Objective To study the pharmacokinetic characteristics of the test formulation of compound lidocaine cream and reference formulation of lidocaine and prilocaine cream in Chinese healthy subjects and to evaluate whether there is bioequivalence between the two formulations.Methods A single-center,single-dose,randomized,open-label,two-period,two-sequence,crossover design was used.This study included 40 healthy subjects,and in each period,test formulation or reference formulation 60 g was applied to the skin in front of both thighs(200 cm2 each side,a total of 400 cm2)under fasting conditions,and the drug was left on for at least 5 h after application.The concentrations of lidocaine and prilocaine in plasma were determined using liquid chromatography-tandem mass spectrometry(LC-MS/MS)method.Pharmacokinetic parameters were calculated using WinNonlin 8.0 software to evaluate the bioequivalence of the two formulations.Results After the application of the test formulation compound lidocaine cream and the reference formulation lidocaine and prilocaine cream on both thighs of the subjects,the pharmacokinetic parameters of lidocaine in plasma were as follows:Cmax were(167.27±91.33)and(156.13±66.86)ng·mL-1,AUC0-t were(1 651.78±685.09)and(1 636.69±617.23)ng·mL-1·h,AUC0-∞ were(1 669.85±684.65)and(1 654.37±618.30)ng·mL-1·h,the adjusted geometric mean ratios were 104.49％,101.88％and 101.89％,respectively,with 90％confidence intervals of 98.18％-111.20％,97.80％-106.13％and 97.87％-106.07％,all within the range of 80.00％-125.00％.The pharmacokinetic parameters of prilocaine in plasma were as follows:Cmax were(95.66±48.84)and(87.52±39.16)ng·mL-1,AUC0-t were(790.86±263.99)and(774.14±256.42)ng·mL-1·h,AUC0_m were(807.27±264.67)and(792.84±254.06)ng·mL-1 h,the adjusted geometric mean ratios were 107.34％,103.55％and 102.98％,respectively with 90％confidence intervals of 101.69％-113.31％,99.94％-107.30％and 99.65％-106.43％,all within the range of 80.00％-125.00％.Conclusion The test formulation compound lidocaine cream and the reference formulation lidocaine and prilocaine cream are bioequivalent.

To explore the quality consistency evaluation method for multi-component traditional Chinese medicine and establish a dissolution evaluation method suitable for the characteristics of multi-component Chinese patent medicine, this study discussed the characteristics and advantages of the flow-through cell method in the dissolution evaluation of Chinese patent medicine by comparing the impact of the small cup method and the flow-through cell method on the dissolution behavior of water-soluble and lipid-soluble major active components of Danshen Tablets. Dissolution tests were performed using the small cup method as described in the 2020 edition of the Chinese Pharmacopoeia and the newly introduced flow-through cell method(closed-loop method) with water solution containing 0.5% SDS as dissolution medium. Cumulative dissolution curves of the water-soluble component salvianolic acid B and the lipid-soluble component tanshinone Ⅱ_A in Danshen Tablets were plotted, and fitting and similarity analysis of the dissolution models was conducted to identify the characteristics and advantages of the flow-through cell method. For the small cup method, 150 mL of water containing 0.5% SDS was used as the dissolution medium, with a rotation speed of 75 r·min~(-1) and a temperature of(37±0.5) ℃, and 3 mL of samples were taken at 15, 30 min, 1, 2, and 4 h, with fresh dissolution medium added at the same temperature and volume. For the flow-through cell method, a closed-loop system was used. Danshen Tablets were placed in the flow-through cell with approximately 6.7 g of glass beads, and 150 mL of water containing 0.5% SDS was used as the dissolution medium. The flow rate was set at 20 mL·min~(-1), and the temperature and sampling were the same as the small cup method. The results showed that compared with the small cup method, the flow-through cell method had stronger discriminative power and higher sensitivity in distinguishing the dissolution behavior of the two components, and could better reflect the differences in formulation quality, especially for water-insoluble lipid-soluble components. Given that there were no essential differences in the in vitro release kinetics between the two methods, the flow-through cell method could not only replace the traditional small cup method but also better guide the formulation development and identify quality issues of formulations.
Salvia miltiorrhiza ; Medicine, Chinese Traditional ; Tablets ; Water ; Lipids ; Solubility

