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Kenji Hashimoto - One of the best experts on this subject based on the ideXlab platform.
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Comparison of antidepressant and side effects in mice after intranasal administration of (R,S)-Ketamine, (R)-Ketamine, and (S)-Ketamine
Pharmacology Biochemistry and Behavior, 2019Co-Authors: Lijia Chang, Kai Zhang, Yaoyu Pu, Youge Qu, Siming Wang, Zhongwei Xiong, Chao Dong, Yuko Fujita, Kenji HashimotoAbstract:Abstract The N-methyl- d -aspartate receptor (NMDAR) antagonist (R,S)-Ketamine produces rapid and sustained antidepressant effects in treatment-resistant patients with depression although intranasal use of (R,S)-Ketamine in Ketamine abusers is popular. In March 5, 2019, nasal spray of (S)-Ketamine for treatment-resistant depression was approved as a new antidepressant by the US Food Drug Administration. Clinical study of (R)-Ketamine is underway. In a chronic social defeat stress (CSDS) model, we compared the antidepressant effects of (R,S)-Ketamine, (R)-Ketamine, and (S)-Ketamine after a single intranasal administration. Furthermore, we also compared the side effects (i.e., locomotion, prepulse inhibition (PPI), abuse liability) of these three compounds in mice. The order of potency of antidepressant effects after a single intranasal administration was (R)-Ketamine > (R,S)-Ketamine > (S)-Ketamine. In contrast, the order of locomotor activity and prepulse inhibition (PPI) deficits after a single intranasal administration was (S)-Ketamine > (R,S)-Ketamine > (R)-Ketamine. In the conditioned place preference (CPP) test, both (S)-Ketamine and (R,S)-Ketamine increased CPP scores in mice after repeated intranasal administration, in a dose dependent manner. In contrast, (R)-Ketamine did not increase CPP scores in mice. These findings suggest that intranasal administration of (R)-Ketamine would be a safer antidepressant than (R,S)-Ketamine and (S)-Ketamine.
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expression of heat shock protein hsp 70 in the retrosplenial cortex of rat brain after administration of r s Ketamine and s Ketamine but not r Ketamine
Pharmacology Biochemistry and Behavior, 2018Co-Authors: Zheng Tian, Chao Dong, Yuko Fujita, Atsuhiro Fujita, Kenji HashimotoAbstract:The N-methyl-d-aspartate receptor (NMDAR) antagonist (R,S)-Ketamine has robust antidepressant effects in depressed patients although it has detrimental side effects such as psychotomimetic and dissociative symptoms. (R,S)-Ketamine is known to cause the expression of heat shock protein HSP-70 (a marker for neuronal injury) in the retrosplenial cortex of rat brain, suggesting that the neuropathological changes may play a role in the detrimental side effects of (R,S)-Ketamine. This study was undertaken to examine whether (R,S)-Ketamine and its two enantiomers, (R)-Ketamine and (S)-Ketamine, causes the expression of HSP-70 in the rat retrosplenial cortex after a single administration. The HSP-70 immunohistochemistry in the rat brain was performed 24 h after intraperitoneal administration of saline (1 ml/kg), (+)-MK-801 (or dizocilpine: 1.0 mg/kg), (R,S)-Ketamine (100 mg/kg), (S)-Ketamine (25, 50, or 75, mg/kg), or (R)-Ketamine (25, 50, or 75 mg/kg). Marked expression of HSP-70 immunoreactivity in the retrosplenial cortex was detected after administration of dizocilpine or (R,S)-Ketamine (100 mg/kg). Higher does (50 and 75 mg/kg) of (S)-Ketamine, but not low dose (25 mg/kg), caused expression of HSP-70 in this region. In contrast, all doses of (R)-Ketamine did not induce the expression of HSP-70 in this region. These findings suggest that marked expression of HSP-70 in the retrosplenial cortex after a single dose of (R,S)-Ketamine or (S)-Ketamine may have detrimental side effects in the rat brain. Therefore, it is likely that (R)-Ketamine is a safer compound in humans than (R,S)-Ketamine and (S)-Ketamine.
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Antidepressant Potential of (R)-Ketamine in Rodent Models: Comparison with (S)-Ketamine.
