Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers.

BACKGROUND: Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine. METHODS: Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites. RESULTS: A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output. CONCLUSIONS: S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to S-ketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner. CLINICAL TRIAL REGISTRATION: Dutch Cochrane Center 5359.

Repurposing of Drugs-The Ketamine Story.

An intranasal formulation of esketamine, the S enantiomer of ketamine, in conjunction with an oral antidepressant, has been approved by the FDA for treating treatment-resistant major depressive disorder (TRD) in 2019, almost 50 years after it was approved as an intravenous anesthetic. In contrast to traditional antidepressants, ketamine shows a rapid (within 2 h) and sustained (∼7 days) antidepressant effect and has significant positive effects on antisuicidal ideation. Ketamine's antidepressant mechanism is predominantly mediated by the N-methyl-d-aspartate receptor (NMDA) receptor, although NMDA-independent mechanisms are not ruled out. At the neurocircuitry level, ketamine affects the brain's reward and mood circuitry located in the corticomesolimbic structures involving the hippocampus, nucleus accumbens, and prefrontal cortex. Repurposing of ketamine for treating TRD provided a new understanding of the pathophysiology of depression, a paradigm shift from monoamine to glutamatergic neurotransmission, thus making it a unique tool to investigate the brain and its complex neurocircuitries.

Violence against women and drug-facilitated sexual assault (DFSA): A review of the main drugs.

Sexual violence is a universal phenomenon without restriction to sex, age, ethnicity or social class that causes devastating effects in the physical and mental health spheres, in the short-term and long-term, such as pregnancy, sexually transmitted infections (STI) and greater susceptibility to psychiatric symptoms, especially depression. Some cases of sexual assault and rape are based on the use of so-called drug-facilitated sexual assault (DFSA), which cause victims' loss of consciousness and inability to defend, making them vulnerable to violence. Thus, this article aimed to review the literature on gender violence and the drugs used to facilitate sexual assault, addressing their mechanism of action and pharmacokinetics, as well as drug detection times in human body and types of forensic identification. It is understood that the knowledge of these drugs and their pharmacological and diagnostic mechanisms should be widely disseminated, especially about sensitivity tests and the time the drug remains in the body, which would validate the promotion of evidence to prove abuse, and, thus, being able to give a promising outcome to cases of aggression, which is extremely beneficial for women.

Predosing Chemical Stability of Admixtures of Propofol, Ketamine, Fentanyl, and Remifentanil.

Admixtures of propofol-ketamine, propofol-ketamine-fentanyl, and propofol-ketamine-remifentanil were subjected to various clinically relevant conditions to study their chemical stability. A novel high-performance liquid chromatography-mass spectrometry method revealed no degradation of any compound by incubation at 37°C, constant mixing, or table-top storage for 6- and 24-hour time periods, except variable recovery of both propofol and fentanyl in the admixtures of propofol-ketamine-fentanyl suggesting possible degradation.

Syntheses, analytical and pharmacological characterizations of the 'legal high' 4-[1-(3-methoxyphenyl)cyclohexyl]morpholine (3-MeO-PCMo) and analogues.

New psychoactive substances (NPS) are commonly referred to as 'research chemicals', 'designer drugs' or 'legal highs'. One NPS class is represented by dissociative anesthetics, which include analogues of the arylcyclohexylamine phencyclidine (PCP), ketamine and diphenidine. A recent addition to the NPS market was 4-[1-(3-methoxyphenyl)cyclohexyl]morpholine (3-MeO-PCMo), a morpholine analogue of 3-MeO-PCP. Although suspected to have dissociative effects in users, information about its pharmacological profile is not available. From clinical and forensic perspectives, detailed analytical data are needed for identification, especially when facing the presence of positional isomers, as these are frequently unavailable commercially. This study presents the analytical and pharmacological characterization of 3-MeO-PCMo along with five additional analogues, namely the 2- and 4-MeO-PCMo isomers, 3,4-methylenedioxy-PCMo (3,4-MD-PCMo), 3-Me-PCMo and PCMo. All six arylcyclohexylmorpholines were synthesized and characterized using chromatographic, mass spectrometric and spectroscopic techniques. The three positional isomers could be differentiated and the identity of 3-MeO-PCMo obtained from an internet vendor was verified. All six compounds were also evaluated for affinity at 46 central nervous system receptors including the N-methyl-d-aspartate receptor (NMDAR), an important target for dissociative anesthetics such as PCP and ketamine. In vitro binding studies using (+)-[3-3 H]-MK-801 in rat forebrain preparations revealed moderate affinity for NMDAR in the rank order of 3-Me >3-MeO > PCMo >3,4-MD > 2-MeO > 4-MeO-PCMo. 3-MeO-PCMo was found to have moderate affinity for NMDAR comparable to that of ketamine, and had an approximate 12-fold lower affinity than PCP. These results support the anecdotal reports of dissociative effects from 3-MeO-PCMo in humans.