Aim To explore the mechanism of process¬ing and increasing efficiency of Arisaematis rhizomz preparatum. Methods UPLC-Q-TOF-MS/MS tech¬nology was used to detect the chemical components be¬fore and after processing of Arisaematis rhizomz prepara¬tum, and its mechanism of action was analysed in the treatment of 44 asthma and phlegm " by using network pharmacology. A rat model of allergic asthma was es- tablished to compare the efficacy of Arisaematis rliizoma before and after processing. Results A total of 27 chemical components were identified, among which cur- cumin ,6-gingerol and other components increased after processing. Combined with the database prediction, the action mechanism of the 36 chemical components in the treatment of 44 asthma and phlegm" diseases was dis¬cussed and predicted through network pharmacology. The results of animal experiments showed that the effect of processed Arisaematis rhizoma on allergic asth¬ma was better than that of Arisaematis rhizoma, but there was no significant difference. Conclusions The addition of curcumin, 6-gingerol, camphor, demethyl- curcumin and other components after the processed Ari¬saematis rhizomz preparatum may be the reason for the synergistic effect of Arisaematis rhizomz preparatum in the treatment of allergic asthma.

A total of 33 pesticides have been banned from Chinese medicinal materials and decoction pieces(plants) according to Chinese Pharmacopoeia(2020 edition). According to the chemical structures, they are mainly divided into seven categories: organophosphorus compounds, organochlorines, carbamates, amidines, sulfonylureas, phenylpyrazoles, and ethers. These banned pesticides exhibit neurotoxicity, reproductive toxicity, immune system toxicity, teratogenicity, carcinogenesis, and mutagenesis, seriously damaging human and animal health. They affect not only the quality and safety of traditional Chinese medicines and resulting products, but also their competitiveness in the international market. Due to the numerous varieties of traditional Chinese medicines and their complex substrates, it is necessary to establish a universal and highly sensitive method for pesticide residue detection. This review systematically summarized the residual status, toxicity, and analytical methods of banned pesticides in traditional Chinese medicines, and forecasted the prospects of different analytical techniques, so as to provide reference for further safety and risk assessment of banned pesticide residues in traditional Chinese medicines, thus ensuring the safe production of traditional Chinese medicines.
China ; Drugs, Chinese Herbal/toxicity* ; Humans ; Medicine, Chinese Traditional ; Organophosphorus Compounds ; Pesticide Residues/toxicity* ; Pesticides/analysis*

To clarify the key quality attributes of substance benchmarks in Danggui Buxue Decoction(DBD), this study prepared 21 batches of DBD substance benchmarks, and established two methods for detecting their fingerprints, followed by the identification of peak attribution and similarity range as well as the determination of extract and transfer rate ranges and contents of index components ferulic acid, calycosin-7-O-β-D-glucoside, and astragaloside Ⅳ. The mass fractions and transfer rates of DBD substance benchmarks from different batches were calculated as follows: ferulic acid(index component in Angelicae Sinensis Radix): 0.037%-0.084% and 31.41%-98.88%; astragaloside Ⅳ(index component in Astragali Radix): 0.021%-0.059% and 32.18%-118.57%; calycosin-7-O-β-D-glucoside: 0.002%-0.023% and 11.51%-45.65%, with the extract rate being 18.4%-36.1%. The similarity of fingerprints among 21 batches of DBD substance benchmarks was all higher than 0.9. The quality control method for DBD substance benchmarks was preliminarily established based on the HPLC fingerprint analysis and index component determination, which has provided a basis for the subsequent development of DBD and the quality control of novel related preparations.
Chromatography, High Pressure Liquid/methods* ; Drugs, Chinese Herbal/standards* ; Quality Control

