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1.
Air Med J ; 40(5): 312-316, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34535237

RESUMO

OBJECTIVE: Rapid sequence intubation (RSI) is often required in managing critically ill patients in the prehospital setting. Although etomidate is a commonly used induction agent for RSI, ketamine has gained new interest in prehospital management with reported neutral hemodynamic effects. Limited data exist to support ketamine as an alternative to etomidate, particularly in the prehospital setting. The purpose of this study was to evaluate hemodynamic changes after the administration of ketamine versus etomidate in prehospital RSI. METHODS: This retrospective study evaluated adult patients undergoing prehospital RSI over 13 months within a regional emergency transport medicine service. Hypotension was defined as a 20% decrease in systolic blood pressure (SBP) within 15 minutes of receiving ketamine or etomidate. Hemodynamic data were collected 15 minutes before and 15 minutes after administration or until additional sedative medications were given. Data were analyzed using SPSS software (Version 21; IBM Corp, Armonk, NY), with P < .05 considered significant. RESULTS: One hundred thirteen patients met the inclusion criteria (ketamine, n = 33; etomidate, n = 80), with the primary reasons for intubation being respiratory failure and trauma. There was no difference between the incidence of patients who experienced a 20% decrease in SBP (16% etomidate vs. 18% ketamine, P = .79). There were no significant differences in SBP pre- to postadministration between ketamine and etomidate. CONCLUSION: No hemodynamic differences occurred between patients who received ketamine versus etomidate for prehospital RSI. Neither drug was associated with an increased need for additional sedatives, and neither drug was associated with an increased first-pass intubation success rate. Larger, prospective, powered studies are required to identify patients who may benefit from either ketamine or etomidate.


Assuntos
Serviços Médicos de Emergência , Etomidato , Ketamina , Adulto , Etomidato/efeitos adversos , Hemodinâmica , Humanos , Hipnóticos e Sedativos/uso terapêutico , Intubação Intratraqueal , Ketamina/efeitos adversos , Estudos Prospectivos , Indução e Intubação de Sequência Rápida , Estudos Retrospectivos
2.
Pediatr Emerg Care ; 37(9): e500-e506, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34463665

RESUMO

OBJECTIVE: To evaluate procedural sedation (PS) in infants/children, performed by emergency physicians in a general (nonpediatric) emergency department (ED). METHODS: Procedural sedation prospectively recorded on a standardized form over 15 years. Demographics, sedatives, and analgesia associations with adverse events were explored with logistic regressions. RESULTS: Of 3274 consecutive PS, 1177 were pediatric: 2 months to 21 years, mean age (±SD) 8.7 ± 5.2 years, 63% boys, 717 White, 435 Black, 25 other. Eight hundred and seventy were American Society of Anesthesiology (ASA) 1, 256 ASA 2, 39 ASA 3, 11 ASA 4, 1 ASA 5. Procedural sedation indications are as follows: fracture reduction (n = 649), dislocation reduction (n = 114), suturing/wound care (n = 244), lumbar puncture (n = 49), incision and drainage (n = 37), foreign body removal (n = 28), other (n = 56). Sedatives were ketamine (n = 762), propofol ( = 354), benzodiazepines (n = 157), etomidate (n = 39), barbiturates (n = 39). There were 47.4% that received an intravenous opioid. Success rate was 100%. Side effects included nausea/vomiting, itching/rash, emergence reaction, myoclonus, paradoxical reaction, cough, hiccups. Complications were oxygen desaturation less than 90%, bradypnea respiratory rate less than 8, apnea, tachypnea, hypotension, hypertension, bradycardia, tachycardia. Normal range of vital signs was age-dependent. Seventy-four PS (6.3%) resulted in a side effect and 8 PS (3.2%) a complication. No one died, required hospital admission, intubation, or any invasive procedure. CONCLUSIONS: Adverse events in infants/children undergoing PS in a general ED are low and comparable to a pediatric ED at a children's hospital. Pediatric PS can be done safely and effectively in a general ED by nonpediatric EM physicians for a wide array of procedures.


