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2.
Anesthesiology ; 133(2): 377-392, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32412932

RESUMO

BACKGROUND: Dexmedetomidine induces a sedative response that is associated with rapid arousal. To elucidate the underlying mechanisms, the authors hypothesized that dexmedetomidine increases the activity of dopaminergic neurons in the ventral tegmental area, and that this action contributes to the unique sedative properties of dexmedetomidine. METHODS: Only male mice were used. The activity of ventral tegmental area dopamine neurons was measured by a genetically encoded Ca indicator and patch-clamp recording. Dopamine neurotransmitter dynamics in the medial prefrontal cortex and nucleus accumbens were measured by a genetically encoded dopamine sensor. Ventral tegmental area dopamine neurons were inhibited or activated by a chemogenetic approach, and the depth of sedation was estimated by electroencephalography. RESULTS: Ca signals in dopamine neurons in the ventral tegmental area increased after intraperitoneal injection of dexmedetomidine (40 µg/kg; dexmedetomidine, 16.917 [14.882; 21.748], median [25%; 75%], vs. saline, -0.745 [-1.547; 0.359], normalized data, P = 0.001; n = 6 mice). Dopamine transmission increased in the medial prefrontal cortex after intraperitoneal injection of dexmedetomidine (40 µg/kg; dexmedetomidine, 10.812 [9.713; 15.104], median [25%; 75%], vs. saline, -0.498 [-0.664; -0.355], normalized data, P = 0.001; n = 6 mice) and in the nucleus accumbens (dexmedetomidine, 8.543 [7.135; 11.828], median [25%; 75%], vs. saline, -0.329 [-1.220; -0.047], normalized data, P = 0.001; n = 6 mice). Chemogenetic inhibition or activation of ventral tegmental area dopamine neurons increased or decreased slow waves, respectively, after intraperitoneal injection of dexmedetomidine (40 µg/kg; delta wave: two-way repeated measures ANOVA, F[2, 33] = 8.016, P = 0.002; n = 12 mice; theta wave: two-way repeated measures ANOVA, F[2, 33] = 22.800, P < 0.0001; n = 12 mice). CONCLUSIONS: Dexmedetomidine activates dopamine neurons in the ventral tegmental area and increases dopamine concentrations in the related forebrain projection areas. This mechanism may explain rapid arousability upon dexmedetomidine sedation.


Assuntos
Dexmedetomidina/farmacologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Hipnóticos e Sedativos/farmacologia , Área Tegmentar Ventral/metabolismo , Animais , Neurônios Dopaminérgicos/química , Neurônios Dopaminérgicos/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Técnicas de Cultura de Órgãos , Fotometria/métodos , Área Tegmentar Ventral/química , Área Tegmentar Ventral/efeitos dos fármacos
3.
Anesth Analg ; 130(5): 1211-1221, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32287128

RESUMO

BACKGROUND: Brain monitors tracking quantitative brain activities from electroencephalogram (EEG) to predict hypnotic levels have been proposed as a labor-saving alternative to behavioral assessments. Expensive clinical trials are required to validate any newly developed processed EEG monitor for every drug and combinations of drugs due to drug-specific EEG patterns. There is a need for an alternative, efficient, and economical method. METHODS: Using deep learning algorithms, we developed a novel data-repurposing framework to predict hypnotic levels from sleep brain rhythms. We used an online large sleep data set (5723 clinical EEGs) for training the deep learning algorithm and a clinical trial hypnotic data set (30 EEGs) for testing during dexmedetomidine infusion. Model performance was evaluated using accuracy and the area under the receiver operator characteristic curve (AUC). RESULTS: The deep learning model (a combination of a convolutional neural network and long short-term memory units) trained on sleep EEG predicted deep hypnotic level with an accuracy (95% confidence interval [CI]) = 81 (79.2-88.3)%, AUC (95% CI) = 0.89 (0.82-0.94) using dexmedetomidine as a prototype drug. We also demonstrate that EEG patterns during dexmedetomidine-induced deep hypnotic level are homologous to nonrapid eye movement stage 3 EEG sleep. CONCLUSIONS: We propose a novel method to develop hypnotic level monitors using large sleep EEG data, deep learning, and a data-repurposing approach, and for optimizing such a system for monitoring any given individual. We provide a novel data-repurposing framework to predict hypnosis levels using sleep EEG, eliminating the need for new clinical trials to develop hypnosis level monitors.


Assuntos
Ondas Encefálicas/fisiologia , Encéfalo/fisiologia , Análise de Dados , Aprendizado Profundo , Sono/fisiologia , Adulto , Idoso , Encéfalo/efeitos dos fármacos , Ondas Encefálicas/efeitos dos fármacos , Dexmedetomidina/administração & dosagem , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Humanos , Hipnóticos e Sedativos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sono/efeitos dos fármacos
4.
Toxicol Appl Pharmacol ; 396: 114994, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32251685

RESUMO

Anticholinergic treatment is key for effective medical treatment of nerve agent exposure. Atropine is included at a 2 mg intramuscular dose in so-called autoinjectors designed for self- and buddy-aid. As patient cohorts are not available, predicting and evaluating the efficacy of medical countermeasures relies on animal models. The use of atropine as a muscarinic antagonist is based on efficacy achieved in studies in a variety of species. The dose of atropine administered varies considerably across these studies. This is a complicating factor in the prediction of efficacy in the human situation, largely because atropine dosing also influences therapeutic efficacy of oximes and anticonvulsants generally part of the treatment administered. To improve translation of efficacy of dosing regimens, including pharmacokinetics and physiology provide a promising approach. In the current study, pharmacokinetics and physiological parameters obtained using EEG and ECG were assessed in naïve rats and in sarin-exposed rats for two anticholinergic drugs, atropine and scopolamine. The aim was to find a predictive parameter for therapeutic efficacy. Scopolamine and atropine showed a similar bioavailability, but brain levels reached were much higher for scopolamine. Scopolamine exhibited a dose-dependent loss of beta power in naïve animals, whereas atropine did not show any such central effect. This effect was correlated with an enhanced anticonvulsant effect of scopolamine compared to atropine. These findings show that an approach including pharmacokinetics and physiology could contribute to improved dose scaling across species and assessing the therapeutic potential of similar anticholinergic and anticonvulsant drugs against nerve agent poisoning.


