Table of Content

Volume 27 Issue 7
26 July 2022

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Bone marrow-derived mesenchymal stem cells ameliorate severe acute pancreatitis-induced lung injury in rats via suppression of ferroptosis

YU Weidi, SONG Zhenshun

2022, 27(7):  721-728.  doi:10.12092/j.issn.1009-2501.2022.07.001

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AIM: To evaluate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) on ferroptosis in lung injury caused by severe acute pancreatitis (SAP).  METHODS: BMSCs were obtained from male SD rats (3 weeks of age). 30 male SD rats (6 weeks of age) were randomly divided into 5 groups: Sham group, SAP group, SAP+PBS group, SAP+BMSCs group, and SAP+BMSCs+ML385 group, with 6 rats in each group. SAP model induced by sodium taurocholate (NaT) was established. Rats in the SAP+MSCs+ML385 group were intraperitoneally injected with ML385 (5 mg/kg) 2h before SAP induction. For PBS control and BMSCs treatment groups, PBS and BMSCs were respectively injected into rats via the tail vein 6 h after creation of the SAP model. All rats were sacrificed 3 days after SAP induction, and pancreas and lung tissue and serum samples were collected. Pancreatic and pulmonary injury was assessed using H&E staining. Serum levels of amylase and lipase and inflammatory factors, as well as tissue levels of iron, malondialdehyde (MDA), glutathione (GSH) were evaluated. The expressions of ferroptosis-associated proteins, including iron responsive element binding protein 2 (IREB2), ferritin heavy chain 1 (FTH1), acyl-CoA synthetase long-chain family member 4 (ACSL4), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11), as well as the expressions of PI3K/AKT/Nrf2 pathway-related proteins were assessed. RESULTS: The serum levels of amylase, lipase and proinflammatory factors, as well as pathological scores were significantly increased after SAP induction (P<0.05). Changes above were effectively alleviated by BMSCs (P<0.05). Compared with SAP group, the iron and MDA contents were decreased, the GSH activity was increased, the expression of IREB2 and ACSL4 were downregulated and the expression of FTH1, GPX4 and SLC7A11 were upregulated in SAP+BMSCs group (P<0.05). Injection of ML385 partially offset the anti-lipid peroxidation effect of BMSCs (P<0.05). In addition, BMSCs upregulated the total protein levels of PI3K and p-AKT, and the nuclear protein level of Nrf2 in lung tissue (P<0.05). CONCLUSION: BMSCs can effectively reduce systemic inflammatory response and local tissue injury in SAP; BMSCs can inhibit iron deposition and lipid peroxidation in SAP-induced lung injury, and the anti-lipid peroxidation effect may be achieved via activating the PI3K/AKT/Nrf2 signaling pathway. 

Amelioration of nebivolol on renal interstitial fibrosis in UUO rats based on proteomic analysis

WU Lijun, Li Xin, CUI Lijuan, LI Xinxin, WANG Yan

2022, 27(7):  729-738.  doi:10.12092/j.issn.1009-2501.2022.07.002

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AIM: To explore the effect and mechanism of nebivolol on renal interstitial fibrosis(RIF) in unilateral ureteral obstruction (UUO) model through TMT proteomics.  METHODS: SD rats were divided into Sham group, UUO group, Neb group(UUO rats treated with nebivolol 10 mg·kg-1·d-1, i.g.). Left kidney was collected from rat on 7th, 14th and 21th day after modeling. HE staining was used to observe renal structure and Masson's staining was used to examine RIF. Proteomic and bioinformatics were conducted to screen and analysis the differential expressed proteins contrary regulated between UUO/Sham and Neb/UUO 21d after obstruction. Western blot were used to confirm protein expressions. RESULTS: Compared with Sham group, RIF in UUO rats aggravated gradually. Administration of nebivolol for 21 d ameliorated RIF in UUO rats. A total of 179 differential expressed proteins contrary regulated were identified shared between UUO/Sham and Neb/UUO groups. KEGG enrichment analysis and PPI showed that these differential expressed proteins were mainly involved in spliceosome pathway. Results of Western blot for Rbm8a, Srsf9 and Sart1 were in line with the results of proteomics. CONCLUSION: Spliceosome may play key role in the amelioration of nebivolol on RIF in UUO rats. 

