Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations.

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Acute Dissociation and Ketamine's Antidepressant and Anti-Suicidal Ideation Effects in a Midazolam-Controlled Trial.

OBJECTIVE: We sought to explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. METHODS: Data from a completed trial in suicidal, depressed participants (n = 40) randomly assigned to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Nonparametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset of participants (n = 28) who provided blood samples immediately post-infusion. RESULTS: Neither acute dissociative nor psychotomimetic effects of ketamine were associated with changes in suicidal ideation or depressive symptoms from pre- to post-infusion. Norketamine had a trend-level, moderate inverse correlation with dissociative symptoms on Day 1 post-injection (P = .064; P =.013 removing 1 outlier). Dehydronorketamine correlated with Clinician-Administered Dissociative States Scale scores at 40 minutes (P = .034), 230 minutes (P = .014), and Day 1 (P = .012). CONCLUSION: We did not find evidence that ketamine's acute, transient dissociative, or psychotomimetic effects are associated with its antidepressant or anti-suicidal ideation actions. The correlation of higher plasma norketamine with lower dissociative symptoms on Day 1 post-treatment suggests dissociation may be more an effect of the parent drug.

Pharmacokinetics of subcutaneous ketamine administration via the Omnipod® system in dogs.

Ketamine is an injectable anesthetic agent with analgesic and antidepressant effects that can prevent maladaptive pain. Ketamine is metabolized by the liver into norketamine, an active metabolite. Prior rodent studies have suggested that norketamine is thought to contribute up to 30% of ketamine's analgesic effect. Ketamine is usually administered as an intravenous (IV) bolus injection or continuous rate infusion (CRI) but can be administered subcutaneously (SC) and intramuscularly (IM). The Omnipod® is a wireless, subcutaneous insulin delivery device that adheres to the skin and delivers insulin as an SC CRI. The Omnipod® was used in dogs for postoperative administration of ketamine as a 1 mg/kg infusion bolus (IB) over 1 hour (h). Pharmacokinetics (PK) showed plasma ketamine concentrations between 42 and 326.1 ng/mL. The median peak plasma concentration was 79.5 (41.9-326.1) ng/mL with a Tmax of 60 (30-75) min. After the same infusion bolus, the corresponding norketamine PK showed plasma drug concentrations between 22.0 and 64.8 ng/mL. The median peak plasma concentration was 43.0 (26.1-71.8) ng/mL with a median Tmax of 75 min. The median peak ketamine plasma concentration exceeded 100 ng/mL in dogs for less than 1 h post infusion. The Omnipod® system successfully delivered subcutaneous ketamine to dogs in the postoperatively.

Ketamine for Refractory Chronic Migraine: An Observational Pilot Study and Metabolite Analysis.

Patients with refractory chronic migraine have substantial disability and have failed many acute and preventive medications. When aggressive intravenous therapy is indicated, both lidocaine and (R,S)-ketamine infusions have been used successfully to provide relief. Retrospective studies have shown that both agents may be associated with short-term analgesia. In this prospective, observational pilot study of 6 patients, we compared the effects of lidocaine and (R,S)-ketamine infusions and performed metabolite analyses of (R,S)-ketamine to determine its metabolic profile in this population. One of (R,S)-ketamine's metabolites, (2R,6R)-hydroxynorketamine, has been shown in animal studies to reduce pain, but human studies in patients undergoing continuous (R,S)-ketamine infusions for migraine are lacking. All 6 patients tolerated both infusions well with mild adverse effects. The baseline mean pain rating (0-10 numeric rating scale) decreased from 7.5 ± 2.2 to 4.7 ± 2.8 by end of lidocaine treatment ( P≤.05 ) but increased to 7.0 ± 1.4 by the postdischarge visit at 4 weeks (P > .05 vs baseline). The baseline mean pain rating prior to ketamine treatment was 7.4 ± 1.4, which decreased to 3.7 ± 2.3 by the end of the hospitalization ( P≤.05 ) but increased to 7.2 ± 1.7 by the postdischarge visit at 6 weeks (P > .05 vs baseline). For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 vs -2.8; P≤.05 ), but this has minimal clinical significance. Ketamine metabolite analysis revealed that (2R,6R)-hydroxynorketamine was the predominant metabolite during most of the infusion, consistent with previous studies.

