Headache disorders affect a large proportion of the global population, and Large Language Models (LLMs) show potential in the provision of online health information services, with their response accuracy and readability requiring verification. This cross-sectional study used an expert panel of five headache specialists and three clinical neuroscience pharmacists to evaluate the quality and readability of LLM(represented by GPT-5-main) generated responses to 53 headache-related public inquiries paired with responses from physicians and pharmacists from Chinese online health communities (OHC)-Haodf.com (Jan 2020 to Dec 2024) via six evaluation dimensions and the AlphaReadabilityChinese tool, with stratified analyses by inquiry difficulty (Level 1: simple; Level 2: complex). The results showed that LLM responses were significantly longer than responses from physicians and pharmacists (P<0.001), with a 27.4% mean accuracy for authorship distinction; LLM produced fewer incorrect contents (PR=0.60, 95% CI=0.50-0.71) and lower harm risk (PR=0.85, 95% CI=0.80-0.91), along with better alignment to medical consensus (PR=1.63, 95% CI=1.40-1.90), relevance (PR=2.32, 95% CI=1.79-3.00) and completeness (PR=2.95, 95% CI=2.31-3.75) than responses from physicians and pharmacists. Stratified analysis indicated that LLM achieved non-inferior health information quality to physicians and pharmacists for Level 1 inquiries (all P>0.05), and we recommend that Level 2 inquiries be subject to human review to optimize safety and relevance. Responses from physicians and pharmacists were significantly more readable than LLM across multiple metrics (all P<0.001). In conclusion, for headache-related enquiries, LLM responses were rated more favorably by experts across multiple dimensions within this dataset and can serve as valuable adjuncts to OHC, independently resolving simple enquiries. However, readability improvements are needed for direct public use, and review of physicians and pharmacists is required for complex cases.

Background: Elderly patients are particularly vulnerable to pulmonary infections due to immune system decline and comorbidities. This study aims to evaluate the distribution of bacterial pathogens, patterns of antimicrobial resistance, medication strategies, and risk factors associated with mortality in elderly patients with pulmonary infections. Methods: Data were collected from electronic medical records, encompassing demographic information, clinical characteristics, laboratory results, treatment strategies, and outcomes. Risk factors associated with mortality were identified using the Least Absolute Shrinkage and Selection Operator regression model and were subsequently validated through multivariable logistic regression. Differences between groups were assessed using the independent t-test or Mann-Whitney U-test for continuous variables, and the chisquare test or Fisher's exact test for categorical variables. Results: 201 patients were included with 70.6% being male. Clinical improvement was observed in 124 patients, while 77 patients died. Gram-negative bacteria were identified as the most common pathogens, with Acinetobacter baumannii (27.5%), Klebsiella pneumoniae (23.5%), and Pseudomonas aeruginosa (13.2%) being the most frequently isolated species. Notably, 66.0% of the bacterial strains were classified as multidrug-resistant. Furthermore, 65.7% of the patients received combination therapy. Seven risk factors associated with mortality were identified. Body mass index emerged as a protective factor, whereas length of duration, gastrointestinal bleeding, respiratory failure, bacteremia, myocardial infarction, and mechanical ventilation significantly increased the risk of death. Conclusion: Respiratory failure, mechanical ventilation, gastrointestinal bleeding, extended hospitalization, bacteremia, myocardial infarction, and malnutrition were key risk factors related to mortality in elderly patients with pulmonary infections. Early identification and intervention targeting these risk factors are crucial for improving clinical outcomes.

Liver fibrosis is a prominent pathological process contributing to death from hepatic diseases, including metabolic dysfunction-associated steatohepatitis (MASH). There is limited treatment for liver fibrosis. Here, we find that upregulation of Rho-associated coiled-coil containing kinase 2 (ROCK2) in liver endothelial cells (ECs) and perivascular hepatic stellate cells (HSCs) causes vascular niche dysfunction and triggers pro-fibrotic angiocrine signaling. Based on the vascular druggable target ROCK2, we developed its selective inhibitor showing anti-fibrotic potency in preclinical models and human patients. The ROCK2-selective inhibitor TDI01 restored vascular phenotype and alleviated fibrosis in rodent and minipig MASH models. A phase 1 clinical trial (ChiCTR2200058868) of TDI01 demonstrated its favorable pharmacokinetics and safety in humans. An extended clinical trial (ChiCTR2400082056) showed a trend toward reducing liver fibrosis in five of six patients after TDI01 treatment. Thus, we discover vascular ROCK2 as a pro-fibrotic target, and development of an inhibitor selectively targeting angiocrine ROCK2 may provide a treatment of liver fibrosis in human patients.

