Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 5.337
Filtrar
1.
Am J Vet Res ; 82(11): 858-864, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34669493

RESUMO

OBJECTIVE: To evaluate the effects of a dexmedetomidine-midazolam-ketamine (DMK) combination administered IM to captive red-footed tortoises (Chelonoidis carbonaria). ANIMALS: 12 healthy adult red-footed tortoises. PROCEDURES: In a prospective experimental study, DMK (0.1, 1.0, and 10 mg/kg, respectively) was administered IM as separate injections into the right antebrachium. Atipamezole (0.5 mg/kg, IM) and flumazenil (0.05 mg/kg, SC) were administered into the left antebrachium 60 minutes later. Times to the first treatment response and maximal treatment effect after DMK administration and time to recovery after reversal agent administration were recorded. Vital signs and reflexes or responses to stimuli were assessed and recorded at predetermined intervals. RESULTS: DMK treatment produced deep sedation or light anesthesia for ≥ 20 minutes in all tortoises. Induction and recovery were rapid, with no complications noted. Median times to first response, maximum effect, and recovery were 4.5, 35, and 14.5 minutes, respectively. Two tortoises required additional reversal agent administration but recovered < 20 minutes after the repeated injections. Mean heart and respiratory rates decreased significantly over time. All animals lost muscle tone in the neck and limbs from 35 to 55 minutes after DMK injection, but other variables including palpebral reflexes, responses to mild noxious stimuli (eg, toe pinching, tail pinching, and saline ([0.9 NaCl] solution injection), and ability to intubate were inconsistent. CONCLUSIONS AND CLINICAL RELEVANCE: DMK administration produced deep sedation or light anesthesia with no adverse effects in healthy adult red-footed tortoises. At the doses administered, deep surgical anesthesia was not consistently achieved. Anesthetic depth must be carefully evaluated before performing painful procedures in red-footed tortoises with this DMK protocol.


Assuntos
Dexmedetomidina , Ketamina , Tartarugas , Animais , Dexmedetomidina/farmacologia , Hipnóticos e Sedativos/farmacologia , Ketamina/farmacologia , Midazolam/farmacologia , Estudos Prospectivos
2.
Transl Psychiatry ; 11(1): 530, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650029

RESUMO

Ketamine elicits rapid and durable antidepressant actions in treatment-resistant patients with mood disorders such as major depressive disorder and bipolar depression. The mechanisms might involve the induction of metaplasticity in brain regions associated with reward-related behaviors, mood, and hedonic drive, particularly the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We have examined if ketamine alters the insertion of the GluA2 subunit of AMPA receptors (AMPAR), which determines calcium permeability of the channel, at glutamatergic synapses onto dopamine (DA) neurons in the VTA and spiny projection neurons (SPNs) in the Core region of the NAc. Mice received one injection of either saline or a low dose of ketamine 24 h before electrophysiological recordings were performed. We found that GluA2-lacking calcium-permeable (CP) AMPARs were present in DA neurons in the VTA of mice treated with saline, and that ketamine-induced the removal of a fraction of these receptors. In NAc SPNs, ketamine induced the opposite change, i.e., GluA2-lacking CP-AMPARs were inserted at glutamatergic synapses. Ketamine-induced metaplasticity was independent of group I metabotropic glutamate receptors (mGluRs) because an agonist of these receptors had similar effects on glutamatergic transmission in mice treated with saline and in mice treated with ketamine in both VTA DA neurons and in the NAc. Thus, ketamine reduces the insertion of CP-AMPARs in VTA DA neurons and induces their insertion in the NAc. The mechanism by which ketamine elicits antidepressant actions might thus involve an alteration in the contribution of GluA2 to AMPARs thereby modulating synaptic plasticity in the mesolimbic circuit.


