To the Editor,Non-human primate(NHP)models are advantageous for mimicking human addiction with high behavioural validity.1 However,current NHP drug addiction models(eg,self-administration)often require a comprehensive...To the Editor,Non-human primate(NHP)models are advantageous for mimicking human addiction with high behavioural validity.1 However,current NHP drug addiction models(eg,self-administration)often require a comprehensive behavioural training paradigm,relatively expensive apparatus and invasive surgical procedures.展开更多
Background Patients with anxious major depressive disorder(MDD)are more likely to have poorer outcomes than those with non-anxious MDD.However,the effect of esketamine on adolescents with anxious versus non-anxious MD...Background Patients with anxious major depressive disorder(MDD)are more likely to have poorer outcomes than those with non-anxious MDD.However,the effect of esketamine on adolescents with anxious versus non-anxious MDD has remained unknown.Aims We compared the efficacy of esketamine in adolescents with MDD and suicidal ideation,both anxious and non-anxious.Methods Fifty-four adolescents with anxious(n=33)and non-anxious(n=21)MDD received three infusions of esketamine 0.25mg/kg or active-placebo(midazolam 0.045 mg/kg)over 5 days,with routine inpatient care and treatment.Suicidal ideation and depressive symptoms were assessed using the Columbia Suicide Severity Rating Scale and the Montgomery-Asberg Depression Rating Scale.Multiple-sample proportional tests were used to compare the differences between groups on treatment outcomes 24 hours after the final infusion(day 6,primacy efficacy endpoint)and throughout the 4-week post-treatment(days 12,19 and 33).Results In subjects who received esketamine,a greater number of patients in the non-anxious group than the anxious group achieved antisuicidal remission on day 6(72.7%vs 18.8%,p=0.015)and day 12(90.9%vs 43.8%,p=0.013),and the non-anxious group had a higher antidepressant remission rate compared with the anxious group on day 33(72.7%vs 26.7%,p=0.045).No significant differences in treatment outcomes were observed between the anxious and non-anxious groups at other time points.Conclusions Three infusions of esketamine as an adjunct to routine inpatient care and treatment had a greater immediate post-treatment antisuicidal effect in adolescents with non-anxious MDD than in those with anxious MDD;however,this benefit was temporary and was not maintained over time.展开更多
The management of patients with concomitant chronic pain (CP) and Major Depressive Disorder (MDD) remains challenging for clinicians. Current chronic pharmacologic management is often unsuccessful, or has intolerable ...The management of patients with concomitant chronic pain (CP) and Major Depressive Disorder (MDD) remains challenging for clinicians. Current chronic pharmacologic management is often unsuccessful, or has intolerable side effects to the patients. While not restricted to patients with chronic pain, these patients are often diagnosed with depression, presenting with symptoms such as poor mood, anhedonia, and altered cognitive processes. It is estimated that a substantial proportion of treated patients do not derive a substantive benefit from traditional pharmacological treatments for depression. The present study involved a retrospective review of cases, exploring the patient-reported satisfaction with and tolerability of a novel use of virtual reality (VR), coined KVR, as an adjunct to intravenous ketamine infusion therapies. Specifically, the ketamine-virtual reality protocol was employed as a potential adjunctive intervention for patients suffering from chronic pain and depression. Visual Analog Scores (VAS) associated with pain were significantly lower on the third than on the first assessment day. Montgomery-?sberg Depression Rating Scale (MADRS) scores improved following infusion and across days (i.e., sessions). Lastly, 2/3 of patients preferred the use of VR with their ketamine infusion. The results are considered in terms of implementing prospective studies to examine whether the combination therapies have a synergistic benefit and the nature and magnitude of clinically meaningful treatment effects, if any.展开更多
Introduction: The use of inhaled ketamine to manage a variety of painful conditions has been endorsed by the American College of Emergency Physicians and the American Academy of Emergency Medicine. Nebulized analgesia...Introduction: The use of inhaled ketamine to manage a variety of painful conditions has been endorsed by the American College of Emergency Physicians and the American Academy of Emergency Medicine. Nebulized analgesia has multiple benefits, including rapid, effective and titratable analgesic delivery. The aim of our study is to assess the efficacy and safety of intranasal analgesic-dose ketamine compared to multimodal analgesia in patients presenting with acute postoperative pain or headache after a spinal anaesthetic in the intensive care unit of obstetrics and gynaecology. Materials and Methods: This was a prospective descriptive study, with hospital Ethics Committee approval and written informed consent from study participants. We compared the effect of nebulized ketamine and multimodal analgesia postoperatively in 120 patients belonging to the physical status I - II of the American Society of Anesthesiologists, in the intensive care unit of obstetrics and gynaecology, at the Ibn Rochd University Hospital Center in Casablanca from June 2021 to June 2022. Results: We included 120 patients in our study divided into two groups of 60 patients: the average age was 35 years, with extremes ranging from 18 to 45 years, All patients were hospitalized for postoperative care: all women underwent locoregional anaesthesia with a standard dose according to the service protocol (10 mg of bupivacaine, 25γ of fentanyl, 100γ of morphine), where pain was the common denominator. Among these patients, 59 were admitted for management of postpartum haemorrhage, 43 for postoperative monitoring, 15 for post-spinal anaesthesia headache and 3 for pelviperitonitis. The results of the pain assessment 30 minutes after the ketamine nebulization were marked by a request for analgesia in 12 patients, which is 20% of group A, including 5 patients, whose visual analogue scale (VAS) on admission was between 5 and 7, and 7 patients whose VAS at admission was ≥8;all these patients received a second dose of ketamine by nebulization;the evaluation 30 min after the second dose was marked by a request for analgesia in 4 patients, which is 7% of Group A;in all these patients the VAS at admission was ≥8. Of the total number of patients of Group A, only 4 received morphine when they were requested for analgesia after the second dose of nebulized ketamine. Conclusion: The primary outcome of nebulized ketamine use is a significant reduction in VAS pain score. We believe that nebulized ketamine has a potential effect of reducing pain in the intensive care unit of obstetrics and gynaecology;this may be an additional analgesic modality for clinicians to provide rapid, effective and non-invasive pain relief.展开更多
