Ketamine for chronic pain: risks and benefits.

Science.gov (United States)

Niesters, Marieke; Martini, Christian; Dahan, Albert

2014-02-01

The anaesthetic ketamine is used to treat various chronic pain syndromes, especially those that have a neuropathic component. Low dose ketamine produces strong analgesia in neuropathic pain states, presumably by inhibition of the N-methyl-D-aspartate receptor although other mechanisms are possibly involved, including enhancement of descending inhibition and anti-inflammatory effects at central sites. Current data on short term infusions indicate that ketamine produces potent analgesia during administration only, while three studies on the effect of prolonged infusion (4-14 days) show long-term analgesic effects up to 3 months following infusion. The side effects of ketamine noted in clinical studies include psychedelic symptoms (hallucinations, memory defects, panic attacks), nausea/vomiting, somnolence, cardiovascular stimulation and, in a minority of patients, hepatoxicity. The recreational use of ketamine is increasing and comes with a variety of additional risks ranging from bladder and renal complications to persistent psychotypical behaviour and memory defects. Blind extrapolation of these risks to clinical patients is difficult because of the variable, high and recurrent exposure to the drug in ketamine abusers and the high frequency of abuse of other illicit substances in this population. In clinical settings, ketamine is well tolerated, especially when benzodiazepines are used to tame the psychotropic side effects. Irrespective, close monitoring of patients receiving ketamine is mandatory, particularly aimed at CNS, haemodynamic, renal and hepatic symptoms as well as abuse. Further research is required to assess whether the benefits outweigh the risks and costs. Until definite proof is obtained ketamine administration should be restricted to patients with therapy-resistant severe neuropathic pain. © 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Ketamine-induced apoptosis in cultured rat cortical neurons

International Nuclear Information System (INIS)

Takadera, Tsuneo; Ishida, Akira; Ohyashiki, Takao

2006-01-01

Recent data suggest that anesthetic drugs cause neurodegeneration during development. Ketamine is frequently used in infants and toddlers for elective surgeries. The purpose of this study is to determine whether glycogen synthase kinase-3 (GSK-3) is involved in ketamine-induced apoptosis. Ketamine increased apoptotic cell death with morphological changes which were characterized by cell shrinkage, nuclear condensation or fragmentation. In addition, insulin growth factor-1 completely blocked the ketamine-induced apoptotic cell death. Ketamine decreased Akt phosphorylation. GSK-3 is known as a downstream target of Akt. The selective inhibitors of GSK-3 prevented the ketamine-induced apoptosis. Moreover, caspase-3 activation was accompanied by the ketamine-induced cell death and inhibited by the GSK-3 inhibitors. These results suggest that activation of GSK-3 is involved in ketamine-induced apoptosis in rat cortical neurons

Inhibition of the L-arginine-nitric oxide pathway mediates the antidepressant effects of ketamine in rats in the forced swimming test.

Science.gov (United States)

Zhang, Guang-Fen; Wang, Nan; Shi, Jin-Yun; Xu, Shi-Xia; Li, Xiao-Min; Ji, Mu-Huo; Zuo, Zhi-Yi; Zhou, Zhi-Qiang; Yang, Jian-Jun

2013-09-01

Converging evidence shows that the acute administration of a sub-anaesthetic dose ketamine produces fast-acting and robust antidepressant properties in patients suffering from major depressive disorder. However, the underlying mechanisms have not been fully elucidated. The present study aimed to investigate the role of the L-arginine-nitric oxide pathway in the antidepressant effects of ketamine in rats performing the forced swimming test (FST). Ketamine (10 mg/kg) significantly decreased immobility times in the FST and the activities of total nitric oxide synthases (T-NOS), inducible NOS (iNOS), and endothelial NOS (eNOS) in the rat hippocampus. Interestingly, the plasma activities of T-NOS, iNOS, and eNOS increased after administration of ketamine. Furthermore, the activities of neuronal NOS (nNOS) did not change significantly in either the hippocampus or plasma after ketamine administration. The antidepressant effects of ketamine were prevented by pre-treatment with l-arginine (750 mg/kg). Pre-treatment with the NOS inhibitor L-NG-nitroarginine methyl ester at a sub-antidepressant dose of 50 mg/kg and ketamine at a sub-antidepressant dose of 3 mg/kg reduced immobility time in the FST compared to treatment with either drug alone. None of the drugs affected crossing and rearing scores in the open field test. These results suggest that the L-arginine-nitric oxide pathway is involved in the antidepressant effects of ketamine observed in rats in the FST and this involvement is characterised by the inhibition of brain T-NOS, iNOS, and eNOS activities. Copyright © 2013 Elsevier Inc. All rights reserved.

Suppressive effects of ketamine on macrophage functions

International Nuclear Information System (INIS)

Chang Yi; Chen, T.-L.; Sheu, J.-R.; Chen, R.-M.

2005-01-01

Ketamine is an intravenous anesthetic agent. Clinically, induction of anesthesia with ketamine can cause immunosuppression. Macrophages play important roles in host defense. In this study, we attempted to evaluate the effects of ketamine on macrophage functions and its possible mechanism using mouse macrophage-like Raw 264.7 cells as the experimental model. Exposure of macrophages to 10 and 100 μM ketamine, which correspond to 0.1 and 1 times the clinically relevant concentration, for 1, 6, and 24 h had no effect on cell viability or lactate dehydrogenase release. When the administered concentration reached 1000 μM, ketamine caused a release of lactate dehydrogenase and cell death. Ketamine, at 10 and 100 μM, did not affect the chemotactic activity of macrophages. Administration of 1000 μM ketamine in macrophages resulted in a decrease in cell migration. Treatment of macrophages with ketamine reduced phagocytic activities. The oxidative ability of macrophages was suppressed by ketamine. Treatment with lipopolysaccharide induced TNF-α, IL-1β, and IL-6 mRNA in macrophages. Administration of ketamine alone did not influence TNF-α, IL-1β, or IL-6 mRNA production. Meanwhile, cotreatment with ketamine and lipopolysaccharide significantly inhibited lipopolysaccharide-induced TNF-α, IL-1β, and IL-6 mRNA levels. Exposure to ketamine led to a decrease in the mitochondrial membrane potential. However, the activity of mitochondrial complex I NADH dehydrogenase was not affected by ketamine. This study shows that a clinically relevant concentration of ketamine (100 μM) can suppress macrophage function of phagocytosis, its oxidative ability, and inflammatory cytokine production possibly via reduction of the mitochondrial membrane potential instead of direct cellular toxicity

Effects of Ketamine and Ketamine Metabolites on Evoked Striatal Dopamine Release, Dopamine Receptors, and Monoamine Transporters

Science.gov (United States)

Can, Adem; Zanos, Panos; Moaddel, Ruin; Kang, Hye Jin; Dossou, Katinia S. S.; Wainer, Irving W.; Cheer, Joseph F.; Frost, Douglas O.; Huang, Xi-Ping

2016-01-01

Following administration at subanesthetic doses, (R,S)-ketamine (ketamine) induces rapid and robust relief from symptoms of depression in treatment-refractory depressed patients. Previous studies suggest that ketamine’s antidepressant properties involve enhancement of dopamine (DA) neurotransmission. Ketamine is rapidly metabolized to (2S,6S)- and (2R,6R)-hydroxynorketamine (HNK), which have antidepressant actions independent of N-methyl-d-aspartate glutamate receptor inhibition. These antidepressant actions of (2S,6S;2R,6R)-HNK, or other metabolites, as well as ketamine’s side effects, including abuse potential, may be related to direct effects on components of the dopaminergic (DAergic) system. Here, brain and blood distribution/clearance and pharmacodynamic analyses at DA receptors (D1–D5) and the DA, norepinephrine, and serotonin transporters were assessed for ketamine and its major metabolites (norketamine, dehydronorketamine, and HNKs). Additionally, we measured electrically evoked mesolimbic DA release and decay using fast-scan cyclic voltammetry following acute administration of subanesthetic doses of ketamine (2, 10, and 50 mg/kg, i.p.). Following ketamine injection, ketamine, norketamine, and multiple hydroxynorketamines were detected in the plasma and brain of mice. Dehydronorketamine was detectable in plasma, but concentrations were below detectable limits in the brain. Ketamine did not alter the magnitude or kinetics of evoked DA release in the nucleus accumbens in anesthetized mice. Neither ketamine’s enantiomers nor its metabolites had affinity for DA receptors or the DA, noradrenaline, and serotonin transporters (up to 10 μM). These results suggest that neither the side effects nor antidepressant actions of ketamine or ketamine metabolites are associated with direct effects on mesolimbic DAergic neurotransmission. Previously observed in vivo changes in DAergic neurotransmission following ketamine administration are likely indirect. PMID

Peripheral lidocaine, but not ketamine inhibit capsaicin-induced hyperalgesia in humans

DEFF Research Database (Denmark)

Gottrup, Hanne; Bach, Flemming Winther; Arendt-Nielsen, Lars

2000-01-01

We examined the effect of the subcutaneous infiltration of ketamine, lidocaine and saline before injury on capsaicin-induced pain and hyperalgesia. Twelve healthy volunteers participated in two separate, randomized, double-blind, placebo-controlled crossover experiments. In experiment 1, 100...... micrograms capsaicin was injected intradermally in one volar forearm 10 min after the skin had been pretreated with lidocaine 20.0 mg in 2.0 ml or 0.9% saline 2.0 ml at the capsaicin injection site. In experiment 2, a similar capsaicin test was given 10 min after the skin had been pretreated with ketamine 5...... and brush stimuli, and areas of brush-evoked and punctate-evoked hyperalgesia. Lidocaine reduced all measures compared with placebo (P ketamine failed to change any measures. Pain scores and areas of hyperalgesia were not affected when the contralateral site was infiltrated with ketamine...

Inhibition of a Descending Prefrontal Circuit Prevents Ketamine-Induced Stress Resilience in Females

DEFF Research Database (Denmark)

Dolzani, S. D.; Baratta, M. V.; Moss, J. M.

2018-01-01

. The NMDA receptor antagonist ketamine has recently emerged as a prophylactic capable of preventing neurochemical and behavioral outcomes of a future stressor. Despite promising results of preclinical studies performed in male rats, the effects of proactive ketamine in female rats remains unknown....... This is alarming given that stress-related disorders affect females at nearly twice the rate of males. Here we explore the prophylactic effects of ketamine on stress-induced anxiety-like behavior and the neural circuit-level processes that mediate these effects in female rats. Ketamine given one week prior...... to an uncontrollable stressor (inescapable tailshock; IS) reduced typical stress-induced activation of the serotonergic (5-HT) dorsal raphe nucleus (DRN) and eliminated DRN-dependent juvenile social exploration (JSE) deficits 24 h after the stressor. Proactive ketamine altered prelimbic cortex (PL) neural ensembles so...

Preliminary evidence that ketamine inhibits spreading depolarizations in acute human brain injury

DEFF Research Database (Denmark)

Sakowitz, Oliver W; Kiening, Karl L; Krajewski, Kara L

2009-01-01

by the noncompetitive N-methyl-d-aspartate receptor antagonist ketamine. This restored electrocorticographic activity. CONCLUSIONS: These anecdotal electrocorticographic findings suggest that ketamine has an inhibitory effect on spreading depolarizations in humans. This is of potential interest for future...

Ketamine

Science.gov (United States)

... Staying Safe Videos for Educators Search English Español Ketamine KidsHealth / For Teens / Ketamine Print en español Ketamina What It Is: Ketamine hydrochloride is a quick-acting anesthetic that is ...

Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

Science.gov (United States)

Dolzani, Samuel D.; Tilden, Scott; Christianson, John P.; Kubala, Kenneth H.; Bartholomay, Kristi; Sperr, Katherine; Ciancio, Nicholas; Watkins, Linda R.; Maier, Steven F.

2016-01-01

Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection. SIGNIFICANCE STATEMENT The reported data show that systemic ketamine, given up to 2 weeks before a stressor, blunts behavioral and neurochemical effects of the stressor. The study also advances understanding of the mechanisms involved and suggests that ketamine acts at the prelimbic cortex to sensitize neurons that project to and inhibit the DRN. PMID:26740657

Effects of ketamine on glucose uptake by glucose transporter type 3 expressed in Xenopus oocytes: The role of protein kinase C

Energy Technology Data Exchange (ETDEWEB)

Tomioka, Shigemasa, E-mail: tomioka@dent.tokushima-u.ac.jp [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Kaneko, Miyuki [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Satomura, Kazuhito [First Department of Oral and Maxillofacial Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan); Mikyu, Tomiko; Nakajo, Nobuyoshi [Department of Dental Anesthesiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Kuramoto-cho 18-15, Tokushima City, Tokushima 770-8504 (Japan)

2009-10-09

We investigated the effects of ketamine on the type 3 facilitative glucose transporter (GLUT3), which plays a major role in glucose transport across the plasma membrane of neurons. Human-cloned GLUT3 was expressed in Xenopus oocytes by injection of GLUT3 mRNA. GLUT3-mediated glucose uptake was examined by measuring oocyte radioactivity following incubation with 2-deoxy-D-[1,2-{sup 3}H]glucose. While ketamine and S(+)-ketamine significantly increased GLUT3-mediated glucose uptake, this effect was biphasic such that higher concentrations of ketamine inhibited glucose uptake. Ketamine (10 {mu}M) significantly increased V{sub max} but not K{sub m} of GLUT3 for 2-deoxy-D-glucose. Although staurosporine (a protein kinase C inhibitor) increased glucose uptake, no additive or synergistic interactions were observed between staurosporine and racemic ketamine or S(+)-ketamine. Treatment with ketamine or S(+)-ketamine partially prevented GLUT3 inhibition by the protein kinase C activator phorbol-12-myrisate-13-acetate. Our results indicate that ketamine increases GLUT3 activity at clinically relevant doses through a mechanism involving PKC inhibition.

Effects of ketamine on glucose uptake by glucose transporter type 3 expressed in Xenopus oocytes: The role of protein kinase C

International Nuclear Information System (INIS)

Tomioka, Shigemasa; Kaneko, Miyuki; Satomura, Kazuhito; Mikyu, Tomiko; Nakajo, Nobuyoshi

2009-01-01

We investigated the effects of ketamine on the type 3 facilitative glucose transporter (GLUT3), which plays a major role in glucose transport across the plasma membrane of neurons. Human-cloned GLUT3 was expressed in Xenopus oocytes by injection of GLUT3 mRNA. GLUT3-mediated glucose uptake was examined by measuring oocyte radioactivity following incubation with 2-deoxy-D-[1,2- 3 H]glucose. While ketamine and S(+)-ketamine significantly increased GLUT3-mediated glucose uptake, this effect was biphasic such that higher concentrations of ketamine inhibited glucose uptake. Ketamine (10 μM) significantly increased V max but not K m of GLUT3 for 2-deoxy-D-glucose. Although staurosporine (a protein kinase C inhibitor) increased glucose uptake, no additive or synergistic interactions were observed between staurosporine and racemic ketamine or S(+)-ketamine. Treatment with ketamine or S(+)-ketamine partially prevented GLUT3 inhibition by the protein kinase C activator phorbol-12-myrisate-13-acetate. Our results indicate that ketamine increases GLUT3 activity at clinically relevant doses through a mechanism involving PKC inhibition.

Anesthetic efficacy of ketamine-diazepam, ketamine-xylazine, and ketamine-acepromazine in Caspian Pond turtles (Mauremys caspica).

Science.gov (United States)

Adel, Milad; Sadegh, Amin Bigham; Arizza, Vincenzo; Abbasi, Hossein; Inguglia, Luigi; Saravi, Hasan Nasrollahzadeh

2017-01-01

The objective of this study was to assess the efficacy of different anesthetic drug combinations on the Caspian Pond turtles ( Mauremys caspica ). Three groups of the Caspian Pond turtles ( n = 6) were anesthetized with three different drug combinations. Initially, a pilot study was conducted to determine the best drug doses for the anesthetization of the turtles, and according to these results, ketamine-diazepam (120 mg/kg ketamine hydrochloride [5%] and 2 mg/kg diazepam [5%]), ketamine-acepromazine (120 mg/kg ketamine hydrochloride [5%] and 1 mg/kg acepromazine [1%]), and ketamine-xylazine (120 mg/kg ketamine hydrochloride [5%] and 1 mg/kg xylazine [2%]) were injected intramuscularly. The onset times of anesthetization and the recovery time were measured. Statistical analysis of the data was performed using one-way analysis of variance followed by t -tests, and P turtles, respectively, compared to that obtained with the ketamine-acepromazine combination and 64% (male turtles) and 50% (female turtles) shorter than that obtained with the ketamine-xylazine combination. Further, the recovery time, in male turtles, was 17% shorter in animals treated with the first drug combination than those treated with the ketamine-acepromazine combination and 37% shorter than those treated with the ketamine-xylazine combination. The recovery time, in female turtles, did not seem to be significantly different among treatments. The study showed that the ketamine-diazepam drug combination is the anesthetic combination with the fastest onset time and shortest recovery time.

R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects

Science.gov (United States)

Yang, C; Shirayama, Y; Zhang, J-c; Ren, Q; Yao, W; Ma, M; Dong, C; Hashimoto, K

2015-01-01

Although the efficacy of racemate ketamine, a rapid onset and sustained antidepressant, for patients with treatment-resistant depression was a serendipitous finding, clinical use of ketamine is limited, due to psychotomimetic side effects and abuse liability. Behavioral and side-effect evaluation tests were applied to compare the two stereoisomers of ketamine. To elucidate their potential therapeutic mechanisms, we examined the effects of these stereoisomers on brain-derived neurotrophic factor (BDNF)–TrkB signaling, and synaptogenesis in selected brain regions. In the social defeat stress and learned helplessness models of depression, R-ketamine showed a greater potency and longer-lasting antidepressant effect than S-ketamine (esketamine). Furthermore, R-ketamine induced a more potent beneficial effect on decreased dendritic spine density, BDNF–TrkB signaling and synaptogenesis in the prefrontal cortex (PFC), CA3 and dentate gyrus (DG) of the hippocampus from depressed mice compared with S-ketamine. However, neither stereoisomer affected these alterations in the nucleus accumbens of depressed mice. In behavioral tests for side effects, S-ketamine, but not R-ketamine, precipitated behavioral abnormalities, such as hyperlocomotion, prepulse inhibition deficits and rewarding effects. In addition, a single dose of S-ketamine, but not R-ketamine, caused a loss of parvalbumin (PV)-positive cells in the prelimbic region of the medial PFC and DG. These findings suggest that, unlike S-ketamine, R-ketamine can elicit a sustained antidepressant effect, mediated by increased BDNF–TrkB signaling and synaptogenesis in the PFC, DG and CA3. R-ketamine appears to be a potent, long-lasting and safe antidepressant, relative to S-ketamine, as R-ketamine appears to be free of psychotomimetic side effects and abuse liability. PMID:26327690

Oral Ketamine in the Palliative Care Setting: A Review of the Literature and Case Report of a Patient With Neurofibromatosis Type 1 and Glomus Tumor-Associated Complex Regional Pain Syndrome

Science.gov (United States)

Soto, Eliezer; Stewart, Douglas R.; Mannes, Andrew J.; Ruppert, Sarah L.; Baker, Karen; Zlott, Daniel; Handel, Daniel; Berger, Ann M.

2014-01-01

Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be effective not only for its anesthetic properties but also for the analgesic and opiate-sparing effects. However, data on efficacy and safety of oral ketamine for the treatment of neuropathic or cancer pain syndromes is limited with most of the evidence based on small clinical trials and anecdotal experiences. In this review, we will analyze the clinical data on oral ketamine in the palliative care setting. After an extensive search using five major databases, a total of 19 relevant articles were included. No official clinical guidelines for the use of oral ketamine in this patient population were found. Studies on oral ketamine for cancer and neuropathic pain have shown mixed results which could be partially due to significant differences in hepatic metabolism. In addition, we will include a case report of a 38-year-old female with neurofibromatosis type 1 (NF1) with history of chronic, severe pain in her fingertips secondary to multiple glomus tumors which evolved into CRPS resistant to multiple therapies but responsive to oral ketamine. Based on our experience with oral ketamine, this drug should be administered after an intravenous trial to monitor response and side effects in patients with an adequate functional status. However, patients in the palliative care and hospice setting, especially the one at the end of their lives, may also benefit from oral ketamine even if an intravenous trial is not feasible. PMID:21803784

Administration of Ketamine Causes Autophagy and Apoptosis in the Rat Fetal Hippocampus and in PC12 Cells

Directory of Open Access Journals (Sweden)

Xinran Li

2018-02-01

Full Text Available Drug abuse during pregnancy is a serious problem. Like alcohol, anticonvulsants, sedatives, and anesthetics, such as ketamine, can pass through the placental barrier and affect the growing fetus. However, the mechanism by which ketamine causes damage to fetal rats is not well understood. Therefore, in this study, we anesthetized pregnant rats with ketamine and evaluated the Total Antioxidant Capacity (T-AOC, Reactive Oxygen Species (ROS, and Malondialdehyde (MDA. Moreover, we determined changes in the levels of Cleaved-Caspase-3 (C-Caspase-3, Beclin-1, B-cell lymphoma-2 (Bcl-2, Bcl-2 Associated X Protein (Bax, Autophagy-related gene 4 (Atg4, Atg5, p62 (SQSTM1, and marker of autophagy Light Chain 3 (LC3. In addition, we cultured PC12 cells in vitro to determine the relationship between ROS, autophagy, and apoptosis following ketamine treatment. The results showed that ketamine induced changes in autophagy- and apoptosis-related proteins, reduced T-AOC, and generated excessive levels of ROS and MDA. In vitro experiments showed similar results, indicating that apoptosis levels can be inhibited by 3-MA. We also found that autophagy and apoptosis can be inhibited by N-acetyl-L-cysteine (Nac. Thus, anesthesia with ketamine in pregnant rats may increase the rate of autophagy and apoptosis in the fetal hippocampus and the mechanism may be through inhibition of antioxidant activity and ROS accumulation.

Dopamine Attenuates Ketamine-Induced Neuronal Apoptosis in the Developing Rat Retina Independent of Early Synchronized Spontaneous Network Activity.

Science.gov (United States)

Dong, Jing; Gao, Lingqi; Han, Junde; Zhang, Junjie; Zheng, Jijian

2017-07-01

Deprivation of spontaneous rhythmic electrical activity in early development by anesthesia administration, among other interventions, induces neuronal apoptosis. However, it is unclear whether enhancement of neuronal electrical activity attenuates neuronal apoptosis in either normal development or after anesthesia exposure. The present study investigated the effects of dopamine, an enhancer of spontaneous rhythmic electrical activity, on ketamine-induced neuronal apoptosis in the developing rat retina. TUNEL and immunohistochemical assays indicated that ketamine time- and dose-dependently aggravated physiological and ketamine-induced apoptosis and inhibited early-synchronized spontaneous network activity. Dopamine administration reversed ketamine-induced neuronal apoptosis, but did not reverse the inhibitory effects of ketamine on early synchronized spontaneous network activity despite enhancing it in controls. Blockade of D1, D2, and A2A receptors and inhibition of cAMP/PKA signaling partially antagonized the protective effect of dopamine against ketamine-induced apoptosis. Together, these data indicate that dopamine attenuates ketamine-induced neuronal apoptosis in the developing rat retina by activating the D1, D2, and A2A receptors, and upregulating cAMP/PKA signaling, rather than through modulation of early synchronized spontaneous network activity.

Chronic postthoracotomy pain and perioperative ketamine infusion.

Science.gov (United States)

Hu, Jie; Liao, Qin; Zhang, Fan; Tong, Jianbin; Ouyang, Wen

2014-06-01

The objectives of this study were to investigate whether continuous intravenous ketamine during the first 72 hours after thoracotomy could reduce the incidence and intensity of chronic postthoracotomy pain (CPTP) and to define the incidence and risk factors of CPTP. Seventy-eight patients receiving thoracotomy for lung tumor (benign or malignant) were randomly divided into two groups: ketamine group (n = 31) and control groups (n = 47). Patients in the ketamine group received intravenous ketamine 1 mg/kg before incision, followed by 2 μg/kg/minute infusion for 72 hours plus sufentanil patient-controlled intravenous analgesia after thoracotomy. Patients in the control group received intravenous a 0.9% normal saline and infusion plus sufentanil patient-controlled intravenous analgesia. The solutions patients received were blinded. The numerical rating scale (NRS) pain scores and the incidence and risk factors of CPTP were recorded during the first 6 months after surgery. Compared with control group, the incidence of chronic pain in the ketamine group did not decrease at 2 months (χ(2) = 1.599, P = .206) and 6 months (χ(2) = 0.368, P = .544) after surgery. Postoperative pain scores in the ketamine group were not significantly different from those of the control group patients at 2 months (U = 677.5, P = .593) and 6 months (U = 690.5, P = .680). The incidence of CPTP was 78.2% (61/78) at 2 months and 53.8% (42/78) at 6 months after surgery. Retractor used time (OR = 5.811, P = .002), inadequate acute pain control (NRS ≥ 5) (OR = 5.425, P = .048), and chemotherapy (OR = 3.784, P = .056) were independent risk factors for chronic postthoracotomy pain. The authors conclude that continuous intravenous ketamine (2 μg/kg/min) during the first 72 hours after thoracotomy was not beneficial to prevent chronic postthoracotomy pain. The independent risk factors for chronic postthoracotomy pain were retractor used time, inadequate acute pain control, and chemotherapy.

Ketamine and international regulations.

Science.gov (United States)

Liao, Yanhui; Tang, Yi-Lang; Hao, Wei

2017-09-01

Ketamine is an anesthetic commonly used in low-income countries and has recently been shown to be effective for treatment-resistant depression. However, the illicit manufacturing, trafficking, and nonmedical use of ketamine are increasing globally, and its illicit use poses major public health challenges in many countries. To review the nonmedical use of ketamine in selected countries and its regulatory control. We conducted a review of literature identified from searches of the China National Knowledge Infrastructure (CNKI) (1979-2016) and PubMed databases, supplemented by additional references identified by the authors. Special attention was given to the regulation of ketamine. Illicit manufacturing, trafficking, and use of ketamine appear to have begun on a large scale in several Asian nations, and it has subsequently spread to other regions. Regulations governing availability of ketamine vary across countries, but there is a clear trend toward tighter regulations. As nonmedical use of ketamine and its harmful consequences have worsened globally, stricter controls are necessary. Appropriate regulation of ketamine is important for international efforts to control ketamine's cross-border trafficking and its nonmedical use.

Xylazine-ketamine immobilization and propofol anesthesia for surgical excision of sebaceous adenoma in a jaguar (Panthera onca

Directory of Open Access Journals (Sweden)

M. Bharathidasan

2014-11-01

Full Text Available Aim: A captive male jaguar (Panthera onca was anaesthetized for surgical excision of a tumor at the left belly fold under xylazine-ketamine immobilization and propofol anesthesia. The objective was to assess the dose of xylazine and ketamine required to abolish ear flick reflex for safe approach when the jaguar was under chemical immobilization and efficacy of propofol induced anesthesia. Materials and Methods: A male jaguar (P. onca aged 14 years and weighing approximately 90 kg was subjected to chemical immobilization using a combination of xylazine and ketamine using a blow pipe. The jaguar was approached after the absence of ear flick reflex and transported to zoo Operation Theater. Propofol was administered intravenously to induce and maintain anesthesia. The tumor was excised using thermocautery and subjected to histopathology. Results: Ear flick reflex was stimulated at 5 and 10 min after immobilization and observed shaking of head and movement of fore limb following administration of xylazine and ketamine. Dose of xylazine and ketamine required for chemical immobilization, characterized by absence of ear flick reflex was 1.0 and 3.5 mg/kg body weight respectively, and was achieved in 13 min. The surgical plane of anesthesia was maintained for 11 min following administration of propofol at a dose of 2 mg/kg body weight intravenously. The jaguar recovered in 41 min following surgery. The excised tumor was confirmed as sebaceous adenoma on histopathological examination. The animal recovered uneventfully, and no recurrence of the tumor was noticed in 3 months follow-up period. Conclusion: The total dose xylazine and ketamine required for chemical immobilization with absence of ear flick reflex was 1.0 and 3.5 mg/kg body weight respectively. Further, administration of propofol intravenously, at a dose of 2 mg/kg maintained anesthesia for 11 min. Histopathological examination of the excised tumor at the belly fold was confirmed as sebaceous

N,N-dimethylglycine differentially modulates psychotomimetic and antidepressant-like effects of ketamine in mice.

Science.gov (United States)

Lin, Jen-Cheng; Chan, Ming-Huan; Lee, Mei-Yi; Chen, Yi-Chyan; Chen, Hwei-Hsien

2016-11-03

Ketamine, a dissociative anesthetic, produces rapid and sustained antidepressant effects at subanesthtic doses. However, it still inevitably induces psychotomimetic side effects. N,N-dimethylglycine (DMG) is a derivative of the amino acid glycine and is used as a dietary supplement. Recently, DMG has been found acting at glycine binding site of the N-methyl-d-aspartate receptor (NMDAR). As blockade of NMDARs is one of the main mechanisms responsible for the action of ketamine on central nervous system, DMG might modulate the behavioral responses to ketamine. The present study determined the effects of DMG on the ketamine-induced psychotomimetic, anesthetic and antidepressant-like effects in mice. DMG pretreatment reversed the ketamine-induced locomotor hyperactivity and impairment in the rotarod performance, novel location and novel object recognition tests, and prepulse inhibition. In addition, DMG alone exhibited antidepressant-like effects in the forced swim test and produced additive effects when combined with ketamine. However, DMG did not affect ketamine-induced anesthesia. These results reveal that DMG could antagonize ketamine's psychotomimetic effects, yet produce additive antidepressant-like effects with ketamine, suggesting that DMG might have antipsychotic potential and be suitable as an add-on therapy to ketamine for patients with treatment-resistant depression. Copyright © 2016 Elsevier Inc. All rights reserved.

Involvement of posterior cingulate cortex in ketamine-induced psychosis relevant behaviors in rats.

Science.gov (United States)

Ma, Jingyi; Leung, L Stan

2018-02-15

The involvement of posterior cingulate cortex (PCC) on ketamine-induced psychosis relevant behaviors was investigated in rats. Bilateral infusion of muscimol, a GABA A receptor agonist, into the PCC significantly antagonized ketamine-induced deficit in prepulse inhibition of a startle reflex (PPI), deficit in gating of hippocampal auditory evoked potentials, and behavioral hyperlocomotion in a dose dependent manner. Local infusion of ketamine directly into the PCC also induced a PPI deficit. Systemic injection of ketamine (3mg/kg,s.c.) induced an increase in power of electrographic activity in the gamma band (30-100Hz) in both the PCC and the hippocampus; peak theta (4-10Hz) power was not significantly altered, but peak theta frequency was increased by ketamine. In order to exclude volume conduction from the hippocampus to PCC, inactivation of the hippocampus was made by local infusion of muscimol into the hippocampus prior to ketamine administration. Muscimol in the hippocampus effectively blocked ketamine-induced increase of gamma power in the hippocampus but not in the PCC, suggesting independent generation of gamma waves in PCC and hippocampus. It is suggested that the PCC is part of the brain network mediating ketamine-induced psychosis related behaviors. Copyright © 2017 Elsevier B.V. All rights reserved.

Oral Ketamine

African Journals Online (AJOL)

Oral Ketamine: A Four-years Experience in ... Key words: Oral Ketamine, Premedication and Oncology. .... form of a letter published in 19835. .... Acta. Anaesthesiol Scandinavica, 1998; 42: 750-758. 4. Murray P. Substitution of another opioid ...

Late preconditioning is blocked by racemic ketamine, but not by S(+)-ketamine

NARCIS (Netherlands)

Müllenheim, J.; Rulands, R.; Wietschorke, T.; Frässdorf, J.; Preckel, B.; Schlack, W.

2001-01-01

Racemic ketamine blocks K(ATP) channels in isolated cells and abolishes short-term cardioprotection against prolonged ischemia. We investigated the effects of racemic ketamine and S(+)-ketamine on ischemic late preconditioning (LPC) in the rabbit heart in vivo. A coronary occluder was chronically

Repeated ketamine administration alters N-methyl-d-aspartic acid receptor subunit gene expression: Implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans

Science.gov (United States)

Lipsky, Robert H

2015-01-01

For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-d-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. PMID:25245072

Repeated ketamine administration alters N-methyl-D-aspartic acid receptor subunit gene expression: implication of genetic vulnerability for ketamine abuse and ketamine psychosis in humans.

Science.gov (United States)

Xu, Ke; Lipsky, Robert H

2015-02-01

For more than 40 years following its approval by the Food and Drug Administration (FDA) as an anesthetic, ketamine, a non-competitive N-methyl-D-aspartic acid (NMDA) receptor antagonist, has been used as a tool of psychiatric research. As a psychedelic drug, ketamine induces psychotic symptoms, cognitive impairment, and mood elevation, which resemble some symptoms of schizophrenia. Recreational use of ketamine has been increasing in recent years. However, little is known of the underlying molecular mechanisms responsible for ketamine-associated psychosis. Recent animal studies have shown that repeated ketamine administration significantly increases NMDA receptor subunit gene expression, in particular subunit 1 (NR1 or GluN1) levels. This results in neurodegeneration, supporting a potential mechanism where up-regulation of NMDA receptors could produce cognitive deficits in chronic ketamine abuse patients. In other studies, NMDA receptor gene variants are associated with addictive behavior. Here, we focus on the roles of NMDA receptor gene subunits in ketamine abuse and ketamine psychosis and propose that full sequencing of NMDA receptor genes may help explain individual vulnerability to ketamine abuse and ketamine-associated psychosis. © 2014 by the Society for Experimental Biology and Medicine.

Ketamine, but not S(+)-ketamine, blocks ischemic preconditioning in rabbit hearts in vivo

NARCIS (Netherlands)

Müllenheim, J.; Frässdorf, J.; Preckel, B.; Thämer, V.; Schlack, W.

2001-01-01

BACKGROUND: Ketamine blocks KATP channels in isolated cells and abolishes the cardioprotective effect of ischemic preconditioning in vitro. The authors investigated the effects of ketamine and S(+)-ketamine on ischemic preconditioning in the rabbit heart in vivo. METHODS: In 46

Is nitric oxide signalling involved in the antidepressant action of ketamine?

DEFF Research Database (Denmark)

Liebenberg, Nico; Müller, Heidi Kaastrup; Elfving, Betina

2012-01-01

Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect in depre......Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect...... in depressed patients following a single intravenous administration that is sustained for ± 7 days. A number of downstream cellular mechanisms appear to mediate the antidepressant action of ketamine, and the majority of evidence point to a rapid activation of protein translation leading to increased synaptic...... receptors, while the uncoupling of the nNOS-NMDA receptor complex prevents NMDA-induced excitotoxicity. Thus, it is possible that the inhibition of nitric oxide (NO) signalling underlies a key upstream mechanism in the antidepressant action of ketamine. Methods: We used a genetic rat model of depression...

Ketamine for pain

Science.gov (United States)

Jonkman, Kelly; Dahan, Albert; van de Donk, Tine; Aarts, Leon; Niesters, Marieke; van Velzen, Monique

2017-01-01

The efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as an analgesic agent is still under debate, especially for indications such as chronic pain. To understand the efficacy of ketamine for relief of pain, we performed a literature search for relevant narrative and systematic reviews and meta-analyses. We retrieved 189 unique articles, of which 29 were deemed appropriate for use in this review. Ketamine treatment is most effective for relief of postoperative pain, causing reduced opioid consumption. In contrast, for most other indications (that is, acute pain in the emergency department, prevention of persistent postoperative pain, cancer pain, and chronic non-cancer pain), the efficacy of ketamine is limited. Ketamine’s lack of analgesic effect was associated with an increase in side effects, including schizotypical effects. PMID:28979762

Ketamine - A Multifaceted Drug.

Science.gov (United States)

Meng, Lingzhong; Li, Jian; Lu, Yi; Sun, Dajin; Tao, Yuan-Xiang; Liu, Renyu; Luo, Jin Jun

There is a petition for tight control of ketamine from the Chinese government to classify ketamine as a Schedule I drug, which is defined as a drug with no currently accepted medical use but a high potential for abuse. However, ketamine has unique properties that can benefit different patient populations. Scholars from the Translational Perioperative and Pain Medicine and the International Chinese Academy of Anesthesiology WeChat groups had an interactive discussion on ketamine, including its current medical applications, future research priorities, and benefits versus risks. The discussion is summarized in this manuscript with some minor edits.

The effects of an intraperitoneal single low dose of ketamine in attenuating the postoperative skin/muscle incision and retraction-induced pain related to the inhibition of N-methyl-D-aspartate receptors in the spinal cord.

Science.gov (United States)

Shen, Yu; Xu, Li; Liu, Ming; Lei, Yishan; Gu, Xiaoping; Ma, Zhengliang

2016-03-11

Chronic postoperative pain (CPOP) is a common clinical problem which might be related to central sensitization. It has been widely accepted that NMDA (N-methyl-D-aspartate) receptors are among the triggers of central sensitization. Ketamine is a non-competitive NMDA receptor antagonist that is widely used in alleviating postoperative pain, but its effect on CPOP has been rarely reported. In the present study, the skin/muscle incision and retraction (SMIR) model was used to investigate the role of NMDARs in chronic postoperative pain and the effect of an intraperitoneal single low dose ketamine (10mg/kg) of attenuating SMIR-induced CPOP. We assessed pain behaviours after a SMIR operation by paw withdrawal threshold (PWMT) and paw withdrawal latency (PWMTL). Western blotting were performed to examine the role of NMDARs in SMIR-induced CPOP and the effect of ketamine on the expression and phosphorylation of NMDARs. The SMIR operation induced long-lasting mechanical hyperalgesia, and the up-regulation of phosphorylated NMDARs and total NMDARs at the spinal level. A single intraperitoneal administration of low dose ketamine (10mg/kg) during surgery alleviated pain behaviors and inhibited the up-regulation of phosphorylated NMDARs and total NMDARs. Our datas suggested that NMDARs play important roles in SMIR-induced CPOP. A single intraperitoneal low dose of ketamine could attenuate SMIR-induced CPOP, which might be associated with the inhibition of NMDARs. Our finding might provide a new, simple method of addressing CPOP. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Investigating nitric oxide signalling involvement in the antidepressant action of ketamine

DEFF Research Database (Denmark)

Liebenberg, Nico; Müller, Heidi Kaastrup; Elfving, Betina

2012-01-01

Stress-induced excessive glutamate transmission at N-methyl-D-aspartate receptors (NMDA-R’s) may underlie a primary mechanism in the physiology that leads to depression, and ketamine, an NMDA-R antagonist, has been shown to rapidly relieve depression in humans. A number of downstream mechanisms...... have been suggested to mediate the antidepressant action of ketamine, including the activation of extracellular-signal-regulated kinases 1/2 (ERK1/2), protein kinase B (or Akt) and the mammalian target of rapamycin (mTOR). However, the mechanism(s) that are affected immediately downstream of NMDA......-R’s remain unclear. Neuronal nitric oxide synthase (nNOS) is directly coupled to and activated by NMDA-R’s, and the uncoupling of the nNOS-NMDA-R complex prevents NMDA-R-mediated excitotoxicity. Therefore, we investigated whether the antidepressant mechanism of ketamine involves the inhibition of nitric...

DSGOST inhibits tumor growth by blocking VEGF/VEGFR2-activated angiogenesis.

Science.gov (United States)

Choi, Hyeong Sim; Lee, Kangwook; Kim, Min Kyoung; Lee, Kang Min; Shin, Yong Cheol; Cho, Sung-Gook; Ko, Seong-Gyu

2016-04-19

Tumor growth requires a process called angiogenesis, a new blood vessel formation from pre-existing vessels, as newly formed vessels provide tumor cells with oxygen and nutrition. Danggui-Sayuk-Ga-Osuyu-Saenggang-Tang (DSGOST), one of traditional Chinese medicines, has been widely used in treatment of vessel diseases including Raynaud's syndrome in Northeast Asian countries including China, Japan and Korea. Therefore, we hypothesized that DSGOST might inhibit tumor growth by targeting newly formed vessels on the basis of its historical prescription. Here, we demonstrate that DSGOST inhibits tumor growth by inhibiting VEGF-induced angiogenesis. DSGOST inhibited VEGF-induced angiogenic abilities of endothelial cells in vitro and in vivo, which resulted from its inhibition of VEGF/VEGFR2 interaction. Furthermore, DSGOST attenuated pancreatic tumor growth in vivo by reducing angiogenic vessel numbers, while not affecting pancreatic tumor cell viability. Thus, our data conclude that DSGOST inhibits VEGF-induced tumor angiogenesis, suggesting a new indication for DSGOST in treatment of cancer.

Ketamine-propofol sedation in circumcision

Directory of Open Access Journals (Sweden)

Handan Gulec

2015-10-01

Full Text Available ABSTRACTBACKGROUND AND OBJECTIVE: To compare the therapeutic effects of ketamine alone or ketamine plus propofol on analgesia, sedation, recovery time, side effects in premedicated children with midazolam-ketamine-atropin who are prepared circumcision operation.METHODS: 60 American Society of Anaesthesiologists physical status I-II children, aged between 3 and 9 years, undergoing circumcision operations under sedation were recruited according to a randomize and double-blind institutional review board-approved protocol. Patients were randomized into two groups via sealed envelope assignment. Both groups were administered a mixture of midazolam 0.05 mg/kg + ketamine 3 mg/kg + atropine 0.02 mg/kg intramuscularly in the presence of parents in the pre-operative holding area. Patients were induced with propofol-ketamine in Group I or ketamine alone in Group II.RESULTS: In the between-group comparisons, age, weight, initial systolic blood pressure, a difference in terms of the initial pulse rate was observed (p > 0.050. Initial diastolic blood pressure and subsequent serial measurements of 5, 10, 15, 20th min, systolic blood pressure, diastolic blood pressure and pulse rate in ketamine group were significantly higher (p < 0.050.CONCLUSION: Propofol-ketamine (Ketofol provided better sedation quality and hemodynamy than ketamine alone in pediatric circumcision operations. We did not observe significant complications during sedation in these two groups. Therefore, ketofol appears to be an effective and safe sedation method for circumcision operation.

Dietary rice bran component γ-oryzanol inhibits tumor growth in tumor-bearing mice.

Science.gov (United States)

Kim, Sung Phil; Kang, Mi Young; Nam, Seok Hyun; Friedman, Mendel

2012-06-01

We investigated the effects of rice bran and components on tumor growth in mice. Mice fed standard diets supplemented with rice bran, γ-oryzanol, Ricetrienol®, ferulic acid, or phytic acid for 2 weeks were inoculated with CT-26 colon cancer cells and fed the same diet for two additional weeks. Tumor mass was significantly lower in the γ-oryzanol and less so in the phytic acid group. Tumor inhibition was associated with the following biomarkers: increases in cytolytic activity of splenic natural killer (NK) cells; partial restoration of nitric oxide production and phagocytosis in peritoneal macrophages increases in released the pro-inflammatory cytokines tumor necrosis factor-α, IL-1β, and IL-6 from macrophages; and reductions in the number of blood vessels inside the tumor. Pro-angiogenic biomarkers vascular endothelial growth factor (VEGF), cyclooxygenase-2 (COX-2), and 5-lipoxygenase-5 (5-LOX) were also significantly reduced in mRNA and protein expression by tumor genes. ELISA of tumor cells confirmed reduced expression of COX-2 and 5-LOX up to 30%. Reduced COX-2 and 5-LOX expression downregulated VEGF and inhibited neoangiogenesis inside the tumors. Induction of NK activity, activation of macrophages, and inhibition of angiogenesis seem to contribute to the inhibitory mechanism of tumor regression by γ-oryzanol. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Current Ketamine Practice: Results of the 2016 American Society of Pain Management Nursing Survey on Ketamine.

Science.gov (United States)

Klaess, Cynthia C; Jungquist, Carla R

2018-06-01

Ketamine is increasingly utilized for a variety of pain management challenges. Audience comments from a ketamine presentation at the 2015 American Society of Pain Management Nursing (ASPMN) Conference reflected wide variation in ketamine practices as well as barriers to use. The goal was to gain a greater understanding of ASPMN member practice patterns and barriers related to ketamine as adjunctive therapy for pain management. A questionnaire survey design was used. Respondents represented 35 states and 2 countries. The participants were 146 respondents from ASPMN membership (1,485 members). The survey was distributed by ASPMN on SurveyMonkey. Practice setting and ketamine administration practices were assessed with areas for comments. Results were reviewed using frequencies to describe responses and formatted into tables. Comments were individually reviewed and grouped into common themes. Administration of ketamine as an analgesic was reported by 63% of respondents. Continuous intravenous ketamine infusions were the most common route of administration (65%); however, wide variability in dosing and length of therapy was reported. A wide variety of practices and challenges related to ketamine utilization were noted. Numerous studies have indicated the analgesic benefits of ketamine in pain management. The lack of practice standardization has created challenges to its consistent use and outcome measurement. Additionally, the off-label use of ketamine for pain management creates its own unique challenges. However, given the current national climate with intense focus on pain management, interdisciplinary practitioners have an ideal opportunity to evaluate ketamine's use in a comprehensive approach to pain management. Copyright © 2018 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Cost-Effectiveness of Postoperative Ketamine in Chiari Decompression.

Science.gov (United States)

McDowell, Michael M; Alhourani, Ahmad; Pearce-Smith, Beverly A; Mazurkiewicz, Anna; Friedlander, Robert M

2018-02-01

In Chiari I patients, postoperative pain and discomfort frequently slow the transition back to the home setting. We sought to determine the effect of standardized ketamine infusion protocols on hospital length of stay (LOS). This retrospective cohort study reviewed 100 consecutive adult patients undergoing Chiari I decompression. Fifty-nine patients were placed on a 2-3 mg/hr ketamine drip until postoperative day 1. This group was compared with a group who received 2-3 mg/hr of ketamine until postoperative day 2 (19 patients) and patients who did not receive ketamine at all (22 patients). Clinical characteristics, opioid use, LOS, and relative hospitalization costs were assessed. All narcotic amounts were converted into milligram equivalents of morphine. LOS of the short-ketamine group was 46.5 hours when compared with the long-ketamine group (66.8 hours) and no-ketamine group (56.9 hours). There was a statistically significant difference when comparing the short-ketamine group with the long-ketamine group and no-ketamine group together (P ketamine protocol was used (P ketamine group, 196 mg in the long-ketamine group, and 187 mg in the no-ketamine group (P = 0.65). No adverse events from ketamine were noted. Ketamine at subanesthetic levels may be an effective tool to facilitate early return home postoperatively and may significantly reduce medical costs. Copyright © 2017 Elsevier Inc. All rights reserved.

[Ketamine as a party drug

NARCIS (Netherlands)

Vroegop, M.P.; Dongen, R.T.M. van; Vantroyen, B.; Kramers, C.

2007-01-01

Ketamine is a new party drug, which is easy to obtain. For this reason, it is possible that physicians will be increasingly confronted with users that have medical problems. Relatively few cases of ketamine intoxication with a fatal outcome have been reported thus far. Ketamine is very

Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-β1.

Science.gov (United States)

Wang, Junpeng; Chen, Yang; Gu, Di; Zhang, Guihao; Chen, Jiawei; Zhao, Jie; Wu, Peng

2017-10-01

Bladder wall fibrosis is a major complication of ketamine-induced cystitis (KC), but the underlying pathogenesis is poorly understood. The aim of the present study was to elucidate the mechanism of ketamine-induced fibrosis in association with epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor-β1 (TGF-β1). Sprague-Dawley rats were randomly distributed into four groups, which received saline, ketamine, ketamine combined with a TGF-β receptor inhibitor (SB-505124) for 16 wk, or 12 wk of ketamine and 4 wk of abstinence. In addition, the profibrotic effect of ketamine was confirmed in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. The ketamine-treated rats displayed voiding dysfunction and decreased bladder compliance. Bladder fibrosis was accompanied by the appearance of a certain number of cells expressing both epithelial and mesenchymal markers, indicating that epithelial cells might undergo EMT upon ketamine administration. Meanwhile, the expression level of TGF-β1 was significantly upregulated in the urothelium of bladders in ketamine-treated rats. Treatment of SV-HUC-1 cells with ketamine increased the expression of TGF-β1 and EMT-inducing transcription factors, resulting in the downregulation of E-cadherin and upregulation of fibronectin and α-smooth muscle actin. Administration of SB-505124 inhibited EMT and fibrosis both in vitro and vivo. In addition, withdrawal from ketamine did not lead to recovery of bladder urinary function or decreased fibrosis. Taken together, our study shows for the first time that EMT might contribute to bladder fibrosis in KC. TGF-β1 may have an important role in bladder fibrogenesis via an EMT mechanism. Copyright © 2017 the American Physiological Society.

Effects of Ketamine on Neuronal Spontaneous Excitatory Postsynaptic Currents and Miniature Excitatory Postsynaptic Currents in the Somatosensory Cortex of Rats

Directory of Open Access Journals (Sweden)

Chengdong Yuan

2016-07-01

Full Text Available Background: Ketamine is a commonly used intravenous anesthetic which produces dissociation anesthesia, analgesia, and amnesia. The mechanism of ketamine-induced synaptic inhibition in high-level cortical areas is still unknown. We aimed to elucidate the effects of different concentrations of ketamine on the glutamatergic synaptic transmission of the neurons in the primary somatosensory cortex by using the whole-cell patch-clamp method. Methods: Sprague-Dawley rats (11–19 postnatal days, n=36 were used to obtain brain slices (300 μM. Spontaneous excitatory postsynaptic currents (data from 40 neurons were recorded at a command potential of -70 mV in the presence of bicuculline (a competitive antagonist of GABAA receptors, 30 μM and strychnine (glycine receptor antagonist, 30 μM. Miniature excitatory postsynaptic currents (data from 40 neurons were also recorded when 1 μM of tetrodotoxin was added into the artificial cerebrospinal fluid. We used GraphPad Prism5for statistical analysis. Significant differences in the mean amplitude and frequency were tested using the Student paired 2-tailed t test. Values of P<0.05 were considered significant. Results: Different concentrations of ketamine inhibited the frequency and amplitude of the spontaneous excitatory postsynaptic currents as well as the amplitude of the miniature excitatory postsynaptic currents in a concentration-dependent manner, but they exerted no significant effect on the frequency of the miniature excitatory postsynaptic currents. Conclusion: Ketamine inhibited the excitatory synaptic transmission of the neurons in the primary somatosensory cortex. The inhibition may have been mediated by a reduction in the sensitivity of the postsynaptic glutamatergic receptors.

Potent inhibition of tumoral hypoxia-inducible factor 1α by albendazole

International Nuclear Information System (INIS)

Pourgholami, Mohammad H; Cai, Zhao Y; Badar, Samina; Wangoo, Kiran; Poruchynsky, Marianne S; Morris, David L

2010-01-01

Emerging reports suggest resistance, increased tumor invasiveness and metastasis arising from treatment with drugs targeting vascular endothelial growth factor (VEGF). It is believed that increased tumoral hypoxia plays a prominent role in the development of these phenomena. Inhibition of tumoral hypoxia inducible factor (HIF-1α) is thus becoming an increasingly attractive therapeutic target in the treatment of cancer. We hypothesized that the anti-VEGF effect of albendazole (ABZ) could be mediated through inhibition of tumoral HIF-1α. In vitro, the effects of ABZ on HIF-1α levels in human ovarian cancer cells (OVCAR-3) were investigated using hypoxic chamber or desferrioxamine (DFO) induced-hypoxia. In vivo, the effects of ABZ (150 mg/kg, i.p., single dose) on the tumor levels of HIF-1α and VEGF protein and mRNA were investigated by western blotting, RT-PCR and real time-PCR. In vitro, ABZ inhibited cellular HIF-1α protein accumulation resulting from placement of cells under hypoxic chamber or exposure to DFO. In vivo, tumors excised from vehicle treated mice showed high levels of both HIF-1α and VEGF. Whereas, tumoral HIF-1α and VEGF protein levels were highly suppressed in ABZ treated mice. Tumoral VEGFmRNA (but not HIF-1αmRNA) was also found to be highly suppressed by ABZ. These results demonstrate for the first time the effects of an acute dose of ABZ in profoundly suppressing both HIF-1α and VEGF within the tumor. This dual inhibition may provide additional value in inhibiting angiogenesis and be at least partially effective in inhibiting tumoral HIF-1α surge, tumor invasiveness and metastasis

Influence of cadmium on ketamine-induced anesthesia and brain microsomal Na[sup +], K[sup +]-ATPase in mice

Energy Technology Data Exchange (ETDEWEB)

Shen, Y.; Sangiah, S. (Oklahoma State Univ., Stillwater, OK (United States))

1994-10-01

Cadmium is a rare metallic element, present in almost all types of food. Shellfish, wheat and rice accumulate very high amounts. Occupational and environmental pollutants are the main sources of cadmium exposure. Cadmium has a very long biologic half-life. Exposure to Cadmium causes anemia, hypertension, hepatic, renal, pulmonary and cardiovascular disorders as well as being a possible mutagen, teratogen and carcinogen. Acute cadmium treatment increased the hexobarbital sleeping time and inhibited hepatic microsomal drug metabolism due to a decrease in cytochrome P[sub 450] content. Cadmium potentiated ethanol-induced sleep in a dose-dependent manner. Cadmium has been shown to inhibit brain microsomal Na[sup +], K[sup +]-ATPase activity in vitro and in vivo. Cadmium and ethanol additively inhibited brain Na[sup +], K[sup +]-ATPase. This might be a direct interaction between cadmium and ethanol in the central nervous system. Ketamine is an intravenous anesthetic agent. It acts on central nervous system and produces [open quotes]dissociative anaesthesia.[close quotes] Ketamine provides adequate surgical anesthesia and is used alone in humans and/or combination with xylazine, an [alpha][sub 2]-adrenergic agonist in animals. It produces CNS depression, analgesia, amnesia, immobility and a feeling of dissociation from the environment. Ketamine is a non-competitive antagonist of the NMDA subset of the glutamate receptor. This perhaps results in an increase in neuronal activity leading to disorganization of normal neurotransmission and produces dissociative anesthetic state. Because it is different from most other anesthetics, ketamine may be expected to have a unique effect on brain biochemical parameters and enzymes. The purpose of this study was to examine the interactions between cadmium and ketamine on the central nervous system and ATPase, in an attempt to further understand the mechanism of action. 12 refs., 3 figs.

Synthesis of isotopically labeled ketamine

OpenAIRE

Stuchlíková, Lucie

2011-01-01

In this work were synthesized ketamine isotopomers. Ketamine is used in human medicine and veterinary sectors. It has very broad spectrum of pharmacological effects: anesthetic, analgesic, hallucinogenic, bronchodilator, cardiovascular and antidepressive, which is currently in the research. At first was synthesized precursor of ketamine, N- desmethylketamine which was subsequently labeled the deuterium, tritium and carbon- 14. For the determination of purity and identity mass spectrometry and...

Effect of the α2 -receptor agonists medetomidine, detomidine, xylazine, and romifidine on the ketamine metabolism in equines assessed with enantioselective capillary electrophoresis.

Science.gov (United States)

Sandbaumhüter, Friederike A; Theurillat, Regula; Bettschart-Wolfensberger, Regula; Thormann, Wolfgang

2017-08-01

The combination of ketamine and an α 2 -receptor agonist is often used in veterinary medicine. Four different α 2 -receptor agonists, medetomidine, detomidine, xylazine, and romifidine, which differ in their chemical structure and thus in selectivity for the α 2 -receptor and in the sedative and analgesic potency, are typically employed during surgery of equines. Recovery following anesthesia with ketamine and an α 2 -receptor agonist is dependent on the α 2 -receptor agonist. This prompted us to investigate (i) the inhibition characteristics for the N-demethylation of ketamine to norketamine and (ii) the formation of the ketamine metabolites norketamine, 6-hydroxynorketamine (6HNK), and 5,6-dehydronorketamine (DHNK) in presence of the four α 2 -receptor agonists and equine liver microsomes. Samples were analyzed with enantioselective capillary electrophoresis using highly sulfated γ-cyclodextrin as chiral selector. All four α 2 -receptor agonists have an impact on the ketamine metabolism. Medetomidine was found to be the strongest inhibitor, followed by detomidine, whereas xylazine and romifidine showed almost no effect on the ketamine N-demethylation in the inhibition studies with a short-incubation period of the reaction mixture. After prolonged incubation, inhibition with xylazine and romifidine was also observed. The formation of 6HNK and DHNK is affected by all selected α 2 -receptor agonists. With medetomidine, levels of these metabolites are reduced compared to the case without an α 2 -receptor agonist. For detomidine, xylazine, and romifidine, the opposite was found. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

21 CFR 522.1222a - Ketamine.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ketamine. 522.1222a Section 522.1222a Food and..., FEEDS, AND RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1222a Ketamine. (a) Specifications. Each milliliter contains ketamine hydrochloride equivalent to 100 milligrams (mg...

Equine cytochrome P450 2B6 — Genomic identification, expression and functional characterization with ketamine

International Nuclear Information System (INIS)

Peters, L.M.; Demmel, S.; Pusch, G.; Buters, J.T.M.; Thormann, W.; Zielinski, J.; Leeb, T.; Mevissen, M.; Schmitz, A.

2013-01-01

Ketamine is an anesthetic and analgesic regularly used in veterinary patients. As ketamine is almost always administered in combination with other drugs, interactions between ketamine and other drugs bear the risk of either adverse effects or diminished efficacy. Since cytochrome P450 enzymes (CYPs) play a pivotal role in the phase I metabolism of the majority of all marketed drugs, drug–drug interactions often occur at the active site of these enzymes. CYPs have been thoroughly examined in humans and laboratory animals, but little is known about equine CYPs. The characterization of equine CYPs is essential for a better understanding of drug metabolism in horses. We report annotation, cloning and heterologous expression of the equine CYP2B6 in V79 Chinese hamster fibroblasts. After computational annotation of all CYP2B genes, the coding sequence (CDS) of equine CYP2B6 was amplified by RT-PCR from horse liver total RNA and revealed an amino acid sequence identity of 77% and a similarity of 93.7% to its human ortholog. A non-synonymous variant c.226G>A in exon 2 of the equine CYP2B6 was detected in 97 horses. The mutant A-allele showed an allele frequency of 82%. Two further variants in exon 3 were detected in one and two horses of this group, respectively. Transfected V79 cells were incubated with racemic ketamine and norketamine as probe substrates to determine metabolic activity. The recombinant equine CYP2B6 N-demethylated ketamine to norketamine and produced metabolites of norketamine, such as hydroxylated norketamines and 5,6-dehydronorketamine. V max for S-/and R-norketamine formation was 0.49 and 0.45 nmol/h/mg cellular protein and K m was 3.41 and 2.66 μM, respectively. The N-demethylation of S-/R-ketamine was inhibited concentration-dependently with clopidogrel showing an IC 50 of 5.63 and 6.26 μM, respectively. The functional importance of the recorded genetic variants remains to be explored. Equine CYP2B6 was determined to be a CYP enzyme involved in

Equine cytochrome P450 2B6 — Genomic identification, expression and functional characterization with ketamine

Energy Technology Data Exchange (ETDEWEB)

Peters, L.M.; Demmel, S. [Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University Bern, Laenggassstr. 124, 3012 Bern (Switzerland); Pusch, G.; Buters, J.T.M. [ZAUM — Center of Allergy and Environment, Helmholtz Zentrum München/Technische Universität München, Biedersteiner Str. 29, 80802 München (Germany); Thormann, W. [Clinical Pharmacology Laboratory, Institute for Infectious Diseases, University of Bern, Murtenstrasse 35, 3010 Bern (Switzerland); Zielinski, J. [Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University Bern, Laenggassstr. 124, 3012 Bern (Switzerland); Leeb, T. [Institute of Genetics, Vetsuisse Faculty, University Bern, Bremgartenstr. 109, 3012 Bern (Switzerland); Mevissen, M. [Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University Bern, Laenggassstr. 124, 3012 Bern (Switzerland); Schmitz, A., E-mail: andrea.schmitz@vetsuisse.unibe.ch [Division Veterinary Pharmacology and Toxicology, Vetsuisse Faculty, University Bern, Laenggassstr. 124, 3012 Bern (Switzerland)

2013-01-01

Ketamine is an anesthetic and analgesic regularly used in veterinary patients. As ketamine is almost always administered in combination with other drugs, interactions between ketamine and other drugs bear the risk of either adverse effects or diminished efficacy. Since cytochrome P450 enzymes (CYPs) play a pivotal role in the phase I metabolism of the majority of all marketed drugs, drug–drug interactions often occur at the active site of these enzymes. CYPs have been thoroughly examined in humans and laboratory animals, but little is known about equine CYPs. The characterization of equine CYPs is essential for a better understanding of drug metabolism in horses. We report annotation, cloning and heterologous expression of the equine CYP2B6 in V79 Chinese hamster fibroblasts. After computational annotation of all CYP2B genes, the coding sequence (CDS) of equine CYP2B6 was amplified by RT-PCR from horse liver total RNA and revealed an amino acid sequence identity of 77% and a similarity of 93.7% to its human ortholog. A non-synonymous variant c.226G>A in exon 2 of the equine CYP2B6 was detected in 97 horses. The mutant A-allele showed an allele frequency of 82%. Two further variants in exon 3 were detected in one and two horses of this group, respectively. Transfected V79 cells were incubated with racemic ketamine and norketamine as probe substrates to determine metabolic activity. The recombinant equine CYP2B6 N-demethylated ketamine to norketamine and produced metabolites of norketamine, such as hydroxylated norketamines and 5,6-dehydronorketamine. V{sub max} for S-/and R-norketamine formation was 0.49 and 0.45 nmol/h/mg cellular protein and K{sub m} was 3.41 and 2.66 μM, respectively. The N-demethylation of S-/R-ketamine was inhibited concentration-dependently with clopidogrel showing an IC{sub 50} of 5.63 and 6.26 μM, respectively. The functional importance of the recorded genetic variants remains to be explored. Equine CYP2B6 was determined to be a CYP

Ketamine for Treatment-Resistant Unipolar Depression

Science.gov (United States)

Mathew, Sanjay J.; Shah, Asim; Lapidus, Kyle; Clark, Crystal; Jarun, Noor; Ostermeyer, Britta; Murrough, James W.

2013-01-01

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD. PMID:22303887

Ketamine

African Journals Online (AJOL)

MJZ

anesthesia in extremely critical conditions (e.g., ... treatment. Some animal studies have shown that ketamine may produce a marked neuroprotective effect mediated ... IM) for pediatric surgery. .... prior personality disorders, excessive noise.

Psychedelics and reconsolidation of traumatic and appetitive maladaptive memories: focus on cannabinoids and ketamine.

Science.gov (United States)

Fattore, Liana; Piva, Alessandro; Zanda, Mary Tresa; Fumagalli, Guido; Chiamulera, Cristiano

2018-02-01

Clinical data with 3,4-methylenedioxymethamphetamine (MDMA) in post-traumatic stress disorder (PTSD) patients recently stimulated interest on the potential therapeutic use of psychedelics in disorders characterized by maladaptive memories, including substance use disorders (SUD). The rationale for the use of MDMA in PTSD and SUD is being extended to a broader beneficial "psychedelic effect," which is supporting further clinical investigations, in spite of the lack of mechanistic hypothesis. Considering that the retrieval of emotional memories reactivates specific brain mechanisms vulnerable to inhibition, interference, or strengthening (i.e., the reconsolidation process), it was proposed that the ability to retrieve and change these maladaptive memories might be a novel intervention for PTSD and SUD. The mechanisms underlying MDMA effects indicate memory reconsolidation modulation as a hypothetical process underlying its efficacy. Mechanistic and clinical studies with other two classes of psychedelic substances, namely cannabinoids and ketamine, are providing data in support of a potential use in PTSD and SUD based on the modulation of traumatic and appetitive memory reconsolidation, respectively. Here, we review preclinical and clinical data on cannabinoids and ketamine effects on biobehavioral processes related to the reconsolidation of maladaptive memories. We report the findings supporting (or not) the working hypothesis linking the potential therapeutic effect of these substances to the underlying reconsolidation process. We also proposed possible approaches for testing the use of these two classes of drugs within the current paradigm of reconsolidation memory inhibition. Metaplasticity may be the process in common between cannabinoids and ketamine/ketamine-like substance effects on the mediation and potential manipulation of maladaptive memories.