Assuntos
Atropina/uso terapêutico , Substâncias para a Guerra Química/envenenamento , Sarina/envenenamento , Escopolamina/uso terapêutico , Animais , Atropina/sangue , Atropina/farmacocinética , Atropina/farmacologia , Química Encefálica/efeitos dos fármacos , Antagonistas Colinérgicos , Eletrocardiografia/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Masculino , Camundongos , Ratos Wistar , Sarina/antagonistas & inibidores , Escopolamina/sangue , Escopolamina/farmacocinética , Escopolamina/farmacologia , Telemetria/métodos
5.
Anesthesiology ; 132(4): 750-762, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32053559

RESUMO

BACKGROUND: Ketamine is a noncompetitive N-methyl-D-aspartate antagonist and is known for unique electrophysiologic profiles in electroencephalography. However, the mechanisms of ketamine-induced unconsciousness are not clearly understood. The authors have investigated neuronal dynamics of ketamine-induced loss and return of consciousness and how multisensory processing is modified in the primate neocortex. METHODS: The authors performed intracortical recordings of local field potentials and single unit activity during ketamine-induced altered states of consciousness in a somatosensory and ventral premotor network. The animals were trained to perform a button holding task to indicate alertness. Air puff to face or sound was randomly delivered in each trial regardless of their behavioral response. Ketamine was infused for 60 min. RESULTS: Ketamine-induced loss of consciousness was identified during a gradual evolution of the high beta-gamma oscillations. The slow oscillations appeared to develop at a later stage of ketamine anesthesia. Return of consciousness and return of preanesthetic performance level (performance return) were observed during a gradual drift of the gamma oscillations toward the beta frequency. Ketamine-induced loss of consciousness, return of consciousness, and performance return are all identified during a gradual change of the dynamics, distinctive from the abrupt neural changes at propofol-induced loss of consciousness and return of consciousness. Multisensory responses indicate that puff evoked potentials and single-unit firing responses to puff were both preserved during ketamine anesthesia, but sound responses were selectively diminished. Units with suppressed responses and those with bimodal responses appeared to be inhibited under ketamine and delayed in recovery. CONCLUSIONS: Ketamine generates unique intracortical dynamics during its altered states of consciousness, suggesting fundamentally different neuronal processes from propofol. The gradually shifting dynamics suggest a continuously conscious or dreaming state while unresponsive under ketamine until its deeper stage with the slow-delta oscillations. Somatosensory processing is preserved during ketamine anesthesia, but multisensory processing appears to be diminished under ketamine and through recovery.


Assuntos
Anestésicos Dissociativos/administração & dosagem , Estado de Consciência/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/administração & dosagem , Neocórtex/efeitos dos fármacos , Inconsciência/induzido quimicamente , Animais , Estado de Consciência/fisiologia , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Infusões Intravenosas , Macaca mulatta , Masculino , Neocórtex/fisiologia , Inconsciência/fisiopatologia
6.
Anesthesiology ; 132(5): 1017-1033, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32032094

RESUMO

BACKGROUND: Investigations of the electrophysiology of gaseous anesthetics xenon and nitrous oxide are limited revealing inconsistent frequency-dependent alterations in spectral power and functional connectivity. Here, the authors describe the effects of sedative, equivalent, stepwise levels of xenon and nitrous oxide administration on oscillatory source power using a crossover design to investigate shared and disparate mechanisms of gaseous xenon and nitrous oxide anesthesia. METHODS: Twenty-one healthy males underwent simultaneous magnetoencephalography and electroencephalography recordings. In separate sessions, sedative, equivalent subanesthetic doses of gaseous anesthetic agents nitrous oxide and xenon (0.25, 0.50, and 0.75 equivalent minimum alveolar concentration-awake [MACawake]) and 1.30 MACawake xenon (for loss of responsiveness) were administered. Source power in various frequency bands were computed and statistically assessed relative to a conscious/pre-gas baseline. RESULTS: Observed changes in spectral-band power (P < 0.005) were found to depend not only on the gas delivered, but also on the recording modality. While xenon was found to increase low-frequency band power only at loss of responsiveness in both source-reconstructed magnetoencephalographic (delta, 208.3%, 95% CI [135.7, 281.0%]; theta, 107.4%, 95% CI [63.5, 151.4%]) and electroencephalographic recordings (delta, 260.3%, 95% CI [225.7, 294.9%]; theta, 116.3%, 95% CI [72.6, 160.0%]), nitrous oxide only produced significant magnetoencephalographic high-frequency band increases (low gamma, 46.3%, 95% CI [34.6, 57.9%]; high gamma, 45.7%, 95% CI [34.5, 56.8%]). Nitrous oxide-not xenon-produced consistent topologic (frontal) magnetoencephalographic reductions in alpha power at 0.75 MACawake doses (44.4%; 95% CI [-50.1, -38.6%]), whereas electroencephalographically nitrous oxide produced maximal reductions in alpha power at submaximal levels (0.50 MACawake, -44.0%; 95% CI [-48.1,-40.0%]). CONCLUSIONS: Electromagnetic source-level imaging revealed widespread power changes in xenon and nitrous oxide anesthesia, but failed to reveal clear universal features of action for these two gaseous anesthetics. Magnetoencephalographic and electroencephalographic power changes showed notable differences which will need to be taken into account to ensure the accurate monitoring of brain state during anaesthesia.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/diagnóstico por imagem , Estado de Consciência/efeitos dos fármacos , Óxido Nitroso/administração & dosagem , Xenônio/administração & dosagem , Adulto , Córtex Cerebral/fisiologia , Estado de Consciência/fisiologia , Estudos Cross-Over , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Voluntários Saudáveis , Humanos , Imagem por Ressonância Magnética/métodos , Magnetoencefalografia/efeitos dos fármacos , Magnetoencefalografia/métodos , Masculino , Método Simples-Cego , Adulto Jovem
7.
Anesthesiology ; 132(5): 1034-1044, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32044799

