Objective To evaluate the pharmacokinetics characteristics of single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects.Methods This was a single-center,randomized,double-blind,placebo-controlled study.Twelve healthy adult Chinese subjects were randomized to receive single-dose of Etripamil nasal spray 70 mg(n=10)or placebo nasal spray(n=2).Blood and urine samples were collected prior and post dose.Etripamil in plasma and urine were analyzed by liquid chromatography-tandem mass spectrometry.The pharmacokinetic parameters were calculated by WinNonlin non-compartmental model.Results Following the single-dose of Etripamil nasal spray 70 mg in healthy adult Chinese subjects,the peak concentration of Etripamil in plasma was quickly attained,with a Cmax of(66.76±56.61)ng·mL-1 and a median(range)tmax of 4.00(3.00-5.00)min.The plasma concentrations of Etripamil had fallen approximately 65％from peak value at 25 min after dosing,and close to 80％within 50 min.The AUC0-last and AUC0-∞ were(3 104.16±2 654.46)and(4 048.77±2 682.38)ng·min·mL-1,respectively.The urine excretion percentage of Etripamil during 24 h was(0.01±0.01)％.Among the 12 subjects who were treated with Etripamil or placebo,10 subjects reported a total of 29 treatment-emergent adverse events(TEAEs).All of the TEAEs were mild in severity.The most common TEAEs were rhinorrhoea and lacrimation increased.Conclusion Etripamil was quickly absorbed after intranasal administration,followed by rapid distribution and elimination(not primarily excreted by renal);Etripamil 70 mg was safe and well tolerated by the healthy Chinese adult subjects.

Statistical analysis was conducted on the quantity of Chinese medicine material and sliced herbal medicine,the species types and medicinal parts of Chinese medicine material and sliced herbal medicine,and the quantity and composition of Chinese patent medicines and single-herb preparations in Chinese Pharmacopoeia of the 2020 edition.The statistical results are available on the web site(http://itcm.hzau.edu.cn/yd/zgyd.htm)for reference.The analysis results showed that:(1)Chinese Pharmacopoeia(Part I)contained a total of 616 kinds of Chinese medicine material and sliced herbal medicine and 47 kinds of plant oils and extracts.The 616 kinds of Chinese medicine material and sliced herbal medicine originated from plants,animals,minerals,microorganisms,artificial or synthetic raw materials,human-sourced products,and products having the origin of both animal and plants.Of the 47 kinds of plant oils and extracts,46 were made from plant sources,and the remaining one,i.e.Cornu Bubali concentrated powder,was made from the animal sources.(2)A total of 421(73.60%)from the 616 kinds of Chinese medicine material and sliced herbal medicine originated from the single species,96(16.78%)originated from 2 kinds of species,40(6.99%)originated from 3 kinds of species,11(1.92%)originated from 4 kinds of species,2(0.35%)originated from 5 kinds of species,and 2(0.35%)originated from 6 kinds of species.Of the 47 kinds of plant oils and extracts,34 originated from the single species,5 originated from 2 kinds of species and 5 originated from 3 kinds of species.(3)The Chinese Pharmacopoeia(Part I)contained a total of 1 605 Chinese patent medicines and single-herb preparations.Except that the composition of Yunnan Baiyao Powder and Yunnan Baiyao Capsules was not issued,the remaining 1 603 types of Chinese patent medicines and single-herb preparations involved a total of 14 329 kinds of medicinal materials.The Chinese medicines with the leading 20 frequency used in the Chinese patent medicines and single-herb preparations recorded in the Chinese Pharmacopoeia of 2020 edition were Glycyrrhizae Radix et Rhizoma,Angelicae Sinensis Radix,Poria,Chuanxiong Rhizoma,Scutellariae Radix,Paeoniae Radix Alba,Astragali Radix,Citri Reticulatae Pericarpium,Rehmanniae Radix,Atractylodis Macrocephalae Rhizoma,Salviae Miltiorrhizae Radix et Rhizoma,Borneolum Syntheticum,Platycodonis Radix,Rhei Radix et Rhizoma,Rehmanniae Radix Preparata,Aucklandiae Radix,Carthami Flos,Ophiopogonis Radix,Codonopsis Radix and Angelicae Dahuricae Radix.The results suggest that there were still problems existing in Chinese Pharmacopoeia of the 2020 edition,i.e.,some of the drugs of Chinese patent medicines were not listed in the Chinese medicine material and sliced herbal medicine,and some of the prepared drugs of Chinese patent medicines were not listed in the Chinese medicine material and sliced herbal medicine,either.The systemic analysis of the general information of Chinese medicinal materials as well as their correlation with Chinese patent medicines in Chinese Pharmacopoeia will provide a reference for further research on the production of Chinese medicine material and sliced herbal medicine and the complete list of drugs in Chinese patent medicines.

