Pharmaceutics
·
2024
·Vol. 16
·期 6
·805
·
IF 4.9
Ailing Wu,Houyin Shi,Luhan Yang,Hao Zhang,Xichen Nan,Dan Zhang,Zhuo Zhang,Chun Zhang,Siwei Chen,Xiujuan Fu,Lilan Ou,Lulu Wang,Yanyan Shi,Hao Liu
Etomidate is a general anesthetic that has shown good hemodynamic stability without significant cardiovascular or respiratory depression. Despite several kinds of dosage forms having been reported for this drug, formulation types are very limited in clinical practice, and brain-targeted formulations for this central nervous system (CNS) drug have been rarely reported. Moreover, studies on the biocompatibility, toxicity, and anesthetic effects of the etomidate preparations in vivo were inadequate. The present study was to develop lactoferrin-modified liposomal etomidate (Eto-lip-LF) for enhanced drug distribution in the brain and improved anesthetic effects. Eto-lip-LF had good stability for storage and hemocompatibility for intravenous injection. Compared with the non-lactoferrin-containing liposomes, the lactoferrin-modified liposomes had notably enhanced brain-targeting ability in vivo, which was probably realized by the binding of transferrin with the transferrin and lactoferrin receptors highly distributed in the brain. Eto-lip-LF had a therapeutic index of about 25.3, higher than that of many other general anesthetics. Moreover, compared with the commercial etomidate emulsion, Eto-lip-LF could better achieve rapid onset of general anesthesia and rapid recovery from anesthesia, probably due to the enhanced drug delivery to the brain. The above results demonstrated the potential of this lactoferrin-modified liposomal etomidate to become an alternative preparation for clinical general anesthesia.
研究领域:
药剂学
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神经科学
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临床医学
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DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2022
·
IF 5.988
Li Yueyue,Li Jingjie,Shi Yuhuan,Zhou Xuhui,Feng Wanqing,Han Lu,Ma Daqing,Jiang Hong,Yuan Yongfang
Background: Emergence agitation (EA) is very common in paediatric patients during recovery from general anaesthesia, but underlying mechanisms remain unknown. This prospective study was designed to profile preoperative urine metabolites and identify potential biomarkers that can predict the occurrence of EA.Methods: A total of 224 patients were screened for recruitment; of those, preoperative morning urine samples from 33 paediatric patients with EA and 33 non-EA gender- and age-matched patients after being given sevoflurane general anaesthesia were analysed by ultra-high-performance liquid chromatography (UHPLC) coupled with a Q Exactive Plus mass spectrometer. Univariate analysis and orthogonal projection to latent structures squares-discriminant analysis (OPLS-DA) were used to analyse these metabolites. The least absolute shrinkage and selection operator (LASSO) regression was used to identify predictive variables. The predictive model was evaluated through the receiver operating characteristic (ROC) analysis and then further assessed with 10-fold cross-validation.Results: Seventy-seven patients completed the study, of which 33 (42.9%) patients developed EA. EA and non-EA patients had many differences in preoperative urine metabolic profiling. Sixteen metabolites including nine aromatic amino acid metabolites, acylcarnitines, pyridoxamine, porphobilinogen, 7-methylxanthine, and 5′-methylthioadenosine were found associated with an increased risk of EA, and they all exhibited higher levels in the EA group than in the non-EA group. The main metabolic pathways involved in these metabolic changes included phenylalanine, tyrosine and tryptophan metabolisms. Among these potential biomarkers, L-tyrosine had the best predictive value with an odds ratio (OR) (95% CI) of 5.27 (2.20–12.63) and the AUC value of 0.81 (0.70–0.91) and was robust with internal 10-fold cross-validation.Conclusion: Urinary aromatic amino acid metabolites are closely associated with EA in paediatric patients, and further validation with larger cohorts and mechanistic studies is needed.Clinical Trial Registration: clinicaltrials.gov, identifier NCT04807998
研究领域:
医学
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麻醉学
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代谢组学
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DOI
PubMed
高影响因子
JOURNAL OF DRUG DELIVERY SCIENCE AND TECHNOLOGY
·
2018
·
IF 2.297
Ailing Wu,Yingying Wang,Su Min,Hao Liu,Fei Xie
Etomidate is one of the most commonly used intravenous ( i.v. ) general anesthetics with rapid onset, minimal impact on breathing and excellent hemodynamic stability. But its application is usually coupled with several disadvantages including inadequate water-solubility for injection and adrenal toxicity in particular. Selective delivery of etomidate to brain via some water-soluble nanocarriers provides a potential way to settle these problems. In this study, etomidate-loaded poloxamer micelles (Eto-SOPM) were prepared using a thin-film hydration method. Soybean oil (SO) was used to enhance the encapsulation of etomidate, which resulted in acceptable drug concentration (2 mg/mL) for injection. The drug release of Eto-SOPM was not significantly hindered by encapsulation or the addition of soybean oil, and was faster than that of the commercially available etomidate fat emulsion (P < 0.001). The in vivo study revealed that the drug potency of etomidate was not significantly affected by encapsulation, and that Eto-SOPM had notably shortened action period as compared with etomidate fat emulsion (P < 0.001). As rapid onset and short action period are two essential requirements of general anesthetics, these results suggested that Eto-SOPM represents a promising etomidate preparation for short-acting general anesthesia and warrants more study in the future.
