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1.
Aerosp Med Hum Perform ; 92(8): 670-675, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34503619

RESUMO

INTRODUCTION: Ketamine is a rapidly acting general anesthetic which is globally used in surgical analgesia, as well as in the management of pain. It is also used as a recreational drug. Because of its widespread use in surgical settings, the use of this drug presents an aeromedical problemin addition, of course, to the underlying condition for which it has been used. The literature around the mechanisms and side effects of ketamine is reasonably mature, and it is possible to make fairly dependable risk management decisions about return to flying based on the information available. Accordingly, following ketamine use it is recommended that aviators be grounded for 48 h following Aviation Medical Examiner review. If review is unavailable, the aviator should be grounded for 1 wk to allow sufficient time to identify the existence of prolonged side effects, such as psychomimetic effects or cognitive changes.Boyd NL, Navathe PD. An update to aircrew grounding periods after ketamine use. Aerosp Med Hum Perform. 2021; 92(8):670-675.


Assuntos
Medicina Aeroespacial , Aviação , Ketamina , Militares , Humanos , Ketamina/efeitos adversos
2.
Transl Psychiatry ; 11(1): 454, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480014

RESUMO

Ketamine has been demonstrated to be a rapid-onset and long-lasting antidepressant, but its underlying molecular mechanisms remain unclear. Recent studies have emerged microRNAs as important modulators for depression treatment. In this study, we report that miR-98-5p is downregulated in the prefrontal cortex and hippocampus of mice subjected to chronic social stress, while overexpressing it by its agonist alleviates depression-like behaviors. More importantly, we demonstrate that miR-98-5p is upregulated by ketamine administration, while inhibition of it by its antagonist blocks the antidepressant effect of ketamine. Our data implicate a novel molecular mechanism underlying the antidepressant effect of ketamine, and that therapeutic strategies targeting miR-98-5p could exert beneficial effects for depression treatment.


Assuntos
Ketamina , MicroRNAs , Animais , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Hipocampo , Camundongos , MicroRNAs/genética , Córtex Pré-Frontal
3.
Int J Mol Sci ; 22(17)2021 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-34502152

RESUMO

Major depressive disorder is a disabling disease with the number of affected individuals increasing each year. Current antidepressant treatments take between three to six weeks to be effective with forty percent of patients being resistant to treatment, making it necessary to search for new antidepressant treatments. Ketamine, a phencyclidine hydrochloride derivative, given intravenously, induces a rapid antidepressant effect in humans. In mice, it causes increased neurogenesis and antidepressant-like effects. However, it also produces psychomimetic effects in humans and in rodents increases the locomotor activity. In contrast, melatonin, a hormone secreted by the pineal gland and synthesized in extrapineal sites, increases new neuron formation and causes antidepressant-like effects in adult rodents with no collateral effects. Here, we assessed the effects of a non-effective dose of ketamine in combination with melatonin (KET/MEL), both on neurogenesis as well as on the antidepressant-like effect in mice. Our results showed that KET/MEL combination increased neurogenesis and produced antidepressant-like effects without altering locomotor activity after both single and triple administration protocols. Our data strongly suggest that KET/MEL combination could be used to simultaneously promote neurogenesis, reverting neuronal atrophy and inducing antidepressant-like effects.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ketamina/uso terapêutico , Melatonina/uso terapêutico , Animais , Antidepressivos/administração & dosagem , Antidepressivos/farmacologia , Combinação de Medicamentos , Sinergismo Farmacológico , Ketamina/administração & dosagem , Ketamina/farmacologia , Masculino , Melatonina/administração & dosagem , Melatonina/farmacologia , Camundongos , Neurogênese/efeitos dos fármacos
4.
Scand J Trauma Resusc Emerg Med ; 29(1): 136, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34526085

