A pharmacodynamic simulation to evaluate tigecycline in treatment of nosocomial pneumonia caused by multidrug-resistant Acinetobacter baumannii.

The shortage of effective antibiotics against multidrug-resistant Acinetobacter baumannii (MDR-Ab) has posed great threat to the public health. But the advent of tigecycline gives us new hope. The goal of our research was to assess the clinical efficacy of tigecycline at different doses by using a pharmacokinetic/pharmacodynamic (PK/PD) model which can incorporate pharmacokinetic data of tigecycline from patients with pneumonia and MICs of MDR-Ab from a tertiary hospital. A 10000-patient Monte-Carlo Simulation based on the PK/PD model was conducted to calculate the probability of target attainment (PTA) and the cumulative fraction of response (CFR) of tigecycline. 97% isolates displayed susceptibility and 3% were tigecycline-intermediate strains and the values of MIC ranged from 0.125 to 4 µ g/ml. A CFR of 61.62% was predicted for tigecycline at current dosage (50 mg q12h). When the dosage was increased, the predicted CFRs for 75 mg q12h, 100 mg q12h, 125 mg q12h, 150 mg q12h were 81.00%, 89.86%, and 94.57%, 96.77%, respectively. Despite presented higher susceptibility, the CFR obtained was not optimal at current dosage. A higher CFR indicating a better clinical efficacy can be gained by the increased dosage.

Bibliometrics analysis based on the Web of Science: Current trends and perspective of gastric organoid during 2010-2023.

BACKGROUND: Three-dimensional organoid culture systems have been established as a robust tool for elucidating mechanisms and performing drug efficacy testing. The use of gastric organoid models holds significant promise for advancing personalized medicine research. However, a comprehensive bibliometric review of this bur-geoning field has not yet been published. AIM: To analyze and understand the development, impact, and direction of gastric organoid research using bibliometric methods using data from the Web of Science Core Collection (WoSCC) database. METHODS: This analysis encompassed literature pertaining to gastric organoids published between 2010 and 2023, as indexed in the WoSCC. CiteSpace and VOSviewer were used to depict network maps illustrating collaborations among authors, institutions and keywords related to gastric organoid. Citation, co-citation, and burst analysis methodologies were applied to assess the impact and progress of research. RESULTS: A total of 656 relevant studies were evaluated. The majority of research was published in gastroenterology-focused journals. Globally, Yana Zavros, Hans Clevers, James M Wells, Sina Bartfeld, and Chen Zheng were the 5 most productive authors, while Hans Clevers, Huch Meritxell, Johan H van Es, Marc Van de Wetering, and Sato Toshiro were the foremost influential scientists in this area. Institutions from the University Medical Center Utrecht, Netherlands Institute for Developmental Biology (Utrecht), and University of Cincinnati (Cincinnati, OH, United States) made the most significant contributions. Currently, gastric organoids are used mainly in studies investigating gastric cancer (GC), Helicobacter pylori-infective gastritis, with a focus on the mechanisms of GC, and drug screening tests. CONCLUSION: Key focus areas of research using gastric organoids include unraveling disease mechanisms and enhancing drug screening techniques. Major contributions from renowned academic institutions highlight this field's dynamic growth.

The dual role of osteopontin in acetaminophen hepatotoxicity.

AIM: Osteopontin (OPN), a multifunctional protein, has been reported to be protoxicant in acetaminophen hepatotoxicity. In this study, the mechanisms underlying the detrimental role of OPN in acetaminophen toxicity were explored. METHODS: Male C57BL/6 (wild-type, WT) and OPN(-/-) mice were administered with acetaminophen (500 mg/kg, ip). After the treatment, serum transaminase (ALT), as well as OPN expression, histology changes, oxidative stress and inflammation response in liver tissue were studied. Freshly isolated hepatocytes of WT and OPN(-/-) mice were prepared. RESULTS: Acetaminophen administration significantly increased OPN protein level in livers of WT mice. OPN expression was mainly localized in hepatic macrophages 6 h after the administration. In OPN(-/-) mice, acetaminophen-induced serum ALT release was reduced, but the centrilobular hepatic necrosis was increased. In OPN(-/-) mice, the expression of CYP2E1 and CYP1A2 in livers was significantly increased; GSH depletion and lipid peroxidation in livers were enhanced. On the other hand, OPN(-/-) mice exhibited less macrophage and neutrophil infiltration and reduced expression of proinflammatory cytokines TNF-α and IL-1α in livers. An anti-OPN neutralizing antibody significantly reduced acetaminophen-induced serum ALT level and inflammatory infiltration in livers of WT mice. CONCLUSION: OPN plays a dual role in acetaminophen toxicity: OPN in hepatocytes inhibits acetaminophen metabolism, while OPN in macrophages enhances acetaminophen toxicity via recruitment of inflammatory cells and production of proinflammatory cytokines.