Objective: Progressive supranuclear palsy (PSP) involves a variety of visual symptoms that are thought to be partially caused by structural abnormalities of the retina. However, the relationship between retinal structural changes, disease severity, and intracranial alterations remains unknown. We investigated distinct retinal thinning patterns and their relationship with clinical severity and intracranial alterations in a PSP cohort. Methods: We enrolled 19 patients with PSP (38 eyes) and 20 age-matched healthy controls (40 eyes). All of the participants underwent peripapillary and macular optical coherence tomography. Brain 11C-2β-carbomethoxy-3β-(4-fluorophenyl) tropane (11C-CFT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography imaging were also performed in patients with PSP. We investigated the association between retinal thickness changes and clinical features, striatal dopamine transporter availability, and cerebral glucose metabolism. Results: The peripapillary retinal nerve fiber layer (pRNFL) and macula were significantly thinner in patients with PSP than in controls. The thickness of the superior sector of the pRNFL demonstrated a significant negative relationship with the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale part III and Hoehn and Yahr staging scale scores. A significant negative correlation was found between outer inferior macular thickness and disease duration. Outer temporal macular thickness was positively correlated with Montreal Cognitive Assessment scores. In PSP, lower outer temporal macular thickness was also positively correlated with decreased dopamine transporter binding in the caudate. Conclusion The pRNFL and macular thinning may be candidate markers for monitoring disease severity. Additionally, macular thinning may be an in vivo indicator of nigrostriatal dopaminergic cell degeneration in PSP patients.

Cancer is one of the major fatal diseases that seriously threaten human health， and its burden needs to be solved urgently. Health technology assessment （HTA） can provide scientific evidence-based basis for cancer diagnosis， treatment， prevention and related policy formulation. Cost-utility analysis is the gold standard for economic evaluation in HTA， and the accurate measurement of its health utility is one of the key elements to determine the accuracy of its results. This article focuses on systematic introduction of direct measures， multi-attribute health utility scales， and mapping methods in the field of cancer measurement and reviews their applications in cancer patients. Among them， direct measures are complex， costly， and require a high level of subject knowledge； multi-attribute health utility measures are currently the preferred method for measuring health utility in cancer patients； with the continuous development and refinement of disease-specific utility measures in multi-attribute health utility instruments， the mapping method may gradually decrease in future applications. This paper can provide a reference for the selection of health utility measurement tools for HTA in the field of cancer， and provide evidence-based basis for optimizing resource allocation and policy formulation in the field of cancer.

