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1.
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
2.
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
3.
Ann Emerg Med ; 78(1): 123-131, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34112540

RESUMO

STUDY OBJECTIVE: To describe out-of-hospital ketamine use, patient outcomes, and the potential contribution of ketamine to patient death. METHODS: We retrospectively evaluated consecutive occurrences of out-of-hospital ketamine administration from January 1, 2019 to December 31, 2019 reported to the national ESO Data Collaborative (Austin, TX), a consortium of 1,322 emergency medical service agencies distributed throughout the United States. We descriptively assessed indications for ketamine administration, dosing, route, transport disposition, hypoxia, hypercapnia, and mortality. We reviewed cases involving patient death to determine whether ketamine could be excluded as a potential contributing factor. RESULTS: Indications for out-of-hospital ketamine administrations in our 11,291 patients were trauma/pain (49%; n=5,575), altered mental status/behavioral indications (34%; n=3,795), cardiovascular/pulmonary indications (13%; n=1,454), seizure (2%; n=248), and other (2%; n=219). The highest median dose was for altered mental status/behavioral indications at 3.7 mg/kg (interquartile range, 2.2 to 4.4 mg/kg). Over 99% of patients (n=11,274) were transported to a hospital. Following ketamine administration, hypoxia and hypercapnia were documented in 8.4% (n=897) and 17.2% (n=1,311) of patients, respectively. Eight on-scene and 120 in-hospital deaths were reviewed. Ketamine could not be excluded as a contributing factor in 2 on-scene deaths, representing 0.02% (95% confidence interval 0.00% to 0.07%) of those who received out-of-hospital ketamine. Among those with in-hospital data, ketamine could not be excluded as a contributing factor in 6 deaths (0.3%; 95% confidence interval 0.1% to 0.7%). CONCLUSION: In this large sample, out-of-hospital ketamine was administered for a variety of indications. Patient mortality was rare. Ketamine could not be ruled out as a contributing factor in 8 deaths, representing 0.07% of those who received ketamine.


Assuntos
Anestésicos Dissociativos/administração & dosagem , Serviços Médicos de Emergência , Ketamina/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
4.
Expert Rev Clin Pharmacol ; 14(9): 1133-1152, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34038314

RESUMO

Introduction: There is increasing interest in the potential for psychedelic drugs such as psilocybin, LSD and ketamine to treat several mental health disorders, with a growing number of randomized controlled trials (RCTs) being conducted to investigate the therapeutic effectiveness of psychedelics.Areas covered: We review previous literature on expectancy effects and blinding in the context of psychedelic RCTs - literature which strongly suggest that psychedelic RCTs might be confounded by de-blinding and expectancy. We conduct systematic reviews of psychedelic RCTs using Medline, PsychInfo and EMBASE (Jan 1990 - Nov 2020) and show that currently reported psychedelic RCTs have generally not reported pre-trial expectancy, nor the success of blinding procedures.Expert opinion: While psychedelic RCTs have generally shown promising results, with large effect sizes reported, we argue that treatment effect sizes in psychedelic RCTs are likely over-estimated due to de-blinding of participants and high levels of response expectancy. We suggest that psychedelic RCTs should routinely measure de-blinding and expectancy. Careful attention should be paid to clinical trial design and the instructions given to participants to allow these confounds to be reduced, estimated and removed from effect size estimates. We urge caution in interpreting effect size estimates from extant psychedelic RCTs.


Assuntos
Alucinógenos/administração & dosagem , Transtornos Mentais/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Fatores de Confusão Epidemiológicos , Alucinógenos/farmacologia , Humanos , Ketamina/administração & dosagem , Ketamina/farmacologia , Dietilamida do Ácido Lisérgico/administração & dosagem , Dietilamida do Ácido Lisérgico/farmacologia , Psilocibina/administração & dosagem , Psilocibina/farmacologia , Projetos de Pesquisa
5.
Orthop Nurs ; 40(3): 189-193, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34004619

RESUMO

Ketamine is a dissociative anesthetic used increasingly as analgesia for different manifestations of pain, including acute, chronic, cancer and perioperative pain as well as pain in the critically ill patient population. Its distinctive pharmacologic properties may provide benefits to individuals suffering from pain, including increased pain control and reduction in opioid consumption and tolerance. Despite wide variability in proposed dosing and method of administration when used for analgesia, it is important all clinicians be familiar with the pharmacodynamics of ketamine in order to appropriately anticipate its therapeutic and adverse effects.