Research on Sustainable Development of Competitive Sports in China Based on PSR and DEA Model.

From the 2008 Beijing Olympic Games to the 2022 Beijing Winter Olympics, the sustainable development of competitive sports has become more and more popular in China. Therefore, for the sustainable development of China's competitive sports, first, the logical relationship of "pressure-state-response" is adopted to select the index system, covering the elements of the economy, society, policy, and so on. Principal component analysis and entropy weight method are used to construct the comprehensive evaluation model of the sustainable development of competitive sports. Second, through the coupling coordination method to study the coordinated development of China's competitive sports and economic society, and then from the perspective of the obstacle factor diagnosis method to determine the obstacles to the sustainable development of China's competitive sports system. Finally, the DEA model is used to predict the development level of competitive sports in China's provinces in the next 10-20 years. The research shows that the overall development level of competitive sports in China is good, but there are certain differences among different regions. Meanwhile, from the forecast results, the development level of competitive sports in Hainan, Shanxi, Anhui, Jiangxi, Inner Mongolia, Gansu, and Ningxia may be greatly improved in the future. Based on the above research conclusions, this study puts forward some suggestions to give full play to the joint and synergistic development effect among different regions, reasonably draw lessons from the advanced experience of competitive sports development at home and abroad, and scientifically construct the comprehensive development system of competitive sports. At the same time, the research of this study provides some reference value for the sustainable development of China's competitive sports and the coordinated development of China's competitive sports and economic society.

Effectiveness and safety of macrolides in cystic fibrosis patients: a meta-analysis and systematic review.

OBJECTIVES: To evaluate the efficacy and safety of macrolides in cystic fibrosis (CF). METHODS: Randomized controlled trials (RCTs) of macrolides for the treatment of CF published in PubMed, the Cochrane Library and Embase were searched. Application of inclusion and exclusion criteria, data extraction, and assessment of methodological quality were independently performed in duplicate. The primary efficacy outcome was the impact on the deterioration of lung function (changes in FEV(1) and FVC). Safety outcomes included adverse events and mortality. RESULTS: Eight RCTs (seven with azithromycin and one with clarithromycin) were found in the systematic review and six RCTs with azithromycin (654 patients) were included in the meta-analysis. Azithromycin treatment showed a significant increase in FEV(1)% (3.22%, 95% CI = 1.38-5.06, P = 0.0006, I(2) = 0%) and FVC% (3.23%, 95% CI = 1.62-4.85, P < 0.0001, I(2) = 0%) compared with placebo. In individuals with baseline Pseudomonas aeruginosa colonization, both FEV(1)% (4.80%, 95% CI = 1.66-7.94, P = 0.003, I(2) = 42%) and FVC% (4.74%, 95% CI = 1.92-7.57, P = 0.001, I(2) = 0%) increased significantly. The incidence rates of the main side effects (cough, headache, abdominal pain, vomiting, nausea and diarrhoea) were not significantly different between the azithromycin-treated group and the placebo group. The RCT of clarithromycin, involving 18 patients, showed its effects on clinical improvement; however, the small sample size made comparisons with azithromycin difficult. CONCLUSIONS: Long-term use of azithromycin can improve lung function, especially for P. aeruginosa-colonized CF patients. There was no evidence of increased adverse events with azithromycin. More data are needed to verify the best azithromycin regimen and to evaluate other macrolides in CF patients.

Iron-Depletion prevents biofilm formation in Pseudomonas Aeruginosa through twitching mobility and quorum sensing.

Influence of iron-depletion on twitching motility and quorum sensing (QS) system in P. aeruginosa was evaluated. The results demonstrated iron-depletion can retard biofilm formation and increase the twitching motility and expression of QS-related genes, suggesting a potential interaction between twitching motility and QS system in P. aeruginosa biofilm formation.