Assuntos
Etomidato , Propofol , Adolescente , Criança , Pré-Escolar , Sedação Consciente , Serviço Hospitalar de Emergência , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Lactente , Masculino
3.
J Forensic Sci ; 66(6): 2532-2538, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34405913

RESUMO

Metomidate and etomidate belong to the non-barbiturate imidazole family of sedative-hypnotics and elicit little analgesic action when used alone. Metomidate, in particular, has little analgesic activity in humans and is, therefore, used for veterinary purposes. In 2019, a Korean woman in her twenties was found unconscious in a motel bath and eventually died. Etomidate, alprazolam, escitalopram, and metomidate were detected in the postmortem specimens. To our knowledge, this is the first case of human metomidate abuse reported in the Republic of Korea. In this research, a simple and reliable method was developed for the analysis of metomidate and etomidate in human blood samples using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Blood samples were deproteinized with acetonitrile, filtered, and analyzed by LC-MS/MS. Linear calibration curves were obtained with six concentrations ranging from 1 to 50 ng/ml for metomidate and 10 to 500 ng/ml for etomidate. The method was validated by assessing the selectivity, linearity, limit of detection (LOD), limit of quantitation (LOQ), intra- and inter-day precision and accuracy, matrix effect, and stability and successfully applied to the analysis of metomidate and etomidate in human blood samples. In a postmortem case, the concentrations of metomidate and etomidate were found to be 8 and 110 ng/ml in femoral blood and 6 and 210 ng/ml in cardiac blood, respectively.


Assuntos
Etomidato/análogos & derivados , Etomidato/sangue , Hipnóticos e Sedativos/sangue , Cromatografia Líquida , Etomidato/envenenamento , Feminino , Toxicologia Forense , Humanos , Hipnóticos e Sedativos/envenenamento , Transtornos Relacionados ao Uso de Substâncias , Espectrometria de Massas em Tandem , Adulto Jovem
5.
J Anesth ; 35(5): 769-770, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34269886
6.
J Aquat Anim Health ; 33(3): 133-138, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34219275

RESUMO

The goals of this study were to investigate the potential use of metomidate for one-step euthanasia of ornamental fish species representing commonly sold families in the ornamental fish trade and to determine a baseline euthanasia dose for most species tested. Metomidate hydrochloride, a rapid-acting, water-soluble, nonbarbiturate hypnotic related to etomidate, was tested at various concentrations and durations for euthanasia of species representing the following freshwater and marine aquarium fish families: Apogonidae, Ariidae, Blenniidae, Callichthyidae, Characidae, Cichlidae, Cyprinidae, Gobiidae, Gyrinocheilidae, Loricariidae, Melanotaeniidae, Osphronemidae, Pimelodidae, Poeciliidae, Pomacentridae, and Pseudochromidae. Fish in each trial were euthanized as a group (n = 1). Most groups contained 10-12 fish. Some higher doses required buffering. Euthanasia was considered successful if all fish in each group did not recover after 6 h in unmedicated water. All species immediately lost buoyancy and equilibrium, dropping to the tank bottom within 1 min and ceasing ventilation typically within minutes. However, reactivity to vibration, sound, or touch was noticeable for varying time periods afterward (8-66 min), so an additional 30 min of exposure after cessation of reactivity was included as part of the protocol. Although some species (Neon Tetras Paracheirodon innesi and Australian Rainbowfish Melanotaenia australis) were euthanized at a concentration of 40 mg/L metomidate for a total exposure time of 38 min, most species tested were successfully euthanized with metomidate at a concentration of 100 mg/L, with total exposure times ranging from 35-96 min. A few catfish species (Otocinclus sp. and Bronze Corydoras Corydoras aeneus) were refractory and recovered after 100 mg/L. However, Otocinclus sp. were successfully euthanized at 250 mg/L, and Bronze Corydoras were euthanized at 1,000 mg/L. Further studies are needed to provide additional data for these and other species and families, for different water chemistry conditions, and for various biological factors to fine-tune dosing regimens.