RESUMO

BACKGROUND: Rapid Sequence Induction (RSI) is used for emergency tracheal intubation to minimise the risk of pulmonary aspiration of stomach contents. Ketamine and propofol are two commonly used induction agents for RSI in trauma patients. Yet, no consensus exists on the optimal induction agent for RSI in the trauma population. The aim of this study was to compare 30-day mortality in trauma patients after emergency intubation prehospitally or within 30 min after arrival in the trauma centre using either ketamine or propofol for RSI. METHODS: In this investigator-initiated, retrospective study we included adult trauma patients emergently intubated with ketamine or propofol registered in the local trauma registry at Rigshospitalet, a tertiary university hospital that hosts a level-1 trauma centre. The primary outcome was 30-day mortality. Secondary outcomes included hospital and Intensive Care Unit length of stay as well as duration of mechanical ventilation. We analysed outcomes using multivariable logistic regression models adjusting for age, sex, injury severity score, shock (systolic blood pressure < 90 mmHg) and Glasgow Coma Scale score before intubation and present results as odds ratios (ORs) with 95% confidence intervals. RESULTS: From January 1st, 2015 through December 31st, 2019 we identified a total of 548 eligible patients. A total of 228 and 320 patients received ketamine and propofol, respectively. The 30-day mortality for patients receiving ketamine and propofol was 20.2% and 22.8% (P = 0.46), respectively. Adjusted OR for 30-day mortality was 0.98 [0.58-1.66], P = 0.93. We found no significant association between type of induction agent and hospital length of stay, Intensive Care Unit length of stay or duration of mechanical ventilation. CONCLUSIONS: In this study, trauma patients intubated with ketamine did not have a lower 30-day mortality as compared with propofol.


Assuntos
Ketamina , Propofol , Adulto , Humanos , Escala de Gravidade do Ferimento , Intubação Intratraqueal , Indução e Intubação de Sequência Rápida , Estudos Retrospectivos
5.
BMC Res Notes ; 14(1): 363, 2021 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-34538274

RESUMO

OBJECTIVE: Neuroscience research using laboratory animals has increased over the years for a number of reasons. Some of these studies require the use of anesthetics for surgical procedures. However, the use of anesthetics promotes several physiological changes that may interfere with experimental results. Although the anesthetics and methods of delivery used to vary, one of the most common is ketamine associated with another compound such as xylazine. We aimed to evaluate the effect of ketamine and xylazine (KX) on corticosterone levels and on the degree of phosphorylation of p44/42 (ERK1/2), Src kinases and calcium/calmodulin-dependent kinase II (CAMKII). We also compared the effects of KX on sleep deprivation, which is known to affect the hormonal profile including corticosterone. RESULTS: We found that the use of KX can increase corticosterone levels and alter the degree of phosphorylation of signaling proteins.


Assuntos
Anestesia , Ketamina , Animais , Corticosterona , Ketamina/farmacologia , Fosforilação , Xilazina/farmacologia
6.
Acta Neurol Taiwan ; 30(1): 35-38, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34549399

RESUMO

PURPOSE: Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) is a rare form of primary headache, classified as trigeminal autonomic cephalalgia. Since the underlying mechanism of the pathogenesis has not yet been determined, a standardized therapeutic strategy for SUNCT is unavailable. We present a case of SUNCT syndrome with successful pain relief by intravenous administration of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist. CASE REPORT: A 56-year-old male patient reported severe throbbing and shooting pain in forehead, temporal and periorbital region. We confirmed conjunctival injection, lacrimation, blepharoptosis, and miosis as symptoms related to autonomic activity, and made a diagnosis of SUNCT based on ICHD-3 beta. Numerous treatments were attempted, including pregabalin, gabapentine, nonsteroidal antiinflammatory drugs, acetaminophen, steroids, antidepressants, triptans, nerve blocks, and intravenous lidocaine with unsatisfactory results. Intravenous administration of ketamine (0.4 mg/kg) for one hour, was found to relieve the severe pain. CONCLUSION: Intravenous ketamine can effectively treat SUNCT syndrome. This case demonstrated that involvement of NMDAR could be one of the mechanisms of SUNCT syndrome pathogenesis and establish a therapeutic strategy for this pain syndrome.