RESUMO

BACKGROUND: General anesthetics-induced changes of electrical oscillations in the basal ganglia may render the identification of the stimulation targets difficult. The authors hypothesized that while sevoflurane anesthesia entrains coherent lower frequency oscillations, it does not affect the identification of the subthalamic nucleus and clinical outcome. METHODS: A cohort of 19 patients with Parkinson's disease with comparable disability underwent placement of electrodes under either sevoflurane general anesthesia (n = 10) or local anesthesia (n = 9). Microelectrode recordings during targeting were compared for neuronal spiking characteristics and oscillatory dynamics. Clinical outcomes were compared at 5-yr follow-up. RESULTS: Under sevoflurane anesthesia, subbeta frequency oscillations predominated (general vs. local anesthesia, mean ± SD; delta: 13 ± 7.3% vs. 7.8 ± 4.8%; theta: 8.4 ± 4.1% vs. 3.9 ± 1.6%; alpha: 8.1 ± 4.1% vs. 4.8 ± 1.5%; all P < 0.001). In addition, distinct dorsolateral beta and ventromedial gamma oscillations were detected in the subthalamic nucleus solely in awake surgery (mean ± SD; dorsal vs. ventral beta band power: 20.5 ± 6.6% vs. 15.4 ± 4.3%; P < 0.001). Firing properties of subthalamic neurons did not show significant difference between groups. Clinical outcomes with regard to improvement in motor and psychiatric symptoms and adverse effects were comparable for both groups. Tract numbers of microelectrode recording, active contact coordinates, and stimulation parameters were also equivalent. CONCLUSIONS: Sevoflurane general anesthesia decreased beta-frequency oscillations by inducing coherent lower frequency oscillations, comparable to the pattern seen in the scalp electroencephalogram. Nevertheless, sevoflurane-induced changes in electrical activity patterns did not reduce electrode placement accuracy and clinical effect. These observations suggest that microelectrode-guided deep brain stimulation under sevoflurane anesthesia is a feasible clinical option.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Estimulação Encefálica Profunda/métodos , Neurônios/efeitos dos fármacos , Doença de Parkinson/terapia , Sevoflurano/administração & dosagem , Núcleo Subtalâmico/efeitos dos fármacos , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Adulto , Idoso , Anestésicos Locais/administração & dosagem , Ritmo beta/efeitos dos fármacos , Ritmo beta/fisiologia , Estudos de Coortes , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neurônios/fisiologia , Doença de Parkinson/fisiopatologia , Núcleo Subtalâmico/fisiologia , Resultado do Tratamento
8.
Anesthesiology ; 132(5): 1003-1016, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32108685

RESUMO

BACKGROUND: Preexisting factors such as age and cognitive performance can influence the electroencephalogram (EEG) during general anesthesia. Specifically, spectral EEG power is lower in elderly, compared to younger, subjects. Here, the authors investigate age-related changes in EEG architecture in patients undergoing general anesthesia through a detailed examination of spectral and entropic measures. METHODS: The authors retrospectively studied 180 frontal EEG recordings from patients undergoing general anesthesia, induced with propofol/fentanyl and maintained by sevoflurane at the Waikato Hospital in Hamilton, New Zealand. The authors calculated power spectral density and normalized power spectral density, the entropic measures approximate and permutation entropy, as well as the beta ratio and spectral entropy as exemplary parameters used in current monitoring systems from segments of EEG obtained before the onset of surgery (i.e., with no noxious stimulation). RESULTS: The oldest quartile of patients had significantly lower 1/f characteristics (P < 0.001; area under the receiver operating characteristics curve, 0.84 [0.76 0.92]), indicative of a more uniform distribution of spectral power. Analysis of the normalized power spectral density revealed no significant impact of age on relative alpha (P = 0.693; area under the receiver operating characteristics curve, 0.52 [0.41 0.63]) and a significant but weak effect on relative beta power (P = 0.041; area under the receiver operating characteristics curve, 0.62 [0.52 0.73]). Using entropic parameters, the authors found a significant age-related change toward a more irregular and unpredictable EEG (permutation entropy: P < 0.001, area under the receiver operating characteristics curve, 0.81 [0.71 0.90]; approximate entropy: P < 0.001; area under the receiver operating characteristics curve, 0.76 [0.66 0.85]). With approximate entropy, the authors could also detect an age-induced change in alpha-band activity (P = 0.002; area under the receiver operating characteristics curve, 0.69 [0.60 78]). CONCLUSIONS: Like the sleep literature, spectral and entropic EEG features under general anesthesia change with age revealing a shift toward a faster, more irregular, oscillatory composition of the EEG in older patients. Age-related changes in neurophysiological activity may underlie these findings however the contribution of age-related changes in filtering properties or the signal to noise ratio must also be considered. Regardless, most current EEG technology used to guide anesthetic management focus on spectral features, and improvements to these devices might involve integration of entropic features of the raw EEG.