<strong>Background</strong>: Inpatient subanaesthetic ketamine infusion for 5 days may improve pain and reduce oral opioid usage in patients with chronic pain. <strong>Objective</strong>: This ...<strong>Background</strong>: Inpatient subanaesthetic ketamine infusion for 5 days may improve pain and reduce oral opioid usage in patients with chronic pain. <strong>Objective</strong>: This study aims to investigate pain and psychological outcomes of ketamine parenteral infusion (0.1 - 0.35 mg/kg/h or maximum 24 mg/hour) for 5 days in patients with chronic refractory pain. The secondary objective is to explore any prognostic pain and psychological factors associated with the successful response to the ketamine treatment. <strong>Methodology</strong>: A prospective longitudinal study of a small cohort (N = 35) of patients with heterogenous chronic refractory pain conditions was conducted from one week to two months follow-up. <strong>Results</strong>: Pain Severity was significantly improved from mean 6.5 to 5.1 (t = 3.77, p < 0.001, d = 0.6) at 1-week and 5.9 (t = 2.14, p = 0.042, d = 0.4) at 2-month;Pain Interference from mean 7.0 to 5.1 (t = 4.99, p < 0.001, d = 0.9) at 1-week and 6.1 (t = 2.16, p = 0.041, d = 0.4) at 2-month;Pain Self-Efficacy Questionnaire (PSEQ) from mean 17 to 24 (t = <span style="white-space:nowrap;"><span style="white-space:nowrap;">−</span></span>3.37, p = 0.002, d = <span style="white-space:nowrap;"><span style="white-space:nowrap;">−</span></span>0.6) at 1-week and 23 (t =<span style="white-space:nowrap;"><span style="white-space:nowrap;">−</span></span>2.60, p = 0.016, d =<span style="white-space:nowrap;">−</span><span style="white-space:nowrap;"></span>0.5) at 2-month;Pain Catastrophizing (PCS) from 28 to 23 (t = 3.4, p = 0.002;d = 0.6) at 1-week and 21 (t = 2.45, p = 0.022, d = 0.5) at 2-month;Depression from mean 21 to 16 (t = 2.16, p = 0.038, d = 0.4) at 1-week and 16 (t = 3.53, p = 0.002, d = 0.7) at 2-month;and oral Morphine Equivalent Daily Dose (oMEDD) reduced from mean 191 mg/day on admission to 122 mg/day at 1-week (t = 2.38, p = 0.023;d = 0.4) and 93 mg/day at 2-month (t = 2.59, p = 0.016;d = 0.5). There was no significant difference between responders and non-responders on baseline psychological measures (t<sub>33</sub> < 1.19, p > 0.244) and pain classifications ( <img src="Edit_c68fc9e4-a875-4b79-b0cf-af146ed090fe.png" alt="" /> = 0.610, p = 0.894). <strong>Conclusion</strong>: Ketamine subanaesthetic dose infusion for 5 days was found to be effective in managing chronic refractory pain with significant opioid reduction and small improvements in all chronic pain outcomes, except anxiety, at 1-week and 2-month follow-up and with minimal severe adverse effects.展开更多
Objective:To investigate the effects of propofol and ketamine on the cognitive function and immune function in young rats.Method:A total of 80 young rats were randomly divided into four groups:Control group,ketamine g...Objective:To investigate the effects of propofol and ketamine on the cognitive function and immune function in young rats.Method:A total of 80 young rats were randomly divided into four groups:Control group,ketamine group(experimental group A),propofol group(experimental group B),ketamine and propofol group(experimental group Q.All rats had continuous injection for three times,serum IL-2,IL-4 and II.-10 and whole brain IL-I P level,hippocampal neuronal apoptosis level were measured.The cognitive ability in rats was tested by water maze.Results:Water maze test showed on the 1st d,the maze test latency of the control group,the experimental group B and the experimental group C water were decreased gradually;Compared with the control group after 3 days,the latency of the experimental group A,experimental group B and experimental group C were all decreased,the crossing circle times were also reduced.Hippocampal neuron apoptosis were(2.3±1.7)%,(14.7±6.9)%,(4.2±3.3)%,(10.2±4.8r%in control group,experimental group A,experimental group B and experimental group C,respectively.The neurons apoptosis of experimental group A was significantly increased.The serum IL-4 and 1L-10 of the experimental group A,experimental group B and experimental group C after anesthesia were significantly higher than the control group.The whole brain IL-1β of the experimental group A,experimental group B and experimental group C were significantly lower than the control group.Conclusions:Propofol can reduce anesthesia effect of ketamine on the cognitive function and immune function in the young rats.展开更多
Ketamine exposure can lead to selective neuroapoptosis in the developing brain.p66ShcA,the cellular adapter protein expressed selectively in immature neurons,is a known pro-apoptotic molecule that triggers neuroapopto...Ketamine exposure can lead to selective neuroapoptosis in the developing brain.p66ShcA,the cellular adapter protein expressed selectively in immature neurons,is a known pro-apoptotic molecule that triggers neuroapoptosis when activated.Sprague-Dawley rats at postnatal day 7 were subcutaneously injected in the neck with ketamine 20 mg/kg,six times at 2-hour intervals.At 0,1,3,and 6 hours after final injection,western blot assay was used to detect the expression of cleaved caspase-3,p66ShcA,and phosphorylated p66ShcA.We found that the expression of activated p66ShcA and caspase-3 increased after ketamine exposure and peaked at 3 hours.The same procedure was performed on a different group of rats.At the age of 4 weeks,spatial learning and memory abilities were tested with the Morris water maze.Latency to find the hidden platform for these rats was longer than it was for control rats,although the residence time in the target quadrant was similar.These findings indicate that ketamine exposure resulted in p66ShcA being activated in the course of an apoptotic cascade during the neonatal period.This may have contributed to the deficit in spatial learning and memory that persisted into adulthood.The experimental protocol was approved by the Institutional Animal Care and Use Committee at the University of Texas at Arlington,USA (approval No.A13.008) on January 22,2013.展开更多
Objective: To discuss the neuron-protective effect and possible mechanism of subanesthestic-dosage ketamine on Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Methods: A total of 3...Objective: To discuss the neuron-protective effect and possible mechanism of subanesthestic-dosage ketamine on Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Methods: A total of 30 mice were divided equally into three groups, model control group(MC group), ketamine treatment group(KT group), and blank control group(BC group), respectively.The Parkinson's disease mice of MC group and KT groups were established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(20 mg/kg/d), while mice in KT group were treated by intraperitoneal injection of subanesthestic-dosage ketamine(8 mg/kg).Differences on behaviors and the number of nigra dopaminergic neurons of mice in each group were compared through the behavioral test and tyrosine hydroxylase immunohistochemistry experiments after the treatments.Furthermore, Western blot was used to test the expression of autophagy-related gene LC3-Ⅱ, Beclin1, Parkin, PINK1,and mTOR.Results: Compared with the BC group, the neuroethology scores were lower and the amount of TH positive cells were less both in MC and MT groups; In KT group, the neuroethology scores were higher and the amount of tyrosine hydroxylase positive cells were significantly more than that in MC group(P < 0.05).Moreover, expression levels of autophagy-related proteins LC3-II, Beclin1, Parkin, and PINK1 were higher, while the mTOR expression level was lower than that in MC group.Conclusions: The subanesthestic-dosage ketamine has some protective effects on the coordinating ability of movement and cognitive ability of Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.This is probably due to that the autophagy activity of cells is activated by subanesthestic-dosage ketamine and that the neurons are protected.展开更多
Male Wistar 7-day-old rats were injected with 40 mg/kg ketamine intraperitoneally, followed by three additional injections of 20 mg/kg ketamine each upon restoration of the righting reflex. Neonatal rats injected with...Male Wistar 7-day-old rats were injected with 40 mg/kg ketamine intraperitoneally, followed by three additional injections of 20 mg/kg ketamine each upon restoration of the righting reflex. Neonatal rats injected with equivalent volumes of saline served as controls. Hippocampal samples were collected at 1,7 or 14 days following administration. Electron microscopy showed that neuronal structure changed noticeably following ketamine treatment. Specifically, microtubular structure became irregular and disorganized. Quantitative real time-PCR revealed that phosphorylated tau mRNA was upregulated after ketamine. Western blot analysis demonstrated that phosphorylated tau levels at serine 396 initially decreased at 1 day after ketamine injection, and then gradually returned to control values. At 14 days after injection, levels of phosphorylated tau were higher in the ketamine group than in the control group. Tau protein phosphorylated at serine 404 significantly increased after ketamine injection and then gradually decreased with time. However, the levels of tau protein at serine 404 were significantly greater in the ketamine group than in the control group until 14 days. The present results indicate that ketamine induces an increase of phosphorylated tau mRNA and excessive phosphorylation of tau protein at serine 404, causing disruption of microtubules in the neonatal rat hippocampus and potentially resulting in damage to hippocampal neurons.展开更多