Synergistic effects of aminoglycosides and fosfomycin on Pseudomonas aeruginosa in vitro and biofilm infections in a rat model.

OBJECTIVES: To study the in vitro and in vivo efficacy of aminoglycosides against Pseudomonas aeruginosa, either alone or in combination with fosfomycin. METHODS: Using an in vitro study to assess inhibition of the growth of P. aeruginosa, MIC(90) and MIC(50) values of amikacin, gentamicin, netilmicin, tobramycin and isepamicin were determined, either alone or in combination with fosfomycin, and then the fractional inhibitory concentration index was calculated. In the biofilm-infected rat model, the efficacy and effects of treatment with isepamicin and fosfomycin on infection were studied. RESULTS: The combinations of amikacin and fosfomycin or isepamicin and fosfomycin showed the most significant synergistic effects against P. aeruginosa as compared with other treatments. In the biofilm-infected rat model, as a single agent, neither isepamicin nor fosfomycin reduced C-reactive protein level and numbers of white blood cells, or reduced the colony counts of the bacteria from both tissue and silica gel tubes. However, the combination of these two agents resulted in a good therapeutic effect. CONCLUSIONS: Combination of aminoglycosides and fosfomycin not only showed a positive effect in vitro but also improved the therapeutic effect in a biofilm-infected rat model. This offers an effective treatment strategy against some therapy-resistant infections.

Effects of iron depletion on antimicrobial activities against planktonic and biofilm Pseudomonas aeruginosa.

OBJECTIVES: Iron plays an important role in the development of Pseudomonas aeruginosa biofilm. Here we evaluated effects of iron depletion on the antimicrobial activity of ceftazidime, tobramycin and ciprofloxacin against planktonic and biofilm Pseudomonas aeruginosa. METHODS: We tested the sensitivities of wild-type PAO1, type-IV pilus mutant PAO-DeltapilHIJK and the quorum-sensing mutant PAO-JP2 P. aeruginosa planktonic cultures and biofilms to antibiotics under iron-depleted conditions. KEY FINDINGS: In planktonic bacteria, the minimum concentration that inhibited visible growth (MIC) of ciprofloxacin was increased slightly in an iron-depleted environment in all three strains, whereas the MIC of tobramycin was similar in iron-depleted and control environments. The MIC of ceftazidime increased in the PAO-JP2 strain when iron was depleted. Tobramycin achieved the best bactericidal effect in biofilms. Viable counts were reduced by one log under iron-depleted conditions in all three strains when tobramycin reached 4 MIC and when ceftazidime and ciprofloxacin reached 8 MIC. CONCLUSIONS: This study suggests that once the biofilm is formed, iron depletion may only slightly promote the bactericidal effect of antibiotics on PAO1, PAO-DeltapilHIJK and PAO-JP2. Although these changes were relatively small, iron as one of the environmental factors should not be ignored when evaluating bactericidal effect of antibiotics. The combination of an iron chelator and antibiotics may have therapeutic value under certain bacterial growth conditions.

Antibacterial activity of allicin alone and in combination with beta-lactams against Staphylococcus spp. and Pseudomonas aeruginosa.

Allicin is one of the most effective compounds isolated from garlic showing antibacterial activity. Determination of MIC alone or in combination with cefazolin/oxacillin against Staphylococcus spp. or with cefoperazone against Pseudomonas aeruginosa showed that allicin alone did not have good antibacterial activity (MIC90>512 microg/ml) but it facilitated antibacterial activity of all three beta-lactams tested at subinhibitory concentrations. In the presence of 1/8 to 1/2 the MIC of allicin, the MIC90 values of cefazolin, oxicillin, and cefoperazone were reduced by 4 approximately 128, 32 approximately 64, and 8 approximately 16 fold, respectively. Thus, allicin-beta-lactam combinations offer promise of clinical utility especially if synergism is demonstrated by in vivo experimental studies.

[Mutant prevention concentrations of fluoroquinolones for Staphylococcus aureus].