Assuntos
Envelhecimento/efeitos dos fármacos , Anestesia Geral/métodos , Anestésicos Inalatórios/administração & dosagem , Eletroencefalografia/efeitos dos fármacos , Entropia , Sevoflurano/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/fisiologia , Eletroencefalografia/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Distribuição Aleatória , Estudos Retrospectivos , Adulto Jovem
9.
Toxicol Lett ; 324: 86-94, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31954867

RESUMO

Organophosphorus nerve agents (NA) inhibit acetylcholinesterase (AChE) which results in the over-stimulation of both the central and peripheral nervous systems, creating a toxic syndrome that can be lethal if left untreated (Cannard, 2006). It is standard practice to treat Sarin (GB) intoxication with an oxime, an antimuscarinic such as atropine and an anticonvulsant. Three common oximes are available: HI-6, Pralidoxime (2-PAM) and Obidoxime (Obi), all possess a nucleophile that can break the NA-AChE covalent bond. However, each oxime's efficacy profile against various agents is different (Thiermann and Worek, 2018). In an effort to broaden therapeutic efficacy against a range of possible NA's, consideration should be given to the use of two oximes in combination. Using a guinea pig model, the first arm of this study was to determine the pharmacokinetics (PK) of HI-6 DMS, 2-PAM chloride and Obi chloride (at autoinjector equivalent doses) following intramuscular (i.m.) co-administration along with atropine to replicate either a single isometrically scaled dose (referred to in this study as a single autoinjector equivalent) of 2-PAM (and equimolar doses of Obi and HI-6) or double doses (referred to in this study as two autoinjector equivalents). The second arm of the study evaluated the efficacy of Obi and 2-PAM individually at a single or double autoinjector dose and also in combination against GB exposure. Pharmacokinetic profiles of each oxime were evaluated for both arms of the study and no significant change in parameters were reported. Improved cholinesterase reactivation was observed in a dose dependent manner with combined therapy showing similar reactivation to individual oximes alone at a two autoinjector equivalent dose. Seizure activity was reduced when combined oxime therapy was administered. This improvement was also reflected in the Racine seizure index score assigned at the end of the experimental period. To the best of our knowledge, this study is the first to evaluate and compare the pharmacokinetics of three oximes and the combination of two oximes (2-PAM and Obi) administered in naïve animals or those exposed to GB. Combined oxime therapy (Obi and 2-PAM) resulted in improved seizure control, increased cholinesterase reactivation peripherally and centrally and improved behavioral signs (Racine score). This study provides evidence that combination of oximes is effective, does not result in adverse events and that the pharmacokinetics of each oxime are not affected when administered in combination.


Assuntos
Agentes Neurotóxicos/envenenamento , Oximas/farmacocinética , Oximas/uso terapêutico , Sarina/envenenamento , Acetilcolinesterase/metabolismo , Animais , Quimioterapia Combinada , Eletrocardiografia/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Cobaias , Masculino , Oximas/administração & dosagem
10.
Anesthesiology ; 132(4): 636-651, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31972655

RESUMO

BACKGROUND: Remimazolam (CNS 7056) is a new ultra-short-acting benzodiazepine for intravenous sedation and anesthesia. Its pharmacokinetics and pharmacodynamics have been reported for bolus administration. This study aimed to investigate the pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion. METHODS: Twenty healthy male volunteers (20 to 38 yr, 64 to 99 kg) received remimazolam as continuous intravenous infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Pharmacokinetics of remimazolam and its metabolite were determined from arterial plasma concentrations. Sedation was assessed using the Modified Observer's Assessment of Alertness and Sedation scale. Pharmacokinetic-pharmacodynamic modeling was performed by population analysis. Hemodynamics and the electrocardiogram were also investigated. RESULTS: Pharmacokinetics was best described by a three-compartment model for remimazolam and a two-compartment model with transit compartment for the metabolite. Remimazolam showed a high clearance (1.15 ± 0.12 l/min, mean ± SD), a small steady-state volume of distribution (35.4 ± 4.2 l) and a short terminal half-life (70 ± 10 min). The simulated context-sensitive halftime after an infusion of 4 h was 6.8 ± 2.4 min. Loss of consciousness was observed 5 ± 1 min after start, and full alertness was regained 19 ± 7 min after stop of infusion. Pharmacodynamics of Modified Observer's Assessment of Alertness and Sedation score was best described by a sigmoid probability model with effect site compartment. The half-maximum effect site concentration for a Modified Observer's Assessment of Alertness and Sedation score less than or equal to 1 was 695 ± 239 ng/ml. The equilibration half-time between central and effect compartment was 2.7 ± 0.6 min. Mean arterial blood pressure decreased by 24 ± 6%, and heart rate increased by 28 ± 15%. Spontaneous breathing was maintained throughout the study. There was no significant prolongation of the QT interval of the electrocardiogram observed. CONCLUSIONS: Remimazolam was characterized by a pharmacokinetic-pharmacodynamic profile with fast onset, fast recovery, and moderate hemodynamic side effects.