Assuntos
Blefaroptose , Ketamina , Síndrome SUNCT , Administração Intravenosa , Cefaleia , Humanos , Ketamina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Síndrome SUNCT/tratamento farmacológico
7.
Int J Mol Sci ; 22(16)2021 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-34445376

RESUMO

Synaptic plasticity is the key to synaptic health, and aberrant synaptic plasticity, which in turn impairs the functioning of large-scale brain networks, has been associated with neurodegenerative and psychiatric disorders. The best known and most studied form of activity-dependent synaptic plasticity remains long-term potentiation (LTP), which is controlled by glutamatergic N-methyl-d-aspartate) receptors (NMDAR) and considered to be a mechanism crucial for cellular learning and memory. Over the past two decades, discrepancies have arisen in the literature regarding the contribution of NMDAR subunit assemblies in the direction of NMDAR-dependent synaptic plasticity. Here, the nonspecific NMDAR antagonist ketamine (5 and 10 mg/kg), and the selective NR2B antagonists CP-101606 and Ro 25-6981 (6 and 10 mg/kg), were administered intraperitoneally in Sprague Dawley rats to disentangle the contribution of NR2B subunit in the LTP induced at the Schaffer Collateral-CA1 synapse using the theta burst stimulation protocol (TBS). Ketamine reduced, while CP-101606 and Ro 25-6981 did not alter the LTP response. The administration of CP-101606 before TBS did not influence the effects of ketamine when administered half an hour after tetanization, suggesting a limited contribution of the NR2B subunit in the action of ketamine. This work confirms the role of NMDAR in the LTP form of synaptic plasticity, whereas specific blockade of the NR2B subunit was not sufficient to modify hippocampal LTP. Pharmacokinetics at the doses used may have contributed to the lack of effects with specific antagonists. The findings refute the role of the NR2B subunit in the plasticity mechanism of ketamine in the model.


Assuntos
Ketamina/administração & dosagem , Fenóis/administração & dosagem , Piperidinas/administração & dosagem , Receptores de N-Metil-D-Aspartato/metabolismo , Sinapses/metabolismo , Animais , Injeções Intraperitoneais , Ketamina/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Fenóis/farmacologia , Piperidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
8.
Exp Eye Res ; 210: 108727, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34390732

RESUMO

Intraocular pressure (IOP) is important for eye health as abnormal levels can led to ocular tissue damage. IOP is typically estimated by tonometry, which only provides snapshots of pressure history. Tonometry also requires subject cooperation and corneal contact that may influence IOP readings. The aim of this research was to investigate IOP dynamics of conscious animals in response to stressors, common anesthetics, tonometry, and temperature manipulations. An eye of male Brown-Norway rats was implanted with a fluid-filled cannula connected to a wireless telemetry system that records IOP continuously. Stress effects were examined by restricting animal movements. Anesthetic effects were examined by varying isoflurane concentration or injecting a bolus of ketamine. Tonometry effects were examined using applanation and rebound tonometers. Temperature effects were examined by exposing anesthetized and conscious animals to warm or cool surfaces. Telemetry recordings revealed that IOP fluctuates spontaneously by several mmHg, even in idle and anesthetized animals. Environmental disturbances also caused transient IOP fluctuations that were synchronous in recorded animals and could last over a half hour. Animal immobilization produced a rapid sustained elevation of IOP that was blocked by anesthetics, whereas little-to-no IOP change was detected in isoflurane- or ketamine-anesthetized animals if body temperature (BT) was maintained. IOP and BT decreased precipitously when heat support was not provided and were highly correlated during surface temperature manipulations. Surface temperature had no impact on IOP of conscious animals. IOP increased slightly during applanation tonometry but not rebound tonometry. The results show that IOP is dynamically modulated by internal and external factors that can activate rapidly and last long beyond the initiating event. Wireless telemetry indicates that animal interaction induces startle and stress responses that raise IOP. Anesthesia blocks these responses, which allows for better tonometry estimates of resting IOP provided that BT is controlled.


Assuntos
Anestésicos Gerais/administração & dosagem , Temperatura Corporal/fisiologia , Pressão Intraocular/fisiologia , Estresse Fisiológico , Tonometria Ocular , Doença Aguda , Anestésicos Dissociativos/administração & dosagem , Anestésicos Inalatórios/administração & dosagem , Animais , Isoflurano/administração & dosagem , Ketamina/administração & dosagem , Masculino , Ratos , Ratos Endogâmicos BN , Telemetria
9.
Psychopharmacology (Berl) ; 238(9): 2555-2568, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34342672