The Journal of pharmacology and experimental therapeutics, 2017Co-Authors: Kenichi Fukumoto, Kenji Hashimoto, Hidetoh Toki, Michihiko Iijima, Takashi Hashihayata, Jun-ichi Yamaguchi, Shigeyuki ChakiAbstract:The rapid-acting and long-lasting antidepressant effects of (R,S)-Ketamine have recently gained much attention. Although (S)-Ketamine has been studied as an active isomer, recent evidence suggests that (R)-Ketamine exhibits longer-lasting antidepressant effects than (S)-Ketamine in rodents. However, the antidepressant potential of (R)-Ketamine has not been fully addressed. In the present study, we compared the antidepressant effects of (R)-Ketamine with those of (S)-Ketamine in animal models of depression, including a model that is refractory to current medications. Both (R)-Ketamine and (S)-Ketamine exhibited antidepressant effects at 30 minutes as well as at 24 hours after administration in forced-swimming and tail-suspension tests in mice. At 48 hours after administration, however, (R)-Ketamine still exerted a significant antidepressant effect in the tail-suspension test, whereas the effect of (S)-Ketamine was no longer observed. Moreover, (R)-Ketamine, but not (S)-Ketamine, significantly reversed the depressive-like behavior induced by repeated treatments with corticosterone in rats at 24 hours after a single administration. This effect was attenuated by an α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist, suggesting the involvement of AMPA receptor stimulation in the effects. Both (R)-Ketamine and (S)-Ketamine exhibited practically the same exposure levels in plasma, brain, and cerebrospinal fluid in mice and rats, and both compounds were rapidly eliminated from plasma (
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r Ketamine shows greater potency and longer lasting antidepressant effects than s Ketamine
Pharmacology Biochemistry and Behavior, 2014Co-Authors: Jichun Zhang, Kenji HashimotoAbstract:Abstract The N-methyl- d -aspartate (NMDA) receptor antagonist Ketamine is one of the most attractive antidepressants for treatment-resistant major depressive disorder (MDD). Ketamine (or RS (±)-Ketamine) is a racemic mixture containing equal parts of R (−)-Ketamine and S (+)-Ketamine. In this study, we examined the effects of R- and S-Ketamine on depression-like behavior in juvenile mice after neonatal dexamethasone (DEX) exposure. In the tail suspension test (TST) and forced swimming test (FST), both isomers of Ketamine significantly attenuated the increase in immobility time, seen in DEX-treated juvenile mice at 27 and 29 h respectively, after Ketamine injections. In the 1% sucrose preference test (SPT), both isomers significantly attenuated the reduced preference for 1% sucrose consumption in DEX-treated juvenile mice, 48 h after a Ketamine injection. Interestingly, when immobility times were tested by the TST and FST at day 7, R-Ketamine, but not S-Ketamine, significantly lowered the increases in immobility seen in DEX-treated juvenile mice. This study shows that a single dose of R-Ketamine produced rapid and long-lasting antidepressant effects in juvenile mice exposed neonatally to DEX. Therefore, R-Ketamine appears to be a potent and safe antidepressant relative to S-Ketamine, since R-Ketamine may be free of psychotomimetic side effects.
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R (−)-Ketamine shows greater potency and longer lasting antidepressant effects than S (+)-Ketamine
Pharmacology biochemistry and behavior, 2013Co-Authors: Jichun Zhang, Kenji HashimotoAbstract:Abstract The N-methyl- d -aspartate (NMDA) receptor antagonist Ketamine is one of the most attractive antidepressants for treatment-resistant major depressive disorder (MDD). Ketamine (or RS (±)-Ketamine) is a racemic mixture containing equal parts of R (−)-Ketamine and S (+)-Ketamine. In this study, we examined the effects of R- and S-Ketamine on depression-like behavior in juvenile mice after neonatal dexamethasone (DEX) exposure. In the tail suspension test (TST) and forced swimming test (FST), both isomers of Ketamine significantly attenuated the increase in immobility time, seen in DEX-treated juvenile mice at 27 and 29 h respectively, after Ketamine injections. In the 1% sucrose preference test (SPT), both isomers significantly attenuated the reduced preference for 1% sucrose consumption in DEX-treated juvenile mice, 48 h after a Ketamine injection. Interestingly, when immobility times were tested by the TST and FST at day 7, R-Ketamine, but not S-Ketamine, significantly lowered the increases in immobility seen in DEX-treated juvenile mice. This study shows that a single dose of R-Ketamine produced rapid and long-lasting antidepressant effects in juvenile mice exposed neonatally to DEX. Therefore, R-Ketamine appears to be a potent and safe antidepressant relative to S-Ketamine, since R-Ketamine may be free of psychotomimetic side effects.