A critical point in chiral chromatography-mass spectrometry analysis of ketamine metabolites.

Ketamine is a widely used dissociative drug, whose quantification in plasma and urine can be of pharmacological, toxicological, and clinical interest. Although tandem mass spectrometry allows the reliable determination of ketamine and its metabolites in biological matrices, the structural similarity between norketamine (main active metabolite) and dehydronorketamine (a less relevant metabolite) can represent a critical aspect. These compounds differ exclusively in two hydrogen atoms, but the consequent two-unit difference in their mass/charge ratio is partially nullified by the isotopic abundance of the chlorine atom present in their structure. This, along with their similar fragmentation pattern, can result in the incorrect identification of the enantiomers of these ketamine metabolites even with triple quadrupole instruments, if shared transitions are monitored after chiral chromatography. The key to prevent norketamine overestimation is therefore observing analyte-specific MS/MS transitions. Here, we describe in detail how we investigated this issue, during the development of an analytical method for ketamine and norketamine enantiomer determination in plasma.

Association of urinary ketamine and APOA1 levels with bladder dysfunction in ketamine abusers revealed via proteomics and targeted metabolite analyses.

Chronic ketamine abuse is associated with bladder dysfunction and cystitis. However, the effects of ketamine abuse on the urinary proteome profile and the correlations among urinary proteins, urinary ketamine (and metabolites) and clinicopathological features of ketamine-induced bladder dysfunction remain to be established. Here, we recruited 56 ketamine abusers (KA) and 40 age-matched healthy controls (HC) and applied the iTRAQ-based proteomics approach to unravel quantitative changes in the urine proteome profile between the two groups. Many of the differentially regulated proteins are involved in the complement and coagulation cascades and/or fibrotic disease. Among them, a significant increase in APOA1 levels in KA relative to control samples (392.1 ± 59.9 ng/ml vs. 13.7 ± 32.6 ng/ml, p < 0.0001) was detected via ELISA. Moreover, urinary ketamine, norketamine and dehydronorketamine contents (measured via LC-SRM-MS) were found to be positively correlated with overactive bladder syndrome score (OABSS) and APOA1 levels with urinary RBC, WBC, OABSS and numeric pain rating scale in KA. Collectively, our results may aid in developing new molecular tool(s) for management of ketamine-induced bladder dysfunction. Moreover, information regarding the differentially regulated proteins in urine of KA provides valuable clues to establish the molecular mechanisms underlying ketamine-induced cystitis.

The Double Face of Ketamine-The Possibility of Its Identification in Blood and Beverages.

The purpose of this study was to develop and validate a high-sensitivity methodology for identifying one of the most used drugs-ketamine. Ketamine is used medicinally to treat depression, alcoholism, and heroin addiction. Moreover, ketamine is the main ingredient used in so-called "date-rape" pills (DRP). This study presents a novel methodology for the simultaneous determination of ketamine based on the Dried Blood Spot (DBS) method, in combination with capillary electrophoresis coupled with a mass spectrometer (CE-TOF-MS). Then, 6-mm circles were punched out from DBS collected on Whatman DMPK-C paper and extracted using microwave-assisted extraction (MAE). The assay was linear in the range of 25-300 ng/mL. Values of limits of detection (LOD = 6.0 ng/mL) and quantification (LOQ = 19.8 ng/mL) were determined based on the signal to noise ratio. Intra-day precision at each determined concentration level was in the range of 6.1-11.1%, and inter-day between 7.9-13.1%. The obtained precision was under 15.0% (for medium and high concentrations) and lower than 20.0% (for low concentrations), which are in accordance with acceptance criteria. Therefore, the DBS/MAE/CE-TOF-MS method was successfully checked for analysis of ketamine in matrices other than blood, i.e., rose wine and orange juice. Moreover, it is possible to identify ketamine in the presence of flunitrazepam, which is the other most popular ingredient used in DRP. Based on this information, the selectivity of the proposed methodology for identifying ketamine in the presence of other components of rape pills was checked.

Treatment response to low-dose ketamine infusion for treatment-resistant depression: A gene-based genome-wide association study.