RESUMO

RATIONALE: Guanosine has been shown to potentiate ketamine's antidepressant-like actions, although its ability to augment the anxiolytic effect of ketamine remains to be determined. OBJECTIVE: This study investigated the anxiolytic-like effects of a single administration with low doses of ketamine and/or guanosine in mice subjected to chronic administration of corticosterone and the role of NLRP3-driven signaling. METHODS: Corticosterone (20 mg/kg, p.o.) was administered for 21 days, followed by a single administration of ketamine (0.1 mg/kg, i.p.), guanosine (0.01 mg/kg, p.o.), or ketamine (0.1 mg/kg, i.p.) plus guanosine (0.01 mg/kg, p.o.). Anxiety-like behavior and NLRP3-related targets were analyzed 24 h following treatments. RESULTS: Corticosterone reduced the time spent in the open arms and the central zone in the elevated plus-maze test and open-field test, respectively. Corticosterone raised the number of unsupported rearings and the number and time of grooming, and decreased the latency to start grooming in the open-field test. Disturbances in regional distribution (increased rostral grooming) and grooming transitions (increased aborted and total incorrect transitions) were detected in corticosterone-treated mice. These behavioral alterations were accompanied by increased immunocontent of Iba-1, ASC, NLRP3, caspase-1, TXNIP, and IL-1ß in the hippocampus, but not in the prefrontal cortex. The treatments with ketamine, guanosine, and ketamine plus guanosine were effective to counteract corticosterone-induced anxiety-like phenotype, but not disturbances in the hippocampal NLRP3 pathway. CONCLUSIONS: Our study provides novel evidence that low doses of ketamine and/or guanosine reverse corticosterone-induced anxiety-like behavior and shows that the NLRP3 inflammasome pathway is likely unrelated to this response.


Assuntos
Ketamina , Animais , Ansiedade/induzido quimicamente , Ansiedade/tratamento farmacológico , Comportamento Animal , Corticosterona , Depressão , Guanosina , Hipocampo , Inflamassomos , Ketamina/farmacologia , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR
10.
J Pharm Biomed Anal ; 205: 114289, 2021 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-34365190

RESUMO

Brain microdialysis samples of intensive care patients treated with the essential anesthetics ketamine, midazolam and propofol were investigated. Importantly, despite decades of clinical use, comprehensive human cerebral pharmacokinetic data of these drugs is still missing. To encounter this apparent lack of knowledge, we combined cerebral microdialysis with leading-edge analytical instrumentation to monitor the neurochemistry of living human patients. For the quantitative analysis, high performing analytical approaches were developed that can handle minute sample volumes and possible ultralow target analyte levels. The developed methods provided detection limits below 100 ng L-1 for all target analytes and high precision (below 4% RSD intraday). Methods were linear between LODs and 100 µg L-1 for ketamine, 75 µg L-1 for midazolam and 10 µg L-1 for propofol respectively, with coefficients of determination R2≥ 0.999. Further, being aware of the error-prone and demanding translation of microdialysis levels to interstitial concentrations, in vitro approaches for recovery testing of microdialysis probes as well as internal normalization approaches were conducted. Thus, we herein report the first cerebral pharmacokinetic data of ketamine, midazolam and propofol determined in microdialysis samples of 15 neurointensive care patients. We could prove blood-brain barrier penetration of all of the investigated anesthetics and could correlate applied dosages and actual brain exposition of ketamine. However, we emphasize the need of an expanded prospective study including individual microdialysis recovery testing as well as matched serum and/or cerebrospinal fluid collection for a more comprehensive cerebral pharmacokinetic understanding.


Assuntos
Anestésicos , Ketamina , Propofol , Anestésicos Intravenosos , Encéfalo , Humanos , Midazolam , Estudos Prospectivos
11.
Life Sci ; 284: 119882, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34384829