OBJECTIVE: To establish a method to measure mutant prevention concentration (MPC) in vitro, and to measure MPC of fluoroquinolones for staphylococcus aureus. METHODS: The staphylococcus aureus strain ATCC25923 and 20 ciprofloxacin-susceptible clinical isolates were enriched in broth, and the bacterial concentrations were adjusted to 10(10) colony forming units per milliliter. The minimal inhibitory concentration (MIC), MIC for 99% of input cells (MIC99), provisional MPC (MPCpr) and MPC of moxifloxacin, gatifloxacin, pasufloxacin and ciprofloxacin for staphylococcus aureus were determined by agar plates dilution method. RESULTS: The MPC of moxifloxacin, gatifloxacin, pasufloxacin and ciprofloxacin for staphylococcus aureus strain ATCC25923 were 0.18, 0.3, 0.75 and 1.8 microg/ml, and the MPC/MIC99 were 9.0, 7.5, 8.0 and 10.6 respectively. The MPC for 90% of the isolates (MPCpr90) of moxifloxacin, gatifloxacin, pasufloxacin and ciprofloxacin for 20 staphylococcus aureus clinical isolates were 1, 1, 4 and 8 microg/ml, and the MPCpr90/MIC90 were 8, 8, 16 and 16 respectively. CONCLUSION: The capacity of moxifloxacin and gatifloxacin for restricting the selection of staphylococcus aureus resistant mutants were stronger than that of pasufloxacin and ciprofloxacin. Combined with pharmacokinetic parameters, moxifloxacin and gatifloxacin may restrict the selective enrichment of resistant mutants among ciprofloxacin-susceptible staphylococcus aureus clinical isolates, and ciprofloxacin is expected to selectively enrich mutants easily.

Determination of thalidomide concentration in human plasma by liquid chromatography-tandem mass spectrometry.

A rapid, sensitive and specific analytical method based on high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed for the determination of thalidomide concentration in human plasma. The analyte and internal standard were extracted by liquid-liquid extraction with ether-dichloromethane (3:2, v/v) and separated on a TC-C(18) column using methanol-10 mM ammonium acetate-formic acid (60:40:0.04, v/v/v) as the mobile phase at a flow rate of 0.9 ml/min. The detection was performed using an API 4000 triple quadrupole mass spectrometer in the positive electrospray ionization (ESI) mode and completed within 3.0 min. The multiple reaction monitoring (MRM) transitions were m/z 259.1→84.0 for the analyte and m/z 195.9→138.9 for temozolomide. The calibration curve exhibited a linear dynamic range of 2-1500 ng/ml (r>0.9991). The intra-and inter-day precisions (as relative standard deviation; RSD) were 6.8-13.5% and 4.3-5.0% respectively and the accuracy (as relative error; RE) was 2.0-3.5%. The recoveries and matrix effects were satisfactory in all the biological matrices examined. This method was successfully used in a pharmacokinetic study of thalidomide in healthy male volunteers receiving an oral administration of a 200-mg dose.

Single-dose pharmacokinetics and safety of iptakalim hydrochloride in Chinese healthy volunteers.

OBJECTIVES: To investigate the safety, pharmacokinetics and food effect of iptakalim in healthy adult Han Chinese volunteers. METHODS: Study 1 was a randomized open-label, Latin square designed, single-dose, three-period, self-control crossover study. Six men and six women received 5, 10 and 20 mg of iptakalim orally. Study 2 was a randomized, open-label, single-dose, two-period, self-control crossover study. Ten men were included and each subject received 5 mg iptakalim orally, fasting and nonfasting. KEY FINDINGS: No adverse effects were reported and no clinically meaningful changes in vital signs were found. Cmax, AUC(0-t) and AUC(0-∞) were proportional over the dose levels of 5, 10 and 20 mg. Tmax, t½ and CL/F were similarly independent of dose level. In the 5 mg and 20 mg group, the Cmax, AUC(0-t) and AUC(0-∞) in women were significantly higher than in men, although they showed no difference after correction by mg/kg doses in the 5 mg group. At the 5-mg dose level, no significant difference in pharmacokinetics was found in nonfasting and fasting subjects. CONCLUSIONS: Single-dose pharmacokinetics of iptakalim showed dose proportionality over the dose levels of 5-20 mg. The pharmacokinetics showed gender differences in the 5 and 20 mg groups. Food had almost no impact on the pharmacokinetics at the 5 mg level.

Treatment of community-acquired pneumonia with moxifloxacin: a meta-analysis of randomized controlled trials.