Michael J Rieder - One of the best experts on this subject based on the ideXlab platform.
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a blinded randomized controlled trial to evaluate Ketamine propofol versus Ketamine alone for procedural sedation in children
Annals of Emergency Medicine, 2011Co-Authors: Amit Shah, Gregory Mosdossy, Shelley Mcleod, Kris R Lehnhardt, Michael Peddle, Michael J RiederAbstract:Study objective The primary objective is to compare total sedation time when Ketamine/propofol is used compared with Ketamine alone for pediatric procedural sedation and analgesia. Secondary objectives include time to recovery, adverse events, efficacy, and satisfaction scores. Methods Children (aged 2 to 17 years) requiring procedural sedation and analgesia for management of an isolated orthopedic extremity injury were randomized to receive either Ketamine/propofol or Ketamine. Physicians, nurses, research assistants, and patients were blinded. Ketamine/propofol patients received an initial intravenous bolus dose of Ketamine 0.5 mg/kg and propofol 0.5 mg/kg, followed by propofol 0.5 mg/kg and saline solution placebo every 2 minutes, titrated to deep sedation. Ketamine patients received an initial intravenous bolus dose of Ketamine 1.0 mg/kg and Intralipid placebo, followed by Ketamine 0.25 mg/kg and Intralipid placebo every 2 minutes, as required. Results One hundred thirty-six patients (67 Ketamine/propofol, 69 Ketamine) completed the trial. Median total sedation time was shorter ( P =0.04) with Ketamine/propofol (13 minutes) than with Ketamine (16 minutes) alone (Δ –3 minutes; 95% confidence interval [CI] –5 to –2 minutes). Median recovery time was faster with Ketamine/propofol (10 minutes) than with Ketamine (12 minutes) alone (Δ –2 minutes; 95% CI –4 to –1 minute). There was less vomiting in the Ketamine/propofol (2%) group compared with the Ketamine (12%) group (Δ –10%; 95% CI –18% to –2%). All satisfaction scores were higher ( P Conclusion When compared with Ketamine alone for pediatric orthopedic reductions, the combination of Ketamine and propofol produced slightly faster recoveries while also demonstrating less vomiting, higher satisfaction scores, and similar efficacy and airway complications.
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A blinded, randomized controlled trial to evaluate Ketamine/propofol versus Ketamine alone for procedural sedation in children.
Annals of emergency medicine, 2010Co-Authors: Amit Shah, Gregory Mosdossy, Shelley Mcleod, Kris R Lehnhardt, Michael Peddle, Michael J RiederAbstract:Study objective The primary objective is to compare total sedation time when Ketamine/propofol is used compared with Ketamine alone for pediatric procedural sedation and analgesia. Secondary objectives include time to recovery, adverse events, efficacy, and satisfaction scores. Methods Children (aged 2 to 17 years) requiring procedural sedation and analgesia for management of an isolated orthopedic extremity injury were randomized to receive either Ketamine/propofol or Ketamine. Physicians, nurses, research assistants, and patients were blinded. Ketamine/propofol patients received an initial intravenous bolus dose of Ketamine 0.5 mg/kg and propofol 0.5 mg/kg, followed by propofol 0.5 mg/kg and saline solution placebo every 2 minutes, titrated to deep sedation. Ketamine patients received an initial intravenous bolus dose of Ketamine 1.0 mg/kg and Intralipid placebo, followed by Ketamine 0.25 mg/kg and Intralipid placebo every 2 minutes, as required. Results One hundred thirty-six patients (67 Ketamine/propofol, 69 Ketamine) completed the trial. Median total sedation time was shorter ( P =0.04) with Ketamine/propofol (13 minutes) than with Ketamine (16 minutes) alone (Δ –3 minutes; 95% confidence interval [CI] –5 to –2 minutes). Median recovery time was faster with Ketamine/propofol (10 minutes) than with Ketamine (12 minutes) alone (Δ –2 minutes; 95% CI –4 to –1 minute). There was less vomiting in the Ketamine/propofol (2%) group compared with the Ketamine (12%) group (Δ –10%; 95% CI –18% to –2%). All satisfaction scores were higher ( P Conclusion When compared with Ketamine alone for pediatric orthopedic reductions, the combination of Ketamine and propofol produced slightly faster recoveries while also demonstrating less vomiting, higher satisfaction scores, and similar efficacy and airway complications.