Assuntos
Analgesia , Anestésicos Dissociativos , Ketamina , Manejo da Dor , Dor Pós-Operatória/tratamento farmacológico , Analgésicos/administração & dosagem , Analgésicos Opioides/uso terapêutico , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/farmacocinética , Dor do Câncer/tratamento farmacológico , Humanos , Ketamina/administração & dosagem , Ketamina/farmacocinética , Medição da Dor
7.
Anesthesiology ; 135(2): 326-339, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34019627

RESUMO

BACKGROUND: The anesthetic ketamine after intravenous dosing is nearly completely metabolized to R- and S-stereoisomers of the active norketamine (analgesic, psychoactive) and 2,6-hydroxynorketamine (potential analgesic, antidepressant) as well as the inactive dehydronorketamine. Oral administration favors the formation of 2,6-hydroxynorketamines via extensive presystemic metabolism. The authors hypothesized that plasma exposure to 2,6-hydroxynorketamines relative to the psychoactive ketamine is greater after prolonged-release ketamine tablets than it is after intravenous ketamine. METHODS: Pharmacokinetics of ketamine after intravenous infusion (5.0 mg) and single-dose administrations of 10, 20, 40, and 80 mg prolonged-released tablets were evaluated in 15 healthy white human subjects by means of a controlled, ascending-dose study. The stereoisomers of ketamine and metabolites were quantified in serum and urine by validated tandem mass-spectrometric assays and evaluated by noncompartmental pharmacokinetic analysis. RESULTS: After 40 mg prolonged-release tablets, the mean ± SD area under the concentrations-time curve ratios for 2,6-hydroxynorketamine/ketamine were 18 ± 11 (S-stereoisomers) and 30 ± 16 (R-stereoisomers) compared to 1.7 ± 0.8 and 3.1 ± 1.4 and after intravenous infusion (both P < 0.001). After 10 and 20 mg tablets, the R-ratios were even greater. The distribution volumes at steady state of S- and R-ketamine were 6.6 ± 2.2 and 5.6 ± 2.1 l/kg, terminal half-lives 5.2 ± 3.4 and 6.1 ± 3.1 h, and metabolic clearances 1,620 ± 380 and 1,530 ± 380 ml/min, respectively. Bioavailability of the 40 mg tablets was 15 ± 8 (S-isomer) and 19 ± 10% (R-isomer) and terminal half-life 11 ± 4 and 10 ± 4 h. About 7% of the dose was renally excreted as S-stereoisomers and 17% as R-stereoisomers. CONCLUSIONS: Prolonged-release ketamine tablets generate a high systemic exposure to 2,6-hydroxynorketamines and might therefore be an efficient and safer pharmaceutical dosage form for treatment of patients with chronic neuropathic pain compared to intravenous infusion.


Assuntos
Analgésicos/metabolismo , Analgésicos/farmacocinética , Ketamina/metabolismo , Ketamina/farmacocinética , Administração Oral , Adulto , Analgésicos/administração & dosagem , Preparações de Ação Retardada , Feminino , Voluntários Saudáveis , Humanos , Ketamina/administração & dosagem , Masculino , Valores de Referência , Adulto Jovem
8.
Am J Emerg Med ; 47: 149-153, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33812331

RESUMO

INTRODUCTION: Ketamine is a phencyclidine derivative first used in clinical practice in the 1970's. Specifically within the emergency department (ED), ketamine is utilized for a wide variety of indications including but not limited to procedural sedation, rapid sequence intubation, agitation, and pain. As providers continue to utilize ketamine more frequently and for additional indications, additional data describing its safety and efficacy in the ED setting is warranted. OBJECTIVES: To describe current trends in ketamine usage within a large tertiary-care Emergency Department. METHODS: All patients receiving intravenous (IV) or intramuscular (IM) ketamine within the Emergency Department between January 1, 2019 and December 31, 2019 were eligible for study inclusion. Patients were excluded from the study if they were less than 18 years of age, pregnant, or incarcerated. Data was collected using a report of ketamine removal from the ED automatic dispensing cabinets, with administration confirmed by electronic medical record review. RESULTS: During the study period, 170 patients received 195 doses of ketamine for the indications of agitation, procedural sedation, rapid sequence intubation, pain, sedation, seizure, status asthmaticus, and unknown. Patients were mostly male (74%) with a mean age of 45 years (range 20-97 years). The most common indications for ketamine administration were agitation and procedural sedation. For agitation, ketamine was utilized as first line therapy in 45% of patients. Seventy-seven percent of these patients did not require an additional sedative agent up to 60 min after ketamine administration. Procedural sedations were most commonly orthopedic reductions, and ketamine was given more frequently in combination with propofol than as monotherapy. Five percent of patients had an adverse event documented in the electronic medical record, with a single incidence of ketamine induced laryngospasm requiring intubation. CONCLUSION: This descriptive review supports the versatility, safety, and efficacy of ketamine use within a large, tertiary-care, academic emergency department. Larger, prospective studies are warranted to draw further conclusions regarding ideal ketamine utilization within the emergency department.


