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1.
Chem Biol Interact ; 319: 109006, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32084352

RESUMO

Ketamine is gaining ground as a potential treating depression because it has a distinct mode of action than typical drugs that influence monoamine neurotransmitters including noradrenaline, dopamine, or serotonin. Ketamine is thought to act by blocking N-methyl-d-aspartate (NMDA) receptors in the brain, which interact with the amino acid neurotransmitter glutamate. The resultant chemical changes in the brain caused by ketamine are not yet fully understood but could involve ketamine-induced gene expression and signaling cascades that act long after the drug has been eliminated from the body. Despite these remarkable effects, the widespread use of ketamine is limited by potential side effects including the emergence reactions (hallucinations, dreams, and out-of-body experiences) by recreational users, who need further study before long-term use of ketamine can be approved for depression. Thus, studies are necessary to further elucidate mechanistic actions of ketamine at cellular and network levels. Thus, we are exploring the involvement of molecular targets for the treatment and psychomimetic phenomena of the ketamine.


Assuntos
Anestésicos Dissociativos/farmacologia , Anestésicos Dissociativos/uso terapêutico , Depressão/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Animais , Encéfalo/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Transdução de Sinais/efeitos dos fármacos
2.
Expert Rev Clin Pharmacol ; 13(2): 135-146, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31990596

RESUMO

Introduction: The use of ketamine infusions for chronic pain has surged, with utilization exceeding the proliferation of knowledge. A proposed mechanism for the long-term benefit in chronic pain is that ketamine may alter the affective-motivational component of pain.Areas covered: In this review, we discuss the classification and various dimensions of pain, and explore the effects of ketamine on different pain categories and components. The relationship between ketamine's action at the NMDA receptor, the development of chronic pain, and the its possible role in preventing the persistence of pain are examined. We also summarize animal models evaluating the antinociceptive effects of ketamine and risk mitigation strategies of ketamine-associated side effects.Expert opinion: Although ketamine exerts most of its analgesic effects via the NMDA receptor, recent evidence suggests that other receptors such as AMPA, and active metabolites such as nor-ketamine, may also play a role in pain relief and alleviation of depression. Data from clinical studies performed in patients with chronic pain and depression, and the observation that ketamine's analgesic benefits outlast its effects on quantitative sensory testing, suggest that the enduring effects on chronic pain may be predominantly due ketamine's ability to modulate the affective-motivational dimension of pain.


Assuntos
Analgésicos/administração & dosagem , Dor Crônica/tratamento farmacológico , Ketamina/administração & dosagem , Analgésicos/efeitos adversos , Analgésicos/farmacologia , Animais , Dor Crônica/fisiopatologia , Depressão/tratamento farmacológico , Depressão/fisiopatologia , Modelos Animais de Doenças , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Infusões Intravenosas , Ketamina/efeitos adversos , Ketamina/farmacologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismo
3.
J Zoo Wildl Med ; 50(4): 868-873, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926517

RESUMO

Blue poison dart frogs (Dendrobates tinctorius azureus) are commonly maintained in zoological institutions and are becoming popular in the pet trade industry. Sedation or light anesthesia is required for safe and effective handling of this species. In this study, the sedative effects of subcutaneously administered alfaxalone-midazolam-dexmedetomidine (AMD) (20, 40, 5 mg/kg, respectively) and ketamine-midazolam-dexmedetomidine (KMD) (100, 40, 5 mg/kg, respectively) were compared in a prospective, randomized, blinded, crossover study in juvenile blue poison dart frogs (n = 10). Both protocols were partially reversed 45 min after administration of either protocol with subcutaneously administered flumazenil (0.05 mg/kg) and atipamezole (50 mg/kg). Heart rate, pulmonic respiratory rate, various reflexes, and behavioral parameters were monitored after drug administration. Both protocols resulted in rapid loss of righting reflex [median (range): AMD, 5 min (5-5 min); KMD, 5 min (5-10 min)]. Time to complete recovery was similar with both protocols (mean ± SD: AMD, 97.5 ± 11.4 min; KMD, 96.5 ± 25.4 min). The AMD protocol resulted in pulmonic respiratory depression, whereas no significant difference in heart rate was found between the two protocols. All frogs were observed eating within 24 hr of chemical restraint. Gastric prolapses occurred in four frogs (AMD 3, KMD 1) that were easily reduced with a cotton-tip application. No other adverse reactions were observed. The results of this study provide two different subcutaneous chemical restraint protocols in juvenile blue poison dart frogs.