Assuntos
Ciclídeos , Etomidato , Animais , Austrália , Etomidato/análogos & derivados , Eutanásia Animal , Peixes
8.
Leg Med (Tokyo) ; 52: 101915, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34091406

RESUMO

Suicide is still an important issue in developed countries. The problem affects all age groups and both sexes, although usually more commonly middle-aged men. Attempted suicides committed by taking drugs ended in death are rare (regardless of gender, age, social group) except among health professionals who have easy access to medications and the knowledge of their use. This paper describes a case of a paramedic's suicide and discusses the literature on the issue of suicides in terms of statistics. The paramedic, who is the subject of this case story suffered from depression and alcohol dependence and committed suicide at work using the medicines available in the Medical Air Rescue service: morphine, diazepam, etomidate and rocuronium. Toxicological studies revealed that the man had also been taking sertraline, a commonly used antidepressant. The reasons for suicide among healthcare professionals are the same as for the general population; however, given the extremely high work-related stress and easy availability of drugs that can be effectively used to commit suicide, a special approach to the issue is necessary.


Assuntos
Suicídio Assistido , Pessoal Técnico de Saúde , Diazepam , Etomidato/efeitos adversos , Humanos , Morfina , Preparações Farmacêuticas , Rocurônio
9.
Clin Pharmacokinet ; 60(10): 1253-1269, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34060021

RESUMO

Etomidate is a hypnotic agent that is used for the induction of anesthesia. It produces its effect by acting as a positive allosteric modulator on the γ-aminobutyric acid type A receptor and thus enhancing the effect of the inhibitory neurotransmitter γ-aminobutyric acid. Etomidate stands out among other anesthetic agents by having a remarkably stable cardiorespiratory profile, producing no cardiovascular or respiratory depression. However, etomidate suppresses the adrenocortical axis by the inhibition of the enzyme 11ß-hydroxylase. This makes the drug unsuitable for administration by a prolonged infusion. It also makes the drug unsuitable for administration to critically ill patients. Etomidate has relatively large volumes of distributions and is rapidly metabolized by hepatic esterases into an inactive carboxylic acid through hydrolyzation. Because of the decrease in popularity of etomidate, few modern extensive pharmacokinetic or pharmacodynamic studies exist. Over the last decade, several analogs of etomidate have been developed, with the aim of retaining its stable cardiorespiratory profile, whilst eliminating its suppressive effect on the adrenocortical axis. One of these molecules, ABP-700, was studied in extensive phase I clinical trials. These found that ABP-700 is characterized by small volumes of distribution and rapid clearance. ABP-700 is metabolized similarly to etomidate, by hydrolyzation into an inactive carboxylic acid. Furthermore, ABP-700 showed a rapid onset and offset of clinical effect. One side effect observed with both etomidate and ABP-700 is the occurrence of involuntary muscle movements. The origin of these movements is unclear and warrants further research.


Assuntos
Anestesia , Etomidato , Etomidato/farmacologia , Humanos , Hipnóticos e Sedativos/farmacologia
10.
Mol Pharmacol ; 100(1): 46-56, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33990405