BACKGROUNDS: Evidence suggested the crucial roles of brain-derived neurotrophic factor (BDNF) and glutamate system functioning in the antidepressant mechanisms of low-dose ketamine infusion in treatment-resistant depression (TRD). METHODS: 65 patients with TRD were genotyped for 684,616 single nucleotide polymorphisms (SNPs). Twelve ketamine-related genes were selected for the gene-based genome-wide association study on the antidepressant effect of ketamine infusion and the resulting serum ketamine and norketamine levels. RESULTS: Specific SNPs and whole genes involved in BDNF-TrkB signaling (i.e., rs2049048 in BDNF and rs10217777 in NTRK2) and the glutamatergic and GABAergic systems (i.e., rs16966731 in GRIN2A) were associated with the rapid (within 240 min) and persistent (up to 2 weeks) antidepressant effect of low-dose ketamine infusion and with serum ketamine and norketamine levels. DISCUSSION: Our findings confirmed the predictive roles of BDNF-TrkB signaling and glutamatergic and GABAergic systems in the underlying mechanisms of low-dose ketamine infusion for TRD treatment.

Influence of formulation and route of administration on ketamine's safety and tolerability: systematic review.

PURPOSE: Ketamine has rapid-onset antidepressant effects in patients with treatment-resistant depression. Common side effects include dissociation (a sense of detachment from reality) and increases in systolic and diastolic blood pressure. The objective of this structured review was to examine the effect of ketamine formulation and route of administration on its pharmacokinetics, safety and tolerability, to identify formulation characteristics and routes of administration that might minimise side effects. METHODS: This was a structured review of published ketamine pharmacokinetics, safety and tolerability data for any ketamine formulation. The ratio of ketamine:norketamine was calculated from reported Cmax values, as a measure of first pass metabolism. The effect of formulation and route of administration on safety was evaluated by measuring mean changes in systolic blood pressure and tolerability by changes in dissociation ratings. Data were correlated using Spearman's method. RESULTS: A total of 41 treatment arms were identified from 21 publications, and included formulation development studies in healthy volunteers, and studies in clinical populations (patients undergoing anaesthesia, or being treated for pain or depression). Ketamine:norketamine ratios were strongly positively correlated with change in dissociation ratings (r = 0.89) and change in blood pressure (r = 0.96), and strongly negatively correlated with ketamine Tmax (r = - 0.87; p < 0.00001 for all). Ketamine Tmax strongly positively correlated with a change in dissociation ratings (r = - 0.96) and change in blood pressure (r = - 0.99; p < 0.00001 for all). CONCLUSION: Ketamine formulations that maximize first pass metabolism and delay Tmax will be better tolerated and safer than formulations which lack those characteristics.

Pharmacokinetics of ketamine and its major metabolites norketamine, hydroxynorketamine, and dehydronorketamine: a model-based analysis.

BACKGROUND: Recent studies show activity of ketamine metabolites, such as hydroxynorketamine, in producing rapid relief of depression-related symptoms and analgesia. To improve our understanding of the pharmacokinetics of ketamine and metabolites norketamine, dehydronorketamine, and hydroxynorketamine, we developed a population pharmacokinetic model of ketamine and metabolites after i.v. administration of racemic ketamine and the S-isomer (esketamine). Pharmacokinetic data were derived from an RCT on the efficacy of sodium nitroprusside (SNP) in reducing the psychotomimetic side-effects of ketamine in human volunteers. METHODS: Three increasing i.v. doses of esketamine and racemic ketamine were administered to 20 healthy volunteers, and arterial plasma samples were obtained for measurement of ketamine and metabolites. Subjects were randomised to receive esketamine/SNP, esketamine/placebo, racemic ketamine/SNP, and racemic ketamine/placebo on four separate occasions. The time-plasma concentration data of ketamine and metabolites were analysed using a population compartmental model approach. RESULTS: The pharmacokinetics of ketamine and metabolites were adequately described by a seven-compartment model with two ketamine, norketamine, and hydroxynorketamine compartments and one dehydronorketamine compartment with metabolic compartments in-between ketamine and norketamine, and norketamine and dehydronorketamine main compartments. Significant differences were found between S- and R-ketamine enantiomer pharmacokinetics, with up to 50% lower clearances for the R-enantiomers, irrespective of formulation. Whilst SNP had a significant effect on ketamine clearances, simulations showed only minor effects of SNP on total ketamine pharmacokinetics. CONCLUSIONS: The model is of adequate quality for use in future pharmacokinetic and pharmacodynamic studies into the efficacy and side-effects of ketamine and metabolites. CLINICAL TRIAL REGISTRATION: Dutch Cochrane Center 5359.

