Synthesis and identification of deschloroketamine metabolites in rats' urine and a quantification method for deschloroketamine and metabolites in rats' serum and brain tissue using liquid chromatography tandem mass spectrometry.

Deschloroketamine (2-(methylamino)-2-phenyl-cyclohexanone) is a ketamine analog belonging to a group of dissociative anesthetics, which have been distributed within the illicit market since 2015. However, it was also being sold as 'ketamine' misleading people to believe that they were getting genuine ketamine. Dissociative anesthetics have also come to the attention of the psychiatric field due to their potential properties in the treatment of depression. At present, there is a dearth of information on deschloroketamine related to its metabolism, biodistribution, and its mechanism of action. We have therefore carried out a metabolomics study for deschloroketamine via non-targeted screening of urine samples employing liquid chromatography combined with high-resolution mass spectrometry. We developed and validated a multiple reaction monitoring method using a triple quadrupole instrument to track metabolites of deschloroketamine. Furthermore, significant metabolites of deschloroketamine, (trans-dihydrodeschloroketamine, cis- and trans-dihydronordeschloroketamine, and nordeschloroketamine), were synthesized in-house. The prepared standards were utilized in the developed multiple reaction monitoring method. The quantification method for serum samples provided intra-day accuracy ranging from 86% to 112% with precision of 3% on average. The concentrations of cis/trans-dihydronordeschloroketamines and trans-dihydrodeschloroketamine were lower than 10 ng/mL, nordeschloroketamine and deschloroketamine ranged from 0.5 to 860 ng/mL in real samples. The quantification method for brain tissue provided intra-day accuracy ranging from 80% to 125% with precision of 7% on average. The concentrations of cis/trans-dihydronordeschloroketamines and trans-dihydrodeschloroketamine ranged from 0.5 to 70 ng/g, nordeschloroketamine and deschloroketamine varied from 0.5 to 4700 ng/g in real samples.

Safety and efficacy of ketamine xylazine along with atropine anesthesia in BALB/c mice

Anesthetics are an indispensable prerequisite for surgical intervention and pharmacological animal studies. The objective of present study was to optimize the dose of ketamine (K) and xylazine (X) along with atropine sulfate (A) in order to achieve surgical tolerance in BALB/c mice. Several doses of ketamine (100, 150, 200 mg/kg) and xylazine (10, 15, 20 mg/kg) were mixed and combination of nine doses (K/X: 100/10, 100/15, 100/20, 150/10, 150/15, 150/20, 200/10,200/15,200/20) were evaluated (n=9 per combination). A constant dose of atropine (0.05 mg/kg) was also used to counter side effect. Time-related parameters were evaluated on the basis of reflexes. KX at dose 200/20 mg/kg produced surgical tolerance in all nine mice with duration 55.00±6.87 minutes. The induction time 0.97±0.09 minutes, sleeping time 90.67±5.81 minutes and immobilization time (102.23±6.83 minutes) were significantly higher than all combination. However, this combination was considered unsafe due to 11 % mortality. While, KX at dose 200/15 mg/kg results in none of the mortality, so was considered as safe. Moreover, this combination produces surgical tolerance in 89 % mice with duration (30.00±7.45 minutes). It was concluded that KX at dose 200/15 mg/kg along with atropine 0.05 mg/kg is safe for performing surgical interventions in BALB/c mice.

Ketamina, una antigua droga que renace ante el dolor: parte I / Ketamine, and old drug coming back for pain management: part I

La Ketamina es una antigua droga usada como inductor anestésico, que debido a sus efectos adversos alucinatorios se subutilizó en las últimas décadas, pero debido al avance de las neurociencias y al conocimiento del dolor, renace como un potente medicamento analgésico (antihiperalgésico). Es un bloqueador no competitivo de los receptores NMDA, que son los receptores que se activan cuando el dolor es intenso, se postula que se podría utilizar para disminuir la percepción del dolor. es un neuromodulador del dolor y potenciador de la acción analgésica de los opioides. Los estudios clínicos han evidenciado su uso en el manejo del dolor postoperatorio dentro de una modalidad multimodal, con menor incidencia de náuseas y vómitos que al usar opioides solos y con reacciones adversas de tipo alucinatorias escasas. Las dosis ideales para los distintos tipos de cirugía, actualmente se basan en opiniones de expertos y se requieren mayores estudios. En dolor neuropático y en dolor por cáncer existe evidencia tipo IV, basadas en serie de casos que muestra ser útil. En tolerancia por opioides y en cronificación del dolor postoperatorio existen buenos estudios, pero aún no concluyentes. En conclusión, la ketamina es un fármaco útil, pero se debe conocer muy bien su farmacología para poder usarlo de manera segura y con un buen criterio clínico para el manejo del dolor moderado y/o intenso.

Ketamine is an old drug used in the induction of anesthesia that due to adverse hallucinatory effects has been under utilized during the past decades. However, the advances in neuroscience and a deeper knowledge of pain, ketamine is reborn as a strong analgesic (antihyperalgesic) aid. Ketamine is a non competitive blocker of NMDA receptors that are activated by severe pain and it could be used in pain reduction. Ketamine is a pain neuromodulator and enhancer of the opioids analgesic action. Clinicals trials showed it can be used in post surgery pain management in a number of ways with lessened side effects sunch as nausea and vomiting and scare hallucinatory effects compared to those caused by opioid treatment alone. the ideal dosage for different types of surgery now relies on the opinion of experts, however, further research is required. In neuropathic and cancer pain there is type IV evidence based on a number of cases that proves to be useful. Good trials, but not yet conclusive have been made in matters of tolerance to opioids and post surgery chronic pain. In conclusion, Ketamine is a useful drug, however, a deep knowledge of the same as well as good judgement are required for using it in moderate and/or severe pain management.

Ketamine, but not propofol, anaesthesia is regulated by metabotropic glutamate 5 receptors.

BACKGROUND: Group I metabotropic glutamate receptors (mGluRs) have been reported to regulate N-methyl-d-aspartate (NMDA) receptor function in various brain regions. The selective mGluR5 antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) can potentiate NMDA antagonists such as PCP and MK-801-induced behavioural responses. In the present study, the role of group I mGluRs on ketamine- and propofol-induced general anaesthesia was examined. METHODS: Mice were pretreated with various doses of the group I mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG), selective mGluR5 agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG), mGluR1 antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (CPCCOEt) and mGluR5 antagonist MPEP followed by administration of ketamine (120 mg kg(-1)) or propofol (140 mg kg(-1)) to induce anaesthesia. The duration of loss of righting reflex was recorded. RESULTS: DHPG and CHPG antagonized and MPEP potentiated ketamine-induced anaesthesia in a dose-dependent manner. CPCCOEt was ineffective. However, propofol-induced anaesthesia was not affected after manipulating mGluR1 and mGluR5 receptors. CONCLUSIONS: mGluR5 receptors play an important role in modulation of anaesthesia induced by ketamine, but not propofol.