RESUMO

Delta selective compound 2 (DS2; 4-chloro-N-[2-(2-thienyl)imidazo[1,2-a]pyridin-3-yl]benzamide) is one of the most widely used tools to study selective actions mediated by δ-subunit-containing GABAA receptors. DS2 was discovered over 10 years ago, but despite great efforts, the precise molecular site of action has remained elusive. Using a combination of computational modeling, site-directed mutagenesis, and cell-based pharmacological assays, we probed three potential binding sites for DS2 and analogs at α 4 ß 1 δ receptors: an α 4 (+) δ (-) interface site in the extracellular domain (ECD), equivalent to the diazepam binding site in αßγ 2 receptors, and two sites in the transmembrane domain (TMD) - one in the α 4 (+) ß 1 (-) and one in the α 4 (-) ß 1 (+) interface, with the α 4 (-) ß 1 (+) site corresponding to the binding site for etomidate and a recently disclosed low-affinity binding site for diazepam. We show that mutations in the ECD site did not abrogate DS2 modulation. However, mutations in the TMD α 4 (+) ß 1 (-) interface, either α 4(S303L) of the α 4 (+) side or ß 1(I289Q) of the ß 1 (-) side, convincingly disrupted the positive allosteric modulation by DS2. This was consistently demonstrated both in an assay measuring membrane potential changes and by whole-cell patch-clamp electrophysiology and rationalized by docking studies. Importantly, general sensitivity to modulators was not compromised in the mutated receptors. This study sheds important light on the long-sought molecular recognition site for DS2, refutes the misconception that the selectivity of DS2 for δ-containing receptors is caused by a direct interaction with the δ-subunit, and instead points toward a functional selectivity of DS2 and its analogs via a surprisingly well conserved binding pocket in the TMD. SIGNIFICANCE STATEMENT: δ-Containing GABAA receptors represent potential drug targets for the treatment of several neurological conditions with aberrant tonic inhibition, yet no drugs are currently in clinical use. With the identification of the molecular determinants responsible for positive modulation by the known compound delta selective compound 2, the ground is laid for design of ligands that selectively target δ-containing GABAA receptor subtypes, for better understanding of tonic inhibition, and ultimately, for rational development of novel drugs.


Assuntos
Benzamidas/farmacologia , Imidazóis/farmacologia , Mutagênese Sítio-Dirigida/métodos , Receptores de GABA-A/química , Receptores de GABA-A/metabolismo , Regulação Alostérica , Benzamidas/química , Sítios de Ligação , Diazepam/farmacologia , Etomidato/farmacologia , Células HEK293 , Humanos , Imidazóis/química , Modelos Moleculares , Conformação Molecular , Simulação de Acoplamento Molecular , Complexos Multiproteicos/química , Complexos Multiproteicos/metabolismo , Ligação Proteica , Domínios Proteicos , Receptores de GABA-A/genética
11.
Drug Deliv ; 28(1): 873-883, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33960250

RESUMO

The aim of this investigation was to develop an etomidate intravenous lipid emulsion (ETM-ILE) and evaluate its properties in vitro and in vivo. Etomidate (ETM) is a hydrophobic drug, and organic solvents must be added to an etomidate injectable solution (ETM-SOL) to aid dissolution, that causes various adverse reactions on injection. Lipid emulsions are a novel drug formulation that can improve drug loading and reduce adverse reactions. ETM-ILE was prepared using high-pressure homogenization. Univariate experiments were performed to select key conditions and variables. The proportion of oil, egg lecithin, and poloxamer 188 (F68) served as variables for the optimization of the ETM-ILE formulation by central composite design response surface methodology. The optimized formulation had the following characteristics: particle size, 168.0 ± 0.3 nm; polydispersity index, 0.108 ± 0.028; zeta potential, -36.4 ± 0.2 mV; drug loading, 2.00 ± 0.01 mg/mL; encapsulation efficiency, 97.65% ± 0.16%; osmotic pressure, 292 ± 2 mOsmol/kg and pH value, 7.63 ± 0.07. Transmission electron microscopy images showed that the particles were spherical or spheroidal, with a diameter of approximately 200 nm. The stability study suggested that ETM-ILE could store at 4 ± 2 °C or 25 ± 2 °C for 12 months. Safety tests showed that ETM-ILE did not cause hemolysis or serious vascular irritation. The results of the pharmacokinetic study found that ETM-ILE was bioequivalent to ETM-SOL. However, a higher concentration of ETM was attained in the liver, spleen, and lungs after administration of ETM-ILE than after administration of ETM-SOL. This study found that ETM-ILE had great potential for clinical applications.