[Safety and efficacy of ketamine for pain relief].

Science.gov (United States)

Niesters, Marieke; Dahan, Albert; van Kleef, Maarten

2016-01-01

Intravenous ketamine treatment is frequently used for the management of chronic pain, especially in those patients who do not benefit from other therapies. In this commentary we discuss the efficacy of ketamine for relief of chronic pain and ketamine's safety profile. A review of the literature indicates that only a few studies show that intravenous ketamine has analgesic effects that persist beyond the infusion period, an effect that occurs in about two-thirds of patients. Ketamine has multiple safety issues, ranging from psychotomimetic and schizotypal symptoms, sympathetic stimulation, tachycardia and hypertension, and damage to the liver and the urogenital tract. Damage to the urogenital tract seems to be restricted to individuals who chronically abuse ketamine. We indicate the need for large randomized trials in which ketamine is compared with an 'active' placebo.

Ketamine-snorting associated cystitis.

Science.gov (United States)

Chen, Chung-Hsien; Lee, Ming-Huei; Chen, Yi-Chang; Lin, Ming-Fong

2011-12-01

Ketamine hydrochloride, commonly used as a pediatric anesthetic agent, is an N-methyl-D-aspartic (NMDA) acid receptor antagonist with rapid onset and short duration of action. It produces a cataleptic-like state where the patient is dissociated from the surrounding environment by direct action on the cortex and limbic system. It has emerged as an increasingly popular choice among young drug users, especially within dance club venues. Cases of bladder dysfunction among recreational ketamine users were reported since Shahani et al first reported nine cases of ketamine-associated ulcerative cystitis in 2007. We report on four patients who had history of ketamine abuse, presenting with dysuria, fluctuating lower urinary tract symptoms (LUTS), lower abdominal or perineal pain, and impaired functional bladder capacities. Urinalysis showed pyuria and microhematuria. Urine culture was sterile. Bladder ulceration with severe diffuse hemorrhage and low bladder capacity were noted under anesthetized cystoscopic examination. Transurethral bladder mucosa biopsy was consistent with chronic cystitis. Cessation of ketamine abuse was the milestone of treatment, followed by the administration of mucosal protective agents, such as pentosan polysulphate or hyaluronic acid. Suprapubic pain was improved in three patients during follow-up. However, the outcome of treatment depends on the severity of the disease process, similar to that of interstitial cystitis (IC). Copyright © 2011. Published by Elsevier B.V.

Immediate ketamine treatment does not prevent posttraumatic stress responses in an animal model for PTSD.

Science.gov (United States)

Juven-Wetzler, Alzbeta; Cohen, Hagit; Kaplan, Zeev; Kohen, Avi; Porat, Oren; Zohar, Joseph

2014-03-01

Clinical studies suggest that administration of ketamine hydrochloride-an antagonist at the N-methyl-d-aspartate ionophore-provides short-term amelioration for depressive symptoms. The effects of a brief course of ketamine given immediately following exposure to psychogenic stress on the behavioral stress responses were assessed in an animal model of posttraumatic stress disorder. Animals exposed to stress were treated 1h later with ketamine (0.5, 5, and 15 mg/kg) or vehicle for three days (N = 107). Outcome measures included behavior in the elevated plus maze (EPM) and acoustic startle response (ASR) tests 30 days after initial exposure and freezing behavior upon exposure to a trauma-cue on day 31. Pre-set cut-off behavioral criteria classified exposed animals according to their EPM and ASR response-patterns into "extreme," "minimal," or "partial" behavioral response for analysis of prevalence rates of "PTSD-like behavior." Circulating corticosterone levels were assessed 20 min after injection of ketamine in exposed and unexposed animals (N = 62). The dexamethasone suppression test was used to assess negative feedback inhibition of the HPA axis. Prevalence rates of extremely-, partially-, or minimally-disrupted behavior demonstrated that ketamine administered immediately following stress exposure was ineffective in alleviating "PTSD-like behavior" at day 30 after exposure. Administration of ketamine was associated with increase in freezing behavior after exposure to a trauma-cue on day 31. Corticosterone levels were significantly suppressed by ketamine only in the exposed animals. Administration of ketamine immediately following trauma-exposure may not only be ineffective but actually detrimental in the long term. A disruption of the post-stress HPA-response has been raised as a contributing factor. © 2013 Published by Elsevier B.V. and ECNP.

Ketamine versus Ketamine / magnesium Sulfate for Procedural Sedation and Analgesia in the Emergency Department: A Randomized Clinical Trial.

Science.gov (United States)

Azizkhani, Reza; Bahadori, Azadeh; Shariati, Mohammadreza; Golshani, Keyhan; Ahmadi, Omid; Masoumi, Babak

2018-01-01

The present study was designed to evaluate the effectiveness of magnesium sulfate (MgSO 4 ) in procedural sedation and analgesia (PSA) when combined with ketamine in patients with fractures in emergency departments and required short and painful emergency procedures. In this study, 100 patients with fractures and dislocations who were presented to the emergency departments and required PSA for short and painful emergency procedures were randomly allocated to groups of ketamine plus MgSO 4 or ketamine alone. Train of four (TOF) stimulation pattern was assessed using nerve stimulator machine and compared between groups. The mean age of studied patients was 46.9 ± 9.3 years old. 48% were male and 52% were female. No significant differences were noted between groups in demographic variables. The status of TOF, 2 min after the injection of ketamine (1.5 mg/kg), in both groups was similar. After the injection of the second dose of ketamine (1 mg/kg) the status of TOF in four patients in ketamine plus MgSO 4 (0.45 mg/kg) group changed, it was three quarters but in ketamine group, the status of TOF in all patients was four quarters. The difference between groups was not statistically significant ( P = 0.12). The findings revealed that for muscle relaxation during medical procedures in the emergency department, ketamine in combination with MgSO 4 with this dose was not effective for muscle relaxation during procedures.

Ketamine in the treatment of acute pain.

Science.gov (United States)

Brinck, Elina; Kontinen, Vesa

2017-01-01

Ketamine is an old anesthetic agent that relieves pain by reducing central sensitization in the central nervous system. This is advantageous for patients suffering from severe pain prior to surgery or are using a strong opioid. The S enantiomer of ketamine used for anesthesia is more powerful than racemic ketamine. The ideal dose of ketamine for pain relief is not yet known, and its adverse effects on the central nervous system, including hallucinations, sedation, and diplopia have limited its use in pain management. The significance of these effects at low doses is probably less than expected, particularly if benzodiazepines or an alpha-2 agonist, such as dexmedetomidine, are administered in addition to ketamine.

Ketamine: A New Antidepressant?

Directory of Open Access Journals (Sweden)

Feride Karacaer

2015-03-01

Full Text Available Standart antidepressants are needed for the many individuals with major depressive disorder. However they do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent studies show that subanesthetic dose of ketamine is efficacy and safety for the treatment of depression. Antidepressant effects of ketamine have been found to be short-lived and its psychotomimetic properties may limit the use of ketamine to depressive patients. Future research studies should focus on identifying predictors of response (pharmalogical and clinical , investigating application of different doses and routes of administration and maintaining antidepressant effect. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2015; 7(1: 30-40

Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression.

Science.gov (United States)

Ho, Ming-Fen; Correia, Cristina; Ingle, James N; Kaddurah-Daouk, Rima; Wang, Liewei; Kaufmann, Scott H; Weinshilboum, Richard M

2018-04-03

Major depressive disorder (MDD) is the most common psychiatric illness worldwide, and it displays a striking sex-dependent difference in incidence, with two thirds of MDD patients being women. Ketamine treatment can produce rapid antidepressant effects in MDD patients, effects that are mediated-at least partially-through glutamatergic neurotransmission. Two active metabolites of ketamine, (2R,6R)-hydroxynorketamine (HNK) and (2S,6S)-HNK, also appear to play a key role in ketamine's rapid antidepressant effects through the activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. In the present study, we demonstrated that estrogen plus ketamine or estrogen plus active ketamine metabolites displayed additive effects on the induction of the expression of AMPA receptor subunits. In parallel, the expression of estrogen receptor alpha (ERα) was also significantly upregulated. Even more striking, radioligand binding assays demonstrated that [ 3 H]-ketamine can directly bind to ERα (K D : 344.5 ± 13 nM). Furthermore, ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites displayed similar affinity for ERα (IC 50 : 2.31 ± 0.1, 3.40 ± 0.2, and 3.53 ± 0.2 µM, respectively) as determined by [ 3 H]-ketamine displacement assays. Finally, induction of AMPA receptors by either estrogens or ketamine and its metabolites was lost when ERα was knocked down or silenced pharmacologically. These results suggest a positive feedback loop by which estrogens can augment the effects of ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites on the ERα-induced transcription of CYP2A6 and CYP2B6, estrogen inducible enzymes that catalyze ketamine's biotransformation to form the two active metabolites. These observations provide novel insight into ketamine's molecular mechanism(s) of action and have potential implications for the treatment of MDD. Copyright © 2018 Elsevier Inc. All rights reserved.

Glycine Transporter Inhibitor Attenuates the Psychotomimetic Effects of Ketamine in Healthy Males: Preliminary Evidence

Science.gov (United States)

D'Souza, Deepak Cyril; Singh, Nagendra; Elander, Jacqueline; Carbuto, Michelle; Pittman, Brian; de Haes, Joanna Udo; Sjogren, Magnus; Peeters, Pierre; Ranganathan, Mohini; Schipper, Jacques

2012-01-01

Enhancing glutamate function by stimulating the glycine site of the NMDA receptor with glycine, -serine, or with drugs that inhibit glycine reuptake may have therapeutic potential in schizophrenia. The effects of a single oral dose of cis-N-methyl-N-(6-methoxy-1-phenyl-1,2,3,4-tetrahydronaphthalen-2-ylmethyl) amino-methylcarboxylic acid hydrochloride (Org 25935), a glycine transporter-1 (GlyT1) inhibitor, and placebo pretreatment on ketamine-induced schizophrenia-like psychotic symptoms, perceptual alterations, and subjective effects were evaluated in 12 healthy male subjects in a randomized, counter-balanced, within-subjects, crossover design. At 2.5 h after administration of the Org 25935 or placebo, subjects received a ketamine bolus and constant infusion lasting 100 min. Psychotic symptoms, perceptual, and a number of subjective effects were assessed repeatedly before, several times during, and after completion of ketamine administration. A cognitive battery was administered once per test day. Ketamine produced behavioral, subjective, and cognitive effects consistent with its known effects. Org 25935 reduced the ketamine-induced increases in measures of psychosis (Positive and Negative Syndrome Scale (PANSS)) and perceptual alterations (Clinician Administered Dissociative Symptoms Scale (CADSS)). The magnitude of the effect of Org 25935 on ketamine-induced increases in Total PANSS and CADSS Clinician-rated scores was 0.71 and 0.98 (SD units), respectively. None of the behavioral effects of ketamine were increased by Org 25935 pretreatment. Org 25935 worsened some aspects of learning and delayed recall, and trended to improve choice reaction time. This study demonstrates for the first time in humans that a GlyT1 inhibitor reduces the effects induced by NMDA receptor antagonism. These findings provide preliminary support for further study of the antipsychotic potential of GlyT1 inhibitors. PMID:22113087

Something new about ketamine for pediatric anesthesia?

Science.gov (United States)

Lois, Fernande; De Kock, Marc

2008-06-01

This review discusses the place of the old anesthetic ketamine in pediatric anesthesia. Despite the availability of modern alternatives, ketamine remains a frequently used drug particularly for anesthesia in high-risk children and for procedures outside the operating room. In adult patients undergoing surgery, a renewed interest in this drug is noted. It is the consequence of recent demonstrations of the following effects. First, ketamine is highly effective against surgery and opiate-induced hyperalgesia. Second, it has original antiproinflammatory properties. In other words, it promotes self-limitation of the inflammatory response that follows surgery. In the pediatric population, these benefits wait to be confirmed. Finally, questions arise about the safety of ketamine anesthesia. Ketamine is a potent proapoptotic drug. In rodents treated during the critical period for central nervous system development, long-term behavioral deficits were noted after an anesthetic dose of ketamine. The exact consequences of these proapoptotic properties on human brain tissue development have to be exactly determined and are still debatable. Ketamine has not yet revealed all its interactions in humans. Recent discoveries indicate interesting properties on the one hand and potentially deleterious effects on the other.

Dioscin inhibits colon tumor growth and tumor angiogenesis through regulating VEGFR2 and AKT/MAPK signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Tong, Qingyi [Regenerative Medicine Research Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041 (China); Qing, Yong, E-mail: qingyongxy@yahoo.co.jp [Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041 (China); Wu, Yang [State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041 (China); Hu, Xiaojuan; Jiang, Lei [Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041 (China); Wu, Xiaohua, E-mail: wuxh@scu.edu.cn [Regenerative Medicine Research Center, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041 (China)

2014-12-01

Dioscin has shown cytotoxicity against cancer cells, but its in vivo effects and the mechanisms have not elucidated yet. The purpose of the current study was to assess the antitumor effects and the molecular mechanisms of dioscin. We showed that dioscin could inhibit tumor growth in vivo and has no toxicity at the test condition. The growth suppression was accompanied by obvious blood vessel decrease within solid tumors. We also found dioscin treatment inhibited the proliferation of cancer and endothelial cell lines, and most sensitive to primary cultured human umbilical vein endothelial cells (HUVECs). What's more, analysis of HUVECs migration, invasion, and tube formation exhibited that dioscin has significantly inhibitive effects to these actions. Further analysis of blood vessel formation in the matrigel plugs indicated that dioscin could inhibit VEGF-induced blood vessel formation in vivo. We also identified that dioscin could suppress the downstream protein kinases of VEGFR2, including Src, FAK, AKT and Erk1/2, accompanied by the increase of phosphorylated P38MAPK. The results potently suggest that dioscin may be a potential anticancer drug, which efficiently inhibits angiogenesis induced by VEGFR2 signaling pathway as well as AKT/MAPK pathways. - Highlights: • Dioscin inhibits tumor growth in vivo and does not exhibit any toxicity. • Dioscin inhibits angiogenesis within solid tumors. • Dioscin inhibits the proliferation, migration, invasion, and tube formation of HUVECs. • Dioscin inhibits VEGF–induced blood vessel formation in vivo. • Dioscin inhibits VEGFR2 signaling pathway as well as AKT/MAPK pathway.

Understanding and Targeting Tumor Microenvironment in Prostate Cancer to Inhibit Tumor Progression and Castration Resistance

Science.gov (United States)

2016-10-01

cancer-secreted chemokine to attract Cxcr2-expressing MDSCs and, correspondingly, pharmacological inhibition of Cxcr2 impeded tumor progression...impact of pharmacological inhibition of Cxcl5 and Cxcr2 on MDSCs using the transwell migration assay 26 . First, anti-Cxcl5 neutralizing antibody...and MRI . (B) Generation of the CPPSML chimera model. (C) Fluorescence microscopy and H&E image of snap frozen prostate tumor from chimera showing that

Racemic ketamine decreases muscle sympathetic activity but maintains the neural response to hypotensive challenges in humans

NARCIS (Netherlands)

Kienbaum, P.; Heuter, T.; Michel, M. C.; Peters, J.

2000-01-01

BACKGROUND: Cardiovascular stimulation and increased catecholamine plasma concentrations during ketamine anesthesia have been attributed to increased central sympathetic activity as well as catecholamine reuptake inhibition in various experimental models. However, direct recordings of efferent

Perioperative Ketamine Administration for Thoracotomy Pain.

Science.gov (United States)

Moyse, Daniel W; Kaye, Alan D; Diaz, James H; Qadri, Muhammad Y; Lindsay, David; Pyati, Srinivas

2017-03-01

Of all the postsurgical pain conditions, thoracotomy pain poses a particular therapeutic challenge in terms of its prevalence, severity, and ensuing postoperative morbidity. Multiple pain generators contribute to the severity of post-thoracotomy pain, and therefore a multimodal analgesic therapy is considered to be a necessary strategy. Along with opioids, thoracic epidural analgesia, and paravertebral blocks, N-Methyl-D-Aspartate (NMDA) receptor antagonists such as ketamine have been used as adjuvants to improve analgesia. We reviewed the evidence for the efficacy of intravenous and epidural administration of ketamine in acute post-thoracotomy pain management, and its effectiveness in reducing chronic post-thoracotomy pain. Systematic literature review and an analytic study of a data subset were performed. We searched PubMed, Embase, and Cochrane reviews using the key terms "ketamine," "neuropathic pain," "postoperative," and "post-thoracotomy pain syndrome." The search was limited to human trials and included all studies published before January 2015. Data from animal studies, abstracts, and letters were excluded. All studies not available in the English language were excluded. The manuscript bibliographies were reviewed for additional related articles. We included randomized controlled trials and retrospective studies, while excluding individual case reports. This systematic literature search yielded 15 randomized control trials evaluating the efficacy of ketamine in the treatment of acute post-thoracotomy pain; fewer studies assessed its effect on attenuating chronic post-thoracotomy pain. The majority of reviewed studies demonstrated that ketamine has efficacy in reduction of acute pain, but the evidence is limited on the long-term benefits of ketamine to prevent post-thoracotomy pain syndrome, regardless of the route of administration. A nested analytical study found there is a statistically significant reduction in acute post-thoracotomy pain with IV or

Ketamine use in current clinical practice

Science.gov (United States)

Gao, Mei; Rejaei, Damoon; Liu, Hong

2016-01-01

After nearly half a century on the market, ketamine still occupies a unique corner in the medical armamentarium of anesthesiologists or clinicians treating pain. Over the last two decades, much research has been conducted highlighting the drug's mechanisms of action, specifically those of its enantiomers. Nowadays, ketamine is also being utilized for pediatric pain control in emergency department, with its anti-hyperalgesic and anti-inflammatory effects being revealed in acute and chronic pain management. Recently, new insights have been gained on ketamine's potential anti-depressive and antisuicidal effects. This article provides an overview of the drug's pharmacokinetics and pharmacodynamics while also discussing the potential benefits and risks of ketamine administration in various clinical settings. PMID:27018176

Ketamine for cancer pain: what is the evidence?

Science.gov (United States)

Jonkman, Kelly; van de Donk, Tine; Dahan, Albert

2017-06-01

In this review, we assess the benefit of ketamine in the treatment of terminal cancer pain that is refractory to opioid treatment and/or complicated by neuropathy. While randomized controlled trials consistently show lack of clinical efficacy of ketamine in treating cancer pain, a large number of open-label studies and case series show benefit. Ketamine is an N-methyl-D-aspartate receptor antagonist that at low-dose has effective analgesic properties. In cancer pain, ketamine is usually prescribed as adjuvant to opioid therapy when pain becomes opioid resistant or when neuropathic pain symptoms dominate the clinical picture. A literature search revealed four randomized controlled trials that examined the benefit of oral, subcutaneous or intravenous ketamine in opioid refractory cancer pain. None showed clinically relevant benefit in relieving pain or reducing opioid consumption. This suggests absence of evidence of benefit for ketamine as adjuvant analgesic in cancer pain. These findings contrast the benefit from ketamine observed in a large number of open-label studies and (retrospective) case series. We relate the opposite outcomes to methodological issues. The complete picture is such that there is still insufficient evidence to state with certainty that ketamine is not effective in cancer pain.

Antidepressant action of ketamine via mTOR is mediated by inhibition of nitrergic Rheb degradation.

Science.gov (United States)

Harraz, M M; Tyagi, R; Cortés, P; Snyder, S H

2016-03-01

As traditional antidepressants act only after weeks/months, the discovery that ketamine, an antagonist of glutamate/N-methyl-D-aspartate (NMDA) receptors, elicits antidepressant actions in hours has been transformative. Its mechanism of action has been elusive, though enhanced mammalian target of rapamycin (mTOR) signaling is a major feature. We report a novel signaling pathway wherein NMDA receptor activation stimulates generation of nitric oxide (NO), which S-nitrosylates glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Nitrosylated GAPDH complexes with the ubiquitin-E3-ligase Siah1 and Rheb, a small G protein that activates mTOR. Siah1 degrades Rheb leading to reduced mTOR signaling, while ketamine, conversely, stabilizes Rheb that enhances mTOR signaling. Drugs selectively targeting components of this pathway may offer novel approaches to the treatment of depression.

Investigating altered nitric oxide signalling as an up-stream mediator of the antidepressant action of ketamine

DEFF Research Database (Denmark)

Liebenberg, N.; Muller, H. K.; Elfving, B.

2012-01-01

Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect in depre......Background and Aim: Stress-induced excessive glutamate transmission at N-methyl-D-aspartate (NMDA) receptors may underlie a major mechanism in the pathophysiology that leads to depression, while ketamine, an NMDA receptor antagonist, has been shown to induce a rapid antidepressant effect...... in depressed patients following a single intravenous administration that is sustained for (plus or minus) 7 days. A number of downstream cellular mechanisms appear to mediate the antidepressant action of ketamine, and the majority of evidence point to a rapid activation of protein translation leading...... to and activated by NMDA receptors, while the uncoupling of the nNOS-NMDA receptor complex prevents NMDA-induced excitotoxicity. Thus, it is possible that the inhibition of nitric oxide (NO) signalling underlies a key upstream mechanism in the antidepressant action of ketamine. Methods: We used a genetic rat model...

Ketamine cystitis: Its urological impact and management

Directory of Open Access Journals (Sweden)

Yao Chou Tsai

2015-09-01

Full Text Available Ketamine, an n-methyl-d-aspartic acid receptor complex antagonist, has been used as an anesthetic and/or analgesic. However, in the past decade, ketamine has been illegally available as a recreational drug in Asian countries and Taiwan. Due to the characteristic of being short-acting, youngsters widely assume that ketamine is not as harmful as other drugs, such as heroin. Consequently, many young patients used this drug for a longer duration before they presented with severe urinary frequency and urgency symptoms. Subsequently, other cases have been reported in Taiwan, Hong Kong, Singapore, Malaysia, and Europe. Ketamine abuse is increasing, with rates of 0.30% in 2006 to 0.40% in 2007 among those in the 16–59 year age group. In general, affected patients tend to be young with a peak age range of 16–35 years. The incidence of lower urinary tract symptoms in ketamine abuse patients is around 30%. The actual underlying pathomechanism of ketamine cystitis (KC and associated pelvic pain remains unclear. It is speculated that chronic contact and stimulation to the bladder or ureteral mucosa due to metabolites of ketamine will result in submucosal edema, vascular ectasia, fibrosis, detrusor muscle inflammation, and fibrosis. Presentations of KC include remarkable dysuria, urinary frequency/urgency, urge incontinence, and bladder pain. Urine culture usually fails to yield any microbiology in KC with bladder pain alone. The majority of patients can enjoy clinical improvement after cessation of ketamine and urological treatment similar to interstitial cystitis/bladder pain syndrome (IC/BPS. However, patients who are still abusing ketamine and/or who have a longer duration of ketamine abuse might suffer from severe bladder pain, which does not respond to empirical oral or intravesical treatments such as hyaluronic acid. Among these patients, most have a remarkably impaired quality of life and are at risk of developing upper urinary tract damage

Ketamine produces lasting disruptions in encoding of sensory stimuli.

Science.gov (United States)

Maxwell, Christina R; Ehrlichman, Richard S; Liang, Yuling; Trief, Danielle; Kanes, Stephen J; Karp, Jonathan; Siegel, Steven J

2006-01-01

The current study analyzed the acute, chronic, and lasting effects of ketamine administration in four inbred mouse strains (C3H/HeHsd, C57BL/6Hsd, FVB/Hsd, and DBA/2Hsd) to evaluate vulnerability to ketamine as a drug of abuse and as a model of schizophrenia. Serum half-life of ketamine was similar between all strains (approximately 13 min). Also, the ratio of brain-to-serum ketamine levels was 3:1. Examination of multiple phases of auditory processing using auditory-evoked potentials (AEPs) following acute ketamine (0, 5, and 20 mg/kg) treatment revealed C3H/HeHsd mice to be most vulnerable to ketamine-induced alterations in AEPs, whereas FVB/Hsd mice exhibited the least electrophysiological sensitivity to ketamine. Overall, the precortical P1-evoked potential component increased in amplitude and latency, whereas the cortically generated N1 and P2 components decreased in amplitude and latency following acute ketamine across all strains. Brain catecholamine analyses indicated that ketamine decreased hippocampus epinephrine levels in C3H/HeHsd but elevated hippocampus epinephrine levels in FVB/Hsd, suggesting one potential mechanism for AEP vulnerability to ketamine. Based on results of the acute study, the immediate and lasting effects of chronic low-dose ketamine on AEPs were examined among C3H/HeHsd (sensitive) and FVB/Hsd (insensitive) mice. We observed a decrement of the N1 amplitude that persisted at least 1 week after the last exposure to ketamine across both strains. This lasting deficit in information processing occurred in the absence of acute changes among the FVB/Hsd mice. Implications for both ketamine abuse and N-methyl-D-aspartate hypofunction models of schizophrenia are discussed.

Spinal conduction block by intrathecal ketamine in dogs.

Science.gov (United States)

Iida, H; Dohi, S; Tanahashi, T; Watanabe, Y; Takenaka, M

1997-07-01

In addition to its use for intravenous (I.V.) anesthesia, ketamine can provide pain relief in humans when administered spinally. To elucidate the mechanisms of intrathecal (I.T.) ketamine analgesia, we observed differences in the effects of I.V. and I.T. ketamine on intraspinal evoked potentials (ISEPs) in 28 dogs anesthetized with pentobarbital. Bipolar extradural electrodes were inserted at the cervical and lumbar regions of the spinal cord for recording descending ISEPs represented by the two negative deflections, Waves I and II. I.V. ketamine 2 and 10 mg/ kg did not affect the amplitude and latency of Wave I, whereas the large dose (10 mg/kg) significantly decreased the amplitude but not the latency of Wave II. I.T. ketamine 1 and 5 mg/kg caused significant dose-dependent decreases in both Wave I and II amplitudes and prolongations of both Wave I and II latencies. These I.T. effects on ISEPs are consistent with previous in vitro observations that ketamine blocks axonal conduction. We conclude that axonal conduction block may contribute to the analgesic mechanism of I.T. ketamine.

Ketamine and the Obstetric Patient

African Journals Online (AJOL)

1974-04-13

Apr 13, 1974 ... Dream recall was more frequent in the ketamine series, but most dreams seemed to be pleasant in nature (Table ID. Total No. of cases. Definite 1Painful factual recall. Painless. Doubtful recall. Ketamine anaesthesia was administered to 135 mothers undergoing Caesarean section. The incidence of aware-.

Effects of the selective 5-HT7 receptor antagonist SB-269970 and amisulpride on ketamine-induced schizophrenia-like deficits in rats.

Directory of Open Access Journals (Sweden)

Agnieszka Nikiforuk

Full Text Available A wide body of evidence suggests that 5-HT7 receptors are implicated in a variety of central nervous system functions, including control of learning and memory processes. According to recent preclinical data, the selective blockade of these receptors may be a potential target for cognitive improvement in schizophrenia. The first aim of the present study was to evaluate the effects of the selective 5-HT7 receptor antagonist, SB-269970, and the antipsychotic drug with a high affinity for 5-HT7 receptors, amisulpride, on ketamine-induced deficits in attentional set-shifting and novel object recognition tasks in rats. Because the role of 5-HT7 receptor blockade in ameliorating positive and negative symptoms of schizophrenia remains equivocal, the second aim of these experiments was to examine the effectiveness of SB-269970 and amisulpride in reversing ketamine-induced deficits in prepulse inhibition of the startle reflex and in social interaction test in rats. The study revealed that acute administration of SB-269970 (1 mg/kg or amisulpride (3 mg/kg ameliorated ketamine-induced cognitive inflexibility and novel object recognition deficit in rats. Both compounds were also effective in attenuating ketamine-evoked disruption of social interactions. In contrast, neither SB-269970 nor amisulpride affected ketamine-disrupted prepulse inhibition or 50 kHz USVs accompanying social behaviour. In conclusion, antagonism of 5-HT7 receptors may represent a useful pharmacological approach in the treatment of cognitive deficits and some negative symptoms of schizophrenia.

The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition.

Science.gov (United States)

Zanos, Panos; Piantadosi, Sean C; Wu, Hui-Qiu; Pribut, Heather J; Dell, Matthew J; Can, Adem; Snodgrass, H Ralph; Zarate, Carlos A; Schwarcz, Robert; Gould, Todd D

2015-10-01

Currently approved antidepressant drug treatment typically takes several weeks to be effective. The noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist ketamine has shown efficacy as a rapid-acting treatment of depression, but its use is associated with significant side effects. We assessed effects following blockade of the glycineB co-agonist site of the NMDA receptor, located on the GluN1 subunit, by the selective full antagonist 7-chloro-kynurenic acid (7-Cl-KYNA), delivered by systemic administration of its brain-penetrant prodrug 4-chlorokynurenine (4-Cl-KYN) in mice. Following administration of 4-Cl-KYN, 7-Cl-KYNA was promptly recovered extracellularly in hippocampal microdialysate of freely moving animals. The behavioral responses of the animals were assessed using measures of ketamine-sensitive antidepressant efficacy (including the 24-hour forced swim test, learned helplessness test, and novelty-suppressed feeding test). In these tests, distinct from fluoxetine, and similar to ketamine, 4-Cl-KYN administration resulted in rapid, dose-dependent and persistent antidepressant-like effects following a single treatment. The antidepressant effects of 4-Cl-KYN were prevented by pretreatment with glycine or the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione (NBQX). 4-Cl-KYN administration was not associated with the rewarding and psychotomimetic effects of ketamine, and did not induce locomotor sensitization or stereotypic behaviors. Our results provide further support for antagonism of the glycineB site for the rapid treatment of treatment-resistant depression without the negative side effects seen with ketamine or other channel-blocking NMDA receptor antagonists. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

3-Bromopyruvate inhibits human gastric cancer tumor growth in nude mice via the inhibition of glycolysis.

Science.gov (United States)

Xian, Shu-Lin; Cao, Wei; Zhang, Xiao-Dong; Lu, Yun-Fei

2015-02-01

Tumor cells primarily depend upon glycolysis in order to gain energy. Therefore, the inhibition of glycolysis may inhibit tumor growth. Our previous study demonstrated that 3-bromopyruvate (3-BrPA) inhibited gastric cancer cell proliferation in vitro . However, the ability of 3-BrPA to suppress tumor growth in vivo, and its underlying mechanism, have yet to be elucidated. The aim of the present study was to investigate the inhibitory effect of 3-BrPA in an animal model of gastric cancer. It was identified that 3-BrPA exhibited strong inhibitory effects upon xenograft tumor growth in nude mice. In addition, the antitumor function of 3-BrPA exhibited a dose-effect association, which was similar to that of the chemotherapeutic agent, 5-fluorouracil. Furthermore, 3-BrPA exhibited low toxicity in the blood, liver and kidneys of the nude mice. The present study hypothesized that the inhibitory effect of 3-BrPA is achieved through the inhibition of hexokinase activity, which leads to the downregulation of B-cell lymphoma 2 (Bcl-2) expression, the upregulation of Bcl-2-associated X protein expression and the subsequent activation of caspase-3. These data suggest that 3-BrPA may be a novel therapy for the treatment of gastric cancer.

Oral ketamine for radiotherapy in children with cancer

International Nuclear Information System (INIS)

Shewale, S.; Saxena, Abha; Trikha, Anjan; Singh, Manorama; Sharief, Abeda

2000-01-01

Children coming for radiotherapy under sedation usually get repeated injections, which cause distress to both the child and the parents. A prospective study was conducted to evaluate the efficacy of oral ketamine for sedation for radiotherapy (RT) in children with cancer. Ten children who received 49 sittings of RT were given 8-15 mg/kg body weight of oral ketamine. The onset time, recovery time, efficacy of sedation and incidence of abnormal movements were compared with another group of 8 children, who received intramuscular ketamine in the dose of 6 mg/kg for a total of 28 sittings of RT. Onset time and recovery time were significantly longer in oral ketamine group as compared to the intramuscular group (p<0.001). Limb movements in patients receiving oral ketamine necessitated further supplement of sedation and interruption of RT. These drawbacks discourage use of oral ketamine as a good sedative for radiotherapy treatment in paediatric oncology patients. (author)

Peripheral analgesic effects of ketamine in acute inflammatory pain

DEFF Research Database (Denmark)

Pedersen, J L; Galle, T S; Kehlet, H

1998-01-01

BACKGROUND. This study examined the analgesic effect of local ketamine infiltration, compared with placebo and systemic ketamine, in a human model of inflammatory pain. METHODS: Inflammatory pain was induced by a burn (at 47 degrees C for 7 min; wound size, 2.5 x 5 cm) on the calf in 15 volunteers...... on 3 separate days with 7-day intervals. They received either (1) subcutaneous infiltration with ketamine in the burn area (local treatment) and contralateral placebo injections, or (2) subcutaneous ketamine contralateral to the burn (systemic treatment) and placebo in the burn area, or (3) placebo...... hyperalgesia. Local ketamine infiltration reduced pain during the burn injury compared with systemic treatment and placebo (P ketamine treatment compared with placebo immediately after injection (P

Cognitive impairments in poly-drug ketamine users.

Science.gov (United States)

Liang, H J; Lau, C G; Tang, A; Chan, F; Ungvari, G S; Tang, W K

2013-11-01

Cognitive impairment has been found to be reversible in people with substance abuse, particularly those using ketamine. Ketamine users are often poly-substance users. This study compared the cognitive functions of current and former ketamine users who were also abusing other psychoactive substances with those of non-users of illicit drugs as controls. One hundred ketamine poly-drug users and 100 controls were recruited. Drug users were divided into current (n = 32) and ex-users (n = 64) according to the duration of abstinence from ketamine (>30 days). The Beck Depression Inventory (BDI), the Hospital Anxiety Depression Scale (HADSA) and the Severity of Dependence Scale (SDS) were used to evaluate depression and anxiety symptoms and the severity of drug use, respectively. The cognitive test battery comprised verbal memory (Wechsler Memory Scale III: Logic Memory and Word List), visual memory (Rey-Osterrieth Complex Figure, ROCF), executive function (Stroop, Wisconsin Card Sorting Test, and Modified Verbal Fluency Test), working memory (Digit Span Backward), and general intelligence (Information, Arithmetic and Digit-Symbol Coding) tests. Current users had higher BDI and HADSA scores than ex-users (p recognition than controls (p = 0.002). No difference was found between the cognitive functions of current and ex-users. Ketamine poly-drug users displayed predominantly verbal and visual memory impairments, which persisted in ex-users. The interactive effect of ketamine and poly-drug use on memory needs further investigation. © 2013 Elsevier Ltd. All rights reserved.

The effect of ketamine on intraspinal acetylcholine release

DEFF Research Database (Denmark)

Abelson, Klas S P; Goldkuhl, Renée Röstlinger; Nylund, Anders

2006-01-01

The general anaesthetic ketamine affects the central cholinergic system in several manners, but its effect on spinal acetylcholine release, which may be an important transmitter in spinal antinociception, is unknown. This study aimed to investigate the effect of ketamine on spinal acetylcholine...... release. Microdialysis probes were placed intraspinally in male rats, and acetylcholine was quantified with HPLC. Anaesthesia was switched from isoflurane (1.3%) to ketamine (150 mg/kg h), which resulted in a 500% increased acetylcholine release. The increase was attenuated during nicotinic receptor...... blockade (50 microM mecamylamine). The nicotinic receptor agonist epibatidine (175 microM) produced a ten-fold higher relative increase of acetylcholine release during isoflurane anaesthesia compared to ketamine anaesthesia (270% to 27%). Intraspinal administration of ketamine and norketamine both...

Combination of aspartic acid and glutamic acid inhibits tumor cell proliferation.

Science.gov (United States)

Yamaguchi, Yoshie; Yamamoto, Katsunori; Sato, Yoshinori; Inoue, Shinjiro; Morinaga, Tetsuo; Hirano, Eiichi

2016-01-01

Placental extract contains several biologically active compounds, and pharmacological induction of placental extract has therapeutic effects, such as improving liver function in patients with hepatitis or cirrhosis. Here, we searched for novel molecules with an anti-tumor activity in placental extracts. Active molecules were separated by chromatographic analysis, and their antiproliferative activities were determined by a colorimetric assay. We identified aspartic acid and glutamic acid to possess the antiproliferative activity against human hepatoma cells. Furthermore, we showed that the combination of aspartic acid and glutamic acid exhibited enhanced antiproliferative activity, and inhibited Akt phosphorylation. We also examined in vivo tumor inhibition activity using the rabbit VX2 liver tumor model. The treatment mixture (emulsion of the amino acids with Lipiodol) administered by hepatic artery injection inhibited tumor cell growth of the rabbit VX2 liver. These results suggest that the combination of aspartic acid and glutamic acid may be useful for induction of tumor cell death, and has the potential for clinical use as a cancer therapeutic agent.

Radiographic assessment of laryngeal reflexes in ketamine-anesthetized cats

International Nuclear Information System (INIS)

Robinson, E.P.; Johnston, G.R.

1986-01-01

The competence of the laryngeal closure reflexes of cats anesthetized with ketamine was assessed. Radiographic evaluations of the respiratory and digestive tracts were made after colloidal barium suspension was instilled into the pharynges of conscious and ketamine-anesthetized cats. There was a significant ketamine dose-related response of spread of contrast medium into the supraglottic laryngeal area and into the stomach 2 minutes after contrast medium was instilled into the pharynx (P less than 0.05). Cats did not aspirate contrast medium into the lower respiratory tract. Three ketamine-anesthetized cats aspirated contrast medium into the subglottic area of the larynx, and 2 of these cats also aspirated the material into the cranial part of the trachea. This material was coughed up and swallowed within 5 minutes. Transit time of contrast medium into the stomach seemed to be increased in 11 of the 15 cats given the larger dosages of ketamine (24, 36, 48 mg/kg of body weight), compared with that in conscious cats and those given ketamine at 12 mg/kg. Competent laryngeal protective reflexes in cats can be maintained with ketamine anesthesia. Contrast radiography could be used as a diagnostic aid in ketamine-anesthetized cats suspected of laryngeal reflex abnormalities

Effects of subanesthetic doses of ketamine in cats with induced experimental endotoxemia

Directory of Open Access Journals (Sweden)

Felipe Hertzing Farias

2015-12-01

and lactate increase from 120 to 360 minutes compared to baseline in all groups. The leukocyte decreased from 60 to 360 minutes in all treatments compared to baseline. It is concluded that ketamine at subanesthetic doses, before or after induction of endotoxemia in cats has minimal cardiovascular effects, but does not inhibit or reverse hyperthermia and leukopenia produced by endotoxemia in cats.

Comparison Of Oral Premedication With Combination Of Midazolam With Ketamine Vs Midazolam Ketamine Alone In Children Children Medical Center (year 2000

Directory of Open Access Journals (Sweden)

Hasani M

2002-09-01

Full Text Available Anxiolysis and sedation with oral midazolam are common practice in pediatric anesthesia. Good or excellent results are seen in only 50% to 80% of cases, so we decided to investigate if addition of a low dose of oral ketamine to midazolam (ketamine2.5 mg /kg ^midazolam 0.25 mg/kg resulted in better premedication compared with oral midazolam 0.5 mg/kg or ketamine 6 mg/kg alone."nMethods and Materials: in a prospective, randomized ,double -blind study we study 105 children (mean age 6 ,range 2-10 yr. undergoing non thoracic and non cardiac surgery of more than 30 min duration. The patients were in ASA 1, 2. After oral premedication the child's condition was evaluated by assigning 1-4 point to the quality of anxiolysis, sedation, and separation from parents in the induction room .The groups were similar in sex, age, weight, intervention and duration of anaesthesia."nResults: The score of sedation before transfer to the operation room was significantly better in the ketamine, midazolam combination group than in the ketamine or midazolam group. Success rates for anxiolysis and behavior at separation were grater than 90%with the combination, approximately 80% with midazolam and 70% with ketamine alone .The incidence of salivation, excitation, nausea and vomiting was grater in the ketamine group but were very low in other groups. During recovery there were no difference in sedation or time of possible discharge."nConclusion: In summery, significantly better anxiolysis and separation were observed with a combination of ketamine and midazolam, even in awake children than with midazolam or ketamine alone. Duration of action and side effects of the combination was similar to those of midazolam.

Use of Ketamine in Elderly Patients with Treatment-Resistant Depression.

Science.gov (United States)

Medeiros da Frota Ribeiro, Carolina; Riva-Posse, Patricio

2017-11-15

The purpose of this paper is to provide a review of the use of ketamine as an antidepressant for treatment-resistant depression (TRD) in the geriatric population. Available treatment options for late-life treatment-resistant depression are limited and include electroconvulsive therapy and transcranial magnetic stimulation as well as possible pharmacologic augmentation. Ketamine has been shown to be a promising treatment in TRD; however, data regarding the use of ketamine in the elderly includes only five case reports. We discuss the use of ketamine for late-life TRD and present two cases where ketamine led to a significant and sustained improvement in depressive symptoms. Ketamine is a promising treatment for geriatric patients with TRD. Further studies in the elderly will provide valuable insights into the use of ketamine for a population much in need of safe and effective treatments for TRD.

Intravenous sub-anesthetic ketamine for perioperative analgesia

Directory of Open Access Journals (Sweden)

Andrew W Gorlin

2016-01-01

Full Text Available Ketamine, an N-methyl-d-aspartate antagonist, blunts central pain sensitization at sub-anesthetic doses (0.3 mg/kg or less and has been studied extensively as an adjunct for perioperative analgesia. At sub-anesthetic doses, ketamine has a minimal physiologic impact though it is associated with a low incidence of mild psychomimetic symptoms as well as nystagmus and double vision. Contraindications to its use do exist and due to ketamine′s metabolism, caution should be exercised in patients with renal or hepatic dysfunction. Sub-anesthetic ketamine improves pain scores and reduces perioperative opioid consumption in a broad range of surgical procedures. In addition, there is evidence that ketamine may be useful in patients with opioid tolerance and for preventing chronic postsurgical pain.

A PK-PD model of ketamine-induced high-frequency oscillations

Science.gov (United States)

Flores, Francisco J.; Ching, ShiNung; Hartnack, Katharine; Fath, Amanda B.; Purdon, Patrick L.; Wilson, Matthew A.; Brown, Emery N.

2015-10-01

Objective. Ketamine is a widely used drug with clinical and research applications, and also known to be used as a recreational drug. Ketamine produces conspicuous changes in the electrocorticographic (ECoG) signals observed both in humans and rodents. In rodents, the intracranial ECoG displays a high-frequency oscillation (HFO) which power is modulated nonlinearly by ketamine dose. Despite the widespread use of ketamine there is no model description of the relationship between the pharmacokinetic-pharmacodynamics (PK-PDs) of ketamine and the observed HFO power. Approach. In the present study, we developed a PK-PD model based on estimated ketamine concentration, its known pharmacological actions, and observed ECoG effects. The main pharmacological action of ketamine is antagonism of the NMDA receptor (NMDAR), which in rodents is accompanied by an HFO observed in the ECoG. At high doses, however, ketamine also acts at non-NMDAR sites, produces loss of consciousness, and the transient disappearance of the HFO. We propose a two-compartment PK model that represents the concentration of ketamine, and a PD model based in opposing effects of the NMDAR and non-NMDAR actions on the HFO power. Main results. We recorded ECoG from the cortex of rats after two doses of ketamine, and extracted the HFO power from the ECoG spectrograms. We fit the PK-PD model to the time course of the HFO power, and showed that the model reproduces the dose-dependent profile of the HFO power. The model provides good fits even in the presence of high variability in HFO power across animals. As expected, the model does not provide good fits to the HFO power after dosing the pure NMDAR antagonist MK-801. Significance. Our study provides a simple model to relate the observed electrophysiological effects of ketamine to its actions at the molecular level at different concentrations. This will improve the study of ketamine and rodent models of schizophrenia to better understand the wide and divergent

Oral ketamine for the treatment of pain and treatment-resistant depression†.

Science.gov (United States)

Schoevers, Robert A; Chaves, Tharcila V; Balukova, Sonya M; Rot, Marije Aan Het; Kortekaas, Rudie

2016-02-01

Recent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications. To review the literature about the dosing regimen, duration, effects and side-effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for treatment-resistant depression and pain. Searches in PubMed with the terms 'oral ketamine', 'depression', 'chronic pain', 'neuropathic pain', 'intravenous ketamine', 'intranasal ketamine' and 'subcutaneous ketamine' yielded 88 articles. We reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects, as well as study quality. Overall, the methodological strength of studies investigating the antidepressant effects of ketamine was considered low, regardless of the route of administration. The doses for depression were in the lower range compared with studies that investigated analgesic use. Studies on pain suggested that oral ketamine may be acceptable for treatment-resistant depression in terms of tolerability and side-effects. Oral ketamine, given for longer time periods in the described doses, appears to be well tolerated, but few studies have systematically examined the longer-term negative consequences. The short- and longer-term depression outcomes as well as side-effects need to be studied with rigorous randomised controlled trials. © The Royal College of Psychiatrists 2016.

Migration inhibition of immune mouse spleen cells by serum from x-irradiated tumor-bearing mice

International Nuclear Information System (INIS)

Moroson, H.

1978-01-01

Tumor-specific antigens of the chemically induced MC 429 mouse fibrosarcoma were detected in a 3 M KCl extract of tumor by the inhibition of migration of specifically immune spleen cells. Using this assay with serum from tumor-bearing mice no tumor antigen was detected in serum of mice bearing small tumors, unless the tumor was exposed to local x irradiation (3000 R) 1 day prior to collection of serum. It was concluded that local x irradiation of tumor caused increased concentration of tumor antigen in the serum. When the tumor was allowed to grow extremely large, with necrosis, then host serum did cause migration inhibition of both nonimmune and immune spleen cells. This migration-inhibition effect was not associated with tumor antigen, but with a nonspecific serum factor

Failure of Ketamine Anesthesia in a Patient with Lamotrigine Overdose

Directory of Open Access Journals (Sweden)

Daniel Kornhall

2014-01-01

Full Text Available Introduction. It is important to know which clinical situations prevent ketamine from working. Case Report. We present the case of the psychiatric inpatient who was admitted to our emergency department after ingesting a toxic dose of lamotrigine, unknown at that time. On admission, she was clearly in distress, displaying extreme agitation and violent ataxic movements. We opted to achieve sedation using intravenous ketamine boluses. Unexpectedly, after being injected with a total of 250 mg ketamine, our patient displayed no signs of dissociative anaesthesia. Discussion. There was no apparent reason for why ketamine failed, but an interaction between lamotrigine and ketamine was suspected. A literature search was performed. Very few articles describe interactions between lamotrigine and ketamine. Experimental studies, however, demonstrate how lamotrigine attenuates the neuropsychiatric effects of ketamine. Ketamine is classically described as an NMDA antagonist. Ketamine’s dissociative effects, however, are thought to be mediated by increased glutamate release via a pathway not dependent on NMDA receptors. Lamotrigine, on the other hand, is known to reduce cortical glutamate release. Conclusion. Lamotrigine reduces the glutamate release needed to mediate ketamine’s dissociative anaesthesia. This is important knowledge for anaesthesiologists in the emergency room where ketamine is often administered to unstable patients.

Brain damages in ketamine addicts as revealed by magnetic resonance imaging

Directory of Open Access Journals (Sweden)

Chunmei eWang

2013-07-01

Full Text Available Ketamine, a known antagonist of N-methyl-D-aspartic (NMDA glutamate receptors, had been used as an anesthetic particularly for pediatric or for cardiac patients. Unfortunately, ketamine has become an abusive drug in many parts of the world while chronic and prolonged usage led to damages of many organs including the brain. However, no studies on possible damages in the brains induced by chronic ketamine abuse have been documented in the human via neuroimaging. This paper described for the first time via employing magnetic resonance imaging (MRI the changes in ketamine addicts of 0.5 to 12 years and illustrated the possible brain regions susceptible to ketamine abuse. Twenty-one ketamine addicts were recruited and the results showed that the lesions in the brains of ketamine addicts were located in many regions which appeared 2-4 years after ketamine addiction. Cortical atrophy was usually evident in the frontal, parietal or occipital cortices of addicts. Such study confirmed that many brain regions in the human were susceptible to chronic ketamine injury and presented a diffuse effect of ketamine on the brain which might differ from other central nervous system (CNS drugs, such as cocaine, heroin and methamphetamine.

A consideration of ketamine dreams.

Science.gov (United States)

Hejja, P; Galloon, S

1975-01-01

This study was designed to see whether covering of the eyes during and after ketamine anaesthesia would reduce the incidence of dreams. One hundred and fifty patients, randomly divided into three groups, underwent therapeutic abortion with ketamine as the sole anaesthesia. One hundred patients had their eyes completely covered, 50 in the operating room only and 50 in the operating room and in the recovery room. The third 50 were controls, with their eyes uncovered. All patients were questioned post-operatively about dreams, nausea and vomiting, headache, dizziness and experiences, and also how frequently they dreamed at home. Although covering the eyes in the recovery room only reduced the incidence of dreams marginally, it became obvious that the patients who dreamed after ketamine (in all 3 groups) were those who normally dreamed at home. There were 82 patients who were recorded as not being home-dreamers, and only two of these dreamed after ketamine. In contrast, of the 68 home-dreamers, 50 dreamed after ketamine, and 17 of these had unpleasant dreams. In the home-dreamers, covering the eyes reduced the incidence of dreams from 86 per cent in Group 1 to 72 per cent in Group 2 and 64 per cent in Group 3. It is suggested that goggles may be advantageous when dealing with home-dreamers, and a question about the patient's tendency to dream should be included in the preoperative questioning. Alterations in premedication and the use of a quiet dark room during recovery may even further reduce unpleasant dreams in this group.

Ketamine for Pain Management-Side Effects & Potential Adverse Events.

Science.gov (United States)

Allen, Cheryl A; Ivester, Julius R

2017-12-01

An old anesthetic agent, ketamine is finding new use in lower doses for analgesic purposes. There are concerns stemming from its potential side effects-specifically psychomimetic effects. These side effects are directly related to dose amount. The doses used for analgesic purposes are much lower than those used for anesthesia purposes. A literature review was performed to ascertain potential side effects and/or adverse events when using ketamine for analgesia purposes. The search included CINAHL, PubMed, and Ovid using the search terms "ketamine," "ketamine infusion," "pain," "adverse events," "practice guideline," and "randomized controlled trial." Searches were limited to full-text, peer-reviewed articles and systematic reviews. Initially 1,068 articles were retrieved. The search was then narrowed by using the Boolean connector AND with various search term combinations. After adjusting for duplication, article titles and abstracts were reviewed, leaving 25 articles for an in-depth analysis. Specific exclusion criteria were then applied. The literature supports the use of ketamine for analgesic purposes, and ketamine offers a nonopioid option for the management of some pain conditions. Because ketamine is still classified as an anesthetic agent, health care institutions should develop their own set of policies and protocols for the administration of ketamine. By using forethought and understanding of the properties of ketamine, appropriate care may be planned to mitigate potential side effects and adverse events so that patients are appropriately cared for and their pain effectively managed. Copyright © 2017 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects.

Science.gov (United States)

Burgdorf, Jeffrey; Zhang, Xiao-lei; Nicholson, Katherine L; Balster, Robert L; Leander, J David; Stanton, Patric K; Gross, Amanda L; Kroes, Roger A; Moskal, Joseph R

2013-04-01

Recent human clinical studies with the NMDA receptor (NMDAR) antagonist ketamine have revealed profound and long-lasting antidepressant effects with rapid onset in several clinical trials, but antidepressant effects were preceded by dissociative side effects. Here we show that GLYX-13, a novel NMDAR glycine-site functional partial agonist, produces an antidepressant-like effect in the Porsolt, novelty induced hypophagia, and learned helplessness tests in rats without exhibiting substance abuse-related, gating, and sedative side effects of ketamine in the drug discrimination, conditioned place preference, pre-pulse inhibition and open-field tests. Like ketamine, the GLYX-13-induced antidepressant-like effects required AMPA/kainate receptor activation, as evidenced by the ability of NBQX to abolish the antidepressant-like effect. Both GLYX-13 and ketamine persistently (24 h) enhanced the induction of long-term potentiation of synaptic transmission and the magnitude of NMDAR-NR2B conductance at rat Schaffer collateral-CA1 synapses in vitro. Cell surface biotinylation studies showed that both GLYX-13 and ketamine led to increases in both NR2B and GluR1 protein levels, as measured by Western analysis, whereas no changes were seen in mRNA expression (microarray and qRT-PCR). GLYX-13, unlike ketamine, produced its antidepressant-like effect when injected directly into the medial prefrontal cortex (MPFC). These results suggest that GLYX-13 produces an antidepressant-like effect without the side effects seen with ketamine at least in part by directly modulating NR2B-containing NMDARs in the MPFC. Furthermore, the enhancement of 'metaplasticity' by both GLYX-13 and ketamine may help explain the long-lasting antidepressant effects of these NMDAR modulators. GLYX-13 is currently in a Phase II clinical development program for treatment-resistant depression.

Differential interaction with the serotonin system by S-ketamine, vortioxetine, and fluoxetine in a genetic rat model of depression.

Science.gov (United States)

du Jardin, Kristian Gaarn; Liebenberg, Nico; Müller, Heidi Kaastrup; Elfving, Betina; Sanchez, Connie; Wegener, Gregers

2016-07-01

The mechanisms mediating ketamine's antidepressant effect have only been partly resolved. Recent preclinical reports implicate serotonin (5-hydroxytryptamine; 5-HT) in the antidepressant-like action of ketamine. Vortioxetine is a multimodal-acting antidepressant that is hypothesized to exert its therapeutic activity through 5-HT reuptake inhibition and modulation of several 5-HT receptors. The objective of this study was to evaluate the therapeutic-like profiles of S-ketamine, vortioxetine, and the serotonin reuptake inhibitor fluoxetine in response to manipulation of 5-HT tone. Flinders Sensitive Line (FSL) rats, a genetic model of depression, were depleted of 5-HT by repeated administration of 4-chloro-DL-phenylalanine methyl ester HCl (pCPA). Using pCPA-pretreated and control FSL rats, we investigated the acute and sustained effects of S-ketamine (15 mg/kg), fluoxetine (10 mg/kg), or vortioxetine (10 mg/kg) on recognition memory and depression-like behavior in the object recognition task (ORT) and forced swim test (FST), respectively. The behavioral phenotype of FSL rats was unaffected by 5-HT depletion. Vortioxetine, but not fluoxetine or S-ketamine, acutely ameliorated the memory deficits of FSL rats in the ORT irrespective of 5-HT tone. No sustained effects were observed in the ORT. In the FST, all three drugs demonstrated acute antidepressant-like activity but only S-ketamine had sustained effects. Unlike vortioxetine, the antidepressant-like responses of fluoxetine and S-ketamine were abolished by 5-HT depletion. These observations suggest that the acute and sustained antidepressant-like effects of S-ketamine depend on endogenous stimulation of 5-HT receptors. In contrast, the acute therapeutic-like effects of vortioxetine on memory and depression-like behavior may be mediated by direct activity at 5-HT receptors.

Subanesthetic, Subcutaneous Ketamine Infusion Therapy in the Treatment of Chronic Nonmalignant Pain.

Science.gov (United States)

Zekry, Olfat; Gibson, Stephen B; Aggarwal, Arun

2016-06-01

This study was designed to describe the efficacy and toxicity of subcutaneous ketamine infusions and sublingual ketamine lozenges for the treatment of chronic nonmalignant pain. Data were collected prospectively on 70 subjects managed in an academic, tertiary care hospital between 2007 and 2012 who received between 3 and 7 days of subanesthetic, subcutaneous ketamine infusion. Data were analyzed for efficacy, adverse effects, and reduction in use of opioid medication. We also analyzed whether subsequent treatment with sublingual ketamine lozenges resulted in longer-term efficacy of the beneficial effects of the initial ketamine infusion. There was a significant reduction in pain intensity measured by numerical rating scale (NRS) from mean of 6.38 before ketamine to 4.60 after ketamine (P ketamine infusion from a mean morphine equivalent dose (MMED) of 216 mg/day before ketamine to 89 mg/day after ketamine (P ketamine infusion was 59%. No subjects increased their use of opioids during their hospitalization for the ketamine infusion. A small proportion of subjects who responded to the infusion were continued on ketamine lozenges. This group was followed for between 3 months and 2 years. The use of ketamine lozenges after the infusion resulted in 31% of these subjects being able to cease their use of opioids compared with only 6% who did not receive ketamine lozenges. Eleven percent of subjects who received lozenges subsequently increased their opioid usage. Adverse effects were fairly common, but only mild, with 46% of patients experiencing light-headedness and dizziness, 25% tiredness and sedation, 12% headaches, 12% hallucinations, and 8% vivid dreams. Adverse effects were easily managed by reducing the rate of the ketamine infusion. The administration of subanesthetic, subcutaneous ketamine infusion was well tolerated, with mostly mild adverse effects and no serious adverse effects. The infusion provided significant pain relief in subjects who had failed a wide

Periostin Limits Tumor Response to VEGFA Inhibition

Directory of Open Access Journals (Sweden)

Ioanna Keklikoglou

2018-03-01

Full Text Available Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs under extended vascular-endothelial growth factor A (VEGFA blockade are dependent on periostin (POSTN, a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA+ stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2, an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs.

Ketamine Dependence in an Anesthesiologist: An Occupational Hazard?

OpenAIRE

Goyal, Shrigopal; Ambekar, Atul; Ray, Rajat

2014-01-01

Substance abuse among medical professionals is a cause for concern. Certain psychotropic substances such as ketamine are at easy dispense to anesthesiologists increasing the likelihood of misuse and dependence and raise several issues including safety of patients. We discuss a case demonstrating ketamine dependence in an anesthesiologist from India. The reported psychotropic effects of ketamine ranged from dissociation and depersonalization to psychotic experiences. There was also development...

Abnormalities in white matter microstructure associated with chronic ketamine use.

Science.gov (United States)

Edward Roberts, R; Curran, H Valerie; Friston, Karl J; Morgan, Celia J A

2014-01-01

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that has been found to induce schizophrenia-type symptoms in humans and is a potent and fast-acting antidepressant. It is also a relatively widespread drug of abuse, particularly in China and the UK. Acute administration has been well characterized, but the effect of extended periods of ketamine use-on brain structure in humans-remains poorly understood. We measured indices of white matter microstructural integrity and connectivity in the brain of 16 ketamine users and 16 poly-drug-using controls, and we used probabilistic tractography to quantify changes in corticosubcortical connectivity associated with ketamine use. We found a reduction in the axial diffusivity profile of white matter in a right hemisphere network of white matter regions in ketamine users compared with controls. Within the ketamine-user group, we found a significant positive association between the connectivity profile between the caudate nucleus and the lateral prefrontal cortex and dissociative experiences. These findings suggest that chronic ketamine use may be associated with widespread disruption of white matter integrity, and white matter pathways between subcortical and prefrontal cortical areas may in part predict individual differences in dissociative experiences due to ketamine use.

Revealing past memories: proactive interference and ketamine-induced memory deficits.

Science.gov (United States)

Chrobak, James J; Hinman, James R; Sabolek, Helen R

2008-04-23

Memories of events that occur often are sensitive to interference from memories of similar events. Proactive interference plays an important and often unexamined role in memory testing for spatially and temporally unique events ("episodes"). Ketamine (NMDA receptor antagonist) treatment in humans and other mammals induces a constellation of cognitive deficits, including impairments in working and episodic memory. We examined the effects of the ketamine (2.5-100 mg/kg) on the acquisition, retrieval, and retention of memory in a delayed-match-to-place radial water maze task that can be used to assess proactive interference. Ketamine (2.5-25 mg/kg, i.p.) given 20 min before the sample trial, impaired encoding. The first errors made during the test trial were predominantly to arms located spatially adjacent to the goal arm, suggesting an established albeit weakened representation. Ketamine (25-100 mg/kg) given immediately after the sample trial had no effect on retention. Ketamine given before the test trial impaired retrieval. First errors under the influence of ketamine were predominantly to the goal location of the previous session. Thus, ketamine treatment promoted proactive interference. These memory deficits were not state dependent, because ketamine treatment at both encoding and retrieval only increased the number of errors during the test session. These data demonstrate the competing influence of distinct memory representations during the performance of a memory task in the rat. Furthermore, they demonstrate the subtle disruptive effects of the NMDA antagonist ketamine on both encoding and retrieval. Specifically, ketamine treatment disrupted retrieval by promoting proactive interference from previous episodic representations.

Versatility of Ketamine

Directory of Open Access Journals (Sweden)

MC Rajesh

2017-07-01

Full Text Available In the present day anaesthesia practice, ketamine is not routinely used as an induction agent. But it is a popular pharmacological agent in variety of pain conditions from nociceptive to neuropathic pains and for paediatric procedural sedation outside operation theatre complex. Of late, there is a renewed enthusiasm with regard to use of Ketamine for variety of indications like pain relief in pre hospital trauma victims, as an antidepressant, anticonvulsant, to prevent post operative sore throat and even in renal colic. Following text is a narrative review on the recent evidences with regard to pharmacology of the agent for its extended indications other than in day to day anaesthesia practice.

A review of the use of ketamine in pain management.

Science.gov (United States)

Tawfic, Qutaiba A

2013-01-01

Ketamine is a noncompetitive antagonist of N-methyl-d-aspartate receptor. It has been widely used in anesthesia and pain management. Ketamine has been administered via the intravenous, intramuscular, subcutaneous, oral, rectal, topical, intranasal, sublingual, epidural, and caudal routes. Ketamine improves postoperative and posttrauma pain scores and reduces opioid consumption. It has special indication for patients with opioid tolerance, acute hyperalgesia, and neuropathic pain. It also has a role in the management of chronic pain including both cancer and noncancer pain. Recreational use of ketamine is increasing as well through different routes of administration like inhalation, smoking, or intravenous injection. Long-time exposure to ketamine, especially in the abusers, may lead to serious side effects. This review is trying to define the role of ketamine in pain management.

Ketamine for Analgosedation in the Intensive Care Unit: A Systematic Review.

Science.gov (United States)

Patanwala, Asad E; Martin, Jennifer R; Erstad, Brian L

2017-07-01

To evaluate the evidence for the use of intravenous ketamine for analgosedation in the intensive care unit. MEDLINE and EMBASE were queried from inception until July 2015. Search terms used included ketamine, intensive care, and critical care. The search retrieved 584 articles to be screened for inclusion. The intent was to include randomized controlled studies using sustained intravenous infusions (>24 hours) of ketamine in the critically ill patients. One trial evaluated opioid consumption as an outcome in postoperative critically ill patients who were randomized to ketamine or saline infusions. The mean cumulative morphine consumption at 48 hours was significantly lower in the ketamine group (58 ± 35 mg) compared to the morphine-only group (80 ± 37 mg; P ketamine in terms of cerebral hemodynamics in patients with traumatic brain injury, improved gastrointestinal motility, and decreased vasopressor requirements. The observational study and case reports suggest that ketamine is safe and effective and may have a role in patients who are refractory to other therapies. Ketamine use may decrease analgesic consumption in the intensive care unit. Additional trials are needed to further delineate the role of ketamine for analgosedation.