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality throughout the world. To investigate whether moxifloxacin monotherapy is associated with better clinical outcomes than other antibiotics recommended for CAP among adults with mild-to-moderate or severe CAP, we performed a meta-analysis. MEDLINE, EMBASE, Web of Science, and the Cochrane Library were searched for randomized control trials (RCTs). The efficacy and safety of moxifloxacin were compared with other antimicrobial agents used to treat CAP. Fourteen RCTs, consisting of 6923 total patients, were included in the meta-analysis. No difference was found regarding the incidence of adverse events and mortality between moxifloxacin and the compared regimens. We found that moxifloxacin is as effective and well-tolerated as other recommended antibiotics for the treatment of CAP and possesses a better pathogen eradication rate than beta-lactam-based therapy.

In vitro activity of two old antibiotics against clinical isolates of methicillin-resistant Staphylococcus aureus.

The objective of this paper was to investigate the in vitro effects of fusidic acid combined with fosfomycin against methicillin-resistant Staphylococcus aureus (MRSA). In all, 196 MRSA strains isolated from three clinical specimens of human infections from hospitals in China were used in this study. The checkerboard method was used to determine whether combinations act synergistically against these strains. The susceptibility results for fusidic acid and fosfomycin were interpreted according to the guidelines of the Clinical and Laboratory Standards Institute. The combination of fusidic acid and fosfomycin demonstrated the following interactions: 87.76% (172/196) synergism, 12.24% (24/196) indifference and no antagonism was seen (minimum and maximum fractional inhibitory concentration index 0.14 and 0.75, respectively). Thus, combinations of fusidic acid and fosfomycin show synergism for most of the MRSA isolates tested in this study, and may be a future therapeutic alternative for infections caused by MRSA.

[Antitumor effect of polysaccharides from cactus pear fruit in S180-bearing mice].

BACKGROUND & OBJECTIVE: Polysaccharide components of some traditional Chinese medicine have certain antitumor effects and can promote immune responses. Extractions from cactus pear fruit can inhibit the proliferation of cervical cancer, ovary cancer and bladder cancer cells, and suppress the growth of ovarian cancer in mice. This study was to observe the antitumor effect of polysaccharides extracted from cactus pear fruit in S180-bearing mice. METHODS: S180-bearing mice were established and divided into five groups: normal saline (NS) group, cyclophosphamide (CTX) group, high, middle and low dose of polysaccharide groups. Tumor inhibition rates, values of thymus index, spleen index, superoxide dismutase (SOD), maleic dialdehyde (MDA) and nitrogen monoxidum (NO) were recorded. Changes in ultra-structures of tumor cells under transmission electron microscopy were observed. RESULTS: The tumor inhibition rates in CTX group, high, middle and low dose groups were 7.78%, 31.13%%, 49.70%, 61.07%, respectively. The thymus index was significantly higher in middle and high dose groups than in NS group [(2.61+/-0.43) mg x g(-1) and (2.65+/-0.73) mg x g(-1) vs. (2.22+/-0.24) mg x g(-1), P<0.05]. The spleen index of high dose group was higher than that of NS group [(6.45+/-0.97) mg x g(-1) vs. (5.42+/-1.13) mg x g(-1),P<0.05]. SOD of middle and high dose groups [(303.12+/-13.03) U/mL and (310.03+/-18.02) U/mL] were higher than that of NS group [(280.12+/-10.01) U/mL](P<0.05). MDA was lower in low, middle and high dose groups [(6.56+/-0.75) nmol/mL, (6.24+/-1.03) nmol/mL and (5.78+/-0.90) nmol/mL, respectively] than that in NS group [(7.39+/-0.51) nmol/mL] (P<0.05). NO was lower in low, middle and high dose groups [(56.12+/-8.60) micromol/L, (50.12+/-10.05) micromol/L, (48.06+/-8.45) micromol/L respectively] than in NS group [(64.14+/-1.25) micromol/L](P<0.05). Under electron microscopy, polysaccharide or CTX treated tumor cells showed typical morphology of early apoptosis with condensed chromatin at the margins of nuclei, disintegrated nucleolus and vacuoles in the cytoplasm. CONCLUSION: Polysaccharides extracted from cactus pear fruit possess certain antitumor effects, which can induce apoptosis, increase antioxidation and promote immune responses.