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Aim: Caffeine is a central nervous system stimulant, used to treat apnea of prematurity. A hydrophilic interaction chromatography–tandem mass spectrometry (HILIC-MS/MS) approach was developed to detect caffeine, paraxanthine, theophylline and theobromine in premature infants. Method: Protein precipitation of plasma samples (10 μl) was carried out by treating with acetonitrile containing caffeine-13C3. The separation was carried out on an ACQUITY HPLC® BEH HILIC column. Caffeine and its metabolites were quantified by multiple reaction monitoring modes with positive electrospray ionization. Results: The established method had a good linear relationship in the range of 0.0600–60.0 μg/ml for caffeine, 0.0250–7.50 μg/ml for theobromine and 0.0150–4.50 μg/ml for paraxanthine and theophylline. Conclusion: A HILIC-MS/MS method was developed and validated to determine caffeine and its major metabolites in plasma of premature infants.

Pivmecillinam, the ester of biologically active antibiotic mecillinam, is an effective oral preparation to treat urinary tract infections. To study pharmacokinetics in humans, LC-MS/MS methods were developed to quantify pivmecillinam and mecillinam in human plasma, respectively. Considering cephalexin as internal standard, analytes were separated on UltimateXB-C18 columns after protein precipitation by acetonitrile. The mobile phase was composed of water containing 0.1% formic acid and methanol. The multiple reactions monitoring transitions of m/z 440.2→167.1, 326.1→167.1, and 348.1→158.1 were selected to inspect pivmecillinam, mecillinam, and the internal standard in positive ion mode. No apparent matrix effect was perceived. Linearities were obtained over calibration ranges of 0.0500-12.0 and 10.0-15,000 ng/mL, respectively. The intraday precisions were below 5.5%, the interday precisions were below 6.1%, and accuracies were within -8.1 to 13.0%. Stability tests were conducted and an acidification step was explored to enhance the stability of pivmecillinam and mecillinam. Further stability was validated under various storage and processing conditions. Both methods were applied to a pharmacokinetic study of pivmecillinam and mecillinam after oral administration of 400 mg pivmecillinam hydrochloride tablets in healthy Chinese subjects.

Aim: HCP002, a phosphate-modified derivative of voriconazole, can improve solubility without using the nephrotoxic solubilizer, sulfobutylether-β-cyclodextrin. To study pharmacokinetics in humans, LC-MS/MS methods to quantify HCP002 in human plasma and urine were developed and validated. Method: After protein precipitation by acetonitrile containing voriconazole-d3, HCP002 was separated on a ZORBAX SB-Aq column, and LCMS/MS analysis was performed in multi-response monitoring mode. Results: The analytical run time was 3 min. Linearity was observed over the ranges of 0.100–40.0 and 0.400–200 μg/ml in plasma and urine, respectively. Precision and accuracy were within acceptable limits. Sample stability was confirmed. Conclusion: Rapid and reproducible methods quantified HCP002 in urine, and plasma samples were established.