Objective:In this study, the role of IL-17 in the pathogenesis of idiopathic myositis (IIM) was preliminarily investigated by detecting the expression of IL-17 in the muscle tissues of patients with idiopathic inflammatory myositis (IIM) and normal controls.Methods:Twenty-eight patients (20 in DM group with dermatomyositis and 8 in ASS group with anti-synthase syndrome) who were diagnosed with IIM after muscle biopsy and autoantibody detection in our hospital for the first time from October 2019 to August 2021 were included. Twelve cases with normal muscle tissue matched for age and sex were included as the control group. Western blot and immunohistochemical techniques were used to detect the expression level of IL-17 in muscle tissue, and enzyme-linked immunosorbent assay (ELISA) was used to detect serum IL-6. Mann-Whitney U rank sum test was used to compare the difference of IL-17 expression in muscle tissue between the two groups, and non-parametric test was used for comparison between multiple groups. Chi-square test and Spearman rank correlation analysis were used, and P<0.05 was considered statistically significant. Results:① The expression level of IL-17 in IIM muscle tissue[1.63(1.30, 2.05)pg/ml was higher than that in control group[1.00(0.96, 1.00)pg/ml, and the difference was statistically significant ( Z=-3.52, P<0.001). The difference be-tween DM[1.94(1.58, 2.14)pg/ml] and ASS[1.22(1.04,1.55)pg/ml was statistically significant ( Z=-3.20, P=0.001). ② Compared with healthy control group [4.08(3.01, 5.67)pg/ml, the expression of IL-6 in ⅡM serum[8.88(4.93, 13.64) was high ( Z=-3.01, P=0.003), which was positively correlated with the expression of IL-17 ( r=0.42, P=0.027). ③ The ex-pression of IL-17 in muscle tissue was higher in IIM associated with muscle weakness[1.91(1.56, 2.14) pg/ml vs 1.50(1.04, 2.00)pg/ml] ( Z=-1.38, P=0.020), dysphagia [2.06(1.99, 2.14)pg/ml vs 1.62(1.52, 2.04)pg/ml] ( Z=-2.74, P=0.010) and skin involvement[1.98(1.57, 2.14)pg/ml vs 1.04(0.86, 1.61)pg/ml] ( Z=-3.20, P<0.010), and the differences were statistically significant ( P<0.05). ④IL-17 was positively correlated with Myoact-total activity ( r=0.51, P=0.006), Myoact-muscle symptom ( r=0.45, P=0.016), erythrocyte sedimen tation ( r=0.48, P=0.020), and myoenzyme increase ( r=0.56, P=0.002). Conclusion:IL-17 and IL-6 are synergistically involved in the pathogenesis of IIM, suggesting that IL-17 is the therapeutic target of IIM.

OBJECTIVE: To observe the effects of electro-scalp acupuncture （ESA） on the expression of microglial markers CD206 and CD32, as well as interleukin (IL)-6, IL-1β, and IL-10 in the ischemic cortex of rats with ischemic stroke, and to explore the mechanisms of ESA on alleviating inflammatory damage of ischemic stroke. METHODS: Sixty 7-week-old male SD rats were randomly selected, with 15 rats assigned to a sham surgery group. The remaining rats were treated with suture method to establish rat model of middle cerebral artery occlusion (MCAO). The rats with successful model were randomly divided into a model group, a VitD₃ group, and an ESA group, with 15 rats in each group. In the ESA group, ESA was performed bilaterally at the "top-temporal anterior oblique line" with disperse-dense wave, a frequency of 2 Hz/100 Hz, and an intensity of 1 mA. Each session lasted for 30 min, once daily, for a total of 7 days. The VitD₃ group were treated with intragastric administration of 1,25-dihydroxyvitamin D₃ (1,25-VitD₃) solution (3 ng/100 g), once daily for 7 days. The neurological deficit scores and neurobehavioral scores were assessed before and after the intervention. After the intervention, the brain infarct volume was evaluated using 2,3,5-triphenyltetrazolium chloride (TTC) staining. Immunofluorescence double staining was performed to detect the protein expression of CD32 and CD206 in the ischemic cortex. Western blot analysis was conducted to measure the protein expression of IL-6, IL-1β, and IL-10 in the ischemic cortex. RESULTS: Compared with the sham surgery group, the model group showed increased neurological deficit scores and neurobehavioral scores (P<0.01), increased brain infarct volume (P<0.01), increased protein expression of CD32, IL-6, and IL-1β in the ischemic cortex (P<0.01), and decreased protein expression of CD206 and IL-10 in the ischemic cortex (P<0.01). Compared with the model group, both the ESA group and the VitD₃ group showed decreased neurological deficit scores and neurobehavioral scores (P<0.01), reduced brain infarct volume (P<0.01), decreased protein expression of CD32, IL-6, and IL-1β in the ischemic cortex (P<0.01), and increased protein expression of CD206 and IL-10 in the ischemic cortex (P<0.01). Compared with the VitD₃ group, the ESA group had lower neurological deficit score (P<0.05), larger brain infarct volume (P< 0.05), and lower protein expression of CD32, CD206, IL-1β, and IL-10 in the ischemic cortex (P<0.01, P<0.05). CONCLUSION ESA could improve neurological function in MCAO rats, and its mechanism may be related to promoting microglial M1-to-M2 polarization and alleviating inflammatory damage.
Male ; Animals ; Rats ; Rats, Sprague-Dawley ; Ischemic Stroke ; Interleukin-10 ; Interleukin-6/genetics* ; Microglia ; Scalp ; Acupuncture Therapy ; Vitamins ; Infarction, Middle Cerebral Artery