Assuntos
Dexmedetomidina/farmacologia , Midazolam/farmacologia , Pregnanodionas/farmacologia , Antagonistas de Receptores Adrenérgicos alfa 2/administração & dosagem , Antagonistas de Receptores Adrenérgicos alfa 2/farmacologia , Envelhecimento , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Anestésicos/administração & dosagem , Anestésicos/farmacologia , Animais , Antídotos/administração & dosagem , Antídotos/farmacologia , Anuros , Sedação Consciente , Estudos Cross-Over , Dexmedetomidina/administração & dosagem , Quimioterapia Combinada , Flumazenil/administração & dosagem , Flumazenil/farmacologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Ketamina/administração & dosagem , Ketamina/farmacologia , Midazolam/administração & dosagem , Pregnanodionas/administração & dosagem
4.
J Zoo Wildl Med ; 50(4): 993-996, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31926534

RESUMO

Seven anesthesia events were performed over 6 wk on a 1.5-yr-old female okapi (Okapia johnstoni) being managed for a fetlock injury. A combination of butorphanol (B) (median; range) (0.045; 0.031-0.046 mg/kg), medetomidine (M) (0.037; 0.031-0.037 mg/kg), ketamine (K) (0.553; 0.536-1.071 mg/kg), and thiafentanil (T) (0.0045; 0.0040-0.0046 mg/kg) was administered in a padded stall. One dart containing all drugs was used for the first two anesthesias. Subsequently, BM was administered 10 min prior to KT using two darts. Time (median; range) from initial injection to first effects (6; 3-7 min) and recumbency (14; 4-20 min) were recorded. Induction quality with the one-dart protocol was poor or fair and was good or excellent with the two-dart protocol. Following recumbency, the okapi was intubated and ventilated, and physiological parameters were recorded. Anesthesia was consistently achieved with BMKT, but induction was smoother with the staged two-dart approach. Neither resedation nor renarcotization was observed post-reversal.


Assuntos
Antílopes/fisiologia , Butorfanol/farmacologia , Fentanila/análogos & derivados , Ketamina/farmacologia , Medetomidina/farmacologia , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Anestesia/veterinária , Animais , Butorfanol/administração & dosagem , Esquema de Medicação , Espécies em Perigo de Extinção , Feminino , Fentanila/administração & dosagem , Fentanila/farmacologia , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/farmacologia , Ketamina/administração & dosagem , Medetomidina/administração & dosagem
6.
Expert Opin Drug Metab Toxicol ; 15(12): 1033-1041, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31693437

RESUMO

Introduction: Chronic neuropathic pain (NP) is an incapacitating illness caused by a lesion of the somatosensory nervous system and is associated with several diseases or syndromes. Since current treatment options lack adequate efficacy in the majority of patients, ketamine is often administered to treat refractory NP.Areas covered: This review gives an overview of new ketamine pharmacokinetic data including data on intranasal and inhaled ketamine. The outcome of seven systematic reviews and meta-analyses, published since 2012, on ketamine efficacy in NP is discussed. The reader will additionally get an understanding of ketamine's complex metabolism with emphasis on the metabolite hydroxynorketamine.Expert opinion: Proof of sustained, large effects of ketamine in the treatment of NP from randomized controlled clinical trials is lacking, although we cannot exclude selective ketamine efficacy in patients with central sensitization, opioid-induced hyperalgesia or opioid tolerance. Interestingly, data from observational trials and case series do suggest the efficacy of ketamine in producing effective pain relief in NP with positive patient-related outcome measures. Additional randomized trials in often ill-defined groups of chronic pain patients are not useful and we suggest to conduct future studies in NP patients with central sensitization and/or with opioid refractory severe NP.