Isavuconazole (ISA) is a triazole antifungal agent that has been approved for the treatment of invasive aspergillosis or mucormycosis in both children and adults. While the pharmacokinetic features of ISA identified during clinical development have not provided a clear need for therapeutic drug monitoring (TDM), emerging evidence suggests that TDM may be warranted in specific clinical scenarios where confirming drug exposure is critical. This article summarizes the populations requiring exposure verification and found subgroups such as paediatric patients, critically ill patients, those on extracorporeal membrane oxygenation (ECMO), renal replacement therapy (RRT), females and patients with high body mass index (BMI) or Sequential Organ Failure Assessment (SOFA) scores appear associated with reduced ISA exposure. Conversely, low BMI, prolonged use, larger dose, liver dysfunction, older age, Asian race, and cotreatment with CYP3A4/5 inhibitors correlate with increased ISA exposure. While the optimal therapeutic range continues to be refined, maintaining trough concentrations between 2.0 mg/L and approximately 5.0 mg/L in these populations is generally supported for these populations to optimize efficacy while minimizing the risk of toxicity.

BACKGROUND:Infection specialists show considerable variation in practice, with some advocating IV-to-oral switch for Gram-positive bloodstream infections (GP-BSIs). The efficacy and safety of early switching remain unclear. METHODS:Systematic review of the efficacy of an early switch to oral antimicrobial therapy in patients with GP-BSIs compared with IV therapy, including treatment failure, all-cause mortality, recurrence, hospital readmission rates, length of hospital stay and adverse events (AEs). PubMed, Embase and the Cochrane Library Database were independently searched up to May 2025. ROBINS-I and ROB-2 tools were used. RESULTS:A total of 27 studies with 6015 patients were included. Although treatment failure in the IV-to-oral group is comparable to that of IV treatment, the 30-day (OR 0.33, 95% CI 0.13, 0.83) and 90-day all-cause mortality (OR 0.59, 95% CI 0.36, 0.97) in patients with GP-BSIs were significantly lower in association with oral switch. Notably, the decline in all-cause mortality rate was more pronounced in the subgroups of S. aureus (OR 0.37, 95% CI 0.26, 0.53), oral conversion time ≥7 days (OR 0.25, 95% CI 0.16, 0.38) and switched to oral non-β-lactam antibiotics (OR 0.58, 95% CI 0.39, 0.86). Moreover, oral switch therapy significantly reduced hospital stay (MD -6.21 days, 95% CI -7.99, -4.43). Recurrence rate, hospital readmission rates and AEs were similar between IV and oral switch groups. CONCLUSIONS:This meta-analysis, although primarily based on observational studies, supports that transitioning from IV to oral therapy constitutes a suitable alternative for patients with GP-BSIs exclusively managed via parenteral administration.

Background:Oxazolidinone antimicrobials, which are effective against multidrug-resistant gram-positive pathogens, face challenges of variable efficacy and safety owing to patient pharmacokinetic differences. Purpose:This study aimed to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to simultaneously quantify multiple oxazolidinone antimicrobials, including linezolid, tedizolid, and contezolid, for therapeutic drug monitoring (TDM) applications. Methods:Chromatographic separation was achieved on a C18 column (100 × 2.1 mm, 3.5 μm) with gradient elution. Detection was performed via positive electrospray ionization (ESI+) in multiple reaction monitoring (MRM) mode, targeting transitions: m/z 338.14→162.8 (linezolid); m/z 371→343.1 (tedizolid) and m/z 409.15→269.14 (contezolid), with voriconazole-d3 as the internal standard. Results:The method was validated using Bioanalytical Method Validation (M10). The method demonstrated high selectivity and wide linear ranges of 50.0-15,000.0 ng/mL for linezolid and contezolid, and 25.0-7500.0 ng/mL for tedizolid, respectively, with a good linearity (R2 > 0.993). The intra- and inter-day accuracy and precision were within acceptable limits. Recovery ranged from 94.4% to 104.2% in plasma, and matrix effects were negligible (CV%<3.6%). Stability experiments confirmed analyte integrity under short-term (8 h at room temperature), long-term (34 days at -80°C for linezolid; 40 days for tedizolid and contezolid), and freeze-thaw conditions. No carry-over contamination was exhibited. This method has been successfully applied to monitor the concentrations of both drugs during the transition between linezolid and contezolid therapy. Conclusion:This validated LC-MS/MS method enables the simultaneous determination of linezolid, tedizolid, and contezolid in human plasma, rendering it promising for pharmacokinetic studies and TDM, and contributing to optimized patient care in complex therapeutic scenarios.

