Anti-Inflammatory and Anti-Oxidant Impacts of Lentinan Combined with Probiotics in Ulcerative Colitis.

Multi-methods have been developed to control ulcerative colitis. This research targeted to probe that lentinan combined with probiotics suppresses inflammation and oxidative stress responses in a dextran sulfate sodium (DSS)-induced colitis model. A mouse model of colitis was induced through oral administration with 2.5% DSS and treated with lentinan and probiotics independently or in combination. Then, bodyweight and Disease Activity Index (DAI) of mice were determined. Histopathology of colon tissue was analyzed, and apoptosis, inflammation and oxidative stress in the colon tissue of mice were observed. An HT-29 cell model of colitis was established by DSS stimulation and cultured with lentinan and/or probiotics to examine cell proliferation and apoptosis. The data discovered that after DSS induction of colitis, mice developed weight loss, increased DAI score, and shortened the length of colon. Also, severe histopathology of the colon, and increased apoptosis, inflammation and oxidative stress were recognizable. Lentinan could alleviate DSS-induced colitis, and the highest dose was the most significant. Probiotics could also relieve UC in mice, and mixed probiotics had a better therapeutic effect than single probiotics. Lentinan combined with probiotics could further alleviate DSS-induced colitis damage. In addition, lentinan combined with probiotics impaired apoptosis and enhanced proliferation of DSS-treated HT-29 cells. In a word, lentinan combined with probiotics reduces the inflammatory response and oxidative stress of UC.

Metabolic characteristics of voriconazole - Induced liver injury in rats.

Voriconazole (VOR) - induced liver injury is a common adverse reaction, and can lead to serious clinical outcomes. It is of great significance to describe the metabolic characteristics of VOR - induced liver injury and to elucidate the potential mechanisms. This study investigated the changes of plasma metabolic profiles in a rat model of VOR - induced liver injury by non - targeted metabolomics. Correlation analysis was performed between differentially expressed metabolites and plasma liver function indexes. The metabolites with strong correlation were determined for their predictive performance for liver injury using receiver operating characteristic (ROC) curve analysis. Potential biomarkers were then screened combined with liver pathological scores. Finally, the expression level of genes that involved in lipid metabolism were determined in rat liver to verify the mechanism of VOR - induced liver injury we proposed. VOR - induced liver injury in rats was characterized by plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, the lipid droplets accumulation in liver, as well as inflammation and fibrosis. Significant changes of plasma metabolites were observed, with a decrease in lipid metabolites accounting for over 50% of all changed metabolites, and alterations of cholesterol and bile acids metabolites. The decrease of 3 phosphatidylcholine (PC) in plasma could indicate the occurrence of VOR - induced liver injury. Decreased fatty acids (FA) oxidation and bile acid excretion might be the potential mechanisms of VOR - induced liver injury. This study provided new insights into the molecular characterization of VOR - induced liver injury.

Apigenin-Mn(II) loaded hyaluronic acid nanoparticles for ulcerative colitis therapy in mice.

Ulcerative colitis (UC) is a chronic idiopathic inflammatory bowel disease characterized by rapid progression and frequent comorbidities that make its treatment challenging. Nanomaterial-based strategies have been extensively studied to target the GI mucosal immune system in recent years. Herein, we propose a novel apigenin-Mn(II) loaded sodium hyaluronate nanoparticles where apigenin (API) was incorporated in the Mn2+ ramework, coated with hyaluronic acid. The apigenin-Mn(II) loaded sodium hyaluronate nanoparticles (API-Mn(II)@HA NPs) exhibited a diameter of 200 nm and were effective against UC. The preparation of the API-Mn(II) complex was relatively simple, and the mechanism underlying its therapeutic effect on UC induced by sodium dextran sulfate (DSS) was studied in detail. We found that API-Mn(II)@HA nanoparticles could effectively repair the intestinal barrier and significantly improve the damaged colon tissue by mediating inflammatory factors. This study provides novel insights on a new kind of active targeted nanoparticle for improving the efficacy of drugs for UC treatment.

Inhibitory effect of ultrasonic stimulation on the voltage-dependent potassium currents in rat hippocampal CA1 neurons.

BACKGROUND: Transcranial ultrasonic stimulation is a novel noninvasive tool for neuromodulation, and has high spatial resolution and deep penetration. Although it can increase excitation of neurons, its effects on neuron are poorly understood. This study was to evaluate effect of ultrasonic stimulation (US) on neurons in vitro. In this paper, the effect of US on the excitability and voltage-dependent [Formula: see text] currents of CA1 pyramidal neurons in the rat hippocampus was studied using patch clamp. RESULTS: Our results suggest that US increased the spontaneous firing rate and inhibited transient outward potassium current ([Formula: see text]) and delayed rectifier potassium current ([Formula: see text]. Furthermore, US altered the activation of [Formula: see text] channels, inactivation and recovery properties of [Formula: see text] channels. After US, the [Formula: see text] activation curves significantly moved to the negative voltage direction and increased its slope factor. Moreover, the data showed that US moved the inactivation curve of [Formula: see text] to the negative voltage and increased the slope factor. Besides, US delayed the recovery of [Formula: see text] channel. CONCLUSIONS: Our data indicate that US can increase excitation of neurons by inhibiting potassium currents. Different US decreased the voltage sensitivity of [Formula: see text] activation differentially. Moreover, the more time is needed for US to make the [Formula: see text] channels open again after inactivating. US may play a physiological role by inhibiting voltage-dependent potassium currents in neuromodulation. Our research can provide a theoretical basis for the future clinical application of ultrasound in neuromodulation.