Assuntos
Transtorno Depressivo Maior , Ketamina , Animais , Cálcio/metabolismo , Humanos , Ketamina/farmacologia , Camundongos , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Permeabilidade , Receptores de AMPA/metabolismo , Área Tegmentar Ventral/metabolismo
3.
J Zoo Wildl Med ; 52(3): 1018-1023, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34687519

RESUMO

This study is aimed at evaluating the efficacy of two protocols for the immobilization of mouflon (Ovis orientalis musimon). Six mouflon were immobilized twice using IM medetomidine 0.07 ± 0.01 mg/kg, ketamine 2.88 ± 0.48 mg/kg, and morphine 0.57 ± 0.09 mg/kg (MKM) or dexmedetomidine 0.04 ± 0.01 mg/kg, ketamine 3.01 ± 0.6 mg/kg, and morphine 0.60 ± 0.12 mg/kg (DKM). Anesthetic times were recorded from injection to initial drug effects, sternal recumbency, lateral recumbency, unresponsiveness to external stimuli, and recovery following atipamezole IM administration. Cardiopulmonary variables (HR in beats/min, RR in breaths/min, mean, systolic, and diastolic noninvasive blood pressure [MAP, SAP, DAP] in mm Hg, oxygen hemoglobin saturation [SpO2)], expired end tidal carbon dioxide [PECO2]), and rectal temperature in °C were monitored and recorded. No statistically significant differences were detected between protocols at any time point and no significant differences were detected in any measured variables at any time point between protocols. However, a significant decrease in the noninvasive blood pressure variables (SAP, MAP, and DAP) and in the RR were detected over time. Both chemical immobilization protocols provided at least 50 min of immobilization in mouflon, allowing minor procedures and tracheal intubation.


Assuntos
Dexmedetomidina , Ketamina , Anestésicos Dissociativos/farmacologia , Animais , Dexmedetomidina/farmacologia , Frequência Cardíaca , Hipnóticos e Sedativos/farmacologia , Imobilização/veterinária , Ketamina/farmacologia , Medetomidina/farmacologia , Morfina/farmacologia , Carneiro Doméstico
4.
Neurocrit Care ; 35(Suppl 2): 135-145, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34657268

RESUMO

BACKGROUND: Spreading depolarization (SD) has been identified as a key mediator of secondary lesion progression after acute brain injuries, and clinical studies are beginning to pharmacologically target SDs. Although initial work has focused on the N-Methyl-D-aspartate receptor antagonist ketamine, there is also interest in alternatives that may be better tolerated. We recently showed that ketamine can inhibit mechanisms linked to deleterious consequences of SD in brain slices. The present study tested the hypothesis that memantine improves recovery of brain slices after SD and explored the effects of memantine in a clinical case targeting SD. METHODS: For mechanistic studies, electrophysiological and optical recordings were made from hippocampal area CA1 in acutely prepared brain slices from mice. SDs were initiated by localized microinjection of K+ in conditions of either normal or reduced metabolic substrate availability. Memantine effects were assessed from intrinsic optical signals and extracellular potential recordings. For the clinical report, a subdural strip electrode was used for continuous electrocorticographic recording after the surgical evacuation of a chronic subdural hematoma. RESULTS: In brain slice studies, memantine (10-300 µM) did not prevent the initiation of SD, but impaired SD propagation rate and recovery from SD. Memantine reduced direct current (DC) shift duration and improved recovery of synaptic potentials after SD. In brain slices with reduced metabolic substrate availability, memantine reduced the evidence of structural disruption after the passage of SD. In our clinical case, memantine did not noticeably immediately suppress SD; however, it was associated with a significant reduction of SD duration and a reduction in the electrocorticographic (ECoG) suppression that occurs after SD. SD was completely suppressed, with improvement in neurological examination with the addition of a brief course of ketamine. CONCLUSIONS: These data extend recent work showing that N-Methyl-D-aspartate receptor antagonists can improve recovery from SD. These results suggest that memantine could be considered for future clinical trials targeting SD, and in some cases as an adjunct or alternative to ketamine.