Luteolin inhibits the Nrf2 signaling pathway and tumor growth in vivo

Energy Technology Data Exchange (ETDEWEB)

Chian, Song; Thapa, Ruby; Chi, Zhexu [Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058 (China); Wang, Xiu Jun [Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058 (China); Tang, Xiuwen, E-mail: xiuwentang@zju.edu.cn [Department of Biochemistry and Genetics, School of Medicine, Zhejiang University, Hangzhou 310058 (China)

2014-05-16

Highlights: • Luteolin inhibits the Nrf2 pathway in mouse liver and in xenografted tumors. • Luteolin markedly inhibits the growth of xenograft tumors. • Luteolin enhances the anti-cancer effect of cisplatin in mice in vivo. • Luteolin could serve as an adjuvant in the chemotherapy of NSCLC. - Abstract: Nuclear factor erythroid 2-related factor 2 (Nrf2) is over-expressed in many types of tumor, promotes tumor growth, and confers resistance to anticancer therapy. Hence, Nrf2 is regarded as a novel therapeutic target in cancer. Previously, we reported that luteolin is a strong inhibitor of Nrf2 in vitro. Here, we showed that luteolin reduced the constitutive expression of NAD(P)H quinone oxidoreductase 1 in mouse liver in a time- and dose-dependent manner. Further, luteolin inhibited the expression of antioxidant enzymes and glutathione transferases, decreasing the reduced glutathione in the liver of wild-type mice under both constitutive and butylated hydroxyanisole-induced conditions. In contrast, such distinct responses were not detected in Nrf2{sup −/−} mice. In addition, oral administration of luteolin, either alone or combined with intraperitoneal injection of the cytotoxic drug cisplatin, greatly inhibited the growth of xenograft tumors from non-small-cell lung cancer (NSCLC) cell line A549 cells grown subcutaneously in athymic nude mice. Cell proliferation, the expression of Nrf2, and antioxidant enzymes were all reduced in tumor xenograft tissues. Furthermore, luteolin enhanced the anti-cancer effect of cisplatin. Together, our findings demonstrated that luteolin inhibits the Nrf2 pathway in vivo and can serve as an adjuvant in the chemotherapy of NSCLC.

The prevalence and natural history of urinary symptoms among recreational ketamine users.

Science.gov (United States)

Winstock, Adam R; Mitcheson, Luke; Gillatt, David A; Cottrell, Angela M

2012-12-01

Study Type--Symptom prevalence (prospective cohort) Level of Evidence 1b. What's known on the subject? and What does the study add? Case series have described lower urinary tract symptoms associated with ketamine use including severe pain, frequency, haematuria and dysuria. Little is known regarding the frequency of symptoms, relationship of symptoms with dose and frequency of use and natural history of symptoms once the ketamine user has stopped. This study describes the prevalence of ketamine use in a population of recreational drug users in a dance music setting. It shows a dose-frequency relationship with ketamine use. It shows that urinary symptoms associated with recreational ketamine use may lead to a considerable demand on health resources in the primary-, secondary- and emergency-care settings. It shows that symptoms may improve once ketamine use is decreased. • To investigate the prevalence and natural history of urinary symptoms in a cohort of recreational ketamine users. • A purposeful sampling technique was used. • Between November 2009 and January 2010 participants were invited to undertake an on-line questionnaire promoted by a national dance music magazine and website. • Data regarding demographics and illicit drug-use were collected. • Among respondents reporting recent ketamine use, additional information detailing their ketamine use, experience of urinary symptoms and use of related healthcare services was obtained. • In all, 3806 surveys were completed, of which 1285 (33.8%) participants reported ketamine use within the last year. • Of the ketamine users, 17% were found to be dependent on the drug; 26.6% (340) of recent ketamine users reported experiencing urinary symptoms. • Urinary symptoms were significantly related to both dose of ketamine used and frequency of ketamine use. • Of 251 users reporting their experience of symptoms over time in relationship to their use of ketamine, 51% reported improvement in urinary symptoms

Comparison of three Ketamine drug combinations for short term ...

African Journals Online (AJOL)

Ketamine (XK) at a dose of 0.05/25mg/kg, acepromazine/ketamine (AK) at a dose of 0.05/25mg/kg and diazepam/ketamine (DK) at a dose of 0.5/25mg/kg were evaluated and compared in five non-fasted West African Dwarf (WAD) goats. The mean ...

Effects of GABA-B receptor positive modulator on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in freely moving rats.

Science.gov (United States)

Ma, Jingyi; Stan Leung, L

2017-10-01

Decreased GABA B receptor function is proposed to mediate some symptoms of schizophrenia. In this study, we tested the effect of CGP7930, a GABA B receptor positive allosteric modulator, on ketamine-induced psychosis-relevant behaviors and hippocampal electrical activity in behaving rats. Electrodes were bilaterally implanted into the hippocampus, and cannulae were placed into the lateral ventricles of Long-Evans rats. CGP7930 or vehicle was injected intraperitoneally (i.p.) or intracerebroventricularly (i.c.v.), alone or 15 min prior to ketamine (3 mg/kg, subcutaneous) injection. Paired click auditory evoked potentials in the hippocampus (AEP), prepulse inhibition (PPI), and locomotor activity were recorded before and after drug injection. CGP7930 at doses of 1 mg/kg (i.p.) prevented ketamine-induced deficit of PPI. CGP7930 (1 mg/kg i.p.) also prevented the decrease in gating of hippocampal AEP and the increase in hippocampal gamma (65-100 Hz) waves induced by ketamine. Unilateral i.c.v. infusion of CGP7930 (0.3 mM/1 μL) also prevented the decrease in gating of hippocampal AEP induced by ketamine. Ketamine-induced behavioral hyperlocomotion was suppressed by 5 mg/kg i.p. CGP7930. CGP7930 alone, without ketamine, did not significantly affect integrated PPI, locomotion, gating of hippocampal AEP, or gamma waves. CGP7930 (1 mg/kg i.p.) increased heterosynaptically mediated paired pulse depression in the hippocampus, a measure of GABA B receptor function in vivo. CGP7930 reduces the behavioral and electrophysiological disruptions induced by ketamine in animals, and the hippocampus may be one of the neural targets where CGP7930 exerts its actions.

Bovine Lactoferrin and Lactoferricin, a Peptide Derived from Bovine Lactoferrin, Inhibit Tumor Metastasis in Mice

Science.gov (United States)

Watanabe, Shikiko; Watanabe, Ryosuke; Hata, Katsusuke; Shimazaki, Kei–ichi; Azuma, Ichiro

1997-01-01

We investigated the effect of a bovine milk protein, lactoferrin (LF–B), and a pepsin–generated peptide of LF–B, lactoferricin (Lfcin–B), on inhibition of tumor metastasis produced by highly metastatic murine tumor cells, B16–BL6 melanoma and L5178Y–ML25 lymphoma cells, using experimental and spontaneous metastasis models in syngeneic mice. The subcutaneous (s.c.) administration of bovine apo–lactoferrin (apo–LF–B, 1 mg/mouse) and Lfcin–B (0.5 mg/monse) 1 day after tumor inoculation significantly inhibited liver and lung metastasis of L5178Y–ML25 cells. However, human apo–lactoferrin (apo–LF–H) and bovine holo–lactoferrin (holo–LF–B) at the dose of 1 mg/mouse failed to inhibit tumor metastasis of L5178Y–ML25 cells. Similarly, the s.c. administration of apo–LF–B as well as Lfcin–B, but not apo–LF–H and holo–LF–B, 1 day after tumor inoculation resulted in significant inhibition of lung metastasis of B16–BL6 cells in an experimental metastasis model. Furthermore, in in vivo analysis for tumor–induced angiogenesis, both apo–LF–B and Lfcin–B inhibited the number of tumor–induced blood vessels and suppressed tumor growth on day 8 after tumor inoculation. However, in a long–term analysis of tumor growth for up to 21 days after tumor inoculation, single administration of apo–LF–B significantly suppressed the growth of B16–BL6 cells throughout the examination period, whereas Lfcin–B showed inhibitory activity only during the early period (8 days). In spontaneous metastasis of B16–BL6 melanoma cells, multiple administration of both apo–LF–B and Lfcin–B into tumor–bearing mice significantly inhibited lung metastasis produced by B16–BL6 cells, though only apo–LF–B exhibited an inhibitory effect on tumor growth at the time of primary tumor amputation (on day 21) after tumor inoculation. These results suggest that apo–LF–B and Lfcin–B inhibit tumor metastasis through different

Bilateral Hydronephrosis and Cystitis Resulting from Chronic Ketamine Abuse

Directory of Open Access Journals (Sweden)

Vu Huy Tran

2014-07-01

Full Text Available Ketamine associated urinary dysfunction has become increasingly more common worldwide. Point-of-care ultrasound (POCUS is an established modality for diagnosing hydronephrosis in the emergency department. We describe a case of a young male ketamine abuser with severe urinary urgency and frequency in which POCUS performed by the emergency physician demonstrated bilateral hydronephrosis and a focally thickened irregular shaped bladder. Emergency physicians should consider using POCUS evaluate for hydronephrosis and bladder changes in ketamine abusers with lower urinary tract symptoms. The mainstay of treatment is discontinuing ketamine abuse. [West J Emerg Med. 2014;15(4:382-384.

Ketamine for pain [version 1; referees: 2 approved

OpenAIRE

Kelly Jonkman; Albert Dahan; Tine van de Donk; Leon Aarts; Marieke Niesters; Monique van Velzen

2017-01-01

The efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as an analgesic agent is still under debate, especially for indications such as chronic pain. To understand the efficacy of ketamine for relief of pain, we performed a literature search for relevant narrative and systematic reviews and meta-analyses. We retrieved 189 unique articles, of which 29 were deemed appropriate for use in this review. Ketamine treatment is most effective for relief of postoperative pain, causing red...

Other drug use does not impact cognitive impairments in chronic ketamine users.

Science.gov (United States)

Zhang, Chenxi; Tang, Wai Kwong; Liang, Hua Jun; Ungvari, Gabor Sandor; Lin, Shih-Ku

2018-05-01

Ketamine abuse causes cognitive impairments, which negatively impact on users' abstinence, prognosis, and quality of life. of cognitive impairments in chronic ketamine users have been inconsistent across studies, possibly due to the small sample sizes and the confounding effects of concomitant use of other illicit drugs. This study investigated the cognitive impairment and its related factors in chronic ketamine users with a large sample size and explored the impact of another drug use on cognitive functions. Cognitive functions, including working, verbal and visual memory and executive functions were assessed in ketamine users: 286 non-heavy other drug users and 279 heavy other drug users, and 261 healthy controls. Correlations between cognitive impairment and patterns of ketamine use were analysed. Verbal and visual memory were impaired, but working memory and executive functions were intact for all ketamine users. No significant cognitive differences were found between the two ketamine groups. Greater number of days of ketamine use in the past month was associated with worse visual memory performance in non-heavy other drug users. Higher dose of ketamine use was associated with worse short-term verbal memory in heavy other drug users. Verbal and visual memory are impaired in chronic ketamine users. Other drug use appears to have no impact on ketamine users' cognitive performance. Copyright © 2018. Published by Elsevier B.V.

Gargling with Ketamine Attenuates the Postoperative Sore Throat

Directory of Open Access Journals (Sweden)

A Rudra

2009-01-01

Full Text Available Postoperative sore throat (POST is a common complication of anaesthesia with endotracheal tube that affects patient satisfaction after surgery. Therefore, this complication remains to be resolved in patients undergoing endotra-cheal intubation. The aim of the study was to compare the effectiveness of ketamine gargles with placebo in prevent-ing POST after endotracheal intubation. Forty patients scheduled for elective surgery under general anaesthesia were randomized into: Group C, water 30 ml; Group K, ketamine 50 mg in water 29 ml. Patients were asked to gargle this mixture for 40 seconds, 5 minutes before induction of anaesthesia. POST was graded at 4, 8 and 24 hours after operation on a four-point scale (0-3. In the Control group POST occurred more frequently, when compared with patients belonging to Ketamine group, at 4, 8, and 24 hours and significantly more patients suffered severe POST in Control group at 8 and 24 hours compared with Ketamine group (P< 0.05. We demonstrated that gargling with ketamine significantly attenuated POST, with no drug-related side effects were observed.

Effects of ketamine on pro-inflammatory mediators in equine models

NARCIS (Netherlands)

Lankveld, D.P.K.

2007-01-01

Ketamine is frequently used in both human and veterinary anaesthesia. Beside its anaesthetic and analgesic effects, ketamine has been demonstrated to possess anti-inflammatory properties in rodents and humans. To date, no data are available on the anti-inflammatory effects of ketamine in horses.

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy.

Science.gov (United States)

Peltoniemi, Marko A; Hagelberg, Nora M; Olkkola, Klaus T; Saari, Teijo I

2016-09-01

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-D-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.

Periostin Limits Tumor Response to VEGFA Inhibition.

Science.gov (United States)

Keklikoglou, Ioanna; Kadioglu, Ece; Bissinger, Stefan; Langlois, Benoît; Bellotti, Axel; Orend, Gertraud; Ries, Carola H; De Palma, Michele

2018-03-06

Resistance to antiangiogenic drugs limits their applicability in cancer therapy. Here, we show that revascularization and progression of pancreatic neuroendocrine tumors (PNETs) under extended vascular-endothelial growth factor A (VEGFA) blockade are dependent on periostin (POSTN), a matricellular protein expressed by stromal cells. Genetic deletion of Postn in RIP1-Tag2 mice blunted tumor rebounds of M2-like macrophages and αSMA + stromal cells in response to prolonged VEGFA inhibition and suppressed PNET revascularization and progression on therapy. POSTN deficiency also impeded the upregulation of basic fibroblast growth factor (FGF2), an adaptive mechanism previously implicated in PNET evasion from antiangiogenic therapy. Higher POSTN expression correlated with markers of M2-like macrophages in human PNETs, and depleting macrophages with a colony-stimulating factor 1 receptor (CSF1R) antibody inhibited PNET revascularization and progression under VEGFA blockade despite continued POSTN production. These findings suggest a role for POSTN in orchestrating resistance to anti-VEGFA therapy in PNETs. Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Ketamine induced renal fibrosis in a ketamine addition rat model

Directory of Open Access Journals (Sweden)

Mei-Yu Jang

2017-09-01

Conclusion: Ketamine treatment not only induced cystitis-like syndrome, but also renal fibrosis. These renal interstitial fibrosis changes may be induced by the TGF-β pathway. These preliminary results can provide valuable information from a clinical perspective.

Targeting tumor multicellular aggregation through IGPR-1 inhibits colon cancer growth and improves chemotherapy.

Science.gov (United States)

Woolf, N; Pearson, B E; Bondzie, P A; Meyer, R D; Lavaei, M; Belkina, A C; Chitalia, V; Rahimi, N

2017-09-18

Adhesion to extracellular matrix (ECM) is crucially important for survival of normal epithelial cells as detachment from ECM triggers specific apoptosis known as anoikis. As tumor cells lose the requirement for anchorage to ECM, they rely on cell-cell adhesion 'multicellular aggregation' for survival. Multicellular aggregation of tumor cells also significantly determines the sensitivity of tumor cells to the cytotoxic effects of chemotherapeutics. In this report, we demonstrate that expression of immunoglobulin containing and proline-rich receptor-1 (IGPR-1) is upregulated in human primary colon cancer. Our study demonstrates that IGPR-1 promotes tumor multicellular aggregation, and interfering with its adhesive function inhibits multicellular aggregation and, increases cell death. IGPR-1 supports colon carcinoma tumor xenograft growth in mouse, and inhibiting its activity by shRNA or blocking antibody inhibits tumor growth. More importantly, IGPR-1 regulates sensitivity of tumor cells to the chemotherapeutic agent, doxorubicin/adriamycin by a mechanism that involves doxorubicin-induced AKT activation and phosphorylation of IGPR-1 at Ser220. Our findings offer novel insight into IGPR-1's role in colorectal tumor growth, tumor chemosensitivity, and as a possible novel anti-cancer target.

Ketamine for pain management in France, an observational survey.

Science.gov (United States)

Martinez, Valeria; Derivaux, Benoit; Beloeil, Helene

2015-12-01

Before updating the French guidelines on postoperative pain treatment in 2015, the Pain Committee of the French Society of Anaesthesiology and Intensive Care (SFAR) conducted a survey on the medical use of ketamine in France. An online questionnaire was nationally distributed to members of SFAR, the French Pain Society (SFETD) and the French Society of Emergency Medicine (SFMU). The questionnaire included questions on demographic data, the type of patients for whom ketamine was prescribed, the doses used, the side effects and safety measures associated with the administration of ketamine. A total of 1388 questionnaires were analysed. Ninety-two percent of the responders declared that they used ketamine. Ketamine was widely used as anti-hyperalgesic medication but the modalities of administration and the doses varied greatly and were not in accordance with the guidelines. Despite the lack of evidence and guidelines, ketamine has also been used to treat acute and chronic pain. Doses, duration and localization of the patients during administration have varied greatly. Psychedelic effects and hallucinations are the most feared side effects. In terms of monitoring during ketamine infusion, 15% of physicians declared that no monitoring was necessary while 59%, 55%, 59% and 77% monitored heart rate, SpO2, blood pressure and level of consciousness, respectively. Anaesthesiologists have integrated the benefit of ketamine in preventing hyperalgesia but there is no consensus on doses and duration. For other indications (acute and chronic pain treatment), toxicity and the absence of significant benefit call for guidelines from scientific societies. Copyright © 2015 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier Masson SAS. All rights reserved.

Role of ketamine in acute postoperative pain management: a narrative review.

Science.gov (United States)

Radvansky, Brian M; Shah, Khushbu; Parikh, Anant; Sifonios, Anthony N; Le, Vanny; Eloy, Jean D

2015-01-01

The objective of this narrative review was to examine the usage of ketamine as a postoperative analgesic agent across a wide variety of surgeries. A literature search was performed using the phrases "ketamine" and "postoperative pain." The authors analyzed the studies that involved testing ketamine's effectiveness at controlling postoperative pain. Effectiveness was assessed through various outcomes such as the amount of opiate consumption, visual analog scale (VAS) pain scores, and persistent postoperative pain at long-term follow-up. While many different administration protocols were evaluated, delivering ketamine both as a pre- or perioperative bolus and postoperative infusion for up to 48 hours appeared to be the most effective. These effects are dose-dependent. However, a number of studies analyzed showed no benefit in using ketamine versus placebo for controlling postoperative pain. While ketamine is a safe and well-tolerated drug, it does have adverse effects, and there are concerns for possible neurotoxicity and effects on memory. In a number of limited situations, ketamine has shown some efficacy in controlling postoperative pain and decreasing opioid consumption. More randomized controlled trials are necessary to determine the surgical procedures and administrations (i.e., intravenous, epidural) that ketamine is best suited for.

Suppressed neural complexity during ketamine- and propofol-induced unconsciousness.

Science.gov (United States)

Wang, Jisung; Noh, Gyu-Jeong; Choi, Byung-Moon; Ku, Seung-Woo; Joo, Pangyu; Jung, Woo-Sung; Kim, Seunghwan; Lee, Heonsoo

2017-07-13

Ketamine and propofol have distinctively different molecular mechanisms of action and neurophysiological features, although both induce loss of consciousness. Therefore, identifying a common feature of ketamine- and propofol-induced unconsciousness would provide insight into the underlying mechanism of losing consciousness. In this study we search for a common feature by applying the concept of type-II complexity, and argue that neural complexity is essential for a brain to maintain consciousness. To test this hypothesis, we show that complexity is suppressed during loss of consciousness induced by ketamine or propofol. We analyzed the randomness (type-I complexity) and complexity (type-II complexity) of electroencephalogram (EEG) signals before and after bolus injection of ketamine or propofol. For the analysis, we use Mean Information Gain (MIG) and Fluctuation Complexity (FC), which are information-theory-based measures that quantify disorder and complexity of dynamics respectively. Both ketamine and propofol reduced the complexity of the EEG signal, but ketamine increased the randomness of the signal and propofol decreased it. The finding supports our claim and suggests EEG complexity as a candidate for a consciousness indicator. Copyright © 2017 Elsevier B.V. All rights reserved.

Ketamine for pain [version 1; referees: 2 approved

Directory of Open Access Journals (Sweden)

Kelly Jonkman

2017-09-01

Full Text Available The efficacy of the N-methyl-D-aspartate receptor antagonist ketamine as an analgesic agent is still under debate, especially for indications such as chronic pain. To understand the efficacy of ketamine for relief of pain, we performed a literature search for relevant narrative and systematic reviews and meta-analyses. We retrieved 189 unique articles, of which 29 were deemed appropriate for use in this review. Ketamine treatment is most effective for relief of postoperative pain, causing reduced opioid consumption. In contrast, for most other indications (that is, acute pain in the emergency department, prevention of persistent postoperative pain, cancer pain, and chronic non-cancer pain, the efficacy of ketamine is limited. Ketamine’s lack of analgesic effect was associated with an increase in side effects, including schizotypical effects.

Effects of Chloramphenicol Pretreatment on Xylazine/ketamine ...

African Journals Online (AJOL)

Keyword: Chloramphenicol, xylazine, ketamine, anaesthesia, cats. The effect of pretreatment with a single intramuscular (im) dose of chloramphenicol (10mg/kg) on the anaethesia induced with im injection of ketamine (25mg/kg) was investigated in five cats premedicated with im xylazine (1.0mg/kg) and atropine ...

COMPARATIVE EFFICACY (SEDATIVE AND ANAESTHETIC OF DETOMIDINE, KETAMINE AND DETOMIDINE-KETAMINE COCKTAIL IN PIGEONS (COLUMBA LIVIA

Directory of Open Access Journals (Sweden)

UZMA F. DURRANI, M. ARIF KHAN1 AND S. SALEEM AHMAD

2008-07-01

Full Text Available A study was conducted to compare the synergistic efficacy of detomidine, ketamine and their cocktail in pigeons (Columba livia. For this study, 15 adult and healthy pigeons were divided into three equal groups A, B and C. Birds of groups A and B were intramuscularly administered detomidine and ketamine @ 1.4 and 60 mg/kg b. wt., respectively. Pigeons of group C received detomidine + Ketamine cocktail @ 0.7 and 30 mg/kg b. wt. Induction of sedation and anaesthesia was smooth in all groups. Mean duration of induction was 11.1 + 2.03, 11.0 + 1.49 and 1.6 + 0.48 minutes in groups A, B, C, respectively. In groups A and B, smooth but light sedation and anaesthesia were observed accompanied by superficial analgesia, while in group C, birds showed deep anaesthesia alongwith deep analgesia. Birds in groups A and C elicited hypothermia, respiratory depression and bradycardia till complete recovery, while group B showed hyperthermia and tachycardia with rapid respiration. In group A, sedation persisted for 54.2 + 21.82 minutes and mean recovery period was 49.9 + 5.91 minutes, while groups B and C had anaesthesia for 47.7 + 8.06 and 103.5 + 27.52 minutes, and recovery periods were 52.6 + 9.64 and 61.3 + 17.26 minutes, respectively. Recovery was rough in group B and smooth in groups A and C. It was concluded that in pigeons, detomidine (alone is safe for handling and for least painful procedures, while detomidine-ketamine cocktail is safe as intramuscular anaesthetic for major surgical procedures. However, ketamine is not a good anaesthetic to be used alone in pigeons.

COMPARISON OF INTRAMUSCULAR FENTANYL-MIDAZOLAM, FENTANYL-MIDAZOLAM-KETAMINE, AND KETAMINE-MEDETOMIDINE FOR IMMOBILIZATION OF JAPANESE MACAQUES ( MACACA FUSCATA).

Science.gov (United States)

Ølberg, Rolf-Arne; Sinclair, Melissa; Barker, Ian K; Crawshaw, Graham

2018-03-01

The combination of fentanyl and midazolam is commonly used as a sedative in humans. The objective of this study was to evaluate the sedative properties and physiological effects of fentanyl-midazolam and fentanyl-midazolam-ketamine compared with medetomidine-ketamine given intramuscularly in Japanese macaques ( Macaca fuscata). In a randomized crossover design, eight Japanese macaques were hand-injected with either 30 μg/kg fentanyl + 0.3 mg/kg midazolam (FM), 15 μg/kg fentanyl + 0.3 mg/kg midazolam + 5.0 mg/kg ketamine (FMK), or 0.05 mg/kg medetomidine + 5.0 mg/kg ketamine (MedK). Heart rate; indirect systolic, mean, and diastolic arterial pressure; respiratory rate; blood gas concentrations; rectal temperature; and duration of immobilization were recorded. Mixed linear models were used to evaluate the effects of drug treatment on all continuous variables, with a significance level of P < 0.05. Only three of seven animals receiving FM were successfully immobilized. All eight animals in both the FMK and MedK treatment groups had a rapid, smooth induction and were successfully immobilized. Both FMK and MedK treatments resulted in significant hypoxia and the animals required supplemental oxygen via face mask. The mean duration of FMK immobilization was 42 ± 10 min, significantly shorter than the 65 ± 14 min for the animals receiving MedK. Immobilization with MedK resulted in significantly lower heart rates, and significantly higher arterial pressure compared with FMK. Hypoventilation was significantly more pronounced in FMK-treated animals compared with MedK treatments. Immobilization with FMK resulted in a gradual, slow recovery whereas MedK-treated animals woke up more rapidly. Fentanyl-midazolam alone is not a useful sedative in Japanese macaques. A combination of fentanyl and midazolam with ketamine can be used as an alternative to medetomidine-ketamine in this species.

Combination of low frequency electroacupuncture plus subdissociative doses of ketamine in post-herpetic neuralgia patients. A pilot study

Directory of Open Access Journals (Sweden)

Bárbara B. Garrido-Suárez

2017-11-01

Full Text Available Context: Pain processing implicates multiple concurrent mechanisms of nociceptive transmission and modulation. Electroacupuncture (EA analgesia involves mainly the activation of the endogenous anti-nociceptive systems that modulate pain transmission in addition to the regulation of glial activity and inhibition of pro-inflammatory cytokines in the spinal cord. Aims: To examine the potential anti-hyperalgesic effects the EA and the combination EA-ketamine in patients with post-herpetic neuralgia (PHN. Methods: Sixty-eight patients with PHN irritable nociceptor type were randomly allocated to 3 groups: group I (n=26, that received treatment with EA (10 Hz, 2-3 mA, 0.5 ms, 20 min/15 sessions alone, group II (n=21 with a combination EA-ketamine (0.25-0.5 mg/kg, i.m. or group III (n=21 with sham EA-ketamine for 15 days. The average daily pain score (ADPS using the Likert scale, area and rate of dynamic allodynia, the rate of thermal allodynia, and frequency of intermittent lancinating pain were evaluated during five visits – before treatment and at 15, 30, 60, 90 days. Results: ADPS and sensory abnormalities decreased significantly concerning baseline data at 90 days in the three groups, but patients treated with the combination EA-ketamine significantly improved compared with the other groups. Conclusions: These results suggest that the combination EA-ketamine shows an early and long-term anti-hyperalgesic effect in PHN patients. However, a controlled clinical trial is necessary to confirm this hypothesis.

Ketamine as an adjuvant to opioids for cancer pain.

Science.gov (United States)

Bell, Rae F; Eccleston, Christopher; Kalso, Eija A

2017-06-28

This is an update of a review first published in 2003 and updated in 2012.Ketamine is a commonly used anaesthetic agent, and in subanaesthetic doses is also given as an adjuvant to opioids for the treatment of refractory cancer pain, when opioids alone or in combination with appropriate adjuvant analgesics prove to be ineffective. Ketamine is known to have psychomimetic (including hallucinogenic), urological, and hepatic adverse effects. To determine the effectiveness and adverse effects of ketamine as an adjuvant to opioids for refractory cancer pain in adults. For this update, we searched MEDLINE (OVID) to December 2016. We searched CENTRAL (CRSO), Embase (OVID) and two clinical trial registries to January 2017. The intervention considered by this review was the addition of ketamine, given by any route of administration, in any dose, to pre-existing opioid treatment given by any route and in any dose, compared with placebo or active control. We included studies with a group size of at least 10 participants who completed the trial. Two review authors independently assessed the search results and performed 'Risk of bias' assessments. We aimed to extract data on patient-reported pain intensity, total opioid consumption over the study period; use of rescue medication; adverse events; measures of patient satisfaction/preference; function; and distress. We also assessed participant withdrawal (dropout) from trial. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation). One new study (185 participants) was identified by the updated search and included in the review. We included a total of three studies in this update.Two small studies, both with cross-over design, with 20 and 10 participants respectively, were eligible for inclusion in the original review. One study with 20 participants examined the addition of intrathecal ketamine to intrathecal morphine, compared with intrathecal morphine alone. The

Cinnamon extract induces tumor cell death through inhibition of NFκB and AP1

International Nuclear Information System (INIS)

Kwon, Ho-Keun; Lee, Sung Haeng; Park, Zee Yong; Im, Sin-Hyeog; Hwang, Ji-Sun; So, Jae-Seon; Lee, Choong-Gu; Sahoo, Anupama; Ryu, Jae-Ha; Jeon, Won Kyung; Ko, Byoung Seob; Im, Chang-Rok

2010-01-01

Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8 + T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFκB and AP1 in mouse melanoma model. Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography) analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer in vitro and in vivo mouse melanoma model. Cinnamon extract strongly inhibited tumor cell proliferation in vitro and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFκB and AP1 activity and their target genes such as Bcl-2, BcL-xL and survivin. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed in vitro. Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFκB and AP1 activities and their target genes in vitro and in vivo mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative medicine for the treatment of diverse cancers

Effects of ketamine administration on mTOR and reticulum stress signaling pathways in the brain after the infusion of rapamycin into prefrontal cortex.

Science.gov (United States)

Abelaira, Helena M; Réus, Gislaine Z; Ignácio, Zuleide M; Dos Santos, Maria Augusta B; de Moura, Airam B; Matos, Danyela; Demo, Júlia P; da Silva, Júlia B I; Michels, Monique; Abatti, Mariane; Sonai, Beatriz; Dal Pizzol, Felipe; Carvalho, André F; Quevedo, João

2017-04-01

Recent studies show that activation of the mTOR signaling pathway is required for the rapid antidepressant actions of glutamate N-methyl-D-aspartate (NMDA) receptor antagonists. A relationship between mTOR kinase and the endoplasmic reticulum (ER) stress pathway, also known as the unfolded protein response (UPR) has been shown. We evaluate the effects of ketamine administration on the mTOR signaling pathway and proteins of UPR in the prefrontal cortex (PFC), hippocampus, amygdala and nucleus accumbens, after the inhibiton of mTOR signaling in the PFC. Male adult Wistar rats received pharmacological mTOR inhibitor, rapamycin (0.2 nmol), or vehicle into the PFC and then a single dose of ketamine (15 mg/kg, i.p.). The immunocontent of mTOR, eukaryotic initiation factor 4E-binding protein 1 (4E-BP1), eukaryotic elongation factor 2 kinase (eEF2K) homologous protein (CHOP), PKR-like ER kinase (PERK) and inositol-requiring enzyme 1 (IRE1) - alpha were determined in the brain. The mTOR levels were reduced in the rapamycin group treated with saline and ketamine in the PFC; p4EBP1 levels were reduced in the rapamycin group treated with ketamine in the PFC and nucleus accumbens; the levels of peEF2K were increased in the PFC in the vehicle group treated with ketamine and reduced in the rapamycin group treated with ketamine. The PERK and IRE1-alpha levels were decreased in the PFC in the rapamycin group treated with ketamine. Our results suggest that mTOR signaling inhibition by rapamycin could be involved, at least in part, with the mechanism of action of ketamine; and the ketamine antidepressant on ER stress pathway could be also mediated by mTOR signaling pathway in certain brain structures. Copyright © 2016 Elsevier Ltd. All rights reserved.

Predictive value of brain perfusion SPECT for ketamine response in hyperalgesic fibromyalgia

Energy Technology Data Exchange (ETDEWEB)

Guedj, Eric; Cammilleri, Serge; Colavolpe, Cecile; Taieb, David; Laforte, Catherine de; Mundler, Olivier [Centre Hospitalo-Universitaire de la Timone, Service Central de Biophysique et de Medecine Nucleaire, Assistance Publique des Hopitaux de Marseille, Marseille Cedex 5 (France); Niboyet, Jean [Clinique La Phoceanne, Unite d' Etude et de Traitement de la Douleur, Marseille (France)

2007-08-15

Ketamine has been used successfully in various proportions of fibromyalgia (FM) patients. However, the response to this specific treatment remains largely unpredictable. We evaluated brain SPECT perfusion before treatment with ketamine, using voxel-based analysis. The objective was to determine the predictive value of brain SPECT for ketamine response. Seventeen women with FM (48 {+-} 11 years; ACR criteria) were enrolled in the study. Brain SPECT was performed before any change was made in therapy in the pain care unit. We considered that a patient was a good responder to ketamine if the VAS score for pain decreased by at least 50% after treatment. A voxel-by-voxel group analysis was performed using SPM2, in comparison to a group of ten healthy women matched for age. The VAS score for pain was 81.8 {+-} 4.2 before ketamine and 31.8 {+-} 27.1 after ketamine. Eleven patients were considered ''good responders'' to ketamine. Responder and non-responder subgroups were similar in terms of pain intensity before ketamine. In comparison to responding patients and healthy subjects, non-responding patients exhibited a significant reduction in bilateral perfusion of the medial frontal gyrus. This cluster of hypoperfusion was highly predictive of non-response to ketamine (positive predictive value 100%, negative predictive value 91%). Brain perfusion SPECT may predict response to ketamine in hyperalgesic FM patients. (orig.)

Predictive value of brain perfusion SPECT for ketamine response in hyperalgesic fibromyalgia

International Nuclear Information System (INIS)

Guedj, Eric; Cammilleri, Serge; Colavolpe, Cecile; Taieb, David; Laforte, Catherine de; Mundler, Olivier; Niboyet, Jean

2007-01-01

Ketamine has been used successfully in various proportions of fibromyalgia (FM) patients. However, the response to this specific treatment remains largely unpredictable. We evaluated brain SPECT perfusion before treatment with ketamine, using voxel-based analysis. The objective was to determine the predictive value of brain SPECT for ketamine response. Seventeen women with FM (48 ± 11 years; ACR criteria) were enrolled in the study. Brain SPECT was performed before any change was made in therapy in the pain care unit. We considered that a patient was a good responder to ketamine if the VAS score for pain decreased by at least 50% after treatment. A voxel-by-voxel group analysis was performed using SPM2, in comparison to a group of ten healthy women matched for age. The VAS score for pain was 81.8 ± 4.2 before ketamine and 31.8 ± 27.1 after ketamine. Eleven patients were considered ''good responders'' to ketamine. Responder and non-responder subgroups were similar in terms of pain intensity before ketamine. In comparison to responding patients and healthy subjects, non-responding patients exhibited a significant reduction in bilateral perfusion of the medial frontal gyrus. This cluster of hypoperfusion was highly predictive of non-response to ketamine (positive predictive value 100%, negative predictive value 91%). Brain perfusion SPECT may predict response to ketamine in hyperalgesic FM patients. (orig.)

Ketamine Causes Mitochondrial Dysfunction in Human Induced Pluripotent Stem Cell-Derived Neurons

Science.gov (United States)

Ito, Hiroyuki; Uchida, Tokujiro; Makita, Koshi

2015-01-01

Purpose Ketamine toxicity has been demonstrated in nonhuman mammalian neurons. To study the toxic effect of ketamine on human neurons, an experimental model of cultured neurons from human induced pluripotent stem cells (iPSCs) was examined, and the mechanism of its toxicity was investigated. Methods Human iPSC-derived dopaminergic neurons were treated with 0, 20, 100 or 500 μM ketamine for 6 and 24 h. Ketamine toxicity was evaluated by quantification of caspase 3/7 activity, reactive oxygen species (ROS) production, mitochondrial membrane potential, ATP concentration, neurotransmitter reuptake activity and NADH/NAD+ ratio. Mitochondrial morphological change was analyzed by transmission electron microscopy and confocal microscopy. Results Twenty-four-hour exposure of iPSC-derived neurons to 500 μM ketamine resulted in a 40% increase in caspase 3/7 activity (P ketamine (100 μM) decreased the ATP level (22%, P ketamine concentration, which suggests that mitochondrial dysfunction preceded ROS generation and caspase activation. Conclusions We established an in vitro model for assessing the neurotoxicity of ketamine in iPSC-derived neurons. The present data indicate that the initial mitochondrial dysfunction and autophagy may be related to its inhibitory effect on the mitochondrial electron transport system, which underlies ketamine-induced neural toxicity. Higher ketamine concentration can induce ROS generation and apoptosis in human neurons. PMID:26020236

Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-Resistant Prostate Cancer

Science.gov (United States)

2017-12-01

AWARD NUMBER: W81XWH-13-1-0163 TITLE: Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer ...Prostate Cancer 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Feng Yang, Ph.D. 5d. PROJECT NUMBER 5e. TASK NUMBER E-Mail: fyang@bcm.edu...W81XWH-13-1-0163 " Novel Therapeutic Targets to Inhibit Tumor Microenvironment Induced Castration-resistant Prostate Cancer " Introduction AR signaling

Pu-erh Tea Inhibits Tumor Cell Growth by Down-Regulating Mutant p53

Science.gov (United States)

Zhao, Lanjun; Jia, Shuting; Tang, Wenru; Sheng, Jun; Luo, Ying

2011-01-01

Pu-erh tea is a kind of fermented tea with the incorporation of microorganisms’ metabolites. Unlike green tea, the chemical characteristics and bioactivities of Pu-erh tea are still not well understood. Using water extracts of Pu-erh tea, we analyzed the tumor cell growth inhibition activities on several genetically engineered mouse tumor cell lines. We found that at the concentration that did not affect wild type mouse embryo fibroblasts (MEFs) growth, Pu-erh tea extracts could inhibit tumor cell growth by down-regulated S phase and cause G1 or G2 arrest. Further study showed that Pu-erh tea extracts down-regulated the expression of mutant p53 in tumor cells at the protein level as well as mRNA level. The same concentration of Pu-erh tea solution did not cause p53 stabilization or activation of its downstream pathways in wild type cells. We also found that Pu-erh tea treatment could slightly down-regulate both HSP70 and HSP90 protein levels in tumor cells. These data revealed the action of Pu-erh tea on tumor cells and provided the possible mechanism for Pu-erh tea action, which explained its selectivity in inhibiting tumor cells without affecting wild type cells. Our data sheds light on the application of Pu-erh tea as an anti-tumor agent with low side effects. PMID:22174618

Mutual enhancement of central neurotoxicity induced by ketamine followed by methamphetamine

International Nuclear Information System (INIS)

Ke, J.-J.; Chen, H.-I.; Jen, C.J.; Kuo, Y.-M.; Cherng, C.G.; Tsai, Y.-P.N.; Ho, M.-C.; Tsai, C.-W.; Lung Yu

2008-01-01

We hereby report that repeated administration of ketamine (350 mg/kg in total) and methamphetamine (30 mg/kg in total) causes specific glutamatergic and dopaminergic neuron deficits, respectively, in adult mouse brain. Acute ketamine did not affect basal body temperature or the later methamphetamine-induced hyperthermia. However, pretreatment with repeated doses of ketamine aggravated methamphetamine-induced dopaminergic terminal loss as evidenced by a drastic decrease in the levels of dopamine, 3,4-dihydroxyphenylacetic acid, and dopamine transporter density as well as poor gait balance performance. In contrast, methamphetamine-induced serotonergic depletion was not altered by ketamine pretreatment. Likewise, the subsequent treatment with methamphetamine exacerbated the ketamine-induced glutamatergic damage as indicated by reduced levels of the vesicular glutamate transporter in hippocampus and striatum and poor memory performance in the Morris water maze. Finally, since activation of the D1 and AMPA/kainate receptors has been known to be involved in the release of glutamate and dopamine, we examined the effects of co-administration of SCH23390, a D1 antagonist, and CNQX, an AMPA/kainate antagonist. Intraventricular CNQX infusion abolished ketamine's potentiation of methamphetamine-induced dopamine neurotoxicity, while systemic SCH23390 mitigated methamphetamine's potentiation of ketamine-induced glutamatergic toxicity. We conclude that repeated doses of ketamine potentiate methamphetamine-induced dopamine neurotoxicity via AMPA/kainate activation and that conjunctive use of methamphetamine aggravates ketamine-induced glutamatergic neurotoxicity possibly via D1 receptor activation

Differential regulation of GluA1 expression by ketamine and memantine.

Science.gov (United States)

Zhang, Ke; Yamaki, Vitor Nagai; Wei, Zhisheng; Zheng, Yu; Cai, Xiang

2017-01-01

Evidence from preclinical and clinical studies shows that ketamine, a noncompetitive NMDA receptor antagonist, exerts rapid and sustained antidepressant responses. However, ketamine's psychotomimetic side effects and abuse liability limit the clinical use of the compound. Interestingly, memantine, another NMDA receptor channel blocker, processes no defined antidepressant property but is much safer and clinical tolerated. Understanding why ketamine but not memantine exhibits rapid antidepressant responses is important to elucidate the cellular signaling underlying the fast antidepressant actions of ketamine and to design a new safer generation of fast-acting antidepressants. Here we show that ketamine but memantine caused a rapid and sustained antidepressant-like responses in forced swim test (FST). Both drugs enhanced GluA1 S845 phosphorylation and potentiated Schaffer collateral-CA1 synaptic transmission. However, ketamine but not memantine elevated the expression of GluA1. Incubating acutely prepared hippocampal slices with ketamine but not memantine enhanced mTOR phosphorylation in a time course parallel to the time course of GluA1 elevation. Our results suggest that distinct properties in regulation of mTOR phosphorylation and synaptic protein expression may underlie the differential effectiveness of ketamine and memantine in their antidepressant responses. Copyright © 2016 Elsevier B.V. All rights reserved.

[No inhibition of intestinal motility following ketamine-midazolam anesthesia. A comparison of anesthesia with enflurane and fentanyl/midazolam].

Science.gov (United States)

Freye, E; Knüfermann, V

1994-02-01

weight. Also, the duration of operation was comparable in all three groups. Mean gastro-coecal transit time was 204 (+/- 19.6, SD) min following enflurane, 302 (+/- 32.8 SD) min following fentanyl/-midazolam and 210 (+/- 28.8 SD) min following ketamine/midazolam anaesthesia. The gastro-intestinal inhibition after the opioid-based anaesthetic technique was significantly prolonged (p constipation, is likely to develop postoperatively. In classical neuroleptanaesthesia and in analgosedation in the ICU, the simultaneous use of the butyrophenone droperidol seems to counteract the inhibition of opioid-related gastrointestinal motility. In cases of opioid-related gastrointestinal atonia a gastrokinetic compound may be necessary to overcome this effect on intestinal motility.

The effects of ketamine on sexual behavior, anxiety, and locomotion in female rats.

Science.gov (United States)

Guarraci, Fay A; Gonzalez, Chantal M F; Lucero, Devon; Womble, Paige D; Abdel-Rahim, Heba; DeVore, Jennie; Kunkel, Marcela Nicole; Quadlander, Emma; Stinnett, Morgan; Boyette-Davis, Jessica

2018-02-01

The present study characterized the effects of ketamine on sexual behavior and anxiety in female rats. In Experiment 1, female subjects received an injection of ketamine (10.0mg/kg) or saline 30min prior to a sexual partner-preference test during which each female subject was given the opportunity to interact with a female stimulus or a sexually vigorous male stimulus. Immediately afterwards, female subjects were tested for locomotion in an open field test. Ketamine-treated subjects spent significantly more time with the male stimulus than saline-treated subjects. No other measures of mating behavior (i.e., paced mating behavior, lordosis) were affected by ketamine. Ketamine also had no effect on locomotion. In Experiment 2, female subjects received an injection of ketamine (10.0mg/kg), or saline daily for 10days to investigate the possibility that sexual dysfunction emerges only after repeated exposure. Similar to the results of Experiment 1, ketamine-treated subjects spent significantly more time with the male stimulus than saline-treated subjects. Chronic ketamine treatment also decreased the likelihood of leaving the male after mounts, without affecting any other measures of sexual behavior. Chronic ketamine had no effect on locomotion. In Experiment 3, female subjects received an injection of ketamine (10.0mg/kg) or saline and were tested for anxiety in an elevated plus maze test and for locomotion in an open field test. Acute ketamine had no effect on anxiety or locomotion. In Experiment 4, female subjects received an injection of ketamine (10.0mg/kg) or saline daily for 10days to investigate the possibility that anxiety emerges only after repeated exposure. Chronic ketamine exposure had no effect on any measure of anxiety. However, chronic ketamine exposure increased locomotion. The results from these experiments indicate that unlike other medications prescribed for depression, neither acute nor chronic ketamine treatment causes anxiety or disruption of

A Comparative pO2 Probe and [18F]-Fluoro-Azomycinarabino-Furanoside ([18F]FAZA) PET Study Reveals Anesthesia-Induced Impairment of Oxygenation and Perfusion in Tumor and Muscle.

Science.gov (United States)

Mahling, Moritz; Fuchs, Kerstin; Thaiss, Wolfgang M; Maier, Florian C; Feger, Martina; Bukala, Daniel; Harant, Maren; Eichner, Martin; Reutershan, Jörg; Lang, Florian; Reischl, Gerald; Pichler, Bernd J; Kneilling, Manfred

2015-01-01

CT26 colon carcinoma-bearing mice were anesthetized with isoflurane (IF) or ketamine/xylazine (KX) while breathing air or oxygen (O2). We performed 10 min static PET scans 1 h, 2 h and 3 h after [18F]FAZA injection and calculated the [18F]FAZA-uptake and tumor-to-muscle ratios (T/M). In another experimental group, we placed a pO2 probe in the tumor as well as in the gastrocnemius muscle to measure the pO2 and perfusion. Ketamine/xylazine-anesthetized mice yielded up to 3.5-fold higher T/M-ratios compared to their isoflurane-anesthetized littermates 1 h, 2 h and 3 h after [18F]FAZA injection regardless of whether the mice breathed air or oxygen (3 h, KX-air: 7.1 vs. IF-air: 1.8, p = 0.0001, KX-O2: 4.4 vs. IF-O2: 1.4, p pO2 probe measurements yielded enhanced intra-tumoral pO2 values in air- and oxygen-breathing ketamine/xylazine-anesthetized mice compared to isoflurane-anesthetized mice (KX-air: 1.01 mmHg, IF-air: 0.45 mmHg; KX-O2 9.73 mmHg, IF-O2: 6.25 mmHg). Muscle oxygenation was significantly higher in air-breathing isoflurane-anesthetized (56.9 mmHg) than in ketamine/xylazine-anesthetized mice (33.8 mmHg, p = 0.0003). [18F]FAZA tumor uptake was highest in ketamine/xylazine-anesthetized mice regardless of whether the mice breathed air or oxygen. The generally lower [18F]FAZA whole-body uptake in isoflurane-anesthetized mice could be due to the higher muscle pO2-values in these mice compared to ketamine/xylazine-anesthetized mice. When performing preclinical in vivo hypoxia PET studies, oxygen should be avoided, and ketamine/xylazine-anesthesia might alleviate the identification of tumor hypoxia areals.

Osteoprotegerin inhibits bone resorption and prevents tumor development in a xenogenic model of Ewing's sarcoma by inhibiting RANKL

Science.gov (United States)

Picarda, Gaëlle; Matous, Etienne; Amiaud, Jérôme; Charrier, Céline; Lamoureux, François; Heymann, Marie-Françoise; Tirode, Franck; Pitard, Bruno; Trichet, Valérie; Heymann, Dominique; Redini, Françoise

2013-01-01

Ewing's sarcoma (ES) associated with high osyeolytic lesions typically arises in the bones of children and adolescents. The development of multi-disciplinary therapy has increased current long-term survival rates to greater than 50% but only 20% for high risk group patients (relapse, metastases, etc.). Among new therapeutic approaches, osteoprotegerin (OPG), an anti-bone resorption molecule may represent a promising candidate to inhibit RANKL-mediated osteolytic component of ES and consequently to limit the tumor development. Xenogenic orthotopic models of Ewing's sarcoma were induced by intra-osseous injection of human TC-71 ES cells. OPG was administered in vivo by non-viral gene transfer using an amphiphilic non ionic block copolymer. ES bearing mice were assigned to controls (no treatment, synthetic vector alone or F68/empty pcDNA3.1 plasmid) and hOPG treated groups. A substantial but not significant inhibition of tumor development was observed in the hOPG group as compared to control groups. Marked bone lesions were revealed by micro-computed tomography analyses in control groups whereas a normal bone micro-architecture was preserved in the hOPG treated group. RANKL over-expressed in ES animal model was expressed by tumor cells rather than by host cells. However, TRAIL present in the tumor microenvironment may interfere with OPG effect on tumor development and bone remodeling via RANKL inhibition. In conclusion, the use of a xenogenic model of Ewing's sarcoma allowed discriminating between the tumor and host cells responsible for the elevation of RANKL production observed in this tumor and demonstrated the relevance of blocking RANKL by OPG as a promising therapy in ES. PMID:26909278

Molecular recognition of ketamine by a subset of olfactory G protein–coupled receptors

Science.gov (United States)

Saven, Jeffery G.; Matsunami, Hiroaki; Eckenhoff, Roderic G.

2015-01-01

Ketamine elicits various neuropharmacological effects, including sedation, analgesia, general anesthesia, and antidepressant activity. Through an in vitro screen, we identified four mouse olfactory receptors (ORs) that responded to ketamine. In addition to their presence in the olfactory epithelium, these G protein (heterotrimeric guanine nucleotide–binding protein)–coupled receptors (GPCRs) are distributed throughout the central nervous system. To better understand the molecular basis of the interactions between ketamine and ORs, we used sequence comparison and molecular modeling to design mutations that (i) increased, reduced, or abolished ketamine responsiveness in responding receptors, and (ii) rendered non-responding receptors responsive to ketamine. We showed that olfactory sensory neurons (OSNs) that expressed distinct ORs responded to ketamine in vivo, suggesting that ORs may serve as functional targets for ketamine. The ability to both abolish and introduce responsiveness to ketamine in GPCRs enabled us to identify and confirm distinct interaction loci in the binding site, which suggested a signature ketamine-binding pocket that may guide exploration of additional receptors for this general anesthetic drug. PMID:25829447

Ketamine for acute neuropathic pain in patients with spinal cord injury.

Science.gov (United States)

Kim, Kyongsong; Mishina, Masahiro; Kokubo, Rinko; Nakajima, Takao; Morimoto, Daijiro; Isu, Toyohiko; Kobayashi, Shiro; Teramoto, Akira

2013-06-01

Ketamine, an N-methyl-d-aspartic acid (NMDA) receptor antagonist, may be useful for treating neuropathic pain, which is often difficult to control. We report a prospective study of 13 patients with acute neuropathic pain due to spinal cord injury (SCI) treated with ketamine. All underwent a test challenge with 5mg ketamine. Patients with satisfactory responses were then treated intravenously and subsequently perorally with ketamine. Pre- and post-treatment pain was recorded on a visual analogue scale. All 13 patients responded positively to the ketamine test challenge and underwent continued ketamine administration. At the cessation of treatment and alter at final follow up, pain was decreased by 74.7% and 96.8%, respectively. The average administration period was 17.2 days; it was longer (59 days) in one patient treated in the subacute phase. All patients suffered allodynia-type pain and experienced 30% or less of their original pain intensity upon test challenge. Side effects were noted in five patients, although their severity did not require treatment cessation. In patients with SCI, ketamine reduced allodynia. Particularly good results were obtained in patients treated in the acute phase and these patients did not experience post-treatment symptom recurrence. Our results suggest that in patients with SCI, ketamine is useful for treating neuropathic pain in the acute phase. Copyright © 2012 Elsevier Ltd. All rights reserved.

Rectal premedication in pediatric anesthesia: midazolam versus ketamine

Directory of Open Access Journals (Sweden)

Moshirian N

2008-06-01

Full Text Available Background: Premedication is widely used in pediatric anesthesia to reduce emotional trauma and ensure smooth induction. The rectal route is one of the most commonly accepted means of drug administration. The aim of our study was to investigate and compare the efficacy of rectally administered midazolam versus that of ketamine as a premedication in pediatric patients.Methods: We performed a prospective randomized double-blinded clinical trial in 64 children, 1 to 10 years of age, randomly allocated into two groups. The midazolam group received 0.5 mg/kg rectal midazolam and the ketamine group received 5 mg/kg rectal ketamine. The preoperative sedation scores were evaluated on a three-point scale. The anxiolysis and mask acceptance scores were evaluated separately on a four-point scale, with ease of parental separation, based on the presence or lack of crying, evaluated on a two-point scale. Results: Neither medication showed acceptable sedation (>75%, with no significant difference in sedation score between the two groups (P=0.725. Anxiolysis and mask acceptance using either midazolam or ketamine were acceptable, with  midazolam performing significantly better than ketamine (P=0.00 and P=0.042, respectively. Ease of parental separation was seen in both groups without significant difference (P=0.288 and no major adverse effects, such as apnea, occurred in either group.Conclusions: Rectal midazolam is more effective than ketamine in anxiolysis and mask acceptance. Although they both can ease separation anxiety in children before surgery, we found neither drug to be acceptable for sedation.

Tumor necrosis factor-alpha inhibits differentiation of myogenic cells in human urethral rhabdosphincter.

Science.gov (United States)

Shinohara, Mayuka; Sumino, Yasuhiro; Sato, Fuminori; Kiyono, Tohru; Hashimoto, Naohiro; Mimata, Hiromitsu

2017-06-01

To examine the inhibitory effects of tumor necrosis factor-α on myogenic differentiation of human urethral rhabdosphincter cells. A rhabdosphincter sample was obtained from a patient who underwent total cystectomy. To expand the lifespan of the primary cultured cells, rhabdosphincter myogenic cells were immortalized with mutated cyclin-dependent kinase 4, cyclin D1 and telomerase. The differential potential of the cells was investigated. The transfected human rhabdosphincter cells were induced for myogenic differentiation with recombinant human tumor necrosis factor-α and/or the tumor necrosis factor-α antagonist etanercept at different concentrations, and activation of signaling pathways was monitored. Human rhabdosphincter cells were selectively cultured for at least 40 passages. Molecular analysis confirmed the expression of myosin heavy chain, which is a specific marker of differentiated muscle cells, significantly increased after differentiation induction. Although tumor necrosis factor-α treatment reduced the myosin heavy chain expression in a concentration-dependent manner, etanercept inhibited this suppression. Tumor necrosis factor-α suppressed phosphorylation of protein kinase B and p38, whereas etanercept pretreatment promoted phosphorylation and myosin heavy chain expression in a concentration-dependent manner. Tumor necrosis factor-α inhibits differentiation of urethral rhabdosphincter cells in part through the p38 mitogen-activated protein kinase and phosphoinositide 3-kinase pathways. Inhibition of tumor necrosis factor-α might be a useful strategy to treat stress urinary incontinence. © 2017 The Japanese Urological Association.

Inhibition of oxidative phosphorylation in ascites tumor mitochondria and cells by intramitochondrial Ca2+.

Science.gov (United States)

Villalobo, A; Lehninger, A L

1980-03-25

Accumulation of Ca2+ (+ phosphate) by respiring mitochondria from Ehrlich ascites or AS30-D hepatoma tumor cells inhibits subsequent phosphorylating respiration in response to ADP. The respiratory chain is still functional since a proton-conducting uncoupler produces a normal stimulation of electron transport. The inhibition of phosphorylating respiration is caused by intramitochondrial Ca2+ (+ phosphate). ATP + Mg2+ together, but not singly, prevents the inhibitory action of Ca2+. Neither AMP, GTP, GDP, nor any other nucleoside 5'-triphosphate or 5'-diphosphate could replace ATP in this effect. Phosphorylating respiration on NAD(NADP)-linked substrates was much more susceptible to the inhibitory effect of intramitochondrial Ca2+ than succinate-linked respiration. Significant inhibition of oxidative phosphorylation is given by the endogenous Ca2+ present in freshly isolated tumor mitochondria. The phosphorylating respiration of permeabilized Ehrlich ascites tumor cells is also inhibited by Ca2+ accumulated by the mitochondria in situ. Possible causes of the Ca2+-induced inhibition of oxidative phosphorylation are considered.

Evaluation of cardiorespiratory and biochemical effects of ketamine-propofol and guaifenesin-ketamine-xylazine anesthesia in donkeys (Equus asinus).

Science.gov (United States)

Molinaro Coelho, Cássia M; Duque Moreno, Juan C; Goulart, Daniel da S; Caetano, Leandro B; Soares, Lorena K; Coutinho, Gustavo H; Alves, Geraldo Es; da Silva, Luiz Antonio F

2014-11-01

To evaluate the cardiorespiratory and biochemical effects of ketamine-propofol (KP) or guaifenesin-ketamine-xylazine (GKX) anesthesia in donkeys. Prospective crossover trial. Eight healthy, standard donkeys, aged 10 ± 5 years and weighing 153 ± 23 kg. Donkeys were premedicated with 1.0 mg kg(-1) of xylazine (IV) in both treatments. Eight donkeys were administered ketamine (1.5 mg kg(-1)) and propofol (0.5 mg kg(-1) for induction, and anesthesia was maintained by constant rate infusion (CRI) of ketamine (0.05 mg kg(-1) minute(-1)) and propofol (0.15 mg kg(-1) minute(-1)) in the KP treatment. After 10 days, diazepam (0.05 mg kg(-1)) and ketamine (2.2 mg kg(-1)) were administered for induction, and anesthesia was maintained by a CRI (2.0 mL kg(-1) hour(-1)) of ketamine (2.0 mg mL(-1), xylazine (0.5 mg mL(-1)) and guaifenesin (50 mg mL(-1)) solution. Quality of anesthesia was assessed along with cardiorespiratory and biochemical measurements. Anesthetic induction took longer in GKX than in KP. The induction was considered good in 7/8 with KP and in 6/8 in GKX. Anesthetic recovery was classified as good in 7/8 animals in both treatments. Xylazine administration decreased heart rate (HR) in both treatments, but in KP the HR increased and was higher than GKX throughout the anesthetic period. Respiratory rate was higher in GKX than in KP. PaO(2) decreased significantly in both groups during the anesthetic period. Glucose concentrations [GLU] increased and rectal temperature and PCV decreased in both treatments. Arterial lactate [LAC] increased at recovery compared with all time points in KP. [GLU] and calcium were higher in GKX than in KP at recovery. These protocols induced significant hypoxemia but no other cardiorespiratory or metabolic changes. These protocols could be used to maintain anesthesia in donkeys, however, they were not tested in animals undergoing surgery. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia

Ketamine changes the local resting-state functional properties of anesthetized-monkey brain.

Science.gov (United States)

Rao, Jia-Sheng; Liu, Zuxiang; Zhao, Can; Wei, Rui-Han; Zhao, Wen; Tian, Peng-Yu; Zhou, Xia; Yang, Zhao-Yang; Li, Xiao-Guang

2017-11-01

Ketamine is a well-known anesthetic. 'Recreational' use of ketamine common induces psychosis-like symptoms and cognitive impairments. The acute and chronic effects of ketamine on relevant brain circuits have been studied, but the effects of single-dose ketamine administration on the local resting-state functional properties of the brain remain unknown. In this study, we aimed to assess the effects of single-dose ketamine administration on the brain local intrinsic properties. We used resting-state functional magnetic resonance imaging (rs-fMRI) to explore the ketamine-induced alterations of brain intrinsic properties. Seven adult rhesus monkeys were imaged with rs-fMRI to examine the fractional amplitude of low-frequency fluctuation (fALFF) and regional homogeneity (ReHo) in the brain before and after ketamine injection. Paired comparisons were used to detect the significantly altered regions. Results showed that the fALFF of the prefrontal cortex (p=0.046), caudate nucleus (left side, p=0.018; right side, p=0.025), and putamen (p=0.020) in post-injection stage significantly increased compared with those in pre-injection period. The ReHo of nucleus accumbens (p=0.049), caudate nucleus (p=0.037), and hippocampus (p=0.025) increased after ketamine injection, but that of prefrontal cortex decreased (pketamine administration can change the regional intensity and synchronism of brain activity, thereby providing evidence of ketamine-induced abnormal resting-state functional properties in primates. This evidence may help further elucidate the effects of ketamine on the cerebral resting status. Copyright © 2017. Published by Elsevier Inc.

Ketamine facilitates extinction of avoidance behavior and enhances synaptic plasticity in a rat model of anxiety vulnerability: Implications for the pathophysiology and treatment of anxiety disorders.

Science.gov (United States)

Fortress, Ashley M; Smith, Ian M; Pang, Kevin C H

2018-05-08

Anxiety disorders and posttraumatic stress disorder (PTSD) share a common feature of pathological avoidance behavior. The Wistar Kyoto (WKY) rat has been used as a model of anxiety vulnerability, expressing a behaviorally inhibited temperament, acquiring avoidance behavior more rapidly and displaying extinction-resistant avoidance compared to Sprague Dawley (SD) rats. Subanesthetic levels of ketamine have gained attention as a rapid antidepressant in treatment-resistant depression. While traditional antidepressants are commonly used to treat anxiety disorders and PTSD, the therapeutic utility of ketamine for these disorders is much less understood. The hippocampus is critical for the actions of antidepressants, is a structure of implicated in anxiety disorders and PTSD, and is necessary for extinction of avoidance in SD rats. WKY rats have impaired hippocampal long-term potentiation (LTP), suggesting that persistent avoidance in WKY rats may be due to deficient hippocampal synaptic plasticity. In the present study, we hypothesized that ketamine would facilitate extinction of avoidance learning in WKY rats, and do so by enhancing hippocampal synaptic plasticity. As predicted, ketamine facilitated extinction of avoidance behavior in a subset of WKY rats (responders), with effects lasting at least three weeks. Additionally, LTP in these rats was enhanced by ketamine. Ketamine was not effective in facilitating avoidance extinction or in modifying LTP in WKY non-responders. The results suggest that subanesthetic levels of ketamine may be useful for treating anxiety disorders by reducing avoidance behaviors when combined with extinction conditions. Moreover, ketamine may have its long-lasting behavioral effects through enhancing hippocampal synaptic plasticity. Copyright © 2018. Published by Elsevier Ltd.

Ketamin genopdaget af både læger og misbrugere

DEFF Research Database (Denmark)

Sørensen, Anne; Barnung, Steen; Rasmussen, Lars Simon

2011-01-01

Ketamine is a unique anaesthetic because it has both hypnotic and analgesic effects and also potential hallucinogenic side effects. Lack of cardiopulmonary depression makes the drug a popular choice for anaesthesia in the prehospital setting. In recent years ketamine has been found to have anti......-hyperalgesic and opioid saving effects, opening to new ways of managing post-operative and chronic pain states. Recreational use of ketamine among night clubbers is increasing and makes acute and chronic symptoms of ketamine abuse a new challenge in emergency departments....

Ketamin genopdaget af både læger og misbrugere

DEFF Research Database (Denmark)

Sørensen, Anne; Barnung, Steen; Rasmussen, Lars Simon

2011-01-01

-hyperalgesic and opioid saving effects, opening to new ways of managing post-operative and chronic pain states. Recreational use of ketamine among night clubbers is increasing and makes acute and chronic symptoms of ketamine abuse a new challenge in emergency departments.......Ketamine is a unique anaesthetic because it has both hypnotic and analgesic effects and also potential hallucinogenic side effects. Lack of cardiopulmonary depression makes the drug a popular choice for anaesthesia in the prehospital setting. In recent years ketamine has been found to have anti...

Ketamin genopdaget af både læger og misbrugere

DEFF Research Database (Denmark)

Sørensen, Anne; Barnung, Steen; Rasmussen, Lars Simon

2011-01-01

Ketamine is a unique anaesthetic because it has both hypnotic and analgesic effects and also potential hallucinogenic side effects. Lack of cardiopulmonary depression makes the drug a popular choice for anaesthesia in the prehospital setting. In recent years ketamine has been found to have anti-h......-hyperalgesic and opioid saving effects, opening to new ways of managing post-operative and chronic pain states. Recreational use of ketamine among night clubbers is increasing and makes acute and chronic symptoms of ketamine abuse a new challenge in emergency departments....

Ketamine. A solution to procedural pain in burned children.

