High-dose Ketamine Research Articles

Chemical immobilisation of the wild Patagonian otter (Lontra provocax) and the North American mink (Neovison vison)

The Patagonian otter (Lontra provocax) is an endangered species endemic to southern Chile and Argentina. Most of its distribution range has recently been occupied by the American mink (Neovison vison). As part of a long-term study on the impact of mink in Patagonia, we assessed five reversible anaesthetic combination protocols in different doses on wild L. provocax and N. vison, and described the occurrence of any adverse effects. We assessed 16 anaesthetic procedures with a combination of ketamine-medetomidine (KET-MED; 6.0±2.8-0.05±0.01 mg/kg IM, respectively) or ketamine-dexmedetomidine (KET-DEX; 4.1±0.9-0.02±0.004 mg/kg IM) in L. provocax and 23 anaesthetic procedures with KET-MED (13.3±4-0.1±0.04 mg/kg IM), KET-DEX (4.8±0.3-0.024±0.001 mg/kg IM) in a low dose of ketamine (LDK) or KET-DEX (10.2±0.9-0.025±0.002 mg/kg IM) in a high dose of ketamine (HDK) in N. vison. Reversal was accomplished using atipamezole at 5 times the dose of MED or 10 times the dose of DEX. All anaesthetic combinations produced complete immobilisation and rapid anaesthetic induction, except for two otters anaesthetised with KET-MED which exhibited a longer time to initial effect. Hypothermia was commonly observed at the end of the anaesthetic procedures. Due to the hypoxemia presented in four otters at the beginning of anaesthesia, it is recommended to use additional oxygen when possible.

Comparison Prophylactic Effects of Gargling Different Doses of Ketamine on Attenuating Postoperative Sore Throat: A Single-Blind Randomized Controlled Trial.

Context:Postoperative sore throat (POST) is a common annoying problem following endotracheal (ET) intubation.Aims:Comparing the impact of low and high doses of ketamine gargle on lowering POST incidence and severity.Settings and Design:96 patients selected for septoplasty surgery under general anesthesia were investigated through a single-blind randomized controlled trial.Methods:This study was performed on three equal groups. Group K and G gargled 50 and 100 mg ketamine, respectively, solved in normal saline and group C gargled pure normal saline for 30 s at 5 min before tracheal intubation. POST severity measured immediately after the entrance to the postanesthetic care unit (PACU) and then 2 h, 4 h, 8 h, and 24 h after operation.Statistical Analysis Used:Collected data were analyzed by the Chi-square test, Mann-Whitney test, Kruskal-Wallis test, one-way analysis of variance (ANOVA) and Friedman test using SPSS version 20.Results:POST incidence and severity in group C were significantly higher than both K and G groups at all times. Although significant differences between low and high doses of ketamine were acknowledged at 8 h post-operation, 100 mg ketamine could attenuate POST severity further than 50 mg at all times.Conclusions:It seems that 100 mg outperformed 50 mg ketamine without rising complications and dissatisfaction for subjects. So, it gives us a powerful reason to suggest gargling 100 mg ketamine for lessening POST incidence and severity.

Prehospital Ketamine Use for Rapid Sequence Intubation: Are Higher Doses Associated With Adverse Events?

ObjectiveKetamine for rapid sequence intubation (RSI) is typically dosed at 1 to 2 mg/kg intravenously. The need to ensure dissociation during RSI led some to administer ketamine at doses greater than 2 mg/kg. This study assessed associations between ketamine dose and adverse events. MethodsThis multisite, retrospective study included adult subjects undergoing RSI with intravenous ketamine. Subjects were categorized into 2 groups: a standard ketamine dose (≤ 2 mg/kg intravenously) or a high dose (> 2 mg/kg intravenously). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for adverse events. ResultsEighty subjects received standard-dose ketamine, and 50 received high-dose ketamine. The high-dose group had a significantly (P < .05) higher proportion of trauma patients, were younger, and had higher predose blood pressure compared with the standard-dose group. High-dose ketamine was associated with greater odds of adverse events including hypotension (OR = 7.0; 95% CI, 3.0-16.6), laryngospasm (OR = 10.8; 95% CI, 1.3-93.4), bradycardia (OR = 7.5; 95% CI, 1.5-36.6), repeat medications (OR = 12.9; 95% CI, 1.5-107.9), oxygen desaturation (OR = 6.0; 95% CI, 1.8-19.9), multiple attempts (OR = 3.2; 95% CI, 1.5-6.8%), and failed airway (OR = 3.6; 95% CI, 1.0-12.7). ConclusionKetamine at higher doses was associated with increased odds of adverse events. Studies assessing adverse events of ketamine at lower than standard doses in shock patients are needed.