Assuntos
Ketamina , Memantina , Animais , Encéfalo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Memantina/farmacologia , Camundongos , Receptores de N-Metil-D-Aspartato
5.
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
6.
Int J Mol Sci ; 22(18)2021 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-34576005

RESUMO

Ischemia is a common cause of acute kidney injury worldwide, frequently occurring in patients undergoing cardiac surgery or admitted to the intensive care unit (ICU). Thus, ischemia-reperfusion injury (IRI) remains one of the main experimental models for the study of kidney diseases. However, the classical technique, based on non-traumatic surgical clamps, suffers from several limitations. It does not allow the induction of multiple episodes of acute kidney injury (AKI) in the same animal, which would be relevant from a human perspective. It also requires a deep and long sedation, raising the question of potential anaesthesia-related biases. We designed a vascular occluding device that can be activated remotely in conscious mice. We first assessed the intensity and the reproducibility of the acute kidney injury induced by this new device. We finally investigated the role played by the anaesthesia in the IRI models at the histological, functional and transcriptomic levels. We showed that this technique allows the rapid induction of renal ischemia in a repeatable and reproducible manner, breaking several classical limitations. In addition, we used its unique specificities to highlight the renal protective effect conferred by the anaesthesia, related to the mitigation of the IRI transcriptomic program.


Assuntos
Anestesia , Ketamina/farmacologia , Nefropatias/metabolismo , Rim/metabolismo , Traumatismo por Reperfusão/metabolismo , Transcriptoma , Xilazina/farmacologia , Animais , Modelos Animais de Doenças , Ketamina/efeitos adversos , Masculino , Camundongos , Xilazina/efeitos adversos
7.
Int J Mol Sci ; 22(17)2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34502248

RESUMO

Esketamine (ESK) has been approved as a rapid-acting intranasal treatment for treatment-resistant depression (TRD). Although existing studies have investigated the efficacy of ESK in the 4-week induction phase, our knowledge about long-term ESK efficacy remains poor. The aim of this systematic review was to summarize the available data on long-term ESK efficacy for TRD. A systematic search was performed including articles in English, up to 31 March 2021. The search found 7 relevant studies, involving 1024 adult TRD patients. Continuing treatment with ESK after the 4-week induction phase may be associated with stable efficacy in relapse prevention among TRD patients. Conversely, the long-term antidepressant effectiveness upon discontinuation of ESK might be limited, although data from three studies had a moderate to high risk of bias. Overall, the results on the effectiveness of this compound in the long term are mixed. According to our findings, ESK treatment should be continued following the induction phase to reach a stable efficacy in relapse prevention, while the long-term antidepressant and anti-suicidal effects of ESK after discontinuation are inconsistent. Currently, the level of proof of ESK efficacy in long-term TRD treatment remains low and more RCTs with larger sample sizes and active comparators are needed.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Ketamina/farmacologia , Administração Intranasal , Antidepressivos/administração & dosagem , Transtorno Depressivo Resistente a Tratamento/patologia , Humanos , Ketamina/administração & dosagem , Prevenção Secundária
8.
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
9.
Vet Anaesth Analg ; 48(5): 707-715, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34332900

RESUMO

OBJECTIVE: To compare ketamine-butorphanol-medetomidine (KBM) with butorphanol-midazolam-medetomidine (BMM) immobilization of serval. STUDY DESIGN: Blinded, randomized trial. ANIMALS: A total of 23 captures [KBM: five females, six males; 10.7 kg (mean); BMM: 10 females, two males; 9.6 kg]. METHODS: Serval were cage trapped and immobilized using the assigned drug combination delivered via a blow dart into gluteal muscles. Prior to darting, a stress score was assigned (0: calm; to 3: markedly stressed). Drug combinations were dosed based on estimated body weights: 8.0, 0.4 and 0.08 mg kg-1 for KBM and 0.4, 0.3 and 0.08 mg kg-1 for BMM, respectively. Time to first handling, duration of anaesthesia and recovery times were recorded. Physiological variables including blood glucose and body temperature were recorded at 5 minute intervals. Atipamezole (5 mg mg-1 medetomidine) and naltrexone (2 mg mg-1 butorphanol) were administered intramuscularly prior to recovery. Data, presented as mean values, were analysed using general linear mixed model and Spearman's correlation (stress score, glucose, temperature); significance was p < 0.05. RESULTS: Doses based on actual body weights were 8.7, 0.4 and 0.09 mg kg-1 for KBM and 0.5, 0.4 and 0.09 mg kg-1 for BMM, respectively. Time to first handling was 10.2 and 13.3 minutes for KBM and BMM, respectively (p = 0.033). Both combinations provided cardiovascular stability during anaesthesia that lasted a minimum of 35 minutes. Recovery was rapid and calm overall, but ataxia was noted in KBM. Stress score was strongly correlated to blood glucose (r2 = 0.788; p = 0.001) and temperature (r2 = 0.634; p = 0.015). CONCLUSIONS AND CLINICAL RELEVANCE: Both combinations produced similar effective immobilization that was cardiovascularly stable in serval. Overall, BMM is recommended because it is fully antagonizable. A calm, quiet environment before drug administration is essential to avoid capture-induced hyperglycaemia and hyperthermia.