Science.gov (United States)

Groeneveld, A; Inkson, T

1992-09-01

Our experience has shown ketamine to be a safe and effective method of providing pain relief during specific procedures in burned children. It renders high doses of narcotics unnecessary and offers children the benefit of general anesthesia without the requirement of endotracheal intubation and a trip to the operating room. The response of parents and staff to the use of ketamine has been positive. Parents often experience feelings of guilt following injury to a child and are eager to employ methods that reduce their child's pain. So far, no parent has refused the administration of ketamine; some have even asked that it be used during subsequent procedures on their child. With adequate pre-procedure teaching, parents are prepared for the possible occurrence of emergent reactions and can assist in reorienting the child during recovery. Staff have found that the stress of doing painful procedures on children is reduced when ketamine is used. The procedures tend to be quicker and the predicament of working on a screaming, agitated child is eliminated. At the same time, nursing staff have had to get used to the nystagmic gaze of the children and accept that these patients are truly anesthetized even though they might move and talk. Despite the success we and others have had with ketamine, several questions about its use in burn patients remain unanswered. The literature does not answer such questions as: Which nursing measures reduce the incidence of emergent reactions? How many ketamine anesthetics can safely be administered to one individual? How does the frequency of administration relate to tolerance in a burn patient? Are there detrimental effects of frequent or long-term use? Clearly, an understanding of these questions is necessary to determine the safe boundaries of ketamine use in burn patients. Ketamine is not a panacea for the problem of pain in burned children. But it is one means of managing procedural pain, which is, after all, a significant clinical

Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

International Nuclear Information System (INIS)

Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng

2015-01-01

Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice. �

Oroxin B selectively induces tumor-suppressive ER stress and concurrently inhibits tumor-adaptive ER stress in B-lymphoma cells for effective anti-lymphoma therapy

Energy Technology Data Exchange (ETDEWEB)

Yang, Ping; Fu, Shilong; Cao, Zhifei; Liao, Huaidong; Huo, Zihe; Pan, Yanyan; Zhang, Gaochuan; Gao, Aidi; Zhou, Quansheng, E-mail: zhouqs@suda.edu.cn

2015-10-15

Cancer cells have both tumor-adaptive and -suppressive endoplasmic reticulum (ER) stress machineries that determine cell fate. In malignant tumors including lymphoma, constant activation of tumor-adaptive ER stress and concurrent reduction of tumor-suppressive ER stress favors cancer cell proliferation and tumor growth. Current ER stress-based anti-tumor drugs typically activate both tumor-adaptive and -suppressive ER stresses, resulting in low anti-cancer efficacy; hence, selective induction of tumor-suppressive ER stress and inhibition of tumor-adaptive ER stress are new strategies for novel anti-cancer drug discovery. Thus far, specific tumor-suppressive ER stress therapeutics have remained absent in clinical settings. In this study, we explored unique tumor-suppressive ER stress agents from the traditional Chinese medicinal herb Oroxylum indicum, and found that a small molecule oroxin B selectively induced tumor-suppressive ER stress in malignant lymphoma cells, but not in normal cells, effectively inhibited lymphoma growth in vivo, and significantly prolonged overall survival of lymphoma-xenografted mice without obvious toxicity. Mechanistic studies have revealed that the expression of key tumor-adaptive ER-stress gene GRP78 was notably suppressed by oroxin B via down-regulation of up-stream key signaling protein ATF6, while tumor-suppressive ER stress master gene DDIT3 was strikingly activated through activating the MKK3-p38 signaling pathway, correcting the imbalance between tumor-suppressive DDIT3 and tumor-adaptive GRP78 in lymphoma. Together, selective induction of unique tumor-suppressive ER stress and concurrent inhibition of tumor-adaptive ER stress in malignant lymphoma are new and feasible approaches for novel anti-lymphoma drug discovery and anti-lymphoma therapy. - Highlights: • Oroxin B selectively induces tumor-suppressive ER stress in B-lymphoma cells. • Oroxin B significantly prolonged overall survival of lymphoma-xenografted mice. �

Ketamine and other glutamate receptor modulators for depression in adults.

Science.gov (United States)

Caddy, Caroline; Amit, Ben H; McCloud, Tayla L; Rendell, Jennifer M; Furukawa, Toshi A; McShane, Rupert; Hawton, Keith; Cipriani, Andrea

2015-09-23

Considering the ample evidence of involvement of the glutamate system in the pathophysiology of depression, pre-clinical and clinical studies have been conducted to assess the antidepressant efficacy of glutamate inhibition, and glutamate receptor modulators in particular. This review focuses on the use of glutamate receptor modulators in unipolar depression. To assess the effects - and review the acceptability - of ketamine and other glutamate receptor modulators in comparison to placebo (or saline placebo), other pharmacologically active agents, or electroconvulsive therapy (ECT) in alleviating the acute symptoms of depression in people with unipolar major depressive disorder. We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialised Register (CCDANCTR, to 9 January 2015). This register includes relevant randomised controlled trials (RCTs) from: the Cochrane Library (all years), MEDLINE (1950 to date), EMBASE (1974 to date), and PsycINFO (1967 to date). We did not apply any restrictions to date, language or publication status. Double- or single-blind RCTs comparing ketamine, memantine, or other glutamate receptor modulators with placebo (or saline placebo), other active psychotropic drugs, or electroconvulsive therapy (ECT) in adults with unipolar major depression. Three review authors independently identified studies, assessed trial quality and extracted data. The primary outcomes for this review were response rate and adverse events. We included 25 studies (1242 participants) on ketamine (9 trials), memantine (3), AZD6765 (3), D-cycloserine (2), Org26576 (2), atomoxetine (1), CP-101,606 (1), MK-0657 (1), N-acetylcysteine (1), riluzole (1) and sarcosine (1). Twenty-one studies were placebo-controlled and the majority were two-arm studies (23 out of 25). Twenty-two studies defined an inclusion criteria specifying the severity of depression; 11 specified at least moderate depression; eight, severe depression; and the remaining three

Ketamine infusion for refractory status epilepticus: A case report of cardiac arrest.

Science.gov (United States)

Koffman, Lauren; Yan Yiu, Ho; Farrokh, Salia; Lewin, John; Geocadin, Romergryko; Ziai, Wendy

2018-01-01

Refractory status epilepticus (RSE) has a high mortality rate and is often difficult to treat. When traditional therapies fail ketamine may be considered. There are limited reports of adverse cardiac events with the use of ketamine for RSE and no reports of cardiac arrest in this context. Evaluate the occurrence of cardiac arrhythmias associated with the use of ketamine for RSE. Retrospective chart review of nine patients who underwent ketamine infusion for RSE. Etiology of refractory status epilepticus included autoimmune/infectious process (Zeiler et al., 2014), ischemic stroke (Bleck, 2005) and subarachnoid hemorrhage (Bleck, 2005). Of the nine patients who received ketamine, two had documented cardiac events; one remained clinically stable and the other developed multiple arrhythmias, including recurrent episodes of asystole. Once ketamine was discontinued the latter patient stabilized with the addition of anti arrhythmic therapy. Ketamine is utilized to treat refractory status epilepticus, but should be used with caution in patients with subarachnoid hemorrhage, as there may be an increased risk of life threatening arrhythmias and cardiac arrest. Copyright © 2017 Elsevier Ltd. All rights reserved.

Role of Ketamine in Acute Postoperative Pain Management: A Narrative Review

Science.gov (United States)

Radvansky, Brian M.; Shah, Khushbu; Parikh, Anant; Sifonios, Anthony N.; Eloy, Jean D.

2015-01-01

Objectives. The objective of this narrative review was to examine the usage of ketamine as a postoperative analgesic agent across a wide variety of surgeries. Design. A literature search was performed using the phrases “ketamine” and “postoperative pain.” The authors analyzed the studies that involved testing ketamine's effectiveness at controlling postoperative pain. Effectiveness was assessed through various outcomes such as the amount of opiate consumption, visual analog scale (VAS) pain scores, and persistent postoperative pain at long-term follow-up. Results. While many different administration protocols were evaluated, delivering ketamine both as a pre- or perioperative bolus and postoperative infusion for up to 48 hours appeared to be the most effective. These effects are dose-dependent. However, a number of studies analyzed showed no benefit in using ketamine versus placebo for controlling postoperative pain. While ketamine is a safe and well-tolerated drug, it does have adverse effects, and there are concerns for possible neurotoxicity and effects on memory. Conclusions. In a number of limited situations, ketamine has shown some efficacy in controlling postoperative pain and decreasing opioid consumption. More randomized controlled trials are necessary to determine the surgical procedures and administrations (i.e., intravenous, epidural) that ketamine is best suited for. PMID:26495312

Fungi & Health: can polysaccharides from the fungus inonotus obliquus (CHAGA) inhibit tumor growth?

DEFF Research Database (Denmark)

Wold, C. W.; Corthay, A.; Kjeldsen, Christian

Inonotus obliquus (Chaga) – a white rot fungus found on birch trees in the northern hemisphere –has been used in traditional medicine in Europe and Asia for centuries. Native peoples have made use of Chaga by brewing it as a tea to treat gastro-intestinal problems, to heal wounds and even to treat...... cancer. The last few decades, studies have found Chaga to contain biologically active substances such as polysaccharides, triterpenoids, polyphenols and melanin. In vivo effects such as tumor growth inhibition have been observed in mice receiving various Chaga extracts. The main hypothesis behind...... the tumor inhibiting effect is two-fold: i) fungal polysaccharides may inhibit tumor growth indirectly by activating certain immune cells such as macrophages and ii) triterpenoids and other steroids from Chaga may give a direct cytotoxic effect against cancer cells. While triterpenoids from Chaga have been...

Pharmacokinetics of S-ketamine during prolonged sedation at the pediatric intensive care unit.

Science.gov (United States)

Flint, Robert B; Brouwer, Carole N M; Kränzlin, Anne S C; Lie-A-Huen, Loraine; Bos, Albert P; Mathôt, Ron A A

2017-11-01

S-ketamine is the S(+)-enantiomer of the racemic mixture ketamine, an anesthetic drug providing both sedation and analgesia. In clinical practice, significant interpatient variability in drug effect of S-ketamine is observed during long-term sedation. The aim of this study was to evaluate the pharmacokinetic variability of S-ketamine in children aged 0-18 years during long-term sedation. Twenty-five children (median age: 0.42 years, range: 0.02-12.5) received continuous intravenous administrations of 0.3-3.6 mg/kg/h S-ketamine for sedation during mechanical ventilation. Infusion rates were adjusted to the desired level of sedation and analgesia based on the COMFORT-B score and Visual Analog Scale. Blood samples were drawn once daily at random time-points, and at 1 and 4 hours after discontinuation of S-ketamine infusion. Time profiles of plasma concentrations of S-ketamine and active metabolite S-norketamine were analyzed using nonlinear mixed-effects modeling software. Clearance and volume of distribution were allometrically scaled using the ¾ power model. A total of 86 blood samples were collected. A 2-compartment and 1-compartment model adequately described the PK of S-ketamine and S-norketamine, respectively. The typical parameter estimates for clearance and central and peripheral volumes of distribution were: CL S - KETAMINE =112 L/h/70 kg, V1 S- KETAMINE =7.7 L/70 kg, V2 S- KETAMINE =545L/70 kg, Q S - kETAMINE =196 L/h/70 kg, and CL S - NORKETAMINE =53 L/h/70 kg. Interpatient variability of CL S - KETAMINE and CL S - NORKETAMINE was considerable with values of 40% and 104%, respectively, leading to marked variability in steady-state plasma concentrations. Substantial interpatient variability in pharmacokinetics in children complicates the development of adequate dosage regimen for continuous sedation. © 2017 John Wiley & Sons Ltd.

Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

Directory of Open Access Journals (Sweden)

Caroline Ann Browne

2013-12-01

Full Text Available Newer antidepressants are needed for the many individuals with major depressive disorder that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamine’s effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse

Macrophage PPARγ inhibits Gpr132 to mediate the anti-tumor effects of rosiglitazone

Science.gov (United States)

Cheng, Wing Yin; Huynh, HoangDinh; Chen, Peiwen; Peña-Llopis, Samuel; Wan, Yihong

2016-01-01

Tumor-associated macrophage (TAM) significantly contributes to cancer progression. Human cancer is enhanced by PPARγ loss-of-function mutations, but inhibited by PPARγ agonists such as TZD diabetes drugs including rosiglitazone. However, it remains enigmatic whether and how macrophage contributes to PPARγ tumor-suppressive functions. Here we report that macrophage PPARγ deletion in mice not only exacerbates mammary tumor development but also impairs the anti-tumor effects of rosiglitazone. Mechanistically, we identify Gpr132 as a novel direct PPARγ target in macrophage whose expression is enhanced by PPARγ loss but repressed by PPARγ activation. Functionally, macrophage Gpr132 is pro-inflammatory and pro-tumor. Genetic Gpr132 deletion not only retards inflammation and cancer growth but also abrogates the anti-tumor effects of PPARγ and rosiglitazone. Pharmacological Gpr132 inhibition significantly impedes mammary tumor malignancy. These findings uncover macrophage PPARγ and Gpr132 as critical TAM modulators, new cancer therapeutic targets, and essential mediators of TZD anti-cancer effects. DOI: http://dx.doi.org/10.7554/eLife.18501.001 PMID:27692066

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial.

Science.gov (United States)

Taylor, Jerome H; Landeros-Weisenberger, Angeli; Coughlin, Catherine; Mulqueen, Jilian; Johnson, Jessica A; Gabriel, Daniel; Reed, Margot O; Jakubovski, Ewgeni; Bloch, Michael H

2018-01-01

Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F 9,115 =2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F 10,141 =0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity

Science.gov (United States)

Liu, Daofeng; Song, Liping; Wei, Jie; Courtney, Amy N.; Gao, Xiuhua; Marinova, Ekaterina; Guo, Linjie; Heczey, Andras; Asgharzadeh, Shahab; Kim, Eugene; Dotti, Gianpietro; Metelitsa, Leonid S.

2012-01-01

Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice. Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15–transduced NKT cells. PMID:22565311

IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity.

Science.gov (United States)

Liu, Daofeng; Song, Liping; Wei, Jie; Courtney, Amy N; Gao, Xiuhua; Marinova, Ekaterina; Guo, Linjie; Heczey, Andras; Asgharzadeh, Shahab; Kim, Eugene; Dotti, Gianpietro; Metelitsa, Leonid S

2012-06-01

Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms. Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α). These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs. Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice. We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells. IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice. Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15-transduced NKT cells.

Ketamine inhibits transcription factors activator protein 1 and nuclear factor-kappaB, interleukin-8 production, as well as CD11b and CD16 expression: studies in human leukocytes and leukocytic cell lines.

NARCIS (Netherlands)

Welters, I.D.; Hafer, G.; Menzebach, A.; Muhling, J.; Neuhauser, C.; Browning, P.; Goumon, Y.

2010-01-01

BACKGROUND: Recent data indicate that ketamine exerts antiinflammatory actions. However, little is known about the signaling mechanisms involved in ketamine-induced immune modulation. In this study, we investigated the effects of ketamine on lipopolysaccharide-induced activation of transcription

Urine metabolomics in rats after administration of ketamine

Directory of Open Access Journals (Sweden)

Wen C

2015-02-01

Full Text Available Congcong Wen,1 Meiling Zhang,2 Jianshe Ma,2 Lufeng Hu,3 Xianqin Wang,2 Guanyang Lin31Laboratory Animal Centre, 2Analytical and Testing Center, 3First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People’s Republic of ChinaAbstract: In this study, we developed a urine metabonomic method, based on gas chromatography–mass spectrometry (GC-MS, to evaluate the effect of ketamine on rats. Pattern recognition analysis, including both principal component analysis and partial least squares discriminate analysis revealed that ketamine (50 mg/kg induced metabolic perturbations. Compared with the control group, at day 7, the level of alanine, butanoic acid, glutamine, butanedioic, trimethylsiloxy, L-aspartic acid, D-glucose, cholesterol, acetamide, and oleic acid of the ketamine group was increased, while the level of 2,3,4-trihydroxybutyric acid, benzene­acetic acid, threitol, ribitol, xylitol, and glycine decreased. At day 14, the level of alanine, ethanedioic acid, L-proline, glycerol, tetradecanoic acid, l-serine, l-phenylalanine, L-aspartic acid, d-glucose, cholesterol, heptadecanoic acid, and acetamide in rat urine of the ketamine group was increased, while the 2,3,4-trihydroxybutyric acid, benzeneacetic acid, d-ribose, threitol, ribitol, glycine, pyrazine, and oleic acid levels decreased. Our results indicate that metabonomic methods based on GC-MS may be useful to elucidate ketamine abuse, through the exploration of biomarkers.Keywords: GC-MS, abuse, biomarker, metabolite

Case report: efficacy and tolerability of ketamine in opioid-refractory cancer pain.

Science.gov (United States)

Amin, Priya; Roeland, Eric; Atayee, Rabia

2014-09-01

A 36-year-old female with metastatic breast cancer involving bones, liver, lung, and pleura/chest wall with worsening back pain received weight-based intravenous (IV) ketamine and was transitioned to oral ketamine for cancer-related neuropathic pain. She had responded poorly to outpatient pain regimen of oxycodone sustained and immediate release, hydromorphone, gabapentin, and duloxetine (approximate 480 mg total oral morphine equivalents [OME]), reporting an initial pain score of 10/10. She was started on hydromorphone parenteral patient-controlled analgesia (PCA) bolus dose in addition to her outpatient regimen. Despite escalating doses of opioids and the addition of a lidocaine 5% patch, the patient's pain remained uncontrolled 6 days after admission. On hospital day 7, utilizing a hospital weight-based ketamine protocol, the patient was started on subanesthetic doses of ketamine at 0.2 mg/kg/h (288 mg/24 h) and titrated over 2 days to 0.4 mg/kg/h (576 mg/24 h). Then, a 3-day rotation from intravenous to oral ketamine was initiated, and the patient was discharged on ketamine oral solution, 75 mg every 8 hours. When the patient's dose was increased to 0.4 mg/kg/h, adequate pain relief was charted by the nurse within 120 minutes, "patient pain free and resting comfortably." Her pain continued to be well managed, with an average pain score of 5/10 with the ketamine continuous infusion and sustained with conversion to oral ketamine without any report of side effects. This was a 37% reduction in pain scores. With the patient's stabilized dose of ketamine, opioid requirements decreased by 61.4% (1017.5 mg reduction in total OME). The use of weight-based dosing of IV continuous infusion and transition to oral ketamine was effective and tolerable in the management of opioid-refractory, neuropathic cancer pain. It is hoped that this case report promotes a discussion regarding ketamine dosing in refractory neuropathic cancer pain.

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

Science.gov (United States)

Wang, Piwen; Solorzano, Walter; Diaz, Tanya; Magyar, Clara E.; Henning, Susanne M.; Vadgama, Jaydutt V.

2017-01-01

The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (< 2μM) significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30-50% at 48h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID) mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50mg/kg (LD) or 100mg/kg (HD) b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD) and 70% (HD) compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its translation to human application

Soluble fibrin inhibits monocyte adherence and cytotoxicity against tumor cells: implications for cancer metastasis

Directory of Open Access Journals (Sweden)

Patel Shonak

2006-08-01

Full Text Available Abstract Background Soluble fibrin (sFn is a marker for disseminated intravascular coagulation and may have prognostic significance, especially in metastasis. However, a role for sFn in the etiology of metastatic cancer growth has not been extensively studied. We have reported that sFn cross-linked platelet binding to tumor cells via the major platelet fibrin receptor αIIbβ3, and tumor cell CD54 (ICAM-1, which is the receptor for two of the leukocyte β2 integrins (αLβ2 and aMβ2. We hypothesized that sFn may also affect leukocyte adherence, recognition, and killing of tumor cells. Furthermore, in a rat experimental metastasis model sFn pre-treatment of tumor cells enhanced metastasis by over 60% compared to untreated cells. Other studies have shown that fibrin(ogen binds to the monocyte integrin αMβ2. This study therefore sought to investigate the effect of sFn on β2 integrin mediated monocyte adherence and killing of tumor cells. Methods The role of sFn in monocyte adherence and cytotoxicity against tumor cells was initially studied using static microplate adherence and cytotoxicity assays, and under physiologically relevant flow conditions in a microscope perfusion incubator system. Blocking studies were performed using monoclonal antibodies specific for β2 integrins and CD54, and specific peptides which inhibit sFn binding to these receptors. Results Enhancement of monocyte/tumor cell adherence was observed when only one cell type was bound to sFn, but profound inhibition was observed when sFn was bound to both monocytes and tumor cells. This effect was also reflected in the pattern of monocyte cytotoxicity. Studies using monoclonal blocking antibodies and specific blocking peptides (which did not affect normal coagulation showed that the predominant mechanism of fibrin inhibition is via its binding to αMβ2 on monocytes, and to CD54 on both leukocytes and tumor cells. Conclusion sFn inhibits monocyte adherence and cytotoxicity of

Psychological effects of ketamine in healthy volunteers - Phenomenological study

NARCIS (Netherlands)

Pomarol-Clotet, E.; Honey, G. D.; Murray, G. K.; Corlett, P. R.; Absalom, A. R.; Lee, M.; McKenna, P. J.; Bullmore, E. T.; Fletcher, P. C.

Background: The psychosis-inducing effect of ketamine is important evidence supporting the glutamate hypothesis of schizophrenia. However, the symptoms the drug produces have not been described systematically. Aim: To examine the effects of ketamine in healthy people using a structured psychiatric

Mechanistic Target of Rapamycin-Independent Antidepressant Effects of (R)-Ketamine in a Social Defeat Stress Model.

Science.gov (United States)

Yang, Chun; Ren, Qian; Qu, Youge; Zhang, Ji-Chun; Ma, Min; Dong, Chao; Hashimoto, Kenji

2018-01-01

The role of the mechanistic target of rapamycin (mTOR) signaling in the antidepressant effects of ketamine is controversial. In addition to mTOR, extracellular signal-regulated kinase (ERK) is a key signaling molecule in prominent pathways that regulate protein synthesis. (R)-Ketamine has a greater potency and longer-lasting antidepressant effects than (S)-ketamine. Here we investigated whether mTOR signaling and ERK signaling play a role in the antidepressant effects of two enantiomers. The effects of mTOR inhibitors (rapamycin and AZD8055) and an ERK inhibitor (SL327) on the antidepressant effects of ketamine enantiomers in the chronic social defeat stress (CSDS) model (n = 7 or 8) and on those of ketamine enantiomers in these signaling pathways in mouse brain regions were examined. The intracerebroventricular infusion of rapamycin or AZD8055 blocked the antidepressant effects of (S)-ketamine, but not (R)-ketamine, in the CSDS model. Furthermore, (S)-ketamine, but not (R)-ketamine, significantly attenuated the decreased phosphorylation of mTOR and its downstream effector, ribosomal protein S6 kinase, in the prefrontal cortex of susceptible mice after CSDS. Pretreatment with SL327 blocked the antidepressant effects of (R)-ketamine but not (S)-ketamine. Moreover, (R)-ketamine, but not (S)-ketamine, significantly attenuated the decreased phosphorylation of ERK and its upstream effector, mitogen-activated protein kinase/ERK kinase, in the prefrontal cortex and hippocampal dentate gyrus of susceptible mice after CSDS. This study suggests that mTOR plays a role in the antidepressant effects of (S)-ketamine, but not (R)-ketamine, and that ERK plays a role in (R)-ketamine's antidepressant effects. Thus, it is unlikely that the activation of mTOR signaling is necessary for antidepressant actions of (R)-ketamine. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Directory of Open Access Journals (Sweden)

Aarron Phensy

2017-06-01

Full Text Available Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH precursor N-acetyl-cysteine (NAC can prevent the development of these behavioral deficits. On postnatal days (PND 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg of ketamine or saline. Two groups (either ketamine or saline treated also received NAC throughout development. In adult animals (PND 70–120 we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.

Oral ketamine for children with chronic pain: a pilot phase 1 study

Science.gov (United States)

Bredlau, Amy-Lee; McDermott, Michael P.; Adams, Heather; Dworkin, Robert H; Venuto, Charles; Fisher, Susan; Dolan, James G; Korones, David N

2013-01-01

Objective To assess whether oral ketamine aids is is safe at higher dosages for sedating children and whether it may be an option for control of chronic pain in children. Study design A prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, three times daily, at dosages ranging from 0.25–1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment. Results Two participants, both treated at 1.5 mg/kg/dose, experienced dose-limiting toxicities (sedation and anorexia). One participant, treated at 1 mg/kg/dose, opted to stop ketamine treatment due to new pain on treatment. Nine participants completed their course of ketamine treatment. Of these 12 children, 5 experienced improvement in their pain scores, two with complete resolution of pain, lasting for more than 4 weeks off ketamine treatment. Conclusion Oral ketamine at dosages of 0.25–1 mg/kg/dose appears to be safe when given for 14 days to children with chronic pain. PMID:23403253

Intramuscular ketamine to facilitate pediatric central vascular access.

Science.gov (United States)

Denmark, T Kent; Hargrove, Jenny R; Brown, Lance

2004-07-01

Obtaining prompt vascular access in young children presenting to the emergency department (ED) is frequently both necessary and technically challenging. The objective of our study was to describe our experience using intramuscular (IM) ketamine to facilitate the placement of central venous catheters in children presenting to our ED needing vascular access in a timely fashion. We performed a retrospective medical record review of all pediatric patients central venous catheter facilitated by the use of IM ketamine. Eleven children met our inclusion criteria. Most of the children were young and medically complicated. The children ranged in age from 6 months to 8 years. The only complication identified was vomiting experienced by an 8-year-old boy. Emergency physicians successfully obtained central venous access in all subjects in the case series. The use of IM ketamine to facilitate the placement of central venous catheters in children who do not have peripheral venous access appears to be helpful. Emergency physicians may find it useful to be familiar with this use of IM ketamine.

Ketamine PCA for treatment of end-of-life neuropathic pain in pediatrics.

Science.gov (United States)

Taylor, Matthew; Jakacki, Regina; May, Carol; Howrie, Denise; Maurer, Scott

2015-12-01

Control of neuropathic pain (NP) for children at end of life is challenging. Ketamine improves control of NP, but its use in children is not well described. We describe a retrospective case review of 14 children with terminal prognoses treated with ketamine patient-controlled analgesia (PCA) for management of opioid-refractory NP at the end of life. Median ketamine dose was 0.06 mg/kg/h (range 0.014-0.308 mg/kg/h) with a 0.05 mg/kg (range 0.03-0.5mg/kg) demand dose available every 15 minutes (range 10-60 minutes). All patients noted subjective pain relief with ketamine, and 79% had no adverse effects. Benzodiazepines limited neuropsychiatric side effects. Ketamine treatment arrested dose escalation of opioids in 64% of patients, and 79% were discharged to home hospice. Ketamine PCA is an effective, well-tolerated therapy for opioid-refractory NP in pediatric end-of-life care. © The Author(s) 2014.

Potential mechanisms for the inhibition of tumor cell growth by manganese superoxide dismutase.

Science.gov (United States)

Kim, K H; Rodriguez, A M; Carrico, P M; Melendez, J A

2001-06-01

Studies from many laboratories have shown that overexpression of manganese superoxide dismutase (MnSOD) inhibits the growth of numerous tumor cell types. The inhibition of tumor cell growth can be attributed to the increase in the steady-state levels of H2O2 as a result of the increased dismuting activity of MnSOD. Here we demonstrate that overexpression of MnSOD enhances the activity of the superoxide (O2*-)-sensitive enzyme aconitase, decreases the intracellular GSH/GSSG ratio, and dose-dependently inhibits pyruvate carboxylase activity. Thus, alterations in the steady-state concentrations of mitochondrial O2*- and H2O2 as a result of MnSOD overexpression can alter the metabolic capacity of the cell leading to inhibition of cell growth. Furthermore, we propose that MnSOD overexpression can modulate the activity of nitric oxide (*NO) by preventing its reaction with O2*-. This hypothesis suggests that the redox environment of the mitochondria can be altered to favor the activity of *NO rather than peroxynitrite (ONOO-) and may explain the enhanced toxicity of *NO-generating compounds toward MnSOD-overexpressing cell lines. These findings indicate that therapeutic strategies targeted at overexpressing MnSOD in tumor tissue may be more effective when used in combination with agents that deplete the oxidant-buffering and enhance the *NO-generating capacity of the tumor and host, respectively.

Ketamine for Depression: Where Do We Go from Here?

Science.gov (United States)

aan het Rot, Marije; Zarate, Carlos A.; Charney, Dennis S.; Mathew, Sanjay J.

2012-01-01

Since publication of the first randomized controlled trial describing rapid antidepressant effects of ketamine, several reports have confirmed the potential utility of this dissociative anesthetic medication for treatment of major depressive episodes, including those associated with bipolar disorder and resistant to other medications and electroconvulsive therapy. These reports have generated several questions with respect to who might respond to ketamine, how, and for how long. To start answering these questions. We used PubMed.gov and ClinicalTrials.gov to perform a systematic review of all available published data on the antidepressant effects of ketamine and of all recently completed, ongoing, and planned studies. To date, 163 patients, primarily with treatment-resistant depression, have participated in case studies, open-label investigations, or controlled trials. All controlled trials have used a within-subject, crossover design with an inactive placebo as the control. Ketamine administration has usually involved an anaesthesiologist infusing a single, subanesthetic, intravenous dose, and required hospitalization for at least 24 hours postinfusion. Response rates in the open-label investigations and controlled trials have ranged from 25% to 85% at 24 hours postinfusion and from 14% to 70% at 72 hours postinfusion. Although adverse effects have generally been mild, some patients have experienced brief changes in blood pressure, heart rate, or respiratory rate. Risk–benefit analyses support further research of ketamine for individuals with severe mood disorders. However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting. PMID:22705040

To use or not to use: an update on licit and illicit ketamine use

Directory of Open Access Journals (Sweden)

Yuet-wah Cheung

2011-03-01

Full Text Available Jih-Heng Li1, Balasingam Vicknasingam2, Yuet-wah Cheung3, Wang Zhou4, Adhi Wibowo Nurhidayat5, Don C Des Jarlais6, Richard Schottenfeld71College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan; 2National Centre for Drug Research, Universiti Sains Malaysia, Malaysia; 3Department of Sociology, The Chinese University of Hong Kong, Hong Kong, China; 4Wuhan Center for Disease Control and Prevention, Wuhan, China; 5Drug Dependence Hospital RSKO, Jakarta, Indonesia; 6Beth Israel Medical Center, New York, NY; 7School of Psychiatry, Yale University, CT, USAAbstract: Ketamine, a derivative of phencyclidine that was developed in the 1960s, is an anesthetic and analgesic with hallucinogenic effects. In this paper, the pharmacological and toxicological effects of ketamine are briefly reviewed. Ketamine possesses a wide safety margin but such a therapeutic benefit is somewhat offset by its emergence phenomenon (mind-body dissociation and delirium and hallucinogenic effects. The increasing abuse of ketamine, initially predominantly in recreational scenes to experience a “k-hole” and other hallucinatory effects but more recently also as a drug abused during the workday or at home, has further pushed governments to confine its usage in many countries. Recently, urinary tract dysfunction has been associated with long-term ketamine use. In some long-term ketamine users, such damage can be irreversible and could result in renal failure and dialysis. Although ketamine has not yet been scheduled in the United Nations Conventions, previous studies using different assessment parameters to score the overall harms of drugs indicated that ketamine may cause more harm than some of the United Nations scheduled drugs. Some countries in Southeast and East Asia have reported an escalating situation of ketamine abuse. Dependence, lower urinary tract dysfunction, and sexual impulse or violence were the most notable among the ketamine-associated symptoms in these

Adjunct Ketamine Use in the Management of Severe Ethanol Withdrawal.

Science.gov (United States)

Pizon, Anthony F; Lynch, Michael J; Benedict, Neal J; Yanta, Joseph H; Frisch, Adam; Menke, Nathan B; Swartzentruber, Greg S; King, Andrew M; Abesamis, Michael G; Kane-Gill, Sandra L

2018-05-08

Ketamine offers a plausible mechanism with favorable kinetics in treatment of severe ethanol withdrawal. The purpose of this study is to determine if a treatment guideline using an adjunctive ketamine infusion improves outcomes in patients suffering from severe ethanol withdrawal. Retrospective observational cohort study. Academic tertiary care hospital. Patients admitted to the ICU and diagnosed with delirium tremens by Diagnostic and Statistical Manual of Mental Disorders V criteria. Pre and post guideline, all patients were treated in a symptom-triggered fashion with benzodiazepines and/or phenobarbital. Postguideline, standard symptom-triggered dosing continued as preguideline, plus, the patient was initiated on an IV ketamine infusion at 0.15-0.3 mg/kg/hr continuously until delirium resolved. Based upon withdrawal severity and degree of agitation, a ketamine bolus (0.3 mg/kg) was provided prior to continuous infusion in some patients. A total of 63 patients were included (29 preguideline; 34 postguideline). Patients treated with ketamine were less likely to be intubated (odds ratio, 0.14; p trend toward a shorter hospitalization.

21 CFR 522.1222 - Ketamine hydrochloride injectable dosage forms.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ketamine hydrochloride injectable dosage forms. 522.1222 Section 522.1222 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... ANIMAL DRUGS § 522.1222 Ketamine hydrochloride injectable dosage forms. ...

Clinical pattern and prevalence of upper gastrointestinal toxicity in patients abusing ketamine.

Science.gov (United States)

Liu, Shirley Yuk Wah; Ng, Stephen Ka Kei; Tam, Yuk Him; Yee, Samuel Chi Hang; Lai, Franco Pui Tak; Hong, Cindy Yuek Lam; Chiu, Philip Wai Yan; Ng, Enders Kwok Wai; Ng, Chi Fai

2017-09-01

Evaluations of upper gastrointestinal toxicity from ketamine abuse are uncommon. This study investigated the clinical pattern of upper gastrointestinal symptoms in patients inhaling ketamine. In a cross-sectional study of 611 consecutive patients who were seeking treatment for ketamine uropathy in a tertiary hospital setting between August 2008 and June 2016, their clinical pattern of upper gastrointestinal symptoms was evaluated and compared with a control population of 804 non-users. A total of 168 (27.5%) patients abusing ketamine (mean age 26.3 years, 58.9% female) reported the presence of upper gastrointestinal symptoms. These symptoms were significantly more prevalent in patients inhaling ketamine than in those who were not (27.5% vs 5.2%, P ketamine abuse before symptom presentation was 5.0 ± 3.1 years. The presenting symptoms included epigastric pain (n = 155, 25.4%), recurrent vomiting (n = 48, 7.9%), anemia (n = 36, 5.9%) and gastrointestinal bleeding (n = 20, 3.3%). Uropathy symptoms were preceded by upper gastrointestinal symptoms for 4.4 ± 3.0 years in 141 (83.9%) patients. Logistic regression showed that elder age (odds ratio [OR] 1.06, P = 0.04), active abuser status (OR 1.60, P = 0.04) and longer duration of ketamine abuse (OR 1.00, P = 0.04) were independent factors associated with upper gastrointestinal toxicity. Although epigastric symptoms are unusual in the young population, upper gastrointestinal toxicity was highly prevalent in those inhaling ketamine. Enquiries about ketamine abuse are recommended when assessing young patients with epigastric symptoms. © 2017 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Studies of the biotransformation and pharmacology of ketamine and its metabolites

International Nuclear Information System (INIS)

Leung, Y.

1986-01-01

The first part of the research is concerned with the synthesis, resolution and metabolism of norketamine, the primary metabolite of ketamine. Incubations of racemic norketamine, individual enantiomers of norketamine and the pseudoracemates in rat liver microsomes revealed stereoselectivity and enantiomeric interactions during the metabolism of norketamine. The second part of the research describes the synthesis of 6-OH-norketamine, the major secondary metabolite of ketamine, and reports on its pharmacological activity and cerebral distribution in the rat. Primary deuterium isotope effects associated with the metabolism and pharmacological activity of ketamine-N-CD 3 were examined in the third part of this research. The last part of the research deals with the effect of diazepam on the metabolic transformation of ketamine to norketamine in the rat. The fractions of ketamine metabolized to norketamine were found not to be different in the presence or the absence of diazepam

Influence of ketamine on regional brain glucose use

International Nuclear Information System (INIS)

Davis, D.W.; Mans, A.M.; Biebuyck, J.F.; Hawkins, R.A.

1988-01-01

The purpose of this study was to determine the effect of different doses of ketamine on cerebral function at the level of individual brain structures as reflected by glucose use. Rats received either 5 or 30 mg/kg ketamine intravenously as a loading dose, followed by an infusion to maintain a steady-state level of the drug. An additional group received 30 mg/kg as a single injection only, and was studied 20 min later, by which time they were recovering consciousness (withdrawal group). Regional brain energy metabolism was evaluated with [6- 14 C]glucose and quantitative autoradiography during a 5-min experimental period. A subhypnotic, steady-state dose (5 mg/kg) of ketamine caused a stimulation of glucose use in most brain areas, with an average increase of 20%. At the larger steady-state dose (30 mg/kg, which is sufficient to cause anesthesia), there was no significant effect on most brain regions; some sensory nuclei were depressed (inferior colliculus, -29%; cerebellar dentate nucleus, -18%; vestibular nucleus, -16%), but glucose use in the ventral posterior hippocampus was increased by 33%. In contrast, during withdrawal from a 30-mg/kg bolus, there was a stimulation of glucose use throughout the brain (21-78%), at a time when plasma ketamine levels were similar to the levels in the 5 mg/kg group. At each steady-state dose, as well as during withdrawal, ketamine caused a notable stimulation of glucose use by the hippocampus

Isolated tumoral pyruvate dehydrogenase can synthesize acetoin which inhibits pyruvate oxidation as well as other aldehydes.

Science.gov (United States)

Baggetto, L G; Lehninger, A L

1987-05-29

Oxidation of 1 mM pyruvate by Ehrlich and AS30-D tumor mitochondria is inhibited by acetoin, an unusual and important metabolite of pyruvate utilization by cancer cells, by acetaldehyde, methylglyoxal and excess pyruvate. The respiratory inhibition is reversed by other substrates added to pyruvate and also by 0.5 mM ATP. Kinetic properties of pyruvate dehydrogenase complex isolated from these tumor mitochondria have been studied. This complex appears to be able to synthesize acetoin from acetaldehyde plus pyruvate and is competitively inhibited by acetoin. The role of a new regulatory pattern for tumoral pyruvate dehydrogenase is presented.

Efficacy of ketamine in improving pain after tonsillectomy in children: meta-analysis.

Science.gov (United States)

Cho, Hye Kyung; Kim, Kyu Won; Jeong, Yeon Min; Lee, Ho Seok; Lee, Yeon Ji; Hwang, Se Hwan

2014-01-01

The goal of this meta-analysis study was to perform a systematic review of the literature on the effects of ketamine on postoperative pain following tonsillectomy and adverse effects in children. Two authors independently searched three databases (MEDLINE, SCOPUS, Cochrane) from their inception of article collection to February 2014. Studies that compared preoperative ketamine administration (ketamine groups) with no treatment (control group) or opioid administration (opioid group) where the outcomes of interest were postoperative pain intensity, rescue analgesic consumption, or adverse effects (sedation, nausea and vomiting, bad dream, worsening sleep pattern, and hallucination) 0-24 hours after leaving the operation room were included in the analysis. The pain score reported by the physician during first 4 hours and need for analgesics during 24 hours postoperatively was significantly decreased in the ketamine group versus control group and was similar with the opioid group. In addition, there was no significant difference between ketamine and control groups for adverse effects during 24 hours postoperatively. In the subgroup analyses (systemic and local administration) regarding pain related measurements, peritonsillar infiltration of ketamine was more effective in reducing the postoperative pain severity and need for analgesics. Preoperative administration of ketamine systemically or locally could provide pain relief without side-effects in children undergoing tonsillectomy. However, considering the insufficient evaluation of efficacy of ketamine according to the administration methods and high heterogeneity in some parameters, further clinical trials with robust research methodology should be conducted to confirm the results of this study.

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

Science.gov (United States)

Robinson, Bonnie L.; Dumas, Melanie; Cuevas, Elvis; Gu, Qiang; Paule, Merle G.; Ali, Syed F.; Kanungo, Jyotshna

2016-01-01

Ketamine, a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1–0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression. PMID:26898327

β-elemene inhibits tumor-promoting effect of M2 macrophages in lung cancer.

Science.gov (United States)

Yu, Xiaomu; Xu, Maoyi; Li, Na; Li, Zongjuan; Li, Hongye; Shao, Shujuan; Zou, Kun; Zou, Lijuan

2017-08-19

Macrophages in tumor are mostly M2-polarized and have been reported to promote tumorigenesis, which are also defined as tumor-associated macrophages (TAMs). β-elemene has therapeutic effects against several cancers, however, it remains unknown whether β-elemene could inhibit cancer by targeting TAMs. Herein, we examined the effect of β-elemene on macrophages to elucidate a novel mechanism of β-elemene in tumor therapy. We showed that the conditioned medium of M2 macrophages promoted lung cancer cells to migration, invasion and epithelial mesenchymal transition, which could be inhibited by β-elemene. Moreover, β-elemene regulated the polarization of macrophages from M2 to M1. β-elemene also inhibited the proliferation, migration, invasion of lung cancer cells and enhanced its radiosensitivity. These results indicate β-elemene suppresses lung cancer by regulating both macrophages and lung cancer cells, it is a promising drug for combination with chemotherapy or radiotherapy. Copyright © 2017 Elsevier Inc. All rights reserved.

Ketamine attenuates the glutamatergic neurotransmission in the ventral posteromedial nucleus slices of rats.

Science.gov (United States)

Fu, Bao; Liu, Chengxi; Zhang, Yajun; Fu, Xiaoyun; Zhang, Lin; Yu, Tian

2017-08-23

Ketamine is a frequently used intravenous anesthetic, which can reversibly induce loss of consciousness (LOC). Previous studies have demonstrated that thalamocortical system is critical for information transmission and integration in the brain. The ventral posteromedial nucleus (VPM) is a critical component of thalamocortical system. Glutamate is an important excitatory neurotransmitter in the brain and may be involved in ketamine-induced LOC. The study used whole-cell patch-clamp to observe the effect of ketamine (30 μM-1000 μM) on glutamatergic neurotransmission in VPM slices. Ketamine significantly decreased the amplitude of glutamatergic spontaneous excitatory postsynaptic currents (sEPSCs), but only higher concentration of ketamine (300 μM and 1000 μM) suppressed the frequency of sEPSCs. Ketamine (100 μM-1000 μM) also decreased the amplitude of glutamatergic miniature excitatory postsynaptic currents (mEPSCs), without altering the frequency. In VPM neurons, ketamine attenuates the glutamatergic neurotransmission mainly through postsynaptic mechanism and action potential may be involved in the process.

Preemptive Analgesic Effect of Ketamine in Children with Lower Abdominal Surgery

Directory of Open Access Journals (Sweden)

Serbülent Gökhan Beyaz

2011-06-01

Full Text Available Objective: Preemptive analgesic effect of low dose ketamine has been supported by clinical studies in adults. The aim of this study was to evaluate the analgesic effect of ketamine applied at different times in children who underwent lower abdominal surgery.Material and Methods: A total of 90 children having ASAI-II physical status between 3 and 12 was randomly divided into three groups as pre, int and post groups. Ketamine were given to these groups in the following manner respectively; 1mg/kg intravenous ketamine before incision (pre-incisional; the same dose ketamine 10 minutes following the first incision (intraoperative; and ketamine at the end of the surgical operation (postoperative. The pain of patients was assessed by postoperative pain scale (CHIPPS in children and infants; the sedation status of children was assessed by Ramsey’s sedation scale. The first analgesic requirement time was recorded.Results: No significant difference was found in demographic characteristics of the three groups (p>0.05. Lower CHIPPS scores were found in Group Post throughout all measurement periods (p<0.05. Group Post was found to have significantly higher sedation levels compared with the other two groups (p=0.003. Conclusion: No analgesic effect was obtained using by pre-incisional and intraoperative i.v.1mg/kg ketamine, during lower abdominal surgery in children. Further studies with different drugs are needed to clarify this topic.

Inhibition of Lysyl Oxidases Impairs Migration and Angiogenic Properties of Tumor-Associated Pericytes

Directory of Open Access Journals (Sweden)

Aline Lopes Ribeiro

2017-01-01

Full Text Available Pericytes are important cellular components of the tumor microenviroment with established roles in angiogenesis and metastasis. These two cancer hallmarks are modulated by enzymes of the LOX family, but thus far, information about LOX relevance in tumor-associated pericytes is lacking. Here, we performed a comparative characterization of normal and tumoral pericytes and report for the first time the modulatory effects of LOX enzymes on activated pericyte properties. Tumoral pericytes isolated from childhood ependymoma and neuroblastoma specimens displayed angiogenic properties in vitro and expressed typical markers, including CD146, NG2, and PDGFRβ. Expression of all LOX family members could be detected in both normal and tumor-associated pericytes. In most pericyte samples, LOXL3 was the family member displaying the highest transcript levels. Inhibition of LOX/LOXL activity with the inhibitor β-aminopropionitrile (βAPN significantly reduced migration of pericytes, while proliferation rates were kept unaltered. Formation of tube-like structures in vitro by pericytes was also significantly impaired upon inhibition of LOX/LOXL activity with βAPN, which induced more prominent effects in tumor-associated pericytes. These findings reveal a novel involvement of the LOX family of enzymes in migration and angiogenic properties of pericytes, with implications in tumor development and in therapeutic targeting tumor microenvironment constituents.

Respiratory complications associated with ketamine anesthesia for ophthalmic procedures following intraocular pressure measurement in children

Directory of Open Access Journals (Sweden)

Lei Wu

2014-01-01

Full Text Available Background: We compared respiratory complications (RCs in children who received intramuscular (IM versus intravenous (IV or no ketamine for intraocular pressure (IOP measurement to test our observation that IM ketamine is associated with higher incidence of RCs. Materials and Methods: We analyzed 149 eye examinations under anesthesia with ketamine in 27 patients and 263 non-ketamine examinations under anesthesia in 81 patients using a mixed effects logistic regression model. Results: IM ketamine was strongly associated with increased odds of RCs compared to no ketamine (odds ratio (OR: 20.23, P < 0.0001 and to IV ketamine (OR: 6.78, P = 0.02, as were higher American Society of Anesthesiologists (ASA classification (OR: 2.60, P = 0.04, and the use of volatile agents (OR: 3.32, P = 0.02. Conclusion: Further studies should be conducted to confirm our observation of increased RCs with IM ketamine.

Rapid and sensitive detection of ketamine in blood using novel fluorescence genosensor.

Science.gov (United States)

Ding, Yanjun; Li, Xingmei; Guo, Yadong; Yan, Jie; Ling, Jiang; Li, Weichen; Lan, Lingmei; Chang, Yunfeng; Cai, Jifeng; Zha, Lagabaiyla

2017-12-01

In recent years, drug abuse has been considered as a most challenging social problem that aroused public attention. Ketamine has increased in unregulated use as a 'recreational drug' in teenagers. However, there is no suitable and maneuverable detection method for ketamine in situ at the moment. Fluorescence sensor technique, with predominant recognition and simple operation, is a good potential application in drug detection. Here, we first reported a highly sensitive and selective fluorescence genosensor for rapid detection of ketamine based on DNA-templated silver nanoclusters (DNA-AgNCs) probes, in which the DNA sequence could specially recognize ketamine with high affinity. Parameters affecting detection efficiency were investigated and optimized. Under optimum conditions, the as-prepared genosensor can allow for the determination of ketamine in the concentration range of 0.0001-20 μg/mL with two linear equations: one is y = 2.84x-7.139 (R 2 = 0.987) for 0.0001-0.1 μg/mL, and the other is y = 1.87x-0.091 (R 2 = 0.962) for 0.1-20 μg/mL, and the estimated detection limit of ketamine is 0.06 ng/mL. Moreover, the feasibility of this proposed method was also demonstrated by analyzing forensic blood samples. Compared with official gas chromatography/mass spectrometry (GC/MS), this fluorescence genosensor is simple, rapid, and accurate for quantitative determination of ketamine in blood for pharmaceutical and forensic analysis. Overall, it is the first report on a fluorescence genosensor for detecting ketamine directly in blood. This research may provide a new insight for the analyst to band fluorescence genosensor technology together with drug monitoring in the battle against drug abuse and forensic examination. Graphical abstract High selectively detection of ketamine using a novel fluorescence genosensor based on DNA-AgNCs probe.

Population pharmacokinetic-pharmacodynamic modeling of ketamine-induced pain relief of chronic pain.

Science.gov (United States)

Dahan, Albert; Olofsen, Erik; Sigtermans, Marnix; Noppers, Ingeborg; Niesters, Marieke; Aarts, Leon; Bauer, Martin; Sarton, Elise

2011-03-01

Pharmacological treatment of chronic (neuropathic) pain is often disappointing. In order to enhance our insight in the complex interaction between analgesic drug and chronic pain relief, we performed a pharmacokinetic-pharmacodynamic (PK-PD) modeling study on the effect of S(+)-ketamine on pain scores in Complex Regional Pain Syndrome type 1 (CRPS-1) patients. Sixty CRPS-1 patients were randomly allocated to received a 100-h infusion of S(+)-ketamine or placebo. The drug infusion rate was slowly increased from 5 mg/h (per 70 kg) to 20 mg/h based upon the effect/side effect profile. Pain scores and drug blood samples were obtained during the treatment phase and pain scores were further obtained weekly for another 11 weeks. A population PK-PD model was developed to analyze the S(+)-ketamine-pain data. Plasma concentrations of S(+)-ketamine and its metabolite decreased rapidly upon the termination of S(+)-ketamine infusion. The chance for an analgesic effect from ketamine and placebo treatment was 67±10% and 23±9% (population value±SE), respectively. The pain data were well described by the PK-PD model with parameters C(50)=10.5±4.8 ng/ml (95% ci 4.37-21.2 ng/ml) and t½ for onset/offset=10.9±4.0 days (5.3-20.5 days). Long-term S(+)-ketamine treatment is effective in causing pain relief in CRPS-1 patients with analgesia outlasting the treatment period by 50 days. These data suggest that ketamine initiated a cascade of events, including desensitization of excitatory receptor systems in the central nervous system, which persisted but slowly abated when ketamine molecules were no longer present. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

Modulatory effect of curcumin on ketamine-induced toxicity in rat thymocytes: Involvement of reactive oxygen species (ROS and the phosphoinositide 3-kinase (PI3K/protein kinase B (Akt pathway

Directory of Open Access Journals (Sweden)

Svetlana Pavlovic

2018-03-01

Full Text Available Ketamine is a widely used anesthetic in pediatric clinical practice. Previous studies have demonstrated that ketamine induces neurotoxicity and has a modulatory effect on the cells of the immune system. Here, we evaluated the potential protective effect and underlying mechanisms of natural phenolic compound curcumin against ketamine-induced toxicity in rat thymocytes. Rat thymocytes were exposed to 100 µM ketamine alone or combined with increasing concentrations of curcumin (0.3, 1, and 3 μM for 24 hours. Cell viability was analyzed with CCK-8 assay kit. Apoptosis was analyzed using flow cytometry and propidium iodide as well as Z-VAD-FMK and Z-LEHD-FMK inhibitors. Reactive oxygen species (ROS production and mitochondrial membrane potential [MMP] were measured by flow cytometry. Colorimetric assay with DEVD-pNA substrate was used for assessing caspase-3 activity. Involvement of phosphoinositide 3-kinase (PI3K/protein kinase B (Akt signaling pathway was tested with Wortmannin inhibitor. Ketamine induced toxicity in cells, increased the number of hypodiploid cells, caspase-3 activity and ROS production, and inhibited the MMP. Co-incubation of higher concentrations of curcumin (1 and 3 μM with ketamine markedly decreased cytotoxicity, apoptosis rate, caspase-3 activity, and ROS production in rat thymocytes, and increased the MMP. Application of Z-VAD-FMK (a pan caspase inhibitor or Z-LEHD-FMK (caspase-9 inhibitor with ketamine effectively attenuated the ketamine-induced apoptosis in rat thymocytes. Administration of Wortmannin (a PI3K inhibitor with curcumin and ketamine significantly decreased the protective effect of curcumin on rat thymocytes. Our results indicate that ketamine-induced toxicity in rat thymocytes mainly occurs through the mitochondria-mediated apoptotic pathway and that the PI3K/Akt signaling pathway is involved in the anti-apoptotic effect of curcumin.

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells

OpenAIRE

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-01-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of newdrug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation o...

Efficacy of Ketamine in Pediatric Sedation Dentistry: A Systematic Review.

Science.gov (United States)

Oh, Samuel; Kingsley, Karl

2018-05-01

Ketamine has been used as a safe and effective sedative to treat adults and children exhibiting high levels of anxiety or fear during dental treatment. Pediatric dentistry often involves patients with high levels of anxiety and fear and possibly few positive dental experiences. Patient management can involve behavioral approaches, as well as the use of sedation or general anesthesia with a variety of agents, including midazolam, diazepam, hydroxyzine, meperidine, and ketamine. The aim of this study was to investigate the clinical efficacy of ketamine use in pediatric sedation dentistry through systematic review and analysis. A systematic review of publications between 1990 and 2015 was conducted using PubMed and MEDLINE databases maintained by the US National Library of Medicine and the National Institutes of Health. The keywords used were (ketamine) AND (dental OR dentistry) AND (sedation). The abstract and title of all potential publications were then screened for clinical trials and to remove non-English articles, non-human or animal trials, and other non-dental or non-relevant studies. A total of 1,657 citations were initially identified, reviewed, and screened, eventually resulting in inclusion of 25 clinical trials in this systematic review. Nineteen studies evaluated ketamine effects in pediatric dental sedation using oral (non-invasive) administration, three involved subcutaneous or intramuscular injection, and three were completed intravenously. Evidence analysis of these trials revealed the majority (n = 22/25) provided strong, positive evidence for the use of ketamine (alone or in combination) to reduce dental anxiety and behavioral non-compliance with the remainder suggesting equivocal results. Additional endpoints evaluated in some studies involved dosage, as well as time to achieve sedation effect. The use of ketamine (alone or in combination) can provide safe, effective, and timely sedation in pediatric patients regardless of the route of

Role of Ketamine in Acute Postoperative Pain Management: A Narrative Review

Directory of Open Access Journals (Sweden)

Brian M. Radvansky

2015-01-01

Full Text Available Objectives. The objective of this narrative review was to examine the usage of ketamine as a postoperative analgesic agent across a wide variety of surgeries. Design. A literature search was performed using the phrases “ketamine” and “postoperative pain.” The authors analyzed the studies that involved testing ketamine’s effectiveness at controlling postoperative pain. Effectiveness was assessed through various outcomes such as the amount of opiate consumption, visual analog scale (VAS pain scores, and persistent postoperative pain at long-term follow-up. Results. While many different administration protocols were evaluated, delivering ketamine both as a pre- or perioperative bolus and postoperative infusion for up to 48 hours appeared to be the most effective. These effects are dose-dependent. However, a number of studies analyzed showed no benefit in using ketamine versus placebo for controlling postoperative pain. While ketamine is a safe and well-tolerated drug, it does have adverse effects, and there are concerns for possible neurotoxicity and effects on memory. Conclusions. In a number of limited situations, ketamine has shown some efficacy in controlling postoperative pain and decreasing opioid consumption. More randomized controlled trials are necessary to determine the surgical procedures and administrations (i.e., intravenous, epidural that ketamine is best suited for.

Ketamine and the metabolite norketamine: persistence and phototransformation toxicity in hospital wastewater and surface water.

Science.gov (United States)

Lin, Angela Yu-Chen; Lee, Wan-Ning; Wang, Xiao-Huan

2014-04-15

Ketamine has been increasingly used both recreationally and medicinally around the world. Although the metabolic pathways to form its metabolite norketamine have been carefully investigated in humans and animals, knowledge of their environmental occurrence and fate is limited. In this study, we investigated the occurrence of ketamine and norketamine in 20 natural bodies of water, effluents from 13 hospitals, two wastewater treatment plants and one water supply plant. Ketamine was found at concentrations as high as 10 μg/L. Ketamine and norketamine were consistently found in similar concentrations (ketamine/norketamine ratio: 0.3-4.6) in the collected water samples, and this ratio similar to that found in urine samples. Dark incubation experiments have shown that ketamine is not susceptible to microbial degradation or hydrolysis. Phototransformation was demonstrated to significantly reduce the concentration of ketamine and norketamine in river waters (t(1/2) = 12.6 ± 0.4 and 10.1 ± 0.4 h, respectively) and resulted in byproducts that are similar to human metabolites. Both direct and indirect photolysis led to the N-demethylation of ketamine to form norketamine and other byproducts, including hydroxy-norketamine (HNK), dehydronorketamine (DNK), hydroxy-ketamine (HK) and isomer forms of ketamine and norketamine. Irradiated solutions exhibited higher toxicity (via the Microtox test). Although a final risk assessment could not be made due to a lack of studies on the chronic effects on aquatic organisms, the high and persistent environmental occurrences of ketamine and norketamine as well as the increasingly acute toxicity of the photo byproducts demonstrate the importance of including metabolites in evaluation of the overall risk of ketamine. Copyright © 2014 Elsevier Ltd. All rights reserved.

Ecotoxicological effect of ketamine: Evidence of acute, chronic and photolysis toxicity to Daphnia magna.

Science.gov (United States)

Li, Shih-Wei; Wang, Yu-Hsiang; Lin, Angela Yu-Chen

2017-09-01

Ketamine has been increasingly used in medicine and has the potential for abuse or illicit use around the world. Ketamine cannot be removed by conventional wastewater treatment plants. Although ketamine and its metabolite norketamine have been detected to a significant degree in effluents and aquatic environments, their ecotoxicity effects in aquatic organisms remain undefined. In this study, we investigated the acute toxicity of ketamine and its metabolite, along with the chronic reproductive toxicity of ketamine (5-100μg/L) to Daphnia magna. Multiple environmental scenarios were also evaluated, including drug mixtures and sunlight irradiation toxicity. Ketamine and norketamine caused acute toxicity to D. magna, with half lethal concentration (LC 50 ) values of 30.93 and 25.35mg/L, respectively, after 48h of exposure. Irradiated solutions of ketamine (20mg/L) significantly increased the mortality of D. magna; pre-irradiation durations up to 2h rapidly increased the death rate to 100%. A new photolysis byproduct (M.W. 241) of norketamine that accumulates during irradiation was identified for the first time. The relevant environmental concentration of ketamine produced significant reproductive toxicity effects in D. magna, as revealed by the reduction of the number of total live offspring by 33.6-49.8% (p ketamine concentration cannot be ignored and warrant further examination. Copyright © 2017 Elsevier Inc. All rights reserved.

COMPARISON OF THREE SHORT-TERM IMMOBILIZATION REGIMES IN WILD VERREAUX'S SIFAKAS (PROPITHECUS VERREAUXI): KETAMINE-XYLAZINE, KETAMINE-XYLAZINE-ATROPINE, AND TILETAMINE-ZOLAZEPAM.

Science.gov (United States)

Springer, Andrea; Razafimanantsoa, Léonard; Fichtel, Claudia; Kappeler, Peter M

2015-09-01

Although research on lemurid primates in Madagascar has been ongoing for several decades, reports on different drug regimes to immobilize wild lemurs are limited. This study compares the efficacy, reliability, and side effects of ketamine-xylazine, ketamine-xylazine-atropine, and tiletamine-zolazepam immobilization in wild Verreaux's sifakas (Propithecus verreauxi). In the course of a long-term study in Kirindy Forest, western Madagascar, eight animals each received a mixture of ketamine (5.32±1.71 mg/kg) and xylazine (0.56±0.19 mg/kg) (KX; 7 males, 1 female) and ketamine (6.58±1.36 mg/kg), xylazine (1.28±0.28 mg/kg), and atropine (0.013±0.003 mg/kg) (KXA; 5 males, 3 females), respectively, and 14 individuals received tiletamine-zolazepam (7.73±1.37 mg/kg) (TZ; 9 males, 5 females). Induction was smooth in all protocols, but showed considerable variation in duration when animals had received KXA. Immobilization as well as recovery lasted significantly longer with TZ than with KX (Pimmobilized with TZ. Heart rate measurement at 10 min after onset of complete immobilization yielded significantly higher values if the animals had been immobilized with TZ compared to KX (Pimmobilized animals, whereas immobilization with TZ resulted in an increase in heart rate. The results suggest that KX produces good, but short, immobilization in Verreaux's sifakas at approximately 5 mg/kg ketamine and 0.5 mg/kg xylazine and a smoother and shorter recovery phase than 5 to 10 mg/kg TZ, whereas adding atropine to KX did not provide any benefits.

Effect of low frequency magnetic fields on melanoma: tumor inhibition and immune modulation

International Nuclear Information System (INIS)

Nie, Yunzhong; Du, Leilei; Mou, Yongbin; Xu, Zhenjun; Weng, Leihua; Du, Youwei; Zhu, Yanan; Hou, Yayi; Wang, Tingting

2013-01-01

We previously found that the low frequency magnetic fields (LF-MF) inhibited gastric and lung cancer cell growth. We suppose that exposure to LF-MF may modulate immune function so as to inhibit tumor. We here investigated whether LF-MF can inhibit the proliferation and metastasis of melanoma and influence immune function. The effect of MF on the proliferation, cell cycle and ultrastracture of B16-F10 in vitro was detected by cell counting Kit-8 assay, flow cytometry, and transmission electron microscopy. Lung metastasis mice were prepared by injection of 2 × 10 5 B16-F10 melanoma cells into the tail vein in C57BL/6 mice. The mice were then exposed to an LF-MF (0.4 T, 7.5 Hz) for 43 days. Survival rate, tumor markers and the innate and adaptive immune parameters were measured. The growth of B16-F10 cells was inhibited after exposure to the LF-MF. The inhibition was related to induction of cell cycle arrest and decomposition of chromatins. Moreover, the LF-MF prolonged the mouse survival rate and inhibited the proliferation of B16-F10 in melanoma metastasis mice model. Furthermore, the LF-MF modulated the immune response via regulation of immune cells and cytokine production. In addition, the number of Treg cells was decreased in mice with the LF-MF exposure, while the numbers of T cells as well as dendritic cells were significantly increased. LF-MF inhibited the growth and metastasis of melanoma cancer cells and improved immune function of tumor-bearing mice. This suggests that the inhibition may be attributed to modulation of LF-MF on immune function and LF-MF may be a potential therapy for treatment of melanoma

Combined MEK and ERK inhibition overcomes therapy-mediated pathway reactivation in RAS mutant tumors.

Directory of Open Access Journals (Sweden)

Mark Merchant

Full Text Available Mitogen-activated protein kinase (MAPK pathway dysregulation is implicated in >30% of all cancers, rationalizing the development of RAF, MEK and ERK inhibitors. While BRAF and MEK inhibitors improve BRAF mutant melanoma patient outcomes, these inhibitors had limited success in other MAPK dysregulated tumors, with insufficient pathway suppression and likely pathway reactivation. In this study we show that inhibition of either MEK or ERK alone only transiently inhibits the MAPK pathway due to feedback reactivation. Simultaneous targeting of both MEK and ERK nodes results in deeper and more durable suppression of MAPK signaling that is not achievable with any dose of single agent, in tumors where feedback reactivation occurs. Strikingly, combined MEK and ERK inhibition is synergistic in RAS mutant models but only additive in BRAF mutant models where the RAF complex is dissociated from RAS and thus feedback productivity is disabled. We discovered that pathway reactivation in RAS mutant models occurs at the level of CRAF with combination treatment resulting in a markedly more active pool of CRAF. However, distinct from single node targeting, combining MEK and ERK inhibitor treatment effectively blocks the downstream signaling as assessed by transcriptional signatures and phospho-p90RSK. Importantly, these data reveal that MAPK pathway inhibitors whose activity is attenuated due to feedback reactivation can be rescued with sufficient inhibition by using a combination of MEK and ERK inhibitors. The MEK and ERK combination significantly suppresses MAPK pathway output and tumor growth in vivo to a greater extent than the maximum tolerated doses of single agents, and results in improved anti-tumor activity in multiple xenografts as well as in two Kras mutant genetically engineered mouse (GEM models. Collectively, these data demonstrate that combined MEK and ERK inhibition is functionally unique, yielding greater than additive anti-tumor effects and

A conjugate of an anti-midkine single-chain variable fragment to doxorubicin inhibits tumor growth

Energy Technology Data Exchange (ETDEWEB)

Zhao, Shuli [Immunology and Reproductive Biology Laboratory, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Nanjing Affiliated First Hospital, Nanjing Medical University, Nanjing (China); Zhao, Guangfeng; Xie, Hao; Huang, Yahong [Immunology and Reproductive Biology Laboratory, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Hou, Yayi [Immunology and Reproductive Biology Laboratory, Medical School & State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing (China); Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing (China)

2012-01-27

Doxorubicin (DOX) was conjugated to a single-chain variable fragment (scFv) against human midkine (MK), and the conjugate (scFv-DOX) was used to target the chemotherapeutic agent to a mouse solid tumor model in which the tumor cells expressed high levels of human MK. The His-tagged recombinant scFv was expressed in bacteria, purified by metal affinity chromatography, and then conjugated to DOX using oxidative dextran (Dex) as a linker. The molecular formula of this immunoconjugate was scFv(Dex){sub 1.3}(DOX){sub 20}. In vitro apoptosis assays showed that the scFv-DOX conjugate was more cytotoxic against MK-transfected human adenocarcinoma cells (BGC823-MK) than untransfected cells (55.3 ± 2.4 vs 22.4 ± 3.8%) for three independent experiments. Nude mice bearing BGC823-MK solid tumors received scFv-DOX or equivalent doses of scFv + DOX for 2 weeks and tumor growth was more effectively inhibited by the scFv-DOX conjugate than by scFv + DOX (51.83% inhibition vs 40.81%). Histological analysis of the tumor tissues revealed that the highest levels of DOX accumulated in tumors from mice treated with scFv-DOX and this resulted in more extensive tumor cell death than in animals treated with the equivalent dose of scFv + DOX. These results show that the scFv-DOX conjugate effectively inhibited tumor growth in vivo and suggest that antigen-specific scFv may be competent drug-carriers.