Postmortem redistribution of ketamine in ocular matrices: A study of forensic relevance.

The present study evaluates the postmortem redistribution of ketamine in ocular matrices, such as vitreous humor, aqueous humor, and ocular tissues in an animal model. To understand the redistribution of ketamine and its metabolite (norketamine) in the ocular matrices, an in vivo study was performed in rabbits. The rabbits were divided into two groups: perimortem and postmortem. The postmortem samples were collected at 17 h after the administration of ketamine (40 mg/kg) intravenously. For a better understanding of the metabolism of ketamine in eyes, an ex vivo study was conducted in goat eyes after administration of ketamine intravitreally. The samples were analyzed by LC-MS/MS and the levels of ketamine and norketamine in these matrices were compared with that of whole blood and plasma. The results of the in vivo study showed a decrease in ketamine levels in whole blood and plasma while an increase in ocular matrices at postmortem. Though, in most cases, this increase/decrease was statistically insignificant. Moreover, there was an increase of norketamine level in ocular matrices. Ex vivo study also shows the presence of norketamine in ocular matrices of goat eyes. The presence of norketamine in goat eyes may be indicative of the metabolism of ketamine in the eyes.

Pharmacokinetic Effects of l-Tetrahydropalmatine on Ketamine in Rat Plasma by Ultraperformance Liquid Chromatography Tandem Mass Spectrometry.

Male Sprague-Dawley rats (n = 18) were randomly divided into three groups: a saline group (20 mL/kg by gavage), a ketamine (KET) group (100 mg/kg by gavage), and a KET (the same routes and doses) combined with levo-tetrahydropalmatine (l-THP; 40 mg/kg by gavage) group (n = 6). Blood samples were acquired at different time points after drug administration. A simple and sensitive ultraperformance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method was established to determine the concentrations of KET and its metabolite, norketamine (NK), in rat plasma. Chromatographic separation was achieved using a BEH C18 column (2.1 mm × 50 mm, 1.7 µm) with chlorpheniramine maleate (Chlor-Trimeton) as an internal standard (IS). The initial mobile phase consisted of acetonitrile-water with 0.1% methanoic acid (80 : 20, v/v). The multiple reaction monitoring (MRM) modes of m/z 238.1→m/z 179.1 for KET, m/z 224.1→m/z 207.1 for NK, and m/z 275→m/z 230 for Chlor-Trimeton (IS) were utilized to conduct a quantitative analysis. Calibration curves of KET and NK in rat plasma demonstrated good linearity in the range of 2.5-500 ng/mL (r > 0.9994), and the lower limit of quantification (LLOQ) was 2.5 ng/mL for both. Moreover, the intra- and interday precision relative standard deviation (RSD) of KET and NK were less than 4.31% and 6.53%, respectively. The accuracies (relative error) of KET and NK were below -1.41% and -6.07%, respectively. The extraction recoveries of KET and NK were more than 81.23 ± 3.45% and 80.42 ± 4.57%, respectively. This sensitive, rapid, and selective UPLC-MS/MS method was successfully applied to study the pharmacokinetic effects of l-THP on KET after gastric gavage. The results demonstrated that l-THP could increase the bioavailability of KET and promote the metabolism of KET. The results showed that l-THP has pharmacokinetics effects on KET in rat plasma.

Targeted mass spectrometry of ketamine and its metabolites cis-6-hydroxynorketamine and norketamine in human blood serum.