Insomnia is extremely common and is a risk factor for a variety of physical and psychological disorders in addition to contributing to the reduced quality of life of patients and the burden of healthcare costs. Although cognitive behavioral therapy is the first-line treatment for insomnia, its difficulty of access and high cost have hindered its application. Therefore, pharmacotherapy remains the common treatment choice for patients and clinicians. Existing chemical drugs including benzodiazepine receptor agonists, dual orexin receptor antagonists, melatonin and its receptor agonists, histamine antagonists, antidepressants, and antipsychotics are able to induce and/or maintain sleep and have good therapeutic effects on acute insomnia, but their efficacy on chronic insomnia is indefinite. Furthermore, they have several side effects and affect sleep structure and physiological function. Under the guiding principle of holistic view and treatment based on syndrome differentiation, traditional Chinese medicine(TCM) has shown a good effect in clinical practice, but with little high-grade clinical evidence. The mechanism, dose, half-life period, adjustment of sleep structure, and side effects of hypnotic drugs are key factors to be considered for clinical use. This paper analyzed and summarized the drugs for insomnia from the above aspects, and is expected to provide references for the application and development of sedative and hypnotic drugs.
Humans ; Sleep Initiation and Maintenance Disorders/chemically induced* ; Quality of Life ; Sleep ; Hypnotics and Sedatives/pharmacology* ; Antidepressive Agents/pharmacology*

In this study, the ovarian surgery (ovariectomy, OVX) was used to establish the osteoporosis mice model of primary menstruation, in order to evaluate the protective effects and mechanisms of Zhibai Dihuang decotion on postmenopausal osteoporosis (PMOP). The animal experimental protocol has been reviewed and approved by Laboratory Animal Ethics Committee of Jinan University (number: 20210315-03), in compliance with the Institutional Animal Care Guidelines. C57BL/6 mice were divided into five groups, including Sham group, OVX group, low (32 g·kg^-1·day^-1) and high dose (64 g·kg^-1·day^-1) of Zhibai Dihuang decotion groups, positive drug group (alendronate, 9.9 mg·kg^-1·q3d). After modeling, mice were given medication intervention for 8 weeks, and then femoral and tibial tissues were taken to detect indicators such as bone microstructure, bone resorption, and oxidative stress. The experimental results showed that after Zhibai Dihuang decotion administration, the bone microstructure damage caused by OVX surgery was alleviated, and the relevant parameters bone mineral density (BMD), bone volume/total volume (BV/TV), trabecular number (Tb. N) and connectivity density (Conn. D) both significantly increased. At the same time, the number of TRAP positive osteoclasts decreased significantly, and the levels of proteins and genes related to osteoclast differentiation decreased, indicating that Zhibai Dihuang decoction could inhibit the increased activity of osteoclast caused by OVX. Afterwards, network pharmacology was used to construct the active compound action target network of Zhibai Dihuang decotion, and it was found that the target genes of its active ingredients were closely related to the oxidative stress pathway. Finally, the detection results of oxidative stress levels in bone tissues showed that after treatment with Zhibai Dihuang decotion, the levels of oxidative stress products 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA) in bone tissues of mice significantly decreased, while the levels of antioxidant stress substance L-glutathione (GSH) increased. These above results indicated that Zhibai Dihuang decotion can regulate the level of oxidative stress in the body and inhibit osteoclast activity, which played a therapeutic role in PMOP, as well as provided theoretical basis for the prevention and treatment of PMOP with traditional Chinese medicine.