OBJECTIVES: To investigate the incidence of extrauterine growth retardation (EUGR) and its risk factors in very preterm infants (VPIs) during hospitalization in China. METHODS: A prospective multicenter study was performed on the medical data of 2 514 VPIs who were hospitalized in the department of neonatology in 28 hospitals from 7 areas of China between September 2019 and December 2020. According to the presence or absence of EUGR based on the evaluation of body weight at the corrected gestational age of 36 weeks or at discharge, the VPIs were classified to two groups: EUGR group (n=1 189) and non-EUGR (n=1 325). The clinical features were compared between the two groups, and the incidence of EUGR and risk factors for EUGR were examined. RESULTS: The incidence of EUGR was 47.30% (1 189/2 514) evaluated by weight. The multivariate logistic regression analysis showed that higher weight growth velocity after regaining birth weight and higher cumulative calorie intake during the first week of hospitalization were protective factors against EUGR (P<0.05), while small-for-gestational-age birth, prolonged time to the initiation of total enteral feeding, prolonged cumulative fasting time, lower breast milk intake before starting human milk fortifiers, prolonged time to the initiation of full fortified feeding, and moderate-to-severe bronchopulmonary dysplasia were risk factors for EUGR (P<0.05). CONCLUSIONS It is crucial to reduce the incidence of EUGR by achieving total enteral feeding as early as possible, strengthening breastfeeding, increasing calorie intake in the first week after birth, improving the velocity of weight gain, and preventing moderate-severe bronchopulmonary dysplasia in VPIs.
Female ; Fetal Growth Retardation ; Gestational Age ; Hospitalization ; Humans ; Incidence ; Infant ; Infant, Newborn ; Infant, Premature ; Infant, Very Low Birth Weight ; Prospective Studies ; Risk Factors

Objective    To explore the safety and feasibility of the establishment method and management strategy of prolonged support model with veno-venous extracorporeal membrane oxygenation (V-V ECMO) under dual lumen cannula (DLC) in conscious sheep. Methods    Three adult male sheep were selected. An Avalon Elite DLC was inserted into the superior vena cava, right atrium, and inferior vena cava through the right jugular vein and was connected with centrifugal pump and oxygenator to establish the extracorporeal membrane oxygenation circuit. All the 3 sheep were transferred into the monitoring cage after operation and were ambulatory after anesthesia recovery. Hemodynamic parameters and extracorporeal membrane oxygenation performance were measured every day. Results    All three sheep survived to the end of the experiment (7 days). In the whole process of the experiment, the basic vital signs of the experimental sheep were stable, and no serious bleeding or thrombotic events occurred. During the experiment, hemoglobin concentration and platelet count were relatively stable, plasma free hemoglobin was maintained at a low level, extracorporeal membrane oxygenation flow rate was stable, and oxygenation performance of oxygenator was good. Conclusion    Prolonged V-V ECMO model in conscious sheep under DLC is feasible and stable.

Doxorubicin (DOX) is an anthracycline antibiotic widely used in the treatment of certain types of tumors. However, DOX have some serious side effects in the body after long-term use, especially acute and chronic cardiotoxicity. This study explored the protective effect of tanshinone I (Tan I) on acute cardiotoxicity induced by DOX and its underlying molecular mechanisms. In vivo and in vitro acute cardiotoxicity models were established by injecting DOX (6 mg·kg^-1, twice per week) into the tail vein of C57 mice and stimulating H9C2 cardiomyocytes with DOX. In in vivo experiments, Tan I (10 mg·kg^-1) was administered daily by oral 5 days before the tail vein injection, till the end of the experiment. The effects of Tan I on mice heart function, myocardial tissue morphology and serological indicators were detected. Animal welfare and experimental procedures followed the regulations of the Animal Ethics Committee of Beijing University of Traditional Chinese Medicine. In in vitro experiments, the specific mechanism of Tan I against oxidative stress was further studied. Immunofluorescence was used to detect the expression of Nrf2 and its transcription into the nucleus. In addition, the levels of oxidative stress related proteins, protein kinase B (Akt), nuclear erythroid factor 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), were detected by Western blot. Finally, AutoDock software was used for molecular docking verification. The results showed that Tan I significantly improved cardiac function in mice. Meanwhile, the expression levels of creatine kinase-MB (CK-MB) and lactic dehydrogenase (LDH) in serum were decreased. Immunofluorescence results indicated that Tan I could increase Nrf2 expression level in H9C2 cells and promote Nrf2 entry into the nucleus. Western blot results also indicated that the levels of oxidative stress related proteins, P-Akt, Nrf2, HO-1 and NQO1 in DOX plus Tan I group were significantly increased compared with DOX group. These results suggest that Tan I can alleviate DOX-induced acute cardiotoxicity by inhibiting oxidative stress through up-regulating the Akt-Nrf2 pathway, thereby alleviating DOX-induced acute myocardial injury.