Inhibitory effect of flufenidone on TGF-β1/Smads pathway in hepatocytes of rats with diethylnitrosamine (DEN)-induced liver injury

WEI Feng, HE Yang, FAN Zhiqiang, LIU Shikun, OUYANG Linqi

2022, 27(7):  739-746.  doi:10.12092/j.issn.1009-2501.2022.07.003

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AIM: To explore the protective effect of fluorofenidone (AKF-PD) on diethylnitrosamine-induced liver injury in rats and its inhibition of the TGF-β1/Smads pathway in hepatocytes.  METHODS: Fifty-five male Sprague Dawley (SD) rats were randomly divided into three groups: model group (DEN group, n=20) were gavaged with DEN (10 mg/kg), 5 times for 14 weeks; control group (n=20) were gavaged with saline with the same volume of the model group; treatment group (DEN+AKF-PD Group, n=15), after 4 weeks of modeling, they were gavaged with AKF-PD (500 mg/kg) daily, and stopped at 14 weeks. At the end of experiment, the rats were killed by anesthesia and spinal dislocation. Masson staining was used to observe collagen deposition; primary hepatocytes were extracted and identified, and the levels of α-smooth muscle actin (α-SMA), TGF-β1, Smad3, and Smad7 mRNA, and the expression of Smad3 and Smad7 proteins in hepatocytes were detected. RESULTS: Compared with the control group, Masson staining showed that collagen deposition increased in the DEN group; AKF-PD treatment could significantly improve liver pathological damage and reduce collagen deposition. In addition, compared with the DEN group, the α-SMA, TGF-β1, and Smad3 mRNA levels of the AKF-PD group were significantly reduced, and the Smad7 mRNA level was increased. Moreover, AKF-PD treatment could dependably reduce the expression of Smad3 and increase Smad7. CONCLUSION: AKF-PD can significantly improve liver injury and fibrosis in rats caused by DEN. This effect may be related to the down-regulation of α-SMA, TGF-β1, and Smad3 mRNA levels in hepatocytes and the increase of Smad7 mRNA levels.

Effects of 2-APB in skin wound healing in mice through down-regulation of TRPM7

LIANG Hongyu, ZHANG Hailin, YIN Huanxin, CHEN Fan, LU Junlin, ZHU Caihong, HU Wei, ZHOU Renpeng

2022, 27(7):  747-753.  doi:10.12092/j.issn.1009-2501.2022.07.004

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AIM: To explore the promoting effect of 2-APB on skin wound healing in mice and its potential mechanism. METHODS: KM mice were divided into 5 groups: control group, DMSO group, low (50 mg/L), medium (100 mg/L) and high (200 mg/L) concentration 2-APB group. On the back of each mouse's skin use a circular punch about 1 cm on both sides of the midline of the spine to make a skin wound with a diameter of 10 mm and as deep as the fascia. The control group was only wrapped with gauze and no drugs were applied; the DMSO group was applied 1 g DMSO/Vaseline ointment per day; in the 2-APB group, apply 1 g of 2-APB/Vaseline ointment at a corresponding concentration every day. Pictures were taken the next day to observe the healing, and the material was taken on the 21st day, HE staining was used to observe the pathological morphology of the wound and western blot to detect TRPM7, TGF-β, collagen-I and IL-1β expression. RESULTS: Compared with the control group and the DMSO group, different concentrations of 2-APB could significantly promote skin wound healing in mice (P<0.01), but there was no significant difference in wound healing rate between the DMSO group and the control group group. The results of HE staining showed that, compared with the control group group and the DMSO group, 2-APB could increase the collagen content of the wound and the thickness of the dermis (P<0.01), but there was no significant difference between the DMSO group and the control group group. At the same time, 2-APB could also significantly increase the expression of TGF-β and Col-I on the wound, and inhibit the expression of TRPM7 and IL-1β. CONCLUSION: Different concentrations of 2-APB (50, 100 and 200 mg/L) can promote skin wound healing, and its mechanism may be related to the inhibition of TRPM7.