Assuntos
Anestésicos Dissociativos/administração & dosagem , Serviço Hospitalar de Emergência/estatística & dados numéricos , Ketamina/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Centros de Atenção Terciária/estatística & dados numéricos
9.
J Stud Alcohol Drugs ; 82(2): 188-196, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33823965

RESUMO

OBJECTIVE: Ketamine is a dissociative anesthetic used in medical practice, used recreationally since the mid-1960s. This study describes trends in ketamine use in sentinel cross-sectional samples of Australians who regularly use illicit stimulants, along with characteristics of consumers. METHOD: Data on trends in recent ketamine use (i.e., use in past 6 months) were drawn from annual interviews (approximately 800/year) with cross-sectional samples of people recruited from Australian state capitals from 2009 to 2019 as part of the Ecstasy and Related Drugs Reporting System (EDRS) study. Characteristics of those reporting recent use were examined in the 2019 EDRS data set (n = 728) using logistic regression. RESULTS: Recent ketamine use increased between 2009 and 2019 (10% to 41%, respectively, p < .001), primarily driven by use among participants recruited in Melbourne (21% to 84%, p < .001) and Sydney (19% to 68%, p < .001). However, frequency of use remained low. In 2019, consumer characteristics associated with use included being born outside of Australia and residing in Sydney or Melbourne (compared with Canberra). CONCLUSIONS: Among EDRS participants in Australia, we observed an increase in recent ketamine use between 2009 and 2019, although indicators of potential problematic use remained low. The increase in recent ketamine use was largely driven by increases in Melbourne and Sydney. Further research on drivers of use in these cities is required to effectively inform harm-reduction strategies.


Assuntos
Ketamina/administração & dosagem , N-Metil-3,4-Metilenodioxianfetamina/administração & dosagem , Transtornos Relacionados ao Uso de Substâncias/epidemiologia , Adulto , Austrália , Estimulantes do Sistema Nervoso Central/administração & dosagem , Estudos Transversais , Feminino , Redução do Dano , Humanos , Drogas Ilícitas , Masculino , Adulto Jovem
10.
Toxicol Appl Pharmacol ; 419: 115519, 2021 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-33823148

RESUMO

The development of refractory status epilepticus (SE) induced by sarin intoxication presents a therapeutic challenge. In our current research we evaluate the efficacy of a delayed combined triple treatment in ending the abnormal epileptiform seizure activity (ESA) and the ensuing of long-term neuronal insult. SE was induced in male Sprague-Dawley rats by exposure to 1.2LD50 sarin insufficiently treated by atropine and TMB4 (TA) 1 min later. Triple treatment of ketamine, midazolam and valproic acid was administered 30 min or 1 h post exposure and was compared to a delayed single treatment with midazolam alone. Toxicity and electrocorticogram activity were monitored during the first week and behavioral evaluation performed 3 weeks post exposure followed by brain biochemical and immunohistopathological analyses. The addition of both single and triple treatments reduced mortality and enhanced weight recovery compared to the TA-only treated group. The triple treatment also significantly minimized the duration of the ESA, reduced the sarin-induced increase in the neuroinflammatory marker PGE2, the brain damage marker TSPO, decreased the gliosis, astrocytosis and neuronal damage compared to the TA+ midazolam or only TA treated groups. Finally, the triple treatment eliminated the sarin exposed increased open field activity, as well as impairing recognition memory as seen in the other experimental groups. The delayed triple treatment may serve as an efficient therapy, which prevents brain insult propagation following sarin-induced refractory SE, even if treatment is postponed for up to 1 h.