研究领域:
药剂学
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麻醉学
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生物医学工程
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DOI
高影响因子
eLife
·
2023
·
IF 7.7
Yang He,Taohui Liu,Quansheng He,Wei Ke,Xiaoyu Li,Jinjin Du,Suixin Deng,Zhenfeng Shu,Jialin Wu,Baozhi Yang,Yuqing Wang,Ying Mao,Yanxia Rao,Yousheng Shu,Bo Peng
General anesthesia leads to a loss of consciousness and an unrousable state in patients. Although general anesthetics are widely used in clinical practice, their underlying mechanisms remain elusive. The potential involvement of nonneuronal cells is unknown. Microglia are important immune cells in the central nervous system (CNS) that play critical roles in CNS function and dysfunction. We unintentionally observed delayed anesthesia induction and early anesthesia emergence in microglia-depleted mice. We found that microglial depletion differentially regulates neuronal activities by suppressing the neuronal network of anesthesia-activated brain regions and activating emergence-activated brain regions. Thus, microglia facilitate and stabilize the anesthesia status. This influence is not mediated by dendritic spine plasticity. Instead, it relies on the activation of microglial P2Y12 and subsequent calcium influx, which facilitates the general anesthesia response. Together, we elucidate the regulatory role of microglia in general anesthesia, extending our knowledge of how nonneuronal cells modulate neuronal activities.
研究领域:
神经科学
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麻醉学
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免疫学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Hao Liu,Jing-Kun Miao,Meng Cai,Lin Gan,Hui-Qing Zhao,Xiao-Feng Lei,Jin Yu
Objective: This study aims to determine the drug concentration of etomidate, remifentanil, and rocuronium bromide for general anesthesia in fetus as well as the placental transport rate between term and preterm delivery, twins, and singleton. Study design: Sixty parturients with 72 fetuses undergoing cesarean section under general anesthesia were included. According to whether the fetus was a twin or premature, parturients were divided into Group I (term singleton), Group II (premature singleton), Group III (term twins), and Group IV (premature twins). The preoperative demographic characteristics and laboratory examination of parturients, hemodynamic indicators, the Apgar score of neonates at 1, 5, and 10 min after delivery and at specific assigned values, umbilical artery blood gas analysis results, neonatal weight, and resuscitative measures were recorded. Anesthetic drug concentrations in maternal arterial (MA), umbilical arterial (UA), and umbilical venous (UV) blood were detected by Ultra Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). Result: No significant differences were observed in the concentrations of etomidate, remifentanil, and rocuronium bromide in MA, UV, and UA blood, or in the UV/MA and UA/UV ratios between term and preterm infants, twins, and singletons. Moreover, there was no variation in the anesthetic drug concentration among each pair of twins. Additionally, no correlation was found between the neonatal weight and the plasma concentrations of anesthetic drugs in UV and UA blood, except for remifentanil in UA blood. Conclusion: Preterm or twin deliveries do not affect the neonatal concentration of etomidate, remifentanil, and rocuronium bromide used in general anesthesia for cesarean sections. Clinical Trial Registration: www.chictr.org.cn , identifier ChiCTR2100046547
研究领域:
妇产科学
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麻醉学
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药理学
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产品关联
DOI
PubMed
高影响因子
Acta Physiologica
·
2023
·
IF 6.3
Hanyu Fu,Jingwei Zhou,Shan Li,Ying Zhang,Zhiyun Chen,Yingying Yang,Anan Li,Dejuan Wang
Aim General anesthesia can induce cognitive deficits in both humans and rodents, correlating with pathological alterations in the hippocampus. However, whether general anesthesia affects olfactory behaviors remains controversial as clinical studies have produced inconsistent results. Therefore, we aimed to investigate how olfactory behaviors and neuronal activity are affected by isoflurane exposure in adult mice. Methods The olfactory detection test, olfactory sensitivity test, and olfactory preference/avoidance test were used to examine olfactory function. In vivo electrophysiology was performed in awake, head-fixed mice to record single-unit spiking and local field potentials in the olfactory bulb (OB). We also performed patch-clamp recordings of mitral cell activity. For morphological studies, immunofluorescence and Golgi–Cox staining were applied. Results Repeated exposure to isoflurane impaired olfactory detection in adult mice. The main olfactory epithelium, the first region exposed to anesthetics, displayed increased proliferation of basal stem cells. In the OB, a crucial hub for olfactory processing, repeated isoflurane exposure increased the odor responses of mitral/tufted cells. Furthermore, the odor-evoked high gamma response was decreased after isoflurane exposure. Whole-cell recordings further indicated that repeated isoflurane exposure increased the excitability of mitral cells, which may be due to weakened inhibitory input in isoflurane-exposed mice. In addition, elevated astrocyte activation and glutamate transporter-1 expression in the OB were observed in isoflurane-exposed mice. Conclusions Our findings indicate that repeated isoflurane exposure impairs olfactory detection by increasing neuronal activity in the OB in adult mice.