Torsten Passie - One of the best experts on this subject based on the ideXlab platform.
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comparative effects of s Ketamine and racemic r s Ketamine on psychopathology state of consciousness and neurocognitive performance in healthy volunteers
European Neuropsychopharmacology, 2021Co-Authors: Torsten Passie, Hansanton Adams, Frank Logemann, Simon D Brandt, Birgitt Wiese, Matthias KarstAbstract:Abstract Ketamine and its (S)-enantiomer show distinct psychological effects that are investigated in psychiatric research. Its antidepressant activity may depend on the extent and quality of these psychological effects which may greatly differ between the enantiomers. Previous data indicate that the (S)-Ketamine isomer is a more potent anesthetic than (R)-Ketamine. In contrast, in subanesthetic doses (R)-Ketamine seems to elicit fewer dissociative and psychotomimetic effects compared to (S)-Ketamine. In this randomized double-blind placebo-controlled trial the effects of (R/S)-Ketamine and (S)-Ketamine on standardized neuropsychological and psychopathological measures were compared. After an initial bolus equipotent subanesthetic doses of (R/S)- and (S)-Ketamine or placebo were given by continuous intravenous infusion to three groups of 10 healthy male volunteers each (n = 30). (R/S)-Ketamine and (S)-Ketamine produced significant psychopathology and neurocognitive impairment compared to placebo. No significant differences were found between (R/S)-Ketamine and (S)-Ketamine. (S)-Ketamine administration did not result in reduced psychopathological symptomatology compared to (R/S)-Ketamine as suggested by previous studies. However, this study revealed a somewhat more “negatively experienced” psychopathology with (S)-Ketamine, which opens questions about potential “protective effects” associated with the (R)-enantiomer against some psychotomimetic effects induced by the (S)-enantiomer. As the antidepressant effect of Ketamine might depend on a pleasant experience of altered consciousness and perceptions and avoidance of anxiety, the ideal Ketamine composition to treat depression should include (R)-Ketamine. Moreover, since preclinical data indicate that (R)-Ketamine is a more potent and longer acting antidepressant compared to (S)-Ketamine and (R/S)-Ketamine, randomized controlled trials on (R)-Ketamine and comparative studies with (S)-Ketamine and (R/S)-Ketamine are eagerly awaited.
Xing-zu Zhu - One of the best experts on this subject based on the ideXlab platform.
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Comparison of psychic emergence reactions after (±)-Ketamine and (+)-Ketamine in mice
Life sciences, 2005Co-Authors: Jing Liu, Xing-zu ZhuAbstract:Ketamine is a racemic mixture containing equal parts of (+)-Ketamine and (-)-Ketamine. The Ketamine enantiomorphs are different in anesthesia and psychic emergence reactions after anesthesia. Therefore, (+)-Ketamine was compared with racemic Ketamine in a number of randomized studies in volunteers and patients. However, their relations remain controversial. In the present studies, the psychic emergence reactions after injection of (+/-)-Ketamine and (+)-Ketamine were compared in mice. At equimolar doses, the (+)-isomers elicited episodes of hypnosis nearly 1.4-fold more potent than those of the racemic Ketamine. After the administration of equihypnotic doses of (+)-Ketamine and (+/-)-Ketamine, the posthypnotic stimulation of locomotor activity, stereotype behavior and 5-HT-induced head-twitch response by the (+)-enantiomorph was significantly less intense than that of racemic Ketamine. In receptor binding test, (+)-Ketamine showed a higher affinity for NMDA receptor than that of (+/-)-Ketamine, while (+)-Ketamine and (+/-)-Ketamine showed no affinity for dopamine D2 and serotonin 5-HT2 receptor. These results suggest that the (+)-Ketamine has fewer posthypnotic side effects than (+/-)-Ketamine when (+)-Ketamine and (+/-)-Ketamine were administered at equihypnotic dosages and that dopamine D2 and serotonin 5-HT2 receptor were not involved in the effects of (+)-Ketamine and (+/-)-Ketamine.
Young-lan Kwak - One of the best experts on this subject based on the ideXlab platform.