Assuntos
Anticonvulsivantes/administração & dosagem , Encéfalo/efeitos dos fármacos , Ketamina/administração & dosagem , Midazolam/administração & dosagem , Sarina , Estado Epiléptico/tratamento farmacológico , Ácido Valproico/administração & dosagem , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Encéfalo/fisiopatologia , Proteínas de Transporte/metabolismo , Dinoprostona/metabolismo , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada , Injeções Intramusculares , Injeções Intraperitoneais , Masculino , Teste de Campo Aberto/efeitos dos fármacos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/patologia , Estado Epiléptico/fisiopatologia , Fatores de Tempo
11.
J Psychiatr Pract ; 27(2): 115-120, 2021 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-33656817

RESUMO

This column reviews the development of intranasal esketamine with particular emphasis on the consistency of the clinical trial results. In the process, it illustrates methodological issues important in the approval process by an agency such as the United States Food and Drug Administration. Topics covered include the importance of study design, the nature of the comparator, and the prespecified statistical analysis plan. The column also discusses what is considered a positive versus a supportive study and the differences between phase 2 and phase 3 studies and the rationale for including both in the development process. While this information is particularly germane to intranasal esketamine, it also serves as a more general example of the drug development and approval process.


Assuntos
Antidepressivos/uso terapêutico , Ensaios Clínicos Fase III como Assunto , Transtorno Depressivo/tratamento farmacológico , Aprovação de Drogas , Ketamina/administração & dosagem , Ketamina/uso terapêutico , Administração Intranasal , Antidepressivos/administração & dosagem , Humanos , Estados Unidos , United States Food and Drug Administration
12.
BMC Vet Res ; 17(1): 122, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33726749

RESUMO

BACKGROUND: The intramuscular injection of ketamine and azaperone was proposed as a suitable anaesthesia for male suckling piglets for surgical castration. However, this can be opposed by massive defensive movements, hypothermia and tachycardia during castration and a long recovery period. The aim of the present study was to test whether the use of S-ketamine and/or a change in the route of application from intramuscular to intranasal could reduce stress responses and the duration of recovery compared to the intramuscular route and the use of racemic ketamine. Seventy-eight healthy, five-day-old male piglets were randomized to six treatment groups in a blinded experimental study, matched by litter and weight. Experimental groups were A (15 mg kg-1 S-ketamine + 2 mg kg-1 azaperone, i.m., surgical castration), B (15 mg kg-1 R/S-ketamine racemate + 2 mg kg-1 azaperone, i.m., surgical castration), C (30 mg kg-1 S-ketamine + 2 mg kg-1 azaperone, i.n., surgical castration), D (15 mg kg-1 R/S-ketamine racemate + 2 mg kg-1 azaperone, i.m.; not castrated), E (positive control group; no anesthesia, surgical castration) and F (negative control group; no anesthesia, not castrated). RESULTS: S-ketamine reduced the defensive movement score during castration to a similar extent to racemic ketamine when administered intramuscularly but not via the intranasal route. However, the effects of S-ketamine (both routes) on the increase in cortisol levels and decrease in body temperature were similar to those induced by racemic ketamine. A reduction of the long recovery time known for ketamine-azaperone anaesthesia could not be achieved with S-ketamine in the given dosage, regardless of the route of application. The intranasal administration of ketamine was difficult with the available formulation as the necessary amount exceeded the capacity of the nose cavity. CONCLUSIONS: Neither the use of S-ketamine nor intranasal administration can be suitable alternatives for the anaesthesia of male suckling piglets for castration.


Assuntos
Anestésicos Dissociativos/administração & dosagem , Ketamina/administração & dosagem , Orquiectomia/veterinária , Suínos/cirurgia , Administração Intranasal/veterinária , Anestesia/veterinária , Animais , Animais Recém-Nascidos/cirurgia , Injeções Intramusculares/veterinária , Masculino , Orquiectomia/métodos , Método Simples-Cego
13.
Life Sci ; 276: 119423, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33785344