Inhibition and mechanism of Xihuang pill on mice bearing hepatoma H22 tumor

LIU Yanzhi, WANG Yan, LIU Kaili, ZHOU Wenhua, ZHU Ping, WANG Yingli, DU Shouying

2022, 27(7):  754-761.  doi:10.12092/j.issn.1009-2501.2022.07.005

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AIM: To study the inhibitory effect of Xihuang Pill on H22 tumor-bearing mice and its related mechanism.  METHODS: The H22 tumor-bearing mouse model was used to analyze the inhibitory effect of Xihuang Pill on tumor; the contents of CD3+, CD4+, and CD8+ cells in blood were determined by flow cytometry; the contents of related factors were determined by enzyme-linked immunosorbent assay. Network pharmacology predicted the relevant pathways of its inhibition of liver cancer, and verified the key protein targets by Western Blot. RESULTS: Xihuang pill administration group could reduce the tumor weight of H22 tumor-bearing mice (P<0.05); increase the thymus index and spleen index (P<0.05), and increase the level of CD4+/CD8+ (P<0.05); The levels of IL-2 and IFN-γ decreased the levels of IL-6 and IL-10 (P<0.05). 77 important active ingredients and 28 core targets were obtained through network pharmacology screening. Western blot verification showed that Xihuang pills had a significant regulatory effect on the key protein targets of PI3K-Akt-MMP9 pathway. CONCLUSION: Xihuang pill has the effect of inhibiting the transplanted tumor of liver cancer and correcting the immune disorder of the tumor-bearing mice.

Design of case report form for oncology clinical trials based on CDASH

CHEN Jianfang, LOU Donghua

2022, 27(7):  762-767.  doi:10.12092/j.issn.1009-2501.2022.07.006

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AIM: To investigate the design significance, method and content of the oncology clinical trial case report form (CRF) based on the clinical data acquisition standards harmonization (CDASH).  METHODS: Compared with CDASH v2.2, the characteristics of oncology clinical trial data were analyzed, and a standardized CRF was designed to meet the actual needs of oncology clinical trials. RESULTS: The CDASH was applied to the design of the CRF of the oncology clinical trial, and the data collection of the oncology clinical trial was standardized, so that the CRF design of the oncology clinical trial was relatively standardized and the data quality was improved. CONCLUSION: The implementation of oncology CRF design based on CDASH can promote the exchange and sharing of oncology clinical research data, which is conducive to improving the reliability of oncology clinical research results. 

Distributions of MTHFR gene polymorphism and its correlation with blood Hcy in patients with hypertension in southern Anhui province

CHEN Wengang, YIN Qin, ZHANG Weiwei, ZHOU Lulu, KOU Wanqing, YUAN Xiaolong

2022, 27(7):  768-774.  doi:10.12092/j.issn.1009-2501.2022.07.007

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AIM: To investigate the distribution characteristics of methylenetetrahydrofolate reductase (MTHFR) gene polymorphism and its correlation with blood Hcy in hypertensive patients and to provide reference for the prevention and treatment of H-type hypertension in southern Anhui Province.  METHODS: A total of 657 hypertensive patients were treated in our hospital from October 2019 to August 2020 were selected as the research objects. The MTHFR C677T and A1298C loci were genotyped by fluorescence staining in situ hybridization, and the blood Hcy concentration was determined by the enzyme cycle method. The distribution characteristics of MTHFR gene in the Han nationality hypertensive population in southern Anhui Province were analyzed, and compared with the reported MTHFR gene distribution data of hypertensive populations in other regions and ethnic groups. RESULTS: Among the 657 patients, the distributions of CC, CT and TT types at the C677T site of MTHFR gene were 212(32.27%), 321(48.86%), 124(18.87%), and the distribution of AA, AC, and TT types at the A1298C site were 467(71.08%), 171(26.03%), 19(2.89%). There was no gender difference in the distribution of the two loci of this gene in the hypertensive population in southern Anhui Province (P>0.05). The distribution frequency of CC genotype at C677T locus is lower than that in Foshan and Guangxi, but higher than that in Henan, Xinjiang and Inner Mongolia; the frequency of CT genotype is higher than that in Foshan and Guangxi; the frequency of TT genotype is higher than that in Foshan and Guangxi. Guangxi region was lower than Henan region, Xinjiang region and Inner Mongolia region, and the difference was statistically significant (P<0.05). The mean blood Hcy of 657 patients was (15.8±7.80) μmol/L, of which 510(77.62%) were in line with the diagnosis of H-type hypertension. The level of Hcy in males was significantly higher than that in females, and the difference was statistically significant (P<0.000 1). Compared with the different genotypes of the C677T locus, the TT type was higher than the CT type and CC type, and the difference was statistically significant (P<0.05). There was no significant difference in Hcy levels between different genotypes at the A1298C locus (P>0.05). CONCLUSION: The distribution of MTHFR gene polymorphism in the Han nationality hypertensive population in southern Anhui is significantly different from other regions, and it is also significantly related to the level of Hcy, which has obvious regional characteristics. The genetic detection technology combined with the determination of Hcy concentration can provide a scientific basis for the prevention and treatment of H-type hypertension in southern Anhui Province.