Histomorphological Effect of Centella Asiatica on Swiss Albino Mice Brain upon Ketamine Anesthetic Induced Memory Impairment

Introduction: Ketamine is a medication mainly used for starting and maintaining anesthesia. It induces a trance-like state while providing pain relief, sedation and memory loss. Ketamine causes morphological changes in the neuronal cells of growing rodent. Centella asiatica is used for memory enhancement in the ayurvadic system of medicine. It has been shown to be useful in improving learning and memory. Centella asiatica leaf extract treatment enhances neuronal dendritic arborization in hippocampus of growing rodent. Materials and Methods: Swiss albino mice were used for our experiment. Ketamine was administered subcutaneously and Centella-asiatica leaf extract was administered orally. Mice brain collected, grossed, processed and finally stained by Hematoxylin and Eosin (H&amp;E) staining process for viewing cellular and tissue structure detail by pathologists. Results: Focal cellular damage was seen in CA2 and CA4 area of cornu ammonis (CA), expanded cytoplasmic eosinophilia saw in the pyramidal cell layers (PY) of CA2, expanded cytoplasmic eosinophilia found with obliteration of neurifibrilary components (NFE), typical pyramidal cell (NPY) in the CA4, ordinary engineering of dentate granule layers (DG) and hardly any cells were found with diminished size in regards to granule layer cells (GC) in the brain hippocampus of the high ketamine prompted mice. In the mouse brain hippocampus for high ketamine- Centella asiatica summed up cell destruction found in the CA1 to CA4 of CA. Expanded cytoplasmic eosinophilia found in the pyramidal cell layers of CA2 than high dose ketamine group. The vast majority of the pyramidal cells were necrotic (PYN) with annihilation of neurofibrilary components (NFE) in the pyramidal cell layers of CA4. Keywords: Centella asiatica, Ketamine and memory impairment. DOI: 10.7176/ALST/82-02 Publication date: October 31 st 2020

Effect of low-dose ketamine on MACBAR of sevoflurane in laparoscopic cholecystectomy: A randomized controlled trial.

Low-dose ketamine can reduce the minimum alveolar concentration of sevoflurane necessary to block the adrenergic response (MACBAR ) in animals. However, the effects of low-dose ketamine on the sevoflurane MACBAR in patients undergoing laparoscopic surgery are unclear. The aim of this study was to investigate the effects of three different low doses of ketamine on the MACBAR of sevoflurane in patients undergoing laparoscopic cholecystectomy. One hundred patients who underwent laparoscopic cholecystectomy were enrolled. After general anaesthesia induction and tracheal intubation, patients received sevoflurane anaesthesia in combination with a loading dose of saline followed by infusion or a loading dose of 0.5mg/kg ketamine followed by a continuous infusion of 5 (K1 group), 10 (K2 group) and 20μg/kg/min (K3 group). The target concentration of end-tidal sevoflurane was maintained for at least 20minutes before carbon dioxide pneumoperitoneum stimulus. The MACBAR of sevoflurane in each group was determined by using an up-and-down sequential allocation technique. Seventy-one patients completed the study. The values of MACBAR for sevoflurane were 5.3% in the K0 , 4.8% in K1 , 3.3% in K2 and 3.2% in K3 groups. The use of ketamine significantly reduced the MACBAR of sevoflurane compared to sevoflurane alone. The K2 and K3 groups showed significantly lower values of MACBAR than that in the K1 group. However, a higher dose of ketamine in the K3 group did not further reduce the sevoflurane MACBAR . The mean arterial blood pressure (MAP) values before pneumoperitoneum in the K2 and the K3 groups were significantly higher compared to those in the K0 and K1 groups. Compared with the values before pneumoperitoneum, the heart rate and MAP after pneumoperitoneum were significantly increased. Overall, the haemodynamics remained stable during the study period in all groups. A loading dose of 0.5mg/kg ketamine followed by a continuous infusion of 10.0μg/kg/min led to a significant decrease in the MACBAR of sevoflurane in patients undergoing laparoscopic cholecystectomy.

Effects of intraarticular ketamine combined with periarticular bupivacaine on postoperative pain after arthroscopic meniscectomy.