RESUMO

In clinical and laboratory practice, the use of anesthetics is essential in order to perform surgeries. Anesthetics, besides causing sedation and muscle relaxation, promote several physiological outcomes, such as psychotomimetic alterations, increased heart rate, and blood pressure. However, studies depicting the behavioral effect induced by ketamine and isoflurane are conflicting. In the present study, we assessed the behavioral effects precipitated by ketamine and isoflurane administration. We have also evaluated the ketamine effect on cell cytotoxicity and viability in an amygdalar neuronal primary cell culture. Ketamine (80 mg/kg) caused an anxiogenic effect in rats exposed to the elevated T-maze test (ETM) 2 and 7 days after ketamine administration. Ketamine (40 and 80 mg/kg) administration also decreased panic-like behavior in the ETM. In the light/dark test, ketamine had an anxiogenic effect. Isoflurane did not change animal behavior on the ETM. Neither ketamine nor isoflurane changed the spontaneous locomotor activity in the open field test. However, isoflurane-treated animals explored less frequently the OF central area seven days after treatment. Neither anesthetic caused oxidative damage in the liver. Ketamine also reduced cellular metabolism and led to neuronal death in amygdalar primary cell cultures. Thus, our work provides evidence that ketamine and isoflurane induce pronounced long lasting anxiety-related behaviors in male rats.


Assuntos
Transtornos de Ansiedade/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Isoflurano/farmacologia , Ketamina/farmacologia , Neurônios/efeitos dos fármacos , Transtorno de Pânico/tratamento farmacológico , Anestésicos Dissociativos/administração & dosagem , Anestésicos Dissociativos/farmacologia , Anestésicos Inalatórios/administração & dosagem , Anestésicos Inalatórios/farmacologia , Animais , Transtornos de Ansiedade/patologia , Transtornos de Ansiedade/psicologia , Isoflurano/administração & dosagem , Ketamina/administração & dosagem , Masculino , Aprendizagem em Labirinto , Neurônios/patologia , Transtorno de Pânico/patologia , Transtorno de Pânico/psicologia , Ratos , Ratos Wistar
14.
Anesthesiology ; 134(5): 734-747, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33684203

RESUMO

BACKGROUND: Anesthetics aim to prevent memory of unpleasant experiences. The amygdala and dorsal anterior cingulate cortex participate in forging emotional and valence-driven memory formation. It was hypothesized that this circuitry maintains its role under sedation. METHODS: Two nonhuman primates underwent aversive tone-odor conditioning under sedative states induced by ketamine or midazolam (1 to 8 and 0.1 to 0.8 mg/kg, respectively). The primary outcome was behavioral and neural evidence suggesting memory formation. This study simultaneously measured conditioned inspiratory changes and changes in firing rate of single neurons in the amygdala and the dorsal anterior cingulate cortex in response to an expected aversive olfactory stimulus appearing during acquisition and tested their retention after recovery. RESULTS: Aversive memory formation occurred in 26 of 59 sessions under anesthetics (16 of 29 and 10 of 30, 5 of 30 and 21 of 29 for midazolam and ketamine at low and high doses, respectively). Single-neuron responses in the amygdala and dorsal anterior cingulate cortex were positively correlated between acquisition and retention (amygdala, n = 101, r = 0.51, P < 0.001; dorsal anterior cingulate cortex, n = 121, r = 0.32, P < 0.001). Neural responses during acquisition under anesthetics were stronger in sessions exhibiting memory formation than those that did not (amygdala median response ratio, 0.52 versus 0.33, n = 101, P = 0.021; dorsal anterior cingulate cortex median response ratio, 0.48 versus 0.32, n = 121, P = 0.012). The change in firing rate of amygdala neurons during acquisition was correlated with the size of stimuli-conditioned inspiratory response during retention (n = 101, r = 0.22 P = 0.026). Thus, amygdala and dorsal anterior cingulate cortex responses during acquisition under anesthetics predicted retention. Respiratory unconditioned responses to the aversive odor anesthetics did not differ from saline controls. CONCLUSIONS: These results suggest that the amygdala-dorsal anterior cingulate cortex circuit maintains its role in acquisition and maintenance of aversive memories in nonhuman primates under sedation with ketamine and midazolam and that the stimulus valence is sufficient to drive memory formation.