Background Triple-negative breast cancer (TNBC) is a subtype of breast cancer that has a relatively poor prognosis after surgery and chemotherapy. The major challenge in the treatment of TNBC is the lack of effective targets and drug resistance, therefore, the search for new and effective drugs for the treatment of TNBC remains a critical clinical need. 3β -o-α -L-rhamnopyranosyl-(1→3)-[β-D-xylopyranosyl-(1→2)]- β-D-glucopyranosyl-(1→4)-[β-D-glucopyranosyl-(1→2)]- α-L-arabinopyranosyl-16α -hydroxy-13,28-epoxy-oleanane (AG) is a kind of triterpenoid saponin from Ardisia gigantifolia stapf. And showed anti-tumor activities against several kinds of cancers especially breast cancer. However, the effects of AG on cancer metastasis, stemness of TNBC and the underlaying mechanism were not very clear. Objective The aim of our study is to further investigate the effects of AG on metastasis and stemness of MDA-MB-231 cells and MCF-10A cells. Methods Cell viability assay of MDA-MB-231 and MCF-10A cells was performed using MTT method. Scratch and transwell invasion assay was used to test cell motility ability. Cell apototise and breast cancer stem marker ALDH was tested by flow cytometry. RNA-seq was used to analyze the AG-related biological process and pathway. Protein levels of Vimentin, E-cadherin, MMP2, p-FAK, FAK, ITGB4 and OCT4 were detected using western blotting. The in vivo antitumor activity of AG was tested using tumor bearing nude mice induced by MDA-MB-231 cells. Results AG inhibited the proliferation of MDA-MB-231 cells dose-dependently. AG suppressed the motility and invasion of MDA-MB-231 cells through influences on Vimention, E-cadherin, MMP2 and CSCs marker OCT. RNA-seq results identified 1516 differentially expressed genes among with 1163 up-regulated and 1353 down-regulated genes. GO and KEGG analysis revealed that these differentially expressed genes were obviously enriched in adhesion, cell migration and pathways in cancer. Meanwhile, AG significantly suppressed p-FAK and ITGB4 does-dependently. Moreover, the effects were restored by EGFR activation. In the in vivo experiment, AG significantly decreased the tumor weight and tumor volume with no statistically significant effects on body weight. Conclusion These findings indicated the inhibiting activities of AG on EMT, stemness and metastasis in breast cancer, and suggested the possibility being used as a potent anti-metastatic agent of AG for the treatment of TNBC.