Assuntos
Butorfanol , Hipnóticos e Sedativos , Ketamina , Medetomidina , Midazolam , Animais , Animais Selvagens , Butorfanol/farmacologia , Feminino , Hipnóticos e Sedativos/farmacologia , Imobilização/veterinária , Ketamina/farmacologia , Masculino , Medetomidina/farmacologia , Midazolam/farmacologia
10.
Vet Anaesth Analg ; 48(5): 716-724, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34340944

RESUMO

OBJECTIVE: To compare effects of intravenous (IV) alfaxalone with ketamine-xylazine combination on anaesthetic induction, recovery and cardiopulmonary variables in mute swans. STUDY DESIGN: Randomized, controlled, clinical study. ANIMALS: A group of 58 mute swans. METHODS: Swans were given either alfaxalone (10 mg kg-1; group A) or a combination of ketamine (12.5 mg kg-1) and xylazine (0.28 mg kg-1) (group KX) IV. Heart and respiratory rates, end-tidal carbon dioxide and peripheral haemoglobin oxygen saturation were recorded at 5 minute intervals during anaesthesia. Time from anaesthetic induction to intubation, from cessation of isoflurane to extubation, to lifting head, sternal recumbency and absence of head/neck ataxia were recorded. Anaesthetic and recovery quality were scored (1 = very poor; 5 = excellent). Data are presented as median (interquartile range). Significance was set at p < 0.05. RESULTS: In group A, 44% (12/27) of swans required mechanical ventilation for 2-14 minutes versus 3.2% (1/31) of swans in group KX (p = 0.0002). Heart rate was higher in group A than in group KX [146 (127-168) versus 65.5 (56-78) beats minute-1, respectively; p < 0.0001]. The isoflurane concentration required to maintain anaesthesia was higher in group A than in group KX [2.5% (2.0-3.0%) versus 1.5% (1.0-2.0%), respectively; p = 0.0001]. Time from cessation of isoflurane administration to lifting head was significantly longer in group A than in group KX [12 (9-17) versus 6 (4-7.75) minutes, respectively; p < 0.0001]. Anaesthesia quality scores were significantly better in group KX than in group A [4 (4-5) versus 4 (3-4), respectively; p = 0.0011], as were recovery scores [4 (3-5) versus 2 (2-3), respectively; p = 0.0005]. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone is a suitable anaesthetic induction agent for use in mute swans. There is a greater incidence of postinduction apnoea and a higher incidence of agitation on recovery with alfaxalone than with ketamine-xylazine.