Objectives This study aims to evaluate the effects of two different doses of intraarticular ketamine on visual analog scale (VAS) scores at rest and movement, time to first analgesic requirement, and 24-h morphine consumption in patients undergoing arthroscopic meniscectomy as well as to assess the frequency of postoperative nausea&vomiting, respiratory depression, pruritus, urinary retention, and constipation and to compare the time to discharge.Patients and methods This prospective randomized double- blind study was performed between August 2013 and August 2014 on 75 patients (32 males, 43 females; mean age 46.7±13 years; range, 18 to 75 years) with American Society of Anesthesiologists scores of I-II scheduled for unilateral meniscectomy. Patients were randomized to receive 0.5 mg.kg-1 ketamine (group K1), 1 mg.kg-1 ketamine (group K2) or saline (group S) to a total volume of 20 mL intraarticularly at the end of the surgery. All patients were performed periarticular 10 mL 0.5% bupivacaine infiltration. Visual analog scale at rest and during passive knee movement was used to evaluate pain both preoperatively and at postoperative 0, 30 min, and 1, 2, 4, 6, 12, and 24 h. Time to first analgesic requirement and morphine consumption were recorded.Results Visual analog scale scores at rest and during movement at postoperative 0 were significantly reduced in group K2 compared with group S (p<0.05). The first analgesic requirement time was significantly longer in group K1 (76.9±25.2 min) and group K2 (93.4±26.1 min) than group S (29.3±7.1 min). Morphine consumption was lower in group K2 compared to group K1 and group S at postoperative 30 min, and 1 and 2 h. However, 24-h morphine consumption was similar in all groups.ConclusionIntraarticular injection of 0.5 mg.kg-1 and 1 mg.kg-1 ketamine for postoperative pain management provided similar analgesic efficacy. However, high dose ketamine more noticeably decreased opioid requirement in the early postoperative period.

Aldh2 gene reduces oxidative stress in the bladder by regulating the NF-κB pathway in a mouse model of ketamine-induced cystitis.

Aldehyde dehydrogenase 2 (aldh2) serves an important role in the development of organ injury. Therefore, the present study investigated the effects of aldh2 on the oxidative stress response in a mouse model of ketamine-induced cystitis (KIC). A total of 60 8-week-old male Institute of Cancer Research wild-type (WT) mice and 45 aldh2 knock-out (KO) mice were randomized to receive low-dose ketamine (30 mg/kg), high-dose ketamine (60 mg/kg) or normal saline (controls). At 4, 8 and 12 weeks post-injection, bladder tissues were harvested and used to investigate the protective mechanisms of aldh2 on bladder function. The results demonstrated that aldh2 KO mice exhibited significant weight loss following chronic ketamine injection compared with that in WT mice. Furthermore, ketamine treatment increased the urination rate (P<0.05), pathological score (P<0.05), levels of the oxidative stress product malondialdehyde (P<0.05) in addition to reducing the expression of the anti-oxidative stress enzyme superoxide dismutase (P<0.05) and glutathione-SH (P<0.05). Oxidative stress in aldh2 KO mice was also found to significantly enhance the expression of proteins associated with the NF-κB signaling pathway, which promoted the expression of inducible nitric oxide synthase (P<0.05) and cyclooxygenase-2 (P<0.05) further. Finally, aldh2 KO mice demonstrated higher severity of fibrosis in the submucosal and muscular layers of the bladder. In conclusion, the present study suggests that aldh2 serves a protective role in preventing inflammation and fibrosis in KIC.

Ketamine to treat super-refractory status epilepticus.

To test ketamine infusion efficacy in the treatment of super-refractory status epilepticus (SRSE), we studied patients with SRSE who were treated with ketamine retrospectively. We also studied the effect of high doses of ketamine on brain physiology as reflected by invasive multimodality monitoring (MMM). We studied a consecutive series of 68 patients with SRSE who were admitted between 2009 and 2018, treated with ketamine, and monitored with scalp EEG. Eleven of these patients underwent MMM at the time of ketamine administration. We compared patients who had seizure cessation after ketamine initiation to those who did not. Mean age was 53 ± 18 years and 46% of patients were female. Seizure burden decreased by at least 50% within 24 hours of starting ketamine in 55 (81%) patients, with complete cessation in 43 (63%). Average dose of ketamine infusion was 2.2 ± 1.8 mg/kg/h, with median duration of 2 (1-4) days. Average dose of midazolam was 1.0 ± 0.8 mg/kg/h at the time of ketamine initiation and was started at a median of 0.4 (0.1-1.0) days before ketamine. Using a generalized linear mixed effect model, ketamine was associated with stable mean arterial pressure (odds ratio 1.39, 95% confidence interval 1.38-1.40) and with decreased vasopressor requirements over time. We found no effect on intracranial pressure, cerebral blood flow, or cerebral perfusion pressure. Ketamine treatment was associated with a decrease in seizure burden in patients with SRSE. Our data support the notion that high-dose ketamine infusions are associated with decreased vasopressor requirements without increased intracranial pressure. This study provides Class IV evidence that ketamine decreases seizures in patients with SRSE.