ObjectiveHematological indicators in the early stage of PD-1 inhibitor treatment may show superior predictive ability of the occurrence of immune related adverse event (irAE) compared to the pre-treatment indicators, as the immune response is modulated during the PD-1 inhibitor treatment. The objective of this study was to investigate the predictive capabilities of biomarkers in the early treatment stage for immune related thyroid dysfunction (irTD), and explore the potential predictive cytokines.MethodsMedical records and blood test results of cancer patients treated with PD-1 inhibitor at a certain medical institution were collected. Logistic regression analysis was utilized to identify the predictive factors of irTD, ROC curves were plotted and the area under the curves (AUC) was calculated. Serum samples were collected before and during early treatment phase, cytokine detection was performed to explore potential predictive cytokines.ResultsA total of 264 patients were enrolled, 58 developed irTD (21.97%), including 31 patients with thyrotoxicosis and 27 with hypothyroidism. There were no significant differences in demographic characteristics, tumor types and PD-1 inhibitors between patients with and without irTD. Multivariate logistic analysis showed that anti-thyroglobulin antibody (TgAb) (OR=2.831, 95%CI: 1.077-7.443, P=0.035) and anti-thyroperoxidase antibody (TPOAb) (OR=9.565, 95%CI: 3.399-26.921, P=0.000) in the early treatment phase were independent predictive factors for irTD, the AUC of early-stage biomarkers was larger than that of pre-treatment (0.655 vs 0.571); low level of TSH at the early stage (OR=0.162, 95%CI: 0.077-0.341, P=0.000) was significantly correlated with thyrotoxicosis; female (OR=3.889, 95%CI: 1.457-10.380, P=0.007) and positive TPOAb (OR=8.678, 95%CI: 2.656-28.357, P=0.000) at the early stage were significantly correlated with hypothyroidism. The AUCs of early-stage biomarkers were larger than that of pre-treatment both in thyrotoxicosis (0.812 vs 0.637) and hypothyroidism patients (0.728 vs 0.710). The increase of IL-16 (adjusted P=0.004), IL-12p70 (adjusted P=0.014), IL-17 (adjusted P=0.014), CCL-15 (adjusted P=0.014) and IL-1a (adjusted P=0.021) in the early treatment phase were positively correlated with irTD.ConclusionsBiomarkers at the early stage of PD-1 inhibitor treatment could predict irTD, and demonstrated stronger predictive ability compared to pre-treatment biomarkers. IL-16, IL-12p70, IL-17, CCL-15 and IL-1a could serve as potential predictive biomarkers for irTD.

Organic‐rich shale in saline lacustrine basins holds significant importance as a source rock for conventional hydrocarbon exploration and has emerged as a prominent target for unconventional hydrocarbon exploration and development in recent years. Based on saline lacustrine basins, this paper provides a summary of the organic matter enrichment mechanisms in saline lacustrine basins, considering sedimentary characteristics, biological activities, factors for the organic matter enrichment and consumption, and hydrocarbon generation. The implications for these factors are discussed in relation to the distribution prediction of high‐quality lacustrine shale district settings and the exploration and development of shale oil. Saline lacustrine basins undergo distinct evolutionary stages, each corresponding to different sedimentary stages involving carbonate minerals, sulphate minerals, and alkaline minerals. Moreover, these basins exhibit diverse biological types and experience extensive biological activities. The prosperity of organisms and the accumulation of sedimentary organic matter are ensured by halophilic organisms. Organic matter enrichment in saline lacustrine basins is influenced by two main aspects: the primary productivity of organic matter, which is promoted by the proliferation of halophilic organisms, and the efficient preservation of organic matter facilitated by the strong reducing environment resulting from promoted water salinity stratification. The organic matter consumption in saline lacustrine basins involves bacterial sulphate reduction (BSR) in the early stages, thermochemical sulphate reduction (TSR) in the late stages, and dilution of salt minerals with higher depositional rates. of the presence of salt beds and saline minerals positively influences hydrocarbon generation and expulsion in organic‐rich shale within saline lacustrine deposition. Consequently, continental saline lacustrine basins in China offer favourable conditions for the formation of organic‐rich shale and present broad prospects for the exploration of shale oil and gas resources.

SHR4640, also named as ruzinurad, is a selective human urate transporter 1 (URAT1) inhibitor developed for the treatment of hyperuricemia and gout. This study evaluated the high-fat, high-calorie food effect on the pharmacokinetics and pharmacodynamics of SHR4640 in healthy Chinese male volunteers. In this open-label, randomized, 2-period crossover phase 1 trial, 14 healthy male subjects were randomized to receive a single 10-mg dose of SHR4640 under both fasted and fed conditions. The washout period was 7 days. Blood samples were collected for pharmacokinetic and pharmacodynamic analysis. Pharmacokinetic parameters were analyzed by a noncompartmental method. The safety of the drug was also evaluated in the trial. A total of 14 healthy male volunteers were enrolled in the study, and finally 13 healthy volunteers completed the study. A single 10-mg dose of SHR4640 was safe and well tolerated in healthy Chinese male volunteers. After single-dose administration of SHR4640, the 90%CIs of the geometric mean ratios of the area under the plasma concentration–time curve from time 0 to the last quantifiable concentration and the area under the plasma concentration–time curve from time 0 to infinity were within the equivalence criteria of 0.80-1.25. The 90%CIs of maximum plasma concentration was slightly outside the lower limit of bioequivalent criteria, with about 13.40% decrease in the fed versus fasted condition. The time to maximum concentration was slightly delayed under the fasted condition. A single 10-mg dose of SHR4640 was safe and well tolerated in this trial. The main pharmacokinetic parameters and serum uric acid lowering of SHR4640 were not affected by food effect; thus, SHR4640 can be recommended to be administered with or without food