The pain following gynecological laparoscopic surgery is less intense than that following open surgery; however, patients often experience visceral pain after the former surgery. The aim of this study was to determine...The pain following gynecological laparoscopic surgery is less intense than that following open surgery; however, patients often experience visceral pain after the former surgery. The aim of this study was to determine the effects of preemptive ketamine on visceral pain in patients undergoing gynecological laparoscopic surgery. Ninety patients undergoing gynecological laparoscopic surgery were randomly assigned to one of three groups. Group 1 received placebo. Group 2 was intravenously injected with preincisional saline and local infiltration with 20 m L ropivacaine(4 mg/m L) at the end of surgery. Group 3 was intravenously injected with preincisional ketamine(0.3 mg/kg) and local infiltration with 20 m L ropivacaine(4 mg/m L) at the end of surgery. A standard anesthetic was used for all patients, and meperidine was used for postoperative analgesia. The visual analogue scale(VAS) scores for incisional and visceral pain at 2, 6, 12, and 24 h, cumulative analgesic consumption and time until first analgesic medication request, and adverse effects were recorded postoperatively. The VAS scores of visceral pain in group 3 were significantly lower than those in group 2 and group 1 at 2 h and 6 h postoperatively(P〈0.05 and P〈0.01, respectively). At 2 h and 6 h, the VAS scores of incisional pain did not differ significantly between groups 2 and 3, but they were significantly lower than those in group 1(P〈0.01). Groups 1 and 2 did not show any differences in visceral pain scores at 2 h and 6 h postoperatively. Moreover, the three groups showed no statistically significant differences in visceral and incisional pain scores at 12 h and 24 h postoperatively. The consumption of analgesics was significantly greater in group 1 than in groups 2 and 3, and the time to first request for analgesics was significantly longer in groups 2 and 3 than in group 1, with no statistically significant difference between groups 2 and 3. However, the three groups showed no significant difference in the incidence of shoulder pain or adverse effects. Preemptive ketamine may reduce visceral pain in patients undergoing gynecological laparoscopic surgery.展开更多
OBJECTIVE Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neur...OBJECTIVE Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neuroinflammation has been suggested to play an important role in neurodegeneration. Meanwhile,ketamine has been showed to modulate the levels of inflammatory cytokines.Therefore,we sought to investigate whether the effects of ketamine on the central nervous system is associated with the inflammatory cytokines. METHODS We established acute(single or multiple intraperitoneal injection) and chronic(six months daily intraperitoneal injection) ketamine administration models in C57BL/6 mice,evaluated the spatial recognition memory and emotional response by applying the Y maze test and open field test. We analyzed the changes of inflammatory cytokines interleukin-6(IL-6),interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) levels in mouse hippocampus,employing Western blot,quantitative reverse transcriptase-polymerase chain reaction(qR T-PCR) and immunohistochemistry. RESULTS Ketamine induced spatial recognition memory deficit,reduced anxiety-like behaviors in mice after chronic administration,and it was dose-dependent. Moreover,we found that ketamine could increase the levels of mouse hippocampal inflammatory cytokines IL-6 and IL-1β after single,multiple and long-term administration in a dose-dependent manner. However,the level of TNF-α expressed differently in mouse hippocampus under different conditions. Single administration of ketamine increased the level of TNF-α,whereas multiple and long-term administration decreased it significantly. We considered that TNF-α might exist bi-directional regulatory pathway,which was associated with the dose and duration of ketamine administration. CONCLUSION Our results suggest that the alterations of inflammatory cytokines IL-6,IL-1β and TNF-α levels may be involved in the neurotoxicity of ketamine.展开更多
Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common ...Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common disorder,affecting 5–15%of the general population.When diagnosed as major depressive disorder(MDD),patients are currentlytreated with pharmacological agents such as serotonin or noradren- aline uptake inhibitors (SSRI or SNRI) or tricyclics.展开更多
Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced man...Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.展开更多
AIM To determine if ketamine sedation is a safe and cost effective way of treating displaced paediatric radial and ulna fractures in the emergency department. METHODS Following an agreed interdepartmental protocol, fr...AIM To determine if ketamine sedation is a safe and cost effective way of treating displaced paediatric radial and ulna fractures in the emergency department. METHODS Following an agreed interdepartmental protocol, fractures of the radius and ulna(moderately to severely displaced) in children between the age of 2 and 16 years old, presenting within a specified 4 mo period, were manipulated in our paediatric emergency department. Verbal and written consent was obtained prior to procedural sedation to ensure parents were informed and satisfied to have ketamine. A single attempt at manipulation was performed. Pre and postmanipulation radiographs were requested and assessed to ensure adequacy of reduction. Parental satisfaction surveys were collected after the procedure to assess the perceived quality of treatment. After closed reduction and cast immobilisation, patients were then followed-up in the paediatric outpatient fracture clinic and functional outcomes measured prospectively. A cost analysis compared to more formal manipulation under a general anaesthetic was also undertaken.RESULTS During the 4 mo period of study, 10 closed, moderate to severely displaced fractures were identified and treated in the paediatric emergency department using our ketamine sedation protocol. These included fractures of the growth plate(3), fractures of both radius and ulna(6) and a single isolated proximal radius fracture. The mean time from administration of ketamine until completion of the moulded plaster was 20 min. The mean time interval from sedation to full recovery was 74 min. We had no cases of unacceptable fracture reduction and no patients required any further manipulation, either in fracture clinic or under a more formal general anaesthetic. There were no serious adverse events in relation to the use of ketamine. Parents, patients and clinicians reported extremely favourable outcomes using this technique. Furthermore, compared to using a manipulation under general anaesthesia, each case performed under ketamine sedation was associated with a saving of £1470, the overall study saving being £14700. CONCLUSION Ketamine procedural sedation in the paediatric population is a safe and cost effective method for the treatment of displaced fractures of the radius and ulna, with high parent satisfaction rates.展开更多