Assuntos
Anestésicos Intravenosos , Animais Selvagens , Ketamina , Pregnanodionas , Xilazina , Anestesia Intravenosa/veterinária , Anestésicos Intravenosos/farmacologia , Animais , Hospitais Veterinários , Ketamina/farmacologia , Pregnanodionas/farmacologia , Xilazina/farmacologia
11.
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
12.
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
13.
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
14.
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
15.
Nurs Stand ; 36(9): 77-81, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34423608

RESUMO

Ketamine is a synthetic drug with unique properties which started to be used therapeutically in humans in the 1970s and is now widely used in all fields of nursing. Ketamine acts on the central nervous system, primarily through inhibiting N-methyl-D-aspartate receptors. However, the precise understanding of its mechanisms of action remains elusive in many respects. Ketamine is frequently used as an anaesthetic in medical and surgical procedures and as an analgesic in children and adults. It is increasingly used in mental health settings to treat depression. It has potential to be used more often in areas such as palliative care and mental health care. This article reviews the physiological and pharmacological properties of ketamine, explores its main therapeutic uses, and considers the associated implications for nursing practice.


Assuntos
Analgésicos , Anestésicos , Ketamina , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Anestésicos/farmacologia , Anestésicos/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Humanos , Ketamina/farmacologia , Ketamina/uso terapêutico
16.
PLoS Comput Biol ; 17(8): e1009280, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34407069

RESUMO

Ketamine is an NMDA receptor antagonist commonly used to maintain general anesthesia. At anesthetic doses, ketamine causes high power gamma (25-50 Hz) oscillations alternating with slow-delta (0.1-4 Hz) oscillations. These dynamics are readily observed in local field potentials (LFPs) of non-human primates (NHPs) and electroencephalogram (EEG) recordings from human subjects. However, a detailed statistical analysis of these dynamics has not been reported. We characterize ketamine's neural dynamics using a hidden Markov model (HMM). The HMM observations are sequences of spectral power in seven canonical frequency bands between 0 to 50 Hz, where power is averaged within each band and scaled between 0 and 1. We model the observations as realizations of multivariate beta probability distributions that depend on a discrete-valued latent state process whose state transitions obey Markov dynamics. Using an expectation-maximization algorithm, we fit this beta-HMM to LFP recordings from 2 NHPs, and separately, to EEG recordings from 9 human subjects who received anesthetic doses of ketamine. Our beta-HMM framework provides a useful tool for experimental data analysis. Together, the estimated beta-HMM parameters and optimal state trajectory revealed an alternating pattern of states characterized primarily by gamma and slow-delta activities. The mean duration of the gamma activity was 2.2s([1.7,2.8]s) and 1.2s([0.9,1.5]s) for the two NHPs, and 2.5s([1.7,3.6]s) for the human subjects. The mean duration of the slow-delta activity was 1.6s([1.2,2.0]s) and 1.0s([0.8,1.2]s) for the two NHPs, and 1.8s([1.3,2.4]s) for the human subjects. Our characterizations of the alternating gamma slow-delta activities revealed five sub-states that show regular sequential transitions. These quantitative insights can inform the development of rhythm-generating neuronal circuit models that give mechanistic insights into this phenomenon and how ketamine produces altered states of arousal.


Assuntos
Encéfalo/efeitos dos fármacos , Eletroencefalografia/métodos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ketamina/farmacologia , Macaca/fisiologia , Algoritmos , Animais , Encéfalo/fisiologia , Ritmo Gama/fisiologia , Humanos , Cadeias de Markov , Probabilidade
17.
Anesthesiology ; 135(4): 633-648, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34270686