Effects of Intraoperative Ketamine on Post-Operative Recovery in Obstructive Sleep Apnea Patients: A Case-Control Study.

ObjectiveTo evaluate the post-operative outcomes of patients with obstructive sleep apnea (OSA) given intraoperative ketamine.Design: case-control studyA total of 574 patients (287 received ketamine and 287 were matched controls) diagnosed with OSA and body mass index (BMI) > 30 who received general anesthesia were included in this study. Patients given intraoperative ketamine were matched (1:1) with those who did not receive ketamine for age, gender, BMI, ethnicity, anesthesia time, intraoperative fentanyl dose, ketamine dose, and surgery type. A sub-analysis was performed based on the dose of ketamine administered and also on the surgery type. Measured outcomes include post-operative pain scores, post-operative opioid requirements, respiratory status, oxygen use, and duration post-operatively.ResultsIntraoperative ketamine use did not decrease pain scores or post-operative opioid use when compared with the control (no intraoperative ketamine) group. Patients who received high-dose ketamine had significantly higher post-operative pain scores (p=0.048) while in the post-anesthesia care unit (PACU) and required supplemental oxygen for a longer period of time (p = 0.030), pain scores were not significant for patients who underwent orthopedic/spine procedures (p = 0.074), and high-dose ketamine group patients who underwent orthopedic/spine surgery required significantly more opioids in the PACU (p = 0.031). Among patients who received low-dose ketamine, those who underwent head, ear, nose, and throat surgery required significantly more opioids in PACU (p = 0.022).ConclusionsLow-dose intraoperative ketamine did not decrease pain scores or post-operative opioid use significantly and did not improve standard respiratory recovery parameters for OSA patients after surgery. Neither low- nor high-dose ketamine demonstrated the anticipated benefits of low pain scores and reduced post-operative opioid use. These outcomes will differ depending on the surgery type and dose of ketamine used.

Transient Dose-dependent Effects of Ketamine on Neural Oscillatory Activity in Wistar-Kyoto Rats

Ketamine is a promising therapeutic for treatment-resistant depression (TRD) but is associated with an array of short-term psychomimetic side-effects. These disparate drug effects may be elicited through the modulation of neural circuit activity. The purpose of this study was to therefore delineate dose- and time-dependent changes in ketamine-induced neural oscillatory patterns in regions of the brain implicated in depression. Wistar-Kyoto rats were used as a model system to study these aspects of TRD neuropathology whereas Wistar rats were used as a control strain. Animals received a low (10 mg/kg) or high (30 mg/kg) dose of ketamine and temporal changes in neural oscillatory activity recorded from the prefrontal cortex (PFC), cingulate cortex (Cg), and nucleus accumbens (NAc) for ninety minutes. Effects of each dose of ketamine on immobility in the forced swim test were also evaluated. High dose ketamine induced a transient increase in theta power in the PFC and Cg, as well as a dose-dependent increase in gamma power in these regions 10-min, but not 90-min, post-administration. In contrast, only low dose ketamine normalized innate deficits in fast gamma coherence between the NAc-Cg and PFC-Cg, an effect that persisted at 90-min post-injection. These low dose ketamine-induced oscillatory alterations were accompanied by a reduction in immobility time in the forced swim test. These results show that ketamine induces time-dependent effects on neural oscillations at specific frequencies. These drug-induced changes may differentially contribute to the psychomimetic and therapeutic effects of the drug.

