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.

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.

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.

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.

Wherefore ketamine?

PURPOSE OF REVIEW: Ketamine has been repeatedly reviewed in this journal but novel developments have occurred in the last few years prompting an update. Interesting recent publications will be highlighted against a background of established knowledge. RECENT FINDINGS: In the field of anesthesia, particularly in pediatrics, some contributions have been made concerning intramuscular versus intravenous induction. The need for anticholinergic adjuvants has also been clarified. Neuroapoptosis has been observed in animals and its implications for human subjects are discussed in a general context of neurotoxicity. The most important developments, however, are in the treatment of pain. Neurological and urological side effects strongly question long-term use. Other potentially beneficial effects have also been reported, such as anti-inflammatory and antidepressive effects. There are also indications that ketamine may attenuate postoperative delirium in coronary by-pass patients. SUMMARY: More questions have arisen than have been answered. Some have very grave implications. The issue of neuroapoptosis must be clarified. The long-term effects must be further investigated. On the bright side the effects on postoperative delirium, as well as the anti-inflammatory and antidepressive effects, might open new vistas for an old drug.

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.

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.

Use of human microsomes and deuterated substrates: an alternative approach for the identification of novel metabolites of ketamine by mass spectrometry.

In vitro biosynthesis using pooled human liver microsomes was applied to help identify in vivo metabolites of ketamine by liquid chromatography (LC)-tandem mass spectrometry. Microsomal synthesis produced dehydronorketamine, seven structural isomers of hydroxynorketamine, and at least five structural isomers of hydroxyketamine. To aid identification, stable isotopes of the metabolites were also produced from tetra-deuterated isotopes of ketamine or norketamine as substrates. Five metabolites (three hydroxynorketamine and two hydroxyketamine isomers) gave chromatographically resolved components with product ion spectra indicating the presence of a phenolic group, with phenolic metabolites being further substantiated by selective liquid-liquid extraction after adjustments to the pH. Two glucuronide conjugates of hydroxynorketamine were also identified. Analysis by LC-coupled ion cyclotron resonance mass spectrometry gave unique masses in accordance with the predicted elemental composition. The metabolites, including the phenols, were subsequently confirmed to be present in urine of subjects after oral ketamine administration, as facilitated by the addition of deuterated metabolites generated from the in vitro biosynthesis. To our knowledge, phenolic metabolites of ketamine, including an intact glucuronide conjugate, are here reported for the first time. The use of biologically synthesized deuterated material as an internal chromatographic and mass spectrometric marker is a viable approach to aid in the identification of metabolites. Metabolites that have particular diagnostic value can be selected as candidates for chemical synthesis of standards.

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.

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).

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.

Use of SPE and LC/TIS/MS/MS for rapid detection and quantitation of ketamine and its metabolite, norketamine, in urine.

Ketamine (K) has become more and more popular for drug abuse in recent years. A lot of pre-treatment work such as extraction and derivatizing increase difficulties in the tests for ketamine in biological specimens. A rapid method to detect and quantitate ketamine and its metabolite norketamine in urine used deuterated dilution followed by solid phase extraction and liquid chromatography/TurboIonSpray/tandem mass spectrometry (LC/TIS/MS/MS) is described. Control recovery for both low and high concentrations can reach to 90%. Ten ketamine positive urines were examinated by this method. Concentrations ranged from 114 to 2925 ng/mL and from 453 to 9805 ng/mL for norketamine. The method was sensitive, specific, accurate and provided easy operation to detect and quantitate ketamine and its metabolites in urine.

[Determination of ketamine and its metabolites in biological samples].

The abuse of ketamine has gained popularity in recent years. It is important to develop rapid and accurate methods to determine ketamine and its metabolites in biological samples. The metabolites of ketamine are norketamine and dehydronorketamine in vivo. At present, there are blood, urine, hair and so on as specimens for detection, while the methods include GC, GC/MS, HPLC, LC/MS, HPCE etc. In this paper, these methods used for ketamine and its metabolites were reviewed in order to provide some preference for the study in relative fields.

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.

[Ketamine]. / Ketamina.

Ketamine is an intravenous drug with special properties that make it the only agent that presently serves as anesthetic, sedative, amnesiac and analgesic. Although it is sometimes forgotten, ketamine is still considered a viable drug. Water soluble, stable and non-irritant when administered intravenously, ketamine has rapid onset after intravenous injection and provides acceptable anesthesia when administered in continuous infusion. There properties make ketamine useful for total intravenous anesthesia. Both propofol and midazolam are effective in reducing ketamine's adverse side effects. Administered in children by oral, nasal, rectal and intramuscular routes, ketamine allows for gentle anesthetic induction. It can also serve as an adjuvant in regional anesthesia to supplement analgesia. In adults ketamine is most often used for major surgery, particularly in the elderly or in high risk patients who are in shock, severely dehydrated or hemodynamically unstable, or in obstetric patients with hypovolemia or hemorrhage. It is probably the anesthetic of choice for patients with hyperreactive airways. Ketamine's strong analgesic effect at subanesthetic doses allows it to be used as an analgesic during postoperative intensive care or as an analgesic-plus-sedative for patients receiving mechanical ventilation. Interest in using ketamine at low doses for cancer and non-cancer patients with chronic pain has grown recently.

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.