Assuntos
Benzodiazepinas/administração & dosagem , Benzodiazepinas/sangue , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/sangue , Adolescente , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Eletrocardiografia/efeitos dos fármacos , Eletrocardiografia/métodos , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Estudos Prospectivos , Adulto Jovem
11.
Anesthesiology ; 132(4): 652-666, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31972657

RESUMO

BACKGROUND: Remimazolam (CNS 7056) is a new ultra-short acting benzodiazepine for IV sedation. This study aimed to investigate the electroencephalogram (EEG) pharmacodynamics of remimazolam infusion. METHODS: Twenty healthy male volunteers received remimazolam as continuous IV infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Continuous EEG monitoring was performed by a neurophysiologic system with electrodes placed at F3, F4, C3, C4, O1, O2, Cz, and Fp1 (10/20 system) and using the Narcotrend Index. Sedation was assessed clinically by using the Modified Observer's Assessment of Alertness and Sedation scale. Pharmacodynamic models were developed for selected EEG variables and Narcotrend Index. RESULTS: EEG changes during remimazolam infusion were characterized by an initial increase in beta frequency band and a late increase in delta frequency band. The EEG beta ratio showed a prediction probability of Modified Observer's Assessment of Alertness and Sedation score of 0.79, and could be modeled successfully using a standard sigmoid Emax model. Narcotrend Index showed a prediction probability of Modified Observer's Assessment of Alertness and Sedation score of 0.74. The time course of Narcotrend Index was described by an extended sigmoid Emax model with two sigmoid terms and different plasma-effect equilibration times. CONCLUSIONS: Beta ratio was identified as a suitable EEG variable for monitoring remimazolam sedation. Narcotrend Index appeared less suitable than the beta ratio for monitoring the sedative effect if remimazolam is administered alone.


Assuntos
Benzodiazepinas/administração & dosagem , Benzodiazepinas/sangue , Eletroencefalografia/efeitos dos fármacos , Hipnóticos e Sedativos/administração & dosagem , Hipnóticos e Sedativos/sangue , Adulto , Estudos Cross-Over , Relação Dose-Resposta a Droga , Eletroencefalografia/métodos , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Estudos Prospectivos
12.
J Pharmacol Sci ; 142(3): 83-92, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31859144

RESUMO

Little is known about how propofol modulates the spike firing correlation between excitatory and inhibitory cortical neurons in vivo. We performed extracellular unit recordings from rat insular cortical neurons, and classified neurons with high spontaneous firing frequency, bursting, and short spike width as high frequency with bursting neurons (HFB; pseudo fast-spiking GABAergic neurons) and other neurons with low spontaneous firing frequency and no bursting were classified as non-HFB. Intravenous administration of propofol (12 mg/kg) from the caudal vein reduced the firing frequency of HFB, whereas propofol initially increased (within 30 s) and then decreased the firing frequency of non-HFB. Both HFB and non-HFB spontaneous action potential discharge was depressed by propofol with a greater depression seen for HFB. Cross-correlograms and auto-correlograms demonstrated propofol-induced increases in the ratio of the peak, which were mostly observed around 0-10 ms divided to baseline amplitude. The analysis of interspike intervals showed a decrease in spike firing at 20-100 Hz and a relative increase at 8-15 Hz. These results suggest that propofol induces a larger suppression of firing frequency in HFB and an enhancement of synchronized neural activities in the α frequency band in the cerebral cortex (192 words).


Assuntos
Córtex Cerebral/fisiologia , Eletroencefalografia/efeitos dos fármacos , Propofol/farmacologia , Potenciais de Ação/efeitos dos fármacos , Animais , Neurônios GABAérgicos/fisiologia , Infusões Intravenosas , Masculino , Propofol/administração & dosagem , Ratos Wistar , Estimulação Química
13.
Epilepsia ; 60(12): 2346-2358, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31705531

RESUMO

OBJECTIVE: To investigate how prolonged seizure activity affects cardiorespiratory function and activity of pre-Bötzinger complex, leading to sudden death. METHODS: Urethane-anesthetized female Long-Evans rats were implanted with nasal thermocouple; venous and arterial cannulae; and electrodes for electrocardiography (ECG) and hippocampal, cortical, and brainstem recording. Kainic acid injection into the ventral hippocampus induced status epilepticus. RESULTS: Seizures caused hypertension, tachycardia, and tachypnea punctuated by recurrent transient apneas. Salivation increased considerably: in 11 of 12 rats, liquid with alkaline pH consistent with saliva was expelled from the mouth. Most transient apneas were obstructive: nasal airflow ceased, while, in 83%, efforts to breathe persisted as continued rhythmic activity of respiratory pre-Bötzinger neurons, inspiratory electromyography (EMG), and excursions of the chest wall and abdomen. Blood pressure oscillated in time with respiratory efforts. This pattern also occurred in a minority of cases (16%) of incomplete apnea, but not in rare cases (1%) of transient central apneas. During transient obstructive apneas, the frequency of all inspiratory efforts decreased abruptly by ~30%, suggesting a resetting of the central respiratory rhythm generator. Twenty-two of thirty-one rats died, due either to obstructive apnea (12) or central apnea following progressive slowing of respiration (10). Most rats dying of central apnea had experienced several transient obstructive apneas. Negative DC field potential shifts of the brainstem followed the final breath, consistent with previous reports on spreading depolarization in mouse models. Timing suggests that the DC shift is a consequence rather than cause of respiratory collapse. Cardiac activity continued for tens of seconds. SIGNIFICANCE: Seizure activity in forebrain induces pronounced autonomic activation and disrupts activity in medullary respiratory centers, resulting in death from either obstructive or central apnea. These results directly inform mechanisms of death in status epilepticus, and indirectly provide clues to mechanisms of sudden unexpected death in epilepsy (SUDEP).