Analgesic Effect of Intraoperative Intravenous S-Ketamine in Opioid-Naïve Patients After Major Lumbar Fusion Surgery Is Temporary and Not Dose-Dependent: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Severe pain often accompanies major spine surgery. Opioids are the cornerstone of postoperative pain management but their use can be limited by numerous side effects. Several studies claim that adjuvant treatment with intravenous (IV) ketamine reduces opioid consumption and pain after back surgery. However, the exact role of ketamine for this indication is yet to be elucidated. We compared 2 different doses of S-ketamine with placebo on postoperative analgesic consumption, pain, and adverse events in adult, opioid-naïve patients after lumbar fusion surgery. One hundred ninety-eight opioid-naïve patients undergoing lumbar spinal fusion surgery were recruited to this double-blind trial and randomly assigned into 3 study groups: Group C (placebo) received a preincisional IV bolus of saline (sodium chloride [NaCl] 0.9%) followed by an intraoperative IV infusion of NaCl 0.9%. Both groups K2 and K10 received a preincisional IV bolus of S-ketamine (0.5 mg/kg); in group K2, this was followed by an intraoperative IV infusion of S-ketamine (0.12 mg/kg/h), while in group K10, it was followed by an intraoperative IV infusion of S-ketamine (0.6 mg/kg/h). Postoperative analgesia was achieved by an IV patient-controlled analgesia (IV PCA) device delivering oxycodone. The primary end point was cumulative oxycodone consumption at 48 hours after surgery. The secondary end points included postoperative pain up to 2 years after surgery, adverse events, and level of sedation and confusion in the immediate postoperative period. The median [interquartile range (IQR)] cumulative oxycodone consumption at 48 hours was 154.5 [120] mg for group K2, 160 [109] mg for group K10, and 178.5 [176] mg for group C. The estimated difference was -24 mg between group K2 and group C (97.5% confidence interval [CI], -73.8 to 31.5; P = .170) and -18.5 mg between group K10 and C (97.5% CI, 78.5-29.5; P = .458). There were no significant differences between groups.Postoperative pain scores were significantly lower in both ketamine treatment groups at the fourth postoperative hour but not later during the 2-year study period.The higher ketamine dose was associated with more sedation. Otherwise, differences in the occurrence of adverse events between study groups were nonsignificant. Neither a 0.12 nor a 0.6 mg/kg/h infusion of intraoperative IV S-ketamine was superior to the placebo in reducing oxycodone consumption at 48 hours after lumbar fusion surgery in an opioid-naïve adult study population. Future studies should assess ketamine's feasibility in specific study populations who most benefit from reduced opioid consumption.

Ketamine Affects the Expression of ErbB4 in the Hippocampus and Prefrontal Cortex of Rats.

Schizophrenia is a severe chronic neuropsychiatric disorder, and its exact pathogenesis remains unclear. This study investigated the effect of ketamine on the expression of ErbB4 (considered a schizophrenia candidate gene) in the hippocampus and prefrontal cortex of rats. Rats were randomly divided into four groups: control, low-dose, medium-dose and high-dose groups. The low-dose, medium-dose and high-dose groups were intraperitoneally injected with 15mg/kg, 30mg/kg and 60mg/kg ketamine, respectively, twice a day (9:00 a.m. and 9:00 p.m.); the control group was administered normal saline. The treatment lasted 7days. After treatment, rats were euthanized, and their brain tissues were collected and then analyzed by immunohistochemistry. The results of immunohistochemistry staining demonstrated that the ErbB4 protein was expressed exclusively in the CA3 region of the hippocampus and the Cg1 region of the prefrontal cortex. Ketamine administration significantly decreased the expression of ErbB4 in a dose-dependent manner. The high-dose ketamine treatment was found to be optimal for establishing a rat model for schizophrenia. Ketamine induced symptoms similar to schizophrenia in humans. The ketamine-induced rat model for schizophrenia constructed in this study provides novel insights to better understand the pathogenic mechanisms of schizophrenia and aid in drug discovery.