RESUMO

AIMS: Sepsis is a life-threatening organ dysfunction syndrome arising from infection-induced uncontrolled systemic inflammatory responses. Patients surviving severe sepsis also exhibit increased mortality due to enhanced vulnerability to infections. In this study, we examined whether (R)-ketamine could prevent against lethal sepsis-induced systemic inflammation and inflammatory organ injury. MAIN METHODS: Septic model was induced by cecal ligation and puncture (CLP) surgery on adult mice. (R)-ketamine (10 or 15 mg/kg) was administrated intraperitoneally (i.p.) 24 h before and/or immediately after CLP. KEY FINDINGS: Combined prophylactic and therapeutic use of (R)-ketamine (10 mg/kg), as well as either prophylactic or therapeutic use of (R)-ketamine at a single dose of 15 mg/kg did not reduce 14-day mortality after CLP. However, combined prophylactic and therapeutic use of (R)-ketamine (15 mg/kg) significantly increased 14-day survival rate, attenuated sepsis-induced marked drop in the rectal temperature and increase in the plasma levels of inflammatory cytokines [i.e., interleukin (IL)-6, IL-17A, tumor necrosis factor (TNF)-α, IL-1ß, and IL-10] 12 h after CLP. Furthermore, (R)-ketamine alleviated sepsis-induced increase in the organ injury markers such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), myocardial kinase (CK-MB), and creatinine 24 h after CLP. Moreover, the increased lung wet/dry weight ratio, pulmonary morphological injury and the pulmonary levels of inflammatory cytokines were also attenuated by (R)-ketamine. SIGNIFICANCE: Combined prophylactic and therapeutic use of (R)-ketamine could attenuate systemic inflammation and inflammatory multi-organ injury in mice after CLP-induced lethal sepsis. Therefore, (R)-ketamine would be a potential prophylactic and therapeutic drug for patients prone to sepsis.


Assuntos
Ceco/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Ketamina/uso terapêutico , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Insuficiência de Múltiplos Órgãos/patologia , Animais , Biomarcadores/metabolismo , Citocinas/sangue , Modelos Animais de Doenças , Inflamação/sangue , Mediadores da Inflamação/sangue , Ketamina/farmacologia , Ligadura , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Insuficiência de Múltiplos Órgãos/sangue , Tamanho do Órgão/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Punções , Sepse/sangue , Sepse/tratamento farmacológico
12.
Geriatr Gerontol Int ; 21(10): 887-892, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34427037

RESUMO

AIM: The number of therapeutic endoscopic procedures in elderly individuals keeps increasing and this population has a high risk of adverse events related to sedation and general anesthesia. However, there is a paucity on data about the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in this population. METHODS: In total, 417 consecutive ERCP procedures were performed in 362 patients between September 2018 and January 2020. Of these, 59 patients (74 sessions) were aged ≥80 years (Group A) and 173 patients (193 procedures) were aged ≤65 years (Group B). We analyzed the prospectively collected data of patient- and procedure-related variables. RESULTS: The procedure time was significantly longer in Group A (P < 0.05). The prevalence of comorbidities, use of anticoagulants and American Society of Anesthesiologists (ASA) physical status classification levels were significantly higher in Group A (P < 0.05). The incidence of periampullary diverticula, malignancy, rate of difficult cannulation, mean number of stones, use of biliary stents and stent dysfunction was also significantly higher in Group A (P < 0.05). The medication doses used were significantly higher and emergence symptoms were significantly more frequent in Group B (P < 0.05). The rates of bleeding, pancreatitis, perforation, cholangitis, hypoxia, hypotension and the length of hospital stay did not significantly differ between the two groups. The overall success rate of the procedure was comparable in the two groups (P = 0.874). CONCLUSIONS: ERCP can be safely performed in elderly patients using a combination of midazolam and ketamine without propofol. The incidence of complications is comparable with that observed in younger patients. Geriatr Gerontol Int 2021; 21: 887-892.


Assuntos
Ketamina , Propofol , Idoso , Colangiopancreatografia Retrógrada Endoscópica/efeitos adversos , Humanos , Ketamina/efeitos adversos , Meperidina/efeitos adversos , Midazolam/efeitos adversos
13.
Medicine (Baltimore) ; 100(29): e26769, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398056