Assuntos
Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Neuralgia/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Dor Crônica/tratamento farmacológico , Dor Crônica/fisiopatologia , Antagonistas de Aminoácidos Excitatórios/farmacocinética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Humanos , Ketamina/farmacocinética , Ketamina/farmacologia , Neuralgia/fisiopatologia
7.
Exp Mol Pathol ; 111: 104318, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31614130

RESUMO

Ketamine is widely used both as anesthetic and abuse drug. In this study, we investigated the effects of a wide range of ketamine concentrations (100-500-1000 µM) on calcium mobilization and the induction of cell death in undifferentiated PC12 cells, 24 h after treatment. Calcium mobilization was measured as the percentage of fluorescence one minute after depolarization by flow cytometry. For the kinetic changes in [Ca2+]c, fluorescence microscopy with Live Imaging was used with a resolution time of 0.87 s (exposure time: 20 ms). Fluo-4 AM was used for both methods. Flow cytometry using TMRE, NAO, and Annexin V-FITC/PI probes were employed for the evaluation of mitochondrial membrane potential (ΔΨm), cardiolipin content and type of cell death respectively. Fluorescence microscopy was used for the evaluation of DNA fragmentation by TUNEL assay with dUTP-conjugated FITC. Results obtained by flow cytometry showed a clear increment in cell response to depolarization after addition of 50 mM and 70 mM KCl in PC12 cells. Simultaneously, cells treated with 100 µM and 500 µM ketamine during 24 h, induced a decreased response to depolarization as compared with control cells. In addition, 1000 µM ketamine induced a similar increase in Fluo4AM fluorescence either after addition of 50 or 70 mM KCl. The kinetic assays showed that after 100 mM KCl, cells pre-treated with ketamine showed a marked decrease in [Ca2+]c as compared with control cells. In the case of 1000 µM ketamine treatment, an increased and sustained [Ca2+]c was observed along the whole assay, indicating a cell disability to maintain calcium homeostasis. Associated with these cytosolic calcium alterations, mitochondrial depolarization, cardiolipin depletion and alteration in Bax protein expression were observed after ketamine treatment. Our data demonstrate that ketamine action in these cells seems to be independent from NMDAR, as observed by the absence of glutamate­calcium response. Acute disturbance in [Ca2+]c could be mediated by the inhibition of VDCCs as part of the molecular mechanism of ketamine cytotoxicity leading to mitochondrial dysfunction and cell death by apoptosis and necrosis.


Assuntos
Canais de Cálcio/metabolismo , Ketamina/farmacologia , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Sinalização do Cálcio/efeitos dos fármacos , Cardiolipinas/metabolismo , Morte Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ketamina/administração & dosagem , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Células PC12 , Cloreto de Potássio/farmacologia , Ratos , Proteína X Associada a bcl-2/metabolismo
9.
Br J Anaesth ; 123(5): 592-600, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31492526

RESUMO

BACKGROUND: Previous work on the electroencephalographic (EEG) effects of anaesthetic doses of ketamine has identified a characteristic signature of increased high frequency (beta-gamma) and theta waves alternating with episodic slow waves. It is unclear which EEG parameter is optimal for pharmacokinetic-pharmacodynamic modelling of the hypnotic actions of ketamine, or which EEG parameter is most closely linked to loss of behavioural responsiveness. METHODS: We re-analysed previously published 128-channel scalp EEG data from 15 subjects who had received a 1.5 mg kg-1 bolus i.v. dose of ketamine. We applied standard sigmoid pharmacokinetic-pharmacodynamic models to the drug-induced changes in slow wave activity, theta, and beta-gamma EEG power; and examined the morphology of the slow waves in the time domain for Fz, F3, T3, P3, and Pz average-referenced channels. RESULTS: Hypnotic doses of ketamine i.v. induced medio-frontal EEG slow waves, and loss of behavioural response when the estimated brain concentration was 1.64 (0.17) µg ml-1. Recovery of responsiveness occurred at 1.06 (0.21) µg.ml-1 after slow wave activity had markedly diminished. Pharmacokinetic-pharmacodynamic modelling fitted best to the slow wave activity and theta power (almost half the beta-gamma channels could not be modelled). Slow wave effect-site equilibration half-time (23 [4] s), and offset, was faster than for theta (47 [22] s). CONCLUSIONS: Changes in EEG slow wave activity after a hypnotic dose of ketamine could be fitted by a standard sigmoid dose-response model. Their onset, but not their offset, was consistently associated with loss of behavioural response in our small study group.


Assuntos
Analgésicos/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiopatologia , Eletroencefalografia/métodos , Ketamina/farmacologia , Adulto , Feminino , Voluntários Saudáveis , Humanos , Masculino , Valores de Referência , Adulto Jovem
10.
Psychiatr Danub ; 31(Suppl 3): 520-523, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488784

RESUMO

Major depressive disorder is one of the most important psychiatric issues worldwide, with important prevalence of treatment-resistant depression (TRD). Non-monoaminergic agents are currently in the spotlight. Objective was to explore for information about mechanisms of action of ketamine, its connections with copper and possible importance for TRD treatment. There are at least few possible pathways for ketamine action in depression in which copper and other divalent ions may show a vital role. There is urgent need for more studies to gather information about correlation between ketamine, copper and antidepressive features of these agents.