To analyze the predictive value of acute phase proteins (APPs) on the prognosis of patients with acute myeloid leukemia (AML).293 AML patients who met the study requirements from January 2015 to April 2021 were collected, their clinical characteristics and pre-treatment APPs levels ［including albumin (ALB), fibrinogen (FIB), C-reactive protein (CRP), Ferritin (FER)］ were followed up and investigated. Pearson correlation coefficient was used to analyze the correlation between APPs. Logistic regression was used to analyze the risk factors for mortality in AML patients. ROC curve was used to analyze the predictive value of APP for mortality in AML patients, and Kaplan-Meier survival analysis was used to compare the effect of APPs on complete remission (CR) rate, overall survival (OS), disease-free survival (DFS), and progression-free survival rate (PFS) of AML patients.Pearson correlation analysis showed that there were negative correlations between ALB and CRP (r=-0.134, P=0002), as well as ALB and FER (r=-0.148, P=0.001). There were correlations between FER and CRP (r=0361, P＜0.001), as well as FER and FIB (r=0.293, P＜0.001). Logistic regression analysis showed that advanced age (50 years) (OR=1.87, 95% CI=1.25-2.15, P＜0.001), relapse after treatment (OR=2.11, 95% CI=111-3.18, P=0.003), FLT3-ITD mutation (OR=2.59, 95% CI=1.10-4.12, P＜0.001), CRP≥524 mg/L (OR=1.21, 95% CI=1.02-2.14, P=0.024), CFA (CFA=CRP*FIB/ ALB)≥3 (OR=2.41, 95% CI=1.65-6.47, P＜0.001), and FER≥1145.58 mg/ml (OR=1.67, 95% CI=1.15-3.75, P＜0.001) were the risk factors for the survival of AML patients. ROC curve analysis showed that FER (AUC=0.752, 95% CI=0.681-0823, P＜0.001, the best cut-off value=1220.56 mg/ml) and CFA (AUC=0.804, 95% CI=0.741-0.868, P＜0.001, the best cut-off value=3.00) had higher predictive value for the survival of AML patients. The remission rate, PFS, DFS, and OS in the low CFA group (CFA≤3) were significantly higher than those in the high CFA group (CFA＞3), and the overall mortality rate was lower than that in the high CFA group; the remission rate, PFS, DFS, and OS in the low FER group (FER≤1220.56 mg/ml) were significantly higher than those in the high FER group (FER＞1220.56 mg/ml), while the overall mortality rate was lower than that in the high FER group, and the difference is statistically significant.The CFA value and FER level before treatment in AML patients can independently predict the prognosis of patients, and high levels of CFA and FER are associated with poor prognosis of AML patients.急性期蛋白对急性髓系白血病患者预后的预测价值.分析急性期蛋白(APPs)对急性髓系白血病（AML）患者预后的预测价值.收集2015年1月-2021年4月符合研究要求的293例AML患者，随访并调查其临床特征和治疗前APP［包括白蛋白(ALB）、纤维蛋白原（FIB）、C-反应蛋白（CRP）、铁蛋白（FER）］。使用Pearson相关系数分析APP间的相关性，使用Logistic回归分析AML患者死亡的危险因素，使用ROC曲线分析APP对AML患者死亡的预测价值，使用Kaplan-Meier生存分析比较APP对AML患者的缓解（CR）率、总体生存期（OS）、无病生存期（DFS）、无进展生存期（PFS）的影响.相关性分析结果显示，ALB与CRP（r=-0.134，P=0.002）和FER（r=-0.148，P=0.001）间存在一定的负相关关系。FER与CRP（r=0.361，P＜0.001）和FIB（r=0.293，P＜0.001）间存在相关关系。Logistic回归分析显示，高龄（＞50岁）（OR=1.87，95% CI=1.25-2.15，P＜0.001）、治疗后复发（OR=2.11，95% CI=1.11-3.18，P=0003）、FLT3-ITD变异（OR=2.59，95% CI=1.10-4.12，P＜0.001）、CRP≥5.24 mg/L（OR=1.21，95% CI=1.02-2.14，P=0.024）、CFA（CFA=CRP*FIB/ALB）≥3（OR=2.41，95% CI=1.65-6.47，P＜0.001）、FER≥1145.58 mg/ml（OR=1.67，95% CI=1.15-3.75，P＜0.001）为AML患者生存的危险因素。ROC曲线分析显示，FER（AUC=0.752，95% CI=0.681-0.823，P＜0.001，最佳切点=1220.56 mg/ml）和CFA（AUC=0.804，95% CI=0.741-0.868，P＜0.001，最佳切点=3.00）对AML患者生存预测价值较高。低CFA组（CFA≤3）的CR率、PFS、DFS、OS均显著高于高CFA组（CFA＞3），而总体死亡率低于高CFA组；低FER组（FER≤1220.56 mg/ml）的CR率、PFS、DFS、OS均显著高于高FER组（FER＞1220.56 mg/ml），而总体死亡率低于高FER组，差异具有统计学意义.AML患者治疗前的CFA值和FER水平可独立预测患者的预后，高水平的CFA和FER与AML患者预后不良相关.

Purpose: Prediction models for acute myeloid leukemia (AML) are useful, but have considerable inaccuracy and imprecision. No current model includes covariates related to immune cells in the AML microenvironment. Here, an immune risk score was explored to predict the survival of patients with AML. Experimental Design: We evaluated the predictive accuracy of several in silico algorithms for immune composition in AML based on a reference of multi-parameter flow cytometry. CIBERSORTx was chosen to enumerate immune cells from public datasets and develop an immune risk score for survival in a training cohort using least absolute shrinkage and selection operator Cox regression model. Results: Six flow cytometry–validated immune cell features were informative. The model had high predictive accuracy in the training and four external validation cohorts. Subjects in the training cohort with low scores had prolonged survival compared with subjects with high scores, with 5-year survival rates of 46% versus 19% (P < 0.001). Parallel survival rates in validation cohorts-1, -2, -3, and -4 were 46% versus 6% (P < 0.001), 44% versus 18% (P = 0.041), 44% versus 24% (P = 0.004), and 62% versus 32% (P < 0.001). Gene set enrichment analysis indicated significant enrichment of immune relation pathways in the low-score cohort. In multivariable analyses, high-risk score independently predicted shorter survival with HRs of 1.45 (P = 0.005), 2.12 (P = 0.004), 2.02 (P = 0.034), 1.66 (P = 0.019), and 1.59 (P = 0.001) in the training and validation cohorts, respectively. Conclusions: Our immune risk score complements current AML prediction models.

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) induced a worldwide pandemic. The main clinical manifestations of COVID-19 patients have been fever, cough, dyspnea, and other respiratory symptoms. However, some patients’ initial symptoms have been nausea, vomiting, diarrhea and other gastrointestinal symptoms, and SARS-CoV-2 RNA could be found in their stool samples. Studies have shown that the gastrointestinal tract highly-expressed angiotensin-converting enzyme 2 is used by SARS-CoV-2 to enter cells. Therefore, exploring the damage caused by SARS-CoV-2 to the gastrointestinal tract and whether it could replicate in the gastrointestinal tract and transmit through fecal-oral route has significance for the diagnosis, treatment and prevention of COVID-19. We combined the current clinical data about COVID-19 patients with gastrointestinal symptoms as well as its pathogenic mechanism and prevention methods herein to review the relationship between the disease and gastrointestinal symptoms.