Assuntos
Tonsila do Cerebelo/fisiologia , Giro do Cíngulo/fisiologia , Ketamina/administração & dosagem , Memória/fisiologia , Midazolam/administração & dosagem , Neurônios/fisiologia , Anestésicos Dissociativos/administração & dosagem , Animais , Aprendizagem da Esquiva/fisiologia , Relação Dose-Resposta a Droga , Hipnóticos e Sedativos/administração & dosagem , Macaca fascicularis , Masculino , Modelos Animais
15.
J Med Life ; 14(1): 87-92, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33767791

RESUMO

Postpartum depression is a common disabling psychosocial disorder that could have adverse effects on the life of the mother, infant, and family. The present study was conducted to evaluate the effect of ketamine on preventing postpartum depression in women undergoing caesarian sections considering the relatively known positive effect of ketamine on major depression. The present double-blind, randomized clinical trial was conducted on 134 women undergoing scheduled caesarian sections. Participants were randomly allocated into two groups of control and intervention. To induce anesthesia, 1-2 mg/kg of body weight of Nesdonal and 0.5 mg/kg of body weight of ketamine were used in the intervention group, while only 3-5 mg/kg of body weight Nesdonal was administered in the control group. Data were gathered using the Edinburgh Postnatal Depression Scale (EPDS) in three stages: before the caesarian section and two and four weeks after the caesarian section. Data were analyzed using variance analysis with repeated measures and the Chi-square test. Results of the present study showed that the mean (± standard deviation) of the depression score in the intervention and control groups were 13.78±3.87 and 13.79±4.78(p = 0.98) before the caesarian section, 11.82±3.41 and 14.34±4.29 (p < 0.001) two weeks after and 10.84±3.48 and 13.09±3.79 (p = 0.001) four weeks after the caesarian section, respectively. Using ketamine in the induction of general anesthesia could be effective in preventing postpartum depression. However, further studies are required to strengthen these findings.


Assuntos
Depressão Pós-Parto/tratamento farmacológico , Ketamina/uso terapêutico , Adulto , Estudos de Casos e Controles , Método Duplo-Cego , Feminino , Humanos , Ketamina/administração & dosagem , Mães/psicologia , Gravidez
16.
Clin J Pain ; 37(4): 295-300, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33555694

RESUMO

OBJECTIVES: The aim was to review current evidence regarding the off-label use of intranasal ketamine for acute pain presenting in the setting of the emergency department, and secondary to pediatric limb injuries, renal colic, digital nerve block, and migraines. RESULTS: In all 5 indications reviewed, ketamine demonstrated efficacy in reducing pain. However, when compared with other agents, ketamine did not demonstrate superiority over opioids in pediatric limb injuries or renal colic and was not as efficacious as standard therapy for migraine relief. Ketamine was also associated with a greater incidence of transient adverse reactions, such as dizziness, bitter aftertaste, fatigue, and vomiting than opioid therapies. DISCUSSION: The current body of evidence is insufficient to support the use of intranasal ketamine over other standard therapies for acute pain. However, current evidence can be used when developing dosing strategies, preparing for adverse reactions, and generating hypotheses for future, more robust research.


Assuntos
Dor Aguda , Ketamina , Dor Aguda/tratamento farmacológico , Administração Intranasal , Analgésicos , Analgésicos Opioides , Criança , Método Duplo-Cego , Humanos , Ketamina/administração & dosagem , Medição da Dor
17.
Pharmacol Biochem Behav ; 203: 173152, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33577868

RESUMO

R-(-)-ketamine has emerged as a potentially improved medication over that of the (S)-isomer (marketed as Spravato for depression). Recent data have suggested (R)-ketamine could have value in the treatment of substance use disorder. The present set of experiments was undertaken to examine whether (R)-ketamine might prevent tolerance development. Rapid ethanol (ETOH) tolerance was studied since racemic ketamine had previously been shown to block this tolerance development in rats. In the present study, male Sprague-Dawley rats were given two large doses of ETOH on Day 1 (2.3 + 1.7 g/kg) and 2.3 g/kg ETOH on Day 2. Animals were tested for effects of 2.3 g/kg ETOH on grip strength, inclined screen performance and rotarod performance on Day 1 with or without (R)-ketamine as a pretreatment. (R)-ketamine alone was tested at the highest dose studied (10 mg/kg) and did not significantly influence any dependent measure. (R)-ketamine (1-10 mg/kg) did not alter the acute effects of ETOH except for enhancing the effects of ETOH on the inclined screen test at 3 mg/kg. Between-subjects analysis documented that tolerance developed to the effects of ETOH only on the measure of grip strength. (R)-ketamine (3 mg/kg) given prior to ETOH on Day 1 exhibited a strong trend toward preventing tolerance development (p = 0.062). The present results extend prior findings on the potential value of (R)-ketamine in substance abuse disorder therapeutics and add to the literature on NMDA receptor blockade as a tolerance-regulating mechanism.