Effect of terlipressin on renal function in cirrhotic patients with esophageal gastric varices bleeding and normal baseline renal function

LIN Xueyan, LIN Zhihui, HUANG Huping

2022, 27(7):  775-784.  doi:10.12092/j.issn.1009-2501.2022.07.008

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AIM: To assess the effect of terlipressin on renal function in cirrhotic patients with esophageal gastric varices bleeding (EGVB) and normal baseline renal function. METHODS: Ninety six cirrhotic patients with EGVB enrolled in Fujian Provincial Hospital form January 2016 to January 2019 were reviewed retrospectively. The renal function and the factors associated with serum creatinine (Cr) reduction were explored. RESULTS: The lowest serum Cr ［(58.41±14.58) μmol/L vs. (66.20±16.27) μmol/L, P=0.015］ and highest eGFR ［(105.16±19.36) mL·min-1·1.73 m-2) vs. (95.62±16.18) mL·min-1·1.73 m-2, P=0.011］ were significantly different between patients treated with terlipressin and somatostatin. Serum Cr was significantly reduced ［(65.18±17.83) μmol/L vs. (58.41±14.58) μmol/L, P=0.001］ and eGFR was significantly elevated ［(98.94±20.25) mL·min-1·1.73 m-2 vs. (105.16±19.36) mL·min-1·1.73 m-2, P<0.001］ during the use of terlipressin. Logistic regression analysis revealed that higher baseline serum Cr was a risk factor for serum Cr reduction during the use of terlipressin (OR=1.076, 95%CI 1.015-1.142, P=0.015). The reduction of serum Cr was not significant after terlipressin was discontinued ［(65.18±17.83) μmol/L vs. (63.56±13.48) μmol/L, P=0.297］. Somatostatin had no effect on serum Cr neither used or not ［(65.82±18.12) μmol/L vs. (66.20±16.27) μmol/L, P=0.766］, ［(65.82±18.12) μmol/L vs. (68.24±17.99) μmol/L, P=0.085］. CONCLUSION: Terlipressin can reduce serum creatinine and elevate eGFR of cirrhotic patients with EGVB and normal baseline renal function, and may be beneficial on preventing renal function impairment in cirrhotic patients with EGVB and normal baseline renal function.

Efficacy and safety of generic and branded atorvastatin in patients with ischemic stroke/transient ischemic attack: A real-world study