A conjugate of an anti-midkine single-chain variable fragment to doxorubicin inhibits tumor growth

International Nuclear Information System (INIS)

Zhao, Shuli; Zhao, Guangfeng; Xie, Hao; Huang, Yahong; Hou, Yayi

2012-01-01

Doxorubicin (DOX) was conjugated to a single-chain variable fragment (scFv) against human midkine (MK), and the conjugate (scFv-DOX) was used to target the chemotherapeutic agent to a mouse solid tumor model in which the tumor cells expressed high levels of human MK. The His-tagged recombinant scFv was expressed in bacteria, purified by metal affinity chromatography, and then conjugated to DOX using oxidative dextran (Dex) as a linker. The molecular formula of this immunoconjugate was scFv(Dex) 1.3 (DOX) 20 . In vitro apoptosis assays showed that the scFv-DOX conjugate was more cytotoxic against MK-transfected human adenocarcinoma cells (BGC823-MK) than untransfected cells (55.3 ± 2.4 vs 22.4 ± 3.8%) for three independent experiments. Nude mice bearing BGC823-MK solid tumors received scFv-DOX or equivalent doses of scFv + DOX for 2 weeks and tumor growth was more effectively inhibited by the scFv-DOX conjugate than by scFv + DOX (51.83% inhibition vs 40.81%). Histological analysis of the tumor tissues revealed that the highest levels of DOX accumulated in tumors from mice treated with scFv-DOX and this resulted in more extensive tumor cell death than in animals treated with the equivalent dose of scFv + DOX. These results show that the scFv-DOX conjugate effectively inhibited tumor growth in vivo and suggest that antigen-specific scFv may be competent drug-carriers

Paliperidone for the treatment of ketamine-induced psychosis: a case report.

Science.gov (United States)

Zuccoli, M L; Muscella, A; Fucile, C; Carrozzino, R; Mattioli, F; Martelli, A; Orengo, S

2014-01-01

Ketamine is an anaesthetic and analgesic drug synthesized in the 1960s from phencyclidine. The recreational use of ketamine increased among the dance culture of techno and house music, in particular in clubs, discotheques, and rave parties. The psychotropic effects of ketamine are now well known and they range from dissociation to positive, negative, and cognitive schizophrenia-like symptoms. We report a case of a chronic oral consumption of ketamine which induced agitation, behavioral abnormalities, and loss of contact with reality in a poly-drug abuser; these symptoms persisted more than two weeks after the drug consumption had stopped. Antipsychotic treatment with paliperidone led to a successful management of the psychosis, getting a complete resolution of the clinical picture. Paliperidone has proven to be very effective in the treatment of ketamine-induced disorders. Moreover, the pharmacological action and metabolism of paliperidone are poorly dependent from the activity of liver enzymes, so that it seems to be one of the best second generation antipsychotics for the treatment of smokers and alcohol abusers.

KETAMINE ABREACTION : A NEW APPROACH TO NARCOANALYSIS

OpenAIRE

Golechha, G.R.; Sethi, I.C.; Misra, S.L.; Jayaprakash, N.P.

1986-01-01

SUMMARY Ketamine is a parenterally administered non barbiturate anaesthetic agent, in use for more than a decade. It is a safer than Na Pentothal. Administered intramuscularly, in dose of 6 to 15 mgm/Kg body wt. it produces dissociative anaesthesia. But, in smaller sub anaesthetic doses it may act as an abreactant. We report in this study the abreaction effect of Ketamine in dose of .5 to 1.5 mgm/kg body wt. given intramuscularly in 30 selected psychiatric cases requiring narcoanalysis for di...

Long-term heavy ketamine use is associated with spatial memory impairment and altered hippocampal activation

Directory of Open Access Journals (Sweden)

Celia J A Morgan

2014-12-01

Full Text Available Ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist, is rising in popularity as a drug of abuse. Preliminary evidence suggests that chronic, heavy ketamine use may have profound effects on spatial memory but the mechanism of these deficits is as yet unclear. This study aimed to examine the neural mechanism by which heavy ketamine use impairs spatial memory processing. In a sample of 11 frequent ketamine users and 15 polydrug controls, matched for IQ, age and years in education. We used fMRI utilising an ROI approach to examine the neural activity of three regions known to support successful navigation; the hippocampus, parahippocampal gyrus and the caudate nucleus during a virtual reality task of spatial memory. Frequent ketamine users displayed spatial memory deficits, accompanied by and related to, reduced activation in both the right hippocampus and left parahippocampal gyrus during navigation from memory, and in the left caudate during memory updating, compared to controls. Ketamine users also exhibited schizotypal and dissociative symptoms that were related to hippocampal activation. Impairments in spatial memory observed in ketamine users are related to changes in medial temporal lobe activation. Disrupted medial temporal lobe function may be a consequence of chronic ketamine abuse and may relate to schizophrenia-like symptomatology observed in ketamine users.

Adverse Events During a Randomized Trial of Ketamine Versus Co-Administration of Ketamine and Propofol for Procedural Sedation in a Pediatric Emergency Department.

Science.gov (United States)

Weisz, Keith; Bajaj, Lalit; Deakyne, Sara J; Brou, Lina; Brent, Alison; Wathen, Joseph; Roosevelt, Genie E

2017-07-01

The co-administration of ketamine and propofol (CoKP) is thought to maximize the beneficial profile of each medication, while minimizing the respective adverse effects of each medication. Our objective was to compare adverse events between ketamine monotherapy (KM) and CoKP for procedural sedation and analgesia (PSA) in a pediatric emergency department (ED). This was a prospective, randomized, single-blinded, controlled trial of KM vs. CoKP in patients between 3 and 21 years of age. The attending physician administered either ketamine 1 mg/kg i.v. or ketamine 0.5 mg/kg and propofol 0.5 mg/kg i.v. The physician could administer up to three additional doses of ketamine (0.5 mg/kg/dose) or ketamine/propofol (0.25 mg/kg/dose of each). Adverse events (e.g., respiratory events, cardiovascular events, unpleasant emergence reactions) were recorded. Secondary outcomes included efficacy, recovery time, and satisfaction scores. Ninety-six patients were randomized to KM and 87 patients were randomized to CoKP. There was no difference in adverse events or type of adverse event, except nausea was more common in the KM group. Efficacy of PSA was higher in the KM group (99%) compared to the CoKP group (90%). Median recovery time was the same. Satisfaction scores by providers, including nurses, were higher for KM, although parents were equally satisfied with both sedation regimens. We found no significant differences in adverse events between the KM and CoKP groups. While CoKP is a reasonable choice for pediatric PSA, our study did not demonstrate an advantage of this combination over KM. Copyright © 2017 Elsevier Inc. All rights reserved.

Halofuginone Inhibits Angiogenesis and Growth in Implanted Metastatic Rat Brain Tumor Model-an MRI Study

Directory of Open Access Journals (Sweden)

Rinat Abramovitch

2004-09-01

Full Text Available Tumor growth and metastasis depend on angiogenesis; therefore, efforts are made to develop specific angiogenic inhibitors. Halofuginone (HF is a potent inhibitor of collagen type α1(I. In solid tumor models, HF has a potent antitumor and antiangiogenic effect in vivo, but its effect on brain tumors has not yet been evaluated. By employing magnetic resonance imaging (MRI, we monitored the effect of HF on tumor progression and vascularization by utilizing an implanted malignant fibrous histiocytoma metastatic rat brain tumor model. Here we demonstrate that treatment with HF effectively and dose-dependently reduced tumor growth and angiogenesis. On day 13, HF-treated tumors were fivefold smaller than control (P < .001. Treatment with HF significantly prolonged survival of treated animals (142%; P = .001. In HF-treated rats, tumor vascularization was inhibited by 30% on day 13 and by 37% on day 19 (P < .05. Additionally, HF treatment inhibited vessel maturation (P = .03. Finally, in HF-treated rats, we noticed the appearance of a few clusters of satellite tumors, which were distinct from the primary tumor and usually contained vessel cores. This phenomenon was relatively moderate when compared to previous reports of other antiangiogenic agents used to treat brain tumors. We therefore conclude that HF is effective for treatment of metastatic brain tumors.

Inhibition of oxidative stress-elicited AKT activation facilitates PPARγ agonist-mediated inhibition of stem cell character and tumor growth of liver cancer cells.

Directory of Open Access Journals (Sweden)

Lanlan Liu

Full Text Available Emerging evidence suggests that tumor-initiating cells (TICs are the most malignant cell subpopulation in tumors because of their resistance to chemotherapy or radiation treatment. Targeting TICs may be a key innovation for cancer treatment. In this study, we found that PPARγ agonists inhibited the cancer stem cell-like phenotype and attenuated tumor growth of human hepatocellular carcinoma (HCC cells. Reactive oxygen species (ROS initiated by NOX2 upregulation were partially responsible for the inhibitory effects mediated by PPARγ agonists. However, PPARγ agonist-mediated ROS production significantly activated AKT, which in turn promoted TIC survival by limiting ROS generation. Inhibition of AKT, by either pharmacological inhibitors or AKT siRNA, significantly enhanced PPARγ agonist-mediated inhibition of cell proliferation and stem cell-like properties in HCC cells. Importantly, in nude mice inoculated with HCC Huh7 cells, we demonstrated a synergistic inhibitory effect of the PPARγ agonist rosiglitazone and the AKT inhibitor triciribine on tumor growth. In conclusion, we observed a negative feedback loop between oxidative stress and AKT hyperactivation in PPARγ agonist-mediated suppressive effects on HCCs. Combinatory application of an AKT inhibitor and a PPARγ agonist may provide a new strategy for inhibition of stem cell-like properties in HCCs and treatment of liver cancer.

Depression in chronic ketamine users: Sex differences and neural bases.

Science.gov (United States)

Li, Chiang-Shan R; Zhang, Sheng; Hung, Chia-Chun; Chen, Chun-Ming; Duann, Jeng-Ren; Lin, Ching-Po; Lee, Tony Szu-Hsien

2017-11-30

Chronic ketamine use leads to cognitive and affective deficits including depression. Here, we examined sex differences and neural bases of depression in chronic ketamine users. Compared to non-drug using healthy controls (HC), ketamine-using females but not males showed increased depression score as assessed by the Center of Epidemiological Studies Depression Scale (CES-D). We evaluated resting state functional connectivity (rsFC) of the subgenual anterior cingulate cortex (sgACC), a prefrontal structure consistently implicated in the pathogenesis of depression. Compared to HC, ketamine users (KU) did not demonstrate significant changes in sgACC connectivities at a corrected threshold. However, in KU, a linear regression against CES-D score showed less sgACC connectivity to the orbitofrontal cortex (OFC) with increasing depression severity. Examined separately, male and female KU showed higher sgACC connectivity to bilateral superior temporal gyrus and dorsomedial prefrontal cortex (dmPFC), respectively, in correlation with depression. The linear correlation of sgACC-OFC and sgACC-dmPFC connectivity with depression was significantly different in slope between KU and HC. These findings highlighted changes in rsFC of the sgACC as associated with depression and sex differences in these changes in chronic ketamine users. Copyright © 2017 Elsevier B.V. All rights reserved.

Sympathetic activity of S-(+-ketamine low doses in the epidural space

Directory of Open Access Journals (Sweden)

Slobodan Mihaljevic

2014-07-01

Full Text Available BACKGROUND AND OBJECTIVES: S-(+-ketamine is an intravenous anaesthetic and sympathomimetic with properties of local anaesthetic. It has an effect of an analgetic and local anaesthetic when administered epidurally, but there are no data whether low doses of S-(+-ketamine have sympathomimetic effects. The aim of this study was to determine whether low doses of S-(+-ketamine, given epidurally together with local anaesthetic, have any effect on sympathetic nervous system, both systemic and below the level of anaesthetic block. METHODS: The study was conducted on two groups of patients to whom epidural anaesthesia was administered to. Local anaesthesia (0.5% bupivacaine was given to one group (control group while local anaesthesia and S-(+-ketamine were given to other group. Age, height, weight, systolic, diastolic and mean arterial blood pressure were measured. Non-competitive enzyme immunochemistry method (Cat Combi ELISA was used to determine the concentrations of catecholamines (adrenaline and noradrenaline. Immunoenzymometric determination with luminescent substrate on a machine called Vitros Eci was used to determine the concentration of cortisol. Pulse transit time was measured using photoplethysmography. Mann-Whitney U-test, Wilcoxon test and Friedman ANOVA were the statistical tests. Blood pressure, pulse, adrenaline, noradrenaline and cortisol concentrations were measured in order to estimate systemic sympathetic effects. RESULTS: 40 patients in the control group were given 0.5% bupivacaine and 40 patients in the test group were given 0.5% bupivacaine with S-(+-ketamine. Value p < 0.05 has been taken as a limit of statistical significance. CONCLUSIONS: Low dose of S-(+-ketamine administered epidurally had no sympathomimetic effects; it did not change blood pressure, pulse, serum hormones or pulse transit time. Low dose of S-(+-ketamine administered epidurally did not deepen sympathetic block. Adding 25 mg of S-(+-ketamine to 0

Morphological and behavioral responses of zebrafish after 24 h of ketamine embryonic exposure

Energy Technology Data Exchange (ETDEWEB)

Félix, Luís M., E-mail: lfelix@utad.pt [Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real (Portugal); Institute for Research and Innovation in Health (i3S), University of Porto (UP), Porto (Portugal); Laboratory Animal Science (LAS), Institute for Molecular and Cell Biology (IBMC), University of Porto - UP, Porto (Portugal); Serafim, Cindy; Martins, Maria J. [Life Sciences and Environment School (ECVA), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real (Portugal); Valentim, Ana M. [Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real (Portugal); Institute for Research and Innovation in Health (i3S), University of Porto (UP), Porto (Portugal); Laboratory Animal Science (LAS), Institute for Molecular and Cell Biology (IBMC), University of Porto - UP, Porto (Portugal); Antunes, Luís M. [Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real (Portugal); Institute for Research and Innovation in Health (i3S), University of Porto (UP), Porto (Portugal); Laboratory Animal Science (LAS), Institute for Molecular and Cell Biology (IBMC), University of Porto - UP, Porto (Portugal); School of Agrarian and Veterinary Sciences (ECAV), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real (Portugal); and others

2017-04-15

Ketamine, one anesthetic used as an illicit drug, has been detected both in freshwater and marine ecosystems. However, knowledge of its impact on aquatic life is still limited. This study aimed to test its effects in zebrafish embryos by analyzing its time- and dose-dependent developmental toxicity and long-term behavioral changes. The 24 h-LC{sub 50} was calculated from percent survival using probit analysis. Based on the 24 h-LC{sub 50} (94.4 mg L{sup −1}), embryos (2 hour post-fertilization - hpf) were divided into four groups, including control, and exposed for 24 h to ketamine concentrations of 50, 70 or 90 mg L{sup −1}. Developmental parameters were evaluated on the course of the experimental period, and anatomical abnormalities and locomotor deficits were analyzed at 144 hpf. Although the portion of ketamine transferred into the embryo was higher in the lowest exposed group (about 0.056 ± 0.020 pmol per embryo), the results showed that endpoints such as increased mortality, edema, heart rate alterations, malformation and abnormal growth rates were significantly affected. At 144 hpf, the developmental abnormalities included thoracic and trunk abnormalities in the groups exposed to 70 and 90 mg L{sup −1}. Defects in cartilage (alcian blue) and bone (calcein) elements also corroborated the craniofacial anomalies observed. A significant up-regulation of the development-related gene nog3 was detected by qRT-PCR at 8 hpf. Early exposure to ketamine also resulted in long-term behavioral changes, such as an increase in thigmotaxis and disruption of avoidance behavior at 144 hpf. Altogether, this study provides new evidence on the ketamine teratogenic potential, indicating a possible pharmacological impact of ketamine in aquatic environments. - Highlights: • 24 h exposure to ketamine increases mortality. • Morphological changes were observed after exposure. • Exposure to ketamine leads to severe craniofacial anomalies. • Developmental gene expression

Morphological and behavioral responses of zebrafish after 24 h of ketamine embryonic exposure

International Nuclear Information System (INIS)

Félix, Luís M.; Serafim, Cindy; Martins, Maria J.; Valentim, Ana M.; Antunes, Luís M.

2017-01-01

Ketamine, one anesthetic used as an illicit drug, has been detected both in freshwater and marine ecosystems. However, knowledge of its impact on aquatic life is still limited. This study aimed to test its effects in zebrafish embryos by analyzing its time- and dose-dependent developmental toxicity and long-term behavioral changes. The 24 h-LC 50 was calculated from percent survival using probit analysis. Based on the 24 h-LC 50 (94.4 mg L −1 ), embryos (2 hour post-fertilization - hpf) were divided into four groups, including control, and exposed for 24 h to ketamine concentrations of 50, 70 or 90 mg L −1 . Developmental parameters were evaluated on the course of the experimental period, and anatomical abnormalities and locomotor deficits were analyzed at 144 hpf. Although the portion of ketamine transferred into the embryo was higher in the lowest exposed group (about 0.056 ± 0.020 pmol per embryo), the results showed that endpoints such as increased mortality, edema, heart rate alterations, malformation and abnormal growth rates were significantly affected. At 144 hpf, the developmental abnormalities included thoracic and trunk abnormalities in the groups exposed to 70 and 90 mg L −1 . Defects in cartilage (alcian blue) and bone (calcein) elements also corroborated the craniofacial anomalies observed. A significant up-regulation of the development-related gene nog3 was detected by qRT-PCR at 8 hpf. Early exposure to ketamine also resulted in long-term behavioral changes, such as an increase in thigmotaxis and disruption of avoidance behavior at 144 hpf. Altogether, this study provides new evidence on the ketamine teratogenic potential, indicating a possible pharmacological impact of ketamine in aquatic environments. - Highlights: • 24 h exposure to ketamine increases mortality. • Morphological changes were observed after exposure. • Exposure to ketamine leads to severe craniofacial anomalies. • Developmental gene expression changes in response to

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells12

OpenAIRE

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-01-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation ...

Effects of Nicotine on the Neurophysiological and Behavioral Effects of Ketamine in Humans

Directory of Open Access Journals (Sweden)

Daniel H Mathalon

2014-01-01

Full Text Available Background: N-methyl-D-aspartate (NMDA receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine modulates putative NMDA receptor hypofunction in the illness. Accordingly, we examined the modulatory effects of brain nicotinic acetylcholine receptor (nAChR stimulation on NMDA receptor hypofunction by examining the interactive effects of nicotine, a nAChR agonist, and ketamine, a noncompetitive NMDA receptor antagonist, on behavioral and neurophysiological measures in healthy human volunteers.Methods: From an initial sample of 17 subjects (age range 18 - 55 years, 8 subjects successfully completed 4 test sessions, each separated by at least 3 days, during which they received ketamine or placebo and two injections of nicotine or placebo in a double-blind, counterbalanced manner. Schizophrenia-like effects (PANSS, perceptual alterations (CADSS, subjective effects (VAS and auditory event-related brain potentials (mismatch negativity, P300 were assessed during each test session.Results: Consistent with existing studies, ketamine induced transient schizophrenia-like behavioral effects. P300 was reduced and delayed by ketamine regardless of whether it was elicited by a target or novel stimulus, while nicotine only reduced the amplitude of P3a. Nicotine did not rescue P300 from the effects of ketamine; the interactions of ketamine and nicotine were not significant. While nicotine significantly reduced MMN amplitude, ketamine did not. Conclusion: Nicotine failed to modulate ketamine-induced schizophrenia-like effects in this preliminary study. Interestingly, ketamine reduced P3b amplitude and nicotine reduced P3a amplitude, suggesting independent roles of NMDA receptor and nAChR in the generation of P3b and P3a, respectively.

IV paracetamol effect on propofol-ketamine consumption in paediatric patients undergoing ESWL.

Science.gov (United States)

Eker, H Evren; Cok, Oya Yalçin; Ergenoğlu, Pınar; Ariboğan, Anış; Arslan, Gülnaz

2012-06-01

Electroshock wave lithotripsy (ESWL) is a painful procedure performed with sedoanalgesia in paediatric patients. The propofol-ketamine combination may be the preferable anaesthesia for this procedure, and propofol-ketamine consumption may be decreased with the administration of intravenous (IV) paracetamol. In this study we investigated the effect of IV paracetamol administration on propofol-ketamine consumption, recovery time and frequency of adverse events in paediatric patients undergoing ESWL. Sixty children, ranging in age from 1 to 10 years and with American Society of Anesthesiologists Physical Status 1-2, were included in this prospective, randomized, double-blinded study. Thirty minutes prior to the procedure children randomly assigned to Group I received IV 15 mg/kg paracetamol, and those randomly assigned to Group II received 1.5 mL/kg IV saline infusion 30 min. The propofol-ketamine combination was prepared by mixing 25 mg propofol and 25 mg ketamine in a total 10 mL solution in the same syringe. After the administration of 0.1 mg/kg midazolam and 10 μg/kg atropine to both groups and during the procedure, the propofol-ketamine combination was administered at 0.5 mg/kg doses to achieve a Wisconsin sedation score of 1 or 2. Oxygen saturation and heart rate were recorded at 5-min intervals. Propofol-ketamine consumption, recovery times and adverse events were also recorded. Demographic data were similar between groups. Propofol-ketamine consumption (Group I, 25.2 ± 17.7 mg; Group II, 35.4 ± 20.1 mg; p = 0.04) and recovery times (Group I, 19.4 ± 7.9 min; Group II, 29.6 ± 11.4 min; p ESWL procedures in paediatric patients and shortens recovery time.

Psychiatric side effects of ketamine in hospitalized medical patients administered subanesthetic doses for pain control.

Science.gov (United States)

Rasmussen, Keith G

2014-08-01

To assess the psychiatric side effects of ketamine when administered in subanesthetic doses to hospitalized patients. It is hypothesized that such effects occur frequently. In this retrospective study, the medical records of 50 patients hospitalized on medical and surgical units at our facility who had continuous intravenous infusions of ketamine for pain or mild sedation were reviewed. Patient progress in the days following the start of ketamine infusion was reviewed and response to ketamine was noted. Twenty-two percent of the patients were noted to have some type of psychiatric reaction to ketamine, including agitation, confusion, and hallucinations. These reactions were relatively short lived, namely, occurring during or shortly after the infusions. No association was found between patient response to ketamine and gender, age, or infusion rate. Awareness of the psychiatric side effects of ketamine is an important consideration for clinicians administering this medication either for pain control or for depressive illness.

Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion

International Nuclear Information System (INIS)

Knobloch, M.; Portier, C.J.; Levionnois, O.L.; Theurillat, R.; Thormann, W.; Spadavecchia, C.; Mevissen, M.

2006-01-01

Ketamine is widely used as an anesthetic in a variety of drug combinations in human and veterinary medicine. Recently, it gained new interest for use in long-term pain therapy administered in sub-anesthetic doses in humans and animals. The purpose of this study was to develop a physiologically based pharmacokinetic (PBPk) model for ketamine in ponies and to investigate the effect of low-dose ketamine infusion on the amplitude and the duration of the nociceptive withdrawal reflex (NWR). A target-controlled infusion (TCI) of ketamine with a target plasma level of 1 μg/ml S-ketamine over 120 min under isoflurane anesthesia was performed in Shetland ponies. A quantitative electromyographic assessment of the NWR was done before, during and after the TCI. Plasma levels of R-/S-ketamine and R-/S-norketamine were determined by enantioselective capillary electrophoresis. These data and two additional data sets from bolus studies were used to build a PBPk model for ketamine in ponies. The peak-to-peak amplitude and the duration of the NWR decreased significantly during TCI and returned slowly toward baseline values after the end of TCI. The PBPk model provides reliable prediction of plasma and tissue levels of R- and S-ketamine and R- and S-norketamine. Furthermore, biotransformation of ketamine takes place in the liver and in the lung via first-pass metabolism. Plasma concentrations of S-norketamine were higher compared to R-norketamine during TCI at all time points. Analysis of the data suggested identical biotransformation rates from the parent compounds to the principle metabolites (R- and S-norketamine) but different downstream metabolism to further metabolites. The PBPk model can provide predictions of R- and S-ketamine and norketamine concentrations in other clinical settings (e.g. horses)

Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization.

Science.gov (United States)

Maher, Dermot P; Chen, Lucy; Mao, Jianren

2017-02-01

Intravenous ketamine infusions have been used extensively to treat often-intractable neuropathic pain conditions. Because there are many widely divergent ketamine infusion protocols described in the literature, the variation in these protocols presents a challenge for direct comparison of one protocol with another and in discerning an optimal protocol. Careful examination of the published literature suggests that ketamine infusions can be useful to treat neuropathic pain and that certain characteristics of ketamine infusions may be associated with better clinical outcomes. Increased duration of relief from neuropathic pain is associated with (1) higher total infused doses of ketamine; (2) prolonged infusion durations, although the rate of infusion does not appear to be a factor; and (3) coadministration of adjunct medications such as midazolam and/or clonidine that mitigate some of the unpleasant psychomimetic side effects. However, there are few studies designed to optimize ketamine infusion protocols by defining what an effective infusion protocol entails with regard to a respective neuropathic pain condition. Therefore, despite common clinical practice, the current state of the literature leaves the use of ketamine infusions without meaningful guidance from high-quality comparative evidence. The objectives of this topical review are to (1) analyze the available clinical evidence related to ketamine infusion protocols and (2) call for clinical studies to identify optimal ketamine infusion protocols tailored for individual neuropathic pain conditions. The Oxford Center for Evidence-Based Medicine classification for levels of evidence was used to stratify the grades of clinical recommendation for each infusion variable studied.

Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity.

Science.gov (United States)

Basciani, Sabrina; Brama, Marina; Mariani, Stefania; De Luca, Gabriele; Arizzi, Mario; Vesci, Loredana; Pisano, Claudio; Dolci, Susanna; Spera, Giovanni; Gnessi, Lucio

2005-03-01

Leydig cell tumors are usually benign tumors of the male gonad. However, if the tumor is malignant, no effective treatments are currently available. Leydig cell tumors express platelet-derived growth factor (PDGF), kit ligand and their respective receptors, PDGFR and c-kit. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the c-kit and PDGFR tyrosine kinases, on the growth of rodent Leydig tumor cell lines in vivo and in vitro, and examined, in human Leydig cell tumor samples, the expression of activated PDGFR and c-kit and the mutations in exons of the c-kit gene commonly associated with solid tumors. Imatinib caused concentration-dependent decreases in the viability of Leydig tumor cell lines, which coincided with apoptosis and inhibition of proliferation and ligand-stimulated phosphorylation of c-kit and PDGFRs. Mice bearing s.c. allografts of a Leydig tumor cell line treated with imatinib p.o., had an almost complete inhibition of tumor growth, less tumor cell proliferation, increased apoptosis, and a lesser amount of tumor-associated mean vessel density compared with controls. No drug-resistant tumors appeared during imatinib treatment but tumors regrew after drug withdrawal. Human Leydig cell tumors showed an intense expression of the phosphorylated form of c-kit and a less intense expression of phosphorylated PDGFRs. No activating mutations in common regions of mutation of the c-kit gene were found. Our studies suggest that Leydig cell tumors might be a potential target for imatinib therapy.

Ketamine coadministration attenuates morphine tolerance and leads to increased brain concentrations of both drugs in the rat

Science.gov (United States)

Lilius, T O; Jokinen, V; Neuvonen, M S; Niemi, M; Kalso, E A; Rauhala, P V

2015-01-01

Background and Purpose The effects of ketamine in attenuating morphine tolerance have been suggested to result from a pharmacodynamic interaction. We studied whether ketamine might increase brain morphine concentrations in acute coadministration, in morphine tolerance and morphine withdrawal. Experimental Approach Morphine minipumps (6 mg·day–1) induced tolerance during 5 days in Sprague–Dawley rats, after which s.c. ketamine (10 mg·kg–1) was administered. Tail flick, hot plate and rotarod tests were used for behavioural testing. Serum levels and whole tissue brain and liver concentrations of morphine, morphine-3-glucuronide, ketamine and norketamine were measured using HPLC-tandem mass spectrometry. Key Results In morphine-naïve rats, ketamine caused no antinociception whereas in morphine-tolerant rats there was significant antinociception (57% maximum possible effect in the tail flick test 90 min after administration) lasting up to 150 min. In the brain of morphine-tolerant ketamine-treated rats, the morphine, ketamine and norketamine concentrations were 2.1-, 1.4- and 3.4-fold, respectively, compared with the rats treated with morphine or ketamine only. In the liver of morphine-tolerant ketamine-treated rats, ketamine concentration was sixfold compared with morphine-naïve rats. After a 2 day morphine withdrawal period, smaller but parallel concentration changes were observed. In acute coadministration, ketamine increased the brain morphine concentration by 20%, but no increase in ketamine concentrations or increased antinociception was observed. Conclusions and Implications The ability of ketamine to induce antinociception in rats made tolerant to morphine may also be due to increased brain concentrations of morphine, ketamine and norketamine. The relevance of these findings needs to be assessed in humans. PMID:25297798

Galectin-1 Inhibitor OTX008 Induces Tumor Vessel Normalization and Tumor Growth Inhibition in Human Head and Neck Squamous Cell Carcinoma Models.

Science.gov (United States)

Koonce, Nathan A; Griffin, Robert J; Dings, Ruud P M

2017-12-09

Galectin-1 is a hypoxia-regulated protein and a prognostic marker in head and neck squamous cell carcinomas (HNSCC). Here we assessed the ability of non-peptidic galectin-1 inhibitor OTX008 to improve tumor oxygenation levels via tumor vessel normalization as well as tumor growth inhibition in two human HNSCC tumor models, the human laryngeal squamous carcinoma SQ20B and the human epithelial type 2 HEp-2. Tumor-bearing mice were treated with OTX008, Anginex, or Avastin and oxygen levels were determined by fiber-optics and molecular marker pimonidazole binding. Immuno-fluorescence was used to determine vessel normalization status. Continued OTX008 treatment caused a transient reoxygenation in SQ20B tumors peaking on day 14, while a steady increase in tumor oxygenation was observed over 21 days in the HEp-2 model. A >50% decrease in immunohistochemical staining for tumor hypoxia verified the oxygenation data measured using a partial pressure of oxygen (pO₂) probe. Additionally, OTX008 induced tumor vessel normalization as tumor pericyte coverage increased by approximately 40% without inducing any toxicity. Moreover, OTX008 inhibited tumor growth as effectively as Anginex and Avastin, except in the HEp-2 model where Avastin was found to suspend tumor growth. Galectin-1 inhibitor OTX008 transiently increased overall tumor oxygenation via vessel normalization to various degrees in both HNSCC models. These findings suggest that targeting galectin-1-e.g., by OTX008-may be an effective approach to treat cancer patients as stand-alone therapy or in combination with other standards of care.

Eletrocardiografia em cães anestesiados com cetamina-s ou cetamina Electrocardiography in dogs anesthetized with s-ketamine or ketamine

Directory of Open Access Journals (Sweden)

Almir Pereira de Souza

2002-10-01

Full Text Available A cetamina, fármaco derivado da fenciclidina, há muito é usada na anestesia veterinária, sendo que o seu isômero (+, a cetamina S, recém-lançada no mercado, tem tido emprego principalmente na anestesia humana. Em vista disso, objetivou-se, com este experimento avaliar comparativamente, as possíveis alterações eletrocardiográficas em cães anestesiados com cetamina S ou cetamina e avaliar as freqüências respiratória e cardíaca, saturação de oxihemoglobina e pressão arterial. Para tanto, foram utilizados 10 cães adultos, machos e fêmeas, sem raça definida e hígidos. Os animais foram distribuídos em dois grupos (G1 e G2 de igual número. Ao G1 administrou-se, por via intramuscular, cetamina S na dose de 20mg/kg, e ao G2, cetamina na mesma dose e via de administração empregados no G1. As observações das variáveis tiveram início imediatamente antes da aplicação dos fármacos (M1 e a cada 10 minutos (M2, M3 e M4, respectivamente. Os dados numéricos foram submetidos ao teste de Tukey, para análises repetidas no grupo, a fim de verificar significado estatístico ou não entre as médias, nos vários momentos, sendo considerado o nível de significância de 5% (pKetamine is a drug derived of the phenciclidine and has been used in veterinary anaesthesia for a long time. Its (+ isomers, s-ketamine, was recently introduced in the clinical practice and has been used mainly in human anaesthesia. So, this experiment was performed to evaluate comparatively possible electrocardiographic changes in dogs anesthetized with S-ketamine or ketamine and also evaluate heart rate, respiratory rate, oxihemoglobine saturation and arterial pressure. Ten adult male and female dogs were used in this study. All dogs were healthy and mix breed. The animals were divided in two equal number groups (G1 and G2. The G1 received 20mg/kg of S-ketamine intra-muscularly and G2 received the same dose of ketamine with the injection protocol. The

Platelet-camouflaged nanococktail: Simultaneous inhibition of drug-resistant tumor growth and metastasis via a cancer cells and tumor vasculature dual-targeting strategy.

Science.gov (United States)

Jing, Lijia; Qu, Haijing; Wu, Dongqi; Zhu, Chaojian; Yang, Yongbo; Jin, Xing; Zheng, Jian; Shi, Xiangsheng; Yan, Xiufeng; Wang, Yang

2018-01-01

Multidrug resistance (MDR) poses a great challenge to cancer therapy. It is difficult to inhibit the growth of MDR cancer due to its chemoresistance. Furthermore, MDR cancers are more likely to metastasize, causing a high mortality among cancer patients. In this study, a nanomedicine RGD-NPVs@MNPs/DOX was developed by encapsulating melanin nanoparticles (MNPs) and doxorubicin (DOX) inside RGD peptide (c(RGDyC))-modified nanoscale platelet vesicles (RGD-NPVs) to efficiently inhibit the growth and metastasis of drug-resistant tumors via a cancer cells and tumor vasculature dual-targeting strategy. Methods: The in vitro immune evasion potential and the targeting performance of RGD-NPVs@MNPs/DOX were examined using RAW264.7, HUVECs, MDA-MB-231 and MDA-MB-231/ADR cells lines. We also evaluated the pharmacokinetic behavior and the in vivo therapeutic performance of RGD-NPVs@MNPs/DOX using a MDA-MB-231/ADR tumor-bearing nude mouse model. Results: By taking advantage of the self-recognizing property of the platelet membrane and the conjugated RGD peptides, RGD-NPVs@MNPs/DOX was found to evade immune clearance and target the αvβ3 integrin on tumor vasculature and resistant breast tumor cells. Under irradiation with a NIR laser, RGD-NPVs@MNPs/DOX produced a multipronged effect, including reversal of cancer MDR, efficient killing of resistant cells by chemo-photothermal therapy, elimination of tumor vasculature for blocking metastasis, and long-lasting inhibition of the expressions of VEGF, MMP2 and MMP9 within the tumor. Conclusion: This versatile nanomedicine of RGD-NPVs@MNPs/DOX integrating unique biomimetic properties, excellent targeting performance, and comprehensive therapeutic strategies in one formulation might bring opportunities to MDR cancer therapy.

Low concentrations of ketamine initiate dendritic atrophy of differentiated GABAergic neurons in culture

International Nuclear Information System (INIS)

Vutskits, Laszlo; Gascon, Eduardo; Potter, Gael; Tassonyi, Edomer; Kiss, Jozsef Z.

2007-01-01

Administration of subanesthetic concentrations of ketamine, a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) type of glutamate receptors, is a widely accepted therapeutic modality in perioperative and chronic pain management. Although extensive clinical use has demonstrated its safety, recent human histopathological observations as well as laboratory data suggest that ketamine can exert adverse effects on central nervous system neurons. To further investigate this issue, the present study was designed to evaluate the effects of ketamine on the survival and dendritic arbor architecture of differentiated γ-aminobutyric acidergic (GABAergic) interneurons in vitro. We show that short-term exposure of cultures to ketamine at concentrations of ≥20 μg/ml leads to a significant cell loss of differentiated cells and that non-cell death-inducing concentrations of ketamine (10 μg/ml) can still initiate long-term alterations of dendritic arbor in differentiated neurons, including dendritic retraction and branching point elimination. Most importantly, we also demonstrate that chronic (>24 h) administration of ketamine at concentrations as low as 0.01 μg/ml can interfere with the maintenance of dendritic arbor architecture. These results raise the possibility that chronic exposure to low, subanesthetic concentrations of ketamine, while not affecting cell survival, could still impair neuronal morphology and thus might lead to dysfunctions of neural networks

Picropodophyllin inhibits tumor growth of human nasopharyngeal carcinoma in a mouse model

International Nuclear Information System (INIS)

Yin, Shu-Cheng; Guo, Wei; Tao, Ze-Zhang

2013-01-01

Highlights: •We identified that PPP inhibits IGF-1R/Akt pathway in NPC cells. •PPP dose-dependently inhibits NPC cell proliferation in vitro. •PPP suppresses tumor growth of NPC in nude mice. •PPP have little effect on microtubule assembly. -- Abstract: Insulin-like growth factor-1 receptor (IGF-1R) is a cell membrane receptor with tyrosine kinase activity and plays important roles in cell transformation, tumor growth, tumor invasion, and metastasis. Picropodophyllin (PPP) is a selective IGF-1R inhibitor and shows promising antitumor effects for several human cancers. However, its antitumor effects in nasopharyngeal carcinoma (NPC) remain unclear. The purpose of this study is to investigate the antitumor activity of PPP in NPC using in vitro cell culture and in vivo animal model. We found that PPP dose-dependently decreased the IGF-induced phosphorylation and activity of IGF-1R and consequently reduced the phosphorylation of Akt, one downstream target of IGF-1R. In addition, PPP inhibited NPC cell proliferation in vitro. The half maximal inhibitory concentration (IC50) of PPP for NPC cell line CNE-2 was ⩽1 μM at 24 h after treatment and ⩽0.5 μM at 48 h after treatment, respectively. Moreover, administration of PPP by intraperitoneal injection significantly suppressed the tumor growth of xenografted NPC in nude mice. Taken together, these results suggest targeting IGF-1R by PPP may represent a new strategy for treatment of NPCs with positive IGF-1R expression

Picropodophyllin inhibits tumor growth of human nasopharyngeal carcinoma in a mouse model

Energy Technology Data Exchange (ETDEWEB)

Yin, Shu-Cheng [Department of Otolaryngology – Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060 (China); Department of Otolaryngology – Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Guo, Wei [Department of Otolaryngology – Head and Neck Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430071 (China); Tao, Ze-Zhang, E-mail: zezhangtao@gmail.com [Department of Otolaryngology – Head and Neck Surgery, Renmin Hospital of Wuhan University, Wuhan 430060 (China)

2013-09-13

Highlights: •We identified that PPP inhibits IGF-1R/Akt pathway in NPC cells. •PPP dose-dependently inhibits NPC cell proliferation in vitro. •PPP suppresses tumor growth of NPC in nude mice. •PPP have little effect on microtubule assembly. -- Abstract: Insulin-like growth factor-1 receptor (IGF-1R) is a cell membrane receptor with tyrosine kinase activity and plays important roles in cell transformation, tumor growth, tumor invasion, and metastasis. Picropodophyllin (PPP) is a selective IGF-1R inhibitor and shows promising antitumor effects for several human cancers. However, its antitumor effects in nasopharyngeal carcinoma (NPC) remain unclear. The purpose of this study is to investigate the antitumor activity of PPP in NPC using in vitro cell culture and in vivo animal model. We found that PPP dose-dependently decreased the IGF-induced phosphorylation and activity of IGF-1R and consequently reduced the phosphorylation of Akt, one downstream target of IGF-1R. In addition, PPP inhibited NPC cell proliferation in vitro. The half maximal inhibitory concentration (IC50) of PPP for NPC cell line CNE-2 was ⩽1 μM at 24 h after treatment and ⩽0.5 μM at 48 h after treatment, respectively. Moreover, administration of PPP by intraperitoneal injection significantly suppressed the tumor growth of xenografted NPC in nude mice. Taken together, these results suggest targeting IGF-1R by PPP may represent a new strategy for treatment of NPCs with positive IGF-1R expression.

Anhedonia as a clinical correlate of suicidal thoughts in clinical ketamine trials.

Science.gov (United States)

Ballard, Elizabeth D; Wills, Kathleen; Lally, Níall; Richards, Erica M; Luckenbaugh, David A; Walls, Tessa; Ameli, Rezvan; Niciu, Mark J; Brutsche, Nancy E; Park, Lawrence; Zarate, Carlos A

2017-08-15

Identifying clinical correlates associated with reduced suicidal ideation may highlight new avenues for the treatment of suicidal thoughts. Anhedonia occurs across psychiatric diagnoses and has been associated with specific neural circuits in response to rapid-acting treatments, such as ketamine. This analysis sought to evaluate whether reductions in suicidal ideation after ketamine administration were related to reduced levels of anhedonia, independent of depressive symptoms. This post-hoc analysis included treatment-resistant patients with either major depressive disorder (MDD) or bipolar disorder (BD) from several clinical trials of ketamine. Anhedonia was assessed using a subscale of the Beck Depression Inventory (BDI) and the Snaith-Hamilton Pleasure Scale (SHAPS). The outcome of interest was suicidal ideation, as measured by a subscale of the Scale for Suicide Ideation (SSI5), one day post-ketamine administration. Anhedonia, as measured by the SHAPS, was associated with suicidal thoughts independent of depressive symptoms both before and after ketamine administration. One day post-ketamine administration, improvements on the SHAPS accounted for an additional 13% of the variance in suicidal thought reduction, beyond the influence of depressive symptoms. The BDI anhedonia subscale was not significantly associated with suicidal thoughts after adjusting for depressive symptoms. Data were limited to patients experiencing a major depressive episode and may not be generalizable to patients experiencing an active suicidal crisis. Suicidal thoughts may be related to symptoms of anhedonia independent of other depressive symptoms. These results have implications for the potential mechanisms of action of ketamine on suicidal thoughts. Published by Elsevier B.V.

Imaging diagnosis of ketamine-induced uropathy

Directory of Open Access Journals (Sweden)

Shu-Huei Shen

2015-09-01

Full Text Available With growing ketamine abuse, ketamine-induced uropathy (KIU has become a vital health issue in recent years. Although the lower urinary tract is the primary affected site, involvement of the upper urinary tract is common, and KIU may progress rapidly. The main objective of a baseline imaging study is evaluating the extent and complications of KIU after excluding other causes of uropathy. A comprehensive strategy for KIU evaluation through imaging is essential for effectively managing complications and preventing further renal function deterioration. In this study, we describe the imaging presentation of KIU and examine the role of various imaging modalities, such as ultrasound, intravenous urography, and computed tomography, in diagnosing patients with KIU.

Immobilization of swift foxes with ketamine hydrochloride-xylazine hydrochloride

Science.gov (United States)

Telesco, R.L.; Sovada, Marsha A.

2002-01-01

There is an increasing need to develop field immobilization techniques that allow researchers to handle safely swift foxes (Vulpes velox) with minimal risk of stress or injury. We immobilized captive swift foxes to determine the safety and effectiveness of ketamine hydrochloride and xylazine hydrochloride at different dosages. We attempted to determine appropriate dosages to immobilize swift foxes for an adequate field-handling period based on three anesthesia intervals (induction period, immobilization period, and recovery period) and physiologic responses (rectal temperature, respiration rate, and heart rate). Between October 1998–July 1999, we conducted four trials, evaluating three different dosage ratios of ketamine and xylazine (2.27:1.2, 5.68:1.2, and 11.4:1.2 mg/kg ketamine:mg/kg xylazine, respectively), followed by a fourth trial with a higher dosage at the median ratio (11.4 mg/kg ketamine:2.4 mg/kg xylazine). We found little difference in induction and recovery periods among trials 1–3, but immobilization time increased with increasing dosage (Pimmobilization period and recovery period increased in trial 4 compared with trials 1–3 (P≤0.03). There was a high variation in responses of individual foxes across trials, making it difficult to identify an appropriate dosage for field handling. Heart rate and respiration rates were depressed but all physiologic measures remained within normal parameters established for domestic canids. We recommend a dosage ratio of 10 mg/kg ketamine to 1 mg/kg xylazine to immobilize swift foxes for field handling.

Ketamin genopdaget af både læger og misbrugere

DEFF Research Database (Denmark)

Sørensen, Anne; Barnung, Steen; Rasmussen, Lars Simon

2011-01-01

-hyperalgesic and opioid saving effects, opening to new ways of managing post-operative and chronic pain states. Recreational use of ketamine among night clubbers is increasing and makes acute and chronic symptoms of ketamine abuse a new challenge in emergency departments....

Inhibition of tumor angiogenesis and tumor growth by the DSL domain of human Delta-like 1 targeted to vascular endothelial cells.

Science.gov (United States)

Zhao, Xing-Cheng; Dou, Guo-Rui; Wang, Li; Liang, Liang; Tian, Deng-Mei; Cao, Xiu-Li; Qin, Hong-Yan; Wang, Chun-Mei; Zhang, Ping; Han, Hua

2013-07-01

The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of new drug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD) motif targeting endothelial cells (ECs). We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2(+) perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

Inhibition of Tumor Angiogenesis and Tumor Growth by the DSL Domain of Human Delta-Like 1 Targeted to Vascular Endothelial Cells

Directory of Open Access Journals (Sweden)

Xing-Cheng Zhao

2013-07-01

Full Text Available The growth of solid tumors depends on neovascularization. Several therapies targeting tumor angiogenesis have been developed. However, poor response in some tumors and emerging resistance necessitate further investigations of newdrug targets. Notch signal pathway plays a pivotal role in vascular development and tumor angiogenesis. Either blockade or forced activation of this pathway can inhibit angiogenesis. As blocking Notch pathway results in the formation of vascular neoplasm, activation of Notch pathway to prevent tumor angiogenesis might be an alternative choice. However, an in vivo deliverable reagent with highly efficient Notch-activating capacity has not been developed. Here, we generated a polypeptide, hD1R, which consists of the Delta-Serrate-Lag-2 fragment of the human Notch ligand Delta-like 1 and an arginine-glycine-aspartate (RGD motif targeting endothelial cells (ECs. We showed that hD1R could bind to ECs specifically through its RGD motif and effectively triggered Notch signaling in ECs. We demonstrated both in vitro and in vivo that hD1R inhibited angiogenic sprouting and EC proliferation. In tumor-bearing mice, the injection of hD1R effectively repressed tumor growth, most likely through increasing tumor hypoxia and tissue necrosis. The amount and width of vessels reduced remarkably in tumors of mice treated with hD1R. Moreover, vessels in tumors of mice treated with hD1R recruited more NG2+ perivascular cells and were better perfused. Combined application of hD1R and chemotherapy with cisplatin and teniposide revealed that these two treatments had additive antitumor effects. Our study provided a new strategy for antiangiogenic tumor therapy.

Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity.

Science.gov (United States)

Mayorek, Nina; Naftali-Shani, Nili; Grunewald, Myriam

2010-09-15

Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX), diclofenac potently inhibits phospholipase A(2) (PLA(2)), thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. We found that diclofenac treatment (30 mg/kg/bw for 11 days) of mice inoculated with PANC02 cells, reduced the tumor weight by 60%, correlating with increased apoptosis of tumor cells. Since this effect was not observed in vitro on cultured PANCO2 cells, we theorized that diclofenac beneficial treatment involved other mediators present in vivo. Indeed, diclofenac drastically decreased tumor vascularization by downregulating VEGF in the tumor and in abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to other COX-2 inhibitors, diclofenac increased arginase activity/arginase 1 protein content in tumor stroma cells, peritoneal macrophages and white blood cells by 2.4, 4.8 and 2 fold, respectively. We propose that the subsequent arginine depletion and decrease in NO levels, both in serum and peritoneal cavity, adds to tumor growth inhibition by malnourishment and poor vasculature development. In conclusion, diclofenac shows pronounced antitumoral properties in pancreatic cancer model that can contribute to further treatment development. The ability of diclofenac to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells provides a tool to study a controversial issue of pro-and antitumoral effects of arginine depletion.

Three-phase Bone Scintigraphy Can Predict the Analgesic Efficacy of Ketamine Therapy in CRPS.

Science.gov (United States)

Sorel, Marc; Beatrix, Jacques-Christian; Locko, Blanche; Armessen, Catherine; Domec, Anne-Marie; Lecompte, Otilia; Boucheneb, Sofiane; Harache, Benoit; Robert, Jacques; Lefaucheur, Jean-Pascal

2018-03-13

The efficacy of ketamine in relieving complex regional pain syndrome (CRPS) lacks predictive factors. The value of three-phase bone scintigraphy (TPBS) was assessed or this purpose. TPBS was performed in 105 patients with unilateral, focal CRPS of type 1 before 5 days of ketamine infusions. Tracer uptake was measured in the region of interest concerned by CRPS and the contralateral homologous region. For the three scintigraphic phases (vascular, tissular, and bone phases), an asymmetry ratio of fixation was calculated between the affected and the unaffected sides (VPr, TPr, and BPr). Ketamine efficacy was assessed on pain intensity scores. Ketamine-induced pain relief did not correlate with VPr, TPr, and BPr, but with the ratios of these ratios: BPr/TPr (r=0.32, P=0.009), BPr/VPr (r=0.34, P=0.005), and TPr/VPr (r=0.23, P=0.02). The optimum cut-off value for predicting the response to ketamine therapy was >1.125 for BPr/TPr, >1.075 for BPr/VPr, and >0.935 for TPr/VPr. The combination of increased values of BPr/TPr, BPr/VPr, and TPr/VPr was extremely significantly associated with ketamine therapy outcome. The relative hyperfixation of the radioactive tracer in the limb region concerned by CRPS in phases 2 and 3 versus phase 1 of TPBS correlated positively to the analgesic efficacy of ketamine. This study shows for the first time the potential predictive value of TPBS regarding ketamine therapy outcome. In addition, these results suggest that the analgesic action of ketamine is not restricted to "central" mechanisms, but may also involve "peripheral" mechanisms related to tissue inflammation and bone remodeling.

Apoptosis-related genes induced in response to ketamine during early life stages of zebrafish.

Science.gov (United States)

Félix, Luís M; Serafim, Cindy; Valentim, Ana M; Antunes, Luís M; Matos, Manuela; Coimbra, Ana M

2017-09-05

Increasing evidence supports that ketamine, a widely used anaesthetic, potentiates apoptosis during development through the mitochondrial pathway of apoptosis. Defects in the apoptotic machinery can cause or contribute to the developmental abnormalities previously described in ketamine-exposed zebrafish. The involvement of the apoptotic machinery in ketamine-induced teratogenicity was addressed by assessing the apoptotic signals at 8 and 24 hpf following 20min exposure to ketamine at three stages of early zebrafish embryo development (256 cell, 50% epiboly and 1-4 somites stages). Exposure at the 256-cell stage to ketamine induced an up-regulation of casp8 and pcna at 8 hpf while changes in pcna at the mRNA level were observed at 24 hpf. After the 50% epiboly stage exposure, the mRNA levels of casp9 were increased at 8 and 24 hpf while aifm1 was affected at 24 hpf. Both tp53 and pcna expressions were increased at 8 hpf. After exposure during the 1-4 somites stage, no meaningful changes on transcript levels were observed. The distribution of apoptotic cells and the caspase-like enzymatic activities of caspase-3 and -9 were not affected by ketamine exposure. It is proposed that ketamine exposure at the 256-cell stage induced a cooperative mechanism between proliferation and cellular death while following exposure at the 50% epiboly, a p53-dependent and -independent caspase activation may occur. Finally, at the 1-4 somites stage, the defence mechanisms are already fully in place to protect against ketamine-insult. Thus, ketamine teratogenicity seems to be dependent on the functional mechanisms present in each developmental stage. Copyright © 2017 Elsevier B.V. All rights reserved.

Mazindol attenuates ketamine-induced cognitive deficit in the attentional set shifting task in rats.

Science.gov (United States)

Nikiforuk, Agnieszka; Gołembiowska, Krystyna; Popik, Piotr

2010-01-01

Cognitive impairments associated with schizophrenia await an effective treatment. In order to model schizophrenia-like cognitive deficits in rats, we evaluated the effects of ketamine, a dissociative anesthetic NMDA/glutamate receptor channel blocker in the attentional set-shifting task (ASST). Acute administration of ketamine (10 but not 3mg/kg) selectively impaired solving of the extradimensional (ED) set-shifting component. Next, we investigated whether the co-administration of mazindol, a dopamine and norepinephrine reuptake inhibitor would protect rats from ketamine-induced deficits. Mazindol dose-dependently and selectively alleviated ketamine-induced ED deficit with a minimal effective dose of 0.5mg/kg. The ED component improvement was noted primarily in ketamine - but not in vehicle co-treated rats, in which the drug facilitated ED shift solving at the dose as high as 5mg/kg. A "positive control", sertindole (2.5mg/kg) also ameliorated ketamine-induced ED deficit. Microdialysis of the prefrontal cortex in a separate group of animals revealed that 2-3h after the administration of 5mg/kg of mazindol and ketamine (i.e., at the time of ED component solving), the extracellular concentrations of dopamine were enhanced by ~300% as compared to the baseline and were intermediate between the mazindol- and ketamine-treated reference groups. However, at that time the levels of norepinephrine, serotonin and glutamate appeared unaffected. We conclude that ketamine may be useful in mimicking deficits specifically related to cognitive inflexibility observed in schizophrenia, and suggest that these anomalies could be ameliorated by mazindol. The beneficial effects of mazindol on ASST performance may have therapeutic implications for the treatment of schizophrenia.

Preemptive effects of epidural s (+ - ketamine or ketamine in the horse's postincisional pain

Directory of Open Access Journals (Sweden)

Nilson Oleskovicz

2006-02-01

Full Text Available The aim of this study was to evaluate the pre-emptive effect of epidural ketamine S (+ (SK or racemic ketamine (RK administration, in post-incisional pain in horses. Were used in a blinded, randomized experimental study, sixteen mixed breed mares, 6±2 years old, weighting 273.2±42.0 kg. An epidural catheter was inserted 24 hours before the trials. The thigh region was shaved bilaterally, and mechanical cutaneous sensibility was measured using von Frey filaments (T-30. Using the left side as the control one, local anesthesia was performed at the right side. Twenty-five minutes later, SK was injected in G1 or RK in G2 through the epidural catheter. Five minutes after the ketamine injection, a 10 cm skin incision was made on the right side, and then sutured. Mechanical post-incisional pain was measured using von Frey filaments, at 1, 3 and 5 cm around the incision at 15 minutes intervals, for 2 hours, then 4, 6 and 8 hours after suturing. No changes were observed in the heart and respiratory rate and rectal temperature among groups or times of each group. Hind limb ataxia was observed in 62.5% and 12.5% of G1 and G2 respectively. SK and RK reduced cutaneous sensibility in the right and the left sides to mechanical postincisional pain during all time of experiment. Epidural SK and RK produce similar post-incisional analgesic effects, did not interfere in the cardio-respiratory parameters. The SK induces more intense ataxia in mares and presents a larger analgesic potency in the first 60 minutes after the administration.

Preventive Treatment with Ketamine Attenuates the Ischaemia-Reperfusion Response in a Chronic Postischaemia Pain Model

Directory of Open Access Journals (Sweden)

Suryamin Liman

2015-01-01

Full Text Available Ischemia and inflammation may be pathophysiological mechanisms of complex regional pain syndrome (CRPS. Ketamine has proposed anti-inflammatory effects and has been used for treating CRPS. This study aimed to evaluate anti-inflammatory and analgesic effects of ketamine after ischaemia-reperfusion injury in a chronic postischaemia pain (CPIP model of CRPS-I. Using this model, ischemia was induced in the hindlimbs of male Sprague-Dawley rats. Ketamine, methylprednisolone, or saline was administered immediately after reperfusion. Physical effects, (oedema, temperature, and mechanical and cold allodynia in the bilateral hindpaws, were assessed from 48 hours after reperfusion. Fewer (56% rats in the ketamine group developed CPIP at the 48th hour after reperfusion (nonsignificant. Ketamine treated rats showed a significantly lower temperature in the ischaemic hindpaw compared to saline (P<0.01 and methylprednisolone (P<0.05 groups. Mechanical and cold allodynia were significantly lower in the ischaemic side in the ketamine group (P<0.05. Proinflammatory cytokines TNF-α and IL-2 were significantly lower at the 48th hour after reperfusion in ketamine and methylprednisolone groups, compared to saline (all P<0.05. In conclusion, immediate administration of ketamine after an ischaemia-reperfusion injury can alleviate pain and inflammation in the CPIP model and has potential to treat postischaemic pain.

Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats.

Science.gov (United States)

Choi, Miyeon; Lee, Seung Hoon; Park, Min Hyeop; Kim, Yong-Seok; Son, Hyeon

2017-08-05

Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine. Copyright © 2017 Elsevier Inc. All rights reserved.

The promise of ketamine for treatment-resistant depression: current evidence and future directions

Science.gov (United States)

DeWilde, Kaitlin E.; Levitch, Cara F.; Murrough, James W.; Mathew, Sanjay J.; Iosifescu, Dan V.

2014-01-01

Major depressive disorder (MDD) is one of the most disabling diseases worldwide and is a significant public health threat. Current treatments for MDD primarily consist of monoamine-targeting agents and have limited efficacy. However, the glutamate neurotransmitter system has recently come into focus as a promising alternative for novel antidepressant treatments. We review the current data on the glutamate NMDA receptor antagonist ketamine, which has been shown in clinical trials to act as a rapid antidepressant in MDD. We also examine ketamine efficacy on dimensions of psychopathology, including anhedonia, cognition, and suicidality, consistent with the NIMH Research Domain Criteria (RDoC) initiative. Other aspects of ketamine reviewed in this paper include safety and efficacy, different administration methods, and the risks of misuse of ketamine outside of medical settings. Finally, we conclude with a discussion of other glutamatergic agents other than ketamine currently being tested as novel antidepressants. PMID:25649308

Ketamine sedation for patients with acute agitation and psychiatric illness requiring aeromedical retrieval.

Science.gov (United States)

Le Cong, Minh; Gynther, Bruce; Hunter, Ernest; Schuller, Peter

2012-04-01

Aeromedical retrieval services face the difficult problem of appropriate levels of sedation for transport of acutely agitated patients to definitive care. This paper describes a technique using ketamine, which is titratable and avoids problems associated with airway management. A 3-year review of a new technique of ketamine sedation by aeromedical retrieval teams from the Cairns base of the Queensland section of the Royal Flying Doctor Service of Australia. Clinical records were systematically reviewed for ketamine administration and signs of adverse events during transport and in the subsequent 72 h. 18 patients were sedated during retrieval with intravenous ketamine. Effective sedation was achieved in all cases, with no significant adverse events noted during retrieval or 72 h afterwards. Ketamine sedation is effective and safe in agitated patients with a psychiatric illness in the aeromedical setting and does not lead to worsening agitation in the subsequent 72-h period.

Estimation of the contribution of norketamine to ketamine-induced acute pain relief and neurocognitive impairment in healthy volunteers

Science.gov (United States)

Olofsen, Erik; Noppers, Ingeborg; Niesters, Marieke; Kharasch, Evan; Aarts, Leon; Sarton, Elise; Dahan, Albert

2012-01-01

Background The N-methyl-D-receptor antagonist ketamine is metabolized in the liver into its active metabolite norketamine. No human data are available on the relative contribution of norketamine to ketamine-induced analgesia and side effects. One approach to assess the ketamine and norketamine contributions is by measuring ketamine-effect at varying ketamine and norketamine plasma concentrations using the CYP450 inducer rifampicin. Methods In 12 healthy male volunteers the effect of rifampicin versus placebo pretreatment on S-ketamine (a 2-h infusion of 20 mg/h)-induced analgesia and cognition was quantified. The relative ketamine and norketamine contribution to effect was estimated using a linear additive population pharmacokinetic-pharmacodynamic model. Results S-ketamine produced significant analgesia, psychotropic effects (drug high), and cognitive impairment (including memory impairment, reduced psychomotor speed, reduced reaction time, reduced cognitive flexibility). Modeling revealed a negative contribution of S-norketamine to S-ketamine-induced analgesia and absence of contribution to cognitive impairment. At ketamine and norketamine effect concentrations of 100 ng/ml and 50 ng/ml, respectievly, the ketamine contribution to analgesia is −3.8 cm (visual analogue pain score) versus a contribution of norketamine of +1.5 cm, causing an overall effect −2.3 cm. The blood-effect-site equilibration half-life ranged from 0 (cognitive flexibility) to 11.8 (pain intensity) min, and averaged across all end-points was 6.1 min. Conclusions This first observation that norketamine produces effects in the opposite direction of ketamine requires further proof. It can explain the observation of ketamine-related excitatory phenomena (such as hyperalgesia and allodynia) upon the termination of ketamine infusions. PMID:22692377

A novel coated silver ketamine(I electrode for potentiometric determination of ketamine hydrochloride in ampoules and urine samples

Directory of Open Access Journals (Sweden)

Hazem M. Abu Shawish

2014-11-01

Full Text Available A new ketamine coated silver electrode (KCSE based on ketamine hydrochloride with sodium tetraphenylborate (KT-TPB as electroactive material has been described. The influence of membrane composition, type of solvent mediators, kind of electroactive materials and interfering ions on the sensor was investigated. The sensor displays Nernstian response of 55.8 ± 0.3 mV/decade over the concentration range of 2.5 × 10−6 to 1.0 × 10−2 M with limit of detection of 8.5 × 10−7 M. The coated wire electrode has short response time ∼8 s and it can be used in pH range of 2.6–6.4. The selective coefficients were determined in relation to several inorganic, organic ions, sugars and some common drug excipients. The KCSE electrode was successfully used for the determination of the ketamine content in ampoule and urine samples with satisfactory results. Statistical student’s t-test and F test showed insignificant systematic error between proposed and official methods.

Oral ketamine for the treatment of pain and treatment-resistant depression

NARCIS (Netherlands)

Schoevers, Robert A.; Chaves, Tharcila V.; Balukova, Sonya M.; Rot, Marije Aan Het; Kortekaas, Rudie

Background Recent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications.

Rapid and Longer-Term Antidepressant Effects of Repeated Ketamine Infusions in Treatment-Resistant Major Depression

NARCIS (Netherlands)

Murrough, James W.; Perez, Andrew M.; Pillemer, Sarah; Stern, Jessica; Parides, Michael K.; aan het Rot, Marije; Collins, Katherine A.; Mathew, Sanjay J.; Charney, Dennis S.; Iosifescu, Dan V.