RESUMO

BACKGROUND: Parabrachial nucleus excitation reduces cortical delta oscillation (0.5 to 4 Hz) power and recovery time associated with anesthetics that enhance γ-aminobutyric acid type A receptor action. The effects of parabrachial nucleus excitation on anesthetics with other molecular targets, such as dexmedetomidine and ketamine, remain unknown. The hypothesis was that parabrachial nucleus excitation would cause arousal during dexmedetomidine and ketamine anesthesia. METHODS: Designer Receptors Exclusively Activated by Designer Drugs were used to excite calcium/calmodulin-dependent protein kinase 2α-positive neurons in the parabrachial nucleus region of adult male rats without anesthesia (nine rats), with dexmedetomidine (low dose: 0.3 µg · kg-1 · min-1 for 45 min, eight rats; high dose: 4.5 µg · kg-1 · min-1 for 10 min, seven rats), or with ketamine (low dose: 2 mg · kg-1 · min-1 for 30 min, seven rats; high dose: 4 mg · kg-1 · min-1 for 15 min, eight rats). For control experiments (same rats and treatments), the Designer Receptors Exclusively Activated by Designer Drugs were not excited. The electroencephalogram and anesthesia recovery times were recorded and analyzed. RESULTS: Parabrachial nucleus excitation reduced delta power in the prefrontal electroencephalogram with low-dose dexmedetomidine for the 150-min analyzed period, excepting two brief periods (peak median bootstrapped difference [clozapine-N-oxide - saline] during dexmedetomidine infusion = -6.06 [99% CI = -12.36 to -1.48] dB, P = 0.007). However, parabrachial nucleus excitation was less effective at reducing delta power with high-dose dexmedetomidine and low- and high-dose ketamine (peak median bootstrapped differences during high-dose [dexmedetomidine, ketamine] infusions = [-1.93, -0.87] dB, 99% CI = [-4.16 to -0.56, -1.62 to -0.18] dB, P = [0.006, 0.019]; low-dose ketamine had no statistically significant decreases during the infusion). Recovery time differences with parabrachial nucleus excitation were not statistically significant for dexmedetomidine (median difference for [low, high] dose = [1.63, 11.01] min, 95% CI = [-20.06 to 14.14, -20.84 to 23.67] min, P = [0.945, 0.297]) nor low-dose ketamine (median difference = 12.82 [95% CI: -3.20 to 39.58] min, P = 0.109) but were significantly longer for high-dose ketamine (median difference = 11.38 [95% CI: 1.81 to 24.67] min, P = 0.016). CONCLUSIONS: These results suggest that the effectiveness of parabrachial nucleus excitation to change the neurophysiologic and behavioral effects of anesthesia depends on the anesthetic's molecular target.


Assuntos
Ritmo Delta/efeitos dos fármacos , Dexmedetomidina/farmacologia , Ácido Glutâmico , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Núcleos Parabraquiais/efeitos dos fármacos , Anestesia/métodos , Anestésicos Dissociativos/farmacologia , Animais , Proteínas de Ligação ao Cálcio/fisiologia , Ritmo Delta/fisiologia , Ácido Glutâmico/fisiologia , Hipnóticos e Sedativos/farmacologia , Masculino , Neurônios/fisiologia , Núcleos Parabraquiais/fisiologia , Ratos , Ratos Sprague-Dawley
18.
Comp Med ; 71(4): 295-301, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34301347

RESUMO

The intestinal microbiota of an organism can significantly alter outcome data in otherwise identical experiments. Occasionally, animals may require sedation or anesthesia for scientific or health-related purposes, and certain anesthetics, such as ketamine, can profoundly affect the gastrointestinal system. While many factors can alter the gut microbiome (GM), the effects of anesthetics on the composition or diversity of the GM have not been established. The goal of the current study was to determine whether daily administration of ketamine would significantly alter the microbiome of CD1 mice. To achieve this goal, female CD1 mice received daily injections of ketamine HCl (100 mg/kg) or the equivalent volume of 0.9% saline for 10 consecutive days. Fecal samples were collected before the first administration and 24 h after the final dose of either ketamine or saline. Samples were analyzed by 16S rRNA sequencing to identify changes between groups in diversity or composition of GM. The study found no significant changes to the GM after serial ketamine administration when treated mice were housed with controls. Therefore, ketamine administration is unlikely to alter the GM of a CD1 mouse and should not serve be a confounding factor in reproducibility of research.