Assuntos
Anestésicos Intravenosos/administração & dosagem , Anestésicos Intravenosos/farmacocinética , Etomidato/administração & dosagem , Etomidato/farmacocinética , Emulsões Gordurosas Intravenosas/química , Anestésicos Intravenosos/farmacologia , Animais , Química Farmacêutica , Estabilidade de Medicamentos , Etomidato/farmacologia , Concentração de Íons de Hidrogênio , Lecitinas/química , Masculino , Tamanho da Partícula , Poloxâmero/química , Coelhos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Óleo de Soja/química , Propriedades de Superfície
12.
Medicine (Baltimore) ; 100(14): e24508, 2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33832062

RESUMO

ABSTRACT: Although electroconvulsive therapy (ECT) is generally a safe therapeutic method, unexpected adverse effects, such as post-ECT delirium, may occur. Despite its harmful consequences, there has been little discussion about the predictors of post-ECT delirium. Thus, the current study aimed to clarify the factors associated with post-ECT delirium by reviewing electronic medical records of 268 bitemporal ECT sessions from December 2006 to July 2018 in a university hospital.Demographic and clinical characteristics of sessions involving patients with or without post-ECT delirium were compared. Multiple logistic regression analysis was applied to analyze the correlation between variables and post-ECT delirium.Post-ECT delirium developed in 23 sessions (8.6%). Of all the demographic and clinical variables measured, only etomidate use was significantly different between delirium-positive and delirium-negative groups after Bonferroni correction. The regression model also indicated that etomidate use to be significantly associated with post-ECT delirium.In this study, etomidate was associated with a higher risk of developing post-ECT delirium, an association that appeared unrelated to other possible measured variables. Practitioners should take into account the risk of post-ECT delirium while choosing anesthetics, so as to prevent early discontinuation before sufficient therapeutic gain is achieved.


Assuntos
Anestésicos/efeitos adversos , Delírio/etiologia , Eletroconvulsoterapia/efeitos adversos , Etomidato/efeitos adversos , Adulto , Anestésicos/administração & dosagem , Estudos de Casos e Controles , Eletroconvulsoterapia/métodos , Etomidato/administração & dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
13.
Int J Med Sci ; 18(10): 2187-2196, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33859526

RESUMO

Introduction: [11C]Metomidate ([11C]MTO), the methyl ester analogue of etomidate, was developed as a positron emission tomography (PET) radiotracer for adrenocortical tumours and has also been suggested for imaging in primary aldosteronism (PA). A disadvantage of [11C]MTO is the rather high non-specific binding in the liver, which impacts both visualization and quantification of the uptake in the right adrenal gland. Furthermore, the short 20-minute half-life of carbon-11 is a logistic challenge in the clinical setting. Objectives: The aim of this study was to further evaluate the previously published fluorine-18 (T1/2=109.5 min) etomidate analogue, para-chloro-2-[18F]fluoroethyl etomidate; [18F]CETO, as an adrenal PET tracer. Methods: In vitro experiments included autoradiography on human and cynomolgus monkey (non-human primate, NHP) tissues and binding studies on adrenal tissue from NHPs. In vivo studies with [18F]CETO in mice, rats and NHP, using PET and CT/MRI, assessed biodistribution and binding specificity in comparison to [11C]MTO. Results: The binding of [18F]CETO in the normal adrenal cortex, as well as in human adrenocortical adenomas and adrenocortical carcinomas, was shown to be specific, both in vitro (in humans) and in vivo (in rats and NHP) with an in vitro Kd of 0.66 nM. Non-specific uptake of [18F]CETO in NHP liver was found to be low compared to that of [11C]MTO. Conclusions: High specificity of [18F]CETO to the adrenal cortex was demonstrated, with in vivo binding properties qualitatively surpassing those of [11C]MTO. Non-specific binding to the liver was significantly lower than that of [11C]MTO. [18F]CETO is a promising new PET tracer for imaging of adrenocortical disease and should be evaluated further in humans.