To develop and verify a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for determining contezolid in plasma and cerebrospinal fluid (CSF). Protein precipitation was performed on samples using linezolid as the internal standard. We used an Agilent EclipsePlus C18 column operating at 0.4 mL/min in conjunction with acetonitrile and water mobile phases for the LC-MS/MS analysis. Using the precursor-product ion pairs 409.15→269.14 (contezolid) and 338.14→195.1 (linezolid), multiple reaction monitoring was used to quantify the compounds. Plasma linearity range was 50.0 to 5000 ng/mL, and CSF was 20.0 to 1000 ng/mL (r2 = 0.999). The inter-batch and intra-batch precisions were ≤2.57% and ≤5.79%, respectively. Plasma recovered 92.94%, and CSF recovered 97.83%. Plasma, CSF, hemolytic plasma, and hyperlipidemic plasma all showed a coefficient of variation ≤ 7.44%. The stability and dilution integrity of this method were also acceptable. The study also demonstrated that artificial CSF can be used as a matrix for the preparation of standard curve samples. A simple and accurate method was developed and validated for the determination of contezolid concentrations in human plasma and CSF, which may be useful for monitoring the therapeutic effect of central nervous system medications.

BackgroundCeftolozane-tazobactam is a novel cephalosporin/beta-lactamase inhibitor combination with activity against Gram-negative bacteria (GNB). We aimed to comprehensively evaluate the clinical efficacy and safety of ceftolozane-tazobactam in treating GNB infections in adult patients.Research design and methodsPubMed, Embase, and Cochrane databases were retrieved until August 2022. Randomized trials and non-randomized controlled studies evaluating ceftolozane-tazobactam and its comparators in adult patients with GNB infections were included.ResultsA total of 13 studies were included. Overall, patients receiving ceftolozane-tazobactam had significant advantages in clinical cure (odds ratio [OR], 1.62; 95% CI, 1.05-2.51) and microbiological eradication (OR, 1.43; 95% CI, 1.19-1.71), especially in Pseudomonas aeruginosa-infected patients. Ceftolozane-tazobactam had a significant advantage in clinical success or microbial eradication compared with polymyxin/aminoglycosides (PL/AG) or levofloxacin. There were no significant differences in adverse events (AEs), Clostridium difficile infection (CDI), and mortality between ceftolozane-tazobactam and comparators. Notably, ceftolozane-tazobactam showed a significantly lower risk of acute kidney injury compared with PL/AG.ConclusionsCeftolozane-tazobactam showed excellent clinical and microbiological efficacy in treating GNB, especially P. aeruginosa-induced infections. The overall safety profile of ceftolozane-tazobactam was comparable to other antimicrobials, with no increased risk of CDI and obvious advantage over antibacterial agents with high nephrotoxicity.

Abstract Methods A retrospective study of 133 non-small cell lung cancer (NSCLC) patients treated with PD-1 inhibitors was performed. Medical records and haematological data were collected. The trends of NLR and PLR during treatment were analysed by the Mann-Whitney U test. Logistic regression was used to investigate the association of irTD, all immune-related adverse events (irAEs) with pre- and post-treatment NLR and PLR. The relationship of these predictive factors with tumour response and survival was estimated using the Chi-squared test or Kaplan‒Meier analysis. Results 30 patients (22.6%) developed irTDs. The NLR showed a significant decreasing trend during treatment. Patients with previous thyroid diseases and lower NLR3w (NLR < 2.3) were significantly associated with irTDs. Pretreatment lower NLR and lower NLR3w were associated with irAEs. There was no difference in tumor response between patients with and without irTDs. PFS was prolonged in patients with irTDs and with lower PLR7w. Conclusions IrTD onset is common in patients receiving PD-1 inhibitors and is associated with prolonged PFS. The NLR3w after receiving PD-1 inhibitors appears to be a factor for identifying NSCLC patients at high-risk of occurring irTD. Post-treatment lower PLR is associated with better PFS.