RESUMO

ABSTRACT: There is evidence for ketamine use in treatment-resistant depression (TRD). Several safety and tolerability concerns arise regarding adverse drug reactions and specific subpopulations. This paper aims to investigate the relationship between dissociative and psychometric measures in course of intravenous ketamine treatment in TRD inpatients with major depressive disorder and bipolar disorder.This study result represents safety data in a population of 49 inpatients with major depressive disorder and bipolar disorder subjects receiving eight 0.5 mg/kg of ketamine intravenous infusions, with a duration of 40 min each, as an add-on treatment to standard-of-care pharmacotherapy, registered in the naturalistic observational protocol of the tertiary reference unit for mood disorders (NCT04226963). The safety psychometrics assessed dissociation and psychomimetic symptomatology with the Clinician-Administered Dissociative States Scale (CADSS) the Brief Psychiatric Rating Scale (BPRS).The significant differences in CADSS scores between measurements in course of the treatment were observed (P = .003). No significant differences between BPRS measurements were made after infusions. In each case, both BPRS and CADSS values dropped to the "absent" level within 1 hour from the infusion. Neither CADSS nor BPRS scores were associated with the treatment outcome.The study demonstrates a good safety profile of intravenous ketamine as an add-on intervention to current psychotropic medication in TRD. The abatement of dissociation was observed in time with no sequelae nor harm. The study provides no support for the association between dissociation and treatment outcome.This study may be underpowered due to the small sample size. The protocol was defined as a study on acute depressive symptomatology without blinding.


Assuntos
Anestésicos Dissociativos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/uso terapêutico , Administração Intravenosa , Adolescente , Adulto , Idoso , Anestésicos Dissociativos/administração & dosagem , Transtornos Dissociativos , Feminino , Humanos , Ketamina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Resultado do Tratamento , Adulto Jovem
14.
Int J Mol Sci ; 22(15)2021 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-34360854

RESUMO

Ketamine is a clinical anesthetic and antidepressant. Although ketamine is a known NMDA receptor antagonist, the mechanisms contributing to antidepression are unclear. This present study examined the loci and duration of ketamine's actions, and the involvement of NMDA receptors. Local field potentials were recorded from the CA1 region of mouse hippocampal slices. Ketamine was tested at antidepressant and anesthetic concentrations. Effects of NMDA receptor antagonists APV and MK-801, GABA receptor antagonist bicuculline, and a potassium channel blocker TEA were also studied. Ketamine decreased population spike amplitudes during application, but a long-lasting increase in amplitudes was seen during washout. Bicuculline reversed the acute effects of ketamine, but the washout increase was not altered. This long-term increase was statistically significant, sustained for >2 h, and involved postsynaptic mechanisms. A similar effect was produced by MK-801, but was only partially evident with APV, demonstrating the importance of the NMDA receptor ion channel block. TEA also produced a lasting excitability increase, indicating a possible involvement of potassium channel block. This is this first report of a long-lasting increase in excitability following ketamine exposure. These results support a growing literature that increased GABA inhibition contributes to ketamine anesthesia, while increased excitatory transmission contributes to its antidepressant effects.


Assuntos
Anestésicos/farmacologia , Antidepressivos/farmacologia , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Hipocampo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologia , Receptores de N-Metil-D-Aspartato/metabolismo
15.
Neuroscience ; 472: 116-127, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34384844

RESUMO

Understanding the different mechanisms associated with different anesthetic targeted receptors is critical towards identifying accurate long-term outcome measures as a result of early-life anesthetic exposure. We examined changes in GABAA receptor mediated neurotransmission by a predominately GABAA receptor targeted anesthetic, sevoflurane or a predominately NMDA receptor targeted anesthetic, ketamine. Postnatal day 7 male mice were exposed to sevoflurane or ketamine and examined as adults for changes in inhibitory neurotransmission and its associated change in induced seizure activity. Paired pulse stimulation experiment showed that early-life sevoflurane treated mice had significantly less hippocampal CA1 inhibition later in life. There was significantly increased CA1 excitatory output in the sevoflurane treated group compared to the no sevoflurane treated group after the GABA agonist muscimol. Similar to our previously established data for early-life sevoflurane, here we established early-life ketamine administration resulted in neurodevelopmental behavioral changes later in life. However, muscimol did not produce a significant difference on the excitatory CA1 output between early-life ketamine group and saline group. While sevoflurane treated mice showed significantly higher induced seizure intensities and shorter latency periods to reach seizure intensity stage 5 (Racine score) compared with no sevoflurane treated mice, this phenomenon was not observed in the ketamine vs. saline treated groups. Early-life sevoflurane, but not ketamine, exposure reduced GABAergic inhibition and enhanced seizure activity later in life. The results indicate that early-life exposure to different anesthetics lead to distinct long-term effects and their unique pathways require mechanistic studies to understand induced long-lasting changes in the brain.