2013-01-01

Background: Ketamine is reported to have rapid antidepressant effects; however, there is limited understanding of the time-course of ketamine effects beyond a single infusion. A previous report including 10 participants with treatment-resistant major depression (TRD) found that six ketamine

Fast screening of ketamine in biological samples based on molecularly imprinted photonic hydrogels

International Nuclear Information System (INIS)

Meng, Liang; Meng, Pinjia; Zhang, Qingqing; Wang, Yanji

2013-01-01

Graphical abstract: A novel label-free colorimetric chemosensor: with the increase in the concentration of ketamine, the Bragg diffraction peak of MIPHs gradually shifted to the longer wavelength region. Accompanying the peak shift, the color change of MIPHs was also observed obviously: from green to red. Highlights: ► We developed the label-free colorimetric MIPHs for handy and fast screening of ketamine. ► The obvious color change of MIPHs was observed upon ketamine. ► The MIPHs exhibited good sensing abilities in an aqueous environment. ► The sensing mechanisms of the water-compatible MIPHs were investigated. ► The MIPHs were employed to screening ketamine in real biological samples. -- Abstract: A novel label-free colorimetric chemosensor was developed for handy and fast screening of ketamine with high sensitivity and specificity based on molecularly imprinted photonic hydrogels (MIPHs) that combined the colloidal-crystal with molecular imprinting technique. The unique inverse opal arrays with a thin polymer wall in which the imprinted nanocavities of ketamine moleculars distributed allowed high sensitive, quick responsive, specific detection of the target analyte, and good regenerating ability in an aqueous environment. Due to the hierarchical inverse opal structural characteristics, the specific ketamine molecular recognition process can induce obvious swelling of the MIPHs to be directly transferred into visually perceptible optical signal (change in color) which can be detected by the naked eye through Bragg diffractive shifts of ordered macroporous arrays. In order to enhance the recognition ability in aqueous environments, the MIPHs were designed as water-compatible and synthesized in a water–methanol system. The molecular recognition mechanisms were investigated. The proposed MIPHs were successfully employed to screen trace level ketamine in human urine and saliva samples, exhibiting high sensitivity, rapid response, and specificity in the

Fast screening of ketamine in biological samples based on molecularly imprinted photonic hydrogels

Energy Technology Data Exchange (ETDEWEB)

Meng, Liang [Department of Forensic Science, People' s Public Security University of China, Beijing (China); Meng, Pinjia, E-mail: mengpinjia@163.com [Department of Forensic Science, People' s Public Security University of China, Beijing (China); Zhang, Qingqing; Wang, Yanji [Department of Forensic Science, People' s Public Security University of China, Beijing (China)

2013-04-10

Graphical abstract: A novel label-free colorimetric chemosensor: with the increase in the concentration of ketamine, the Bragg diffraction peak of MIPHs gradually shifted to the longer wavelength region. Accompanying the peak shift, the color change of MIPHs was also observed obviously: from green to red. Highlights: ► We developed the label-free colorimetric MIPHs for handy and fast screening of ketamine. ► The obvious color change of MIPHs was observed upon ketamine. ► The MIPHs exhibited good sensing abilities in an aqueous environment. ► The sensing mechanisms of the water-compatible MIPHs were investigated. ► The MIPHs were employed to screening ketamine in real biological samples. -- Abstract: A novel label-free colorimetric chemosensor was developed for handy and fast screening of ketamine with high sensitivity and specificity based on molecularly imprinted photonic hydrogels (MIPHs) that combined the colloidal-crystal with molecular imprinting technique. The unique inverse opal arrays with a thin polymer wall in which the imprinted nanocavities of ketamine moleculars distributed allowed high sensitive, quick responsive, specific detection of the target analyte, and good regenerating ability in an aqueous environment. Due to the hierarchical inverse opal structural characteristics, the specific ketamine molecular recognition process can induce obvious swelling of the MIPHs to be directly transferred into visually perceptible optical signal (change in color) which can be detected by the naked eye through Bragg diffractive shifts of ordered macroporous arrays. In order to enhance the recognition ability in aqueous environments, the MIPHs were designed as water-compatible and synthesized in a water–methanol system. The molecular recognition mechanisms were investigated. The proposed MIPHs were successfully employed to screen trace level ketamine in human urine and saliva samples, exhibiting high sensitivity, rapid response, and specificity in the

Ultrastructure of canine meninges after repeated epidural injection of S(+)-ketamine.

Science.gov (United States)

Acosta, Alinne; Gomar, Carmen; Bombí, Josep A; Graça, Dominguita L; Garrido, Marta; Krauspenhar, Cristina

2006-01-01

The safety of ketamine when administered by the spinal route must be confirmed in various animal species before it is approved for use in humans. This study evaluates the ultrastructure of canine meninges after repeated doses of epidural S(+)-ketamine. Five dogs received S(+)-ketamine 5%, 1 mg/kg, twice a day for 10 days through an epidural catheter with its tip located at the L5 level. One dog received the same volume of normal saline at the same times. The spinal cord and meninges were processed for histopathological and ultrastructural studies. Clinical effects were assessed after each injection. Motor and sensory block appeared after each injection of S(+)-ketamine, but not in the dog receiving saline. No signs of clinical or neurologic alterations were observed. Using light microscopy, no meningeal layer showed alterations except focal infiltration at the catheter tip level by macrophages, lymphocytes, and a few mast cells. The cells of different layers were studied by electron microscopy and interpreted according to data from human and other animal species because no ultrastructural description of the canine meninges is currently available. There were no cellular signs of inflammation, phagocytosis, or degeneration in meningeal layers and no signs of atrophy, compression, or demyelinization in the areas of dorsal root ganglia and spinal cord around the arachnoid. These findings were common for dogs receiving S(+)-ketamine and the dog receiving saline. Repeated doses of epidural S(+)-ketamine 5%, 1 mg/kg, twice a day for 10 days was not associated to cellular alterations in canine meninges.

Haloperidol counteracts the ketamine-induced disruption of processing negativity, but not that of the P300 amplitude

DEFF Research Database (Denmark)

Oranje, Bob; Gispen-de Wied, Christine C; Westenberg, Herman G M

2009-01-01

. Besides exerting an antagonistic effect on NMDA receptors, they have agonistic effects on dopamine D2 receptors. Can haloperidol (D2 antagonist) counteract the disruptive effects of ketamine on psychophysiological parameters of human attention? In a randomized, double-blind, placebo-controlled experiment...... 18 healthy male volunteers received placebo/placebo, placebo/ketamine (0.3 mg/kg i.v.) and haloperidol (2 mg)/ketamine (0.3 mg/kg i.v.) on three separate test days, after which they were tested in an auditory selective-attention paradigm. Haloperidol/ketamine reduced task performance compared...... to placebo/placebo, while the task performance in these two treatments did not differ from placebo/ketamine. Furthermore, placebo/ketamine reduced processing negativity compared to both placebo/placebo and haloperidol/ketamine, while processing negativity did not differ between placebo...

Ketamine and phencyclidine: the good, the bad and the unexpected

Science.gov (United States)

Lodge, D; Mercier, M S

2015-01-01

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. PMID:26075331

Anti-angiogenic SPARC peptides inhibit progression of neuroblastoma tumors

Directory of Open Access Journals (Sweden)

Tian Yufeng

2010-06-01

Full Text Available Abstract Background New, more effective strategies are needed to treat highly aggressive neuroblastoma. Our laboratory has previously shown that full-length Secreted Protein Acidic and Rich in Cysteine (SPARC and a SPARC peptide corresponding to the follistatin domain of the protein (FS-E potently block angiogenesis and inhibit the growth of neuroblastoma tumors in preclinical models. Peptide FS-E is structurally complex and difficult to produce, limiting its potential as a therapeutic in the clinic. Results In this study, we synthesized two smaller and structurally more simple SPARC peptides, FSEN and FSEC, that respectively correspond to the N-and C-terminal loops of peptide FS-E. We show that both peptides FSEN and FSEC have anti-angiogenic activity in vitro and in vivo, although FSEC is more potent. Peptide FSEC also significantly inhibited the growth of neuroblastoma xenografts. Histologic examination demonstrated characteristic features of tumor angiogenesis with structurally abnormal, tortuous blood vessels in control neuroblastoma xenografts. In contrast, the blood vessels observed in tumors, treated with SPARC peptides, were thin walled and structurally more normal. Using a novel method to quantitatively assess blood vessel abnormality we demonstrated that both SPARC peptides induced changes in blood vessel architecture that are consistent with blood vessel normalization. Conclusion Our results demonstrate that SPARC peptide FSEC has potent anti-angiogenic and anti-tumorigenic effects in neuroblastoma. Its simple structure and ease of production indicate that it may have clinical utility in the treatment of high-risk neuroblastoma and other types of pediatric and adult cancers, which depend on angiogenesis.

21 CFR 522.1222b - Ketamine hydrochloride with promazine hydrochloride and aminopentamide hydrogen sulfate injection.

Science.gov (United States)

2010-04-01

... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Ketamine hydrochloride with promazine... RELATED PRODUCTS IMPLANTATION OR INJECTABLE DOSAGE FORM NEW ANIMAL DRUGS § 522.1222b Ketamine.... Ketamine hydrochloride, (±),-2-(o-chlorophenyl)-2-(methylamino) cyclohexanone hydrochloride, with promazine...

Modulation of NMDA receptor function by ketamine and magnesium: Part I

NARCIS (Netherlands)

Liu, H. T.; Hollmann, M. W.; Liu, W. H.; Hoenemann, C. W.; Durieux, M. E.

2001-01-01

N-methyl-D-aspartate (NMDA) receptors are important components of pain processing. Ketamine and Mg2+ block NMDA receptors and might therefore be useful analgesics, and combinations of Mg2+ and ketamine provide more effective analgesia. We investigated their interactions at NMDA receptors. Xenopus

Short- and long-term antidepressant effects of ketamine in a rat chronic unpredictable stress model.

Science.gov (United States)

Jiang, Yinghong; Wang, Yiqiang; Sun, Xiaoran; Lian, Bo; Sun, Hongwei; Wang, Gang; Du, Zhongde; Li, Qi; Sun, Lin

2017-08-01

This research was aimed to evaluate the behaviors of short- or long-term antidepressant effects of ketamine in rats exposed to chronic unpredictable stress (CUS). Ketamine, a glutamate noncompetitive NMDA receptor antagonist, regulates excitatory amino acid functions, such as anxiety disorders and major depression, and plays an important role in synaptic plasticity and learning and memory. After 42 days of CUS model, male rats received either a single injection of ketamine (10 mg/kg; day 43) or 15 daily injections (days 43-75). The influence of ketamine on behavioral reactivity was assessed 24 hr (short-term) or 7 weeks after ketamine treatment (long-term). Behavioral tests used to assess the effects of these treatments included the sucrose preference (SP), open field (OF), elevated plus maze (EPM), forced swimming (FS), and water maze (WM) to detect anxiety-like behavior (OF and EPM), forced swimming (FS), and water maze (WM). Results: Short-term ketamine administration resulted in increases of body weight gain, higher sensitivity to sucrose, augmented locomotor activity in the OF, more entries into the open arms of the EPM, along increased activity in the FS test; all responses indicative of reductions in depression/despair in anxiety-eliciting situations. No significant differences in these behaviors were obtained under conditions of long-term ketamine administration ( p  > .05). The CUS + Ketamine group showed significantly increased activity as compared with the CUS + Vehicle group for analysis of the long-term effects of ketamine (* p   .05). Taken together these findings demonstrate that a short-term administration of ketamine induced rapid antidepressant-like effects in adult male rats exposed to CUS conditions, effects that were not observed in response to the long-term treatment regime.

S -ketamine compared to etomidate during electroconvulsive therapy in major depression.

Science.gov (United States)

Zavorotnyy, Maxim; Kluge, Ina; Ahrens, Kathrin; Wohltmann, Thomas; Köhnlein, Benjamin; Dietsche, Patricia; Dannlowski, Udo; Kircher, Tilo; Konrad, Carsten

2017-12-01

Objective of the study was to compare two commonly used anesthetic drugs, S-ketamine and etomidate, regarding their influence on seizure characteristics, safety aspects, and outcome of electroconvulsive therapy (ECT) in major depression. Treatment data of 60 patients who underwent a total number of 13 ECTs (median) because of the severe or treatment-resistant major depressive disorder (DSM-IV) were analyzed. Etomidate, mean dosage (SD) = 0.25 (0.04) mg/kg, was used for anesthesia in 29 participants; 31 patients received S-ketamine, mean dosage (SD) = 0.96 (0.26) mg/kg. Right unilateral brief pulse ECTs were performed. The number of ECTs was individually adjusted to clinical needs, mean (SD) = 13.0 (4.3). Seizure characteristics, adverse events, and the clinical global impression (CGI) scores were compared between the both groups during ECT series. In the S-ketamine group, a lower initial seizure threshold (p = 0.014), stimulation charge (p ketamine might hold a potential to become a clinically favorable anesthetic agent during ECT. However, the current findings should be interpreted with caution, and further prospective randomized clinical trials are required. Also, specific adverse effects profile of S-ketamine, especially with regard to the cardiovascular risk, needs to be taken into account.

Ketamine as a Rapid Treatment for Post-Traumatic Stress Disorder

Science.gov (United States)

2011-10-01

Post - traumatic stress disorder ( PTSD ) is a debilitating anxiety disorder characterized by intrusive re-experiences of the traumatic events...08-1-0602 TITLE: Ketamine as a Rapid Treatment for Post - Traumatic Stress Disorder PRINCIPAL INVESTIGATOR: Dennis Charney...dissociative effects of ketamine but not have any sustained anxiolytic and antidepressant effects. Forty individuals diagnosed with post - traumatic

N-acetylcysteine prevents ketamine-induced adverse effects on development, heart rate and monoaminergic neurons in zebrafish.

Science.gov (United States)

Robinson, Bonnie; Dumas, Melanie; Gu, Qiang; Kanungo, Jyotshna

2018-06-08

N-acetylcysteine, a precursor molecule of glutathione, is an antioxidant. Ketamine, a pediatric anesthetic, has been implicated in cardiotoxicity and neurotoxicity including modulation of monoaminergic systems in mammals and zebrafish. Here, we show that N-acetylcysteine prevents ketamine's adverse effects on development and monoaminergic neurons in zebrafish embryos. The effects of ketamine and N-acetylcysteine alone or in combination were measured on the heart rate, body length, brain serotonergic neurons and tyrosine hydroxylase-immunoreactive (TH-IR) neurons. In the absence of N-acetylcysteine, a concentration of ketamine that produces an internal embryo exposure level comparable to human anesthetic plasma concentrations significantly reduced heart rate and body length and those effects were prevented by N-acetylcysteine co-treatment. Ketamine also reduced the areas occupied by serotonergic neurons in the brain, whereas N-acetylcysteine co-exposure counteracted this effect. TH-IR neurons in the embryo brain and TH-IR cells in the trunk were significantly reduced with ketamine treatment, but not in the presence of N-acetylcysteine. In our continued search for compounds that can prevent ketamine toxicity, this study using specific endpoints of developmental toxicity, cardiotoxicity and neurotoxicity, demonstrates protective effects of N-acetylcysteine against ketamine's adverse effects. This is the first study that shows the protective effects of N-acetylcysteine on ketamine-induced developmental defects of monoaminergic neurons as observed in a whole organism. Published by Elsevier B.V.

Diclofenac inhibits tumor growth in a murine model of pancreatic cancer by modulation of VEGF levels and arginase activity.

Directory of Open Access Journals (Sweden)

Nina Mayorek

Full Text Available BACKGROUND: Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX, diclofenac potently inhibits phospholipase A(2 (PLA(2, thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. METHODOLOGY/PRINCIPAL FINDINGS: We found that diclofenac treatment (30 mg/kg/bw for 11 days of mice inoculated with PANC02 cells, reduced the tumor weight by 60%, correlating with increased apoptosis of tumor cells. Since this effect was not observed in vitro on cultured PANCO2 cells, we theorized that diclofenac beneficial treatment involved other mediators present in vivo. Indeed, diclofenac drastically decreased tumor vascularization by downregulating VEGF in the tumor and in abdominal cavity fluid. Furthermore, diclofenac directly inhibited vascular sprouting ex vivo. Surprisingly, in contrast to other COX-2 inhibitors, diclofenac increased arginase activity/arginase 1 protein content in tumor stroma cells, peritoneal macrophages and white blood cells by 2.4, 4.8 and 2 fold, respectively. We propose that the subsequent arginine depletion and decrease in NO levels, both in serum and peritoneal cavity, adds to tumor growth inhibition by malnourishment and poor vasculature development. CONCLUSION/SIGNIFICANCE: In conclusion, diclofenac shows pronounced antitumoral properties in pancreatic cancer model that can contribute to further treatment development. The ability of diclofenac to induce arginase activity in tumor stroma, peritoneal macrophages and white blood cells provides a tool to study a controversial issue of pro-and antitumoral effects of arginine depletion.

Longitudinal Effects of Ketamine on Dendritic Architecture In Vivo in the Mouse Medial Frontal Cortex123

Science.gov (United States)

Phoumthipphavong, Victoria; Barthas, Florent; Hassett, Samantha

2016-01-01

Abstract A single subanesthetic dose of ketamine, an NMDA receptor antagonist, leads to fast-acting antidepressant effects. In rodent models, systemic ketamine is associated with higher dendritic spine density in the prefrontal cortex, reflecting structural remodeling that may underlie the behavioral changes. However, turnover of dendritic spines is a dynamic process in vivo, and the longitudinal effects of ketamine on structural plasticity remain unclear. The purpose of the current study is to use subcellular resolution optical imaging to determine the time course of dendritic alterations in vivo following systemic ketamine administration in mice. We used two-photon microscopy to visualize repeatedly the same set of dendritic branches in the mouse medial frontal cortex (MFC) before and after a single injection of ketamine or saline. Compared to controls, ketamine-injected mice had higher dendritic spine density in MFC for up to 2 weeks. This prolonged increase in spine density was driven by an elevated spine formation rate, and not by changes in the spine elimination rate. A fraction of the new spines following ketamine injection was persistent, which is indicative of functional synapses. In a few cases, we also observed retraction of distal apical tuft branches on the day immediately after ketamine administration. These results indicate that following systemic ketamine administration, certain dendritic inputs in MFC are removed immediately, while others are added gradually. These dynamic structural modifications are consistent with a model of ketamine action in which the net effect is a rebalancing of synaptic inputs received by frontal cortical neurons. PMID:27066532

Ketamine Metabolites Enantioselectively Decrease Intracellular D-Serine Concentrations in PC-12 Cells.

Directory of Open Access Journals (Sweden)

Nagendra S Singh

Full Text Available D-Serine is an endogenous NMDA receptor co-agonist that activates synaptic NMDA receptors modulating neuronal networks in the cerebral cortex and plays a key role in long-term potentiation of synaptic transmission. D-serine is associated with NMDA receptor neurotoxicity and neurodegeneration and elevated D-serine concentrations have been associated with Alzheimer's and Parkinsons' diseases and amyotrophic lateral sclerosis. Previous studies have demonstrated that the ketamine metabolites (rac-dehydronorketamine and (2S,6S-hydroxynorketamine decrease intracellular D-serine concentrations in a concentration dependent manner in PC-12 cells. In the current study, PC-12 cells were incubated with a series of ketamine metabolites and the IC50 values associated with attenuated intracellular D-serine concentrations were determined. The results demonstrate that structural and stereochemical features of the studied compounds contribute to the magnitude of the inhibitory effect with (2S,6S-hydroxynorketamine and (2R,6R-hydroxynorketamine displaying the most potent inhibition with IC50 values of 0.18 ± 0.04 nM and 0.68 ± 0.09 nM. The data was utilized to construct a preliminary 3D-QSAR/pharmacophore model for use in the design of new and more efficient modulators of D-serine.

Meta-analysis of short- and mid-term efficacy of ketamine in unipolar and bipolar depression.

Science.gov (United States)

Romeo, Bruno; Choucha, Walid; Fossati, Philippe; Rotge, Jean-Yves

2015-12-15

Among treatments currently assessed in major depression, ketamine, has been proposed of great interest, especially because of its very rapid action. However, the time-course of the antidepressive action of ketamine remained unclear. In the present meta-analysis, we provided a clear and objective view regarding the putative antidepressive effect of ketamine and its time-course. We searched the MEDLINE and PsycINFO databases through December 2013, without limits on year of publication, using the key words ketamine and synonyms for mood disorder or episode. Six randomized, double-blind and placebo-controlled trials of ketamine in major depression (n=103 patients) were thus identified. Authors were contacted and they all provided original data necessary for this meta-analysis. Standardized mean differences (SMD) were calculated between the depression scores in ketamine and placebo groups at days 1, 2, 3-4, 7 and 14. Ketamine showed an overall antidepressive efficacy from day 1 to day 7. However, the maintenance of its efficacy over time failed to reach significance in bipolar depression after day 3-4. Significant SMDs were not explained by demographic or clinical characteristics of included samples. The present meta-analysis provides a high level of evidence that ketamine has a rapid antidepressive action during one week, especially in unipolar disorder. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Comparison of nasal Midazolam with Ketamine versus nasal Midazolam as a premedication in children

Directory of Open Access Journals (Sweden)

Sonal S Khatavkar

2014-01-01

Full Text Available Background: T his study was done to compare effects of intranasal midazolam and intranasal midazolam with ketamine for premedication of children aged 1-12 yrs undergoing intermediate and major surgeries. Aims: Midazolam and Ketamine have already been used as premedicants in children. Our aim was to find out advantage of combination of midazolam with ketamine over midazolam by nasal route. Methods: Sixty children of age group 1-12 yrs of American Society of Anesthesiologists (ASA grade 1 and 2 were selected. Group A- midazolam (0.2 mg/kg, Group B- midazolam (0.15 mg/kg + ketamine 1 mg/kg. Both groups received drug intranasally 30 min before surgery in recovery room with monitored anesthesia care. Onset of sedation, sedation score, emotional reaction, intravenous cannula acceptance, and mask acceptance were studied. Statistical Analysis: Unpaired t test and chi square test. Results: Sedation score, anxiolysis, attitude, reaction to intravenous cannulation, face mask acceptance, and emotional reaction were significantly better in midazolam with ketamine group. Intra operatively, in both groups, pulse rate, oxygen saturation, and respiratory rate had no significant difference; also, post operatively, no significant difference was observed in above parameters, post operative analgesia was significantly better in midazolam with ketamine group. Conclusions: Intra nasal premedication allows rapid and predictable sedation in children. Midazolam as well as combination of Midazolam with ketamine gives good level of sedation and comfort. But quality of sedation, analgesia, and comfort is significantly better in midazolam with ketamine group. No significant side effects were observed in both groups.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models

Directory of Open Access Journals (Sweden)

Rahul Jandial

2018-01-01

Full Text Available Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1 to detoxify the toxic glycolytic byproduct methylglyoxal (MG and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs. Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM, the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA approaches. Inhibition of GLO1 with S-(p-bromobenzyl glutathione dicyclopentyl ester (p-BrBzGSH(Cp2 increased levels of the DNA-AGE N2-1-(carboxyethyl-2′-deoxyguanosine (CEdG, a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE; and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p-BrBzGSH(Cp2 exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Inhibition of GLO1 in Glioblastoma Multiforme Increases DNA-AGEs, Stimulates RAGE Expression, and Inhibits Brain Tumor Growth in Orthotopic Mouse Models.

Science.gov (United States)

Jandial, Rahul; Neman, Josh; Lim, Punnajit P; Tamae, Daniel; Kowolik, Claudia M; Wuenschell, Gerald E; Shuck, Sarah C; Ciminera, Alexandra K; De Jesus, Luis R; Ouyang, Ching; Chen, Mike Y; Termini, John

2018-01-30

Cancers that exhibit the Warburg effect may elevate expression of glyoxylase 1 (GLO1) to detoxify the toxic glycolytic byproduct methylglyoxal (MG) and inhibit the formation of pro-apoptotic advanced glycation endproducts (AGEs). Inhibition of GLO1 in cancers that up-regulate glycolysis has been proposed as a therapeutic targeting strategy, but this approach has not been evaluated for glioblastoma multiforme (GBM), the most aggressive and difficult to treat malignancy of the brain. Elevated GLO1 expression in GBM was established in patient tumors and cell lines using bioinformatics tools and biochemical approaches. GLO1 inhibition in GBM cell lines and in an orthotopic xenograft GBM mouse model was examined using both small molecule and short hairpin RNA (shRNA) approaches. Inhibition of GLO1 with S -( p -bromobenzyl) glutathione dicyclopentyl ester ( p- BrBzGSH(Cp)₂) increased levels of the DNA-AGE N ²-1-(carboxyethyl)-2'-deoxyguanosine (CEdG), a surrogate biomarker for nuclear MG exposure; substantially elevated expression of the immunoglobulin-like receptor for AGEs (RAGE); and induced apoptosis in GBM cell lines. Targeting GLO1 with shRNA similarly increased CEdG levels and RAGE expression, and was cytotoxic to glioma cells. Mice bearing orthotopic GBM xenografts treated systemically with p -BrBzGSH(Cp)₂ exhibited tumor regression without significant off-target effects suggesting that GLO1 inhibition may have value in the therapeutic management of these drug-resistant tumors.

Reduction of central neuropathic pain with ketamine infusion in a patient with Ehlers-Danlos syndrome: a case report.

Science.gov (United States)

Lo, Tony Chung Tung; Yeung, Stephen Tung; Lee, Sujin; Skavinski, Kira; Liao, Solomon

2016-01-01

Ehlers-Danlos syndrome frequently causes acute and chronic pain because of joint subluxations and dislocations secondary to hypermobility. Current treatments for pain related to Ehlers-Danlos syndrome and central pain syndrome are inadequate. This case report discusses the therapeutic use of ketamine intravenous infusion as an alternative. A 27-year-old Caucasian female with a history of Ehlers-Danlos syndrome and spinal cord ischemic myelopathy resulting in central pain syndrome, presented with severe generalized body pain refractory to multiple pharmacological interventions. After a 7-day course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit, the patient reported a dramatic reduction in pain levels from 7-8 out of 10 to 0-3 out of 10 on a numeric rating scale and had a significant functional improvement. The patient tolerated a reduction in her pain medication regimen, which originally included opioids, gabapentin, pregabalin, tricyclic antidepressants, and nonsteroidal anti-inflammatory drugs. Ketamine infusion treatment has been used in various pain syndromes, including central neuropathic pain, ischemic pain, and regional pain syndrome. Reports have suggested that ketamine modulates pain by the regression of N-methyl-D-aspartate receptor to a resting state. As such, propagation of nociceptive signal to brain is interrupted allowing for the restoration of physiological balance between pain inhibition and facilitation. The present report shows that this treatment option can be used in patients with refractory central pain syndrome in the setting of spinal cord myelopathy secondary to Ehlers-Danlos syndrome. In addition, as seen in this case, this protocol can potentially decrease the chronic use of pain medication, such as opioids.

Combination therapy with gefitinib and doxorubicin inhibits tumor growth in transgenic mice with adrenal neuroblastoma

International Nuclear Information System (INIS)

Kawano, Kumi; Hattori, Yoshiyuki; Iwakura, Hiroshi; Akamizu, Takashi; Maitani, Yoshie

2013-01-01

Highly relevant mouse models of human neuroblastoma (NB) are needed to evaluate new therapeutic strategies against NB. In this study, we characterized transgenic mice with bilateral adrenal tumors. On the basis of information from the tumoral gene expression profiles, we examined the antitumor effects of unencapsulated and liposomal doxorubicin (DXR), alone and in combination with gefitinib, on adrenal NB. We showed that intravenous injection of unencapsulated or liposomal DXR alone inhibited tumor growth in a dose-dependent manner, as assessed by magnetic resonance imaging (MRI). However, liposomal DXR did not exhibit greater antitumor effect than unencapsulated DXR. Immunohistochemical analysis revealed that the adrenal tumor vasculature with abundant pericyte coverage was a less leaky structure for liposomes. Combination therapy with unencapsulated or liposomal DXR plus gefitinib strongly suppressed tumor growth and delayed tumor regrowth than treatment with unencapsulated or liposomal DXR alone, even at a lower dose of DXR. Dynamic contrast-enhanced MRI analysis revealed that gefitinib treatment increased blood flow in the tumor, indicating that gefitinib treatment changes the tumor vascular environment in a manner that may increase the antitumor effect of DXR. In conclusion, the combination of gefitinib and DXR induces growth inhibition of adrenal NBs in transgenic mice. These findings will provide helpful insights into new treatments for NB

Ketamine displaces the novel NMDA receptor SPET probe [123I]CNS-1261 in humans in vivo

International Nuclear Information System (INIS)

Stone, James M.; Erlandsson, Kjell; Arstad, Erik; Bressan, Rodrigo A.; Squassante, Lisa; Teneggi, Vincenza; Ell, Peter J.; Pilowsky, Lyn S.

2006-01-01

[ 123 I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [ 123 I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [ 123 I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [ 123 I]CNS-1261 V T in most of the brain regions examined (P 123 I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site

Inhibition of hepatocyte gap junctional intercellular communication by tumor promoters

International Nuclear Information System (INIS)

Ruch, R.J.

1988-01-01

The mechanisms by which tumor promoters enhance neoplasia are poorly understood. One effect common to most tumor promoters is their ability to inhibit the cell-to-cell exchange of small molecules and ions through gap junctions, i.e., gap junctional intercellular communication (IC). IC maybe necessary for normal growth control and the loss of IC may predispose cells to enhanced growth. In the present studies, the effects of liver tumor promoters and other agents on IC between rodent hepatocytes in primary culture has been studied. IC was detected between hepatocytes: (1) autoradiographically following the passage and incorporation of [5- 3 H]uridine nucleotides from pre-labeled donor hepatocytes to non-labeled, adjacent recipient hepatocytes and (2) by fluorescence microscopy after microinjection of fluorescent Lucifer Yellow CH dye into hepatocytes and visualizing dye spread into adjacent hepatocytes

Genetically engineered endostatin-lidamycin fusion proteins effectively inhibit tumor growth and metastasis

International Nuclear Information System (INIS)

Jiang, Wen-guo; Zhen, Yong-su; Lu, Xin-an; Shang, Bo-yang; Fu, Yan; Zhang, Sheng-hua; Zhou, Daifu; Li, Liang; Li, Yi; Luo, Yongzhang

2013-01-01

Endostatin (ES) inhibits endothelial cell proliferation, migration, invasion, and tube formation. It also shows antiangiogenesis and antitumor activities in several animal models. Endostatin specifically targets tumor vasculature to block tumor growth. Lidamycin (LDM), which consists of an active enediyne chromophore (AE) and a non-covalently bound apo-protein (LDP), is a member of chromoprotein family of antitumor antibiotics with extremely potent cytotoxicity to cancer cells. Therefore, we reasoned that endostatin-lidamycin (ES-LDM) fusion proteins upon energizing with enediyne chromophore may obtain the combined capability targeting tumor vasculature and tumor cell by respective ES and LDM moiety. In this study, we designed and obtained two new endostatin-based fusion proteins, endostatin-LDP (ES-LDP) and LDP-endostatin (LDP-ES). In vitro, the antiangiogenic effect of fusion proteins was determined by the wound healing assay and tube formation assay and the cytotoxicity of their enediyne-energized analogs was evaluated by CCK-8 assay. Tissue microarray was used to analyze the binding affinity of LDP, ES or ES-LDP with specimens of human lung tissue and lung tumor. The in vivo efficacy of the fusion proteins was evaluated with human lung carcinoma PG-BE1 xenograft and the experimental metastasis model of 4T1-luc breast cancer. ES-LDP and LDP-ES disrupted the formation of endothelial tube structures and inhibited endothelial cell migration. Evidently, ES-LDP accumulated in the tumor and suppressed tumor growth and metastasis. ES-LDP and ES show higher binding capability than LDP to lung carcinoma; in addition, ES-LDP and ES share similar binding capability. Furthermore, the enediyne-energized fusion protein ES-LDP-AE demonstrated significant efficacy against lung carcinoma xenograft in athymic mice. The ES-based fusion protein therapy provides some fundamental information for further drug development. Targeting both tumor vasculature and tumor cells by endostatin

Ketamine versus propofol for strabismus surgery in children

Directory of Open Access Journals (Sweden)

Ayse Mizrak

2010-07-01

Full Text Available Ayse Mizrak1, Ibrahim Erbagci2, Tulin Arici1, Ibrahim Ozcan1, Gurkan Tatar2, Unsal Oner11Anesthesiology and Reanimation, Gaziantep University School of Medicine, Gaziantep, Turkey; 2The Department of Ophthalmology, Gaziantep University School of Medicine, Gaziantep, TurkeyPurpose: To compare the effects of intravenous infusion of ketamine and propofol anesthesia in children undergoing strabismus surgery. Methods: Sixty pediatric patients aged 4–11 years were enrolled for the study. Patients in Group K were infused ketamine 1–3 mg/kg/hr (n = 30 and patients in Group P were infused with propofol6–9 mg/kg/hr (n = 30. After giving fentanyl 1 µg/kg and rocuronium bromide 0.5 mg/kg, patients were intubated.Results: The consumption of anesthetics (P = 0.0001 and antiemetics (P = 0.004, the incidence of ­oculocardiac reflex (P = 0.02 in Group K were significantly lower than in Group P. The recovery time (P = 0.008, postoperative agitation score (P = 0.005, Face Pain Scale (P = 0.001, Ramsay Sedation Score (P = 0.01 during awakening and at postoperative 30th min (P = 0.02 in Group K were significantly lower than in Group P. The postoperative agitation score ­during awakening was significantly lower than the preoperative values in Group K (P = 0.0001.Conclusions: The infusion of ketamine is more advantageous than the infusion of propofol in children for use in strabismus surgery.Keywords: ketamine, propofol, pediatrics, strabismus, surgery

Berberine suppresses tumorigenicity and growth of nasopharyngeal carcinoma cells by inhibiting STAT3 activation induced by tumor associated fibroblasts

International Nuclear Information System (INIS)

Tsang, Chi Man; Cheung, Yuk Chun; Lui, Vivian Wai-Yan; Yip, Yim Ling; Zhang, Guitao; Lin, Victor Weitao; Cheung, Kenneth Chat-Pan; Feng, Yibin; Tsao, Sai Wah

2013-01-01

Cortidis rhizoma (Huanglian) and its major therapeutic component, berberine, have drawn extensive attention in recent years for their anti-cancer properties. Growth inhibitory effects of berberine on multiple types of human cancer cells have been reported. Berberine inhibits invasion, induces cell cycle arrest and apoptosis in human cancer cells. The anti-inflammatory property of berberine, involving inhibition of Signal Transducer and Activator of Transcription 3 (STAT3) activation, has also been documented. In this study, we have examined the effects of berberine on tumorigenicity and growth of nasopharyngeal carcinoma (NPC) cells and their relationship to STAT3 signaling using both in vivo and in vitro models. Berberine effectively inhibited the tumorigenicity and growth of an EBV-positive NPC cell line (C666-1) in athymic nude mice. Inhibition of tumorigenic growth of NPC cells in vivo was correlated with effective inhibition of STAT3 activation in NPC cells inside the tumor xenografts grown in nude mice. In vitro, berberine inhibited both constitutive and IL-6-induced STAT3 activation in NPC cells. Inhibition of STAT3 activation by berberine induced growth inhibition and apoptotic response in NPC cells. Tumor-associated fibroblasts were found to secret IL-6 and the conditioned medium harvested from the fibroblasts also induced STAT3 activation in NPC cells. Furthermore, STAT3 activation by conditioned medium of tumor-associated fibroblasts could be blocked by berberine or antibodies against IL-6 and IL-6R. Our observation that berberine effectively inhibited activation of STAT3 induced by tumor-associated fibroblasts suggests a role of berberine in modulating the effects of tumor stroma on the growth of NPC cells. The effective inhibition of STAT3 activation in NPC cells by berberine supports its potential use in the treatment of NPC

Ketamine alters lateral prefrontal oscillations in a rule-based working memory task.

Science.gov (United States)

Ma, Liya; Skoblenick, Kevin; Johnston, Kevin; Everling, Stefan

2018-02-02

Acute administration of N-methyl-D-aspartate receptor (NMDAR) antagonists in healthy humans and animals produces working memory deficits similar to those observed in schizophrenia. However, it is unclear whether they also lead to altered low-frequency (rule-based prosaccade and antisaccade working memory task, both before and after systemic injections of a subanesthetic dose (delay periods and inter-trial intervals. It also increased task-related alpha-band activities, likely reflecting compromised attention. Beta-band oscillations may be especially relevant to working memory processes, as stronger beta power weakly but significantly predicted shorter saccadic reaction time. Also in beta band, ketamine reduced the performance-related oscillation as well as the rule information encoded in the spectral power. Ketamine also reduced rule information in the spike-field phase consistency in almost all frequencies up to 60Hz. Our findings support NMDAR antagonists in non-human primates as a meaningful model for altered neural oscillations and synchrony, which reflect a disorganized network underlying the working memory deficits in schizophrenia. SIGNIFICANCE STATEMENT Low doses of ketamine-an NMDA receptor blocker-produce working memory deficits similar to those observed in schizophrenia. In the LPFC, a key brain region for working memory, we found that ketamine altered neural oscillatory activities in similar ways that differentiate schizophrenic patients and healthy subjects, during both task and non-task periods. Ketamine induced stronger gamma (30-60Hz) and weaker beta (13-30Hz) oscillations, reflecting local hyperactivity and reduced long-range communications. Furthermore, ketamine reduced performance-related oscillatory activities, as well as the rule information encoded in the oscillations and in the synchrony between single cell activities and oscillations. The ketamine model helps link the molecular and cellular basis of neural oscillatory changes to the working

Comparison between intravenous and intramuscular administration of ketamine in children sedation referred to emergency department

Directory of Open Access Journals (Sweden)

Behnaz Boroumand Rezazadeh

2014-12-01

Full Text Available Ketamine, among wide variety of sedative drugs, has shown beneficial effects when using during the procedural sedation, specifically in pediatrics. Various parameters should be considered in order to perform a safe and effective procedural sedation including optimum dosage of the sedative, administration methods of sedation, and need for applying any adjuvant drug. In this study, we aimed to review the studies, which have compared the efficacy of the different ways of the injection of ketamine such as intravenous or intramuscular ketamine application. Based on data obtained from the related articles, efficacy and safety of these two methods of ketamine usage in the pediatric procedural sedation were widely similar, but the intravenously administration of the ketamine can be proposed as the preferable mode.

Ketamine for pain in adults and children with cancer: a systematic review and synthesis of the literature.

Science.gov (United States)

Bredlau, Amy Lee; Thakur, Rajbala; Korones, David Nathan; Dworkin, Robert H

2013-10-01

Chronic cancer pain is often refractory and difficult to treat. Ketamine is a medication with evidence of efficacy in the treatment of chronic pain. This article presents a synthesis of the data on ketamine for refractory cancer pain in adults and children. There are five randomized, double-blind, controlled trials of ketamine use in cancer pain that demonstrate improvement in pain for some patients. There are six prospective, uncontrolled trials in cancer pain that also demonstrate improvement in pain scores for some patients. There are no randomized, controlled trials in children with cancer pain, although there are a few studies reflecting improved pain control with ketamine for children with cancer pain. Adverse events for adults on ketamine are most commonly somnolence, feelings of insobriety, nausea/vomiting, hallucinations, depersonalization/derealization, and drowsiness. However, when ketamine is combined with benzodiazepines, feelings of insobriety, hallucinations, and depersonalization/derealization are not reported. Children on ketamine have had few reported adverse effects, which include sedation, anorexia, urinary retention, and myoclonic movements. Recommended ketamine infusion dosages are from 0.05 to 0.5 mg/kg/h (intravenous or subcutaneous). Recommended oral dosages of ketamine are 0.2-0.5 mg/kg/dose two to three times daily with a maximum of 50 mg/dose three times daily. Despite limitations in the breadth and depth of data available, there is evidence that ketamine may be a viable option for treatment-refractory cancer pain. Wiley Periodicals, Inc.

Preemptive analgesia by peritonsillar ketamine versus ropivacaine for post-tonsillectomy pain in children

Directory of Open Access Journals (Sweden)

Manal S. Farmawy

2014-01-01

Conclusion: Perincisional peritonsillar infiltration of both ropivacaine and ketamine was effective in reduction of post-tonsillectomy pain. Ropivacaine was superior to ketamine in reduction of time to first analgesic demand.

Prevalence and Perception of Ketamine Use among Young Danish Night Clubbers:

DEFF Research Database (Denmark)

Ravn, Signe; Demant, Jakob

2012-01-01

AIMS – This article describes the prevalence of ketamine use among Danish recreational drug users and provides a contextual understanding of ketamine use within this group. METHODS AND DATA – The analysis is based on a mixed-methods night club study combining a survey among guests in night clubs (N...

Severe toxic damage to the rabbit spinal cord after intrathecal administration of preservative-free S(+)-ketamine

NARCIS (Netherlands)

Vranken, Jan H.; Troost, Dirk; de Haan, Peter; Pennings, Fritz A.; van der Vegt, Marinus H.; Dijkgraaf, Marcel G. W.; Hollmann, Markus W.

2006-01-01

BACKGROUND: Ketamine and S(+)-ketamine have been advocated for neuraxial use in the management of postoperative pain and severe intractable pain syndromes unresponsive to opioid escalation. Although clinical experience has accumulated with S(+)-ketamine, safety data on toxicity in the central

Molecular Imaging on the Cerebral Pathological Damage Target of Ketamine Dependence

Directory of Open Access Journals (Sweden)

YANG Hong-jie1,2;HU Shu1;JIA Shao-wei1;GAO Zhou1;WANG Tong3;ZHAO Zheng-qin1

2014-02-01

Full Text Available To study the cerebral pathological damage target which result from abusing ketamine through molecular imaging techniques， 20 cases of ketamine dependent patients looking for treatment at the Peking University Shenzhen Hospital and 31 healthy volunteers were included in this study, all of them got brain SPECT DAT imaging. The results were analyzed by SPSS 16.0. The bilateral caudate nucleus and putamen of healthy volunteers were roughly equally large, and the radioactive distribution of DAT in healthy volunteers were uniform and symmetrical. The bilateral corpora striatum showed typical “panda eyes” pattern. But the bilateral corpora striatum of ketamine dependent patients got smaller in shape, got disorders in pattern, and the radioactive distribution of DAT reduced or defected or even got disturbance and with much more non-specific radioactive. The V, m and Ra of bilateral corpora striatum in ketamine dependent patients were （21.03±3.15） cm3, （22.08±3.31） g and （5.37±1.08） %, respectively, which were significantly lower than the healthy volunteers (p<0.01. The cerebral pathological damage target which resulted from abusing ketamine was similar to those of compound codeine phosphate antitussive solution dependence, heroin dependence and MDMA dependence, all of these psychoactive substances damaged the function of DAT.

Low-Dose Ketamine Infusion for Emergency Department Patients with Severe Pain.

Science.gov (United States)

Ahern, Terence L; Herring, Andrew A; Miller, Steve; Frazee, Bradley W

2015-07-01

Use of low-dose ketamine infusions in the emergency department (ED) has not previously been described, despite routine use in perioperative and other settings. Our hypothesis was that a low-dose ketamine bolus followed by continuous infusion would 1) provide clinically significant and sustained pain relief; 2) be well tolerated; and 3) be feasible in the ED. We prospectively administered 15 mg intravenous ketamine followed immediately by continuous ketamine infusion at 20 mg/h for 1 hour. Optional morphine (4 mg) was offered at 20, 40, and 60 minutes. Pain intensity, vitals signs, level of sedation, and adverse reactions were assessed for 120 minutes. A total of 38 patients were included with a median initial numerical rating scale (NRS) pain score of 9. At 10 minutes, the median reduction in pain score was 4, with 7 patients reporting a score of 0. At 60 and 120 minutes, 25 and 26 patients, respectively, reported clinically significant pain reduction (decrease NRS score > 3). Heart rate, blood pressure, respiratory rate, and oxygen saturation remained stable. Mild or moderate side effects including dizziness, fatigue, and headache were common. Patient satisfaction was high; 85% reported they would have this medication again for similar pain. A low-dose ketamine infusion protocol provided significant pain relief with mostly mild side effects and no severe adverse events. Wiley Periodicals, Inc.

STREET KETAMINE-ASSOCIATED BLADDER DYSFUNCTION: AN EMERGING HEALTH PROBLEM

Directory of Open Access Journals (Sweden)

TEH GC

2009-08-01

Full Text Available Introduction: Ketamine is frequently abused nowadays as a recreational drug. Case reports are emerging since 2007 to describe a new clinical entity of severe bladder dysfunction associated with chronic abuse of street ketamine. Clinical presentation: Severe lower urinary tract symptoms of urinary frequency and urgency which are refractory to conventional treatment. Quality of life is adversely affected as a consequence. Chronic kidney disease will develop in advanced cases. Investigation findings: The urine is sterile on culture. Ultrasound will show reduced bladder capacity with thickened bladder wall. In advanced stage, hydronephrosis and renal impairment will develop. Treatment: Patients should be advised to stop street ketamine use immediately. Anticholinergic medication could be tried to alleviate the symptoms. Refractory cases with dilatation of the upper urinary tract might need urinary diversion. Conclusion: Awareness of this new condition is essential in diagnosis. Early intervention offers better treatment outcome.

Cocaine potentiates ketamine-induced loss of the righting reflex and sleeping time in mice. Role of catecholamines.

Science.gov (United States)

Vanderwende, C; Spoerlein, M T; Lapollo, J

1982-07-01

Cocaine in graded doses potentiated ketamine-induced loss of the righting reflex and sleeping time. Potentiation of drug-induced sleep with cocaine was not a generalized phenomenon inasmuch as it had no effect on sleep induced by pentobarbital or hexobarbital and decreased sleep induced by phenobarbital. Pentylenetetrazole reduced ketamine sleep but d-amphetamine had a potentiative action. dl-alpha-Methyl-p-tyrosine methyl ester itself increased both the number losing the righting reflex and the sleeping time induced by ketamine. However, the effect cocaine on sleeping time was blocked 3 h after the dl-alpha-methyl-p-tyrosine methyl ester was given. The alpha and beta adrenergic blocking drugs, phenoxybenzamine and propranolol, increased the number of animals losing the righting reflex with ketamine, and phenoxybenzamine lengthened the sleeping time. Alpha and beta adrenergic agonists, l-phenylephrine and isoproterenol, increased the number of animals going to sleep with ketamine but did not significantly alter how long they would sleep. The agonists had no effect on the cocaine interaction with ketamine, whereas the antagonists blocked the effect of cocaine. Both stimulation and blockade of dopamine receptors led to increased loss of the righting reflex and sleeping time with ketamine but only receptor blockade antagonized the effect of cocaine on ketamine-induced sleep. Thus, both the noradrenergic and dopaminergic systems appear to be involved in the ability of cocaine to potentiate ketamine-induced sleep.

Arctigenin inhibits prostate tumor cell growth in vitro and in vivo

Directory of Open Access Journals (Sweden)

Piwen Wang

2017-06-01

Full Text Available The low bioavailability of most phytochemicals limits their translation to humans. We investigated whether arctigenin, a novel anti-inflammatory lignan from the seeds of Arctium lappa, has favorable bioavailability/potency against prostate cancer. The anticarcinogenic activity of arctigenin was investigated both in vitro using the androgen-sensitive LNCaP and LAPC-4 human prostate cancer cells and pre-malignant WPE1-NA22 cells, and in vivo using xenograft mouse models. Arctigenin at lower doses (<2 μM significantly inhibited the proliferation of LNCaP and LAPC-4 cells by 30–50% at 48 h compared to control, and inhibited WPE1-NA22 cells by 75%, while did not affect normal prostate epithelial cells. Male severe combined immunodeficiency (SCID mice were implanted subcutaneously with LAPC-4 cells for in vivo studies. In one experiment, the intervention started one week after tumor implantation. Mice received arctigenin at 50 mg/kg (LD or 100 mg/kg (HD b.w. daily or vehicle control by oral gavage. After 6 weeks, tumor growth was inhibited by 50% (LD and 70% (HD compared to control. A stronger tumor inhibitory effect was observed in a second experiment where arctigenin intervention started two weeks prior to tumor implantation. Arc was detectable in blood and tumors in Arc groups, with a mean value up to 2.0 μM in blood, and 8.3 nmol/g tissue in tumors. Tumor levels of proliferation marker Ki67, total and nuclear androgen receptor, and growth factors including VEGF, EGF, and FGF-β were significantly decreased by Arc, along with an increase in apoptosis marker of Bax/Bcl-2 ratio. Genes responsive to arctigenin were identified including TIMP3 and ZNF185, and microRNAs including miR-126-5p, and miR-21-5p. This study provides the first in vivo evidence of the strong anticancer activity of arctigenin in prostate cancer. The effective dose of arctigenin in vitro is physiologically achievable in vivo, which provides a high promise in its

5-Hydroxytryptamine-Independent Antidepressant Actions of (R)-Ketamine in a Chronic Social Defeat Stress Model.

Science.gov (United States)

Zhang, Kai; Dong, Chao; Fujita, Yuko; Fujita, Atsuhiro; Hashimoto, Kenji

2018-02-01

Previous reports suggest that 5-hydroxytryptamine might play a role in the antidepressant actions of (R,S)-ketamine. However, its role in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, is unknown. This study was conducted to examine whether 5-hydroxytryptamine depletion affects the antidepressant actions of (R)-ketamine in a chronic social defeat stress model. An inhibitor of 5-hydroxytryptamine synthesis, para-chlorophenylalanine methyl ester hydrochloride (300 mg/kg, twice daily for 3 consecutive days), or vehicle was administered to control and chronic social defeat stress-susceptible mice. Levels of 5-hydroxytryptamine and its metabolite, 5-hydroxyindoleacetic acid, in mouse brain regions were measured using high-performance liquid chromatography. Furthermore, antidepressant effects of (R)-ketamine (10 mg/kg) in the vehicle- and para-chlorophenylalanine methyl ester hydrochloride-treated susceptible mice were assessed using tail suspension test and 1% sucrose preference test. para-Chlorophenylalanine methyl ester hydrochloride treatment caused marked reductions of 5-hydroxytryptamine and 5-hydroxyindoleacetic acid in the brain regions of control and chronic social defeat stress susceptible mice. In the tail suspension test, (R)-ketamine significantly attenuated the increased immobility time in the chronic social defeat stress-susceptible mice with or without 5-hydroxytryptamine depletion. In the sucrose preference test (2 and 5 days after a single dose), (R)-ketamine significantly enhanced reduced sucrose consumption in the chronic social defeat stress-susceptible mice with or without 5-hydroxytryptamine depletion. These findings show that 5-hydroxytryptamine depletion did not affect the antidepressant effects of (R)-ketamine in a chronic social defeat stress model. Therefore, it is unlikely that 5-hydroxytryptamine plays a major role in the antidepressant actions of (R)-ketamine. © The Author 2017. Published by Oxford

Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats.

Science.gov (United States)

Strong, C E; Schoepfer, K J; Dossat, A M; Saland, S K; Wright, K N; Kabbaj, M

2017-07-15

Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction. Copyright © 2017. Published by Elsevier Ltd.

Effects of ketamine and alfaxalone on application of a feline pain assessment scale.

Science.gov (United States)

Buisman, Mandy; Wagner, Marika C; Hasiuk, Michelle Mm; Prebble, Melanie; Law, Laura; Pang, Daniel Sj

2016-08-01

The objective of this study was to compare the effects of ketamine and alfaxalone on the application of a validated feline-specific multidimensional composite pain scale (UNESP-Botucatu MCPS). In a prospective, randomized, blinded, crossover trial, 11 adult cats (weight 4.4 ± 0.6 kg) were given dexmedetomidine (15 μg/kg) and hydromorphone (0.05 mg/kg) with either alfaxalone (2 mg/kg) or ketamine (5 mg/kg) as a single intramuscular injection for the induction of general anesthesia. After orotracheal intubation, general anesthesia (without surgery) was maintained for 32 mins with isoflurane, followed by atipamezole. The following parameters were recorded at baseline, 1-8 h and 24 h post-extubation: pain (pain expression and psychomotor subscales) and sedation scale scores. Alfaxalone treatment injection sites were examined for inflammation at baseline, postinjection, and 8 h and 24 h post-extubation. Psychomotor scores were higher with ketamine at hours 1 (3.5 [0-5.0], P ketamine group crossed the analgesic intervention threshold. In contrast, pain expression scores did not differ significantly between treatments at any time (P >0.05); one cat from each group crossed the analgesic intervention threshold. Sedation was greater with ketamine (1 [0-3], P = 0.02) than alfaxalone (0 [0-1]) 1 h post-extubation. No cats had visible inflammation at the injection sites at any time. Ketamine has a confounding effect on the psychomotor subscale of the pain scale studied, which may lead to erroneous administration of rescue analgesia. In contrast, alfaxalone was not associated with significant increases in either pain subscale. These effects of ketamine should be considered when evaluating acute postoperative pain in cats. © The Author(s) 2015.

Clonidine versus ketamine to prevent tourniquet pain during intravenous regional anesthesia with lidocaine.

Science.gov (United States)

Gorgias, N K; Maidatsi, P G; Kyriakidis, A M; Karakoulas, K A; Alvanos, D N; Giala, M M

2001-01-01

Both clonidine and ketamine have been found to prolong the action of local anesthetics through a peripheral mechanism. Our study compares the efficacy of a low dose of clonidine or ketamine separately added to intravenous regional anesthesia (IVRA) with lidocaine to prevent tourniquet pain. We conducted a prospective randomized double-blinded study in 45 patients undergoing hand or forearm surgery, with anticipated duration exceeding 1 hour under IVRA. Proximal cuff inflation of a double tourniquet was followed by administration of 40 mL of lidocaine 0.5% and either saline, 1 microg/kg clonidine, or 0.1 mg/kg ketamine. When anesthesia was established, the inflation of the proximal and distal cuff was interchanged. Thereafter, tourniquet pain was rated on a visual analog scale (VAS) every 10 minutes. Intraoperatively, boluses of 25 microg fentanyl were provided for tourniquet pain treatment when required, and total fentanyl consumption was recorded. Patients receiving plain lidocaine persistently reported the highest pain scores among groups (P <.001) 20 minutes after distal cuff inflation. Differences between the groups with additional treatment were noted 50 minutes after distal cuff inflation and until the end of the observation, with significantly lower VAS ratings (P <.001 to P <.01) in ketamine-treated patients. Total fentanyl consumption was significantly decreased by ketamine (70.00 +/- 25.35 microg) or clonidine (136.67 +/- 39.94 microg) compared with the plain lidocaine group (215.33 +/- 52.33 microg) (P <.001 between all groups). The addition of clonidine 1 microg/kg or ketamine 0.1 mg/kg to lidocaine for IVRA delays the onset of unbearable tourniquet pain and decreases analgesic consumption for tourniquet pain relief, although ketamine has a more potent effect.

Opposite effects of ketamine and deep brain stimulation on rat thalamocortical information processing.

Science.gov (United States)

Kulikova, Sofya P; Tolmacheva, Elena A; Anderson, Paul; Gaudias, Julien; Adams, Brendan E; Zheng, Thomas; Pinault, Didier

2012-11-01

Sensory and cognitive deficits are common in schizophrenia. They are associated with abnormal brain rhythms, including disturbances in γ frequency (30-80 Hz) oscillations (GFO) in cortex-related networks. However, the underlying anatomofunctional mechanisms remain elusive. Clinical and experimental evidence suggests that these deficits result from a hyporegulation of glutamate N-methyl-D-aspartate receptors. Here we modeled these deficits in rats with ketamine, a non-competitive N-methyl-D-aspartate receptor antagonist and a translational psychotomimetic substance at subanesthetic doses. We tested the hypothesis that ketamine-induced sensory deficits involve an impairment of the ability of the thalamocortical (TC) system to discriminate the relevant information from the baseline activity. Furthermore, we wanted to assess whether ketamine disrupts synaptic plasticity in TC systems. We conducted multisite network recordings in the rat somatosensory TC system, natural stimulation of the vibrissae and high-frequency electrical stimulation (HFS) of the thalamus. A single systemic injection of ketamine increased the amount of baseline GFO, reduced the amplitude of the sensory-evoked TC response and decreased the power of the sensory-evoked GFO. Furthermore, cortical application of ketamine elicited local and distant increases in baseline GFO. The ketamine effects were transient. Unexpectedly, HFS of the TC pathway had opposite actions. In conclusion, ketamine and thalamic HFS have opposite effects on the ability of the somatosensory TC system to discriminate the sensory-evoked response from the baseline GFO during information processing. Investigating the link between the state and function of the TC system may conceptually be a key strategy to design innovative therapies against neuropsychiatric disorders. © 2012 The Authors. European Journal of Neuroscience © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Long-Term Stability of Tramadol and Ketamine Solutions for Patient-Controlled Analgesia Delivery.

Science.gov (United States)

Gu, Junfeng; Qin, Wengang; Chen, Fuchao; Xia, Zhongyuan

2015-08-26

Subanesthetic doses of ketamine as an adjuvant to tramadol in patient-controlled analgesia (PCA) for postoperative pain have been shown to improve the quality of analgesia. However, there are no such commercially available drug mixtures, and the stability of the combination has rarely been assessed. Admixtures were assessed for periods of up to 14 days at 4°C and 25°C. Three different mixtures of tramadol and ketamine (tramadol 5.0 mg/mL + ketamine 0.5 mg/mL, tramadol 5.0 mg/mL + ketamine 1.0 mg/mL, and tramadol 5.0 mg/mL + ketamine 2.0 mg/mL) were prepared in polyolefin bags by combining these 2 drugs with 0.9% sodium chloride (normal saline [NS]). The chemical stability of the admixtures was evaluated by a validated high-performance liquid chromatography (HPLC) method and by measurement of pH values. Solution appearance and color were assessed by observing the samples against black and white backgrounds. Solutions were considered stable if they maintained 90% of the initial concentration of each drug. The percentages of initial concentration of tramadol and ketamine in the various solutions remained above 98% when stored at 4°C or 25°C over the testing period. No changes in color or turbidity were observed in any of the prepared solutions. Throughout this period, pH values remained stable. The results indicate that the drug mixtures of tramadol with ketamine in NS for PCA delivery systems were stable for 14 days when stored in polyolefin bags at 4°C or 25°C.

Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial.

Science.gov (United States)

Rigo, Flavia Karine; Trevisan, Gabriela; Godoy, Maria C; Rossato, Mateus Fortes; Dalmolin, Gerusa D; Silva, Mariane A; Menezes, Mirian S; Caumo, Wolnei; Ferreira, Juliano

2017-03-01

Methadone and ketamine are used in neuropathic pain management. However, the benefits of both drugs association are uncertain in the treatment of neuropathic pain. Our primary objective was test the hypothesis that oral methadone combined with oral ketamine is more effective than oral methadone or ketamine alone in reducing neuropathic pain. We conducted a randomized, double blind, active-controlled parallel-group clinical trial. Forty-two patients with neuropathic pain refractory to conventional therapy were randomly assigned to receive oral methadone (n = 14), ketamine (n = 14), or methadone plus ketamine (n = 14) over a 3-month period. During these 90 days, we observed pain scores using a visual analogical scale (VAS), allodynia, burning/shooting pain, and some side effects. All treatments were effective in reducing pain scores by at least 40%. However, a significant improvement in pain was observed only in the ketamine alone group compared with both the methadone or methadone/ketamine groups. No significant differences were observed among the treatment groups for the reduction of burning or shooting pain, while ketamine alone was more effective than methadone or methadone/ketamine for the reduction of allodynia. Formal assessment for awareness of the allocation was not performed, some co-intervention bias may have occurred, our results could be only relevant to the patient population investigated and the use of VAS as the primary outcome detect changes in pain intensity but not to assess neuropathic pain symptoms. This study indicates that ketamine was better than methadone or methadone/ketamine for treating neuropathic pain.Key words: Multimodal analgesia, refractory pain, NMDA receptor, opioid.

Intravenous ketamine is as effective as midazolam/fentanyl for procedural sedation and analgesia in the emergency department.

Science.gov (United States)

Jamal, S M; Fathil, S M; Nidzwani, M M; Ismail, A K; Yatim, F M

2011-08-01

The study compared the effectiveness of ketamine and midazolam/fentanyl as procedural sedation and analgesia agents for reduction of fractures and dislocated joints. Forty-one adult patients were enrolled by convenience sampling. They were randomized to receive ketamine or midazolam/fentanyl. Depth of sedation, pain score, procedural outcome and memory of the procedure were documented. The ketamine group had deeper sedation, but there was no statistical difference in other variables between the two groups. Three patients in the midazolam/fentanyl group had oxygen desaturation. More adverse effects were associated with ketamine. Intravenous ketamine is as effective as midazolam/fentanyl for procedural sedation.

Neuropathological findings after continuous intrathecal administration of S(+)-ketamine for the management of neuropathic cancer pain

NARCIS (Netherlands)

Vranken, J. H.; Troost, D.; Wegener, J. T.; Kruis, M. R.; van der Vegt, M. H.

2005-01-01

Questions have been raised about the potential neurotoxicity of the neuraxial use of ketamine although ketamine and its active enantiomer S(+)-ketamine have been used intrathecally and epidurally (caudally) for the management of perioperative pain and in a variety of chronic pain syndromes. Clinical

MUC16 provides immune protection by inhibiting synapse formation between NK and ovarian tumor cells

Directory of Open Access Journals (Sweden)

Migneault Martine

2010-01-01

Full Text Available Abstract Background Cancer cells utilize a variety of mechanisms to evade immune detection and attack. Effective immune detection largely relies on the formation of an immune synapse which requires close contact between immune cells and their targets. Here, we show that MUC16, a heavily glycosylated 3-5 million Da mucin expressed on the surface of ovarian tumor cells, inhibits the formation of immune synapses between NK cells and ovarian tumor targets. Our results indicate that MUC16-mediated inhibition of immune synapse formation is an effective mechanism employed by ovarian tumors to evade immune recognition. Results Expression of low levels of MUC16 strongly correlated with an increased number of conjugates and activating immune synapses between ovarian tumor cells and primary naïve NK cells. MUC16-knockdown ovarian tumor cells were more susceptible to lysis by primary NK cells than MUC16 expressing controls. This increased lysis was not due to differences in the expression levels of the ligands for the activating receptors DNAM-1 and NKG2D. The NK cell leukemia cell line (NKL, which does not express KIRs but are positive for DNAM-1 and NKG2D, also conjugated and lysed MUC16-knockdown cells more efficiently than MUC16 expressing controls. Tumor cells that survived the NKL challenge expressed higher levels of MUC16 indicating selective lysis of MUC16low targets. The higher csMUC16 levels on the NKL resistant tumor cells correlated with more protection from lysis as compared to target cells that were never exposed to the effectors. Conclusion MUC16, a carrier of the tumor marker CA125, has previously been shown to facilitate ovarian tumor metastasis and inhibits NK cell mediated lysis of tumor targets. Our data now demonstrates that MUC16 expressing ovarian cancer cells are protected from recognition by NK cells. The immune protection provided by MUC16 may lead to selective survival of ovarian cancer cells that are more efficient in

Retinoid inhibition of in vitro invasion of human amnion basement membrane by human tumor cells

International Nuclear Information System (INIS)

Fazely, F.; Ledinko, N.; Smith, D.J.

1986-01-01

The biological activity of retinoids was assayed in an in vitro quantitative assay of human tumor cell invasion using human amnion basement membrane (BM). The effects measured were the inhibition of tumor cell migration through the BM and tumor cell degradative enzyme activity on 14 C-proline labeled collagenous and noncollagenous components of the BM. The human lung carcinoma A549 or the human Ewing's sarcoma TC-106 cell lines treated with retinoids for two days were incubated on the BM in the absence of retinoids. A dose-dependent inhibition of cell invasion was produced by retinoids. Among the retinoids tested, the most powerful was retinol acetate which inhibited invasion by 50% of A549 cells at a concentration of 0.009 μg/mL, and of TC-106 cells at 0.07 μg/mL. Retinol acetate inhibited A549 and TC-106 cell growth by approximately 50% at levels over 100-fold higher than those needed for antiinvasive activity. Retinol acetate was about 20 times more potent than retinoic acid and 30 times more potent than retinol palmitate. The model system will be useful for investigating antiinvasive activity of other retinoids as well as other compounds

Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine

Directory of Open Access Journals (Sweden)

Soichiro Ide

2017-11-01

Full Text Available We investigated the rapid and sustained antidepressant effects of enantiomers of ketamine in N-methyl-d-aspartate (NMDA receptor GluN2D subunit knockout (GluN2D-KO mice. Intraperitoneal administration of ketamine or its enantiomers 10 min before the tail-suspension test exerted significant antidepressant effects on restraint stress-induced depression in both wildtype and GluN2D-KO mice. The antidepressant effects of (RS-ketamine and (S-ketamine were sustained 96 h after the injection in both wildtype and GluN2D-KO mice, but such sustained antidepressant effects of (R-ketamine were only observed in wildtype mice. These data suggest that the GluN2D subunit is critical for the sustained antidepressant effects of (R-ketamine.

