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Ketamine, pharmacokinetics

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https://www.readbyqxmd.com/read/29895202/the-effect-of-route-of-administration-on-the-enantioselective-pharmacokinetics-of-ketamine-and-norketamine-in-rats
#1
Martin Le Nedelec, Paul Glue, Helen Winter, Chelsea Goulton, Natalie J Medlicott
BACKGROUND: Ketamine has been shown to produce a rapid and potent antidepressant response in patients with treatment-resistant depression. Currently ketamine is most commonly administered as a 40-minute intravenous infusion, though it is unknown whether this is the optimal route of administration. AIMS: To determine the plasma concentration time course of the R- and S-enantiomers of ketamine and norketamine following administration of ketamine by four different routes of administration...
June 1, 2018: Journal of Psychopharmacology
https://www.readbyqxmd.com/read/29893929/no-sex-specific-differences-in-the-acute-antidepressant-actions-of-r-ketamine-in-an-inflammation-model
#2
Lijia Chang, Hidetoh Toki, Youge Qu, Yuko Fujita, Akiko Mizuno-Yasuhira, Jun-Ichi Yamaguchi, Shigeyuki Chaki, Kenji Hashimoto
Background: Although previous reports suggest sex-specific differences in the antidepressant actions of (R,S)-ketamine, these differences in the antidepressant actions of (R)-ketamine, which is more potent than (S)-ketamine, are unknown. Methods: Saline or (R)-ketamine was administered 23 hours post lipopolysaccharide (LPS) administration to adult male or female mice. Subsequently, antidepressant effects were assessed using a forced swimming test (FST). Furthermore, the concentration of (R)-ketamine and its two major metabolites, (R)-norketamine and (2R,6R)-hydroxynorketamine (HNK), was measured in the plasma and brain after the administration of (R)-ketamine in the mice...
June 9, 2018: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/29803629/the-neurobiology-of-depression-ketamine-and-rapid-acting-antidepressants-is-it-glutamate-inhibition-or-activation
#3
REVIEW
Chadi G Abdallah, Gerard Sanacora, Ronald S Duman, John H Krystal
The discovery of the antidepressant effects of ketamine has opened a breakthrough opportunity to develop a truly novel class of safe, effective, and rapid-acting antidepressants (RAADs). In addition, the rapid and robust biological and behavioral effects of ketamine offered a unique opportunity to utilize the drug as a tool to thoroughly investigate the neurobiology of stress and depression in animals, and to develop sensitive and reproducible biomarkers in humans. The ketamine literature over the past two decades has considerably enriched our understanding of the mechanisms underlying chronic stress, depression, and RAADs...
May 25, 2018: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/29771709/combined-recirculatory-compartmental-population-pharmacokinetic-modeling-of-arterial-and-venous-plasma-s-and-r-ketamine-concentrations
#4
Thomas K Henthorn, Michael J Avram, Albert Dahan, Lars L Gustafsson, Jan Persson, Tom C Krejcie, Erik Olofsen
BACKGROUND: The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(-) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations. METHODS: S(+) or R(-) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers...
May 16, 2018: Anesthesiology
https://www.readbyqxmd.com/read/29702122/temporally-dissociable-effects-of-ketamine-on-neuronal-discharge-and-gamma-oscillations-in-rat-thalamo-cortical-networks
#5
Maria Amat-Foraster, Anders A Jensen, Niels Plath, Kjartan F Herrik, Pau Celada, Francesc Artigas
BACKGROUND: Sub-anesthetic doses of the non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonist ketamine evoke transient psychotomimetic effects, followed by persistent antidepressant effects in treatment-resistant depressed patients and rodents through still poorly understood mechanisms. Since phencyclidine (PCP) disinhibits thalamo-cortical networks by blocking NMDA-Rs on GABAergic neurons of the reticular thalamic nucleus (RtN), we examined ketamine's actions in the same areas...