LIANG Meifang, CHEN Qingzhuang, YANG Peiqun, WANG Yong

2022, 27(7):  785-792.  doi:10.12092/j.issn.1009-2501.2022.07.009

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AIM: In this study, we assessed the safety and efficacy of generic and branded atorvastatin in patients with ischemic stroke/transient ischemic attack in real-world practice.  METHODS: Patients admitted for ischemic stroke/transient ischemic attack between January 1, 2018 and March 31, 2021 who continually received atorvastatin for ≥6 months after diagnosis were included. Safety and efficacy endpoints in patients receiving the generic atorvastatin were compared with those of patients receiving the branded medication. Propensity score matching was applied to control confounders. RESULTS: There were 665 patients in our final analysis, 302 in the branded group and 363 in the generic group. After propensity score matching, patients who received generic atorvastatin did not show a greater incidence of Ischemic Stroke/transient ischemic attack recurrence or onset of coronary heart disease. Similar changes in NIHSS and mRS scores were observed between the generic and branded groups. Consistent results were found in rates of hepatobiliary laboratory abnormalities and the compound adverse event profile of an elevated creatine kinase level, elevated aspartate aminotransferase/alanine aminotransferase levels, and intracranial hemorrhage. Results were consistent before and after propensity score matching. CONCLUSION: Both generic and branded atorvastatin are equally effective in preventing stroke recurrence and improving neurological deficits in patients with ischemic stroke/transient ischemic attack. Both treatments are generally well tolerated by patients.

Clinical study of new and conventional antiepileptic drugs with newly diagnosed partial epilepsy

YAN Yukui, HU Jianqin, ZHANG Bing

2022, 27(7):  793-799.  doi:10.12092/j.issn.1009-2501.2022.07.010

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AIM: To compare the early response to the new and traditional antiepileptic drugs (AEDs) in the treatment of partial epilepsy. METHODS: Patients from neurology Department of Huzhou Central Hospital between January 2013 and June 2018 were included; outcomes included time to first seizure, time to treatment failure and 6-month, 1- and 2-year seizure-free rates were compared. RESULTS: A total of 250 patients with partial epilepsy were divided into carbamazepine (CBZ) group (n=62), levetiracetam (LEV) group (n=67), oxcarbazepine (OXC) group (n=63), and lamotrigine (LTG) group (n=58). In terms of time to first seizure after monotherapy, CBZ and OXC were equivalent (P=0.635), while CBZ was superior to LTG (P<0.001) and LEV (P=0.005); regarding time to treatment failure, CBZ and LTG had the same response (P=0.721), while CBZ was superior to OXC and LEV (P=0.008 and P=0.018, respectively). For the "6-month seizure-free" rate, differences were not statistically significant. For the "1- and 2-year seizure-free" rates, CBZ > LTG > OXC > LEV, and CBZ was superior to OXC and LEV (all P<0.05), but not LTG (P>0.05). A total of 25 patients had adverse reactions; with CBZ (19.3%) more often than LTG (8.6%), OXC (7.9%), or LEV (4.5%). CONCLUSION: Treatment response to CBZ is superior compared to that of OXC and LEV, especially in the early stages of treatment, and equivalent to that of LTG, but the incidence of side effects is higher as well.

Research progress of virus-mediated gene therapy in type 2 diabetes mellitu

LU Senlin, LIU Xinyuan, WANG Jili, HUANG Xiaofei

2022, 27(7):  800-807.  doi:10.12092/j.issn.1009-2501.2022.07.011

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Type 2 diabetes mellitus results from a combination of genetic and lifestyle factors, and the prevalence of T2DM is increasing worldwide. At present, there are many drawbacks in the clinical treatment of T2DM, so there is an urgent need for a new treatment method for improvement. In recent years, gene therapy has been proved to reverse T2DM related symptoms such as insulin resistance at the animal level, and no obvious side effects such as hypoglycemia have been found. Therefore, gene therapy may be the main development direction of T2DM therapy in the future. This article reviews the role of fibroblast growth factor related genes such as fibroblast growth factor 21, glucagon like peptide-1, peroxisome proliferator activated receptor and insulin in glucose and lipid metabolism and the development of T2DM, and summarized the application of various viral vectors in gene therapy of T2DM. The significance and existing problems of gene therapy in T2DM are discussed, and the possible development direction of gene therapy T2DM in the future is prospected.