Ketamine blocks bursting in the lateral habenula to rapidly relieve depression.

Science.gov (United States)

Yang, Yan; Cui, Yihui; Sang, Kangning; Dong, Yiyan; Ni, Zheyi; Ma, Shuangshuang; Hu, Hailan

2018-02-14

The N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine has attracted enormous interest in mental health research owing to its rapid antidepressant actions, but its mechanism of action has remained elusive. Here we show that blockade of NMDAR-dependent bursting activity in the 'anti-reward center', the lateral habenula (LHb), mediates the rapid antidepressant actions of ketamine in rat and mouse models of depression. LHb neurons show a significant increase in burst activity and theta-band synchronization in depressive-like animals, which is reversed by ketamine. Burst-evoking photostimulation of LHb drives behavioural despair and anhedonia. Pharmacology and modelling experiments reveal that LHb bursting requires both NMDARs and low-voltage-sensitive T-type calcium channels (T-VSCCs). Furthermore, local blockade of NMDAR or T-VSCCs in the LHb is sufficient to induce rapid antidepressant effects. Our results suggest a simple model whereby ketamine quickly elevates mood by blocking NMDAR-dependent bursting activity of LHb neurons to disinhibit downstream monoaminergic reward centres, and provide a framework for developing new rapid-acting antidepressants.

Tumor-targeted inhibition by a novel strategy - mimoretrovirus expressing siRNA targeting the Pokemon gene.

Science.gov (United States)

Tian, Zhiqiang; Wang, Huaizhi; Jia, Zhengcai; Shi, Jinglei; Tang, Jun; Mao, Liwei; Liu, Hongli; Deng, Yijing; He, Yangdong; Ruan, Zhihua; Li, Jintao; Wu, Yuzhang; Ni, Bing

2010-12-01

Pokemon gene has crucial but versatile functions in cell differentiation, proliferation and tumorigenesis. It is a master regulator of the ARF-HDM2-p53 and Rb-E2F pathways. The facts that the expression of Pokemon is essential for tumor formation and many kinds of tumors over-express the Pokemon gene make it an attractive target for therapeutic intervention for cancer treatment. In this study, we used an RNAi strategy to silence the Pokemon gene in a cervical cancer model. To address the issues involving tumor specific delivery and durable expression of siRNA, we applied the Arg-Gly-Asp (RGD) peptide ligand and polylysine (K(18)) fusion peptide to encapsulate a recombinant retrovirus plasmid expressing a siRNA targeting the Pokemon gene and produced the 'mimoretrovirus'. At charge ratio 2.0 of fusion peptide/plasmid, the mimoretrovirus formed stable and homogenous nanoparticles, and provided complete DNase I protection and complete gel retardation. This nanoparticle inhibited SiHa cell proliferation and invasion, while it promoted SiHa cell apoptosis. The binding of the nanoparticle to SiHa cells was mediated via the RGD-integrin α(v)β(3) interaction, as evidenced by the finding that unconjugated RGD peptide inhibited this binding significantly. This tumor-targeting mimoretrovirus exhibited excellent anti-tumor capacity in vivo in a nude mouse model. Moreover, the mimoretrovirus inhibited tumor growth with a much higher efficiency than recombinant retrovirus expressing siRNA or the K(18)/P4 nanoparticle lacking the RGD peptide. Results suggest that the RNAi/RGD-based mimoretrovirus developed in this study represents a novel anti-tumor strategy that may be applicable to most research involving cancer therapy and, thus, has promising potential as a cervical cancer treatment.

Distinct retrosplenial cortex cell populations and their spike dynamics during ketamine-induced unconscious state.

Directory of Open Access Journals (Sweden)

Grace E Fox

Full Text Available Ketamine is known to induce psychotic-like symptoms, including delirium and visual hallucinations. It also causes neuronal damage and cell death in the retrosplenial cortex (RSC, an area that is thought to be a part of high visual cortical pathways and at least partially responsible for ketamine's psychotomimetic activities. However, the basic physiological properties of RSC cells as well as their response to ketamine in vivo remained largely unexplored. Here, we combine a computational method, the Inter-Spike Interval Classification Analysis (ISICA, and in vivo recordings to uncover and profile excitatory cell subtypes within layers 2&3 and 5&6 of the RSC in mice within both conscious, sleep, and ketamine-induced unconscious states. We demonstrate two distinct excitatory principal cell sub-populations, namely, high-bursting excitatory principal cells and low-bursting excitatory principal cells, within layers 2&3, and show that this classification is robust over the conscious states, namely quiet awake, and natural unconscious sleep periods. Similarly, we provide evidence of high-bursting and low-bursting excitatory principal cell sub-populations within layers 5&6 that remained distinct during quiet awake and sleep states. We further examined how these subtypes are dynamically altered by ketamine. During ketamine-induced unconscious state, these distinct excitatory principal cell subtypes in both layer 2&3 and layer 5&6 exhibited distinct dynamics. We also uncovered different dynamics of local field potential under various brain states in layer 2&3 and layer 5&6. Interestingly, ketamine administration induced high gamma oscillations in layer 2&3 of the RSC, but not layer 5&6. Our results show that excitatory principal cells within RSC layers 2&3 and 5&6 contain multiple physiologically distinct sub-populations, and they are differentially affected by ketamine.

Ketamine produces antidepressant-like effects through phosphorylation-dependent nuclear export of histone deacetylase 5 (HDAC5) in rats

Science.gov (United States)

Choi, Miyeon; Lee, Seung Hoon; Wang, Sung Eun; Ko, Seung Yeon; Song, Mihee; Choi, June-Seek; Duman, Ronald S.; Son, Hyeon

2015-01-01

Ketamine produces rapid antidepressant-like effects in animal assays for depression, although the molecular mechanisms underlying these behavioral actions remain incomplete. Here, we demonstrate that ketamine rapidly stimulates histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in rat hippocampal neurons through calcium/calmodulin kinase II- and protein kinase D-dependent pathways. Consequently, ketamine enhanced the transcriptional activity of myocyte enhancer factor 2 (MEF2), which leads to regulation of MEF2 target genes. Transfection of a HDAC5 phosphorylation-defective mutant (Ser259/Ser498 replaced by Ala259/Ala498, HDAC5-S/A), resulted in resistance to ketamine-induced nuclear export, suppression of ketamine-mediated MEF2 transcriptional activity, and decreased expression of MEF2 target genes. Behaviorally, viral-mediated hippocampal knockdown of HDAC5 blocked or occluded the antidepressant effects of ketamine both in unstressed and stressed animals. Taken together, our results reveal a novel role of HDAC5 in the actions of ketamine and suggest that HDAC5 could be a potential mechanism contributing to the therapeutic actions of ketamine. PMID:26647181

Upper urinary tract damage caused by ketamine snorting—A report of nine cases

Directory of Open Access Journals (Sweden)

Hsiang-Ying Lee

2015-09-01

Conclusion: To the best of our knowledge, currently there is no standard therapy for ketamine-induced nephropathy, we therefore supplied a therapeutic choice for those ketamine abuser combined with hydronephrosis and/or acute kidney injury.

Influence of clonidine and ketamine on m-RNA expression in a model of opioid-induced hyperalgesia in mice.

Directory of Open Access Journals (Sweden)

Henning Ohnesorge

Full Text Available We investigated the influence of morphine and ketamine or clonidine in mice on the expression of genes that may mediate pronociceptive opioid effects.C57BL/6 mice received morphine injections thrice daily using increasing doses (5-20 mg∙kg(-1 for 3 days (sub-acute, n=6 or 14 days (chronic, n=6 and additionally either s-ketamine (5 mg∙kg(-1, n=6 or clonidine (0.1 mg∙kg(-1, n=6. Tail flick test and the assessment of the mechanical withdrawal threshold of the hindpaw was performed during and 4 days after cessation of opioid treatment. Upon completion of the behavioural testing the mRNA-concentration of the NMDA receptor (NMDAR1 and β-arrestin 2 (Arrb2 were measured by PCR.Chronic opioid treatment resulted in a delay of the tail flick latency with a rapid on- and offset. Simultaneously the mice developed a static mechanical hyperalgesia with a delayed onset that that outlasted the morphine treatment. Sub-acute morphine administration resulted in a decrease of NMDAR1 and Arrb2 whereas during longer opioid treatment the expression NMDAR1 and Arrb2 mRNA increased again to baseline values. Coadministration of s-ketamine or clonidine resulted in a reversal of the mechanical hyperalgesia and inhibited the normalization of NMDAR1 mRNA expression but had no effect on the expression of Arrb2 mRNA.In the model of chronic morphine therapy the antinociceptive effects of morphine are represented by the thermal analgesia while the proniceptive effects are represented by the mechanical hyperalgesia. The results indicate that the regulation of the expression of NMDAR1 and Arrb2 may be associated to the development of OIH in mice.The results indicate that co-administration of clonidine or ketamine may influence the underlying mechanisms of OIH.

[Ketamine--anticonvulsive and proconvulsive actions].

Science.gov (United States)

Kugler, J; Doenicke, A

1994-11-01

Animal experimentation has revealed that ketamine has anticonvulsive properties. Changes in the EEG have also been reported in animals; these have been designated non-convulsive generalized electrographic seizures because of their similarities to epileptiform potentials, even though there are no recognizable signs of seizures. The cataleptic condition of the cats in which these changes were observed led to the conclusion that ketamine could cause petit mal seizures, which took the course of petit mal status. Ketamine was therefore also seen as a dangerous anaesthetic agent predisposing to convulsions, the use of which could lead to status epilepticus and irreversible brain damage. These conflicts of opinion should be resolved, as they are based on various misconceptions. (1) The terminology used for epilepsy by specialized clinicians is not always correctly applied in the context of animal experimentation. (2) The activation of epileptiform potentials in the EEG of animals cannot be interpreted as a reliable sign of epileptogenic efficiency in humans. (3) Too little regard is paid to the different actions of anaesthetic agents in various sites of the brain, at different doses and with different routes of administration. (4) The statistical significance and biological relevance of the study results are inadequate because the numbers of observations are too small. Epileptologists regret the insufficiency of animal models as paradigma for the study of efficiency of antiepileptic drugs in humans. The degree by which extensor spasms in the front paw of Gerbils of rats induced by pentylentetrazol or electric current are reduced after application of an anticonvulsive drug is no reliable measure of its anticonvulsive effect in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

Ameliorating treatment-refractory depression with intranasal ketamine: potential NMDA receptor actions in the pain circuitry representing mental anguish.

Science.gov (United States)

Opler, Lewis A; Opler, Mark G A; Arnsten, Amy F T

2016-02-01

This article reviews the antidepressant actions of ketamine, an N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, and offers a potential neural mechanism for intranasal ketamine's ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5-40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (eg, Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia.

Diclofenac Inhibits Tumor Growth in a Murine Model of Pancreatic Cancer by Modulation of VEGF Levels and Arginase Activity

OpenAIRE

Mayorek, Nina; Naftali-Shani, Nili; Grunewald, Myriam

2010-01-01

BACKGROUND: Diclofenac is one of the oldest anti-inflammatory drugs in use. In addition to its inhibition of cyclooxygenases (COX), diclofenac potently inhibits phospholipase A(2) (PLA(2)), thus yielding a broad anti-inflammatory effect. Since inflammation is an important factor in the development of pancreatic tumors we explored the potential of diclofenac to inhibit tumor growth in mice inoculated with PANCO2 cells orthotopically. METHODOLOGY/PRINCIPAL FINDINGS: We found that diclofenac tre...

The monoaminergic pathways and inhibition of monoamine transporters interfere with the antidepressive-like behavior of ketamine

Directory of Open Access Journals (Sweden)

Glauce Socorro de Barros Viana

2018-06-01

Full Text Available Ketamine (KET, a NMDA receptor antagonist, has been studied for its rapid and efficacious antidepressant effect, even for the treatment-resistant depression. Although depression is a major cause of disability worldwide, the treatment can be feasible, affordable and cost-effective, decreasing the population health burden. We evaluated the antidepressive-like effects of KET and its actions on monoamine contents (DA and its metabolites, as well as 5-HT and on tyrosine hydroxylase (TH. In addition DAT and SERT (DA and 5-HT transporters, respectively were also assessed. Male Swiss mice were divided into Control and KET-treated groups. The animals were acutely treated with KET (2, 5 or 10 mg/kg, i.p. and subjected to the forced swimming test, for evaluation of the antidepressive-like behavior. Imipramine and fluoxetine were used as references. The results showed that KET decreased dose-dependently the immobility time and shortly after the test, the animals were euthanized for striatal dissections and monoamine determinations. In addition, the brain (striata, hippocampi and prefrontal cortices was immunohistochemically processed for TH, DAT and SERT. KET at its higher dose increased DA and its metabolites (DOPAC and HVA and mainly 5-HT contents, in mice striata, effects associated with increases in TH and decreases in DAT immunoreactivities. Furthermore, reductions in SERT immunoreactivities were observed in the striatum and hippocampus. The results indicate that KET antidepressive-like effect probably involves, among other factors, monoaminergic pathways, as suggested by the increased striatal TH immunoreactivity and reduced brain DA (DAT and 5-HT (SERT transporters. Keywords: Ketamine, Antidepressive effect, Dopaminergic neurotransmission, Serotonergic neurotransmission, Monoamine transporters

Oridonin inhibits tumor growth and metastasis through anti-angiogenesis by blocking the Notch signaling.

Directory of Open Access Journals (Sweden)

Yanmin Dong

Full Text Available While significant progress has been made in understanding the anti-inflammatory and anti-proliferative effects of the natural diterpenoid component Oridonin on tumor cells, little is known about its effect on tumor angiogenesis or metastasis and on the underlying molecular mechanisms. In this study, Oridonin significantly suppressed human umbilical vascular endothelial cells (HUVECs proliferation, migration, and apillary-like structure formation in vitro. Using aortic ring assay and mouse corneal angiogenesis model, we found that Oridonin inhibited angiogenesis ex vivo and in vivo. In our animal experiments, Oridonin impeded tumor growth and metastasis. Immunohistochemistry analysis further revealed that the expression of CD31 and vWF protein in xenografts was remarkably decreased by the Oridonin. Furthermore, Oridonin reinforced endothelial cell-cell junction and impaired breast cancer cell transendothelial migration. Mechanistically, Oridonin not only down-regulated Jagged2 expression and Notch1 activity but also decreased the expression of their target genes. In conclusion, our results demonstrated an original role of Oridonin in inhibiting tumor angiogenesis and propose a mechanism. This study also provides new evidence supporting the central role of Notch in tumor angiogenesis and suggests that Oridonin could be a potential drug candidate for angiogenesis related diseases.

Experimental assessment of the role of the blood flow inhibition in hyperglycemia-enhanced radiation injury to tumor

International Nuclear Information System (INIS)

Kozin, S.V.; Sevast'yanov, A.I.; Yarmonenko, S.P.

1986-01-01

Experimental assessment of the role of the blood flow inhibition in enhancement of radiation injury to tumors using short-term hyperglycemia was provided. Experiments on mice with Ehrlich solid carcinoma showed the dependence of a rise of the antitumor effect of preceding radiation induced by glucose and glucose combined with mexamin on a degree of the blood flow inhibition under the influence of these modifying agents. It was established that a considerable enhancement of radiation injury occured but in such tumors where short-term hyperglycemia and mexamin decreased the blood flow level not less than 5-10 fold as estimated by 133 Xe clearance. The results of the above experiments showed that the noticeable inhibition of the blood flow in tumors was a necessary tough, probably, not the only condition for a high efficacy of short-term hyperglycemia used an ajuvant to radiotherapy

SAMHD1 is down regulated in lung cancer by methylation and inhibits tumor cell proliferation

International Nuclear Information System (INIS)

Wang, Jia-lei; Lu, Fan-zhen; Shen, Xiao-Yong; Wu, Yun; Zhao, Li-ting

2014-01-01

Highlights: • SAMHD1 expression level is down regulated in lung adenocarcinoma. • The promoter of SAMHD1 is methylated in lung adenocarcinoma. • Over expression of SAMHD1 inhibits the proliferation of lung cancer cells. - Abstract: The function of dNTP hydrolase SAMHD1 as a viral restriction factor to inhibit the replication of several viruses in human immune cells was well established. However, its regulation and function in lung cancer have been elusive. Here, we report that SAMHD1 is down regulated both on protein and mRNA levels in lung adenocarcinoma compared to adjacent normal tissue. We also found that SAMHD1 promoter is highly methylated in lung adenocarcinoma, which may inhibit its gene expression. Furthermore, over expression of the SAMHD1 reduces dNTP level and inhibits the proliferation of lung tumor cells. These results reveal the regulation and function of SAMHD1 in lung cancer, which is important for the proliferation of lung tumor cells

Validating the pivotal role of the immune system in low-dose radiation-induced tumor inhibition in Lewis lung cancer-bearing mice.

Science.gov (United States)

Zhou, Lei; Zhang, Xiaoying; Li, Hui; Niu, Chao; Yu, Dehai; Yang, Guozi; Liang, Xinyue; Wen, Xue; Li, Min; Cui, Jiuwei

2018-04-01

Although low-dose radiation (LDR) possesses the two distinct functions of inducing hormesis and adaptive responses, which result in immune enhancement and tumor inhibition, its clinical applications have not yet been elucidated. The major obstacle that hinders the application of LDR in the clinical setting is that the mechanisms underlying induction of tumor inhibition are unclear, and the risks associated with LDR are still unknown. Thus, to overcome this obstacle and elucidate the mechanisms mediating the antitumor effects of LDR, in this study, we established an in vivo lung cancer model to investigate the participation of the immune system in LDR-induced tumor inhibition and validated the pivotal role of the immune system by impairing immunity with high-dose radiation (HDR) of 1 Gy. Additionally, the LDR-induced adaptive response of the immune system was also observed by sequential HDR treatment in this mouse model. We found that LDR-activated T cells and natural killer cells and increased the cytotoxicity of splenocytes and the infiltration of T cells in the tumor tissues. In contrast, when immune function was impaired by HDR pretreatment, LDR could not induce tumor inhibition. However, when LDR was administered before HDR, the immunity could be protected from impairment, and tumor growth could be inhibited to some extent, indicating the induction of the immune adaptive response by LDR. Therefore, we demonstrated that immune enhancement played a key role in LDR-induced tumor inhibition. These findings emphasized the importance of the immune response in tumor radiotherapy and may help promote the application of LDR as a novel approach in clinical practice. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Demonstration of analgesic effect of intranasal ketamine and intranasal fentanyl for postoperative pain after pediatric tonsillectomy.

Science.gov (United States)

Yenigun, Alper; Yilmaz, Sinan; Dogan, Remzi; Goktas, Seda Sezen; Calim, Muhittin; Ozturan, Orhan

2018-01-01

Tonsillectomy is one of the oldest and most commonly performed surgical procedure in otolaryngology. Postoperative pain management is still an unsolved problem. In this study, our aim is to demonstrate the efficacy of intranasal ketamine and intranasal fentanyl for postoperative pain relief after tonsillectomy in children. This randomized-controlled study was conducted to evaluate the effects of intranasal ketamine and intranasal fentanyl in children undergoing tonsillectomy. Tonsillectomy performed in 63 children were randomized into three groups. Group I received: Intravenous paracetamol (10 mg/kg), Group II received intranasal ketamine (1.5 mg/kg ketamine), Group III received intranasal fentanyl (1.5 mcg/kg). The Children's Hospital of Eastern Ontario Pain Scale (CHEOPS) and Wilson sedation scale scores were recorded at 15, 30, 60 min, 2 h, 6hr, 12 h and 24 h postoperatively. Patients were interviewed on the day after surgery to assess the postoperative pain, nightmares, hallucinations, nausea, vomiting and bleeding. Intranasal ketamine and intranasal fentanyl provided significantly stronger analgesic affects compared to intravenous paracetamol administration at postoperative 15, 30, 60 min and at 2, 6, 12 and 24 h in CHEOPS (p ketamine administration group. No such sedative effect was seen in the groups that received intranasal fentanyl and intravenous paracetamol in Wilson Sedation Scale (p ketamine and intranasal fentanyl were more effective than paracetamol for postoperative analgesia after pediatric tonsillectomy. Sedative effects were observed in three patients with the group of intranasal ketamine. There was no significant difference in the efficacy of IN Ketamine and IN Fentanyl for post-tonsillectomy pain. Copyright © 2017 Elsevier B.V. All rights reserved.

Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine.

Science.gov (United States)

Ide, Soichiro; Ikekubo, Yuiko; Mishina, Masayoshi; Hashimoto, Kenji; Ikeda, Kazutaka

2017-11-01

We investigated the rapid and sustained antidepressant effects of enantiomers of ketamine in N-methyl-d-aspartate (NMDA) receptor GluN2D subunit knockout (GluN2D-KO) mice. Intraperitoneal administration of ketamine or its enantiomers 10 min before the tail-suspension test exerted significant antidepressant effects on restraint stress-induced depression in both wildtype and GluN2D-KO mice. The antidepressant effects of (RS)-ketamine and (S)-ketamine were sustained 96 h after the injection in both wildtype and GluN2D-KO mice, but such sustained antidepressant effects of (R)-ketamine were only observed in wildtype mice. These data suggest that the GluN2D subunit is critical for the sustained antidepressant effects of (R)-ketamine. Copyright © 2017 The Authors. Production and hosting by Elsevier B.V. All rights reserved.

Ketamine displaces the novel NMDA receptor SPET probe [{sup 123}I]CNS-1261 in humans in vivo

Energy Technology Data Exchange (ETDEWEB)

Stone, James M. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom)]. E-mail: j.stone@iop.kcl.ac.uk; Erlandsson, Kjell [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Arstad, Erik [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Bressan, Rodrigo A. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Squassante, Lisa [GlaxoSmithKline (GSK), Verona 37135 (Italy); Teneggi, Vincenza [GlaxoSmithKline (GSK), Verona 37135 (Italy); Ell, Peter J. [Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom); Pilowsky, Lyn S. [Institute of Psychiatry, King' s College London, De Crespigny Park London, SE5 8AF (United Kingdom); Institute of Nuclear Medicine, University College London, London, W1N 8AA (United Kingdom)

2006-02-15

[{sup 123}I]CNS-1261 [N-(1-naphthyl)-N'-(3-iodophenyl)-N-methylguanidine] is a high-affinity SPET ligand with selectivity for the intrachannel PCP/ketamine/MK-801 site of the N-methyl-D-aspartate (NMDA) receptor. This study evaluated the effects of ketamine (a specific competitor for the intrachannel PCP/ketamine/MK-801 site) on [{sup 123}I]CNS-1261 binding to NMDA receptors in vivo. Ten healthy volunteers underwent 2 bolus-plus-infusion [{sup 123}I]CNS-1261 scans, one during placebo and the other during a ketamine challenge. Ketamine administration led to a significant decrease in [{sup 123}I]CNS-1261 V {sub T} in most of the brain regions examined (P<.05). [{sup 123}I]CNS-1261 appears to be a specific ligand in vivo for the intrachannel PCP/ketamine/MK-801 NMDA binding site.

Adverse Events With Ketamine Versus Ketofol for Procedural Sedation on Adults: A Double-blind, Randomized Controlled Trial.

Science.gov (United States)

Lemoel, Fabien; Contenti, Julie; Giolito, Didier; Boiffier, Mathieu; Rapp, Jocelyn; Istria, Jacques; Fournier, Marc; Ageron, François-Xavier; Levraut, Jacques

2017-12-01

The goal of our study was to compare the frequency and severity of recovery reactions between ketamine and ketamine-propofol 1:1 admixture ("ketofol"). We performed a multicentric, randomized, double-blind trial in which adult patients received emergency procedural sedations with ketamine or ketofol. Our primary outcome was the proportion of unpleasant recovery reactions. Other outcomes were frequency of interventions required by these recovery reactions, rates of respiratory or hemodynamic events, emesis, and satisfaction of patients as well as providers. A total of 152 patients completed the study, 76 in each arm. Compared with ketamine, ketofol determined a 22% reduction in recovery reactions incidence (p ketamine. We found a significant reduction in recovery reactions and emesis frequencies among adult patients receiving emergency procedural sedations with ketofol, compared with ketamine. © 2017 by the Society for Academic Emergency Medicine.

Splenectomy inhibits non-small cell lung cancer growth by modulating anti-tumor adaptive and innate immune response

Science.gov (United States)

Levy, Liran; Mishalian, Inbal; Bayuch, Rachel; Zolotarov, Lida; Michaeli, Janna; Fridlender, Zvi G

2015-01-01

It has been shown that inhibitors of the immune system reside in the spleen and inhibit the endogenous antitumor effects of the immune system. We hypothesized that splenectomy would inhibit the growth of relatively large non-small lung cancer (NSCLC) tumors by modulating the systemic inhibition of the immune system, and in particular Myeloid Derived Suppressor Cells (MDSC). The effect of splenectomy was evaluated in several murine lung cancer models. We found that splenectomy reduces tumor growth and the development of lung metastases, but only in advanced tumors. In immune-deficient NOD-SCID mice the effect of splenectomy on tumor growth and metastatic spread disappeared. Splenectomy significantly reduced the presence of MDSC, and especially monocytic-MDSC in the circulation and inside the tumor. Specific reduction of the CCR2+ subset of monocytic MDSC was demonstrated, and the importance of the CCL2-CCR2 axis was further shown by a marked reduction in CCL2 following splenectomy. These changes were followed by changes in the macrophages contents of the tumors to become more antitumorigenic, and by increased activation of CD8+ Cytotoxic T-cells (CTL). By MDSC depletion, and adoptive transfer of MDSCs, we demonstrated that the effect of splenectomy on tumor growth was substantially mediated by MDSC cells. We conclude that the spleen is an important contributor to tumor growth and metastases, and that splenectomy can blunt this effect by depletion of MDSC, changing the amount and characteristics of myeloid cells and enhancing activation of CTL. PMID:26137413

Ketamine-associated lower urinary tract destruction: a new radiological challenge

Energy Technology Data Exchange (ETDEWEB)

Mason, K., E-mail: k.mason@doctors.org.u [Bristol Royal Infirmary, Bristol (United Kingdom); Cottrell, A.M. [North Bristol NHS Trust, Bristol (United Kingdom); Corrigan, A.G. [Bristol Royal Infirmary, Bristol (United Kingdom); Gillatt, D.A.; Mitchelmore, A.E. [North Bristol NHS Trust, Bristol (United Kingdom)

2010-10-15

Aim: Ketamine is a short-acting dissociative anaesthetic whose hallucinogenic side effects have led to an increase in its illicit use amongst club and party goers. There is a general misconception amongst users that it is a safe drug with few long term side effects, however ketamine abuse is associated with severe urinary tract dysfunction. Presenting symptoms include urinary frequency, nocturia, dysuria, haematuria and incontinence. Materials and methods: We describe the radiological findings found in a series of 23 patients, all with a history of ketamine abuse, who presented with severe lower urinary tract symptoms (LUTS). Imaging techniques used included ultrasonography (US), intravenous urography (IVU), and computed tomography (CT). These examinations were reviewed to identify common imaging findings. All patients with positive imaging findings had also undergone cystoscopy and bladder wall biopsies, which confirmed the diagnosis. The patients in this series have consented to the use of their data in the ongoing research into ketamine-induced bladder pathology. Results: Ultrasound demonstrated small bladder volume and wall thickening. CT revealed marked, generalized bladder wall thickening, mucosal enhancement, and perivesical inflammation. Ureteric wall thickening and enhancement were also observed. In advanced cases ureteric narrowing and strictures were identified using both CT and IVU. Correlation of clinical history, radiological and pathological findings was performed to confirm the diagnosis. Conclusion: This case series illustrates the harmful effects of ketamine on the urinary tract and the associated radiological findings. Delayed diagnosis can result in irreversible renal tract damage requiring surgical intervention. It is important that radiologists are aware of this emerging clinical entity as early diagnosis and treatment are essential for successful management.

The Risk of Upper Urinary Tract Involvement in Patients With Ketamine-Associated Uropathy

Directory of Open Access Journals (Sweden)

Chi-Hang Yee

2017-06-01

Full Text Available Purpose The aims of this study were to investigate the prevalence of upper tract involvement in ketamine-associated uropathy, and to determine the predictors of hydronephrosis in patients with a history of ketamine abuse. Methods This was a cross-sectional study of a prospective cohort of patients with ketamine-associated uropathy. Data including demographics, pattern of ketamine abuse, pelvic pain and urgency or frequency (PUF symptom score, uroflowmetry (UFM parameters, serum renal function, and liver function tests were collected. Upon consultation, ultrasonography was performed to assess the function of the urinary system. Results From December 2011 to October 2015, we treated 572 patients with ketamine-associated uropathy. Of these patients, 207 (36.2% had managed to achieve abstinence at the time of their first consultation. Ninety-six patients (16.8% in the cohort were found to have hydronephrosis on ultrasonography. Univariate analysis identified age, duration of ketamine abuse, PUF symptom score, voided volume on UFM, serum creatinine levels >100 μmol/L, and an abnormal serum liver enzyme profile as factors associated with hydronephrosis. Logistic regression revealed the following parameters to be statistically related to hydronephrosis: age (adjusted odds ratio [OR], 1.090; 95% confidence interval [CI], 1.020–1.166; P=0.012, functional bladder capacity (adjusted OR, 0.997; 95% CI, 0.995–0.999; P=0.029, serum creatinine >100 μmol/L (adjusted OR, 3.107; 95% CI, 1.238–7.794; P=0.016, and an abnormal serum liver enzyme profile (adjusted OR, 1.967; 95% CI, 1.213–3.187; P=0.006. Conclusions Ketamine-associated uropathy can involve the upper urinary tract. Patient demographics as well as investigations of UFM, renal function tests, and liver function tests may allow us to identify at-risk patients.

Effects of combined ketamine/xylazine anesthesia on light induced retinal degeneration in rats.

Directory of Open Access Journals (Sweden)

Blanca Arango-Gonzalez

Full Text Available OBJECTIVES: To explore the effect of ketamine-xylazine anesthesia on light-induced retinal degeneration in rats. METHODS: Rats were anesthetized with ketamine and xylazine (100 and 5 mg, respectively for 1 h, followed by a recovery phase of 2 h before exposure to 16,000 lux of environmental illumination for 2 h. Functional assessment by electroretinography (ERG and morphological assessment by in vivo imaging (optical coherence tomography, histology (hematoxylin/eosin staining, TUNEL assay and immunohistochemistry (GFAP and rhodopsin staining were performed at baseline (ERG, 36 h, 7 d and 14 d post-treatment. Non-anesthetized animals treated with light damage served as controls. RESULTS: Ketamine-xylazine pre-treatment preserved retinal function and protected against light-induced retinal degeneration. In vivo retinal imaging demonstrated a significant increase of outer nuclear layer (ONL thickness in the non-anesthetized group at 36 h (p0.05, indicating a stabilizing and/or protective effect with regard to phototoxicity. Histology confirmed light-induced photoreceptor cell death and Müller cells gliosis in non-anesthetized rats, especially in the superior hemiretina, while ketamine-xylazine treated rats showed reduced photoreceptor cell death (TUNEL staining: p<0.001 after 7 d, thicker ONL and longer IS/OS. Fourteen days after light damage, a reduction of standard flash induced a-wave amplitudes and a-wave slopes (p = 0.01 and significant alterations in parameters of the scotopic sensitivity function (e.g. Vmax of the Naka Rushton fit p = 0.03 were observed in non-treated vs. ketamine-xylazine treated animals. CONCLUSIONS: Our results suggest that pre-treatment with ketamine-xylazine anesthesia protects retinas against light damage, reducing photoreceptor cell death. These data support the notion that anesthesia with ketamine-xylazine provides neuroprotective effects in light-induced cell damage.

Comparison of pregabalin versus ketamine in postoperative pain management in breast cancer surgery

Directory of Open Access Journals (Sweden)

Essam Mahran

2015-01-01

Full Text Available Background: Breast surgery compromises one of the most common cancer surgeries in females and commonly followed by acute postoperative pain. Pregabalin and ketamine have been used in many previous studies and was found to have a good analgesic profile. We assumed that pregabalin and ketamine can be used in control of postoperative pain in female patients undergoing breast cancer surgery. Material and Methods: Ninety female patients scheduled for cancer breast surgery were allocated in three groups (30 patients each, control group (group c received preoperative placebo, pregabalin group (group p received oral 150 mg pregabalin 1 h before surgery, ketamine group (group k received intravenous (IV 0.5 mg/kg ketamine with induction of anesthesia followed by 0.25 mg/kg/h IV throughout the surgery. All patients received general anesthesia and after recovery, the three groups were assessed in the first postoperative 24 h for postoperative visual analog scale (VAS , total 24 h morphine consumption, incidence of postoperative nausea and vomiting (PONV, sedation score >2 and any complications from the drugs used in the study. Results: The use of pregabalin or ketamine was found to reduce total postoperative morphine consumption with P 2. Conclusion: The use of preoperative oral 150 mg pregabalin 1 h before surgery or IV 0.5 mg ketamine with induction of anesthesia can reduce postoperative opioid consumption in breast cancer surgery without change in sedation or PONV and with a good safety profile.

Analysis of print news media framing of ketamine treatment in the United States and Canada from 2000 to 2015.

Directory of Open Access Journals (Sweden)

Melvyn W B Zhang

Full Text Available There are multifaceted views on the use of ketamine, a potentially addictive substance, to treat mental health problems. The past 15 years have seen growing media coverage of ketamine for medical and other purposes. This study examined the print news media coverage of medical and other uses of ketamine in North America to determine orientations and trends over time.Print newspaper coverage of ketamine from 2000 to 2015 was reviewed, resulting in 43 print news articles from 28 North American newspapers. A 55-item structured coding instrument was applied to assess news reports of ketamine. Items captured negative and positive aspects, therapeutic use of ketamine, and adverse side effects. Chi-squares tested for changes in trends over time.In the 15-year reviewed period, the three most frequent themes related to ketamine were: abuse (68.2%, legal status (34.1%, and clinical use in anesthesia (31.8%. There was significant change in trends during two periods (2000-2007 and 2008-2015. In 2008-2015, print news media articles were significantly more likely to encourage clinical use of ketamine to treat depression (p = 0.002, to treat treatment resistant depression (p = 0.043, and to claim that ketamine is more effective than conventional antidepressants (p = 0.043.Our review found consistent positive changes in the portrayals of ketamine by the print news media as a therapeutic antidepressant that mirror the recent scientific publications. These changes in news media reporting might influence the popularity of ketamine use to treat clinical depression. Guidance is required for journalists on objective reporting of medical research findings, including limitations of current research evidence and potential risks of ketamine.

Analysis of print news media framing of ketamine treatment in the United States and Canada from 2000 to 2015.

Science.gov (United States)

Zhang, Melvyn W B; Hong, Ying X; Husain, Syeda F; Harris, Keith M; Ho, Roger C M

2017-01-01

There are multifaceted views on the use of ketamine, a potentially addictive substance, to treat mental health problems. The past 15 years have seen growing media coverage of ketamine for medical and other purposes. This study examined the print news media coverage of medical and other uses of ketamine in North America to determine orientations and trends over time. Print newspaper coverage of ketamine from 2000 to 2015 was reviewed, resulting in 43 print news articles from 28 North American newspapers. A 55-item structured coding instrument was applied to assess news reports of ketamine. Items captured negative and positive aspects, therapeutic use of ketamine, and adverse side effects. Chi-squares tested for changes in trends over time. In the 15-year reviewed period, the three most frequent themes related to ketamine were: abuse (68.2%), legal status (34.1%), and clinical use in anesthesia (31.8%). There was significant change in trends during two periods (2000-2007 and 2008-2015). In 2008-2015, print news media articles were significantly more likely to encourage clinical use of ketamine to treat depression (p = 0.002), to treat treatment resistant depression (p = 0.043), and to claim that ketamine is more effective than conventional antidepressants (p = 0.043). Our review found consistent positive changes in the portrayals of ketamine by the print news media as a therapeutic antidepressant that mirror the recent scientific publications. These changes in news media reporting might influence the popularity of ketamine use to treat clinical depression. Guidance is required for journalists on objective reporting of medical research findings, including limitations of current research evidence and potential risks of ketamine.

COMPARATIVE EFFICACY OF DETOMIDINE AND DETOMIDINE - KETAMINE COCKTAIL IN QUAILS

Directory of Open Access Journals (Sweden)

U. F. Durrani, M. Ashraf and A. Khalid¹

2005-10-01

Full Text Available Twenty adult healthy quails (Coturnix coturnix were divided into two equal groups. One group was administered detomidine (2.4 mg/kg, I/M and other group was administered detomidine-ketamine cocktail (1.2 mg/kg + 30 mg/kg, I/M. Detomidine slowly and smoothly induced a light sedation accompanied by superficial analgesia, hypoventilation, hypothermia and bradycardia in all birds. Detomidine-ketamine cocktail rapidly and smoothly induced a deep anaesthesia accompanied by deep analgesia, hypoventilation, hypothermia and bradycardia and complete loss of all reflexes in all birds. In both groups, recovery from sedation and anaesthesia was smooth and of short duration. From this study it was concluded that for minor and least painful procedures in quails detomidine can be used alone, while for major and painful surgical procedures detomidine-ketamine combination should be preferred.

Ketamine administration in depressive disorders: a systematic review and meta-analysis.

Science.gov (United States)

Fond, Guillaume; Loundou, Anderson; Rabu, Corentin; Macgregor, Alexandra; Lançon, Christophe; Brittner, Marie; Micoulaud-Franchi, Jean-Arthur; Richieri, Raphaelle; Courtet, Philippe; Abbar, Mocrane; Roger, Matthieu; Leboyer, Marion; Boyer, Laurent

2014-09-01

Ketamine's efficacy in depressive disorders has been established in several controlled trials. The aim of the present study was to determine whether or not ketamine administration significantly improves depressive symptomatology in depression and more specifically in major depressive disorder (MDD), bipolar depression, resistant depression (non-ECT studies), and as an anesthetic agent in electroconvulsive therapy (ECT) for resistant depression (ECT studies). Secondary outcomes were the duration of ketamine's effect, the efficacy on suicidal ideations, the existence of a dose effect, and the safety/tolerance of the treatment. Studies were included if they met the following criteria (without any language or date restriction): design: randomized controlled trials, intervention: ketamine administration, participants: diagnosis of depression, and evaluation of severity based on a validated scale. We calculated standardized mean differences (SMDs) with 95 % confidence intervals (CIs) for each study. We used fixed and random effects models. Heterogeneity was assessed using the I2 statistic. We included nine non-ECT studies in our quantitative analysis (192 patients with major depressive disorder and 34 patients with bipolar depression). Overall, depression scores were significantly decreased in the ketamine groups compared to those in the control groups (SMD = -0.99; 95 % CI -1.23, -0.75; p depression (SMD = -1.34; 95 % CI -1.94, -0.75), and in drug-free patients as well as patients under medication. Four ECT trials (118 patients) were included in our quantitative analysis. One hundred and three patients were diagnosed with major depressive disorder and 15 with bipolar depression. Overall, depression scores were significantly improved in the 58 patients receiving ketamine in ECT anesthesia induction compared to the 60 patients (SMD = -0.56; 95 % CI -1.10, -0.02; p = 0.04; I2 = 52.4 %). The duration of ketamine's effects was assessed in only two non

Characterization of Compounds with Tumor-Cell Proliferation Inhibition Activity from Mushroom (Phellinus baumii) Mycelia Produced by Solid-State Fermentation.

Science.gov (United States)

Zhang, Henan; Shao, Qian; Wang, Wenhan; Zhang, Jingsong; Zhang, Zhong; Liu, Yanfang; Yang, Yan

2017-04-27

The inhibition of tumor-cell proliferationbyan organicsolvent extract from the solid-state fermentation of Phellinus baumii mycelia inoculated in rice medium was investigated in vitro. The active compounds inhibiting tumor-cell proliferation were characterized. Results revealed that all (petroleum ether, chloroform, ethyl acetate, and butanol) fractions inhibited tumor-cell proliferation in a dose-dependent fashion. The ethyl acetate extract had the highest inhibitory effecton tumor-cell proliferation, and the butanol fraction had the lowest. Six compounds were isolated and purified from the ethyl acetate extract of P. baumii mycelia by the tandem application of silica-gel column chromatography (SGCC), high-speed countercurrent chromatography (HSCCC), and preparative HPLC. These compounds were identified by NMR and electrospray ionization-mass spectrometry (ESI-MS) spectroscopic methods as ergosterol (RF1), ergosta-7,22-dien-3β-yl pentadecanoate (RF3), 3,4-dihydroxy benzaldehyde(RF6), inoscavinA (RF7), baicalein(RF10), and 24-ethylcholesta-5,22-dien-3β-ol (RF13). To further clarify the activity of these compounds, the cell-proliferation-inhibition tests of these compounds on various tumor cells were carried out and evaluatedin vitro. Results suggested that compounds RF6, RF7, and RF10 had potent inhibition effects on the proliferation of a series of tumor cell lines, including K562, L1210, SW620, HepG2, LNCaP, and MCF-7cells. These findings indicated that P. baumii mycelia produced by solid-state fermentation in rice canbe used to obtain active compounds with the ability to inhibittumor-cell proliferation.

Murine macrophage heparanase: inhibition and comparison with metastatic tumor cells

International Nuclear Information System (INIS)

Savion, N.; Disatnik, M.H.; Nevo, Z.

1987-01-01

Circulating macrophages and metastatic tumor cells can penetrate the vascular endothelium and migrate from the circulatory system to extravascular compartments. Both activated murine macrophages and different metastatic tumor cells attach, invade, and penetrate confluent vascular endothelial cell monolayer in vitro, by degrading heparan sulfate proteoglycans in the subendothelial extracellular matrix. The sensitivity of the enzymes from the various sources degrading the heparan sulfate proteoglycan was challenged and compared by a series of inhibitors. Activated macrophages demonstrate a heparanase with an endoglycosidase activity that cleaves from the [ 35 S]O 4 - -labeled heparan sulfate proteoglycans of the extracellular matrix 10 kDa glycosaminoglycan fragments. The degradation of [ 35 S]O 4 - -labeled extracellular matrix proteoglycans by the macrophages' heparanase is significantly inhibited in the presence of heparan sulfate (10μg/ml), arteparon (10μg/ml), and heparin at a concentration of 3 μg/ml. Degradation of this heparan sulfate proteoglycan is a two-step sequential process involving protease activity followed by heparanase activity. B16-BL6 metastatic melanoma cell heparanase, which is also a cell-associated enzyme, was inhibited by heparin to the same extent as the macrophage haparanase. On the other hand, heparanase of the highly metastatic variant (ESb) of a methylcholanthrene-induced T lymphoma, which is an extracellular enzyme released by the cells to the incubation medium, was more sensitive to heparin and arteparon than the macrophages' heparanase. These results may indicate the potential use of heparin or other glycosaminoglycans as specific and differential inhibitors for the formation in certain cases of blood-borne tumor metastasis

Low-dose ketamine infusion for labor analgesia: A double-blind, randomized, placebo controlled clinical trial

Directory of Open Access Journals (Sweden)

Sam Joel

2014-01-01

Full Text Available Background: Most primary and secondary level hospitals in developing countries provide inadequate labor analgesia due to various medical, technical and economic reasons. This clinical trial was an effort to study the efficacy, safety and feasibility of intravenous (IV ketamine to provide labor analgesia. Materials and Methods: A total of 70 parturients were consented and randomly assigned to receive either IV ketamine or 0.9% saline. A loading dose of ketamine (0.2 mg/kg was followed-by an infusion (0.2 mg/kg/h until the delivery of the neonate. Similar volume of saline was infused in the placebo-group. Intramuscular meperidine was the rescue analgesic in both groups. The pain score, hemodynamic parameters of mother and fetus and the anticipated side-effects of ketamine were observed for. The newborn was assessed by the Neonatologist. Results: The pain score showed a decreasing trend in the ketamine group and after the 1 st h more than 60% of women in the ketamine group had pain relief, which was statistically significant. There was no significant clinical change in the maternal hemodynamics and fetal heart rate. However, 17 (48.5% of them had transient light headedness in the ketamine group. All the neonates were breast fed and the umbilical cord blood pH was between 7.1 and 7.2. The overall satisfaction was significantly high in the intervention group (P = 0.028. Conclusion: A low-dose ketamine infusion (loading dose of 0.2 mg/kg delivered over 30 min, followed-by an infusion at 0.2 mg/kg/h could provide acceptable analgesia during labor and delivery.

Ketamine as an Adjunct to Opioids for Acute Pain in the Emergency Department: A Randomized Controlled Trial.

Science.gov (United States)

Bowers, Karen J; McAllister, Kelly B; Ray, Meredith; Heitz, Corey

2017-06-01

This study had five objectives: 1) to measure and compare total opioid use and number of opioid doses in patients treated with opioids versus ketamine in conjunction with opioids; 2) to measure pain scores up to 2 hours after presentation in the ED patient with pain, comparing standard opioid pain control to ketamine in conjunction with opioids; 3) to compare patient satisfaction with pain control using opioids alone versus ketamine in conjunction with opioids; 4) to monitor and compare side effects in patients treated with opioids versus ketamine in conjunction with opioids; and 5) to identify effect variation between different subgroups of patients, with the purpose of focusing future research. We hypothesized that low-dose ketamine, compared to placebo, as an adjunctive treatment to opioids would result in better pain control over 2 hours and greater patient satisfaction with pain control; further, this protocol will result in a lower opioid dosage over 2 hours. This was a randomized, double-blinded, placebo-controlled trial at a single academic emergency department evaluating the use of ketamine versus placebo in conjunction with opioids for moderate to severe pain. Subjects with a continued high level of pain after an initial dose of opioid analgesia were randomized to receive either 0.1 mg/kg ketamine or placebo prior to protocol-based dosing of additional opioid analgesia, if required. Over 120 minutes, subjects were assessed for pain level (0-10), satisfaction with pain control (0-4), side effects, sedation level, and need for additional pain medication. Total opioid dose, including the initial dose, was compared between groups. Sixty-three subjects were randomized to the placebo group and 53 to the ketamine group. No significant differences were found in demographics between the groups. Patients receiving ketamine reported lower pain scores over 120 minutes than patients receiving placebo (p = 0.015). Total opioid dose was lower in the ketamine group

Ketamine as an Analgesic Adjuvant in Adult Trauma Intensive Care Unit Patients With Rib Fracture.

Science.gov (United States)

Walters, Mary K; Farhat, Joseph; Bischoff, James; Foss, Mary; Evans, Cory

2018-03-01

Rib fracture associated pain is difficult to control. There are no published studies that use ketamine as a therapeutic modality to reduce the amount of opioid to control rib fracture pain. To examine the analgesic effects of adjuvant ketamine on pain scale scores in trauma intensive care unit (ICU) rib fracture. This retrospective, case-control cohort chart review evaluated ICU adult patients with a diagnosis of ≥1 rib fracture and an Injury Severity Score >15 during 2016. Patients received standard-of-care pain management with the physician's choice analgesics with or without ketamine as a continuous, fixed, intravenous infusion at 0.1 mg/kg/h. A total of 15 ketamine treatment patients were matched with 15 control standard-of-care patients. Efficacy was measured via Numeric Pain Scale (NPS)/Behavioral Pain Scale (BPS) scores, opioid use, and ICU and hospital length of stay. Safety of ketamine was measured by changes in vital signs, adverse effects, and mortality. Average NPS/BPS, severest NPS/BPS, and opioid use were lower in the ketamine group than in controls (NPS: 4.1 vs 5.8, P rib fracture.

COMPARATIVE EFFICACY OF DETOMIDINE AND DETOMIDINE - KETAMINE COCKTAIL IN QUAILS

OpenAIRE

U. F. Durrani, M. Ashraf and A. Khalid¹

2005-01-01

Twenty adult healthy quails (Coturnix coturnix) were divided into two equal groups. One group was administered detomidine (2.4 mg/kg, I/M) and other group was administered detomidine-ketamine cocktail (1.2 mg/kg + 30 mg/kg, I/M). Detomidine slowly and smoothly induced a light sedation accompanied by superficial analgesia, hypoventilation, hypothermia and bradycardia in all birds. Detomidine-ketamine cocktail rapidly and smoothly induced a deep anaesthesia accompanied by deep analgesia, hypove...

Ketamine infusion was effective for severe pain of Non-Hodgkin lymphoma

Directory of Open Access Journals (Sweden)

Tomoki Nishiyama

2017-10-01

Full Text Available A 52 years old man with a Non-Hodgkin lymphoma had severe pain at right buttock and lower leg. Sustained-release tablet of morphine 90 mg/day, intravenous morphine 40 mg/day, granisetron 9 mg/day, metoclopramide 30 mg/day, domperidone suppository 60 mg/day, intravenous hydroxyzine 25 mg/day, and haloperidol 20 mg/day did not decrease pain and side effects. Intravenous ketamine 10 mg in 15 min was quite effective for analgesia. Then infusion of ketamine started with 7 mg/h and increased to 10 mg/h with morphine 20 mg/day, which could control pain well with no side effects until his death. Keywords: Ketamine, Morphine, Cancer pain, Terminal

Anestesi Infus Gravimetrik Ketamin dan Propofol pada Anjing (THE GRAVIMETRIC INFUSION ANAESTHESIA WITH KETAMINE AND PROPOFOL IN DOGS

Directory of Open Access Journals (Sweden)

I Gusti Ngurah Sudisma

2014-08-01

Full Text Available This study aim was to evaluate quality of anaesthesia by using gravimetric infusion anaesthesia withketamine and propofol in dogs. The quality of anaesthesia, duration of actions, and the physiological responsseof anaesthesia were evaluated in twenty domestic dogs. Anaesthesia was induced intramuscularly withatropine (0.03 mg/kg-xylazine (2 mg/kg (AX, intravenously ketamine-propofol (KP (4 mg/kg, andmaintained with continuous intravenous infusion with pre-mixed propofol (P and normal saline containing2 mg/ml of propofol and 2 mg/ml of ketamine (K. Domestic stray dogs were randomly divided into fivegroups. Groups AXKP-K2P2, AXKP-K4P4, and AXKP-K6P6 were treated with ketamine-propofol the dose0.2 mg/kg/minute, 0.4 and 0.6 mg/kg/minute respectively, while group AXKP-P4 was given propofol 0.4 mg/kg/minute and group AXKP-I was given isoflurane 1-2%. Heart rate (HR, respiratory rate (RR,electrocardiogram (ECG, blood oxygen saturation (SpO2, end tidal CO2 (ET CO2, and capillary refill time(CRT were measured. No significant difference (P>0.05 found between the groups in anaesthetion times.All groups showed rapid and smooth inductions, prolonged surgical stage, and rapid recovery. Groups AXKPK2P2and AXKP-K4P4 showed minimal physiological effect on the dogs. The HR, RR, ET CO2, SpO2, CRT,and ECG wave were stabl. Combination of AXKP-K6P6 induced SpO2 depression, increased and instabilityof HR, RR and ET CO2. Groups AXKP-P4 showed decreased of HR and respiratory depression. All anaestheticcombinations showed no significant influence (P>0.05 on the electricity of the dog’s heart. The combinationof ketamine-propofol at dose 0.2 and 0.4 mg/kg/minute were found to be better as an application formaintaining anaesthesia by gravimetric continuous intravenous infusion. The method is a suitablealternative for inhalation anaesthesia in dogs.

Ketamine Use for Successful Resolution of Post-ERCP Acute Pancreatitis Abdominal Pain

Directory of Open Access Journals (Sweden)

Suneel M. Agerwala

2017-01-01

Full Text Available We report a case in which a patient with intractable pain secondary to post-endoscopic retrograde cholangiopancreatography (ERCP acute pancreatitis is successfully treated with a subanesthetic ketamine infusion. Shortly after ERCP, the patient reported severe stabbing epigastric pain. She exhibited voluntary guarding and tenderness without distension. Amylase and lipase levels were elevated. Pain persisted for hours despite hydromorphone PCA, hydromorphone boluses, fentanyl boluses, and postprocedure anxiolytics. Pain management was consulted and a ketamine infusion was trialed, leading to a dramatic reduction in pain. This case suggests that ketamine may be a promising option in treating intractable pain associated with ERCP acute pancreatitis.

Molecular mechanisms involved in the inhibition of tumor cells proliferation exposed to elevated concentrations of the epidermal growth factor

International Nuclear Information System (INIS)

Guillen, Isabel A; Berlanga, Jorge; Camacho, Hanlet

2013-01-01

The EGF promotes inhibition of cell proliferation in vitro and in vivo models depending on its concentration, application schema and the type of tumor cells on which it acts. Our research hypothesis was based on the fact that the EGF varies the expression of genes involved in a negative regulation of tumor cell lines proliferation carrying high levels of its receptor (EGFR). Our objectives were, to obtain information about the effect of EGF on tumor cell proliferation in vitro and in vivo models and, know the gene expression patterns of a group of genes involved in cancer signaling pathways and EGFR. The results showed that EGF at nanomolar concentrations inhibits the tumor cells proliferation bearing high levels of EGFR and, promotes the survival of treated animals, establishing a direct relationship between the inhibition of cell proliferation, high concentrations of EGF and, high amount of EGFR in the cells. The differential gene expression profile showed a variation in a group of genes which exert a powerful control over the cell cycle progression, gene transcription and apoptosis. It was concluded that the inhibition of tumor cell proliferation by the action of EGF is due to activation of molecular mechanisms controlling cell cycle progression. This work won the Annual Award of the Cuban Academy of Sciences in 2012

Electroporation driven delivery of both an IL-12 expressing plasmid and cisplatin synergizes to inhibit B16 melanoma tumor growth through an NK cell mediated tumor killing mechanism.

Science.gov (United States)

Kim, Ha; Sin, Jeong-Im

2012-11-01

Combined therapy using chemotherapeutic drugs and immunotherapeutics offers some promise for treating patients with cancer. In this study, we evaluated whether cisplatin delivered by intratumoral (IT)-electroporation (EP) might enhance antitumor activity against established B16 melanoma and whether further addition of intramuscular (IM)-EP of IL-12 cDNA to IT-EP of cisplatin might augment antitumor therapeutic activity, with a focus on the underlining antitumor mechanism(s). When tumor (7 mm)-bearing animals were treated locally with cisplatin by IT-EP, they showed tumor growth inhibition significantly more than those without IT-EP. Moreover, IL-12 cDNA delivered by IM-EP was also able to inhibit tumor growth significantly more than control vector delivery. This tumor growth inhibition was mediated by NK cells, but not CD4+ T or CD8+ T cells, as determined by immune cell subset depletion and IFN-γ induction. Moreover, concurrent therapy using IT-EP of cisplatin plus IM-EP of IL-12 cDNA displayed antitumor therapeutic synergy. This therapeutic synergy appeared to be mediated by increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. Taken together, these data support that cisplatin delivery by IT-EP plus IL-12 gene delivery by IM-EP are more effective at inducing antitumor therapeutic responses through increased sensitivity of cisplatin-treated tumors to NK cell-mediated tumor killing. This combined approach might have some implication for treating melanoma in patients.

Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma.

Science.gov (United States)

Mazzocca, Antonio; Fransvea, Emilia; Dituri, Francesco; Lupo, Luigi; Antonaci, Salvatore; Giannelli, Gianluigi

2010-02-01

Tumor-stroma interactions in hepatocellular carcinoma (HCC) are of key importance to tumor progression. In this study, we show that HCC invasive cells produce high levels of connective tissue growth factor (CTGF) and generate tumors with a high stromal component in a xenograft model. A transforming growth factor beta (TGF-beta) receptor inhibitor, LY2109761, inhibited the synthesis and release of CTGF, as well as reducing the stromal component of the tumors. In addition, the TGF-beta-dependent down-regulation of CTGF diminished tumor growth, intravasation, and metastatic dissemination of HCC cells by inhibiting cancer-associated fibroblast proliferation. By contrast, noninvasive HCC cells were found to produce low levels of CTGF. Upon TGF-beta1 stimulation, noninvasive HCC cells form tumors with a high stromal content and CTGF expression, which is inhibited by treatment with LY2109761. In addition, the acquired intravasation and metastatic spread of noninvasive HCC cells after TGF-beta1 stimulation was blocked by LY2109761. LY2109761 interrupts the cross-talk between cancer cells and cancer-associated fibroblasts, leading to a significant reduction of HCC growth and dissemination. Interestingly, patients with high CTGF expression had poor prognosis, suggesting that treatment aimed at reducing TGF-beta-dependent CTGF expression may offer clinical benefits. Taken together, our preclinical results indicate that LY2109761 targets the cross-talk between HCC and the stroma and provide a rationale for future clinical trials.

Preliminary analysis of positive and negative syndrome scale in ketamine-associated psychosis in comparison with schizophrenia.

Science.gov (United States)

Xu, Ke; Krystal, John H; Ning, Yuping; Chen, Da Chun; He, Hongbo; Wang, Daping; Ke, Xiaoyin; Zhang, Xifan; Ding, Yi; Liu, Yuping; Gueorguieva, Ralitza; Wang, Zuoheng; Limoncelli, Diana; Pietrzak, Robert H; Petrakis, Ismene L; Zhang, Xiangyang; Fan, Ni

2015-02-01

Studies of the effects of the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, ketamine, have suggested similarities to the symptoms of schizophrenia. Our primary goal was to evaluate the dimensions of the Positive and Negative Syndrome Scale (PANSS) in ketamine users (acute and chronic) compared to schizophrenia patients (early and chronic stages). We conducted exploratory factor analysis for the PANSS from four groups: 135 healthy subject administrated ketamine or saline, 187 inpatients of ketamine abuse; 154 inpatients of early course schizophrenia and 522 inpatients of chronic schizophrenia. Principal component factor analyses were conducted to identify the factor structure of the PANSS. Factor analysis yielded five factors for each group: positive, negative, cognitive, depressed, excitement or dissociation symptoms. The symptom dimensions in two schizophrenia groups were consistent with the established five-factor model (Wallwork et al., 2012). The factor structures across four groups were similar, with 19 of 30 symptoms loading on the same factor in at least 3 of 4 groups. The factors in the chronic ketamine group were more similar to the factors in the two schizophrenia groups rather than to the factors in the acute ketamine group. Symptom severities were significantly different across the groups (Kruskal-Wallis χ(2)(4) = 540.6, p Symptoms in the two ketamine groups were milder than in the two schizophrenia groups (Cohen's d = 0.7). Our results provide the evidence of similarity in symptom dimensions between ketamine psychosis and schizophrenia psychosis. The interpretations should be cautious because of potential confounding factors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Safety-efficacy balance of S-ketamine and S-norketamine in acute and chronic pain

OpenAIRE

Noppers, Ingeborg Marieke

2011-01-01

The balance between safety and efficacy is important in pharmacotherapy. When the indication of a registered drug shifts to another disease or a different patient population, studies on safety and efficacy need to be performed. Ketamine is a relatively ‘old’ drug and used for almost 50 years as an anesthetic. Recently there has been a renewed interest for the treatment of therapy-resistant chronic pain with subanesthetic doses of ketamine. This thesis describes the effects of S-ketamine in pa...

Human Sulfatase 2 inhibits in vivo tumor growth of MDA-MB-231 human breast cancer xenografts

International Nuclear Information System (INIS)

Peterson, Sarah M; Concino, Michael F; Liaw, Lucy; Martini, Paolo GV; Iskenderian, Andrea; Cook, Lynette; Romashko, Alla; Tobin, Kristen; Jones, Michael; Norton, Angela; Gómez-Yafal, Alicia; Heartlein, Michael W

2010-01-01

Extracellular human sulfatases modulate growth factor signaling by alteration of the heparin/heparan sulfate proteoglycan (HSPG) 6-O-sulfation state. HSPGs bind to numerous growth factor ligands including fibroblast growth factors (FGF), epidermal growth factors (EGF), and vascular endothelial growth factors (VEGF), and are critically important in the context of cancer cell growth, invasion, and metastasis. We hypothesized that sulfatase activity in the tumor microenvironment would regulate tumor growth in vivo. We established a model of stable expression of sulfatases in the human breast cancer cell line MDA-MB-231 and purified recombinant human Sulfatase 2 (rhSulf2) for exogenous administration. In vitro studies were performed to measure effects on breast cancer cell invasion and proliferation, and groups were statistically compared using Student's t-test. The effects of hSulf2 on tumor progression were tested using in vivo xenografts with two methods. First, MDA-MB-231 cells stably expressing hSulf1, hSulf2, or both hSulf1/hSulf2 were grown as xenografts and the resulting tumor growth and vascularization was compared to controls. Secondly, wild type MDA-MB-231 xenografts were treated by short-term intratumoral injection with rhSulf2 or vehicle during tumor growth. Ultrasound analysis was also used to complement caliper measurement to monitor tumor growth. In vivo studies were statistically analyzed using Student's t test. In vitro, stable expression of hSulf2 or administration of rhSulf2 in breast cancer cells decreased cell proliferation and invasion, corresponding to an inhibition of ERK activation. Stable expression of the sulfatases in xenografts significantly suppressed tumor growth, with complete regression of tumors expressing both hSulf1 and hSulf2 and significantly smaller tumor volumes in groups expressing hSulf1 or hSulf2 compared to control xenografts. Despite significant suppression of tumor volume, sulfatases did not affect vascular

Comparison of the preventive analgesic effect of rectal ketamine and rectal acetaminophen after pediatric tonsillectomy

Directory of Open Access Journals (Sweden)

S Morteza Heidari

2012-01-01

Full Text Available Objectives: There is a little data about rectal administration of Ketamine as a postoperative analgesic, so we compared the efficacy of rectal ketamine with rectal acetaminophen, which is applied routinely for analgesia after painful surgeries like tonsillectomy. Methods: In this single-blinded comparative trial, we enrolled 70 children undergoing elective tonsillectomy, and divided them randomly in two groups. Patients received rectal ketamine (2 mg / kg or rectal acetaminophen (20 mg / kg at the end of surgery. The children′s Hospital of Eastern Ontario Pain scale was used to estimate pain in children. Also the vital signs, Wilson sedation scale, and side effects in each group were noted and compared for 24 hours. Results: The ketamine group had a lower pain score at 15 minutes and 60 minutes after surgery in Recovery (6.4 ± 0.8, 7.4 ± 1 vs. 7.1 ± 1.2, 7.8 ± 1.2 in the acetaminophen group, P < 0.05 and one hour and two hours in the ward (7.2 ± 0.7, 7 ± 0.5 vs. 7.9 ± 1.2, 7.5 ± 1.2 in the acetaminophen group, P < 0.05, with no significant differences till 24 hours. Dreams and hallucinations were not reported in the ketamine group. Systolic blood pressure was seen to be higher in the ketamine group (104.4 ± 7.9 vs. 99.8 ± 7.7 in the acetaminophen group and nystagmus was reported only in the ketamine group (14.2%. Other side effects were equivalent in both the groups. Conclusions: With low complications, rectal ketamine has analgesic effects, especially in the first hours after surgery in comparison with acetaminophen, and it can be an alternative analgesic with easy administration in children after tonsillectomy.

S-ketamine influences strategic allocation of attention but not exogenous capture of attention.