研究领域:
神经科学
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麻醉学
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行为科学
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DOI
PubMed
高影响因子
Frontiers in Neuroscience
·
2022
·
IF 5.152
Xiaojun Zhang,Wensi Wu,Zhenzhen Zheng,Liang Li,Junjun Chen,Junying Zhong,Le Zhao,Jiawei Chen,Zhi Wang,Fanqing Meng
Background: Prolonged exposure to general anesthesia (GA) results in long-lasting cognitive impairment, especially during critical stages of brain development. An exaggerated neuroinflammation induced by anesthesia is generally considered to be a key cause of cognitive impairment. Materials and methods: Postnatal day 7 (PND 7) mice were exposed to GA by isoflurane inhalation for 6 h or mock anesthesia. Disodium cromoglycate (DSCG) was intraperitoneally injected daily for 2 weeks, beginning from 30 min before anesthesia. The post-anesthesia evaluation included behavioral tests, toluidine blue staining, immunofluorescence and western blot. Results: Our results demonstrated the long-term cognition were impaired after 6 h GA exposure in neonatal mice. DSCG treatment ameliorated early mast cells (MCs) degranulation and mast cell tryptase (MCT) expression, which helps to attenuate subsequent neuroinflammation, activation of microglia and astrocytes, and damage to oligodendrocytes and synapses to improve cognitive impairment. Conclusion: Disodium cromoglycate could effectively improve long-term cognitive impairment after GA exposure in neonatal mice.
研究领域:
神经科学
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药理学
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儿科
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麻醉学
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产品关联
DOI
PubMed
高影响因子
METABOLIC BRAIN DISEASE
·
2020
·Vol. 35
·期 2
·373-383
·
IF 2.726
Zhou Yiying,Wu Xiang,Ye Luying,Bai Yujing,Zhang Hui,Xuan Zhenquan,Feng Yi,Zhang Panpan,Chen Yi,Yan Yushan,Zhu Binbin,Cui Wei
Postoperative cognitive dysfunction (POCD) is a common neurological disease affecting the elderly patients after surgery. Unfortunately, no effective treatment for this disease has been discovered. Edaravone, a clinical-used free radical scavenger, at 3 mg/kg has been reported to prevent neuroinflammation induced by the combination of surgery and lipopolysaccharide in adult rodents. However, we found that edaravone at such low concentration could not inhibit POCD in aged mice. Instead, edaravone at 33.2 mg/kg significantly prevented recognition and spatial cognitive dysfunctions in 14 month aged mice after abdominal surgery under general anesthesia with isoflurane. Furthermore, edaravone significantly prevented the increase of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) induced by abdominal surgery in aged mice. Edaravone could also decrease glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule-1 (Iba-1) positive areas in the hippocampal regions of surgery mice, suggesting that edaravone might inhibit surgery-induced over-activation of microglia and astrocytes. Moreover, edaravone substantially increased the expression of PSD-95 and pSer9-glycogen synthase kinase-3β (pSer9-GSK3β) as demonstrated by Western blotting assay. Furthermore, the activity of acetylcholinesterase (AChE) is decreased in the mice in edaravone group. All these results suggested that edaravone at high concentrations could inhibit surgery-induced cognitive impairments in aged animals, possibly via the attenuation of neuroinflammation, the increase of synaptic proteins, and the elevation of cholinergic transmission, providing a further support that edaravone might be developed as a treatment of POCD.
研究领域:
药理学
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神经科学
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麻醉学
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老年医学
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产品关联
DOI
PubMed
高影响因子
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