate. In vitro autoradiography was performed on rat brain slices with [18 F]PSS232 to prove direct competition of the drugs for mGluR5...
August 29, 2018: Pharmaceuticals
https://read.qxmd.com/read/30116859/plasma-metabolomic-profiling-of-a-ketamine-and-placebo-crossover-trial-of-major-depressive-disorder-and-healthy-control-subjects
#15
Ruin Moaddel, Michelle Shardell, Mohammed Khadeer, Jacqueline Lovett, Bashkim Kadriu, Sarangan Ravichandran, Patrick J Morris, Peixiong Yuan, Craig J Thomas, Todd D Gould, Luigi Ferrucci, Carlos A Zarate
(R,S)-Ketamine produces rapid, robust, and sustained antidepressant effects in major depressive disorder. Specifically, its pharmacological efficacy in treatment refractory depression is considered a major breakthrough in the field. However, the mechanism of action of ketamine's rapid effect remains to be determined. In order to identify pathways that are responsible for ketamine's effect, a targeted metabolomic approach was carried out using a double-blind, placebo-controlled crossover design, with infusion order randomized with medication-free patients with treatment-resistant major depressive disorder (29 subjects) and healthy controls (25 subjects)...
October 2018: Psychopharmacology
https://read.qxmd.com/read/30091858/semimechanistic-population-pharmacokinetic-model-to-predict-the-drug-drug-interaction-between-s-ketamine-and-ticlopidine-in-healthy-human-volunteers
#16
Muhammad W Ashraf, Marko A Peltoniemi, Klaus T Olkkola, Pertti J Neuvonen, Teijo I Saari
Low-dose oral S-ketamine is increasingly used in chronic pain therapy, but extensive cytochrome P450 (CYP) mediated metabolism makes it prone to pharmacokinetic drug-drug interactions (DDIs). In our study, concentration-time data from five studies were used to develop a semimechanistic model that describes the ticlopidine-mediated inhibition of S-ketamine biotransformation. A mechanistic model was implemented to account for reversible and time-dependent hepatic CYP2B6 inactivation by ticlopidine, which causes elevated S-ketamine exposure in vivo...
October 2018: CPT: Pharmacometrics & Systems Pharmacology
https://read.qxmd.com/read/30085944/stereoselective-ketamine-metabolism-by-genetic-variants-of-cytochrome-p450-cyp2b6-and-cytochrome-p450-oxidoreductase
#17
Pan-Fen Wang, Alicia Neiner, Evan D Kharasch
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Human ketamine N-demethylation to norketamine in vitro at therapeutic concentrations is catalyzed predominantly by the cytochrome P4502B6 isoform (CYP2B6). The CYP2B6 gene is highly polymorphic. CYP2B6.6, the protein encoded by the common variant allele CYP2B6*6, exhibits diminished ketamine metabolism in vitro compared with wild-type CYP2B6.1. The gene for cytochrome P450 oxidoreductase (POR), an obligatory P450 coenzyme, is also polymorphic...
October 2018: Anesthesiology
https://read.qxmd.com/read/30054846/first-in-human-evaluation-of-18-f-pk-209-a-pet-ligand-for-the-ion-channel-binding-site-of-nmda-receptors
#18
Jasper van der Aart, Sandeep S V Golla, Marieke van der Pluijm, Lothar A Schwarte, Robert C Schuit, Pieter J Klein, Athanasios Metaxas, Albert D Windhorst, Ronald Boellaard, Adriaan A Lammertsma, Bart N M van Berckel
BACKGROUND: Efforts to develop suitable positron emission tomography (PET) tracers for the ion channel site of human N-methyl-D-aspartate (NMDA) receptors have had limited success. [18 F]PK-209 is a GMOM derivative that binds to the intrachannel phencyclidine site with high affinity and selectivity. Primate PET studies have shown that the volume of distribution in the brain was reduced by administration of the NMDA receptor antagonist MK-801, consistent with substantial specific binding...
July 27, 2018: EJNMMI Research
https://read.qxmd.com/read/30041987/rapid-antidepressant-effect-of-s-ketamine-in-schizophrenia
#19
Lucie Bartova, Konstantinos Papageorgiou, Ivan Milenkovic, Markus Dold, Ana Weidenauer, Matthaeus Willeit, Dietmar Winkler, Siegfried Kasper
Rapid anti-suicidal and antidepressant effects of ketamine have repeatedly been confirmed in unipolar and bipolar depression. Although meaningful antidepressant efficacy of ketamine has also been shown in depressed patients with a history of psychotic symptoms, its administration in psychotic disorders has largely been neglected due to its potential to exacerbate dissociative or psychotic symptoms. Presenting a case of a young female inpatient suffering from schizophrenia with a severe post-psychotic depression, we demonstrate a robust anti-suicidal and antidepressant effect of S-ketamine infusions administered thrice weekly for 3 weeks in total...
August 2018: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
https://read.qxmd.com/read/30032169/role-of-inflammatory-bone-markers-in-the-antidepressant-actions-of-r-ketamine-in-a-chronic-social-defeat-stress-model
#20
Kai Zhang, Min Ma, Chao Dong, Kenji Hashimoto
Background: A recent study demonstrated that inflammatory bone markers play a role in the antidepressant functions of (R,S)-ketamine in treatment-resistant patients with depression. We examined the effect of inflammatory bone markers in the antidepressant functions of (R)-ketamine and (S)-ketamine in a chronic social defeat stress model. Methods: Behavioral tests for antidepressant actions were performed after a single administration of (R)-ketamine or (S)-ketamine...
November 1, 2018: International Journal of Neuropsychopharmacology
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