Flowering is an important process for the reproduction of higher plants. Up to this point, the studies on flowering have mostly focused on the model plant Arabidopsis thaliana, and the flowering mechanism of fruit trees remains mostly unknown. The diversity of the flowering time of loquat (Eriobotrya japonica Lindl.) makes it an ideal material to study the regulation of flowering. In this study, we first observed the inflorescence bud differentiation in two varieties of loquat that had different blooming times (cv. Dawuxing (E. japonica), that blooms in the fall and cv. Chunhua (E. japonica×Eriobotrya bengalensis Hook. f.) that blooms in the spring) and found that the starting time of inflorescence bud differentiation and the speed of inflorescence development were responsible for the difference in blooming times. The determination of endogenous phytohormones by high performance liquid chromatography (HPLC) indicated that abscisic acid (ABA), zeatin (ZT), and gibberellin (GA3) promoted flowering in loquat, while indole-3-acetic acid (IAA) was mainly involved in inflorescence bud differentiation in Chunhua. A transcription level analysis illustrated that multiple flowering-related genes could respond to different signals, integrate to the TFL1, AP1 and FT genes, and then synergistically regulate flowering in loquat. Thus, this study provides a new insight into flowering regulation mechanisms in loquat.

Sitafloxacin, a new fluoroquinolone, has strong antibacterial activity. We evaluated the effects of sitafloxacin granules in single‐dose and multidose cohorts and the effects of ABCB1, UGT1A1, and UGT1A9 genetic polymorphisms on the pharmacokinetics (PK) of sitafloxacin in healthy subjects. The single‐dose study included 3 fasted cohorts receiving 50, 100, and 200 mg of sitafloxacin granules and 1 cohort receiving 50 mg of sitafloxacin granules with a high‐fat meal. The multidose study included 1 cohort receiving 100 mg of sitafloxacin granules once daily for 5 days. PK parameters were calculated using noncompartmental parameters based on concentration‐time data. The genotypes for ABCB1, UGT1A1, and UGT1A9 single‐nucleotide polymorphisms were determined using Sanger sequencing. Subsequently, the association between sitafloxacin PK parameters and target single‐nucleotide polymorphisms was analyzed. Sitafloxacin granules were well tolerated up to 200 and 100 mg in the single‐dose and multidose studies, respectively. Sitafloxacin AUC and Cmax increased linearly within the detection range, and a steady state was reached within 3 days after the administration of multiple oral doses. Our findings showed that Cmax was lower in the ABCB1 (rs1045642) mutation group, whereas t1/2 was longer in the UGT1A1 (rs2741049) and UGT1A9 (rs3832043) mutation groups. In conclusion, sitafloxacin granules were safe at single doses and multiple doses up to 200 and 100 mg/day, respectively, with a linear plasma PK profile. However, ABCB1 (rs1045642), UGT1A1 (rs2741049), and UGT1A9 (rs3832043) genetic polymorphisms are likely to influence the Cmax or t1/2 and thereby merit further clinical evaluation.

To better understand the fruit flesh coloration mechanism of peach (Prunus persica), the composition and accumulation of carotenoids were compared, the expression profile of key genes involved in carotenoid biosynthetic and catabolic pathways was performed, and the differentially expressed genes were identified using “Piqiutao” (white fruit flesh) and its mutant yellow “Piqiutao” at different fruit development stages. The results showed that the total carotenoid content in yellow “Piqiutao” was remarkably higher than that of “Piqiutao,” and the accumulation of β-cryptoxanthin, α-carotene, and β-carotene was significantly different, which was most likely caused by the differential expression of CCD4. Therefore, CCD4 may be an essential gene that causes the yellow fruit flesh of yellow “Piqiutao.” However, the coding region sequence of CCD4 was entirely identical, and the intron was inserted by a retrotransposon in “Piqiutao” and its mutant, indicating that the expression difference was not caused by the sequence mutation and retrotransposon insertion.

Regadenoson, the first selective adenosine A

Background: Many clinical studies have shown a correlation between proton pump inhibitors (PPIs) and osteoporosis or fractures. The purposes of this study were to establish a murine model of chronic oral administration of PPIs to verify whether PPIs caused bone metabolic impairment, and to investigate the relevant molecular mechanism underlying the effects of PPIs on MC3T3-E1 mouse osteoblasts.Methods: Lansoprazole-induced bone loss model was employed to investigate the damage effects of PPIs. In vivo, immunohistochemistry and HE staining, micro-CT analysis, blood biochemical tests were used to evaluate the effect of lansoprazole on bone injury in mice. In vitro, the effects and related signaling pathway of lansoprazole on MC3T3-E1 cells were investigated by CCK8, EDU kit, flow cytometry, laser confocal, patch clamp, PCR and Western blotting, etc.Results: After 6 months of lansoprazole gavage in ICR mice, micro-CT results showed that compared with the vehicle group, the bone mineral density (BMD) of high-dose group was significantly decreased (PConclusion: Long-term administration of LPZ induced osteoporotic symptoms in mice, and LPZ triggered calcium elevation in osteoblasts in a concentration dependent manner, intracellular calcium ([Ca2+] persisted at a high concentration thereby causing endoplasmic reticulum stress (ERS) and inducing osteoblasts apoptosis.