A model of cerebral ischemia and reperfusion was established in mice.Mice were treated with ketamine via intraperitoneal injection immediately following ischemia or ischemia/reperfusion.Ketamine did not remarkably cha...A model of cerebral ischemia and reperfusion was established in mice.Mice were treated with ketamine via intraperitoneal injection immediately following ischemia or ischemia/reperfusion.Ketamine did not remarkably change infarct volume in mice immediately following ischemia,but injection immediately following ischemia/reperfusion significantly decreased infarct volume.Ketamine injection immediately after ischemia or ischemia/reperfusion inhibited c-Jun protein expression in mouse hippocampus,but nuclear factor kappa B expression was unaltered.In addition,the Longa scale score for neural impairment was not reduced in mice following cerebral ischemia/reperfusion.These results indicate that ketamine can protect mice against cerebral ischemia and reperfusion injury by modulating c-Jun protein expression in mouse hippocampus.展开更多
Ketarnine (KTM), a N-methyl-D-aspartate (NMDA) receptor antagonist, was found to has an anti-inflammatory effect, but some patients suffered from exacerbated pro-inflammatory reactions after anesthesia with KTM. T...Ketarnine (KTM), a N-methyl-D-aspartate (NMDA) receptor antagonist, was found to has an anti-inflammatory effect, but some patients suffered from exacerbated pro-inflammatory reactions after anesthesia with KTM. The present study was aimed to examine the underlying mechanism of pro-inflammatory effects of KTM. In this study, RAW264.7 cells were exposed to KTM and NMDA alone or combined for 30 min before lipopolysaccharide (LPS) stimulation. The expression levels of IL-6 and TNF-α were detected by RT-PCR and ELISA, and those of NMDA receptors by RT-PCR in RAW264.7 cells. Additionally, the TLR4 expression was determined by RT-PCR and flow cytometry, respectively. The results showed that in RAW264.7 cells, KTM alone promoted the TLR4 expression, but did not increase the expression of IL-6 or TNF-α. In the presence of LPS, KTM caused a signifi- cantly higher expression of IL-6 and TNF-a than LPS alone. NMDA could neither alter the IL-6 and TNF-α mRNA expression, nor reverse the enhanced expression of IL-6 and TNF-α mRNA by KTM in LPS-challenged cells. After TLR4-siRNA transfection, RAW264.7 cells pretreated with KTM no longer promoted the IL-6 and TNF-α expression in the presence of LPS. In conclusion, KTM accelerated LPS-induced inflammation in RAW264.7 cells by promoting TLR4 expression, independent of NMDA receptor.展开更多
Objective:To investigate the effects of propofol and ketamine on seizure duration,hemodynamics,and recovery of electroconvulsive therapy(ECT).Methods:This prospective randomized trial included patients who had undergo...Objective:To investigate the effects of propofol and ketamine on seizure duration,hemodynamics,and recovery of electroconvulsive therapy(ECT).Methods:This prospective randomized trial included patients who had undergone ECT under anesthesia.Patients received injection of propofol 1.5 mg/kg i.v.(the propofol group)or ketamine 0.8-1.2 mg/kg i.v.(the ketamine group)during ECT.Seizure duration,hemodynamics,and recovery were recorded and compared between the two groups.Results:This trial included 44 patinets with 22 patients receiving propofol and 22 patients receiving ketamine.The total dose of propofol and ketamine was(105.68±25.27)mg and(81.36±24.55)mg,respectively.The motor seizure and electroencephalogram seizure duration were prolonged in the ketamine group(P<0.001).The hemodynamics at the admission of the two groups were comparable(P>0.05);however,the mean systolic blood pressure during the procedure was significantly higher in the ketamine group(P=0.04).Besides,spontaneous eye-opening in the ketamine group took longer than that of the propofol group(P=0.001).Conclusion:Both propofol and ketamine are safe as anesthetic agents for modified ECT,and ketamine provides a longer seizure duration without hemodynamic instability or any significant complication.展开更多
BACKGROUND:Pain in the emergency department(ED)is common but undertreated.The objective of this study was to examine the efficacy and safety of intranasal(IN)ketamine used as an analgesic for patients with acute injur...BACKGROUND:Pain in the emergency department(ED)is common but undertreated.The objective of this study was to examine the efficacy and safety of intranasal(IN)ketamine used as an analgesic for patients with acute injury with moderate to severe pain.METHODS:This study was a cross sectional,observational study of patients more than 8 years old experiencing moderate to severe pain[visual analog score(VAS)>50 mm].The initial dose of IN ketamine was 0.7 mg/kg with an additional dose of 0.3 mg/kg if VAS was more than 50 mm after 15minutes.Pain scores and vital signs were recorded at 0,15,30 and 60 minutes.Side-effects,sedation level and patient's satisfaction were also recorded.The primary outcome was the number of patients achieving≥20 mm reductions in VAS at 15 minutes.Other secondary outcome measures were median reduction in VAS at 15,30 and 60 minutes,changes of vital signs,adverse events,satisfaction of patients,and need for additional ketamine.RESULTS:Thirty-four patients with a median age of 29.5 years(IQR 17.5–38)were enrolled,and they had an initial median VAS of 80 mm(IQR 67–90).The VAS decreased more than 20 mm at15 minutes in 27(80%)patients.The reduction of VAS from baseline to 40 mm(IQR 20–40),20 mm(IQR 14–20)and 20 mm(IQR 10–20)respectively at 15,30 and 60 minutes(P<0.001).No critical changes of vital signs were noted and adverse effects were mild and transient.CONCLUSION:This study showed that IN ketamine is an analgesic choice for patients with acute injury in moderate to severe pain in an overcrowded and resource limited ED.展开更多
Major depressive disorder(MDD)is a common,serious,debilitating condition affecting 350 million people worldwide,which remains to be unsatisfactorily treated with 53%of patients still complaining of symptoms after comp...Major depressive disorder(MDD)is a common,serious,debilitating condition affecting 350 million people worldwide,which remains to be unsatisfactorily treated with 53%of patients still complaining of symptoms after completing their courses with the correct dosage.Ketamine,which was approved by the Food and Drug Administration in 2019,is a potential treatment option for those recalcitrant cases.The mechanism of ketamine is not fully understood,but as type it is classified as an N-methyl-D-aspartate(NMDA)glutamate receptor antagonist,and can be given intravenously,intranasally and orally.It is used to treat treatment-resistant depression,depression associated with suicidal ideation,mood and anxiety disorders and depressions associated with either type of bipolar disorder.Although ketamine is considered relatively safe,several side effects have been reported with the major ones being psychiatric in the form of worsening mood,anxiety and agitation;psychotomimetic in the form of dissociation,perceptual disturbance and abnormal sensations;cardiovascular in the form of increased blood pressure and increased heart rate;and neurological in the form of headache and dizziness.Ketamine is still not approved worldwide for usage in patients with treatment-resistant MDD,but if it is approved sometime in the future with relatively fewer side effects,it is expected to significantly save millions of dollars spent yearly on patients with treatment-resistant depression and that will lift this major burden off the shoulders of healthcare professionals.This study was designed to measure the effects of ketamine,an NMDA receptor antagonist,on patients with treatment-resistant MDD and to analyse the concept that makes it different and relatively safer than other major antidepressants like selective serotonin reuptake inhibitors,monoamine oxidase inhibitors and TCAs(tricyclic antidepressants).展开更多
基金This study was financially supported by the National Natural Science Foundation of China(81822017,82171493,52003021)the Lingang Laboratory(LG-QS-202203-10)the Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(20181715).
文摘To the Editor,Non-human primate(NHP)models are advantageous for mimicking human addiction with high behavioural validity.1 However,current NHP drug addiction models(eg,self-administration)often require a comprehensive behavioural training paradigm,relatively expensive apparatus and invasive surgical procedures.