Science.gov (United States)

Fuchs, Isabella; Ansorge, Ulrich; Huber-Huber, Christoph; Höflich, Anna; Lanzenberger, Rupert

2015-09-01

We investigated whether s-ketamine differentially affects strategic allocation of attention. In Experiment 1, (1) a less visible cue was weakly masked by the onsets of competing placeholders or (2) a better visible cue was not masked because it was presented in isolation. Both types of cue appeared more often opposite of the target (75%) than at target position (25%). With this setup, we tested for strategic attention shifts to the opposite side of the cues and for exogenous attentional capture toward the cue's side in a short cue-target interval, as well as for (reverse) cueing effects in a long cue-target interval after s-ketamine and after placebo treatment in a double-blind within-participant design. We found reduced strategic attention shifts after cues presented without placeholders for the s-ketamine compared to the placebo treatment in the short interval, indicating an early effect on the strategic allocation of attention. No differences between the two treatments were found for exogenous attentional capture by less visible cues, suggesting that s-ketamine does not affect exogenous attentional capture in the presence of competing distractors. Experiment 2 confirmed that the competing onsets of the placeholders prevented the strategic cueing effect. Taken together, the results indicate that s-ketamine affects strategic attentional capture, but not exogenous attentional capture. The findings point to a more prominent role of s-ketamine during top-down controlled forms of attention that require suppression of automatic capture than during automatic capture itself. Copyright © 2015 Elsevier Inc. All rights reserved.

A Case Report: Subanesthetic Ketamine Infusion for Treatment of Cancer-Related Pain Produces Urinary Urge Incontinence.

Science.gov (United States)

Vickers, Barbara A; Lee, Wayne; Hunsberger, Joann

2017-05-01

Oncology patients undergoing treatment can experience substantial pain related to their disease or prescribed therapy. Ketamine infusions at subanesthetic doses have been used at our institution to supplement the pain management regimens of 262 patients. We present 2 cases in which young adult patients being treated with subanesthetic ketamine for cancer-related pain experienced urinary urgency and incontinence after initiation or increase of the ketamine infusion. This adverse effect has not been reported previously at this dosing range. These case reports suggest that subanesthetic ketamine infusions may cause side effects that previously have been reported only at anesthetic or abuse doses.

Wogonin inhibits tumor angiogenesis via degradation of HIF-1α protein

International Nuclear Information System (INIS)

Song, Xiuming; Yao, Jing; Wang, Fei; Zhou, Mi; Zhou, Yuxin; Wang, Hu; Wei, Libin; Zhao, Li; Li, Zhiyu; Lu, Na; Guo, Qinglong

2013-01-01

Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found that wogonin decreased the expression of HIF-1α by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1α by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel–Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1α. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1α and promoted its degradation in proteasome. We also found that wogonin could inhibit nuclear translocation of HIF-1α. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1α in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1α directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1α and provided a new insight into the mechanisms of wogonin against cancers. - Highlights: • Wogonin is an all around inhibitor of VEGF signaling. • We firstly demonstrate that wogonin inhibits secretion of VEGF by decreasing HIF-1α. • Wogonin enhances PDH and VHL expression and inhibits Hsp90 function. �

Wogonin inhibits tumor angiogenesis via degradation of HIF-1α protein

Energy Technology Data Exchange (ETDEWEB)

Song, Xiuming; Yao, Jing; Wang, Fei; Zhou, Mi; Zhou, Yuxin; Wang, Hu; Wei, Libin; Zhao, Li; Li, Zhiyu; Lu, Na, E-mail: luna555@163.com; Guo, Qinglong, E-mail: anticancer_drug@yahoo.com.cn

2013-09-01

Wogonin, a plant-derived flavone, has been shown recently to have antitumor effects. However, the mechanisms that wogonin inhibits tumor angiogenesis are not well known. In this study, we investigated the effects of wogonin on expression of hypoxia-inducible factor-1α (HIF-1α) and secretion of vascular endothelial growth factor (VEGF) in tumor cells. We found that wogonin decreased the expression of HIF-1α by affecting its stability and reduced the secretion of VEGF, which suppressed angiogenesis in cancer. Wogonin promoted the degradation of HIF-1α by increasing its prolyl hydroxylation, which depended on prolyl hydroxylase (PHD) and the von Hippel–Lindau tumor suppressor (VHL). Intriguingly, wogonin impeded the binding between heat-shock protein 90 (Hsp90) and HIF-1α. In addition, wogonin down-regulated the Hsp90 client proteins EGFR, Cdk4 and survivin, but did not affect the level of Hsp90. Wogonin also increased ubiquitination of HIF-1α and promoted its degradation in proteasome. We also found that wogonin could inhibit nuclear translocation of HIF-1α. Electrophoresis mobility shift assay (EMSA) showed that wogonin decreased the binding activity of exogenous consensus DNA oligonucleotide with HIF-1α in nuclear extracts from MCF-7 cells. Chromatin immunoprecipitation (ChIP) assay also revealed that HIF-1α directly binded to endogenous hypoxia-responsive element (HRE) and this binding was significantly decreased in MCF-7 cells treated with wogonin. Preliminary results indicated in vivo activity of wogonin against xenograft-induced angiogenesis in nude mice. Taken together, the results suggested that wogonin was a potent inhibitor of HIF-1α and provided a new insight into the mechanisms of wogonin against cancers. - Highlights: • Wogonin is an all around inhibitor of VEGF signaling. • We firstly demonstrate that wogonin inhibits secretion of VEGF by decreasing HIF-1α. • Wogonin enhances PDH and VHL expression and inhibits Hsp90 function. �

Biochemical Effects of Xylazine, Propofol, and Ketamine in West African Dwarf Goats

Directory of Open Access Journals (Sweden)

Ukwueze Celestine Okwudili

2014-01-01

Full Text Available Anaesthesia was induced in West African Dwarf (WAD goats using different combinations of propofol (P, xylazine (X, and ketamine (K, and the biochemical effect of the drugs determined. Twenty male (WAD goats were randomly assigned to five treatment groups viz. Control (C (2.5 mL IV normal saline; group K + X (5 mg/kg IV ketamine + 0.05 mg/kg IV xylazine, group P + X (5 mg/kg IV propofol + 0.05 mg/kg IV xylazine, group P + K (propofol 5 mg/kg IV + ketamine 5 mg/kg IV, and group P + K + X (propofol 2.5 mg/kg IV + ketamine 2.5 mg/kg IV + xylazine 0.05 mg/kg IV, respectively. There was increase (P0.05 in serum creatinine. These biochemical changes were transient. P + K + X would be the best drug combinations considering the biochemical parameter measured. However, data on blood glucose, ALT, BUN, and cortisol levels in an anaesthsized goat should be interpreted with caution in order to avoid erroneous interpretation in these animals.

Effect of ketamine dose on self-rated dissociation in patients with treatment refractory anxiety disorders.

Science.gov (United States)

Castle, Cameron; Gray, Andrew; Neehoff, Shona; Glue, Paul

2017-10-01

Patients receiving ketamine for refractory depression and anxiety report dissociative symptoms in the first 60 min post-dose. The most commonly used instrument to assess this is the Clinician-Administered Dissociative States Scale (CADSS), developed based on the assessment of patients with dissociative symptoms. Its psychometric properties for ketamine-induced dissociation have not been reported. We evaluated these from a study using 0.25-1 mg/kg ketamine and midazolam (as an active control) in 18 patients with treatment-resistant anxiety. Dissociation ratings were increased by ketamine in a dose-dependent manner. In contrast, midazolam showed no effect on ratings of dissociation. For individual CADSS items, the magnitude of change and the ketamine dose at which changes were observed were not homogenous. The Cronbach alpha for the total scale was high (0.937), with acceptable item-rest correlations for almost all individual items. Purposefully removing items to maximise alpha did not lead to meaningful improvements. Acceptable internal consistency was still observed after removing items which lacked evidence of responsiveness at lower doses. The high Cronbach alpha values identified in this study suggests that the CADSS is an internally consistent instrument for evaluating ketamine-induced dissociation in clinical trials in anxiety, although it does not capture symptoms such as thought disorder.

Chronic inhibition of tumor cell-derived VEGF enhances the malignant phenotype of colorectal cancer cells

International Nuclear Information System (INIS)

Yamagishi, Naoko; Teshima-Kondo, Shigetada; Masuda, Kiyoshi; Nishida, Kensei; Kuwano, Yuki; Dang, Duyen T; Dang, Long H; Nikawa, Takeshi; Rokutan, Kazuhito

2013-01-01

Vascular endothelial growth factor-a (VEGF)-targeted therapies have become an important treatment for a number of human malignancies. The VEGF inhibitors are actually effective in several types of cancers, however, the benefits are transiently, and the vast majority of patients who initially respond to the therapies will develop resistance. One of possible mechanisms for the acquired resistance may be the direct effect(s) of VEGF inhibitors on tumor cells expressing VEGF receptors (VEGFR). Thus, we investigated here the direct effect of chronic VEGF inhibition on phenotype changes in human colorectal cancer (CRC) cells. To chronically inhibit cancer cell-derived VEGF, human CRC cell lines (HCT116 and RKO) were chronically exposed (2 months) to an anti-VEGF monoclonal antibody (mAb) or were disrupted the Vegf gene (VEGF-KO). Effects of VEGF family members were blocked by treatment with a VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI). Hypoxia-induced apoptosis under VEGF inhibited conditions was measured by TUNEL assay. Spheroid formation ability was assessed using a 3-D spheroid cell culture system. Chronic inhibition of secreted/extracellular VEGF by an anti-VEGF mAb redundantly increased VEGF family member (PlGF, VEGFR1 and VEGFR2), induced a resistance to hypoxia-induced apoptosis, and increased spheroid formation ability. This apoptotic resistance was partially abrogated by a VEGFR-TKI, which blocked the compensate pathway consisted of VEGF family members, or by knockdown of Vegf mRNA, which inhibited intracellular function(s) of all Vegf gene products. Interestingly, chronic and complete depletion of all Vegf gene products by Vegf gene knockout further augmented these phenotypes in the compensate pathway-independent manner. These accelerated phenotypes were significantly suppressed by knockdown of hypoxia-inducible factor-1α that was up-regulated in the VEGF-KO cell lines. Our findings suggest that chronic inhibition of tumor cell-derived VEGF

Combination of Vorinostat and caspase-8 inhibition exhibits high anti-tumoral activity on endometrial cancer cells.

Science.gov (United States)

Bergadà, Laura; Sorolla, Annabel; Yeramian, Andree; Eritja, Nuria; Mirantes, Cristina; Matias-Guiu, Xavier; Dolcet, Xavier

2013-08-01

Histone deacetylase inhibitors such as Vorinostat display anti-neoplastic activity against a variety of solid tumors. Here, we have investigated the anti-tumoral activity of Vorinostat on endometrial cancer cells. We have found that Vorinostat caused cell growth arrest, loss of clonogenic growth and apoptosis of endometrial cancer cells. Vorinostat-induced the activation of caspase-8 and -9, the initiators caspases of the extrinsic and the intrinsic apoptotic pathways, respectively. Next, we investigated the role of the extrinsic pathway in apoptosis triggered by Vorinostat. We found that Vorinostat caused a dramatic decrease of FLIP mRNA and protein levels. However, overexpression of the long from of FLIP did not block Vorinostat-induced apoptosis. To further investigate the role of extrinsic apoptotic pathway in Vorinostat-induced apoptosis, we performed an shRNA-mediated knock-down of caspase-8. Surprisingly, downregulation of caspase-8 alone caused a marked decrease in clonogenic ability and reduced the growth of endometrial cancer xenografts in vivo, revealing that targeting caspase-8 may be an attractive target for anticancer therapy on endometrial tumors. Furthermore, combination of caspase-8 inhibition and Vorinostat treatment caused an enhancement of apoptotic cell death and a further decrease of clonogenic growth of endometrial cancer cells. More importantly, combination of Vorinostat and caspase-8 inhibition caused a nearly complete inhibition of tumor xenograft growth. Finally, we demonstrate that cell death triggered by Vorinostat alone or in combination with caspase-8 shRNAs was inhibited by the anti-apoptotic protein Bcl-XL. Our results suggest that combinatory therapies using Vorinostat treatment and caspase-8 inhibition can be an effective treatment for endometrial carcinomas. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Pilot Randomized Controlled Trial of Titrated Subcutaneous Ketamine in Older Patients with Treatment-Resistant Depression.

Science.gov (United States)

George, Duncan; Gálvez, Verònica; Martin, Donel; Kumar, Divya; Leyden, John; Hadzi-Pavlovic, Dusan; Harper, Simon; Brodaty, Henry; Glue, Paul; Taylor, Rohan; Mitchell, Philip B; Loo, Colleen K

2017-11-01

To assess the efficacy and safety of subcutaneous ketamine for geriatric treatment-resistant depression. Secondary aims were to examine if repeated treatments were safe and more effective in inducing or prolonging remission than a single treatment. In this double-blind, controlled, multiple-crossover study with a 6-month follow-up (randomized controlled trial [RCT] phase), 16 participants (≥60 years) with treatment-resistant depression who relapsed after remission or did not remit in the RCT were administered an open-label phase. Up to five subcutaneous doses of ketamine (0.1, 0.2, 0.3, 0.4, and 0.5 mg/kg) were administered in separate sessions (≥1 week apart), with one active control (midazolam) randomly inserted (RCT phase). Twelve ketamine treatments were given in the open-label phase. Mood, hemodynamic, and psychotomimetic outcomes were assessed by blinded raters. Remitters in each phase were followed for 6 months. Seven of 14 RCT-phase completers remitted with ketamine treatment. Five remitted at doses below 0.5 mg/kg. Doses ≥ 0.2 mg/kg were significantly more effective than midazolam. Ketamine was well tolerated. Repeated treatments resulted in higher likelihood of remission or longer time to relapse. Results provide preliminary evidence for the efficacy and safety of ketamine in treating elderly depressed. Dose titration is recommended for optimizing antidepressant and safety outcomes on an individual basis. Subcutaneous injection is a practical method for giving ketamine. Repeated treatments may improve remission rates (clinicaltrials.gov; NCT01441505). Copyright © 2017 American Association for Geriatric Psychiatry. All rights reserved.

Improved methods for thermal rearrangement of alicyclic α-hydroxyimines to α-aminoketones: synthesis of ketamine analogues as antisepsis candidates.

Science.gov (United States)

Elhawi, Hagit; Eini, Hadar; Douvdevani, Amos; Byk, Gerardo

2012-06-04

Ketamine is an analgesic/anesthetic drug, which, in combination with other drugs, has been used as anesthetic for over 40 years. Ketamine induces its analgesic activities by blocking the N-methyl-D-aspartate (NMDA) receptor in the central nervous system (CNS). We have reported that low doses of ketamine administrated to patients before incision significantly reduced post-operative inflammation as reflected by reduced interleukin-6 (IL-6) sera-levels. Our data demonstrated in a rat model of Gram-negative bacterial-sepsis that if we inject a low dose of ketamine following bacterial inoculation we reduce mortality from approximately 75% to 25%. Similar to what we have observed in operated patients, the levels of TNF-α and IL-6 in ketamine-treated rats were significantly lower than in septic animals not treated with ketamine. On the base of these results, we have designed and synthesized series of new analogues of ketamine applying a thermal rearrangement of alicyclic α-hydroxyimines to a-aminoketones in parallel arrays. One of the analogues (compound 6e) displayed high activity in down-regulating the levels of IL-6 and TNF-α in vivo as compared to ketamine.

Long-Term Intravenous Ketamine for Analgesia in a Child with Severe Chronic Intestinal Graft versus Host Disease

Directory of Open Access Journals (Sweden)

Jennifer Busse

2015-01-01

Full Text Available Ketamine is reported to be an effective adjuvant to opioids in the treatment of refractory cancer pain; however, the use of high doses of ketamine for extended periods in pediatric patients has not been described. We present a five-year-old male with grade IV intestinal GVHD whose abdominal pain required both hydromorphone and ketamine for a period of over four months. There was no evidence of hepatotoxicity, hemorrhagic cystitis, or other adverse effects. Possible withdrawal symptoms were mild and were readily mitigated by gradually weaning ketamine.

Development of a checklist of short-term and long-term psychological symptoms associated with ketamine use.

Science.gov (United States)

Fan, Ni; Xu, Ke; Ning, Yuping; Wang, Daping; Ke, Xiaoyin; Ding, Yi; Sun, Bin; Zhou, Chao; Deng, Xuefeng; Rosenheck, Robert; He, Hongbo

2015-06-25

Ketamine is an increasingly popular drug of abuse in China but there is currently no method for classifying the psychological effects of ketamine in individuals with ketamine dependence. Develop a scale that characterizes the acute and long-term psychological effects of ketamine use among persons with ketamine dependence. We developed a preliminary symptom checklist with 35 dichotomous ('yes' or 'no') items about subjective feelings immediately after ketamine use and about perceived long-term effects of ketamine use that was administered to 187 inpatients with ketamine dependence recruited from two large hospitals in Guangzhou, China. Exploratory factor analysis (EFA) was conducted on a randomly selected half of thesample to reduce the items and to identify underlying constructs. Confirmatory factor analysis (CFA) was conducted on the second half of the sample to assess the robustness of the identified factor structure. Among the 35 symptoms, the most-reported acute effects were 'floating or circling' (94%), 'euphoric when listening to rousing music' (86%), and 'feeling excited, talkative, and full of energy' (67%). The mostreported long-term symptoms were 'memory impairment' (93%), 'personality changes' (86%), and 'slowed reactions' (81%). EFA resulted in a final 22-item scale best modelled by a four-factor model: two factors representing chronic symptoms (social withdrawal and sleep disturbances), one about acute psychoticlike symptoms, and one that combined acute drug-related euphoria and longer-term decreased libido. CFA showed that these 4 factors accounted for 50% of the total variance of the final 22-item scale and that the model fit was fair (Goodness of Fit Index, GIF=83.3%; Root Mean Square Error of Approximation, RMSEA=0.072). A four-factor model including social withdrawal, sleep disturbance, psychotic-like symptoms, and euphoria at the time of drug use provides a fair description of the short-term and long-term psychological symptoms associated with

Anorectal manometry with and without ketamine for evaluation of defecation disorders in children.

Science.gov (United States)

Keshtgar, A S; Choudhry, M S; Kufeji, D; Ward, H C; Clayden, G S

2015-03-01

Anorectal manometry (ARCM) provides valuable information in children with chronic constipation and fecal incontinence but may not be tolerated in the awake child. This study aimed to evaluate the effect of ketamine anesthesia on the assessment of anorectal function by manometry and to evaluate defecation dynamics and anal sphincter resting pressure in the context of pathophysiology of chronic functional (idiopathic) constipation and soiling in children. This was a prospective study of children who were investigated for symptoms of chronic constipation and soiling between April 2001 and April 2004. We studied 52 consecutive children who had awake ARCM, biofeedback training and endosonography (awake group) and 64 children who had ketamine anesthesia for ARCM and endosonography (ketamine group). We age matched 31 children who had awake anorectal studies with 27 who had ketamine anesthesia. The children in awake and ketamine groups were comparable for age, duration of bowel symptoms and duration of laxative treatments. ARCM profile was comparable between the awake and the ketamine groups with regard to anal sphincter resting pressure, rectal capacity, amplitude of rectal contractions, frequency of rectal and IAS contractions and functional length of anal canal. Of 52 children who had awake ARCM, dyssynergia of the EAS muscles was observed in 22 (42%) and median squeeze pressure was 87mm Hg (range 25-134). The anal sphincter resting pressure was non-obstructive and comparable to healthy normal children. Rectoanal inhibitory reflex was seen in all children excluding diagnosis of Hirschsprung disease. Ketamine anesthesia does not affect quantitative or qualitative measurements of autonomic anorectal function and can be used reliably in children who will not tolerate the manometry while awake. Paradoxical contraction of the EAS can only be evaluated in the awake children and should be investigated further as the underlying cause of obstructive defecation in patients with

The use of sub-anesthetic intravenous ketamine and adjuvant dexmedetomidine when treating acute pain from CRPS.

Science.gov (United States)

Nama, Sharanya; Meenan, Daniel R; Fritz, William T

2010-01-01

Complex regional pain syndrome (CRPS) is a pain condition of the extremities that presents with pain and allodynia, decreased range of motion, swelling and skin changes. There are 2 forms of CRPS - Type I which does not have demonstrable nerve lesions and Type 2, which has evidence of obvious nerve damage. Management of refractory CRPS has been challenging. Some studies have revealed that the N-methyl-D-aspartic acid receptor (NMDAR) may be involved in the etiology of the pain in CRPS and perhaps that a NMDA receptor antagonist like ketamine is a potential treatment for CRPS. However, the side effect profile of ketamine is concerning, and limiting the adverse effects of the drug is beneficial. Dexmedetomidine is an alpha 2 agonist similar to clonidine with analgesic properties that can be used in combination with ketamine to provide additional analgesia in CRPS. This case describes the treatment of acute pain symptoms from Chronic Regional Pain Syndrome-Type 1 (CRPS-1) with sub-anesthetic intravenous infusion of ketamine with adjunct dexmedetomidine. A 47-year-old female patient presented with severe pain, burning and allodynia from CRPS-1 refractory to conventional therapy. She was then admitted to a monitored bed, received a sub-anesthetic intravenous infusion of ketamine with adjunct dexmedetomidine for 19 hours and subsequently discharged with complete resolution of her pain and associated symptoms. Here, the synergistic effect of the ketamine and dexmedetomidine together is shown to provide excellent symptom relief while decreasing the total ketamine administered. The combination minimized unwanted side effects and eliminated the need for intensive care unit admission secondary to anesthetic doses of ketamine.

An effective dose of ketamine for eliminating pain during injection of propofol: a dose response study.

Science.gov (United States)

Wang, M; Wang, Q; Yu, Y Y; Wang, W S

2013-09-01

Ketamine can completely eliminate pain associated with propofol injection. However, the effective dose of ketamine to eliminate propofol injection pain has not been determined. The purpose of this study was to determine the effective dose of ketamine needed to eliminate pain in 50% and 95% of patients (ED50 and ED95, respectively) during propofol injections. This study was conducted in a double-blinded fashion and included 50 patients scheduled for elective gynecological laparoscopy under general anesthesia. The initial dose of ketamine used in the first patient was 0.25mg/kg. The dosing modifications were in increments or decrements of 0.025 mg/kg. Ketamine was administered 15 seconds before injecting propofol (2.5mg/kg), which was injected at a rate of 1mL/s. Patients were asked to rate their pain during propofol injection every 5s econds using a 0-3 pain scale. The highest pain score was recorded. The ED50, ED95 and 95% confidence intervals (CI) were determined by probit analyses. The dose of ketamine ranged from 0.175 to 0.275 mg/kg. The ED50 and ED95 of ketamine for eliminating pain during propofol injection were 0.227 mg/kg and 0.283 mg/kg, respectively (95%CI: 0.211-0.243 mg/kg and 0.26-0.364 mg/kg, respectively). Ketamine at an approximate dose of 0.3mg/kg was effective in eliminating pain during propofol injection. Copyright © 2013 Société française d’anesthésie et de réanimation (Sfar). Published by Elsevier SAS. All rights reserved.

A systematic review and meta-analysis of ketamine for the prevention of persistent post-surgical pain.

Science.gov (United States)

McNicol, E D; Schumann, R; Haroutounian, S

2014-11-01

While post-operative pain routinely resolves, persistent post-surgical pain (PPSP) is common in certain surgeries; it causes disability, lowers quality of life and has economic consequences. The objectives of this systematic review and meta-analysis were to evaluate the effectiveness of ketamine in reducing the prevalence and severity of PPSP and to assess safety associated with its use. We searched the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE through December 2012 for articles in any language. We included randomized, controlled trials in adults in which ketamine was administered perioperatively via any route. Seventeen studies, the majority of which administered ketamine intravenously, met all inclusion criteria. The overall risk of developing PPSP was not significantly reduced at any time point in the ketamine group vs. placebo, nor did comparisons of pain severity scores reach statistical significance. Sensitivity analysis of exclusively intravenous ketamine studies included in this meta-analysis demonstrated statistically significant reductions in risk of developing PPSP at 3 and 6 months (P = 0.01 and P = 0.04, respectively). Adverse event rates were similar between ketamine and placebo groups. The study data from our review are heterogeneous and demonstrate efficacy of intravenously administered ketamine only in comparison with placebo. Highly variable timing and dosing of ketamine in these studies suggest that no unifying effective regimen has emerged. Future research should focus on clinically relevant outcomes, should stratify patients with pre-existing pain and possible central sensitization and should enroll sufficiently large numbers to account for loss to follow-up in long-term studies. © 2014 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Comparison of efficacy of prophylactic ketamine and dexmedetomidine on postoperative bladder catheter-related discomfort

Directory of Open Access Journals (Sweden)

Başak Akça

2016-01-01

Full Text Available Objectives: To compare the effects of prophylactic ketamine and dexmedetomidine on postoperative bladder catheter-related discomfort/pain in patients undergoing cystoscopy. Methods: This prospective study was conducted on 75 American Society of Anesthesiologists (ASA I-II patients between 18-75 years of age and undergoing cystoscopy between November 2011 and June 2012 at Hacettepe University Hospital, Ankara, Turkey. Patients were randomly assigned to one of the 3 groups to receive 1 μ/kg dexmedetomidine, 250 μ/kg intravenous ketamine, or normal saline. All patients were questioned regarding probe-related discomfort, patient satisfaction, and pain at the end of the operation 0 (t0 and 15 (t1, 60 (t2, 120 (t3, and 360 (t4 minutes postoperatively. Evaluations were performed in person at the post-anesthesia care unit, or in ambulatory surgery rooms, or by phone calls. Results: Pain incidence in the dexmedetomidine and ketamine groups (p=0.042 was significantly lower than that in the control group (p=0.044.The sedation scores recorded at t0 in the dexmedetomidine and ketamine groups (p=0.004 were significantly higher than that of the control group (p=0.017. Patient groups were similar regarding the rate of hallucinations experienced at t1, no patients experienced hallucinations at t2, t3, or t4. Significantly more patients experienced hallucinations at t0 in the ketamine group than in the dexmedetomidine group (p=0.034 and the control group (p=0.005. Conclusion: Dexmedetomidine and ketamine had similar analgesic effects in preventing catheter-related pain; however, dexmedetomidine had a more acceptable side effect profile. To identify the optimal doses of dexmedetomidine and ketamine, more large-scale interventional studies are needed.

Performance on a probabilistic inference task in healthy subjects receiving ketamine compared with patients with schizophrenia

Science.gov (United States)

Almahdi, Basil; Sultan, Pervez; Sohanpal, Imrat; Brandner, Brigitta; Collier, Tracey; Shergill, Sukhi S; Cregg, Roman; Averbeck, Bruno B

2012-01-01

Evidence suggests that some aspects of schizophrenia can be induced in healthy volunteers through acute administration of the non-competitive NMDA-receptor antagonist, ketamine. In probabilistic inference tasks, patients with schizophrenia have been shown to ‘jump to conclusions’ (JTC) when asked to make a decision. We aimed to test whether healthy participants receiving ketamine would adopt a JTC response pattern resembling that of patients. The paradigmatic task used to investigate JTC has been the ‘urn’ task, where participants are shown a sequence of beads drawn from one of two ‘urns’, each containing coloured beads in different proportions. Participants make a decision when they think they know the urn from which beads are being drawn. We compared performance on the urn task between controls receiving acute ketamine or placebo with that of patients with schizophrenia and another group of controls matched to the patient group. Patients were shown to exhibit a JTC response pattern relative to their matched controls, whereas JTC was not evident in controls receiving ketamine relative to placebo. Ketamine does not appear to promote JTC in healthy controls, suggesting that ketamine does not affect probabilistic inferences. PMID:22389244

BRAF inhibition is associated with increased clonality in tumor-infiltrating lymphocytes

Science.gov (United States)

Cooper, Zachary A; Frederick, Dennie T; Juneja, Vikram R; Sullivan, Ryan J; Lawrence, Donald P; Piris, Adriano; Sharpe, Arlene H; Fisher, David E; Flaherty, Keith T; Wargo, Jennifer A

2013-01-01

There have been significant advances with regard to BRAF-targeted therapies against metastatic melanoma. However, the majority of patients receiving BRAF inhibitors (BRAFi) manifest disease progression within a year. We have recently shown that melanoma patients treated with BRAFi exhibit an increase in melanoma-associated antigens and in CD8+ tumor-infiltrating lymphocytes in response to therapy. To characterize such a T-cell infiltrate, we analyzed the complementarity-determining region 3 (CDR3) of rearranged T-cell receptor (TCR) β chain-coding genes in tumor biopsies obtained before the initiation of BRAFi and 10–14 d later. We observed an increase in the clonality of tumor-infiltrating lymphocytes in 7 of 8 patients receiving BRAFi, with a statistically significant 21% aggregate increase in clonality. Over 80% of individual T-cell clones detected after initiation of BRAFi treatment were new clones. Interestingly, the comparison of tumor infiltrates with clinical responses revealed that patients who had a high proportion of pre-existing dominant clones after the administration of BRAFi responded better to therapy than patients who had a low proportion of such pre-existing dominant clones following BRAFi. These data suggest that although the inhibition of BRAF in melanoma patients results in tumor infiltration by new lymphocytes, the response to treatment appears to be related to the presence of a pre-existing population of tumor-infiltrating T-cell clones. PMID:24251082

NMDA receptor antagonist ketamine impairs feature integration in visual perception.

Science.gov (United States)

Meuwese, Julia D I; van Loon, Anouk M; Scholte, H Steven; Lirk, Philipp B; Vulink, Nienke C C; Hollmann, Markus W; Lamme, Victor A F

2013-01-01

Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA) receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.

NMDA receptor antagonist ketamine impairs feature integration in visual perception.

Directory of Open Access Journals (Sweden)

Julia D I Meuwese

Full Text Available Recurrent interactions between neurons in the visual cortex are crucial for the integration of image elements into coherent objects, such as in figure-ground segregation of textured images. Blocking N-methyl-D-aspartate (NMDA receptors in monkeys can abolish neural signals related to figure-ground segregation and feature integration. However, it is unknown whether this also affects perceptual integration itself. Therefore, we tested whether ketamine, a non-competitive NMDA receptor antagonist, reduces feature integration in humans. We administered a subanesthetic dose of ketamine to healthy subjects who performed a texture discrimination task in a placebo-controlled double blind within-subject design. We found that ketamine significantly impaired performance on the texture discrimination task compared to the placebo condition, while performance on a control fixation task was much less impaired. This effect is not merely due to task difficulty or a difference in sedation levels. We are the first to show a behavioral effect on feature integration by manipulating the NMDA receptor in humans.

Memantine reverses social withdrawal induced by ketamine in rats.

Science.gov (United States)

Uribe, Ezequiel; Landaeta, José; Wix, Richard; Eblen, Antonio

2013-03-01

The objective of this study was to determine the effect of memantine on schizophrenia-like symptoms in a ketamine-induced social withdrawal model in rats. We examined therapeutic effects of memantine, an NMDA antagonist, and haloperidol, a classic antipsychotic drug, on this behavioral model. Administration of memantine (10 or 15 mg·kg(-1)) significantly reduced ketamine-induced social withdrawal, and this effect was more effective than that of haloperidol (0.25 mg·kg(-1)) by restoring the social interaction between rats with no modification in general motor activity. These results suggest that memantine could have a therapeutic potential for schizophrenia.

Lack of Antidepressant Effects of (2R,6R)-Hydroxynorketamine in a Rat Learned Helplessness Model: Comparison with (R)-Ketamine.

Science.gov (United States)

Shirayama, Yukihiko; Hashimoto, Kenji

2018-01-01

(R)-Ketamine exhibits rapid and sustained antidepressant effects in animal models of depression. It is stereoselectively metabolized to (R)-norketamine and subsequently to (2R,6R)-hydroxynorketamine in the liver. The metabolism of ketamine to hydroxynorketamine was recently demonstrated to be essential for ketamine's antidepressant actions. However, no study has compared the antidepressant effects of these 3 compounds in animal models of depression. The effects of a single i.p. injection of (R)-ketamine, (R)-norketamine, and (2R,6R)-hydroxynorketamine in a rat learned helplessness model were examined. A single dose of (R)-ketamine (20 mg/kg) showed an antidepressant effect in the rat learned helplessness model. In contrast, neither (R)-norketamine (20 mg/kg) nor (2R,6R)-hydroxynorketamine (20 and 40 mg/kg) did so. Unlike (R)-ketamine, its metabolite (2R,6R)-hydroxynorketamine did not show antidepressant actions in the rat learned helplessness model. Therefore, it is unlikely that the metabolism of ketamine to hydroxynorketamine is essential for ketamine's antidepressant actions. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Recombinant tumor necrosis factor alpha inhibits growth of methylcholanthrene-induced sarcoma and enhances natural killer activity of tumor-infiltrating lymphocytes in aging rats

International Nuclear Information System (INIS)

Ziolkowska, Maria; Nowak Joanna, J.; Janiak, Marek; Ryzewska, Alicja

1994-01-01

The effect of recombinant human tumor necrosis factors alpha (rHuTNF-α) on the growth of immunogenic, methylcholanthrene-induced sarcoma (MC-Sa) and natural killer (NK) cell activity of tumor-infiltrating lymphocytes (TIL) in adult and aging rats was investigated. In both groups of animals the growth of transplantable MC-Sa was markedly and similarly inhibited by multiple intratumoral (i.t.) injections of rHuTF-α. This effect was accompanied by stimulation of NK activity of tumor-infiltrating lymphocytes in adult as well as in aging rats. Studies ''in vitro'' demonstrated additionally that rHuTNF-α was a potent stimulator of NK but not of ADCC (antibody-dependent cellular cytotoxicity) activity of spleen lymphocytes from healthy animals. Our results indicate that the antitumor effect of TNF-α is comparable in adult and in aging rats bearing immunogenic MC-Sa. The inhibition of MC-Sa growth may be attributed not only to the TNF-α-induced necrosis of the neoplastic tissue but also to the ''in vivo'' stimulatory effect of this cytokine upon the NK-type function of lymphocytes infiltrating the tumor mass. (author). 31 refs, 5 figs, 2 tabs

AMELIORATING TREATMENT-REFRACTORY DEPRESSION WITH INTRANASAL KETAMINE: POTENTIAL NMDA RECEPTOR ACTIONS IN THE PAIN CIRCUITRY REPRESENTING MENTAL ANGUISH

Science.gov (United States)

Opler, Lewis A.; Opler, Mark G.; Arnsten, Amy F.T.

2014-01-01

This paper reviews the anti-depressant actions of the N-methyl-D-aspartame glutamate receptor (NMDAR) antagonist, ketamine, and offers a potential neural mechanism for intranasal ketamine’s ultra-rapid actions based on the key role of NMDAR in the nonhuman primate prefrontal cortex (PFC). Although intravenous ketamine infusions can lift mood within hours, the current review describes how intranasal ketamine administration can have ultra-rapid antidepressant effects, beginning within minutes (5–40 minutes) and lasting hours, but with repeated treatments needed for sustained antidepressant actions. Research in rodents suggests that increased synaptogenesis in PFC may contribute to the prolonged benefit of ketamine administration, beginning hours after administration. However, these data cannot explain the relief that occurs within minutes of intranasal ketamine delivery. We hypothesize that the ultra-rapid effects of intranasal administration in humans may be due to ketamine blocking the NMDAR circuits that generate the emotional representations of pain (e.g. Brodmann Areas 24 and 25, insular cortex), cortical areas that can be overactive in depression and which sit above the nasal epithelium. In contrast, NMDAR blockade in the dorsolateral PFC following systemic administration of ketamine may contribute to cognitive deficits. This novel view may help to explain how intravenous ketamine can treat the symptoms of depression yet worsen the symptoms of schizophrenia. PMID:25619798

Subanesthetic ketamine infusions for the treatment of children and adolescents with chronic pain: a longitudinal study.

Science.gov (United States)

Sheehy, Kathy A; Muller, Elena A; Lippold, Caroline; Nouraie, Mehdi; Finkel, Julia C; Quezado, Zenaide M N

2015-12-01

Chronic pain is common in children and adolescents and is often associated with severe functional disability and mood disorders. The pharmacological treatment of chronic pain in children and adolescents can be challenging, ineffective, and is mostly based on expert opinions and consensus. Ketamine, an N-methyl-D-aspartate receptor antagonist, has been used as an adjuvant for treatment of adult chronic pain and has been shown, in some instances, to improve pain and decrease opioid-requirement. We examined the effects of subanesthetic ketamine infusions on pain intensity and opioid use in children and adolescents with chronic pain syndromes treated in an outpatient setting. Longitudinal cohort study of consecutive pediatric patients treated with subanesthetic ketamine infusions in a tertiary outpatient center. Outcome measurements included self-reported pain scores (numeric rating scale) and morphine-equivalent intake. Over a 15-month period, 63 children and adolescents (median age 15, interquartile range 12-17 years) with chronic pain received 277 ketamine infusions. Intravenous administration of subanesthetic doses of ketamine to children and adolescents on an outpatient basis was safe and not associated with psychotropic effects or hemodynamic perturbations. Overall, ketamine significantly reduced pain intensity (p pain reduction in patients with complex regional pain syndrome (CRPS) than in patients with other chronic pain syndromes (p = 0.029). Ketamine-associated reductions in pain scores were the largest in postural orthostatic tachycardia syndrome (POTS) and trauma patients and the smallest in patients with chronic headache (p = 0.007). In 37% of infusions, patients had a greater than 20 % reduction in pain score. Conversely, ketamine infusions did not change overall morphine-equivalent intake (p = 0.3). These data suggest that subanesthetic ketamine infusion is feasible in an outpatient setting and may benefit children and adolescents with chronic pain

Exosome derived from epigallocatechin gallate treated breast cancer cells suppresses tumor growth by inhibiting tumor-associated macrophage infiltration and M2 polarization

International Nuclear Information System (INIS)

Jang, Ji-Young; Lee, Jong-Kuen; Jeon, Yoon-Kyung; Kim, Chul-Woo

2013-01-01

Tumor-associated macrophages (TAM) play an important role in tumor microenvironment. Particularly, M2 macrophages contribute to tumor progression, depending on the expression of NF-κB. Tumor-derived exosomes can modulate tumor microenvironment by transferring miRNAs to immune cells. Epigallocatechin gallate (EGCG) has well known anti-tumor effects; however, no data are available on the influence of EGCG on communication with cancer cells and TAM. Murine breast cancer cell lines, 4T1, was used for in vivo and ex vivo studies. Exosome was extracted from EGCG-treated 4T1 cells, and the change of miRNAs was screened using microarray. Tumor cells or TAM isolated from murine tumor graft were incubated with exosomes derived from EGCG-treated and/or miR-16 inhibitor-transfected 4T1 cells. Chemokines for monocytes (CSF-1 and CCL-2), cytokines both with high (IL-6 and TGF-β) and low (TNF-α) expression in M2 macrophages, and molecules in NF-κB pathway (IKKα and Iκ-B) were evaluated by RT-qPCR or western blot. EGCG suppressed tumor growth in murine breast cancer model, which was associated with decreased TAM and M2 macrophage infiltration. Expression of chemokine for monocytes (CSF-1 and CCL-2) were low in tumor cells from EGCG-treated mice, and cytokines of TAM was skewed from M2- into M1-like phenotype by EGCG as evidenced by decreased IL-6 and TGF-β and increased TNF-α. Ex vivo incubation of isolated tumor cells with EGCG inhibited the CSF-1 and CCL-2 expression. Ex vivo incubation of TAM with exosomes from EGCG-treated 4T1 cells led to IKKα suppression and concomitant I-κB accumulation; increase of IL-6 and TGF-β; and, decrease of TNF-α. EGCG up-regulated miR-16 in 4T1 cells and in the exosomes. Treatment of tumor cells or TAM with exosomes derived from EGCG-treated and miR-16-knock-downed 4T1 cells restored the above effects on chemokines, cytokines, and NF-κB pathway elicited by EGCG-treated exosomes. Our data demonstrate that EGCG up-regulates miR-16 in

Ketamine is a potent antidepressant in two rodent models of depression

DEFF Research Database (Denmark)

Mathe, A.; Sousa, V.; Fischer, C. W.

2013-01-01

pathophysiological factor and converging evidence indicates that other systems, such as the glutamatergic are of paramount importance. Indeed, work at the Yale University, NIMH, and Icahn School of Medicine at Mount Sinai demonstrated the marked antidepressant effects of intravenously infused ketamine to treatment...... resistant patients diagnosed with major depressive disorder. In order to better understand the mechanisms of ketamine effects we decided to test it on animal models. Methods: All experiments were approved by the Karolinska Institutet's Committee for Animal Protection. Two rat models, bred at the Karolinska...... Institutet, the Flinders Sensitive Line (FSL) and their controls, the Flinders Resistant Line (FRL), and the SERT KO (homozygous, heterozygous, and the wild type rats) were used. Male animals were injected 10 mg ketamine/kg body weight or vehicle and the Open Field Test (OF) and Forced Swim Test (FST...

Long-term exposure to hypoxia inhibits tumor progression of lung cancer in rats and mice

International Nuclear Information System (INIS)

Yu, Lunyin; Hales, Charles A

2011-01-01

Hypoxia has been identified as a major negative factor for tumor progression in clinical observations and in animal studies. However, the precise role of hypoxia in tumor progression has not been fully explained. In this study, we extensively investigated the effect of long-term exposure to hypoxia on tumor progression in vivo. Rats bearing transplanted tumors consisting of A549 human lung cancer cells (lung cancer tumor) were exposed to hypoxia for different durations and different levels of oxygen. The tumor growth and metastasis were evaluated. We also treated A549 lung cancer cells (A549 cells) with chronic hypoxia and then implanted the hypoxia-pretreated cancer cells into mice. The effect of exposure to hypoxia on metastasis of Lewis lung carcinoma in mice was also investigated. We found that long-term exposure to hypoxia a) significantly inhibited lung cancer tumor growth in xenograft and orthotopic models in rats, b) significantly reduced lymphatic metastasis of the lung cancer in rats and decreased lung metastasis of Lewis lung carcinoma in mice, c) reduced lung cancer cell proliferation and cell cycle progression in vitro, d) decreased growth of the tumors from hypoxia-pretreated A549 cells, e) decreased Na + -K + ATPase α1 expression in hypoxic lung cancer tumors, and f) increased expression of hypoxia inducible factors (HIF1α and HIF2α) but decreased microvessel density in the lung cancer tumors. In contrast to lung cancer, the growth of tumor from HCT116 human colon cancer cells (colon cancer tumor) was a) significantly enhanced in the same hypoxia conditions, accompanied by b) no significant change in expression of Na + -K + ATPase α1, c) increased HIF1α expression (no HIF2α was detected) and d) increased microvessel density in the tumor tissues. This study demonstrated that long-term exposure to hypoxia repressed tumor progression of the lung cancer from A549 cells and that decreased expression of Na + -K + ATPase was involved in hypoxic

The role of ketamine in the treatment of chronic cancer pain

OpenAIRE

ZGAIA, ARMEANA OLIMPIA; IRIMIE, ALEXANDRU; SANDESC, DOREL; VLAD, CATALIN; LISENCU, COSMIN; ROGOBETE, ALEXANDRU; ACHIMAS-CADARIU, PATRICIU

2015-01-01

Background and aim Ketamine is a drug used for the induction and maintenance of general anesthesia, for the treatment of postoperative and posttraumatic acute pain, and more recently, for the reduction of postoperative opioid requirements. The main mechanism of action of ketamine is the antagonization of N-methyl-D-aspartate (NMDA) receptors that are associated with central sensitization. In the pathogenesis of chronic pain and particularly in neuropathic pain, an important role is played by ...

Shikonin Inhibits the Proliferation of Human Breast Cancer Cells by Reducing Tumor-Derived Exosomes

Directory of Open Access Journals (Sweden)

Yao Wei

2016-06-01

Full Text Available Shikonin is a naphthoquinone isolated from the traditional Chinese medicine Lithospermum. It has been used in the treatment of various tumors. However, the effects of shikonin on such diseases have not been fully elucidated. In the present study, we detected the exosome release of a breast cancer cell line (MCF-7 with shikonin treatment and found a positive relationship between the level of secreted exosomes and cell proliferation. We next analyzed miRNA profiles in MCF-7 cells and exosomes and found that some miRNAs are specifically sorted and abundant in exosomes. Knockdown of the most abundant miRNAs in exosomes and the MCF-7 proliferation assay showed that miR-128 in exosomes negatively regulates the level of Bax in MCF-7 recipient cells and inhibits cell proliferation. These results show that shikonin inhibits the proliferation of MCF-7 cells through reducing tumor-derived exosomal miR-128. The current study suggests that shikonin suppresses MCF-7 growth by the inhibition of exosome release.

Inhibition of c-Jun N-terminal kinase sensitizes tumor cells to flavonoid-induced apoptosis through down-regulation of JunD

International Nuclear Information System (INIS)

Kook, Sung-Ho; Son, Young-Ok; Jang, Yong-Suk; Lee, Kyung-Yeol; Lee, Seung-Ah; Kim, Beom-Soo; Lee, Hyun-Jeong; Lee, Jeong-Chae

2008-01-01

Reduction of susceptibility to apoptosis signals is a crucial step in carcinogenesis. Therefore, sensitization of tumor cells to apoptosis is a promising therapeutic strategy. c-Jun NH 2 -terminal kinase (JNK) has been implicated in stress-induced apoptosis. However, many studies also emphasize the role of JNK on cell survival, although its mechanisms are not completely understood. Previously, we found that inhibition of JNK activity promotes flavonoid-mediated apoptosis of human osteosarcoma cells. We thus determined whether inhibition of JNK sensitizes tumor cells to a bioflavonoid-induced apoptosis, and whether this effect of JNK is a general effect. As the results, quercetin and genistein as well as a flavonoid fraction induced apoptosis of tumor cells, which was further accelerated by specific JNK inhibitor, SP600125 or by small interfering RNA specific to JNK1/2. This effect was specific to types of cells because it was further apparent in tumorigenic cell lines. Inhibition of JNK by SP600125 also reduced flavonoid-stimulated nuclear induction of JunD which was known to have protective role in apoptosis, whereas JNK inhibition alone had little effect on apoptosis. The flavonoid-induced apoptosis of tumor cells was significantly enhanced by transfecting them with antisense JunD oligonucleotides. These results suggest that inhibition of JNK facilitates flavonoid-induced apoptosis through down-regulation of JunD, which is further sensitive to tumor cells. Therefore, combination with a specific JNK inhibitor further enhances the anti-cancer and chemopreventive potential of bio-flavonoids

Efficacy and safety of ketamine for the management of refractory status epilepticus (RSE) in adults

International Nuclear Information System (INIS)

Liaqat, J.; Raja, W.; Wali, W.

2018-01-01

Objective: To determine the efficacy and safety of ketamine (KE) in the management of refractory status epilepticus (RSE) in adults. Study Design: Open Label, unblinded prospective case series. Place and Duration of Study: The study was conducted at Neurology Department Military Hospital Rawalpindi, from Jan 2014 to Dec 2014. Material and Methods: All the patients with status epilepticus, from Jan 2014 to Dec 2014 were treated with ketamine in addition to benzodiazepines, phenytoin and levitricetam. Ketamine was the last drug added and if seizures were still not controlled then anesthetic agents like thiopental and propofol were used. Results: Between Jan 2014 and Dec 2014, twenty patients received IV Ketamine. In 18 patients RSE lasted for more than 24 hours, with a median of 4 days (range 1-8 days). Mean duration of seizures in the study group was 4.45 days (SD 2.01). Ketamine was successful in terminating seizure activity in 40% (n=8) patients while it failed in 15% (n=3) patients. There was additional 15% (n=3) partial response in the form of initial control but these patients had later breakthrough or with drawl seizures. Twenty five percent (n=5) of the patients died during the treatment while in one patient ketamine had to be stopped because of intolerable side effects. In our patients the adverse effects of ketamine included sepsis (35%, 5, n=7), shock (10%, n=2) and pneumonia (10%, n=2). Conclusion: In this small, open-label, unblinded study KE appears effective and safe in treating RSE in adults. Larger, randomized studies will help to confirm data emerging from this preliminary study. (author)

Cue-Induced Brain Activation in Chronic Ketamine-Dependent Subjects, Cigarette Smokers, and Healthy Controls: A Task Functional Magnetic Resonance Imaging Study

Directory of Open Access Journals (Sweden)

Yanhui Liao

2018-03-01

Full Text Available BackgroundObservations of drug-related cues may induce craving in drug-dependent patients, prompting compulsive drug-seeking behavior. Sexual dysfunction is common in drug users. The aim of the study was to examine regional brain activation to drug (ketamine, cigarette smoking associated cues and natural (sexual rewards.MethodsA sample of 129 [40 ketamine use smokers (KUS, 45 non-ketamine use smokers (NKUS and 44 non-ketamine use non-smoking healthy controls (HC] participants underwent functional magnetic resonance imaging (fMRI while viewing ketamine use related, smoking and sexual films.ResultsWe found that KUS showed significant increased activation in anterior cingulate cortex and precuneus in response to ketamine cues. Ketamine users (KUS showed lower activation in cerebellum and middle temporal cortex compared with non-ketamine users (NKUS and HC in response to sexual cues. Smokers (KUS and NKUS showed higher activation in the right precentral frontal cortex in response to smoking cues. Non-ketamine users (NKUS and HC showed significantly increased activation of cerebellum and middle temporal cortex while viewing sexual cues.ConclusionThese findings clearly show the engagement of distinct neural circuitry for drug-related stimuli in chronic ketamine users. While smokers (both KUS and NKUS showed overlapping differences in activation for smoking cues, the former group showed a specific neural response to relevant (i.e., ketamine-related cues. In particular, the heightened response in anterior cingulate cortex may have important implications for how attentionally salient such cues are in this group. Ketamine users (KUS showed lower activation in response to sexual cues may partly reflect the neural basis of sexual dysfunction.

Improved Methods for Thermal Rearrangement of Alicyclic α-Hydroxyimines to α-Aminoketones: Synthesis of Ketamine Analogues as Antisepsis Candidates

Directory of Open Access Journals (Sweden)

Gerardo Byk

2012-06-01

Full Text Available Ketamine is an analgesic/anesthetic drug, which, in combination with other drugs, has been used as anesthetic for over 40 years. Ketamine induces its analgesic activities by blocking the N-methyl-D-aspartate (NMDA receptor in the central nervous system (CNS. We have reported that low doses of ketamine administrated to patients before incision significantly reduced post-operative inflammation as reflected by reduced interleukin-6 (IL-6 sera-levels. Our data demonstrated in a rat model of Gram-negative bacterial-sepsis that if we inject a low dose of ketamine following bacterial inoculation we reduce mortality from approximately 75% to 25%. Similar to what we have observed in operated patients, the levels of TNF-α and IL-6 in ketamine-treated rats were significantly lower than in septic animals not treated with ketamine. On the base of these results, we have designed and synthesized series of new analogues of ketamine applying a thermal rearrangement of alicyclic α-hydroxyimines to a-aminoketones in parallel arrays. One of the analogues (compound 6e displayed high activity in down-regulating the levels of IL-6 and TNF-α in vivo as compared to ketamine.

Epithelial-mesenchymal transition increases tumor sensitivity to COX-2 inhibition by apricoxib.

Science.gov (United States)

Kirane, Amanda; Toombs, Jason E; Larsen, Jill E; Ostapoff, Katherine T; Meshaw, Kathryn R; Zaknoen, Sara; Brekken, Rolf A; Burrows, Francis J

2012-09-01

Although cyclooxygenase-2 (COX-2) inhibitors, such as the late stage development drug apricoxib, exhibit antitumor activity, their mechanisms of action have not been fully defined. In this study, we characterized the mechanisms of action of apricoxib in HT29 colorectal carcinoma. Apricoxib was weakly cytotoxic toward naive HT29 cells in vitro but inhibited tumor growth markedly in vivo. Pharmacokinetic analyses revealed that in vivo drug levels peaked at 2-4 µM and remained sufficient to completely inhibit prostaglandin E(2) production, but failed to reach concentrations cytotoxic for HT29 cells in monolayer culture. Despite this, apricoxib significantly inhibited tumor cell proliferation and induced apoptosis without affecting blood vessel density, although it did promote vascular normalization. Strikingly, apricoxib treatment induced a dose-dependent reversal of epithelial-mesenchymal transition (EMT), as shown by robust upregulation of E-cadherin and the virtual disappearance of vimentin and ZEB1 protein expression. In vitro, either anchorage-independent growth conditions or forced EMT sensitized HT29 and non-small cell lung cancer cells to apricoxib by 50-fold, suggesting that the occurrence of EMT may actually increase the dependence of colon and lung carcinoma cells on COX-2. Taken together, these data suggest that acquisition of mesenchymal characteristics sensitizes carcinoma cells to apricoxib resulting in significant single-agent antitumor activity.

Inhibition of cyclic AMP response element-directed transcription by decoy oligonucleotides enhances tumor-specific radiosensitivity

Energy Technology Data Exchange (ETDEWEB)

Park, Serk In, E-mail: serkin@korea.edu [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); The BK21 Plus Program for Biomedical Sciences, Korea University College of Medicine, Seoul (Korea, Republic of); Department of Medicine and Center for Bone Biology, Vanderbilt University School of Medicine, Nashville, TN (United States); Park, Sung-Jun [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); Laboratory of Obesity and Aging Research, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD (United States); Lee, Junghan; Kim, Hye Eun; Park, Su Jin; Sohn, Jeong-Won [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of); Park, Yun Gyu, E-mail: parkyg@korea.ac.kr [Department of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul (Korea, Republic of)

2016-01-15

The radiation stress induces cytotoxic responses of cell death as well as cytoprotective responses of cell survival. Understanding exact cellular mechanism and signal transduction pathways is important in improving cancer radiotherapy. Increasing evidence suggests that cyclic AMP response element binding protein (CREB)/activating transcription factor (ATF) family proteins act as a survival factor and a signaling molecule in response to stress. We postulated that CREB inhibition via CRE decoy oligonucleotide increases tumor cell sensitization to γ-irradiation-induced cytotoxic stress. In the present study, we demonstrate that CREB phosphorylation and CREB DNA-protein complex formation increased in time- and radiation dose-dependent manners, while there was no significant change in total protein level of CREB. In addition, CREB was phosphorylated in response to γ-irradiation through p38 MAPK pathway. Further investigation revealed that CREB blockade by decoy oligonucleotides functionally inhibited transactivation of CREB, and significantly increased radiosensitivity of multiple human cancer cell lines including TP53- and/or RB-mutated cells with minimal effects on normal cells. We also demonstrate that tumor cells ectopically expressing dominant negative mutant CREB (KCREB) and the cells treated with p38 MAPK inhibitors were more sensitive to γ-irradiation than wild type parental cells or control-treated cells. Taken together, we conclude that CREB protects tumor cells from γ-irradiation, and combination of CREB inhibition plus ionizing radiation will be a promising radiotherapeutic approach. - Highlights: • γ-Irradiation induced CREB phosphorylation and CRE-directed transcription in tumor. • γ-Irradiation-induced transcriptional activation of CREB was via p38 MAPK pathway. • CRE blockade increased radiosensitivity of tumor cells but not of normal cells. • CRE decoy oligonucleotides or p38 MAPK inhibitors can be used as radiosensitizers.

Inhibition of cyclic AMP response element-directed transcription by decoy oligonucleotides enhances tumor-specific radiosensitivity

International Nuclear Information System (INIS)

Park, Serk In; Park, Sung-Jun; Lee, Junghan; Kim, Hye Eun; Park, Su Jin; Sohn, Jeong-Won; Park, Yun Gyu

2016-01-01

The radiation stress induces cytotoxic responses of cell death as well as cytoprotective responses of cell survival. Understanding exact cellular mechanism and signal transduction pathways is important in improving cancer radiotherapy. Increasing evidence suggests that cyclic AMP response element binding protein (CREB)/activating transcription factor (ATF) family proteins act as a survival factor and a signaling molecule in response to stress. We postulated that CREB inhibition via CRE decoy oligonucleotide increases tumor cell sensitization to γ-irradiation-induced cytotoxic stress. In the present study, we demonstrate that CREB phosphorylation and CREB DNA-protein complex formation increased in time- and radiation dose-dependent manners, while there was no significant change in total protein level of CREB. In addition, CREB was phosphorylated in response to γ-irradiation through p38 MAPK pathway. Further investigation revealed that CREB blockade by decoy oligonucleotides functionally inhibited transactivation of CREB, and significantly increased radiosensitivity of multiple human cancer cell lines including TP53- and/or RB-mutated cells with minimal effects on normal cells. We also demonstrate that tumor cells ectopically expressing dominant negative mutant CREB (KCREB) and the cells treated with p38 MAPK inhibitors were more sensitive to γ-irradiation than wild type parental cells or control-treated cells. Taken together, we conclude that CREB protects tumor cells from γ-irradiation, and combination of CREB inhibition plus ionizing radiation will be a promising radiotherapeutic approach. - Highlights: • γ-Irradiation induced CREB phosphorylation and CRE-directed transcription in tumor. • γ-Irradiation-induced transcriptional activation of CREB was via p38 MAPK pathway. • CRE blockade increased radiosensitivity of tumor cells but not of normal cells. • CRE decoy oligonucleotides or p38 MAPK inhibitors can be used as radiosensitizers.

Differential psychopathology and patterns of cerebral glucose utilisation produced by (S)- and (R)-ketamine in healthy volunteers using positron emission tomography (PET)

NARCIS (Netherlands)

Vollenweider, FX; Leenders, KL; Oye, [No Value; Hell, D; Angst, J

Until recently, racemic ketamine (S-ketamine/R-ketamine=50:50) has been used to study NMDA receptor hypofunction in relation to pathophysiological models of schizophrenia. Ketamine given to normal humans in subanesthetic doses produces a model psychosis including both positive and negative symptoms

Ketamine as a first-line treatment for severely agitated emergency department patients.

Science.gov (United States)

Riddell, Jeff; Tran, Alexander; Bengiamin, Rimon; Hendey, Gregory W; Armenian, Patil

2017-07-01

Emergency physicians often need to control agitated patients who present a danger to themselves and hospital personnel. Commonly used medications have limitations. Our primary objective was to compare the time to a defined reduction in agitation scores for ketamine versus benzodiazepines and haloperidol, alone or in combination. Our secondary objectives were to compare rates of medication redosing, vital sign changes, and adverse events in the different treatment groups. We conducted a single-center, prospective, observational study examining agitation levels in acutely agitated emergency department patients between the ages of 18 and 65 who required sedation medication for acute agitation. Providers measured agitation levels on a previously validated 6-point sedation scale at 0-, 5-, 10-, and 15-min after receiving sedation. We also assessed the incidence of adverse events, repeat or rescue medication dosing, and changes in vital signs. 106 patients were enrolled and 98 met eligibility criteria. There was no significant difference between groups in initial agitation scores. Based on agitation scores, more patients in the ketamine group were no longer agitated than the other medication groups at 5-, 10-, and 15-min after receiving medication. Patients receiving ketamine had similar rates of redosing, changes in vital signs, and adverse events to the other groups. In highly agitated and violent emergency department patients, significantly fewer patients receiving ketamine as a first line sedating agent were agitated at 5-, 10-, and 15-min. Ketamine appears to be faster at controlling agitation than standard emergency department medications. Copyright © 2017 Elsevier Inc. All rights reserved.

8-O-Acetyl Shanzhiside Methylester From Lamiophlomis Rotata Reduces Neuropathic Pain by Inhibiting the ERK/TNF-α Pathway in Spinal Astrocytes

Directory of Open Access Journals (Sweden)

Wei Zhang

2018-03-01

Full Text Available Lamiophlomis rotata (L. rotata; Benth. Kudo is an effective traditional herb in the clinical treatment of chronic pain syndromes in China. 8-O-acetyl shanzhiside methylester (8-OaS, a chief component in L. rotata, possesses potent immunosuppressive activities and favorable analgesic effects. This study was proposed to compare the analgesic effects of 8-OaS with those of lidocaine and ketamine in a spinal nerve ligation (SNL model by behavioral tests, and then investigated its effects upon the expression of spinal glial fibrillary acidic protein (GFAP, phosphorylated extracellular regulated protein kinases (pERK and tumor necrosis factor-alpha (TNF-α via immunofluorescence staining and western blot analyses. The data showed consecutive intrathecal injection of 8-OaS for 2 weeks brought about remarkable palliation of neuropathic pain (NP, possessing similar anti-allodynia effects with those of lidocaine and ketamine. Two weeks after surgery, pERK within the spinal dorsal horn was mainly expressed in astrocytes more than neurons and microglia, and 8-OaS inhibited spinal astrocytic activation and TNF-α expression. Finally, co-treatment of 8-OaS and PD98059 (an Extracellular signal-regulated kinase, ERK inhibitor did not lead to remarkable increase in pain relief or TNF-α expression comparing to rats treated with 8-OaS or PD98059 alone. In conclusion, the anti-nociceptive effects of 8-OaS in the condition of NP relied on the inhibition of SNL-induced astrocyte activation, probably via the down-regulation of the ERK/TNF-α pathway.

Effects of Subanesthetic Ketamine on Pain and Cognitive Functions in TIVA

Directory of Open Access Journals (Sweden)

Yeliz Ozhan

2014-03-01

Full Text Available Aim: It was aimed to compare the effects of subanesthetic dose ketamine on analgesic consumption, cognitive functions, perioperative hemodynamics and postoperative recovery in patients scheduled for laparoscopic cholecystectomy under total intravenous anesthesia (TIVA. Material and Method: The study was approved by Institutional Ethics Committee and all patients gave written informed consent. Sixty ASA I-III patients aged 20-70 years scheduled for elective laparoscopic cholecystectomy were randomly assigned into 2 groups [group 1 (TIVA-ketamine and group 2 (TIVA]. Both groups underwent Mini Mental Test (MMT before the operation. In the group 1, 0.25 mg.kg-1 ketamine was given 2 minutes before induction via intravenous route. Anesthesia was induced by using 2mg.kg-1 propofol, 1µg.kg-1fentanyl (iv and 0.6 mg.kg-1 rocuronium (iv in both groups. Anesthesia was maintained by 5-8mg.kg-1.h-1 propofol, 0,15µg kg-1 remifentanil (iv and 50:50 mixtures of O2 and air. Postoperative pain management was achieved by tramadol HCl via patient-controlled analgesia (PCA device. Total dose within 24 hours was recorded. Hemodynamic parameters during surgery and times to extubation, eye opening, receiving verbal commands and orientation time were recorded. Ramsey sedation score (RSS and Aldrete recovery score (ARS were recorded after extubation. MMT was repeated on the postoperative hour 24. Results: Hemodynamic parameters were found to be similar in both groups. Total analgesic consumption was found to be significantly lower in patients received ketamine (p0.05. Discussion: Addition of subanesthetic dose ketamine to total intravenous anesthesia had no adverse effect on intraoperative hemodynamic parameters; it provided more effective postoperative analgesia; however, we think that a meticulous monitoring is required during early postoperative period as it prolonged awakening and recovery times.

Transient mTOR inhibition facilitates continuous growth of liver tumors by modulating the maintenance of CD133+ cell populations.

Directory of Open Access Journals (Sweden)

Zhaojuan Yang

Full Text Available The mammalian target of the rapamycin (mTOR pathway, which drives cell proliferation, is frequently hyperactivated in a variety of malignancies. Therefore, the inhibition of the mTOR pathway has been considered as an appropriate approach for cancer therapy. In this study, we examined the roles of mTOR in the maintenance and differentiation of cancer stem-like cells (CSCs, the conversion of conventional cancer cells to CSCs and continuous tumor growth in vivo. In H-Ras-transformed mouse liver tumor cells, we found that pharmacological inhibition of mTOR with rapamycin greatly increased not only the CD133+ populations both in vitro and in vivo but also the expression of stem cell-like genes. Enhancing mTOR activity by over-expressing Rheb significantly decreased CD133 expression, whereas knockdown of the mTOR yielded an opposite effect. In addition, mTOR inhibition severely blocked the differentiation of CD133+ to CD133- liver tumor cells. Strikingly, single-cell culture experiments revealed that CD133- liver tumor cells were capable of converting to CD133+ cells and the inhibition of mTOR signaling substantially promoted this conversion. In serial implantation of tumor xenografts in nude BALB/c mice, the residual tumor cells that were exposed to rapamycin in vivo displayed higher CD133 expression and had increased secondary tumorigenicity compared with the control group. Moreover, rapamycin treatment also enhanced the level of stem cell-associated genes and CD133 expression in certain human liver tumor cell lines, such as Huh7, PLC/PRC/7 and Hep3B. The mTOR pathway is significantly involved in the generation and the differentiation of tumorigenic liver CSCs. These results may be valuable for the design of more rational strategies to control clinical malignant HCC using mTOR inhibitors.