Assuntos
Córtex Suprarrenal/diagnóstico por imagem , Etomidato/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/administração & dosagem , Neoplasias do Córtex Suprarrenal/diagnóstico , Animais , Avaliação Pré-Clínica de Medicamentos , Etomidato/administração & dosagem , Etomidato/farmacocinética , Radioisótopos de Flúor/administração & dosagem , Radioisótopos de Flúor/farmacocinética , Humanos , Hiperaldosteronismo/diagnóstico , Macaca fascicularis , Camundongos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Ratos , Distribuição Tecidual
14.
Best Pract Res Clin Endocrinol Metab ; 35(1): 101490, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33707082

RESUMO

Medical therapy is essential in the management of patients with Cushing's syndrome (CS) when curative surgery has failed, surgery is not feasible, when awaiting radiation effect, and in recurrent cases of CS. Steroidogenesis inhibitors have a rapid onset of action and are effective in reducing hypercortisolism, however, adverse effects, including adrenal insufficiency require very close patient monitoring. Osilodrostat is the only steroidogenesis inhibitor to have been assessed in prospective randomized controlled trials and approved for Cushing's disease (CD) by the US Food and Drug Administration and for CS by the European Medical Agency (EMA). Osilodrostat has been shown to be highly effective at maintaining normal urinary free cortisol in patients with CD. Drugs such as metyrapone, ketoconazole (both EMA approved), and etomidate lack prospective evaluation(s). There is, however, considerable clinical experience and retrospective data that show a very wide efficacy range in treating patients with CS. In the absence of head-to-head comparative clinical trials, therapy choice is determined by the specific clinical setting, risk of adverse events, cost, availability, and other factors. In this review practical points to help clinicians who are managing patients with CS being treated with steroidogenesis inhibitors are presented.


Assuntos
Síndrome de Cushing/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Imidazóis/uso terapêutico , Piridinas/uso terapêutico , Síndrome de Cushing/epidemiologia , Síndrome de Cushing/metabolismo , Citocromo P-450 CYP11B2/antagonistas & inibidores , Etomidato/uso terapêutico , Humanos , Hidrocortisona/uso terapêutico , Cetoconazol/uso terapêutico , Metirapona/uso terapêutico , Hipersecreção Hipofisária de ACTH/tratamento farmacológico , Hipersecreção Hipofisária de ACTH/epidemiologia , Hipersecreção Hipofisária de ACTH/metabolismo , Padrões de Prática Médica/normas , Padrões de Prática Médica/estatística & dados numéricos , Esteroides/biossíntese
15.
Mol Pharmacol ; 99(6): 426-434, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33766924

RESUMO

The anesthetic etomidate modulates synaptic α1ß2/3γ2 GABAA receptors via binding sites located in transmembrane ß+/α- interfaces. Various approaches indicate that etomidate binds near ß2/3M286 side chains, including recent cryogenic electron microscopy images in α1ß2γ2L receptors under nonphysiologic conditions with ∼3.5-Å resolution. We hypothesized that substituted cysteine modification and protection experiments using variably sized n-alkyl-methanethiosulfonate (MTS) reagents could precisely estimate the distance between bound etomidate and ß3M286 side chains in activated functional receptors. Using voltage-clamp electrophysiology in Xenopus oocytes expressing α1ß3M286Cγ2L GABAA receptors, we measured functional changes after exposing GABA-activated receptors to n-alkyl-MTS reagents, from methyl-MTS to n-decyl-MTS. Based on previous studies using a large sulfhydryl reagent, we anticipated that cysteine modifications large enough to overlap etomidate sites would cause persistently increased GABA sensitivity and decreased etomidate modulation and that etomidate would hinder these modifications, reducing effects. Based on altered GABA or etomidate sensitivity, ethyl-MTS and larger n-alkyl-MTS reagents modified GABA-activated α1ß3M286Cγ2L GABAA receptors. Receptor modification by n-propyl-MTS or larger reagents caused persistently increased GABA sensitivity and decreased etomidate modulation. Receptor-bound etomidate blocked ß3M286C modification by n-propyl-MTS, n-butyl-MTS, and n-hexyl-MTS. In contrast, GABA sensitivity was unaltered by receptor exposure to methyl-MTS or ethyl-MTS, and ethyl-MTS modification uniquely increased etomidate modulation. These results reveal a "cut-on" between ethyl-MTS and n-propyl-MTS, from which we infer that -S-(n-propyl) is the smallest ß3M286C appendage that overlaps with etomidate sites. Molecular models of the native methionine and -S-ethyl and -S-(n-propyl) modified cysteines suggest that etomidate is located between 1.7 and 3.0 Å from the ß3M286 side chain. SIGNIFICANCE STATEMENT: Precise spatial relationships between drugs and their receptor sites are essential for mechanistic understanding and drug development. This study combined electrophysiology, a cysteine substitution, and n-alkyl-methanethiosulfonate modifiers, creating a precise molecular ruler to estimate the distance between a α1ß3γ2L GABA type A receptor residue and etomidate bound in the transmembrane ß+/α- interface.