Assuntos
Anestésicos Intravenosos/administração & dosagem , Tronco Encefálico/fisiopatologia , Hipocampo/fisiopatologia , Ácido Caínico/toxicidade , Convulsões/fisiopatologia , Apneia do Sono Tipo Central/fisiopatologia , Animais , Tronco Encefálico/efeitos dos fármacos , Morte Súbita , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Hipocampo/efeitos dos fármacos , Ratos , Ratos Long-Evans , Convulsões/induzido quimicamente , Apneia do Sono Tipo Central/induzido quimicamente
14.
Epilepsia ; 60(12): 2459-2465, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31755996

RESUMO

OBJECTIVE: To screen a library of potential therapeutic compounds for a woman with Lennox-Gastaut syndrome due to a Y302C GABRB3 (c.905A>G) mutation. METHODS: We compared the electrophysiological properties of cells with wild-type or the pathogenic GABRB3 mutation. RESULTS: Among 1320 compounds, multiple candidates enhanced GABRB3 channel conductance in cell models. Vinpocetine, an alkaloid derived from the periwinkle plant with anti-inflammatory properties and the ability to modulate sodium and channel channels, was the lead candidate based on efficacy and safety profile. Vinpocetine was administered as a dietary supplement over 6 months, reaching a dosage of 20 mg three times per day, and resulted in a sustained, dose-dependent reduction in spike-wave discharge frequency on electroencephalograms. Improved language and behavior were reported by family, and improvements in global impression of change surveys were observed by therapists blinded to intervention. SIGNIFICANCE: Vinpocetine has potential efficacy in treating patients with this mutation and possibly other GABRB3 mutations or other forms of epilepsy. Additional studies on pharmacokinetics, potential drug interactions, and safety are needed.


Assuntos
Síndrome de Lennox Gastaut/tratamento farmacológico , Síndrome de Lennox Gastaut/genética , Mutação/genética , Medicina de Precisão/métodos , Receptores de GABA-A/genética , Alcaloides de Vinca/uso terapêutico , Adulto , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Células HEK293 , Humanos , Síndrome de Lennox Gastaut/diagnóstico , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Alcaloides de Vinca/farmacologia , Ácido gama-Aminobutírico/farmacologia
15.
Anesthesiology ; 131(6): 1223-1238, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31567365

RESUMO

BACKGROUND: The population pharmacodynamics of propofol and sevoflurane with or without opioids were compared using the endpoints no response to calling the person by name, tolerance to shake and shout, tolerance to tetanic stimulus, and two versions of a processed electroencephalographic measure, the Patient State Index (Patient State Index-1 and Patient State Index-2). METHODS: This is a reanalysis of previously published data. Volunteers received four anesthesia sessions, each with different drug combinations of propofol or sevoflurane, with or without remifentanil. Nonlinear mixed effects modeling was used to study the relationship between drug concentrations, clinical endpoints, and Patient State Index-1 and Patient State Index-2. RESULTS: The C50 values for no response to calling the person by name, tolerance to shake and shout, and tolerance to tetanic stimulation for propofol (µg · ml) and sevoflurane (vol %; relative standard error [%]) were 1.62 (7.00)/0.64 (4.20), 1.85 (6.20)/0.90 (5.00), and 2.82 (15.5)/0.91 (10.0), respectively. The C50 values for Patient State Index-1 and Patient State Index-2 were 1.63 µg · ml (3.7) and 1.22 vol % (3.1) for propofol and sevoflurane. Only for sevoflurane was a significant difference found in the pharmacodynamic model for Patient State Index-2 compared with Patient State Index-1. The pharmacodynamic models for Patient State Index-1 and Patient State Index-2 as a predictor for no response to calling the person by name, tolerance to shake and shout, and tetanic stimulation were indistinguishable, with Patient State Index50 values for propofol and sevoflurane of 46.7 (5.1)/68 (3.0), 41.5 (4.1)/59.2 (3.6), and 29.5 (12.9)/61.1 (8.1), respectively. Post hoc C50 values for propofol and sevoflurane were perfectly correlated (correlation coefficient = 1) for no response to calling the person by name and tolerance to shake and shout. Post hoc C50 and Patient State Index50 values for propofol and sevoflurane for tolerance to tetanic stimulation were independent within an individual (correlation coefficient = 0). CONCLUSIONS: The pharmacodynamics of propofol and sevoflurane were described on both population and individual levels using a clinical score and the Patient State Index. Patient State Index-2 has an improved performance at higher sevoflurane concentrations, and the relationship to probability of responsiveness depends on the drug used but is unaffected for Patient State Index-1 and Patient State Index-2.