Voriconazole (VRC) is a first-line drug for the treatment of invasive fungal infections (IFIs) and an inhibitor of CYP3A activity. The aims of this study are to investigate the influence of related factors on the plasma concentration of voriconazole and the effect of voriconazole on the activity of CYP3A in patients with haematological malignancies.A total of 89 patients received an initial dose of 6 mg/kg followed by 4 mg/kg every 12 h were included in the study. Blood samples were collected before and 2 h after administration for subsequent testing and for the extraction of DNA samples. Voriconazole and voriconazole N-oxide in the plasma were detected by LC-MS/MS. The effect of voriconazole on CYP3A activity was evaluated by the ratio of the endogenous biomarkers 6β-hydroxycortisol and cortisol.During the study period, the overall incidence of adverse reactions was 33.6% (with no deaths). The metabolite type of CYP2C19 and combined use of CYP2C19 enzyme inhibitors both had a significant impact on voriconazole exposure. Voriconazole has a long-lasting and potent inhibitory effect on CYP3A activity. The exposure of CYP3A substrate in combination with metabolic enzyme inhibitors voriconazole could increase. Therefore, the combination uses with voriconazole need to be considered carefully and assessed adequately.

Objective This study was conducted to evaluate the difference in acid inhibition function among lansoprazole (LPZ), pantoprazole (PPZ), and their respective stereoisomers following single and multiple intravenous doses in healthy Chinese subjects. Materials and methods The dosage groups were set as follows: 30 mg single and multiple intravenous administrations of LPZ or R-LPZ, 40 mg single and multiple intravenous administrations of PPZ or S-PPZ. Subjects received an intravenous infusion of LPZ, R-LPZ, PPZ, or S-PPZ injection in sterile saline solution (100 mL/h, 60 minutes), respectively. The intragastric pH was sampled every second for 24 hours at baseline and for 24 hours after drug administration. The baseline-adjusted pharmacodynamic (PD) parameters include ΔMean (pH), ΔMedian (pH), ΔTpH≥3 (%), ΔTpH≥4 (%), ΔTpH≥6 (%), and ΔAUECph-tτ1-τ2. The PD parameters were evaluated in different time intervals (0 - 24 hours, 0 - 4 hours and 14 - 24 hours). Results After a single dose, the ΔTpH≥4 (%) of R-LPZ, LPZ, S-PPZ and PPZ was 56.6 ± 19.6, 53.1 ± 23.3, 35.6 ± 24.9 and 26.8 ± 30.2, respectively. The ΔTpH≥6 (%) was 50.7 ± 26.1, 41.4 ± 26.2, 25.4 ± 24.9 and 22.1 ± 27.6, respectively. The ΔAUECph-τ1-τ was 45,564 ± 16,107, 41,798 ± 16,153, 31,914 ± 17,304 and 20,744 ± 21,500, respectively. Statistically significant differences were found with R-LPZ vs. S-PPZ, R-LPZ vs. PPZ, LPZ vs. S-PPZ and LPZ vs. PPZ. The average TpH≥4 of R-LPZ, LPZ, S-PPZ, and PPZ was (47.2 ± 26.1) minutes, (49.6 ± 19.3) minutes, (56.1 ± 23.7) minutes, and (72.1 ± 27.3) minutes, respectively. Statistically significant differences were found with R-LPZ vs. PPZ (p = 0.009) and LPZ vs. PPZ (p = 0.019). After multiple doses, the ΔTpH≥4 (%) of R-LPZ, LPZ, S-PPZ, and PPZ was 71.7 ± 20.2, 63.5 ± 19.4, 59.5 ± 17.8 and 64.0 ± 22.4, respectively. The ΔTpH≥6 (%) was 64.0 ± 22.2, 52.0 ± 19.2, 49.6 ± 20.4 and 50.9 ± 23.8, respectively. The ΔAUECph-τ1-τ was 326,149 ± 94,839, 288,565 ± 93,279, 296,189 ± 83,412 and 300,960 ± 108,057, respectively. No statistically significant differences were found in baseline-adjusted PD parameters during all time periods after multiple doses. Conclusion After a single dose, the mean gastric pH inhibition value of R-LPZ was the highest, followed by LPZ, then S-PPZ and PPZ. R-LPZ and LPZ provided significantly better pH control compared with PPZ and S-PPZ in healthy subjects. The onset time of R-LPZ was the fastest and R-LPZ can provide better acid inhibition during sleeping time. After multiple doses, the mean values in all PD parameters of R-LPZ were the highest, the values of LPZ, S-PPZ, and PPZ were similar. However, no significant difference was found in acid inhibition among these four drugs after multiple doses.