Background. To explore the use of teicoplanin among Chinese patients with Gram-positive infections in a tertiary hospital. Methods. The medical records of patients, who were monitored for teicoplanin plasma concentration (TPC) from December 2017 to February 2019, were collected. By combining the therapeutic drug monitoring (TDM) and nonlinear mixed-effects model, a population pharmacokinetic (PPK) model of teicoplanin was established. Results. The proportions of TPCs lower and higher than 10 mg/L were nearly the same (102 vs. 108 cases). A two-compartment model of teicoplanin PPK in Chinese patients was established. Compared with 400 mg, the 600 mg regimen was more able to reach the target concentration (10 mg/L), especially for high-weight patients. Conclusions. The standard regimen of teicoplanin, 400 mg, failed to reach the target value in the present population. Moreover, the 600 mg regimen was feasible for high-weight patients based on TDM and individualized pharmacokinetic dosing adjustment.

Carbonate-rich shale in salt lakes has become a potential target for petroleum exploration. A full understanding of storage space development characteristics is the basis for the efficient development of this kind of shale. In this study, the complex mineral composition and multiple pore structure of a typical carbonate-rich shale from the Paleogene Xin'gouzui Formation in the Jianghan Basin were systematically analyzed. The mixed shale and dolomitic shale were the main lithofacies types in the study area. Both of them were dominated by interparticle (interP) pores. However, their pore sizes are noticeably different. Pores with a size of <100 nm are the main compositions of the mixed shale, with an average volume proportion of 78.24%. Conversely, the dolomitic shale develops mainly micro-sized pores and micro-fractures, with a ratio of 70.46%. The difference in pore structure for different types of shales is closely associated with mineral composition. When particles of different sizes are mixed, most of the interP pores are prone to be filled by fine minerals (e.g., clay), resulting in relatively small pore sizes for the mixed shale. Homogeneous carbonate minerals are favorable for the residual of larger size interP pores. However, recrystallization and secondary enlargement of carbonate minerals can also lead to a significant decrease in pore diameter of interP pores. With these results, a storage space development model for different lithofacies shales was established. This work is crucial to further reveal the reservoir mechanisms and hydrocarbon scales of an argillaceous dolomite reservoir.

This study assessed the safety, tolerability, and PK/PD of HSK7653 tablets in Chinese patients with type 2 diabetes mellitus (T2DM). This was a Phase IIa, multicenter, randomized, double-blind, placebo-controlled, and dose-increasing study with 48 Chinese diabetes patients. Subjects were randomly assigned to placebo and 10/25/50 mg dose groups, and they received oral administration once every two weeks for a total of six times. Safety and tolerability were assessed throughout this study, and PK/PD parameters were analyzed using non-compartment model with WinNonlin. The three doses of HSK7653 were well tolerated, and the incidence of TEAE and ADR was not significantly increased compared with the placebo group. Cmax increased linearly with the increasing dose, and the mean t1/2 was 64.0–87.0 h. The first dose and last dose PK parameters were similar. After oral administration of 10–50 mg HSK7653 every two weeks, the average Rac_Cmax and Rac_AUC were 0.9–1.0 and 1.0–1.1 respectively; therefore, HSK7653 was not accumulated in vivo. All three doses significantly inhibited DPP-4 activity and increased plasma GLP-1 level and serum insulin levels. When the plasma concentration of HSK7653 was ≥ 20.0 ng/mL, the DPP-4 inhibition rate in all subjects was maintained at > 80.0 www.chinadrugtrials.org.cn ).