April 24, 2018: Neuropharmacology
https://www.readbyqxmd.com/read/29677389/population-pharmacokinetics-of-intramuscular-and-intravenous-ketamine-in-children
#6
Christoph P Hornik, Daniel Gonzalez, John van den Anker, Andrew M Atz, Ram Yogev, Brenda B Poindexter, Kee Chong Ng, Paula Delmore, Barrie L Harper, Chiara Melloni, Andrew Lewandowski, Casey Gelber, Michael Cohen-Wolkowiez, Jan Hau Lee
Ketamine is an N-methyl D-aspartate receptor antagonist used off-label to facilitate dissociative anesthesia in children undergoing invasive procedures. Available for both intravenous and intramuscular administration, ketamine is commonly used when vascular access is limited. Pharmacokinetic (PK) data in children are sparse, and the bioavailability of intramuscular ketamine in children is unknown. We performed 2 prospective PK studies of ketamine in children receiving either intramuscular or intravenous ketamine and combined the data to develop a pediatric population PK model using nonlinear mixed-effects methods...
April 20, 2018: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/29674491/ketamine-pharmacokinetics-and-pharmacodynamics-are-altered-by-p-glycoprotein-and-breast-cancer-resistance-protein-efflux-transporters-in-mice
#7
Samit Ganguly, John C Panetta, Jessica K Roberts, Erin G Schuetz
To understand the systemic impact of breast cancer resistance protein (Bcrp) and P-glycoprotein (Pgp) deletion, untargeted metabolomics was performed on cerebral spinal fluid (CSF) and plasma of wild-type (WT) and Pgp and Bcrp double-knockout (dKO) rats anesthetized with ketamine-xylazine. We unexpectedly found elevated ketamine levels in both CSF and plasma of dKO versus WT rats. Therefore, the effect of these transporters was investigated on the 1) oral and intraperitoneal serum pharmacokinetics (PK) of ketamine, using a liquid chromatography method (high-performance liquid chromatography with ultraviolet detection), and 2) the anesthetic effect of ketamine using a duration of loss-of-righting reflex (dLORR) test in WT, Bcrp knockout (KO), Pgp KO, and Pgp/Bcrp dKO mice...
July 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
https://www.readbyqxmd.com/read/29576122/ketamine-and-norketamine-attenuate-oxycodone-tolerance-markedly-less-than-that-of-morphine-from-behaviour-to-drug-availability
#8
T Lilius, E Kangas, M Niemi, P Rauhala, E Kalso
BACKGROUND: Ketamine attenuates morphine tolerance by antagonising N-methyl-d-aspartate receptors. However, a pharmacokinetic interaction between morphine and ketamine has also been suggested. The interaction between oxycodone and ketamine is unclear. We studied the effects of ketamine and norketamine on the attenuation of morphine and oxycodone tolerance focusing on both the pharmacodynamic and pharmacokinetic interactions. METHODS: Morphine 9.6 mg day-1 or oxycodone 3...
April 2018: British Journal of Anaesthesia
https://www.readbyqxmd.com/read/29507385/lack-of-metabolism-in-r-ketamine-s-antidepressant-actions-in-a-chronic-social-defeat-stress-model
#9
Kai Zhang, Yuko Fujita, Kenji Hashimoto
Since the metabolism of (R,S)-ketamine to (2R,6R)-hydroxynorketamine (HNK) is reported to be essential for ketamine's antidepressant effects, there is an increasing debate about antidepressant effects of (2R,6R)-HNK. Using pharmacokinetic and behavioral techniques, we investigated whether intracerebroventricular (i.c.v.) infusion of (R)-ketamine or (2R,6R)-HNK show antidepressant effects in a chronic social defeat stress (CSDS) model of depression. Low levels of (2R,6R)-HNK in the brain after i.c.v. infusion of (R)-ketamine were detected, although brain levels of (2R,6R)-HNK were markedly lower than those after i...
March 5, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29458790/non-pharmacological-interventions-and-non-fentanyl-pharmacological-treatments-for-breakthrough-cancer-pain-a-systematic-and-critical-review
#10
REVIEW
Sebastiano Mercadante
BACKGROUND: Oral opioids or other pharmacological or non-pharmacological interventions are often suggested in the management of breakthrough cancer pain (BTcP). The aim of this systematic and critical review was to analyse and critically comment the evidence of any non-fentanyl therapies proposed for BTcP. METHODS: A systematic literature search was carried out to find studies providing clinical data on any treatment excluding fentanyl products. RESULTS: No data exist about the use of oral opioids...