An overview of emerging and new psychoactive substances in the United Kingdom.

The purpose of this review is to identify emerging or new psychoactive substances (NPS) by undertaking an online survey of the UK NPS market and to gather any data from online drug forums and published literature. Drugs from four main classes of NPS were identified: psychostimulants, dissociative anaesthetics, hallucinogens (phenylalkylamine-based and lysergamide-based materials) and finally benzodiazepines. For inclusion in the review, the 'user reviewers' on drugs forums were selected based on whether or not the particular NPS of interest was used alone or in combination. NPS that were used alone were considered. Each of the classes contained drugs that are modelled on existing illegal materials and will be covered by the UK New Psychoactive Substances Bill in 2016.

Assessment of stability of ketamine-xylazine preparations with or without acepromazine using high performance liquid chromatography-mass spectrometry.

The objective of this study was to evaluate the stability of 3 distinct preparations of ketamine and xylazine, with or without acepromazine, stored at room temperature or at 4°C for 1, 2, and 3 mo. Drug concentrations were compared to fresh solutions, using a high performance liquid chromatography-mass spectrometry/selected-ion monitoring (HPLC-MS/SIM) assay. The concentrations of ketamine and xylazine, diluted in physiological saline, did not change over time at room temperature or at 4°C. However, acepromazine concentrations decreased over time when stored at room temperature. In contrast, undiluted ketamine-xylazine preparations gradually decreased in concentration when stored at room temperature. All of the drug concentrations remained above 90% of their original concentration when stored at 4°C. In conclusion, when diluted in physiological saline, ketamine-xylazine cocktails can be stored for 3 mo, whereas undiluted cocktails can lose efficacy over 3 mo at room temperature. Storage at 4°C could preserve drug stability.

Cette étude vise à évaluer la stabilité de trois préparations de kétamine et xylazine avec ou sans acépromazine gardées à température pièce, ou à 4°C, pour 1, 2 et 3 mois. Les concentrations des drogues ont été comparées à des solutions fraiches, toutes analysées par HPLC-MS/SIM. Les concentrations de kétamine et xylazine, des solutions diluées dans la saline physiologique, sont restées constantes indépendamment du temps et de la température de conservation, par contre la concentration d'acépromazine a diminué dans les préparations gardées à température pièce. En contraste, les concentrations des préparations pures de kétamine et xylazine conservées à température pièce ont diminué avec le temps. En conclusion, la kétamine et la xylazine en cocktail avec du salin peuvent être utilisés pour une période de 3 mois, par contre, conservées à température pièce, les concentrations diminuent progressivement en préparation pure. La conservation des préparations à 4°C favorise la stabilité des drogues.(Traduit par les auteurs).

A genosensor based on CPE for study the interaction between ketamine as an anesthesia drug with DNA.

The electrochemical oxidation of ketamine as an analgesia and anesthesia drug and its interaction with DNA was studied at carbon paste electrode (CPE) using voltammetric techniques. Ketamine showed one irreversible oxidation peak nearly around +1.14 V vs. Ag|AgCl|KCl (3 M) only in Britton buffer (pH 7.00). The effect of scan rate on the cyclic voltammetric behavior of ketamine was investigated at the CPE and binding constant of ketamine and DNA was also calculated. The binding mode of DNA and ketamine was elucidated by differential pulse voltammetry and UV-vis spectroscopy techniques. Based on these results, interaction between ketamine and single-stranded DNA was of electrostatic mode, while between double-stranded DNA and ketamine was of groove binding. Ketamine showed a special affinity toward guanine bases of DNA. Also, ketamine was employed as an electrochemical indicator for detection of DNA hybridization. The difference between the oxidation peak current of the DNA probe modified CPE in the presence and absence of ketamine (ΔI) was enhanced with increasing ketamine concentration and a detection limit of 1.98 nM was evaluated. To further investigate the selectivity of this biosensor, some noncomplementary sequences were used. Finally, the proposed method was successfully used for voltammetric determination of ketamine in real samples.