Assuntos
Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Cobre/metabolismo , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/metabolismo , Ketamina/farmacologia , Ketamina/uso terapêutico , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Transtorno Depressivo Resistente a Tratamento/metabolismo , Humanos
11.
Psychiatr Danub ; 31(Suppl 3): 554-560, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31488790

RESUMO

Bipolar depression (BD) is among the most severe psychiatric disorders. A significant number of patients do not achieve an entirely symptom-free state and experience residual sub-syndromal depression. Most of the treatment options approved for bipolar depression give no rapid symptom improvement. Ketamine is an anaesthetic medication that acts as an antagonist of the NMDA receptor and has antidepressant potential. Due to its unique way of action, ketamine seems to be crucial for the treatment of anhedonia. This review paper aims to provide an overview of the efficacy of ketamine infusions in bipolar depression with a focus on anhedonia Literature suggests that intravenous ketamine 0.5 mg/kg over 40 min weekly could be useful in the treatment of bipolar depression with prominent anhedonia, but there is still a small number of studies that examine the efficacy of ketamine infusions in BD. In conclusion, ketamine should be considered as a valuable treatment option for patients with BD and anhedonia.


Assuntos
Anedonia/efeitos dos fármacos , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/psicologia , Depressão/complicações , Depressão/tratamento farmacológico , Ketamina/farmacologia , Ketamina/uso terapêutico , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Bipolar/complicações , Humanos
12.
Vet Anaesth Analg ; 46(5): 662-666, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31371196

RESUMO

OBJECTIVE: To establish and compare the effectiveness of two medetomidine-based immobilization protocols in Persian fallow deer (Dama dama mesopotamica). STUDY DESIGN: Prospective, randomized, blinded clinical study. ANIMALS: A group of 31 captive Persian fallow deer. METHODS: Deer scheduled for translocation were immobilized with a combination of medetomidine (76 ± 11 µg kg-1) and ketamine (1.0 ± 0.2 mg kg-1) (MK; n = 15) or medetomidine (77 ± 11 µg kg-1) and midazolam (0.10 ± 0.01 mg kg-1) (MM; n = 16) administered intramuscularly. An observer unaware of group assignments recorded times to immobilization and recovery, monitored physiologic variables and scored the quality of induction, immobilization and recovery (scale 1-5: 1, poor; 5, excellent). Atipamezole was administered for reversal. Data analysis was performed using the t test, the Mann-Whitney U test, the chi-square test and the Fisher's exact test. Significance was set at p < 0.05. RESULTS: Data are presented as mean ± standard deviation or median (range). Time to induce immobilization was 9 ± 4 and 10 ± 4 minutes in the MK and MM groups, respectively. Immobilization quality score was 5 (1-5) following both combinations. Hemoglobin oxygen saturation (SpO2) was significantly lower in the MK (80 ± 8%) than in the MM group (87 ± 8%) although respiratory frequency did not differ between MK and MM (11 ± 5 and 10 ± 2 breaths minute-1, respectively). Recovery times were 13 ± 6 (MK) and 14 ± 7 minutes (MM) and did not differ between groups. No morbidities or mortalities were recorded during 1 month after immobilization. CONCLUSIONS AND CLINICAL RELEVANCE: The MK and MM combinations produced sufficient immobilization in captive Persian fallow deer for short nonpainful procedures. Based on the SpO2 values, the MM combination may be associated with less respiratory depression; nevertheless, both combinations may result in a decrease in SpO2.


Assuntos
Anestésicos Dissociativos/farmacologia , Cervos/fisiologia , Imobilização/veterinária , Ketamina/farmacologia , Medetomidina/farmacologia , Midazolam/farmacologia , Anestésicos Dissociativos/administração & dosagem , Animais , Animais Selvagens , Comportamento Animal/efeitos dos fármacos , Método Duplo-Cego , Quimioterapia Combinada/veterinária , Feminino , Ketamina/administração & dosagem , Masculino , Medetomidina/administração & dosagem , Midazolam/administração & dosagem , Estudos Prospectivos
13.
Int Immunopharmacol ; 75: 105788, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377587