Assuntos
Anestésicos Inalatórios , Ketamina , Animais , Encéfalo/metabolismo , Ketamina/toxicidade , Masculino , Camundongos , Receptores de GABA-A/metabolismo , Sevoflurano , Transmissão Sináptica
16.
Neuroscience ; 472: 128-137, 2021 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-34400248

RESUMO

Ketamine, an N-methyl-d-aspartate receptor (NMDAR) blocker, is gaining ground as a treatment option for depression. The occurrence of persistent psychosis and cognitive impairment after repeated use of ketamine remains a concern. N, N-dimethylglycine (DMG) is a nutrient supplement and acts as an NMDAR glycine site partial agonist. The objective of this study was to assess whether DMG could potentially prevent the behavioral and synaptic deficits in mice after repeated ketamine exposure. Male ICR mice received ketamine (20 mg/kg) from postnatal day (PN) 33-46, twice daily, for 14 days. The locomotor activity, novel location recognition test (NLRT), novel object recognition test (NORT), social interaction test, head twitch response induced by serotonergic hallucinogen, and the basal synaptic transmission and long-term potentiation (LTP) in the hippocampal slices were monitored after repeated ketamine treatment. Furthermore, the protective effects of repeated combined administration of DMG (30 and 100 mg/kg) with ketamine on behavioral abnormalities and synaptic dysfunction were assessed. The results showed that mice exhibited memory impairments, social withdrawal, increased head twitch response, reduced excitatory synaptic transmission, and lower LTP after repeated ketamine exposure. The ketamine-induced behavioral and synaptic deficits were prevented by co-treatment with DMG. In conclusion, these findings may pave a new path forward to developing a combination formula with ketamine and DMG for the treatment of depression and other mood disorders.


Assuntos
Ketamina , Animais , Ketamina/toxicidade , Potenciação de Longa Duração , Masculino , Camundongos , Camundongos Endogâmicos ICR , Receptores de N-Metil-D-Aspartato , Sarcosina/análogos & derivados
17.
Clin Drug Investig ; 41(9): 817-823, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34368943

RESUMO

BACKGROUND AND OBJECTIVE: Ketamine is an N-methyl-D-aspartate receptor (NMDA) antagonist used widely as an intravenous analgesic for treatment of acute pain. Its use as oral and sublingual analgesics is not well studied. This study aims to compare the clinical efficacy and tolerability of oral (PO) versus sublingual (SL) ketamine lozenges in adult patients with moderate-to-severe breakthrough pain. METHODS: The study had a randomized, double-blind crossover design in 23 inpatients requiring ketamine as rescue analgesics when pain scores exceeded 4/10 on the Numerical Rating Scales. Each participant received either SL 50 mg ketamine lozenge and PO placebo lozenge or SL placebo lozenge and PO 50 mg ketamine lozenge in two treatment periods with a minimum 24-h washout. Pain scores and adverse effects were documented half hourly for the first 2 h, then one hourly for the next 2 h after treatment. The time to first effect and time to meaningful pain relief were recorded. Patients reported their satisfaction and a global impression of change (GIC) at the end of each treatment period. Data were analysed using random effects regression models. RESULTS: Sixteen subjects completed both days, 7 completed 1 day. Time to first effect was 13.1 min PO versus 6.6 min SL (p = 0.069), time to meaningful pain relief was 29.4 min PO versus 10.8 min SL (p = 0.02). Pain scores were not significantly different at all time points post-treatment. Satisfaction and GIC scores were similar for both groups. Overall, adverse events occurred more often with SL administration (p = 0.02). CONCLUSIONS: Sublingual administration of ketamine led to a faster onset of pain relief (but also a higher adverse event rate), but in all other aspects treatment with ketamine given sublingually and orally produced similar analgesic effects. ACTRN: ACTRN12621000240842, 08/03/2021, retrospectively registered.