Assuntos
Microbioma Gastrointestinal , Ketamina , Animais , Fezes , Feminino , Ketamina/farmacologia , Camundongos , RNA Ribossômico 16S/genética , Reprodutibilidade dos Testes
19.
Vet Anaesth Analg ; 48(5): 663-670, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34266761

RESUMO

OBJECTIVE: To assess anesthetic induction, recovery quality and cardiopulmonary variables after intramuscular (IM) injection of three drug combinations for immobilization of horses. STUDY DESIGN: Randomized, blinded, three-way crossover prospective design. ANIMALS: A total of eight healthy adult horses weighing 470-575 kg. METHODS: Horses were administered three treatments IM separated by ≥1 week. Combinations were tiletamine-zolazepam (1.2 mg kg-1), ketamine (1 mg kg-1) and detomidine (0.04 mg kg-1) (treatment TKD); ketamine (3 mg kg-1) and detomidine (0.04 mg kg-1) (treatment KD); and tiletamine-zolazepam (2.4 mg kg-1) and detomidine (0.04 mg kg-1) (treatment TD). Parametric data were analyzed using mixed model linear regression. Nonparametric data were compared using Skillings-Mack test. A p value <0.05 was considered statistically significant. RESULTS: All horses in treatment TD became recumbent. In treatments KD and TKD, one horse remained standing. PaO2 15 minutes after recumbency was significantly lower in treatments TD (p < 0.0005) and TKD (p = 0.001) than in treatment KD. Times to first movement (25 ± 15 minutes) and sternal recumbency (55 ± 11 minutes) in treatment KD were faster than in treatments TD (57 ± 17 and 76 ± 19 minutes; p < 0.0005, p = 0.001) and TKD (45 ± 18 and 73 ± 31 minutes; p = 0.005, p = 0.021). There were no differences in induction quality, muscle relaxation score, number of attempts to stand or recovery quality. CONCLUSIONS AND CLINICAL RELEVANCE: In domestic horses, IM injections of tiletamine-zolazepam-detomidine resulted in more reliable recumbency with a longer duration when compared with ketamine-detomidine and tiletamine-zolazepam-ketamine-detomidine. Recoveries were comparable among protocols.


Assuntos
Anestésicos , Cavalos , Ketamina , Anestésicos/farmacologia , Animais , Combinação de Medicamentos , Frequência Cardíaca/efeitos dos fármacos , Ketamina/farmacologia , Estudos Prospectivos , Tiletamina/farmacologia
20.
Psychopharmacology (Berl) ; 238(10): 2743-2753, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34313805

RESUMO

RATIONALE: (R)-Ketamine produced beneficial effects in a variety of models of inflammatory diseases, including low dose of bacterial lipopolysaccharide (LPS) (0.5-1.0 mg/kg)-induced endotoxemia. LPS-treated mice have been used as animal model of delirium. OBJECTIVES: We investigated the effects of (R)-ketamine in neuroinflammation and cognitive impairment in rodents after administration of high dose of LPS. METHODS: LPS (5 mg/kg) or saline was administered intraperitoneally (i.p.) to mice. (R)-Ketamine (10 mg/kg) was administrated i.p. 24 h before and/or 10 min after LPS injection. RESULTS: LPS (5.0 mg/kg) caused a remarkable splenomegaly and increased plasma levels of pro-inflammatory cytokines [i.e., interleukin (IL-6), IL-17A, and interferon (IFN)-γ]. There were positive correlations between spleen weight and plasma cytokines levels. Furthermore, LPS led to increased levels of pro-inflammatory cytokines in the prefrontal cortex (PFC) and hippocampus. Moreover, LPS impaired the natural and learned behaviors, as demonstrated by a decrease in the number of mice's entries and duration in the novel arm in the Y maze test and an increase in the latency of mice to eat the food in the buried food test. Interestingly, the treatment with (R)-ketamine (twice 24 h before and 10 min after LPS injection) significantly attenuated LPS-induced splenomegaly, central and systemic inflammation, and cognitive impairment. CONCLUSION: Our results highlighted the importance of combined prophylactic and therapeutic use of (R)-ketamine in the attenuation of LPS-induced systemic inflammation, neuroinflammation, and cognitive impairment in mice. It is likely that (R)-ketamine could be a prophylactic drug for delirium.


Assuntos
Delírio , Ketamina , Animais , Citocinas , Endotoxinas , Ketamina/farmacologia , Lipopolissacarídeos , Aprendizagem em Labirinto , Camundongos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...