RESUMO

Depression has become a common mental illness, and studies have shown that neuroinflammation is associated with depression. Ketamine is a rapid antidepressant. In order to obtain better antidepressant effects, it is necessary to explore the efficacy of combination therapy with ketamine and other antidepressants. DHA is an unsaturated fatty acid with excellent application prospects due to its safety and antidepressant effects. This study was designed to investigate the effect of ketamine combined with DHA on lipopolysaccharide-induced depression-like behavior. In behavioral experiments, lipopolysaccharide prolongs the immobility time of the forced swimming and tail suspension tests in rats and reduces the sucrose preference. The combination of ketamine and DHA can reverse these changes and work better than the single application. Nissl staining showed that ketamine combined with DHA can reverse the nerve damage caused by lipopolysaccharide. Cell morphology observation the combination of ketamine and DHA group was more complete than that of LPS group. The combination of ketamine and DHA significantly decreased the levels of IL-1, IL-6 and TNF-ɑin hippocampus and PC12 cells and increased the content of BDNF. Immunofluorescence results showed that ketamine combined with DHA can effectively inhibit PP65 nuclear translocation. Western blot results showed that ketamine combined with DHA can effectively inhibit the expression of NF-KB in hippocampus and PC12 cells, and increase the expression of P-CREB and BDNF. In summary, the combination of ketamine with DHA may be a more effective treatment for depression caused by inflammation and is mediated by inhibition of the inflammatory pathway.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ketamina/uso terapêutico , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Citocinas/metabolismo , Depressão/induzido quimicamente , Ácidos Docosa-Hexaenoicos/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Ketamina/farmacologia , Lipopolissacarídeos , Masculino , NF-kappa B/metabolismo , Células PC12 , Ratos , Ratos Wistar
14.
Am J Vet Res ; 80(9): 878-884, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31449443

RESUMO

OBJECTIVE: To evaluate the effects of injectable dexmedetomidine-ketamine-midazolam (DKM) and isoflurane inhalation (ISO) anesthetic protocols on selected ocular variables in captive black-tailed prairie dogs (Cynomys ludovicianus; BTPDs). ANIMALS: 9 zoo-kept BTPDs. PROCEDURES: The BTPDs received dexmedetomidine hydrochloride (0.25 mg/kg, IM), ketamine hydrochloride (40 mg/kg, IM), and midazolam hydrochloride (1.5 mg/kg, IM) or inhalation of isoflurane and oxygen in a randomized complete crossover design (2-day interval between anesthetic episodes). Pupil size, globe position, tear production, and intraocular pressure measurements were recorded at 5, 30, and 45 minutes after induction of anesthesia. For each BTPD, a phenol red thread test was performed in one randomly selected eye and a modified Schirmer tear test I was performed in the other eye. Intraocular pressure was measured by rebound tonometry. RESULTS: Compared with findings for the DKM protocol, pupil size was smaller at all time points when the BTPDs underwent the ISO protocol. Globe position remained central during anesthesia with the DKM protocol, whereas it varied among central, ventromedial, and ventrolateral positions during anesthesia with the ISO protocol. Tear production and intraocular pressure decreased significantly over time when the BTPDs underwent either protocol. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that ophthalmic examination findings for anesthetized BTPDs can be influenced by the anesthetic protocol used. The DKM protocol may result in more consistent pupil size and globe position, compared with that achieved by use of the ISO protocol. Tear production and intraocular pressure measurements should be conducted promptly after induction of anesthesia to avoid the effect of anesthetic episode duration on these variables.


Assuntos
Anestesia/veterinária , Anestésicos Inalatórios/farmacologia , Olho/efeitos dos fármacos , Sciuridae , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/farmacologia , Animais , Animais de Zoológico , Dexmedetomidina/farmacologia , Pressão Intraocular/efeitos dos fármacos , Isoflurano/farmacologia , Ketamina/farmacologia , Masculino , Midazolam/farmacologia , Lágrimas/efeitos dos fármacos
15.
J Zoo Wildl Med ; 50(2): 457-460, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31260214

RESUMO

Two anesthetic protocols in adult giraffe were compared by retrospective study. Thirteen anesthesia records for medetomidine-ketamine (MK) and seven for medetomidine-ketamine with a potent opioid (MKO) were evaluated for differences in demographic, behavioral, drug, and respiratory parameters. Giraffe stood significantly more quickly with MKO vs MK though MK animals were physically restrained to preclude premature standing as part of normal recovery practices (5.5 min vs 21.4 min, P = 0.01). Regurgitation was recorded in 5/13 and resedation in 4/13 MK animals. The range of values for blood lactate was higher in MKO (5.18-11.25 mM/L) than in MK giraffe (0.78-6.08 mM/L). Despite limitations of a retrospective study, both MK and MKO giraffe anesthesia protocols exhibit benefits and side effects. Awareness and management of these factors will improve outcomes until standardized, prospective studies of giraffe immobilization offer more comprehensive guidance on protocol selection.