S-ketamine versus racemic ketamine in dogs: their relative potency as induction agents.

OBJECTIVE: To determine the potency ratio between S-ketamine and racemic ketamine as inductive agents for achieving tracheal intubation in dogs. STUDY DESIGN: Prospective, randomized, 'blinded', clinical trial conducted in two consecutive phases. ANIMALS: 112 client-owned dogs (ASA I or II). METHODS: All animals were premedicated with intramuscular acepromazine (0.02 mg kg(-1)) and methadone (0.2 mg kg(-1)). In phase 1, midazolam (0.2 mg kg(-1)) with either 3 mg kg(-1) of racemic ketamine (group K) or 1.5 mg kg(-1) of S-ketamine (group S) was administered IV, for induction of anaesthesia and intubation. Up to two additional doses of racemic (1.5 mg kg(-1)) or S-ketamine (0.75 mg kg(-1)) were administered if required. In phase 2, midazolam (0.2 mg kg(-1)) with 1 mg kg(-1) of either racemic ketamine (group K) or S-ketamine (group S) was injected and followed by a continuous infusion (1 mg kg minute(-1)) of each respective drug. Differences between groups were statistically analyzed via t-test, Fisher exact test and ANOVA for repeated measures. RESULTS: Demographics and quality and duration of premedication, induction and intubation were comparable among groups. During phase 1 it was possible to achieve tracheal intubation after a single dose in more dogs in group K (n = 25) than in group S (n = 16) (p = 0.046). A dose of 3 mg kg(-1) S-ketamine allowed tracheal intubation in the same number of dogs as 4.5 mg kg(-1) of racemic ketamine. The estimated potency ratio was 1.5:1. During phase 2, the total dose (mean ± SD) of S-ketamine (4.02 ±1.56 mg kg(-1)) and racemic ketamine (4.01 ± 1.42) required for tracheal intubation was similar. CONCLUSION AND CLINICAL RELEVANCE: Racemic and S-ketamine provide a similar quality of anaesthetic induction and intubation. S-ketamine is not twice as potent as racemic ketamine and, if infused, the potency ratio is 1:1.

Simultaneous determination of psychoactive compounds in foodstuffs using micellar liquid chromatography with direct injection.

Amicellar liquid chromatographic procedure was developed for the simultaneous determination of three commonly used stupefacients, lidocaine, ketamine and diazepam, using a C18 reversed-phase column. A micellar mobile phase 0.15 M sodium dodecyl sulfate and 6% (v/v) pentanol, pH 7, and UV detection at 230 nm were used to determine the three stupefacients in food samples. Using the selected mobile phase, the stupefacients were eluted in less than 10 min with linearity (r = 0.998), LOD (range: 0.004-0.03 ppm), LOQ (range: 0.004-0.03 ppm), intraday and interday precision (below 2.84%), and mean recoveries (range: 79.11-110.16%) in the different foodstuffs were in accordance with the internationally established acceptance criteria. Validation of the developed method was performed on the basis of International Conference on Harmonization validation guidelines. The optimized and validated micellar liquid chromatographic method was successfully applied in the determination of lidocaine, diazepam, and ketamine in a real food sample (mango drink) and in spiked food samples (banana, ladoo, soft drink, tea). The developed method could also be easily used by law enforcement laboratories and hospitals for routine analysis.

From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs.