BACKGROUND Acute myocardial infarction (AMI) is a leading cause of mortality. Early reperfusion to restore blood flow is crucial to successful treatment. In the current reperfusion regimen, an increasing number of patients have benefited from direct percutaneous coronary intervention (PCI). In order to understand whether there is a correlation between the components of coronary thrombosis and the absence of reflow or slow blood flow after coronary stent implantation in direct PCI, we collected data on direct PCI cases in our hospital between January 2016 and November 2018. AIM To investigate the correlation between intracoronary thrombus components and coronary blood flow after stent implantation in direct PCI in AMI. METHODS We enrolled 154 patients (85 male and 69 female, aged 36–81 years) with direct PCI who underwent thrombus catheter aspiration within < 3, 3–6 or 6–12 h of onset of AMI between January 2016 and November 2018. The thrombus was removed for pathological examination under a microscope. The patients of the three groups according to the onset time of AMI were further divided into those with a white or red thrombus. The thrombolysis in myocardial infarction (TIMI) blood flow after stent implantation was recorded based on digital subtraction angiography during PCI. The number of patients with no-reflow and slow blood flow in each group was counted. Statistical analysis was performed based on data such as onset time, TIMI blood flow. RESULTS There were significant differences in thrombus components between the patients with acute ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction (P < 0.01). In the group with PCI < 3 h after onset of AMI, there was no significant difference in the incidence of no-reflow and slow-flow between the white and red thrombus groups. In the groups with PCI 3-6 and 6-12 h after onset of AMI, there was a significant difference in the incidence of no-reflow and slow-flow between the white and red thrombus groups (P < 0.01). There was a significant correlation between the onset time of AMI and the occurrences of no-reflow and slow blood flow during PCI (P < 0.01). CONCLUSION In direct PCI, the onset time of AMI and color of coronary thrombus are often used to predict whether there will be no reflow or slow blood flow after stent implantation.

An array-point-raft wave energy converter (ARR WEC) integrating multiple-point absorption and raft type wave energy capturing technologies is proposed and experimentally investigated in this study. A 10 kW pilot device was developed, and a three-month real sea test was carried out in the Taiwan Strait, China. The experimental results confirmed the feasibility and effectiveness of the new system. The overall performance, heaving performance, power output and wave energy conversion efficiency of the pilot APR WEC running under random waves are reported and analyzed in detail. The heaving motions of the oscillating buoys and the instantaneous and average power output of the permanent magnet generator (PMG) are affected significantly by the number of oscillating buoys used to collect wave energy. More oscillating buoys used increase the production of electricity and improve the power quality, but lead to the reduction of energy conversion efficiency in long wave periods. The increase of electrical resistance of PMG results in an increased wave conversion efficiency. The experimental results obtained are valuable in the optimal design and operation of the ARR WEC system proposed.

We develop a new closed-form representation for the molar Gibbs free energies of gaseous substances. The predicted molar Gibbs free energies are in excellent agreement with the experimental data in a wide temperature range for three gases under consideration, and the average absolute deviations of the predicted results from the experimental data are 0.06155%, 0.0708% and 0.16696% for the gases Cl2, Br2, and HCl, respectively. The proposed model is away from the need of a large amount of experimental spectroscopy data, and only related to the dissociation energy, equilibrium bond length, and equilibrium vibration frequency.

We aimed to investigate the role of intracellular imatinib concentration in drug resistance and the expression of candidate drug transporters in gastrointestinal stromal tumor (GIST) cell lines.The imatinib concentrations were measured by the liquid chromatography-tandem mass spectrometry (LC-MS/MS). The expression of candida te drug transporters was detected by qRT-PCR.The tissue imatinib concentrations in imatinib resistant patients were significantly lower than that of sensitive patients (p .05). Compared with parental cell lines, the intracellular imatinib concentration was notably lower in imatinib resistant GIST cell lines. For candidate transporters, MRP1 and BCRP were overexpressed in resistant GIST cell lines.The intracellular imatinib concentration may play a crucial role in imatinib resistance and the intracellular differences of imatinib concentration may be induced by the upregulation of efflux transporters. Our study highlights the importance of intracellular imatinib concentration and the potential of using imatinib transporters as therapeutic targets for patients with GIST.

We present a universal efficient closed-form representation for the molar enthalpy of gaseous substances. The predicted molar enthalpy values show excellent agreements compared to the experimental data in a wide temperature range for the gases CO, HCl, and BF. The proposed model is away from the need of plenty of experimental spectroscopy data, and depends on only four molecular constants, for which the experimental values can be easily found in the literature.

A Cu-catalyzed stereospecific denitro silylation of β-nitroalkenes with silanes for the synthesis of vinylsilanes using DTBP as the oxidant was developed. This method presented an inexpensive and non-toxic catalytic system with an appropriate substrate scope. This approach is (E)-specific and produced an important class of vinylsilanes in good yields.