Assuntos
Analgésicos Opioides/farmacologia , Anestesia/veterinária , Girafas , Ketamina/farmacologia , Medetomidina/farmacologia , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/efeitos adversos , Anestésicos Dissociativos/farmacologia , Animais , Feminino , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Hipnóticos e Sedativos/farmacologia , Injeções Intramusculares , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Masculino , Medetomidina/administração & dosagem , Medetomidina/efeitos adversos , Estudos Retrospectivos
17.
Eur J Pharmacol ; 860: 172547, 2019 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-31348905

RESUMO

Ketamine's clinical use began in the 1970s. Physicians benefited from its safety and ability to induce short-term anesthesia and analgesia. The psychodysleptic effects caused by the drug called its further clinical use into question. Despite these unpleasant effects, ketamine is still applied in veterinary medicine, field medicine, and specialist anesthesia. Recent intensive research brought into light new possible applications of this drug. It began to be used in acute, chronic and cancer pain management. Most interesting reports come from research on the antidepressive and antisuicidal properties of ketamine giving hope for the creation of an effective treatment for major depressive disorder. Other reports highlight the possible use of ketamine in treating addiction, asthma and preventing cancer growth. Besides clinical use, the drug is also applied to in animal model of schizophrenia. It seems that nowadays, with numerous possible applications, the use of ketamine has returned; to its former glory. Nevertheless, the drug must be used with caution because still the mechanisms by which it executes its functions and long-term effects of its use are not fully known. This review aims to discuss the well-known and new promising applications of ketamine.


Assuntos
Ketamina/farmacologia , Anestesia , Animais , Humanos , Ketamina/química , Ketamina/farmacocinética
18.
Pharmacol Biochem Behav ; 184: 172742, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31348944

RESUMO

Ketamine has become increasingly popular in adolescent drug abusers worldwide. Meanwhile, alcohol is usually used by ketamine users. However, little work has been conducted to examine the chronic combined effects of ketamine and ethanol on adolescent brain. Here we probed into the effects of chronic administration of ketamine at recreational doses alone or combined with ethanol on behaviors and neuron damage in an adolescent rat model. 28-day old rats were treated with either 20 or 30 mg/kg ketamine plus or not plus 10% ethanol daily for 21 days. Depressive like behaviors, anxiety like behavior and memory impairment were tested using open field test, forced swimming test, elevated plus maze and Morris water maze. Apoptosis in prefrontal cortex (PFC) and hippocampus (HIP) were determined by the TdT-mediated dUTP Nick-End Labeling (TUNEL) and protein and mRNA levels of caspase-3, Bax and Bcl-2. Results show that co-application of ketamine and ethanol significantly increased immobility time in the forced swimming test, up-regulated TUNEL positive cells and both protein and mRNA expressions of caspase-3 and Bax, compared with the control group and ketamine and ethanol use alone groups in the PFC, but not in the HIP. Our study suggests that chronic co-administration of ketamine and ethanol results in depressive-like behavior and the caspase-dependent apoptosis in the PFC of adolescent rats' brains.


Assuntos
Anestésicos Dissociativos/farmacologia , Apoptose/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Depressores do Sistema Nervoso Central/farmacologia , Etanol/farmacologia , Hipocampo/efeitos dos fármacos , Ketamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Anestésicos Dissociativos/administração & dosagem , Animais , Ansiedade/induzido quimicamente , Caspase 3/genética , Caspase 3/metabolismo , Depressores do Sistema Nervoso Central/administração & dosagem , Depressão/induzido quimicamente , Etanol/administração & dosagem , Hipocampo/metabolismo , Ketamina/administração & dosagem , Masculino , Memória/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
19.
Transl Psychiatry ; 9(1): 172, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253763