PCP or phencyclidine was discovered in 1956 and soon became a popular street drug. Dissociatives including PCP, ketamine, and dextromethorphan have been used non-medically for their mind-altering effects for over 60 years. Many of these compounds have also been used clinically and in legitimate research. At least 14 derivatives of PCP were sold for non-medical and illict use from the late 1960s until the 1990s. With the advent of the Internet, the drug market underwent a dramatic evolution. While initially gray-market chemical vendors offering dextromethorphan and ketamine thrived, most recently the market has shifted to legal high and online-based research chemical vendors. Starting with the first dissociative research chemical, 4-MeO-PCP in 2008, the dissociative research chemical market has rapidly evolved and currently comprises at least 12 dissociatives, almost half of which were unknown in the scientific literature prior to their introduction. Several of these, including methoxetamine, have reached widespread use internationally. A historical account of non-medical use of over 30 dissociative compounds was compiled from a diverse collection of sources. The first complete portrait of this underground market is presented along with the relevant legal, technological, and scientific developments which have driven its evolution.

[Ketamine for treatment of acute depression]. / Ketamin til akut depressionsbehandling.

In clinical trials a single dose of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine has shown a rapid antidepressant effect in patients with treatment-resistant depression and bipolar depression. The implications of glutaminergic mechanisms in depression and the rapid effect of a single dose of ketamine could open new pathways to understand the pathophysiology of depression and the development of novel rapid-acting antidepressant drugs.

Structure of the pentameric ligand-gated ion channel GLIC bound with anesthetic ketamine.

Pentameric ligand-gated ion channels (pLGICs) are targets of general anesthetics, but a structural understanding of anesthetic action on pLGICs remains elusive. GLIC, a prokaryotic pLGIC, can be inhibited by anesthetics, including ketamine. The ketamine concentration leading to half-maximal inhibition of GLIC (58 µM) is comparable to that on neuronal nicotinic acetylcholine receptors. A 2.99 Å resolution X-ray structure of GLIC bound with ketamine revealed ketamine binding to an intersubunit cavity that partially overlaps with the homologous antagonist-binding site in pLGICs. The functional relevance of the identified ketamine site was highlighted by profound changes in GLIC activation upon cysteine substitution of the cavity-lining residue N152. The relevance is also evidenced by changes in ketamine inhibition upon the subsequent chemical labeling of N152C. The results provide structural insight into the molecular recognition of ketamine and are valuable for understanding the actions of anesthetics and other allosteric modulators on pLGICs.

Inhibition of cytochrome P450 enzymes involved in ketamine metabolism by use of liver microsomes and specific cytochrome P450 enzymes from horses, dogs, and humans.

OBJECTIVE: To identify and characterize cytochrome P450 enzymes (CYPs) responsible for the metabolism of racemic ketamine in 3 mammalian species in vitro by use of chemical inhibitors and antibodies. SAMPLE: Human, canine, and equine liver microsomes and human single CYP3A4 and CYP2C9 and their canine orthologs. PROCEDURES: Chemical inhibitors selective for human CYP enzymes and anti-CYP antibodies were incubated with racemic ketamine and liver microsomes or specific CYPs. Ketamine N-demethylation to norketamine was determined via enantioselective capillary electrophoresis. RESULTS: The general CYP inhibitor 1-aminobenzotriazole almost completely blocked ketamine metabolism in human and canine liver microsomes but not in equine microsomes. Chemical inhibition of norketamine formation was dependent on inhibitor concentration in most circumstances. For all 3 species, inhibitors of CYP3A4, CYP2A6, CYP2C19, CYP2B6, and CYP2C9 diminished N-demethylation of ketamine. Anti-CYP3A4, anti-CYP2C9, and anti-CYP2B6 antibodies also inhibited ketamine N-demethylation. Chemical inhibition was strongest with inhibitors of CYP2A6 and CYP2C19 in canine and equine microsomes and with the CYP3A4 inhibitor in human microsomes. No significant contribution of CYP2D6 to ketamine biotransformation was observed. Although the human CYP2C9 inhibitor blocked ketamine N-demethylation completely in the canine ortholog CYP2C21, a strong inhibition was also obtained by the chemical inhibitors of CYP2C19 and CYP2B6. Ketamine N-demethylation was stereoselective in single human CYP3A4 and canine CYP2C21 enzymes. CONCLUSIONS AND CLINICAL RELEVANCE: Human-specific inhibitors of CYP2A6, CYP2C19, CYP3A4, CYP2B6, and CYP2C9 diminished ketamine N-demethylation in dogs and horses. To address drug-drug interactions in these animal species, investigations with single CYPs are needed.