The feasibility of taking the ratio of 6β-hydroxycortisol (6β-OHCOR) to cortisol (COR) in plasma as a biomarker to reflect CYP3A4 activity needs to be verified, but the low concentration of 6β-OHCOR which is an endogenous substance in plasma presents a challenge for determination. In this study, a Liquid chromatography with tandem mass spectrometry (LC–MS/MS) method was established to simultaneously quantify the COR and 6β-OHCOR in plasma with COR-d4 and 6β-OHCOR-d4 as internal standards (ISs). Plasma samples were treated by protein precipitation using acetonitrile. Separation with a gradient elution within 5 min was achieved on C18+ column utilizing 5 mM ammonium formate and methanol. An API 4,000 MS in multiple reaction monitoring mode with transitions of 407.1 → 361.1 and 423.1 → 347.1 was utilized. Albumin solution was used as a surrogate matrix, with good linearities over the concentration of 1.20–300 ng/mL for COR and 0.0400–10.0 ng/mL for 6β-OHCOR. The precisions for intrarun and interrun were

A convenient and sensitive liquid chromatography–tandem mass spectrometry method was established to simultaneously quantify voriconazole (VRZ) and its metabolite, voriconazole N-oxide (VNO), in human urine. Voriconazole-d3 and voriconazole-d3 N-oxide were used as isotopic internal standards. Samples were processed by protein precipitation and separated using a ZORBAX SB-Aq column (1.8 μm, 2.1 × 50 mm). Mass spectrometry was performed using an API 4000 mass spectrometry by positive electrospray ionization. The flow rate was 0.6 mL/min. Gradient elution was performed with methanol and 0.1% formic acid as the organic and water phase, respectively. The VRZ and VNO calibration curves ranged from 20.0 to 7200 ng/mL in human urine. The specificity, matrix effect, extraction recovery, intra/inter-run precision, accuracy and stability were validated for both VRZ and VNO in human urine. The developed method was used to study urinary excretion after intravenous injection of 4 mg/kg VRZ in healthy Chinese subjects.

Imatinib (IM), a milestone drug used in the field of molecular targeted therapy, has been reported to cause serious adverse liver effects, including liver failure and even death. Immune-mediated injury and mitochondrial dysfunction are involved in drug-induced liver injury. However, the mechanism of IM-induced hepatotoxicity remains unclear and warrants further study. In our study, Sprague Dawley rats were administered IM by gavage with 50 mg/kg body weight (BW) once daily for 10 days. Drug-induced liver injury accompanied by inflammatory infiltration was observed in rats following IM exposure, and the expression of NOD-like receptor protein 3 (NLRP3) inflammasome-related proteins was significantly increased compared with that of the control. HepG2 cells were exposed to 0-100 μM IM for 24 h. The results showed that IM decreased cell viability in a dose-dependent manner. Moreover, IM induced a state of obvious oxidative stress and activation of nuclear factor kappa B (NF-κB) in cells, which resulted in the activation of NLRP3 inflammasomes, including caspase 1 cleavage and IL-1β release. These results were significantly reduced after the use of the antioxidants N-acetyl-l-cysteine or the NF-κB inhibitor pyrrolidine di-thio-carbamate. Furthermore, NLRP3 knockdown significantly reduced the release of inflammatory cytokines and improved cell viability. In summary, our data demonstrated that oxidative stress and NLRP3 inflammasome activation are involved in the process of IM-induced hepatotoxicity. The results of this study provide a reference for the prevention and treatment of IM-induced hepatotoxicity.

Background The corosolic acid (CA), also known as plant insulin, is a pentacyclic triterpenoid extracted from plants such as Lagerstroemia speciosa. It has been shown to have anti-diabetic, anti-inflammatory and anti-tumor effects. Its structural analogs ursolic acid (UA), oleanolic acid (OA), maslinic acid (MA), asiatic acid (AA) and betulinic acid (BA) display similar individual pharmacological activities to those of CA. However, there is no systematic review documenting pharmacological activities of CA and its structural analogues. This study aims to fill this gap in literature. Purpose This systematic review aims to summarize the medical applications of CA and its analogues. Methods A systematic review summarizes and compares the extraction techniques, pharmacokinetic parameters, and pharmacological effects of CA and its structural analogs. Hypoglycemic effect is one of the key inclusion criteria for searching Web of Science, PubMed, Embase and Cochrane databases up to October 2020 without language restrictions. ‘corosolic acid’, ‘ursolic acid’, ‘oleanolic acid’, ‘maslinic acid’, ‘asiatic acid’, ‘betulinic acid’, ‘extraction’, ‘pharmacokinetic’, ‘pharmacological’ were used to extract relevant literature. The PRISMA guidelines were followed. Results At the end of the searching process, 140 articles were selected for the systematic review. Information of CA and five of its structural analogs including UA, OA, MA, AA and BA were included in this review. CA and its structural analogs are pentacyclic triterpenes extracted from plants and they have low solubilities in water due to their rigid scaffold and hydrophobic properties. The introduction of water-soluble groups such as sugar or amino groups could increase the solubility of CA and its structural analogs. Their biological activities and underlying mechanism of action are reviewed and compared. Conclusion CA and its structural analogs UA, OA, MA, AA and BA are demonstrated to show activities in lowering blood sugar, anti-inflammation and anti-tumor. Their oral absorption and bioavailability can be improved through structural modification and formulation design. CA and its structural analogs are promising natural product-based lead compounds for further development and mechanistic studies.