Ketamine (KET) was originally developed as an anesthetic agent but has also attracted attention for further clinical applications such as medical treatment of depression or pain. The use of KET induces dissociation and emergence delirium. Due to these effects, KET has a high potential for abuse. In order to investigate metabolization of KET or to confirm misuse of KET, highly sensitive analytical methods that cover KET and its metabolites are necessary. A new analytical approach for simultaneous analysis of KET and its metabolites cis-6-hydroxynorketamine (HNK) and norketamine (NK) was established. The compounds were extracted from human blood serum by ultrafiltration and solid phase extraction with subsequent vacuum evaporation. The compounds were analyzed by non-enantioselective ultra-high performance micro-flow liquid chromatography (Waters ACQUITY UPLC® M-Class HSS T3 column, 0.1% formic acid and acetonitrile with 0.1% formic acid, 14 µL/min flow rate) coupled with tandem mass spectrometry in positive scheduled multiple reaction monitoring mode. Validation parameters such as linearity, precision, recovery, accuracy, stability, limit of detection (LOD), and limit of quantification (LOQ) were proven. LOD for KET and NK was 0.08 ng/mL and LOQ were 0.5 ng/mL and 0.6 ng/mL, respectively. For HNK, LOD was 0.1 ng/mL and LOQ 0.8 ng/mL. The method was then successfully applied to quantify KET, HNK, and NK in blood serum samples from subjects who received KET intravenously. A novel method for the simultaneous analysis of KET, NK, and HNK was established. This new method could now be used for clinical trials investigating KET and its metabolites HNK and NK or for forensic analysis in order to confirm KET abuse.

Ascending-Dose Study of Controlled-Release Ketamine Tablets in Healthy Volunteers: Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability.

Parenteral ketamine has fast-onset antidepressant and antianxiety effects; however, it causes dissociation, hypertension, and tachycardia shortly after dosing. Ketamine's antidepressant effects may be due to active metabolites rather than to ketamine itself. We hypothesized that oral controlled-release ketamine tablets would improve safety and tolerability compared with injected ketamine by reducing peak ketamine exposures compared with dosing by injection. In this randomized, placebo-controlled ascending-dose study, ketamine doses of 60, 120, or 240 mg or matching placebo (single dose followed by every-12-hours dosing for 5 doses) were given to 24 healthy volunteers. Pharmacokinetics, pharmacodynamics (brain-derived neurotropic factor), adverse events, and vital signs were assessed up to 72 hours. Drug release occurred over ∼10 hours, with most drug substance present as norketamine (∼90%). Area under the concentration-time curve and peak concentration were dose proportional. Elimination half-life was prolonged (7-9 hours) compared with published data from immediate-release oral formulations. There were no changes in blood pressure or heart rate after any dose. Mild dissociation was reported after 240 mg but not lower doses; mean dissociation ratings in this group were minimal (1-2/76). There were no clinically significant changes in ECGs or safety laboratory tests at any time. Compared with injected ketamine, oral controlled-release ketamine tablets did not increase blood pressure or heart rate, and only at doses of 240 mg was dissociation of mild intensity reported. Reducing and delaying ketamine peak concentration by oral dosing with controlled-release ketamine tablets improve this drug's tolerability for patients with depression/anxiety.

Application of petal-shaped ionic liquids modified covalent organic frameworks for one step cleanup and extraction of general anesthetics in human plasma samples.

Here, the novel petal-shaped ionic liquids modified covalent organic frameworks (PS-IL-COFs) particles have been synthesized by using ionic liquids as modifying agent, which could be beneficial to avoid the aggregation of COFs during the preparation and improve its dispersing performance. The novel PS-IL-COFs particles have been used and evaluated in the one step cleanup and extraction (OSCE) procedure for human plasma prior to the analysis of 3 general anesthetics by liquid chromatography-tandem quadrupole mass spectrometry (LC-MS/MS). In the OSCE procedure, human plasma samples are directly mixed with extraction solvent and PS-IL-COFs particles, and the extraction and cleanup procedure have been carried out simultaneously. Compared with the Oasis PRiME HLB cartridge method, the OSCE procedure using PS-IL-COFs particles as sorbents is much more effective for the minimization of ion suppression resulted from blood phospholipids. Under optimal conditions, the PS-IL-COFs particles show higher cleanup efficiency of 3 general anesthetics with recoveries in the range of 82.5%-115%. The limits of quantification (LOQs) for propofol, ketamine and etomidate are 0.18 µg/L, 0.15 µg/L and 0.016 µg/L, respectively. Validation results on linearity, specificity, precision and trueness, as well as on the application to analysis of general anesthetics in a case of a 54-year-old female suffered gallstone demonstrate the applicability to clinical studies.