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The immunomodulatory effect of Ketamine in colorectal cancer surgery: a randomized-controlled trial
Canadian Journal of Anesthesia Journal canadien d'anesthésie, 2021Co-Authors: Jin Sun Cho, Na Young Kim, Jae-kwang Shim, Ji Hae Jun, Sugeun Lee, Young-lan KwakAbstract:Purpose Ketamine’s inhibitory action on the N -methyl- d -aspartate receptor and anti-inflammatory effects may provide beneficial immunomodulation in cancer surgery. We investigated the effect of subanesthetic-dose Ketamine as an adjunct to desflurane anesthesia on natural killer (NK) cell activity and inflammation in patients undergoing colorectal cancer surgery. Methods A total of 100 patients were randomly assigned to a control or Ketamine group. The Ketamine group received a bolus of 0.25 mg·kg^−1 Ketamine five minutes before the start of surgery, followed by an infusion 0.05 mg·kg^−1·hr^−1 until the end of surgery; the control group received a similar amount of normal saline. We measured NK cell activity and proinflammatory cytokines (interleukin-6 [IL-6] and tumour necrosis factor-α [TNF-α]) before surgery and one, 24, and 48 hr after surgery. C-reactive protein (CRP) was measured before surgery and one, three, and five days after surgery. Carcinoembryonic antigen and cancer recurrence/metastasis were assessed two years after surgery. Results The NK cell activity was significantly decreased after surgery in both groups, but the change was not different between groups in the linear mixed model analysis ( P = 0.47). Changes in IL-6, TNF-α, CRP, and carcinoembryonic antigen levels were not different between groups ( P = 0.27, 0.69, 0.99, and 0.97, respectively). Cancer recurrence within 2 years after surgery was similar between groups (10% vs 8%, P = 0.62). Conclusions Intraoperative low-dose Ketamine administration did not convey any favourable impacts on overall postoperative NK cell activity, inflammatory responses, and prognosis in colorectal cancer surgery patients. Trial registration www.clinicaltrial.gov (NCT03273231); registered 6 September 2017. Objectif L’action inhibitrice de la kétamine sur le récepteur du N -méthyle-D-aspartate et ses effets anti-inflammatoires pourraient procurer une immunomodulation bénéfique lors d’une chirurgie oncologique. Nous avons étudié l’effet de la kétamine en dose sous-anesthésique en complément à une anesthésie au desflurane sur l’activité des cellules tueuses naturelles (NK) et l’inflammation chez les patients subissant une chirurgie de cancer colorectal. Méthode Au total, 100 patients ont été randomisés à un groupe témoin ou kétamine. Le groupe kétamine a reçu un bolus de 0,25 mg·kg^−1 de kétamine cinq minutes avant le début de la chirurgie, suivi d’une perfusion de 0,05 mg·kg^−1·h^−1 jusqu’à la fin de la chirurgie; le groupe témoin a reçu une quantité similaire de solution physiologique salée. Nous avons mesuré l’activité des cellules NK et des cytokines pro-inflammatoires (interleukine-6 [IL-6] et facteur de nécrose tumorale α [TNF-α]) avant la chirurgie et une, 24 et 48 heures après la chirurgie. La protéine C réactive (CRP) a été mesurée avant la chirurgie puis un, trois et cinq jours après la chirurgie. L’antigène carcinoembryonnaire et la récurrence du cancer ou les métastases ont été évalués deux ans après la chirurgie. Résultats L’activité des cellules NK a été significativement réduite après la chirurgie dans les deux groupes, mais le changement ne différait pas entre les groupes dans l’analyse de modèle mixte linéaire ( P = 0,47). Les changements dans les taux d’IL-6, de TNF-α, de CRP, et d’antigène carcinoembryonnaire n’étaient pas différents entre les groupes ( P = 0,27, 0,69, 0,99 et 0,97, respectivement). La récidive du cancer au cours des deux années suivant la chirurgie était similaire entre les groupes (10 % vs 8 %, P = 0,62). Conclusion L’administration peropératoire de kétamine de faible dose ne s’est pas traduite par un quelconque impact favorable sur l’activité postopératoire g des cellules NK, la réaction inflammatoire, et le pronostic chez les patients de chirurgie de cancer colorectal. Enregistrement de l’étude www.ClinicalTrials.gov (NCT03273231); enregistrée le 6 septembre 2017.