Ketamine induces immediate and delayed alterations of OCD-like behavior.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by intrusive obsessive thoughts and/or compulsive behaviors. Currently, serotonin reuptake inhibitors (SRIs) provide the only pharmacological monotherapy for OCD, but response rates are insufficient. Ketamine, a noncompetitive NMDA receptor antagonist, was reported to have rapid, sustained therapeutic effects in OCD patients. However, the mechanisms remain unknown. Here, we aimed to provide a platform for investigating mechanisms underlying anti-OCD effects of ketamine treatment by assessing whether ketamine pretreatment could alleviate 5-HT1B receptor (5-HT1BR)-induced OCD-like behavior in mice. We assessed whether acute ketamine (0, 3, 10, 30 mg/kg), administered at two pretreatment time points (30 min, 24 h), would modulate 5-HT1BR-induced OCD-like behavior in mice. Behavioral measures were perseverative hyperlocomotion in the open field and deficits in prepulse inhibition (PPI) induced by acute pharmacological 5-HT1BR challenge. Three milligrams per kilogram of ketamine reduced 5-HT1BR-induced perseverative hyperlocomotion, but not PPI deficits, 24 h postinjection. In contrast, higher doses of ketamine were either ineffective (10 mg/kg) or exacerbated (30 mg/kg) 5-HT1BR-induced perseverative hyperlocomotion 30 min postinjection. At 24 h postinjection, 30 mg/kg ketamine reduced perseverative hyperlocomotion across all groups. Our results suggest that the 5-HT1BR-induced model of OCD-like behavior is sensitive to a low dose of ketamine, a potential fast-acting anti-OCD treatment, and may provide a tool for studying mechanisms underlying the rapid therapeutic effects of ketamine in OCD patients.

Intraperitoneal injection of ketamine enhances apoptosis in urothelium via autophagy in rats

Ketamine abusing is associated with ulcerative cystitis, but the mechanisms remain unclear. This study aimed to investigate the existence of ketamine-induced symptom in a rat model and evaluate the underlining mechanisms. Sprague-Dawley rats were chosen and randomly divided into 12 groups (n = 8), such as the control group, low dose of ketamine (10 mg/kg/day), middle dose of ketamine (30 mg/kg/day) and high dose of ketamine (50 mg/kg/day) groups. The experimental groups were administrated ketamine i.p. daily, whereas the control groups were administrated with saline. After 1, 3, and 6 months of treatment, the bladder tissues were collected. Haematoxylin and eosin (HE) staining and a transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay were used to evaluate the bladder epithelium pathology and urothelial apoptosis, respectively. The protein expression levels of LC3, p62, Beclin1 were assessed by Western blotting. HE staining results of the experimental rats showed the bladder tissue denudation of the urothelial epithelium with edema and congestion compared with the control groups. TUNEL staining showed a significantly higher number of apoptotic cells in experimental groups than in the control groups. The protein LC3 and Beclin1 had significantly higher levels compared with control groups. The protein p62 had lower levels compared with control groups. The expression levels correlated with contraction of ketamine and treatment time. HE staining, TUNEL staining and Western blot results showed dose-dependent, time-dependent autophage in ketamine-treated rats. All the results suggested that autophagy proteins might be involved in inflammatory response in rats.

Neuropsychological Assessment of Learning and Memory in Rats Following Ketamine Exposure during Late Adolescence

With the prevalent issue of drug abuse in society, research regarding the effects of ketamine, a drug frequently abused by youth in club settings, has increased. Despite its potential for misuse, ketamine has demonstrated potential as a fast-acting antidepressant and seems to work well for relieving treatment-resistant depression. However, previous research has shown ketamine use may cause impairments in frontal and medial temporal lobe functioning, leading to problems with memory. While under the influence of ketamine, individuals also display problems with spatial working memory when compared to individuals not dosed with ketamine. The majority of previous research has examined the short-term impact of ketamine use with studies on neurodevelopment largely confined to postnatal exposure. In the present study, the long-term effects on memory caused by repeated ketamine exposure during late adolescence were examined. Rats were used as nonhuman models in order to investigate the cognitive risks resulting from chronic use of ketamine. The results indicated that low-ketamine dosed rats demonstrated significantly better spatial memory recall compared to high-ketamine dosed rats. In addition, high-ketamine dosed rats appeared to struggle more with working memory than the rats in the low-ketamine and control groups. Similarly, both drug groups showed significantly more working memory and reference memory errors than the control group. This indicates that higher doses of ketamine during late adolescence may cause working and spatial memory impairments later in life.

Nifedipine toxicity is exacerbated by acetyl l-carnitine but alleviated by low-dose ketamine in zebrafish in vivo.