基金funded by Guangzhou Science and Technology Planning Project of Guangdong(202103000032)Science and Technology Plan Project of Guangdong Province(2019B030316001)+1 种基金Guangdong Basic and Applied Basic Research Foundation(2019A1515011366,2022A1515011567)National Natural Science Foundation of China(81801343).
文摘Background Patients with anxious major depressive disorder(MDD)are more likely to have poorer outcomes than those with non-anxious MDD.However,the effect of esketamine on adolescents with anxious versus non-anxious MDD has remained unknown.Aims We compared the efficacy of esketamine in adolescents with MDD and suicidal ideation,both anxious and non-anxious.Methods Fifty-four adolescents with anxious(n=33)and non-anxious(n=21)MDD received three infusions of esketamine 0.25mg/kg or active-placebo(midazolam 0.045 mg/kg)over 5 days,with routine inpatient care and treatment.Suicidal ideation and depressive symptoms were assessed using the Columbia Suicide Severity Rating Scale and the Montgomery-Asberg Depression Rating Scale.Multiple-sample proportional tests were used to compare the differences between groups on treatment outcomes 24 hours after the final infusion(day 6,primacy efficacy endpoint)and throughout the 4-week post-treatment(days 12,19 and 33).Results In subjects who received esketamine,a greater number of patients in the non-anxious group than the anxious group achieved antisuicidal remission on day 6(72.7%vs 18.8%,p=0.015)and day 12(90.9%vs 43.8%,p=0.013),and the non-anxious group had a higher antidepressant remission rate compared with the anxious group on day 33(72.7%vs 26.7%,p=0.045).No significant differences in treatment outcomes were observed between the anxious and non-anxious groups at other time points.Conclusions Three infusions of esketamine as an adjunct to routine inpatient care and treatment had a greater immediate post-treatment antisuicidal effect in adolescents with non-anxious MDD than in those with anxious MDD;however,this benefit was temporary and was not maintained over time.
文摘The management of patients with concomitant chronic pain (CP) and Major Depressive Disorder (MDD) remains challenging for clinicians. Current chronic pharmacologic management is often unsuccessful, or has intolerable side effects to the patients. While not restricted to patients with chronic pain, these patients are often diagnosed with depression, presenting with symptoms such as poor mood, anhedonia, and altered cognitive processes. It is estimated that a substantial proportion of treated patients do not derive a substantive benefit from traditional pharmacological treatments for depression. The present study involved a retrospective review of cases, exploring the patient-reported satisfaction with and tolerability of a novel use of virtual reality (VR), coined KVR, as an adjunct to intravenous ketamine infusion therapies. Specifically, the ketamine-virtual reality protocol was employed as a potential adjunctive intervention for patients suffering from chronic pain and depression. Visual Analog Scores (VAS) associated with pain were significantly lower on the third than on the first assessment day. Montgomery-?sberg Depression Rating Scale (MADRS) scores improved following infusion and across days (i.e., sessions). Lastly, 2/3 of patients preferred the use of VR with their ketamine infusion. The results are considered in terms of implementing prospective studies to examine whether the combination therapies have a synergistic benefit and the nature and magnitude of clinically meaningful treatment effects, if any.
文摘Introduction: The use of inhaled ketamine to manage a variety of painful conditions has been endorsed by the American College of Emergency Physicians and the American Academy of Emergency Medicine. Nebulized analgesia has multiple benefits, including rapid, effective and titratable analgesic delivery. The aim of our study is to assess the efficacy and safety of intranasal analgesic-dose ketamine compared to multimodal analgesia in patients presenting with acute postoperative pain or headache after a spinal anaesthetic in the intensive care unit of obstetrics and gynaecology. Materials and Methods: This was a prospective descriptive study, with hospital Ethics Committee approval and written informed consent from study participants. We compared the effect of nebulized ketamine and multimodal analgesia postoperatively in 120 patients belonging to the physical status I - II of the American Society of Anesthesiologists, in the intensive care unit of obstetrics and gynaecology, at the Ibn Rochd University Hospital Center in Casablanca from June 2021 to June 2022. Results: We included 120 patients in our study divided into two groups of 60 patients: the average age was 35 years, with extremes ranging from 18 to 45 years, All patients were hospitalized for postoperative care: all women underwent locoregional anaesthesia with a standard dose according to the service protocol (10 mg of bupivacaine, 25γ of fentanyl, 100γ of morphine), where pain was the common denominator. Among these patients, 59 were admitted for management of postpartum haemorrhage, 43 for postoperative monitoring, 15 for post-spinal anaesthesia headache and 3 for pelviperitonitis. The results of the pain assessment 30 minutes after the ketamine nebulization were marked by a request for analgesia in 12 patients, which is 20% of group A, including 5 patients, whose visual analogue scale (VAS) on admission was between 5 and 7, and 7 patients whose VAS at admission was ≥8;all these patients received a second dose of ketamine by nebulization;the evaluation 30 min after the second dose was marked by a request for analgesia in 4 patients, which is 7% of Group A;in all these patients the VAS at admission was ≥8. Of the total number of patients of Group A, only 4 received morphine when they were requested for analgesia after the second dose of nebulized ketamine. Conclusion: The primary outcome of nebulized ketamine use is a significant reduction in VAS pain score. We believe that nebulized ketamine has a potential effect of reducing pain in the intensive care unit of obstetrics and gynaecology;this may be an additional analgesic modality for clinicians to provide rapid, effective and non-invasive pain relief.
文摘<strong>Background</strong>: Inpatient subanaesthetic ketamine infusion for 5 days may improve pain and reduce oral opioid usage in patients with chronic pain. <strong>Objective</strong>: This study aims to investigate pain and psychological outcomes of ketamine parenteral infusion (0.1 - 0.35 mg/kg/h or maximum 24 mg/hour) for 5 days in patients with chronic refractory pain. The secondary objective is to explore any prognostic pain and psychological factors associated with the successful response to the ketamine treatment. <strong>Methodology</strong>: A prospective longitudinal study of a small cohort (N = 35) of patients with heterogenous chronic refractory pain conditions was conducted from one week to two months follow-up. <strong>Results</strong>: Pain Severity was significantly improved from mean 6.5 to 5.1 (t = 3.77, p < 0.001, d = 0.6) at 1-week and 5.9 (t = 2.14, p = 0.042, d = 0.4) at 2-month;Pain Interference from mean 7.0 to 5.1 (t = 4.99, p < 0.001, d = 0.9) at 1-week and 6.1 (t = 2.16, p = 0.041, d = 0.4) at 2-month;Pain Self-Efficacy Questionnaire (PSEQ) from mean 17 to 24 (t = <span style="white-space:nowrap;"><span style="white-space:nowrap;">−</span></span>3.37, p = 0.002, d = <span style="white-space:nowrap;"><span style="white-space:nowrap;">−</span></span>0.6) at 1-week and 23 (t =<span style="white-space:nowrap;"><span style="white-space:nowrap;">−</span></span>2.60, p = 0.016, d =<span style="white-space:nowrap;">−</span><span style="white-space:nowrap;"></span>0.5) at 2-month;Pain Catastrophizing (PCS) from 28 to 23 (t = 3.4, p = 0.002;d = 0.6) at 1-week and 21 (t = 2.45, p = 0.022, d = 0.5) at 2-month;Depression from mean 21 to 16 (t = 2.16, p = 0.038, d = 0.4) at 1-week and 16 (t = 3.53, p = 0.002, d = 0.7) at 2-month;and oral Morphine Equivalent Daily Dose (oMEDD) reduced from mean 191 mg/day on admission to 122 mg/day at 1-week (t = 2.38, p = 0.023;d = 0.4) and 93 mg/day at 2-month (t = 2.59, p = 0.016;d = 0.5). There was no significant difference between responders and non-responders on baseline psychological measures (t<sub>33</sub> < 1.19, p > 0.244) and pain classifications ( <img src="Edit_c68fc9e4-a875-4b79-b0cf-af146ed090fe.png" alt="" /> = 0.610, p = 0.894). <strong>Conclusion</strong>: Ketamine subanaesthetic dose infusion for 5 days was found to be effective in managing chronic refractory pain with significant opioid reduction and small improvements in all chronic pain outcomes, except anxiety, at 1-week and 2-month follow-up and with minimal severe adverse effects.