Clinical application and research progress of inhaled methoxyflurane

DAI Jingyi, WANG Jingjing, ZHANG Jing, YU Jicheng, LI Nanyang, HUANG Zhiwei

2022, 27(7):  808-813.  doi:10.12092/j.issn.1009-2501.2022.07.012

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As a fluorinated hydrocarbon anesthetic, methoxyflurane may cause serious adverse reactions such as renal damage under anesthetic doses, but its analgesic effect at sub-anaesthetic doses is safe, high tolerability, and short-term acute Good choice for analgesia. This article describes the pharmacokinetics, clinical validity, adverse reactions and clinical application of methoxyflurane, and explores the feasibility of methoxyflurane as an analgesic in clinical application. Methoxyflurane is convenient to use as an inhaled analgesic. It can provide patients with emergency analgesia without intravenous administration. It is a good choice for emergency analgesia in pre-hospital and emergency settings.

Dual role of miRNA in breast cancer

WU Shuai, YANG Jun, ZHENG Yun

2022, 27(7):  814-821.  doi:10.12092/j.issn.1009-2501.2022.07.013

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Breast cancer is the most common malignant tumor in women all over the world. It is a heterogeneous disease, and the exact cause of which is still unclear. However, breast cancer is composed of different subtypes with great differences in clinical characteristics, genetic background, and molecular markers. MicroRNAs (miRNAs) are small non-coding RNAs that regulate genes involved in various stages of key cellular processes after transcription. Persistent dysregulation of miRNAs plays a critical role in the malignant transformation of breast cancer cells, acting as carcinogens or tumor suppressors depending on their cellular environment. As a promising biomarker, dysregulation of miRNA expression seems to open up new opportunities for the diagnosis and prognosis of various cancers. Many studies have revealed the exact functions of miRNAs in different cancer types, however, the results have been inconsistent and further research is needed to determine the underlying mechanisms. In this review, miRNA is associated with the genetic and molecular background of breast cancer, the dual role of miRNA in breast can is described and summarized.

Application and progress of pharmacodynamics study in bioequivalence evaluation of orally inhaled drug products

GU Yifei, CHU Nannan, HUANG Kai, QUE Linling, ZHANG Jisheng, XIANG Xuemei, HE Qing

2022, 27(7):  822-833.  doi:10.12092/j.issn.1009-2501.2022.07.014

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Orally inhaled drug products (OIDPs) play a great role in the pharmacological treatment of chronic obstructive pulmonary disease (COPD) and asthma. There is an unmet clinical need for OIDPs. Pharmacodynamics-Bioequivalence studies (PD-BE) are recommended by several national guidelines as important research methods for bioequivalence study of OIDPs. It can effectively bridge the gap between in vitro studies and PK-BE studies in evaluating the efficacy and safety consistency of generic drugs with the original drugs. There are two research methods for PD-BE, using a diastolic model or an excitation model. The different methods use different metrics to evaluate efficacy. The more commonly used metrics include Forced Expiratory Volume in the First Second (FEV1), Specific Airway Conductance (sGaw), Peripheral Airway Resistance (R5-20), and stimulant concentration/dose (PC20/PD20). PD-BE studies using FEV1 as an efficacy metric is also recommended by the FDA (Food and Drug Administration), EMA (European Medicines Agency) and NMPA (National Medical Products Administration) guidelines and is widely accepted by investigators. In such PD-BE studies, the trial protocols for different OIDPs drugs are relatively consistent in terms of trial design, trial data processing, and equivalence evaluation criteria, while there are detailed differences in terms of target population, single/multiple dosing, dose administration, and collection site design. This paper reviews the progress of PD-BE studies in the bioequivalence evaluation of OIDPs by combining national guidelines and PD-BE-related studies of OIDPs published in the last five years, with a view to providing important theoretical information for PD-BE studies of OIDPs. 

New narcotic analgesics: esketamine

JIA Tao, TENG Jinliang

2022, 27(7):  834-840.  doi:10.12092/j.issn.1009-2501.2022.07.015

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Esketamine is an excellent anesthetic with higher potency than ketamine, fast onset of action, rapid elimination from the body, mild respiratory depression, and little impact on the circulatory system. It has unique advantages in the field of clinical anesthesia and analgesia. Its sub-anesthetic dose regimen is the most widely used in various surgeries and short examinations. Compared with traditional ketamine, the dose required for anesthesia effect and mental side effects are lower, and the analgesic effect is stronger. It has great clinical application prospects.