Assuntos
Dor Aguda , Ketamina , Dor Aguda/diagnóstico , Dor Aguda/tratamento farmacológico , Administração Sublingual , Adulto , Analgésicos/uso terapêutico , Analgésicos Opioides/uso terapêutico , Método Duplo-Cego , Humanos , Ketamina/uso terapêutico , Manejo da Dor , Resultado do Tratamento
18.
Curr Opin Anaesthesiol ; 34(5): 556-562, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34435599

RESUMO

PURPOSE OF REVIEW: The antidepressant effect of subanesthetic doses of ketamine was recognized 20 years ago. This review briefly summarizes the current understanding of the antidepressant mechanisms and the available clinical research on the use of racemic ketamine and enantiomer esketamine for depression. RECENT FINDINGS: The antidepressant effect of subanesthetic doses of ketamine is currently considered to be predominantly mediated by improved neuroplasticity in cortico-limbic areas in the brain. Single dose of 0.5 mg/kg of ketamine infused intravenously over 40 min, or single intranasal dose of esketamine cause rapid antidepressant and antisuicidal effects within hours of administration, and the antidepressant effect may last up to a week. Repeated administration of nasal spray esketamine is considered to prevent relapse of depression. Longitudinal studies are currently insufficient. When used in various doses for anesthetic induction for electroconvulsive therapy, ketamine improves seizure quality and may possibly diminish posttherapy cognitive impairment. SUMMARY: A rapid onset antidepressive effect of ketamine and esketamine has been proven conclusively. The results of extensive basic science research of the mechanism of action of low-dose ketamine doses has led to an alternative hypothesis of the pathophysiology of depression and the development of a novel neurotrophic concept of depression. Further longitudinal studies are warranted to determine the safety and efficacy of repeated administration of ketamine and its analogs to prevent relapse and recurrence of depression.


Assuntos
Eletroconvulsoterapia , Ketamina , Administração Intranasal , Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Humanos
19.
Braz J Med Biol Res ; 54(11): e11503, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34431874

RESUMO

The mixture of ketamine and xylazine is widely used for the auditory brainstem response (ABR) measurement. Esketamine is twice as potent as ketamine. Our objective was to assess the influence of esketamine in mice undergoing cochlear function measurement including ABR and distortion product otoacoustic emission (DPOAE) measurement. C57Bl/6J mice were treated with an equivalent dose of analgesia and received either a single intraperitoneal (ip) injection of 100 mg/kg ketamine and 25 mg/kg xylazine or 50 mg/kg esketamine and 25 mg/kg xylazine. Hearing thresholds, peak latencies of waves I and V, and DPOAE thresholds were recorded. Time to loss of righting and time to regain righting were also assessed. We found that hearing thresholds, the peak latencies of waves I and V, and DPOAE thresholds were similar between the two groups (all P>0.05). Time to regain righting was significantly shorter in the esketamine group (P<0.001) than in the ketamine group. We concluded that when using equivalent doses of analgesia, esketamine may be an ideal substitute for ketamine during cochlear function test.


Assuntos
Ketamina , Animais , Potenciais Evocados Auditivos do Tronco Encefálico , Camundongos , Emissões Otoacústicas Espontâneas , Xilazina
20.
Environ Toxicol Pharmacol ; 87: 103714, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34302971

RESUMO

Persistent ketamine use causes susceptibility to addiction and bladder toxicity. We examined the association of lower urinary tract symptoms and levels of Nectin-4, a member of the cell adhesion molecules that is essential for maintaining the urothelium barrier in chronic ketamine abusers. We measured the plasma levels of Nectin-4 in 88 patients with ketamine dependence and 69 controls. Patients with ketamine dependence were assessed for ketamine use variables, psychological symptoms, and lower urinary tract symptoms. We found Nectin-4 levels were increased in ketamine-dependent patients compared to the controls (p < 0.0001). Patients with urinary tract symptoms exhibited lower Nectin-4 levels than those without (p = 0.021). Our results suggest an up-regulation of Nectin-4 following chronic and heavy ketamine use. Patients with ketamine dependence with a compromised upregulation of Nectin-4 are likely to have more severe urinary tract symptoms. The mechanisms underlying the involvement of Nectin-4 in ketamine addiction and bladder toxicity warrant future investigation.


Assuntos
Moléculas de Adesão Celular/sangue , Antagonistas de Aminoácidos Excitatórios/toxicidade , Ketamina/toxicidade , Sintomas do Trato Urinário Inferior/sangue , Transtornos Relacionados ao Uso de Substâncias/sangue , Adulto , Feminino , Humanos , Sintomas do Trato Urinário Inferior/etiologia , Masculino , Transtornos Relacionados ao Uso de Substâncias/complicações , Adulto Jovem
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