February 2018: Critical Reviews in Oncology/hematology
https://www.readbyqxmd.com/read/29396996/intranasal-ketamine-and-its-potential-role-in-cancer-related-pain
#11
REVIEW
Vinita Singh, Theresa W Gillespie, Robert Donald Harvey
Cancer-related pain continues to be a significant therapeutic challenge, made more difficult by contemporary opioid use and diversion concerns. Conventional treatment using a tiered approach of nonsteroidal antiinflammatory drugs (NSAIDs), opioids, and adjuvant agents is limited; and alternatives are needed for patients with rapidly progressing pain and those who develop hyperalgesia and tolerance to opioids. Ketamine, an N-methyl-d-aspartate (NMDA) selective antagonist, has historically been used for anesthesia in adult and pediatric populations but has also been investigated for depression, bipolar disorder, and general and postoperative pain management...
March 2018: Pharmacotherapy
https://www.readbyqxmd.com/read/29229209/randomized-double-blind-placebo-controlled-dose-escalation-study-investigation-of-the-safety-pharmacokinetics-and-antihyperalgesic-activity-of-l-4-chlorokynurenine-in-healthy-volunteers
#12
Mark Wallace, Alexander White, Kathy A Grako, Randal Lane, Allen Jo Cato, H Ralph Snodgrass
BACKGROUND AND AIMS: Neuropathic pain is a significant medical problem needing more effective treatments with fewer side effects. Overactive glutamatergic transmission via N-methyl-d-aspartate receptors (NMDARs) are known to play a role in central sensitization and neuropathic pain. Although ketamine, a NMDAR channel-blocking antagonist, is often used for neuropathic pain, its side-effect profile and abusive potential has prompted the search for a safer effective oral analgesic. A novel oral prodrug, AV-101 (l-4 chlorokynurenine), which, in the brain, is converted into one of the most potent and selective GlyB site antagonists of the NMDAR, has been demonstrated to be active in animal models of neuropathic pain...
October 2017: Scandinavian Journal of Pain
https://www.readbyqxmd.com/read/29196879/the-feasibility-of-physiologically-based-pharmacokinetic-modeling-in-forensic-medicine-illustrated-by-the-example-of-morphine
#13
Nadine Schaefer, Daniel Moj, Thorsten Lehr, Peter H Schmidt, Frank Ramsthaler
In forensic medicine, expert opinion is often required concerning dose and time of intake of a substance, especially in the context of fatal intoxications. In the present case, a 98-year-old man died 4 days after admission to a hospital due to a femur neck fracture following a domestic fall in his retirement home. As he had obtained high morphine doses in the context of palliative therapy and a confusion of his supplemental magnesium tablets with a diuretic by the care retirement home was suspected by the relatives, a comprehensive postmortem examination was performed...
March 2018: International Journal of Legal Medicine
https://www.readbyqxmd.com/read/29171155/interactions-of-2s-6s-2r-6r-hydroxynorketamine-a-secondary-metabolite-of-r-s-ketamine-with-morphine
#14
Tuomas O Lilius, Hanna Viisanen, Viljami Jokinen, Mikko Niemi, Eija A Kalso, Pekka V Rauhala
Ketamine and its primary metabolite norketamine attenuate morphine tolerance by antagonising N-methyl-d-aspartate (NMDA) receptors. Ketamine is extensively metabolized to several other metabolites. The major secondary metabolite (2S,6S;2R,6R)-hydroxynorketamine (6-hydroxynorketamine) is not an NMDA antagonist. However, it may modulate nociception through negative allosteric modulation of α7 nicotinic acetylcholine receptors. We studied whether 6-hydroxynorketamine could affect nociception or the effects of morphine in acute or chronic administration settings...