SARS-CoV-2 infection causes complicated clinical manifestations with variable multi-organ injuries, however, the underlying mechanism, in particular immune responses in different organs, remains elusive. In this study, comprehensive transcriptomic alterations of 14 tissues from rhesus macaque infected with SARS-CoV-2 were analyzed. Compared to normal controls, SARS-CoV-2 infection resulted in dysregulation of genes involving diverse functions in various examined tissues/organs, with drastic transcriptomic changes in cerebral cortex and right ventricle. Intriguingly, cerebral cortex exhibited a hyperinflammatory state evidenced by significant upregulation of inflammation response-related genes. Meanwhile, expressions of coagulation, angiogenesis and fibrosis factors were also up-regulated in cerebral cortex. Based on our findings, neuropilin 1 (NRP1), a receptor of SARS-CoV-2, was significantly elevated in cerebral cortex post infection, accompanied by active immune response releasing inflammatory factors and signal transmission among tissues, which enhanced infection of the central nervous system (CNS) in a positive feedback way, leading to viral encephalitis. Overall, our study depicts a multi-tissue/organ transcriptomic landscapes of rhesus macaque with early infection of SARS-CoV-2, and provides important insights into the mechanistic basis for COVID-19-associated clinical complications.
Animals ; COVID-19/genetics* ; Macaca mulatta ; SARS-CoV-2/genetics* ; Transcriptome

Objective: To evaluate the relationship of serum uric acid with prediabetes and newly detected type 2 diabetes mellitus (T2DM) in adults. Methods: Data were obtained from the baseline investigation of Songjiang Peak-Plan cohort. According to the baseline fasting plasma glucose and glycosylated hemoglobin, the eligible subjects were divided into normal blood sugar group, prediabetes group, and newly detected T2DM group. Unconditional logistic regression model was used to explore the effect of serum uric acid level on prediabetes and newly detected T2DM, and restricted cubic spline (RCS) function was used to explore the nonlinear dose-response relationship of serum uric acid level with the prevalence of prediabetes and newly detected T2DM. Results: A total of 30 375 subjects were included in the analysis, with an average age of (55.36±11.52) years, and 60.2% (18 299) of them were women. The baseline survey found that the prevalence of prediabetes was 38.6% (11 739 cases), and the prevalence of newly detected T2DM was 6.6% (1 992 cases). Logistic regression analysis showed that, in women, for every 10µmol/L increase in serum uric acid, the risk of developing prediabetes and T2DM s increased by 2.4% (OR=1.024, 95%CI: 1.018-1.030), and 1.5% (OR=1.015, 95%CI: 1.005-1.025), respectively; in men, for every 10 µmol/L increase in serum uric acid, the risk of developing prediabetes and T2DM decreased by 0.8% (OR=0.992, 95%CI: 0.987-0.998) and 5.0% (OR=0.950, 95%CI: 0.939-0.960), respectively. The RCS function showed that the serum uric acid level showed a nonlinear dose-response relationship with newly detected T2DM (P=0.017), but not with prediabetes (P=0.670) in women and showed a nonlinear dose-response relationship with both prediabetes (P=0.040) and newly detected T2DM (P<0.001) in men. Conclusions: Adult women are at increased risk of prediabetes and newly detected T2DM with increase of serum uric acid level, and adult men are at decreased risk of newly diagnosed T2DM with the increase of serum uric acid level. There was no significant relationship between serum uric acid level and prediabetes in men.
Adult ; Male ; Female ; Humans ; Middle Aged ; Aged ; Prediabetic State/epidemiology* ; Uric Acid ; Diabetes Mellitus, Type 2/epidemiology* ; Glycated Hemoglobin ; Fasting