基金supported by Youth Innovation Fund of The First Affiliated Hospital of Zhengzhou University(2012-2015)National Natural Science Foundation(81200909)
文摘Objective:To investigate the effects of propofol and ketamine on the cognitive function and immune function in young rats.Method:A total of 80 young rats were randomly divided into four groups:Control group,ketamine group(experimental group A),propofol group(experimental group B),ketamine and propofol group(experimental group Q.All rats had continuous injection for three times,serum IL-2,IL-4 and II.-10 and whole brain IL-I P level,hippocampal neuronal apoptosis level were measured.The cognitive ability in rats was tested by water maze.Results:Water maze test showed on the 1st d,the maze test latency of the control group,the experimental group B and the experimental group C water were decreased gradually;Compared with the control group after 3 days,the latency of the experimental group A,experimental group B and experimental group C were all decreased,the crossing circle times were also reduced.Hippocampal neuron apoptosis were(2.3±1.7)%,(14.7±6.9)%,(4.2±3.3)%,(10.2±4.8r%in control group,experimental group A,experimental group B and experimental group C,respectively.The neurons apoptosis of experimental group A was significantly increased.The serum IL-4 and 1L-10 of the experimental group A,experimental group B and experimental group C after anesthesia were significantly higher than the control group.The whole brain IL-1β of the experimental group A,experimental group B and experimental group C were significantly lower than the control group.Conclusions:Propofol can reduce anesthesia effect of ketamine on the cognitive function and immune function in the young rats.
基金supported by the National Natural Science Foundation of China,No.81200851(to DL)the National Institutes of Health of the USA,No.NS 040723(to QL)
文摘Ketamine exposure can lead to selective neuroapoptosis in the developing brain.p66ShcA,the cellular adapter protein expressed selectively in immature neurons,is a known pro-apoptotic molecule that triggers neuroapoptosis when activated.Sprague-Dawley rats at postnatal day 7 were subcutaneously injected in the neck with ketamine 20 mg/kg,six times at 2-hour intervals.At 0,1,3,and 6 hours after final injection,western blot assay was used to detect the expression of cleaved caspase-3,p66ShcA,and phosphorylated p66ShcA.We found that the expression of activated p66ShcA and caspase-3 increased after ketamine exposure and peaked at 3 hours.The same procedure was performed on a different group of rats.At the age of 4 weeks,spatial learning and memory abilities were tested with the Morris water maze.Latency to find the hidden platform for these rats was longer than it was for control rats,although the residence time in the target quadrant was similar.These findings indicate that ketamine exposure resulted in p66ShcA being activated in the course of an apoptotic cascade during the neonatal period.This may have contributed to the deficit in spatial learning and memory that persisted into adulthood.The experimental protocol was approved by the Institutional Animal Care and Use Committee at the University of Texas at Arlington,USA (approval No.A13.008) on January 22,2013.
基金supported by National Natural Science Foundation of China(No.81600940)the Science of Technology project of Henan,China(No.142102310246)
文摘Objective: To discuss the neuron-protective effect and possible mechanism of subanesthestic-dosage ketamine on Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.Methods: A total of 30 mice were divided equally into three groups, model control group(MC group), ketamine treatment group(KT group), and blank control group(BC group), respectively.The Parkinson's disease mice of MC group and KT groups were established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(20 mg/kg/d), while mice in KT group were treated by intraperitoneal injection of subanesthestic-dosage ketamine(8 mg/kg).Differences on behaviors and the number of nigra dopaminergic neurons of mice in each group were compared through the behavioral test and tyrosine hydroxylase immunohistochemistry experiments after the treatments.Furthermore, Western blot was used to test the expression of autophagy-related gene LC3-Ⅱ, Beclin1, Parkin, PINK1,and mTOR.Results: Compared with the BC group, the neuroethology scores were lower and the amount of TH positive cells were less both in MC and MT groups; In KT group, the neuroethology scores were higher and the amount of tyrosine hydroxylase positive cells were significantly more than that in MC group(P < 0.05).Moreover, expression levels of autophagy-related proteins LC3-II, Beclin1, Parkin, and PINK1 were higher, while the mTOR expression level was lower than that in MC group.Conclusions: The subanesthestic-dosage ketamine has some protective effects on the coordinating ability of movement and cognitive ability of Parkinson's disease mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.This is probably due to that the autophagy activity of cells is activated by subanesthestic-dosage ketamine and that the neurons are protected.
基金supported by the project of the Ministry of Education, Zhejiang Province, China, No. Y201017446 and Y201121392the project of the Bureau of Chinese Medicine, Zhejiang Province, China, No. 2011ZA067
文摘Male Wistar 7-day-old rats were injected with 40 mg/kg ketamine intraperitoneally, followed by three additional injections of 20 mg/kg ketamine each upon restoration of the righting reflex. Neonatal rats injected with equivalent volumes of saline served as controls. Hippocampal samples were collected at 1,7 or 14 days following administration. Electron microscopy showed that neuronal structure changed noticeably following ketamine treatment. Specifically, microtubular structure became irregular and disorganized. Quantitative real time-PCR revealed that phosphorylated tau mRNA was upregulated after ketamine. Western blot analysis demonstrated that phosphorylated tau levels at serine 396 initially decreased at 1 day after ketamine injection, and then gradually returned to control values. At 14 days after injection, levels of phosphorylated tau were higher in the ketamine group than in the control group. Tau protein phosphorylated at serine 404 significantly increased after ketamine injection and then gradually decreased with time. However, the levels of tau protein at serine 404 were significantly greater in the ketamine group than in the control group until 14 days. The present results indicate that ketamine induces an increase of phosphorylated tau mRNA and excessive phosphorylation of tau protein at serine 404, causing disruption of microtubules in the neonatal rat hippocampus and potentially resulting in damage to hippocampal neurons.