[Ketamine is used again by both physicians and addicts]. / Ketamin genopdaget af både læger og misbrugere.

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.

Comparison of the effects of racemic ketamine and S-ketamine for anesthesia in Rheem gazelles (Gazella subgutturosa marica) and Subgutturosa gazelles (Gazella subgutturosa subgutturosa).

OBJECTIVE: To evaluate effects of racemic ketamine and S-ketamine in gazelles. ANIMALS: 21 male gazelles (10 Rheem gazelles [Gazella subgutturosa marica] and 11 Subgutturosa gazelles [Gazella subgutturosa subgutturosa]), 6 to 67 months old and weighing (mean±SD) 19 ± 3 kg. PROCEDURES: In a randomized, blinded crossover study, a combination of medetomidine (80 µg/kg) with racemic ketamine (5 mg/kg) or S-ketamine (3 mg/kg) was administered i.m.. Heart rate, blood pressure, respiratory rate, rectal temperature, and oxygen saturation (determined by means of pulse oximetry) were measured. An evaluator timed and scored induction of, maintenance of, and recovery from anesthesia. Medetomidine was reversed with atipamezole. The alternate combination was used after a 4-day interval. Comparisons between groups were performed with Wilcoxon signed rank and paired t tests. RESULTS: Anesthesia induction was poor in 2 gazelles receiving S-ketamine, but other phases of anesthesia were uneventful. A dominant male required an additional dose of S-ketamine (0.75 mg/kg, i.m.). After administration of atipamezole, gazelles were uncoordinated for a significantly shorter period with S-ketamine than with racemic ketamine. Recovery quality was poor in 3 gazelles with racemic ketamine. No significant differences between treatments were found for any other variables. Time from drug administration to antagonism was similar between racemic ketamine (44.5 to 53.0 minutes) and S-ketamine (44.0 to 50.0 minutes). CONCLUSIONS AND CLINICAL RELEVANCE: Administration of S-ketamine at a dose 60% that of racemic ketamine resulted in poorer induction of anesthesia, an analogous degree of sedation, and better recovery from anesthesia in gazelles with unremarkable alterations in physiologic variables, compared with racemic ketamine.

Comparison of racemic ketamine and S-ketamine as agents for the induction of anaesthesia in goats.

OBJECTIVE: To compare racemic ketamine and S-ketamine as induction agents prior to isoflurane anaesthesia. STUDY DESIGN: Prospective, blinded, randomized experimental study. ANIMALS: Thirty-one healthy adult goats weighing 39-86 kg. METHODS: Goats were premedicated with xylazine (0.1 mg kg(-1)) intravenously (IV) given over 5 minutes. Each goat was assigned randomly to one of two treatments for IV anaesthetic induction: group RK (15 goats) racemic ketamine (3 mg kg(-1)) and group SK (16 goats) S-ketamine (1.5 mg kg(-1)). Time from end-injection to recumbency was measured and quality of anaesthetic induction and condition for endotracheal intubation were scored. Anaesthesia was maintained with isoflurane in oxygen for 90 minutes. Heart rate, invasive arterial blood pressure, oxygen saturation, temperature, end-tidal carbon dioxide and isoflurane were recorded every 5 minutes. Arterial blood samples were taken for analysis every 30 minutes. Recovery time to recurrence of swallowing reflex, to first head movement and to standing were recorded and recovery quality was scored. Two-way repeated measures anova, Mann-Whitney and a Mantel-Cox tests were used for statistical analysis as relevant with a significance level set at p<0.05. RESULTS: Induction of anaesthesia was smooth and uneventful in all goats. There was no statistical difference between groups in any measured parameter. Side effects following anaesthetic induction included slight head or limb twitching, moving forward and backward, salivation and nystagmus but were minimal. Endotracheal intubation was achieved in all goats at first or second attempt. Recovery was uneventful on all occasions. All goats were quiet and needed only one or two attempts to stand. CONCLUSIONS AND CLINICAL RELEVANCE: S-ketamine at half the dose rate of racemic ketamine in goats sedated with xylazine and thereafter anaesthetised with isoflurane induces the same clinically measurable effects.