Assuntos
Alcoolismo/tratamento farmacológico , Tolerância a Medicamentos , Etanol/administração & dosagem , Ketamina/administração & dosagem , Ketamina/química , Animais , Comportamento Animal/efeitos dos fármacos , Força da Mão , Isomerismo , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores
18.
Am J Emerg Med ; 43: 54-58, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33524683

RESUMO

INTRODUCTION: There are no emergent pharmaceutical interventions for acute suicidal ideation, a common presenting complaint in the ED. Ketamine is a NMDA agonist frequently used by ED physicians for sedation and analgesia. Prior evidence from studies conducted in inpatient psychiatry units suggests that ketamine may have a role in alleviating treatment-resistant depression as well as suicidal ideation. METHODS: PubMed, MEDLINE, and Cochrane reviews were queried for articles related to keywords ketamine, suicidality, suicidal ideation, and emergency department/room. Relevant articles were selected and reviewed by two separate authors. RESULTS: Three relevant, prospective studies were identified with a mean sample size of 25.7. Each was performed using 0.2 mg/kg ketamine for individuals receiving active treatment. Each study reported a decrease in depressive symptoms among those receiving ketamine. One study reported a significant reduction in SI when compared to placebo at 90 min that became non-significant by 230 min. No significant adverse events were reported in any study. CONCLUSION: Current evidence suggests that ketamine is a promising, safe potential intervention for acute suicidality in the ED. Convincing evidence for efficacy of ketamine for acute suicidal ideation remains lacking, and this promising potential intervention should be further investigated.


Assuntos
Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Ideação Suicida , Adolescente , Adulto , Idoso , Transtorno Depressivo/complicações , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
19.
BMC Pregnancy Childbirth ; 21(1): 121, 2021 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-33563234

RESUMO

BACKGROUND: Anesthesia in lactating women is frequently indicated for time-sensitive procedures such as postpartum tubal ligation. Ketamine and diazepam are two of the most commonly used anesthetic agents in low resource settings, but their safety profile in lactating women has not been established. METHODS: Medical records of post-partum tubal ligations between 2013 and 2018 at clinics of the Shoklo Malaria Research Unit were reviewed for completeness of key outcome variables. Logistic regression identified presence or absence of associations between drug doses and adverse neonatal outcomes: clinically significant weight loss (≥95th percentile) and neonatal hyperbilirubinemia requiring phototherapy. RESULTS: Of 358 records reviewed, 298 were lactating women with singleton, term neonates. There were no severe outcomes in mothers or neonates. On the first postoperative day 98.0% (290/296) of neonates were reported to be breastfeeding well and 6.4% (19/298) had clinically significant weight loss. Phototherapy was required for 13.8% (41/298) of neonates. There was no association between either of the outcomes and increasing ketamine doses (up to 3.8 mg/kg), preoperative oral diazepam (5 mg), or increasing lidocaine doses (up to 200 mg). Preoperative oral diazepam resulted in lower doses of intraoperative anesthetics. Doses of intravenous diazepam above 0.1 mg/kg were associated with increased risk (adjusted odds ratio per 0.1 mg/kg increase, 95%CI) of weight loss (1.95, 95%CI 1.13-3.35, p = 0.016) and jaundice requiring phototherapy (1.87, 95%CI 1.11-3.13, p = 0.017). CONCLUSIONS: In resource-limited settings ketamine use appears safe in lactating women and uninterrupted breastfeeding should be encouraged and supported. Preoperative oral diazepam may help reduce intraoperative anesthetic doses, but intravenous diazepam should be used with caution and avoided in high doses in lactating women.


Assuntos
Aleitamento Materno , Diazepam/administração & dosagem , Ketamina/administração & dosagem , Período Pós-Parto , Esterilização Tubária , Adjuvantes Anestésicos/administração & dosagem , Adulto , Analgésicos/administração & dosagem , Feminino , Humanos , Recém-Nascido , Lactação , Pessoa de Meia-Idade , Pré-Medicação , Estudos Retrospectivos , Tailândia , Adulto Jovem
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