Calcium channel blocker (CCB) poisoning is a common and sometimes life-threatening emergency. Our previous studies have shown that acetyl l-carnitine (ALCAR) prevents cardiotoxicity and developmental toxicity induced by verapamil, a CCB used to treat patients with hypertension. Here, we tested whether toxicities of nifedipine, a dihydropyridine CCB used to treat hypertension, can also be mitigated by co-treatment with ALCAR. In the zebrafish embryos at three different developmental stages, nifedipine induced developmental toxicity with pericardial sac edema in a dose-dependent manner, which were surprisingly exacerbated with ALCAR co-treatment. Even with low-dose nifedipine (5μm), when the pericardial sac looked normal, ALCAR co-treatment showed pericardial sac edema. We hypothesized that toxicity by nifedipine, a vasodilator, may be prevented by ketamine, a known vasoconstrictor. Nifedipine toxicity in the embryos was effectively prevented by co-treatment with low (subanesthetic) doses (25-100μm added to the water) of ketamine, although a high dose of ketamine (2mm added to the water) partially prevented the toxicity.As expected of a CCB, nifedipine either in the presence or absence of ketamine-reduced metabolic reactive oxygen species (ROS), a downstream product of calcium signaling, in the rapidly developing digestive system. However, nifedipine induced ROS in the trunk region that showed significantly stunted growth indicating that the tissues under stress potentially produced pathologic ROS. To the best of our knowledge, these studies for the first time show that nifedipine and the dietary supplement ALCAR together induce adverse effects while providing evidence on the therapeutic efficacy of subanesthetic doses of ketamine against nifedipine toxicity in vivo.

Ketamine Infusions for Chronic Pain: A Systematic Review and Meta-analysis of Randomized Controlled Trials

IV ketamine is widely used to treat patients with chronic pain, yet the long-term impact remains uncertain. We synthesized evidence from randomized control trials to investigate the effectiveness of IV ketamine infusions for pain relief in chronic conditions and to determine whether any pain classifications or treatment regimens are associated with greater benefit. We searched Medline, Embase, and Google Scholar, as well as the clinicaltrials.gov website from inception through December 16, 2017 for randomized control trials comparing IV ketamine to placebo infusions for chronic pain that reported outcomes for ≥48 hours after the intervention. Three authors independently screened the studies, pooled the data, and appraised risk of bias. Random-effects model was used to calculate weighted mean differences for pain scores and secondary outcomes. Our primary outcome was the lowest recorded pain score ≥48 hours after cessation of treatment. Secondary outcomes included responder rate and adverse effects. Among 696 studies assessed for eligibility, 7 met inclusion criteria. All studies except one were at high risk of bias. These studies randomly assigned 211 patients with neuropathic (n = 2), mixed (n = 2), and nonneuropathic (nociplastic or nociceptive) (n = 3) pain. Three studies reported significant analgesic benefit favoring ketamine, with the meta-analysis revealing a small effect up to 2 weeks after the infusion (mean difference in pain scores, -1.83 points on a 0-10 numerical rating scale; 95% CI, -2.35 to -1.31 points; P < .0001). In the 3 studies that reported responder rates, the proportion with a positive outcome was greater in the ketamine than in the placebo group (51.3% vs 19.4%; relative risk, 2.43; 95% CI, 1.10-5.40; P = .029; I = 0.0%). No differences were noted based on pain classification or condition. Compared to low-dose ketamine studies and investigations that evaluated non-complex regional pain syndrome conditions, a small but nonsignificant greater reduction in pain scores was found among studies that either utilized high-dose ketamine therapy (P = .213) or enrolled complex regional pain syndrome patients (P = .079). Evidence suggests that IV ketamine provides significant short-term analgesic benefit in patients with refractory chronic pain, with some evidence of a dose-response relationship. Larger, multicenter studies with longer follow-ups are needed to better select patients and determine the optimal treatment protocol.

Sex-dependent changes in ketamine-induced locomotor activity and ketamine pharmacokinetics in preweanling, adolescent, and adult rats

Although ketamine has long been known to increase locomotor activity, only recently was it realized that this behavioral effect varies according to both sex and age. The purpose of the present study was threefold: first, to measure the locomotor activating effects of ketamine in male and female rats across early ontogeny and into adulthood; second, to assess ketamine and norketamine pharmacokinetics in the dorsal striatum and hippocampus of the same age groups; and, third, to use curvilinear regression to determine the relationship between locomotor activity and dorsal striatal concentrations of ketamine and norketamine. A high dose of ketamine (80 mg/kg, i.p.) was administered in order to examine the complete cycle of locomotor responsiveness across a 280-min testing session. In separate groups of rats, the dorsal striata and hippocampi were removed at 10 time points (0–360 min) after ketamine administration and samples were assayed for ketamine, norketamine, and dopamine using HPLC. In female rats, ketamine produced high levels of locomotor activity that varied only slightly among age groups. Male preweanling rats responded like females, but adolescent and adult male rats exhibited lesser amounts of ketamine-induced locomotor activity. Ketamine and norketamine pharmacokinetics, especially peak values and area under the curve, generally mirrored age- and sex-dependent differences in locomotor activity. Among male rats and younger female rats, dorsal striatal ketamine and norketamine levels accounted for a large proportion of the variance in locomotor activity. In adult female rats, however, an additional factor, perhaps involving other ketamine and norketamine metabolites, was influencing locomotor activity.