SHR4640, also named as ruzinurad, is a selective human urate transporter 1 (URAT1) inhibitor developed for the treatment of hyperuricemia and gout. This study evaluated the high-fat, high-calorie food effect on the pharmacokinetics and pharmacodynamics of SHR4640 in healthy Chinese male volunteers. In this open-label, randomized, 2-period crossover phase 1 trial, 14 healthy male subjects were randomized to receive a single 10-mg dose of SHR4640 under both fasted and fed conditions. The washout period was 7 days. Blood samples were collected for pharmacokinetic and pharmacodynamic analysis. Pharmacokinetic parameters were analyzed by a noncompartmental method. The safety of the drug was also evaluated in the trial. A total of 14 healthy male volunteers were enrolled in the study, and finally 13 healthy volunteers completed the study. A single 10-mg dose of SHR4640 was safe and well tolerated in healthy Chinese male volunteers. After single-dose administration of SHR4640, the 90%CIs of the geometric mean ratios of the area under the plasma concentration-time curve from time 0 to the last quantifiable concentration and the area under the plasma concentration-time curve from time 0 to infinity were within the equivalence criteria of 0.80-1.25. The 90%CIs of maximum plasma concentration was slightly outside the lower limit of bioequivalent criteria, with about 13.40% decrease in the fed versus fasted condition. The time to maximum concentration was slightly delayed under the fasted condition. A single 10-mg dose of SHR4640 was safe and well tolerated in this trial. The main pharmacokinetic parameters and serum uric acid lowering of SHR4640 were not affected by food effect; thus, SHR4640 can be recommended to be administered with or without food

Youkenafil hydrochloride is a novel selective phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. Its safety, tolerability, and pharmacokinetics were evaluated in healthy Chinese male volunteers. In addition, this study explored the effect of food on the pharmacokinetic parameters of youkenafil hydrochloride. The study was divided into 3 trials: a single ascending dose (25, 50, 100, 150, or 200 mg youkenafil), multiple dose (50, 100, or 150 mg youkenafil once daily for 7 consecutive days), and food effect (50 mg youkenafil single dose). The overall tolerability of youkenafil was good. Youkenafil was rapidly absorbed after a single oral dose. Food intake impeded absorption efficiency but had no significant effect on area under the plasma concentration-time curve values. The mean accumulation ratio in area under the plasma concentration-time curve and maximum plasma concentration ranged from 1.3 to 1.6 and from 1.2 to 1.4 after once-daily dosing. There was no apparent accumulation following consecutive administration for 7 days. Less than 1% of the dose was found in urine as the intact drug for all dose groups. Single-dose youkenafil up to 200 mg and multiple doses up to 150 mg were generally safe and well tolerated.

Youkenafil hydrochloride is a novel selective phosphodiesterase type 5 inhibitor for the treatment of erectile dysfunction. Its safety, tolerability, and pharmacokinetics were evaluated in healthy Chinese male volunteers. In addition, this study explored the effect of food on the pharmacokinetic parameters of youkenafil hydrochloride. The study was divided into 3 trials: a single ascending dose (25, 50, 100, 150, or 200 mg youkenafil), multiple dose (50, 100, or 150 mg youkenafil once daily for 7 consecutive days), and food effect (50 mg youkenafil single dose). The overall tolerability of youkenafil was good. Youkenafil was rapidly absorbed after a single oral dose. Food intake impeded absorption efficiency but had no significant effect on area under the plasma concentration–time curve values. The mean accumulation ratio in area under the plasma concentration–time curve and maximum plasma concentration ranged from 1.3 to 1.6 and from 1.2 to 1.4 after once-daily dosing. There was no apparent accumulation following consecutive administration for 7 days. Less than 1% of the dose was found in urine as the intact drug for all dose groups. Single-dose youkenafil up to 200 mg and multiple doses up to 150 mg were generally safe and well tolerated.

In the working process of quadrupole composite rail electromagnetic launcher, there will be many phenomena such as structural deformation, temperature change and electromagnetic interference. At the same time, it involves the multi field effects of electromagnetic field, temperature field and structural field, and its action mechanism is quite complex. In this paper, the finite element analysis software ANSYS is used to simulate the electromagnetic structure, electromagnetic temperature and electromagnetic temperature structure of the quadrupole composite rail electromagnetic launcher, and to explore its multi physical field characteristics under the action of different factors. The simulation results show that the simulation model can reflect the actual phenomena in the process of electromagnetic launch. The different temperature rise of each component of the launcher at the end of the launch will cause different degrees of deformation of the armature and rail. Therefore, the influence of thermal stress should be fully considered when design-ing the device structure and adding excitation.