Assuntos
Anestésicos Intravenosos/farmacologia , Cisteína/química , Etomidato/farmacologia , Indicadores e Reagentes/química , Mesilatos/química , Receptores de GABA-A/efeitos dos fármacos , Animais , Feminino , Humanos , Xenopus laevis , Ácido gama-Aminobutírico/farmacologia
16.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 46(1): 39-46, 2021 Jan 28.
Artigo em Inglês, Chinês | MEDLINE | ID: mdl-33678635

RESUMO

OBJECTIVES: To explore the effect of etomidate on the neuronal activity of ventral thalamic reuniens nucleus and the underlying mechanisms. METHODS: Whole-cell patch clamp method was used to explore the effect of etomidate on the activity of ventral thalamic reuniens neurons in the acute brain slices obtained from 4-5 weeks old C57BL/6J mice. The electrophysiological characteristics of ventral thalamic reuniens neurons were recorded in the current clamp mode, and then the effects of etomidate (0.5, 2.0, 8.0 µmol/L etomidate groups) and intralipid (intralipid group) on the discharge frequency and membrane potential of ventral thalamic reuniens neurons were recorded. During the experiment, the ventral thalamic reuniens neuron firing rates (RNFRs) were recorded as FB, FD and Fw before, after administration, and after elution; and the membrane potential was recorded as MPB and MPD before, after administration. The chlorine channel of gamma-amino butyric acid Type A (GABAA) receptor was blocked with 100 µmol/L picrotoxin (PTX). The RNFRs were recorded as FBS, FETO and FETO+PTX before, after perfusing etomidate with sub-anesthesia concentration (0.5 µmol/L) and after perfusing both PTX and etomidate. RESULTS: In the intralipid group, there was no significant difference among the FB, FD and Fw (P>0.05). But in the etomidate groups (0.5, 2.0, 8.0 µmol/L), the FD was less than the FB, there was significant difference (all P<0.01); the Fw was higher than the FD, there was significant difference (all P<0.05). Moreover, there was significant difference in the inhibitory degree of the RNFRs between the 0.5 µmol/L etomidate group and the 8.0 µmol/L etomidate group (P<0.05). In the experiment to explore the mechanism of etomidate (0.5 µmol/L), the FETO was compared with the FBS, there was significant difference (P<0.01); but when the FETO+PTX was compared with the FBS, there was no significant difference (P>0.05). CONCLUSIONS: Etomidate can inhibit the activity of ventral thalamic reuniens neurons in concentration-dependent manner, and which is reversible. Etomidate with sub-anesthetic concentration inhibits the activity of ventral thalamic reuniens neurons via targeting the GABAA receptor.


Assuntos
Etomidato , Animais , Etomidato/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios , Técnicas de Patch-Clamp , Receptores de GABA-A
17.
J Trauma Acute Care Surg ; 90(6): 1009-1013, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33657073