Assuntos
Anestésicos Inalatórios/sangue , Anestésicos Intravenosos/sangue , Eletroencefalografia/efeitos dos fármacos , Propofol/sangue , Sevoflurano/sangue , Vigília/efeitos dos fármacos , Adolescente , Adulto , Idoso , Anestésicos Inalatórios/administração & dosagem , Anestésicos Intravenosos/administração & dosagem , Estudos Cross-Over , Eletroencefalografia/métodos , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Propofol/administração & dosagem , Sevoflurano/administração & dosagem , Vigília/fisiologia , Adulto Jovem
16.
Epilepsia ; 60(11): 2314-2324, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31608439

RESUMO

OBJECTIVE: More than one-third of patients with temporal lobe epilepsy (TLE) continue to have seizures despite treatment with antiepileptic drugs, and many experience severe drug-related side effects, illustrating the need for novel therapies. Selective expression of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) allows cell-type-specific reduction of neuronal excitability. In this study, we evaluated the effect of chemogenetic suppression of excitatory pyramidal and granule cell neurons of the sclerotic hippocampus in the intrahippocampal mouse model (IHKA) for temporal lobe epilepsy. METHODS: Intrahippocampal IHKA mice were injected with an adeno-associated viral vector carrying the genes for an inhibitory DREADD hM4Di in the sclerotic hippocampus or control vector. Next, animals were treated systemically with different single doses of clozapine-N-oxide (CNO) (1, 3, and 10 mg/kg) and clozapine (0.03 and 0.1 mg/kg) and the effect on spontaneous hippocampal seizures, hippocampal electroencephalography (EEG) power, fast ripples (FRs) and behavior in the open field test was evaluated. Finally, animals received prolonged treatment with clozapine for 3 days and the effect on seizures was monitored. RESULTS: Treatment with both CNO and clozapine resulted in a robust suppression of hippocampal seizures for at least 15 hours only in DREADD-expressing animals. Moreover, total EEG power and the number of FRs were significantly reduced. CNO and/or clozapine had no effects on interictal hippocampal EEG, seizures, or locomotion/anxiety in the open field test in non-DREADD epileptic IHKA mice. Repeated clozapine treatment every 8 hours for 3 days resulted in almost complete seizure suppression in DREADD animals. SIGNIFICANCE: This study shows the potency of chemogenetics to robustly and sustainably suppress spontaneous epileptic seizures and pave the way for an epilepsy therapy in which a systemically administered exogenous drug selectively modulates specific cell types in a seizure network, leading to a potent seizure suppression devoid of the typical drug-related side effects.


Assuntos
Anticonvulsivantes/administração & dosagem , Epilepsia do Lobo Temporal/genética , Epilepsia do Lobo Temporal/prevenção & controle , Convulsões/genética , Convulsões/prevenção & controle , Animais , Clozapina/administração & dosagem , Clozapina/análogos & derivados , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Epilepsia do Lobo Temporal/fisiopatologia , Vetores Genéticos/administração & dosagem , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Ácido Caínico/administração & dosagem , Ácido Caínico/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Convulsões/fisiopatologia
17.
Anesthesiology ; 131(6): 1239-1253, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31567366

RESUMO

BACKGROUND: Functional brain connectivity studies can provide important information about changes in brain-state dynamics during general anesthesia. In adults, γ-aminobutyric acid-mediated agents disrupt integration of information from local to the whole-brain scale. Beginning around 3 to 4 months postnatal age, γ-aminobutyric acid-mediated anesthetics such as sevoflurane generate α-electroencephalography oscillations. In previous studies of sevoflurane-anesthetized infants 0 to 3.9 months of age, α-oscillations were absent, and power spectra did not distinguish between anesthetized and emergence from anesthesia conditions. Few studies detailing functional connectivity during general anesthesia in infants exist. This study's aim was to identify changes in functional connectivity of the infant brain during anesthesia. METHODS: A retrospective cohort study was performed using multichannel electroencephalograph recordings of 20 infants aged 0 to 3.9 months old who underwent sevoflurane anesthesia for elective surgery. Whole-brain functional connectivity was evaluated during maintenance of a surgical state of anesthesia and during emergence from anesthesia. Functional connectivity was represented as networks, and network efficiency indices (including complexity and modularity) were computed at the sensor and source levels. RESULTS: Sevoflurane decreased functional connectivity at the δ-frequency (1 to 4 Hz) in infants 0 to 3.9 months old when comparing anesthesia with emergence. At the sensor level, complexity decreased during anesthesia, showing less whole-brain integration with prominent alterations in the connectivity of frontal and parietal sensors (median difference, 0.0293; 95% CI, -0.0016 to 0.0397). At the source level, similar results were observed (median difference, 0.0201; 95% CI, -0.0025 to 0.0482) with prominent alterations in the connectivity between default-mode and frontoparietal regions. Anesthesia resulted in fragmented modules as modularity increased at the sensor (median difference, 0.0562; 95% CI, 0.0048 to 0.1298) and source (median difference, 0.0548; 95% CI, -0.0040 to 0.1074) levels. CONCLUSIONS: Sevoflurane is associated with decreased capacity for efficient information transfer in the infant brain. Such findings strengthen the hypothesis that conscious processing relies on an efficient system of integrated information transfer across the whole brain.


Assuntos
Anestésicos Inalatórios/administração & dosagem , Encéfalo/efeitos dos fármacos , Estado de Consciência/efeitos dos fármacos , Ritmo Delta/efeitos dos fármacos , Rede Nervosa/efeitos dos fármacos , Sevoflurano/administração & dosagem , Encéfalo/fisiologia , Estudos de Coortes , Estado de Consciência/fisiologia , Ritmo Delta/fisiologia , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Rede Nervosa/fisiologia , Estudos Retrospectivos , Inconsciência/induzido quimicamente , Inconsciência/fisiopatologia
18.
Neurochem Res ; 44(11): 2566-2576, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31535354