Purpose To evaluate the tolerability, safety, pharmacokinetics and drug interaction of cefotaxime sodium-tazobactam sodium injection (6:1) in Chinese healthy subjects. The results of the safety and pharmacokinetic studies supported further clinical trials. Method A randomized, single-blind, ascending dose, placebo-controlled, single-center study was conducted. Sixty healthy subjects (38 males, 22 females) participated in this study. For the single-dose part, 0.47, 1.17, 2.34, 3.51, and 4.68 g of cefotaxime sodium-tazobactam sodium injection (6:1) was administered. For the multiple-dose part, the subjects were administered 2.34 and 3.51 g cefotaxime sodium-tazobactam sodium injection (6:1) three times a day for 7 consecutive days. For the drug interaction part, the subjects received 2.0 g cefotaxime sodium and 0.34 g tazobactam sodium alone and in combination. Results Most adverse events and adverse drug reactions were mild. Moderate rash was considered a serious adverse event because of prolongation of hospitalization. The main pharmacokinetic parameters of cefotaxime and tazobactam had no significance difference between the 1.17, 2.34, and 3.51 g dose cohorts and between genders. There was no difference in trough concentrations on days 6, 7, and 8. The R C max and R AUC were (0.921 ± 0.070) and (0.877 ± 0.057) for cefotaxime, and (0.913 ± 0.046) and (0.853 ± 0.060) for tazobactam, respectively. Following the administration of cefotaxime and tazobactam alone and in combination, the 90% confidence intervals of the geometric mean ratios for C max and AUC were within the predetermined range of 80-125%. In the single-dose part, the renal cumulative excretion ratios were (51.7 ± 6.2)% for cefotaxime, and (84.3 ± 8.1)% for tazobactam. There was no significant difference in the maximum excretion rates and cumulative excretion ratios for cefotaxime and tazobactam, alone or in combination. Conclusions Cefotaxime sodium-tazobactam sodium injection (6:1) was well-tolerated at doses of 0.47 to 4.68 g. The pharmacokinetics of cefotaxime and tazobactam were reported as linear over a dose range of 1.17-3.51 g. Cefotaxime was partially excreted via urine, whereas tazobactam was mainly excreted via urine. There was no significant accumulation after administration over 7 consecutive days. The pharmacokinetics and excretion of cefotaxime and tazobactam were not affected by the co-administration of cefotaxime-tazobactam.

Objective This study evaluated different influences of 14 single nucleotide polymorphisms (SNPs) and demographic factors leading to individual differences in the antihypertensive efficacy of felodipine in healthy Chinese subjects. Materials and methods 24 subjects were sequenced for candidate SNPs. Plasma samples were obtained as clinical trial protocol, and were determined by a HPLC-MS/MS method. Pharmacokinetic parameters were calculated by WinNonlin 6.0. Statistical analysis was mainly performed by SPSS 22.0. A multiple linear regression model provided different weight coefficients of different demographic and genetic factors. Results The trend of Cmax is almost consistent with AUCss increase, but tmax of individuals is different; the antihypertensive effect of felodipine is individually different. A significant association was observed between systolic blood pressure decrease (ΔSBP) and SNPs of CACNA1C, CACNA1D, GNB3 respectively, while CACNA1C and CACNA1 were associated with diastolic blood pressure decrease (ΔDBP). CYP3A5 rs766746 and CYP3A4 rs2242480 were linked with Cmax and AUCss, and ABCB1 rs1045642 was associated with T1/2. Significant relationships were shown between AUCss and ΔSBP (p = 0.022) as well as Cmax and ΔSBP (p = 0.015). Conclusion The efficacy of felodipine is individually different, influenced especially by CACNA1C rs1051375 and ABCB1 rs1045642. ΔDBP is associated with ΔSBP in multiple-dosing of felodipine in healthy Chinese subjects.

The aim of this study was to analyze the clinical data, discharge rate, and fatality rate of COVID‐19 patients for clinical help. The clinical data of COVID‐19 patients from December 2019 to February 2020 were retrieved from four databases. We statistically analyzed the clinical symptoms and laboratory results of COVID‐19 patients and explained the discharge rate and fatality rate with a single‐arm meta‐analysis. The available data of 1994 patients in 10 literatures were included in our study. The main clinical symptoms of COVID‐19 patients were fever (88.5%), cough (68.6%), myalgia or fatigue (35.8%), expectoration (28.2%), and dyspnea (21.9%). Minor symptoms include headache or dizziness (12.1%), diarrhea (4.8%), nausea and vomiting (3.9%). The results of the laboratory showed that the lymphocytopenia (64.5%), increase of C‐reactive protein (44.3%), increase of lactic dehydrogenase (28.3%), and leukocytopenia (29.4%) were more common. The results of single‐arm meta‐analysis showed that the male took a larger percentage in the gender distribution of COVID‐19 patients 60% (95% CI [0.54, 0.65]), the discharge rate of COVID‐19 patients was 52% (95% CI [0.34,0.70]), and the fatality rate was 5% (95% CI [0.01,0.11])., Research Highlights Our study explored the clinical and epidemiological characteristics of COVID‐19 patients, and proposed the need to focus on other systemic symptoms such as the gastrointestinal tract firstly, which could be of use for clinical work.