RESUMO

Ketamine acts as a rapid clinical antidepressant at 25 min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine's antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depressed positive cognitive state (PC) rat strains. Four parallel rat groups underwent stress-escape testing and a week later received either S-ketamine (12 NC, 13 PC) or saline (12 NC, 12 PC). We acquired resting-state functional magnetic resonance imaging time series before injection and at 30 min and 48 h after injection. Graph analysis was used to calculate brain network properties. We identified ketamine's distinct action over time in a qualitative manner. The rapid response entailed robust and strain-independent topological modifications in cognitive, sensory, emotion, and reward-related circuitry, including regions that exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine's dissociative and antidepressant properties. At 48 h ketamine had mainly strain-specific action normalizing habenula, midline thalamus, and hippocampal connectivity measures in depressed rats. As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine's procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine's distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing.


Assuntos
Antidepressivos/farmacologia , Cérebro/efeitos dos fármacos , Conectoma , Depressão/tratamento farmacológico , Ketamina/farmacologia , Rede Nervosa/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Cérebro/diagnóstico por imagem , Cérebro/fisiopatologia , Modelos Animais de Doenças , Habenula/diagnóstico por imagem , Habenula/efeitos dos fármacos , Habenula/fisiopatologia , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Imagem por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Ratos , Ratos Sprague-Dawley , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Tálamo/fisiopatologia
20.
Vet Anaesth Analg ; 46(4): 466-475, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31176572

RESUMO

OBJECTIVE: To compare immobilization efficacy of a nonpotent opioid drug combination, ketamine-butorphanol-medetomidine (KBM) to the preferred etorphine-azaperone (EA) combination in zebras. STUDY DESIGN: Randomized crossover trial. ANIMALS: A group of ten adult zebra (six females and four male). METHODS: KBM and EA were administered once to the zebras in random order by dart, 3 weeks apart. Once a zebra was recumbent and instrumented, physiological parameters were measured and recorded at 5-minute intervals until 20 minutes. Antagonist drugs were administered at 25 minutes. KBM was antagonised using atipamezole (7.5 mg mg-1 medetomidine dose) and naltrexone (2 mg mg-1 butorphanol dose). EA was antagonized using naltrexone (20 mg mg-1 etorphine dose). Induction and recovery (following antagonist administration) times were recorded. Physiological parameters, including invasive blood pressure and blood gas analysis, were compared between combinations using a general linear mixed model. Data are reported as mean ± standard deviation or median (interquartile range). RESULTS: The doses of KBM and EA administered were 3.30 ± 0.18, 0.40 ± 0.02 and 0.16 ± 0.01 mg kg-1; and 0.02 ± 0.001 and 0.20 ± 0.01 mg kg-1, respectively. KBM and EA induction times were 420 (282-564) and 240 (204-294) seconds, respectively (p = 0.03). Zebras remained recumbent throughout the study procedures. Systolic blood pressure (226 ± 42 and 167 ± 42 mmHg) and oxygen partial pressure (64 ± 12 and 47 ± 13 mmHg) were higher for KBM compared to EA (p < 0.01). Recovery time, after administering antagonists, was 92 (34-1337) and 26 (22-32) seconds for KBM and EA, respectively (p = 0.03). CONCLUSIONS AND CLINICAL RELEVANCE: Compared to EA, KBM also immobilized zebras effectively. Systemic hypertension and moderate hypoxaemia are clinical concerns of KBM and severe hypoxaemia is a concern of EA. This occurrence of hypoxaemia highlights the importance of oxygen administration during immobilization.


Assuntos
Analgésicos Opioides/farmacologia , Anestésicos Dissociativos/farmacologia , Equidae , Hipnóticos e Sedativos/farmacologia , Imobilização/veterinária , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Anestésicos Dissociativos/administração & dosagem , Animais , Animais Selvagens , Azaperona/administração & dosagem , Azaperona/efeitos adversos , Azaperona/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Butorfanol/administração & dosagem , Butorfanol/farmacologia , Estudos Cross-Over , Combinação de Medicamentos , Etorfina/administração & dosagem , Etorfina/efeitos adversos , Etorfina/farmacologia , Feminino , Hipertensão/induzido quimicamente , Hipertensão/veterinária , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/efeitos adversos , Hipóxia/induzido quimicamente , Hipóxia/veterinária , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Ketamina/farmacologia , Masculino , Medetomidina/administração & dosagem , Medetomidina/efeitos adversos , Medetomidina/farmacologia , Oxigênio/administração & dosagem , Distribuição Aleatória
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