Pharmacokinetics, absolute bioavailability and tolerability of ketamine after intranasal administration to dexmedetomidine sedated dogs.

Intranasal ketamine has recently gained interest in human medicine, not only for its sedative, anaesthetic or analgesic properties, but also in the management of treatment resistant depression, where it has been shown to be an effective, fast acting alternative treatment. Since several similarities are reported between human psychiatric disorders and canine anxiety disorders, intranasal ketamine could serve as an alternative treatment for anxiety disordered dogs. However, to the authors knowledge, intranasal administration of ketamine and its pharmacokinetics have never been described in dogs. Therefore, this study aimed to examine the pharmacokinetics, absolute bioavailability and tolerability of intranasal ketamine administration compared with intravenous administration. Seven healthy, adult laboratory Beagle dogs were included in this randomized crossover study. The dogs received 2 mg/kg body weight ketamine intravenously (IV) or intranasally (IN), with a two-week wash-out period. Prior to ketamine administration, dogs were sedated intramuscularly with dexmedetomidine. Venous blood samples were collected at fixed times until 480 min post-administration and ketamine plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. Cardiovascular parameters and sedation scores were recorded at the same time points. Non-compartmental pharmacokinetic analysis revealed a rapid (Tmax = 0.25 ± 0.14 h) and complete IN bioavailability (F = 147.65 ± 49.97%). Elimination half-life was similar between both administration routes (T1/2el IV = 1.47 ± 0.24 h, T1/2el IN = 1.50 ± 0.97 h). Heart rate and sedation scores were significantly higher at 5 and 10 min following IV administration compared to IN administration, but not at the later time-points.

Effects of ketamine in patients with treatment-refractory generalized anxiety and social anxiety disorders: Exploratory double-blind psychoactive-controlled replication study.

BACKGROUND: We previously reported that ketamine has anxiolytic effects in patients with treatment-resistant generalized anxiety and social anxiety disorders. AIMS: The purpose of this study was to replicate our earlier report about ketamine's anxiolytic activity, using a more robust study design. METHODS: This was a double-blind, psychoactive-controlled ascending dose study in 12 patients with treatment-resistant generalized anxiety and social anxiety disorders who were not currently depressed. Ascending doses of ketamine (0.25, 0.5, 1 mg/kg) were administered at weekly intervals, and midazolam 0.01 mg/kg, the control, was randomly inserted into the ketamine dose sequence. Assessments included ratings of anxiety and dissociation, safety and tolerability, and blood samples for ketamine pharmacokinetics and BDNF concentrations. RESULTS: Improvements in anxiety ratings occurred within an hour of ketamine dosing, and persisted for up to 1 week. A dose-response profile was noted for anxiolytic effects, dissociative side effects, and changes in blood pressure and heart rate after ketamine dosing. Midazolam had minor brief effects on anxiety ratings. Ketamine was safe and well tolerated. Ketamine pharmacokinetics were correlated with dissociation ratings. Serum BDNF concentrations declined over time and were similar for all treatments. CONCLUSIONS: Ketamine may be a potential therapeutic option for patients with treatment-resistant generalized anxiety and social anxiety disorders.

Pharmacokinetics of an intravenous constant rate infusion of a morphine-lidocaine-ketamine combination in Holstein calves undergoing umbilical herniorrhaphy.