Proton pump inhibitors, including omeprazole, rabeprazole, lansoprazole, and pantoprazole, achieved simultaneous enantioselective determination in the human plasma by chiral liquid chromatography-tandem mass spectrometry. The four corresponding stable isotope-labeled proton pump inhibitors were adopted as the internal standards. Each enantiomer and the internal standards were extracted with acetonitrile containing 0.1% ammonia, then separated with a Chiralpak IC column (5 µm, 4.6 mm × 150 mm) within 10 min. The mobile phase was composed of acetonitrile-ammonium acetate (10 mM) containing 0.2% acetic acid (50:50, v/v). To quantify all enantiomers, an API 4000 tandem mass spectrometer was used, and multiple reaction monitoring transitions were performed on m/z 360.1→242.1, 384.1→200.1, 370.1→252.1, and 346.1→198.1, respectively. No significant matrix effect was observed for all analytes. The calibration curve for all enantiomers were linear from 1.25 to 2500 ng/mL. The precisions for intra- and inter-run were < 14.2%, and the accuracy fell in the interval of -5.3 to 8.1%. Stability of samples was confirmed under the storage and processing conditions. The developed method was also suitable for separation and determination of ilaprazole enantiomers. The validated method combining the equilibrium dialysis method was applied to the protein binding ratio studies of four pairs proton pump inhibitor enantiomers in human plasma.

English Medium Instruction (EMI) is an ongoing graduates teaching reform program for domestic universities to accommodate the upcoming international enrollments and educations. Presented in this paper are my many years of experiences in the practice of the EMI of ‘Introduction to the Theory of Elasticity’ for the graduate students major in process equipment and control engineering at Zhengzhou University. These experiences involve the preparations for setting up the EMI course, making syllabus, selecting textbook, writing lesson plan, preparing for classes, class lecturing, homework and examinations. The purpose is to share them with all EMI colleagues, hoping to initiate a discussion on this topic, get responses from other colleagues, facilitate exchanges of teaching experiences, promote common improvements, and contribute to the extending and spreading of the EMI for graduate students in China.

Pregnant women are more likely to be affected by restless legs syndrome (RLS) than the general population. Restless legs syndrome during pregnancy is associated with adverse maternal and fetal outcomes. Currently unknown is the worldwide and regional prevalence of RLS in pregnant women. We performed a meta-analysis to provide a full profile of the prevalence of RLS during pregnancy. A systematic search of the PubMed, Medline, EMBASE, and Web of Science databases was performed to identify studies that were published up to April 2017, followed by random-effects meta-analyses. A total of 196 articles were identified, among which 27 longitudinal and cross-sectional observational studies with 51,717 pregnant subjects were included in the analysis. The pooled overall prevalence of RLS across all three trimesters was 21%. According to the regional classification of the World health organization, the prevalence of RLS during pregnancy in the European Region, Western Pacific Region, Eastern Mediterranean Region, and Region of the Americas was 22%, 14%, 30%, and 20%, respectively. The regional prevalence in the African Region and South-East Asia Region was not assessed because of insufficient data. We also analyzed the prevalence of RLS in the first, second, and third trimesters of pregnancy, and the rates of RLS were 8%, 16%, and 22%, respectively. We also found that the high prevalence of RLS decreased to 4% after delivery. No publication bias was found in these analyses. The findings emphasize the high occurrence of RLS during pregnancy. Future studies should examine the effects of RLS during pregnancy on maternal and fetal outcomes.

The present study proposed a floating multi-body wave energy converter composed of a floating central platform, multiple oscillating bodies and multiple actuating arms. The relative motions between the oscillating bodies and the floating central platform capture multi-point wave energy simultaneously. The converter was simplified as a forced vibration system with three degrees of freedom, namely two heave motions and one rotational motion. The expressions of the amplitude-frequency response and the wave energy capture width were deduced from the motion equations of the converter. Based on the built mathematical model, the effects of the PTO damping coefficient, the PTO elastic coefficient, the connection length between the oscillating body and central platform, and the total number of oscillating bodies on the performance of the wave energy converter were investigated. Numerical results indicate that the dynamical properties and the energy conversion efficiency are related not only to the incident wave circle frequency but also to the converter's physical parameters and interior PTO coefficients. By adjusting the connection length, higher wave energy absorption efficiencies can be obtained. More oscillating bodies installed result in more stable floating central platform and higher wave energy conversion efficiency.