RESUMO

Epilepsy is a chronic neurological disease. Astrogliosis is an important pathological change in epileptic lesions. Studies have reported that ibuprofen can affect autophagy and/or inhibit cell proliferation in many diseases. This study investigated the effect and significance of ibuprofen on autophagy of astrocytes during pentylenetetrazol (PTZ) induced epilepsy. 60 male Sprague-Dawley (SD) rats were randomly divided into five groups: control group (received normal saline), PTZ group, 3-methyladenine (3-MA) + PTZ group, ibuprofen + PTZ group and 3-MA + ibuprofen + PTZ group. Dose of each agent was 35 mg/kg (PTZ), 10 mg/kg (3-MA) and 30 mg/kg (ibuprofen) and all drugs were administered intraperitoneally 15 times on alternate days (29 days). Human astrocytes were cultured in vitro. Behavioral performance (i.e., latency, grade and duration of seizures) and EEG of rats were observed and recorded. Proliferation of astrocytes was detected by CCK-8 method. Immunofluorescence and Western blot test were used to detect the expression of LC3 and GFAP. Mean number, grade and duration of seizures were markedly reduced in ibuprofen + PTZ group and 3-MA + ibuprofen + PTZ group (P < 0.05). Similarly, peak of EEG waves were markedly reduced in ibuprofen + PTZ group and 3-MA + ibuprofen + PTZ group (P < 0.05). Compared to the control group, the level of LC3 in ibuprofen group was significantly increased in vitro (P < 0.05). While, levels of LC3 were significantly higher and that of GFAP were significantly lower in ibuprofen + PTZ group (P < 0.05) compared to PTZ group in vivo. Ibuprofen reduces the proliferation of astrocytes by increasing autophagy, thus affecting the development of epilepsy. Therefore, ibuprofen may be used as an adjuvant to improve efficacy of treatment in epilepsy.


Assuntos
Astrócitos/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Ibuprofeno/uso terapêutico , Animais , Astrócitos/patologia , Encéfalo/metabolismo , Encéfalo/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Epilepsia/induzido quimicamente , Proteína Glial Fibrilar Ácida/metabolismo , Humanos , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Pentilenotetrazol , Ratos Sprague-Dawley
19.
Ann Neurol ; 86(6): 939-950, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31525273

RESUMO

OBJECTIVE: Temporal lobe epilepsy (TLE) is a devastating disease in which seizures persist in 35% of patients despite optimal use of antiseizure drugs. Clinical and preclinical evidence implicates seizures themselves as one factor promoting epilepsy progression. What is the molecular consequence of a seizure that promotes progression? Evidence from preclinical studies led us to hypothesize that activation of tropomyosin kinase B (TrkB)-phospholipase-C-gamma-1 (PLCγ1) signaling induced by a seizure promotes epileptogenesis. METHODS: To examine the effects of inhibiting TrkB signaling on epileptogenesis following an isolated seizure, we implemented a modified kindling model in which we induced a seizure through amygdala stimulation and then used either a chemical-genetic strategy or pharmacologic methods to disrupt signaling for 2 days following the seizure. The severity of a subsequent seizure was assessed by behavioral and electrographic measures. RESULTS: Transient inhibition of TrkB-PLCγ1 signaling initiated after an isolated seizure limited progression of epileptogenesis, evidenced by the reduced severity and duration of subsequent seizures. Unexpectedly, transient inhibition of TrkB-PLCγ1 signaling initiated following a seizure also reverted a subset of animals to an earlier state of epileptogenesis. Remarkably, inhibition of TrkB-PLCγ1 signaling in the absence of a recent seizure did not reduce severity of subsequent seizures. INTERPRETATION: These results suggest a novel strategy for limiting progression or potentially ameliorating severity of TLE whereby transient inhibition of TrkB-PLCγ1 signaling is initiated following a seizure. ANN NEUROL 2019;86:939-950.


Assuntos
Excitação Neurológica/fisiologia , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Quinases/metabolismo , Convulsões/tratamento farmacológico , Convulsões/enzimologia , Transdução de Sinais/fisiologia , Animais , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Feminino , Excitação Neurológica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos
20.
J Nerv Ment Dis ; 207(10): 863-868, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31365433

RESUMO

The aim is to examine the cognitive domains, behavioral domains, and electroencephalogram (EEG) findings in children of mothers with idiopathic generalized epilepsy who had been exposed to antiepileptic drugs (AEDs) in utero. Forty school-aged children born to 23 mothers with idiopathic generalized epilepsy were compared with 40 healthy children born to 34 healthy mothers. Stanford-Binet Intelligence Scale was applied to all children to assess their cognitive functions. Child Behavior Checklist was used to assess their behavioral characteristics. EEG was done for the epileptic mothers and their children. Children exposed to AEDs showed significantly lower scores in the verbal reasoning, visual reasoning, and global intelligence quotient (IQ). There was a significantly positive correlation between children's global IQ and maternal global IQ. Multiple regression analysis showed that in utero exposure to valproate and maternal IQ were the most independent factors affecting children's IQ. EEG findings of participating children were normal. Exposure to valproic acid during fetal life and maternal IQ represent confounding factors affecting the IQ of children with in utero exposure to AEDs.


Assuntos
Anticonvulsivantes/efeitos adversos , Avaliação Educacional/métodos , Epilepsia Generalizada/epidemiologia , Complicações na Gravidez/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Adulto , Estudos de Casos e Controles , Criança , Pré-Escolar , Estudos Transversais , Eletroencefalografia/efeitos dos fármacos , Eletroencefalografia/métodos , Epilepsia Generalizada/complicações , Epilepsia Generalizada/tratamento farmacológico , Feminino , Humanos , Testes de Inteligência , Masculino , Gravidez , Complicações na Gravidez/tratamento farmacológico , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Estudantes/psicologia
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