OBJECTIVE: To describe the pharmacokinetics of morphine, lidocaine, and ketamine associated with IV administration of a constant rate infusion (CRI) of a morphine-lidocaine-ketamine (MLK) combination to calves undergoing umbilical herniorrhaphy. ANIMALS: 20 weaned Holstein calves with umbilical hernias. PROCEDURES: Calves were randomly assigned to receive a CRI of an MLK solution (0.11 mL/kg/h; morphine, 4.8 µg/kg/h; lidocaine, 2.1 mg/kg/h; and ketamine, 0.42 mg/kg/h) for 24 hours (MLK group) or 2 doses of flunixin meglumine (1.1 mg/kg, IV, q 24 h) and a CRI of saline (0.9% NaCl) solution (0.11 mL/kg/h) for 24 hours (control group). For all calves, the CRI was begun after anesthesia induction. Blood samples were obtained immediately before and at predetermined times for 120 hours after initiation of the assigned treatment. Noncompartmental analysis was used to estimate pharmacokinetic parameters for the MLK group. RESULTS: During the CRI, steady-state serum concentrations were achieved for lidocaine and ketamine, but not morphine. Mean terminal half-life was 4.1, 0.98, and 1.55 hours and area under the concentration-time curve was 41, 14,494, and 7,426 h•µg/mL for morphine, lidocaine, and ketamine, respectively. After the CRI, the mean serum drug concentration at steady state was 6.3, 616.7, and 328 ng/mL for morphine, lidocaine, and ketamine, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: During the CRI of the MLK solution, steady-state serum concentrations were achieved for lidocaine and ketamine, but not morphine, likely owing to the fairly long half-life of morphine. Kinetic analyses of MLK infusions in cattle are necessary to establish optimal dosing protocols.

Subanesthetic Dose of Ketamine Improved CFA-induced Inflammatory Pain and Depression-like Behaviors Via Caveolin-1 in Mice.

BACKGROUND: Ketamine, a commonly used nonbarbiturate anesthetic drug, possesses antidepressant properties at subanesthetic doses; however, the underlying mechanisms remain unclear. MATERIALS AND METHODS: The analgesic and antidepressant effects of ketamine were explored using a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model in vivo. Mice were first divided into sham or CFA injection group randomly, and were observed for mechanical hyperalgesia, depression-like behavior, and mRNA expression of caveolin-1. Then ketamine was administered in CFA-treated mice at day 7. RESULTS: The behavioral testing results revealed mechanical hyperalgesia and depression in mice from days 7 to 21 after CFA injection. Ketamine reversed depression-like behaviors induced by CFA injection. It also restored the brain-regional expression levels of caveolin-1 in CFA-treated mice. In addition, caveolin-1 mRNA and protein expression were increased in the prefrontal cortex and nucleus accumbens of CFA-treated mice. However, ketamine reversed the increase in caveolin-1 expression in the ipsilateral and contralateral prefrontal cortex and nucleus accumbens, supporting the distinct roles of specific brain regions in the regulation of pain and depression-like behaviors. CONCLUSIONS: In CFA-treated mice that exhibited pain behavior and depression-like behavior, ketamine reversed depression-like behavior. The prefrontal cortex and nucleus accumbens are the important brain regions in this regulation network. Despite these findings, other molecules and their mechanisms in the signal pathway, as well as other regions of the brain in the pain matrix, require further exploration.

A randomized, placebo-controlled, phase 1 study to evaluate the effects of TAK-063 on ketamine-induced changes in fMRI BOLD signal in healthy subjects.

RATIONALE: Phosphodiesterase 10A inhibitor TAK-063 has shown effects that suggest efficacy in schizophrenia treatment. OBJECTIVE: This randomized, double-blind, placebo-controlled, incomplete-crossover study investigated effects of single oral administration of TAK-063 on ketamine-induced changes in blood oxygen level-dependent (BOLD) signal in healthy males. METHODS: Healthy men aged 18 to 45 years with normal magnetic resonance imaging (MRI) scans and electroencephalogram measurements at screening were eligible. Each subject was randomized to one of nine treatment schedules: all subjects received placebo and two of three doses of TAK-063 followed by ketamine. The primary endpoint was ketamine-induced brain activity in select regions of the brain during resting state. Secondary endpoints included pharmacokinetic parameters of TAK-063, proportion of subjects with treatment-emergent adverse events (AEs), and percentage of subjects meeting criteria for abnormal safety laboratory tests and vital sign measurements. RESULTS: The study comprised 27 subjects. Prior to ketamine infusion, TAK-063 exerted region-specific effects on resting state functional MRI (fMRI) BOLD signal. After ketamine administration, TAK-063 reduced the Cohen's effect size for resting-state fMRI BOLD signal in key brain regions examined, and exerted similar effects on BOLD signal during the working memory task across all doses. TAK-063 was safe and well tolerated. CONCLUSIONS: Our results are consistent with non-clinical studies of ketamine and TAK-063 and clinical studies of ketamine and risperidone. It is unknown whether these data are predictive of potential antipsychotic efficacy, and further analyses are required.