基金supported by the Key Technologies R&D program of Henan Province,China(No.201503178)
文摘The pain following gynecological laparoscopic surgery is less intense than that following open surgery; however, patients often experience visceral pain after the former surgery. The aim of this study was to determine the effects of preemptive ketamine on visceral pain in patients undergoing gynecological laparoscopic surgery. Ninety patients undergoing gynecological laparoscopic surgery were randomly assigned to one of three groups. Group 1 received placebo. Group 2 was intravenously injected with preincisional saline and local infiltration with 20 m L ropivacaine(4 mg/m L) at the end of surgery. Group 3 was intravenously injected with preincisional ketamine(0.3 mg/kg) and local infiltration with 20 m L ropivacaine(4 mg/m L) at the end of surgery. A standard anesthetic was used for all patients, and meperidine was used for postoperative analgesia. The visual analogue scale(VAS) scores for incisional and visceral pain at 2, 6, 12, and 24 h, cumulative analgesic consumption and time until first analgesic medication request, and adverse effects were recorded postoperatively. The VAS scores of visceral pain in group 3 were significantly lower than those in group 2 and group 1 at 2 h and 6 h postoperatively(P〈0.05 and P〈0.01, respectively). At 2 h and 6 h, the VAS scores of incisional pain did not differ significantly between groups 2 and 3, but they were significantly lower than those in group 1(P〈0.01). Groups 1 and 2 did not show any differences in visceral pain scores at 2 h and 6 h postoperatively. Moreover, the three groups showed no statistically significant differences in visceral and incisional pain scores at 12 h and 24 h postoperatively. The consumption of analgesics was significantly greater in group 1 than in groups 2 and 3, and the time to first request for analgesics was significantly longer in groups 2 and 3 than in group 1, with no statistically significant difference between groups 2 and 3. However, the three groups showed no significant difference in the incidence of shoulder pain or adverse effects. Preemptive ketamine may reduce visceral pain in patients undergoing gynecological laparoscopic surgery.
文摘OBJECTIVE Ketamine is an injectable anesthetic and recreational drug of abuse commonly used worldwide. Many experimental studies have shown that ketamine can impair cognitive function and induce psychotic states. Neuroinflammation has been suggested to play an important role in neurodegeneration. Meanwhile,ketamine has been showed to modulate the levels of inflammatory cytokines.Therefore,we sought to investigate whether the effects of ketamine on the central nervous system is associated with the inflammatory cytokines. METHODS We established acute(single or multiple intraperitoneal injection) and chronic(six months daily intraperitoneal injection) ketamine administration models in C57BL/6 mice,evaluated the spatial recognition memory and emotional response by applying the Y maze test and open field test. We analyzed the changes of inflammatory cytokines interleukin-6(IL-6),interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) levels in mouse hippocampus,employing Western blot,quantitative reverse transcriptase-polymerase chain reaction(qR T-PCR) and immunohistochemistry. RESULTS Ketamine induced spatial recognition memory deficit,reduced anxiety-like behaviors in mice after chronic administration,and it was dose-dependent. Moreover,we found that ketamine could increase the levels of mouse hippocampal inflammatory cytokines IL-6 and IL-1β after single,multiple and long-term administration in a dose-dependent manner. However,the level of TNF-α expressed differently in mouse hippocampus under different conditions. Single administration of ketamine increased the level of TNF-α,whereas multiple and long-term administration decreased it significantly. We considered that TNF-α might exist bi-directional regulatory pathway,which was associated with the dose and duration of ketamine administration. CONCLUSION Our results suggest that the alterations of inflammatory cytokines IL-6,IL-1β and TNF-α levels may be involved in the neurotoxicity of ketamine.
基金funded by Ministry of Education,University and Research(MIUR)ex-60% research fund University of Brescia,Italy
文摘Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common disorder,affecting 5–15%of the general population.When diagnosed as major depressive disorder(MDD),patients are currentlytreated with pharmacological agents such as serotonin or noradren- aline uptake inhibitors (SSRI or SNRI) or tricyclics.
基金supported by the Key Project of the National Natural Science Foundation of China(81920108018 to T.L.and P.S.)Ministry of Science and Technology of the People’s Republic of China(2022ZD0205200)+4 种基金Natural Science Foundation of Sichuan Province(2022NSFSC1607)Key R&D Program of Zhejiang(2022C03096 to T.L.)Special Foundation for Brain Research from Science and Technology Program of Guangdong(2018B030334001)Project for Hangzhou Medical Disciplines of Excellence&Key Project for Hangzhou Medical Disciplines。
文摘Ketamine, a rapid-acting antidepressant drug, has been used to treat major depressive disorder and bipolar disorder(BD). Recent studies have shown that ketamine may increase the potential risk of treatment-induced mania in patients. Ketamine has also been applied to establish animal models of mania. At present, however, the underlying mechanism is still unclear. In the current study, we found that chronic lithium exposure attenuated ketamine-induced mania-like behavior and c-Fos expression in the medial prefrontal cortex(mPFC) of adult male mice. Transcriptome sequencing was performed to determine the effect of lithium administration on the transcriptome of the PFC in ketamine-treated mice, showing inactivation of the phosphoinositide 3-kinase(PI3K)-protein kinase B(AKT) signaling pathway. Pharmacological inhibition of AKT signaling by MK2206(40 mg/kg), a selective AKT inhibitor, reversed ketamine-induced mania.Furthermore, selective knockdown of AKT via AAVAKT-sh RNA-EGFP in the mPFC also reversed ketamine-induced mania-like behavior. Importantly,pharmacological activation of AKT signaling by SC79(40 mg/kg), an AKT activator, contributed to mania in low-dose ketamine-treated mice. Inhibition of PI3K signaling by LY294002(25 mg/kg), a specific PI3K inhibitor, reversed the mania-like behavior in ketamine-treated mice. However, pharmacological inhibition of mammalian target of rapamycin(mTOR)signaling with rapamycin(10 mg/kg), a specific mTOR inhibitor, had no effect on ketamine-induced mania-like behavior. These results suggest that chronic lithium treatment ameliorates ketamine-induced mania-like behavior via the PI3K-AKT signaling pathway, which may be a novel target for the development of BD treatment.
文摘AIM To determine if ketamine sedation is a safe and cost effective way of treating displaced paediatric radial and ulna fractures in the emergency department. METHODS Following an agreed interdepartmental protocol, fractures of the radius and ulna(moderately to severely displaced) in children between the age of 2 and 16 years old, presenting within a specified 4 mo period, were manipulated in our paediatric emergency department. Verbal and written consent was obtained prior to procedural sedation to ensure parents were informed and satisfied to have ketamine. A single attempt at manipulation was performed. Pre and postmanipulation radiographs were requested and assessed to ensure adequacy of reduction. Parental satisfaction surveys were collected after the procedure to assess the perceived quality of treatment. After closed reduction and cast immobilisation, patients were then followed-up in the paediatric outpatient fracture clinic and functional outcomes measured prospectively. A cost analysis compared to more formal manipulation under a general anaesthetic was also undertaken.RESULTS During the 4 mo period of study, 10 closed, moderate to severely displaced fractures were identified and treated in the paediatric emergency department using our ketamine sedation protocol. These included fractures of the growth plate(3), fractures of both radius and ulna(6) and a single isolated proximal radius fracture. The mean time from administration of ketamine until completion of the moulded plaster was 20 min. The mean time interval from sedation to full recovery was 74 min. We had no cases of unacceptable fracture reduction and no patients required any further manipulation, either in fracture clinic or under a more formal general anaesthetic. There were no serious adverse events in relation to the use of ketamine. Parents, patients and clinicians reported extremely favourable outcomes using this technique. Furthermore, compared to using a manipulation under general anaesthesia, each case performed under ketamine sedation was associated with a saving of £1470, the overall study saving being £14700. CONCLUSION Ketamine procedural sedation in the paediatric population is a safe and cost effective method for the treatment of displaced fractures of the radius and ulna, with high parent satisfaction rates.