Hiperglikemia Tidak Menyebabkan Perubahan Bobot Badan dan Jumlah Neuron Mienterik Nitrergik Usus Halus Tikus Wistar (Rattus norvegicus)

Digestive dysfunction is a common symptom of diabetes. Diabetes can lead to the loss of enteric neurons as well as nerve dysfunction and gastrointestinal complications. There has been no complete report of mienteric nitrergic of small intestines on hyperglycaemia condition, so the purpose of this study was to assess changes of nitrergic neural profile of small intestines on hyperglycemic Wistar strain rats (Rattus norvegicus). Twelve rats were adapted for 3 days, then they were randomly divided into 3 groups namely group I (K-1, as control), group II (K-2), and group III (K-3). Before treatment all rats were fasted for 12 hours, rats K-1 were induced with 1.0 ml of buffer citrate single peritoneal dose; rats K-2 were induced with 40 mg streptozotocin (STZ)/ kg body weight of single peritoneal dose; and rats K-3 were induced with 45 mg STZ /kg body weight of single peritoneal dose. On the 1st and 5th days after STZ induction, blood was collected through the coccigea vein to measure blood glucose levels and weigh the weight. On the day 5th the rats were uthanated with a high dose of ketamine, dissected and taken small intestines (duodenum, jejunum, and ileum) for staining with Nicotinamide Adenine Dinucleotide Phosphate-diaphorase (NADPH-d). Morphometric changes of nitrergic neurons of the small intestine segments were observed. The results showed that on the 5th day increased blood glucose levels of the K-2 and K-3 groups were significantly higher than K-1 (P &lt;0.01). The weight of three groups did not show any significant improvement difference (P&gt; 0.05). The number of neurons in the duodenum, jejunum and ileum of K-2 group increased higher than that of K-1 and K-3 groups. These results indicate that in hyperglycaemic states, the number of nitrergic neurons increases (K-2 group), and there is a significant decrease in the number of neurons (group K-3) compared with K-1 and K-2 groups (P &lt;0.01). The results of this study concluded, that the STZ induction treatment causes hyperglycemia. Hyperglycemia does not affect to the body weight and the number of nitrergic neurons of small intestines in Wistar strain rats (Rattus norvegicus).

P.1.15 Impaired diacylglycerol kinase eta function in bipolar patient-derived human induced pluripotent stem cells

Although ketamine has long been known to increase locomotor activity, only recently was it realized that this behavioral effect varies according to both sex and age. The purpose of the present study was threefold: first, to measure the locomotor activating effects of ketamine in male and female rats across early ontogeny and into adulthood; second, to assess ketamine and norketamine pharmacokinetics in the dorsal striatum and hippocampus of the same age groups; and, third, to use curvilinear regression to determine the relationship between locomotor activity and dorsal striatal concentrations of ketamine and norketamine. A high dose of ketamine (80 mg/kg, i.p.) was administered in order to examine the complete cycle of locomotor responsiveness across a 280-min testing session. In separate groups of rats, the dorsal striata and hippocampi were removed at 10 time points (0–360 min) after ketamine administration and samples were assayed for ketamine, norketamine, and dopamine using HPLC. In female rats, ketamine produced high levels of locomotor activity that varied only slightly among age groups. Male preweanling rats responded like females, but adolescent and adult male rats exhibited lesser amounts of ketamine-induced locomotor activity. Ketamine and norketamine pharmacokinetics, especially peak values and area under the curve, generally mirrored age- and sex-dependent differences in locomotor activity. Among male rats and younger female rats, dorsal striatal ketamine and norketamine levels accounted for a large proportion of the variance in locomotor activity. In adult female rats, however, an additional factor, perhaps involving other ketamine and norketamine metabolites, was influencing locomotor activity.