RESUMO

BACKGROUND: Several options exist for induction agents during rapid sequence intubation (RSI) in trauma patients, including etomidate, ketamine, and propofol. These drugs have reported variable hemodynamic effects (hypotension with propofol and sympathomimetic effects with ketamine) that could affect trauma resuscitations. The purpose of this study was to compare the hemodynamic effects of these three induction agents during emergency department RSI in adult trauma. We hypothesized that these drugs would display a differing hemodynamic profile during RSI. METHODS: We performed a retrospective (2014-2019), multicenter trial of adult (≥18 years) trauma patients admitted to eight ACS-verified Level I trauma centers who underwent emergency department RSI. Variables collected included systolic blood pressure (SBP) and pulse before and after RSI. The primary outcomes were change in heart rate and SBP before and after RSI. RESULTS: There were 2,092 patients who met criteria, 85% received etomidate (E), 8% ketamine (K), and 7% propofol (P). Before RSI, the ketamine group had a lower SBP (E, 135 vs. K, 125 vs. P, 135 mm Hg, p = 0.04) but there was no difference in pulse (E, 104 vs. K, 107 vs. P, 105 bpm, p = 0.45). After RSI, there were no differences in SBP (E, 135 vs. K, 130 vs. P, 133 mm Hg, p = 0.34) or pulse (E, 106 vs. K, 110 vs. P, 104 bpm, p = 0.08). There was no difference in the average change of SBP (E, 0.2 vs. K, 5.2 vs. P, -1.8 mm Hg, p = 0.4) or pulse (E, 1.7 vs. K, 3.5 bpm vs. P, -0.96, p = 0.24) during RSI. CONCLUSION: Contrary to our hypothesis, there was no difference in the hemodynamic effect for etomidate versus ketamine versus propofol during RSI in trauma patients. LEVEL OF EVIDENCE: Therapeutic, Level IV.


Assuntos
Hemodinâmica/efeitos dos fármacos , Hipnóticos e Sedativos/administração & dosagem , Indução e Intubação de Sequência Rápida/métodos , Ferimentos e Lesões/cirurgia , Adulto , Serviço Hospitalar de Emergência/estatística & dados numéricos , Etomidato/administração & dosagem , Etomidato/efeitos adversos , Feminino , Humanos , Hipnóticos e Sedativos/efeitos adversos , Ketamina/administração & dosagem , Ketamina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Propofol/efeitos adversos , Indução e Intubação de Sequência Rápida/efeitos adversos , Estudos Retrospectivos , Centros de Traumatologia/estatística & dados numéricos , Adulto Jovem
18.
J Small Anim Pract ; 62(6): 437-441, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33565094

RESUMO

OBJECTIVES: To determine the frequency, severity and duration of adverse events including myoclonus, pain on injection, hypersalivation, regurgitation and apnoea after administration of midazolam or saline followed by etomidate in hydromorphone premedicated dogs. MATERIALS AND METHODS: Dogs undergoing elective dental prophylaxis or soft tissue surgeries were enrolled in this randomised trial. Dogs were premedicated with hydromorphone 0.1 mg/kg IV. Sixty seconds later, midazolam 0.3 mg/kg or saline at an equivalent volume was administered IV. Sixty seconds after that, etomidate 1.5 mg/kg IV was administered over 60 seconds. Additional doses of 0.5 mg/kg etomidate were administered until endotracheal intubation was successful. Observers were blinded to the treatment. Frequency, duration and a severity score of 0 to 3 were recorded for myoclonus, pain on injection, hypersalivation and regurgitation. Duration of apnoea and frequency of any additional complications was recorded. RESULTS: Forty variable breed healthy dogs were enrolled in the study. Myoclonus, pain on injection, regurgitation, hypersalivation, gagging, tachypnoea and pigmenturia occurred, respectively, in 10%, 40%, 0%, 15%, 35%, 25% and 5% of dogs in the saline group and 0%, 65%, 0%, 10%, 45%, 15% and 5% of dogs in the midazolam group. Apnoea occurred for 115 seconds (range 0 to 660 seconds) and 160 seconds (range 0 to 600 seconds) in the saline and midazolam groups, respectively. Two dogs developed pigmenturia. The trial was stopped early due to the occurrence of pigmenturia. CLINICAL SIGNIFICANCE: Due to early stopping of the trial, the predefined sample size was not reached. Further investigation is needed to determine if midazolam reduced the incidence of adverse events or improved the induction quality when combined with hydromorphone and etomidate.


Assuntos
Doenças do Cão , Etomidato , Mioclonia , Anestésicos Intravenosos , Animais , Doenças do Cão/induzido quimicamente , Cães , Etomidato/efeitos adversos , Hidromorfona/efeitos adversos , Midazolam/efeitos adversos , Mioclonia/induzido quimicamente , Mioclonia/veterinária
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