May 2018: Basic & Clinical Pharmacology & Toxicology
https://www.readbyqxmd.com/read/29126076/a-rapid-and-sensitive-chiral-lc-ms-ms-method-for-the-determination-of-ketamine-and-norketamine-in-mouse-plasma-brain-and-cerebrospinal-fluid-applicable-to-the-stereoselective-pharmacokinetic-study-of-ketamine
#15
Hidetoh Toki, Takuya Ichikawa, Akiko Mizuno-Yasuhira, Jun-Ichi Yamaguchi
A novel method for the rapid and sensitive chiral determination of ketamine and norketamine in mouse plasma, brain and cerebrospinal fluid (CSF) was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This method reduces the required matrix volume, compared with a previously reported chiral assay method for ketamine and norketamine. The method involves the deproteinization of a small amount of biological matrix (corresponding to 5μL of plasma, 10mg of brain, or 2.5μL of CSF) using a water-miscible organic solvent containing2 H4 -norketamine as an internal standard, the direct injection of the organic supernatant into an LC-MS/MS system, chiral separation on a CHIRALPAK AS-3R column (4...
January 30, 2018: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/29049110/evidence-for-the-efficacy-of-systemic-opioid-sparing-analgesics-in-pediatric-surgical-populations-a-systematic-review
#16
REVIEW
Alyssa Zhu, Hubert A Benzon, T Anthony Anderson
While a large number of studies has examined the efficacy of opioid-sparing analgesics in adult surgical populations, fewer studies are available to guide postoperative pain treatment in pediatric patients. We systematically reviewed available publications on the use of systemic nonopioid agents for postoperative analgesia in pediatric surgical populations. A comprehensive literature search identified meta-analyses and randomized controlled trials (RCTs) assessing the effects of systemic, nonopioid agents on postoperative narcotic requirements or pain scores in pediatric surgical populations...
November 2017: Anesthesia and Analgesia
https://www.readbyqxmd.com/read/29030928/pharmacokinetics-of-s-ketamine-during-prolonged-sedation-at-the-pediatric-intensive-care-unit
#17
Robert B Flint, Carole N M Brouwer, Anne S C Kränzlin, Loraine Lie-A-Huen, Albert P Bos, Ron A A Mathôt
BACKGROUND: 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. AIMS: 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...
November 2017: Paediatric Anaesthesia
https://www.readbyqxmd.com/read/28976571/ketamine-and-norketamine-stability-in-whole-blood-at-ambient-and-4%C3%A2-c-conditions
#18
Benjamin Duy Tran, Ganesh S Moorthy, Athena F Zuppa
A study was implemented to describe the pharmacokinetics (PK) of ketamine (K) and its metabolite norketamine (NK) in critically ill adults. Conducting studies in these subjects is hindered by the immediate need to process and freeze samples obtained in a busy intensive care setting. The ability to store unprocessed samples at room temperature for an extended time period would overcome this barrier. Stability and blood to plasma partitioning of K and NK were investigated in whole blood for up to 120 h at room temperature and 4°C...
March 2018: Biomedical Chromatography: BMC
https://www.readbyqxmd.com/read/28918327/determination-of-ketamine-and-its-main-metabolites-by-liquid-chromatography-coupled-to-tandem-mass-spectrometry-in-pig-plasma-comparison-of-extraction-methods
#19
Cindy Ramiole, Benoit D'Hayer, Vincent Boudy, Josette Legagneux, Julien Fonsart, Pascal Houzé
A rapid, sensitive and specific liquid chromatography coupled to tandem mass spectrometry method was developed for the simultaneous quantification pig plasma of ketamine and its two principal metabolites, norketamine and dehydronorketamine. Three extraction procoles were assessed including acetonitrile precipitation, Oase™ microplate extraction, and liquid-liquid extraction. Oase™ microplate extraction induced no significant matrix effect, important signal/noise ratio and good recoveries, ranging from 82 to 87% for the considered compounds...
November 30, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28888484/prediction-of-human-efficacious-antidepressant-doses-using-the-mouse-forced-swim-test
#20
Eunice Yuen, Steven Swanson, Jeffrey M Witkin
The forced swim test (FST) is a commonly used preclinical animal behavioural model for prediction of antidepressant activity in humans. While the FST may qualitatively predict efficacy, less is known about the quantitative translation of FST data to human efficacious doses. Assessing quantitative translation allows better predictions of human efficacious doses and a higher chance of success in the drug development process. Dose-response and time-course FST experiments were carried out on mice using four marketed antidepressants (citalopram, desipramine, bupropion, desvenlafaxine) in addition to ketamine, all with varying mechanisms of action...
October 2017: Pharmacology, Biochemistry, and Behavior
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