Objective: To development the prognostic nomogram for malignant pleural mesothelioma (MPM). Methods: Two hundred and ten patients pathologically confirmed as MPM were enrolled in this retrospective study from 2007 to 2020 in the People's Hospital of Chuxiong Yi Autonomous Prefecture, the First and Third Affiliated Hospital of Kunming Medical University, and divided into training (n=112) and test (n=98) sets according to the admission time. The observation factors included demography, symptoms, history, clinical score and stage, blood cell and biochemistry, tumor markers, pathology and treatment. The Cox proportional risk model was used to analyze the prognostic factors of 112 patients in the training set. According to the results of multivariate Cox regression analysis, the prognostic prediction nomogram was established. C-Index and calibration curve were used to evaluate the model's discrimination and consistency in raining and test sets, respectively. Patients were stratified according to the median risk score of nomogram in the training set. Log rank test was performed to compare the survival differences between the high and low risk groups in the two sets. Results: The median overall survival (OS) of 210 MPM patients was 384 days (IQR=472 days), and the 6-month, 1-year, 2-year, and 3-year survival rates were 75.7%, 52.6%, 19.7%, and 13.0%, respectively. Cox multivariate regression analysis showed that residence (HR=2.127, 95% CI: 1.154-3.920), serum albumin (HR=1.583, 95% CI: 1.017-2.464), clinical stage (stage Ⅳ: HR=3.073, 95% CI: 1.366-6.910) and the chemotherapy (HR=0.476, 95% CI: 0.292-0.777) were independent prognostic factors for MPM patients. The C-index of the nomogram established based on the results of Cox multivariate regression analysis in the training and test sets were 0.662 and 0.613, respectively. Calibration curves for both the training and test sets showed moderate consistency between the predicted and actual survival probabilities of MPM patients at 6 months, 1 year, and 2 years. The low-risk group had better outcomes than the high-risk group in both training (P=0.001) and test (P=0.003) sets. Conclusion: The survival prediction nomogram established based on routine clinical indicators of MPM patients provides a reliable tool for prognostic prediction and risk stratification.
Humans ; Mesothelioma, Malignant ; Prognosis ; Nomograms ; Retrospective Studies ; Proportional Hazards Models

In recent years, liver fibrosis has become a hotspot in the field of liver diseases. MicroRNA(miRNA)-mediated Nod-like receptor pyrin domain containing 3(NLRP3) inflammasome activation is pivotal in the pathogenesis of liver fibrosis. The present study mainly discussed the role of miRNA-mediated NLRP3 inflammasome activation in the pathogenesis of liver fibrosis. Different miRNA molecules regulated liver fibrosis by mediating NLRP3 inflammasome activation, including miRNA-350-3 p(miR-350-3 p)/interleukin-6(IL-6)-mediated signal transducer and activator of transcription 3(STAT3)/c-myc signaling pathway, miR-148 a-induced autophagy and apoptosis of hepatic stellate cells via hedgehog signaling pathway, miR-155-mediated NLRP3 inflammasome by the negative feedback of the suppressor of cytokine signaling-1(SOCS-1), miR-181 a-mediated downstream NLRP3 inflammatory pathway activation through mitogen-activated protein kinase kinase(MEK)/extracellular signal-regulated kinase(ERK)/nuclear transcription factor κB(NF-κB) inflammatory pathway, miR-21-promoted expression of NF-κB and NLRP3 of RAW264.7 cells in mice by inhibiting tumor necrosis factor-α inducible protein 3(A20), and miR-20 b-promoted expression of IL-1β and IL-18 by activating NLRP3 signaling pathway. Additionally, the anti-liver fibrosis mechanism of different active components in Chinese medicines(such as Curcumae Rhizoma, Glycyrrhizae Radix et Rhizoma, Aurantii Fructus, Polygoni Cuspidati Rhizoma et Radix, Moutan Cortex, Paeoniae Radix Alba, Epimedii Folium, and Cinnamomi Cortex) was also explored based on the anti-liver fibrosis effect of miRNA-mediated NLRP3 inflammasome activation.
Animals ; Hedgehog Proteins ; Inflammasomes/metabolism* ; Interleukin-6 ; Liver Cirrhosis/metabolism* ; Medicine, Chinese Traditional ; Mice ; MicroRNAs/genetics* ; NF-kappa B/metabolism* ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism* ; Proto-Oncogene Proteins c-myc/metabolism* ; Signal Transduction