基金supported by the Medical and Health Research Guidance Program of the Hubei Provincial Department of Health,No. 2001WZ01514
文摘A model of cerebral ischemia and reperfusion was established in mice.Mice were treated with ketamine via intraperitoneal injection immediately following ischemia or ischemia/reperfusion.Ketamine did not remarkably change infarct volume in mice immediately following ischemia,but injection immediately following ischemia/reperfusion significantly decreased infarct volume.Ketamine injection immediately after ischemia or ischemia/reperfusion inhibited c-Jun protein expression in mouse hippocampus,but nuclear factor kappa B expression was unaltered.In addition,the Longa scale score for neural impairment was not reduced in mice following cerebral ischemia/reperfusion.These results indicate that ketamine can protect mice against cerebral ischemia and reperfusion injury by modulating c-Jun protein expression in mouse hippocampus.
基金supported by grants from the National Natural Science Foundation of China(No.30972837,and No.81201454)
文摘Ketarnine (KTM), a N-methyl-D-aspartate (NMDA) receptor antagonist, was found to has an anti-inflammatory effect, but some patients suffered from exacerbated pro-inflammatory reactions after anesthesia with KTM. The present study was aimed to examine the underlying mechanism of pro-inflammatory effects of KTM. In this study, RAW264.7 cells were exposed to KTM and NMDA alone or combined for 30 min before lipopolysaccharide (LPS) stimulation. The expression levels of IL-6 and TNF-α were detected by RT-PCR and ELISA, and those of NMDA receptors by RT-PCR in RAW264.7 cells. Additionally, the TLR4 expression was determined by RT-PCR and flow cytometry, respectively. The results showed that in RAW264.7 cells, KTM alone promoted the TLR4 expression, but did not increase the expression of IL-6 or TNF-α. In the presence of LPS, KTM caused a signifi- cantly higher expression of IL-6 and TNF-a than LPS alone. NMDA could neither alter the IL-6 and TNF-α mRNA expression, nor reverse the enhanced expression of IL-6 and TNF-α mRNA by KTM in LPS-challenged cells. After TLR4-siRNA transfection, RAW264.7 cells pretreated with KTM no longer promoted the IL-6 and TNF-α expression in the presence of LPS. In conclusion, KTM accelerated LPS-induced inflammation in RAW264.7 cells by promoting TLR4 expression, independent of NMDA receptor.
文摘Objective:To investigate the effects of propofol and ketamine on seizure duration,hemodynamics,and recovery of electroconvulsive therapy(ECT).Methods:This prospective randomized trial included patients who had undergone ECT under anesthesia.Patients received injection of propofol 1.5 mg/kg i.v.(the propofol group)or ketamine 0.8-1.2 mg/kg i.v.(the ketamine group)during ECT.Seizure duration,hemodynamics,and recovery were recorded and compared between the two groups.Results:This trial included 44 patinets with 22 patients receiving propofol and 22 patients receiving ketamine.The total dose of propofol and ketamine was(105.68±25.27)mg and(81.36±24.55)mg,respectively.The motor seizure and electroencephalogram seizure duration were prolonged in the ketamine group(P<0.001).The hemodynamics at the admission of the two groups were comparable(P>0.05);however,the mean systolic blood pressure during the procedure was significantly higher in the ketamine group(P=0.04).Besides,spontaneous eye-opening in the ketamine group took longer than that of the propofol group(P=0.001).Conclusion:Both propofol and ketamine are safe as anesthetic agents for modified ECT,and ketamine provides a longer seizure duration without hemodynamic instability or any significant complication.
文摘BACKGROUND:Pain in the emergency department(ED)is common but undertreated.The objective of this study was to examine the efficacy and safety of intranasal(IN)ketamine used as an analgesic for patients with acute injury with moderate to severe pain.METHODS:This study was a cross sectional,observational study of patients more than 8 years old experiencing moderate to severe pain[visual analog score(VAS)>50 mm].The initial dose of IN ketamine was 0.7 mg/kg with an additional dose of 0.3 mg/kg if VAS was more than 50 mm after 15minutes.Pain scores and vital signs were recorded at 0,15,30 and 60 minutes.Side-effects,sedation level and patient's satisfaction were also recorded.The primary outcome was the number of patients achieving≥20 mm reductions in VAS at 15 minutes.Other secondary outcome measures were median reduction in VAS at 15,30 and 60 minutes,changes of vital signs,adverse events,satisfaction of patients,and need for additional ketamine.RESULTS:Thirty-four patients with a median age of 29.5 years(IQR 17.5–38)were enrolled,and they had an initial median VAS of 80 mm(IQR 67–90).The VAS decreased more than 20 mm at15 minutes in 27(80%)patients.The reduction of VAS from baseline to 40 mm(IQR 20–40),20 mm(IQR 14–20)and 20 mm(IQR 10–20)respectively at 15,30 and 60 minutes(P<0.001).No critical changes of vital signs were noted and adverse effects were mild and transient.CONCLUSION:This study showed that IN ketamine is an analgesic choice for patients with acute injury in moderate to severe pain in an overcrowded and resource limited ED.
文摘Major depressive disorder(MDD)is a common,serious,debilitating condition affecting 350 million people worldwide,which remains to be unsatisfactorily treated with 53%of patients still complaining of symptoms after completing their courses with the correct dosage.Ketamine,which was approved by the Food and Drug Administration in 2019,is a potential treatment option for those recalcitrant cases.The mechanism of ketamine is not fully understood,but as type it is classified as an N-methyl-D-aspartate(NMDA)glutamate receptor antagonist,and can be given intravenously,intranasally and orally.It is used to treat treatment-resistant depression,depression associated with suicidal ideation,mood and anxiety disorders and depressions associated with either type of bipolar disorder.Although ketamine is considered relatively safe,several side effects have been reported with the major ones being psychiatric in the form of worsening mood,anxiety and agitation;psychotomimetic in the form of dissociation,perceptual disturbance and abnormal sensations;cardiovascular in the form of increased blood pressure and increased heart rate;and neurological in the form of headache and dizziness.Ketamine is still not approved worldwide for usage in patients with treatment-resistant MDD,but if it is approved sometime in the future with relatively fewer side effects,it is expected to significantly save millions of dollars spent yearly on patients with treatment-resistant depression and that will lift this major burden off the shoulders of healthcare professionals.This study was designed to measure the effects of ketamine,an NMDA receptor antagonist,on patients with treatment-resistant MDD and to analyse the concept that makes it different and relatively safer than other major antidepressants like selective serotonin reuptake inhibitors,monoamine oxidase inhibitors and TCAs(tricyclic antidepressants).