Antibiotic consumption versus the prevalence of carbapenem-resistant Gram-negative bacteria at a tertiary hospital in China from 2011 to 2017.

PURPOSE: China launched a 3-year rectification scheme on the clinical use of antibiotics in 2011, and a specific scheme on carbapenem use in February 2017. This study investigated the trends in and correlations between antibiotic consumption and the prevalence of carbapenem-resistant Gram-negative bacteria (CRGN) at a tertiary hospital during these years, particularly in carbapenem consumption. METHODS: The data were collected calculated per quarter from 2011 to 2017. The trends in antibiotic consumption and resistance were analyzed by regression analysis, while Spearman correlation analysis was used to assess the correlations. RESULT: The total consumption of antibiotics halved during the 7-year study period, from 770.15 DDDs/1000 PDs in quarter 1 of 2011 to 395.07 DDDs/1000 PDs in quarter 4 of 2017. Meantime, carbapenem consumption showed the significant increase, from 28.71 DDDs/1000 PDs to 49.2 DDDs/1000 PDs. The detection rates of CRGN (carbapenem-resistant Klebsiella pneumonia, Acinetobacter baumannii, and Pseudomonas aeruginosa) remained stable (P>0.05). The positive correlation was only discovered between the resistance rate of carbapenem-resistant K. pneumonia and the usage of carbapenems, which included meropenem and imipenem, with coefficients of 0.543, 0.537, and 0.497 (P<0.05), respectively. There was no more significant correlation in this study. CONCLUSION: The total consumption of antibiotics reduced significantly in the analysed hospital, which could be related to the antimicrobial stewardship programme. However, the carbapenem consumption was increased. The specific index should be established to limit the application of carbapenems. This study identified the positive correlation between the detection rate of carbapenem-resistant K. pneumonia and carbapenem consumption. More research is needed to confirm the impact of restricting and appropriated use of carbapenems on the prevalence of CRGN.

Colon-targeting mutual prodrugs of 5-aminosalicylic acid and butyrate for the treatment of ulcerative colitis.

The aim of this study was to design and synthesize four colon-targeting mutual prodrugs of 5-aminosalicylic acid (5-ASA) and butyrate, and evaluate their therapeutic effects on ulcerative colitis. Herein, 5-ASB, 5-ASDB, Ols-DB and Ols-DBP were prepared and characterized, and their lipophilicity, solubility, in vitro and in vivo stability were investigated. Finally, the ameliorative effects of the prodrugs on experimental colitis were evaluated via a series of indicators, including the body weight and survival rates of mice, the colon index and colonic damage score, the disease activity index, the myeloperoxidase activity and levels of superoxide dismutase, malondialdehyde, glutathione and glutathione peroxidase in colonic tissues. As a result, 5-ASB was very stable but Ols-DB showed extreme instability in the environment of the gastrointestinal tract, while 5-ASDB and Ols-DBP showed desirable colon-targeting properties. The four prodrugs all had certain therapeutic effects on the experimental colitis. When orally administered to mice, 5-ASDB and Ols-DBP had significantly greater effects than the mixture of 5-ASA and sodium butyrate. Ols-DB was used as an enema and could be as effective as 5-ASDB and Ols-DBP. In addition, the therapeutic effects of the synthesized prodrugs might be associated with their anti-oxidative damage ability.

Population Pharmacokinetics of Tigecycline in Critically Ill Patients with Severe Infections.

We sought to describe the population pharmacokinetics of tigecycline in critically ill patients and to determine optimized dosing regimens of tigecycline for different bacterial infections. This prospective study included 10 critically ill patients given a standard dose of tigecycline. Blood samples were collected during one dosing interval and were analyzed using validated chromatography. Population pharmacokinetics and Monte Carlo dosing simulations were undertaken using Pmetrics. Three target exposures, expressed as ratios of the 24-h area under the curve to MICs (AUC0-24/MIC), were evaluated (≥17.9 for skin infections, ≥6.96 for intra-abdominal infections, ≥4.5 for hospital-acquired pneumonia). The median age, total body weight, and body mass index (BMI) were 67 years, 69.1 kg, and 24.7 kg/m2, respectively. A two-compartment linear model best described the time course of tigecycline concentrations. The parameter estimates (expressed as means ± standard deviations [SD]) from the final model were as follows: clearance (CL), 7.50 ± 1.11 liters/h; volume in the central compartment, 72.50 ± 21.18 liters; rate constant for tigecycline distribution from the central to the peripheral compartment, 0.31 ± 0.16 h-1; and rate constant for tigecycline distribution from the peripheral to the central compartment, 0.29 ± 0.30 h-1 A larger BMI was associated with increased CL of tigecycline. Licensed doses were found to be sufficient for Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, and methicillin-resistant Staphylococcus aureus for an AUC0-24/MIC target of 4.5 or 6.96. For a therapeutic target of 17.9, an increased tigecycline dose is required, especially for patients with higher BMI. The dosing requirements of tigecycline differ with the indication, with pathogen susceptibility, and potentially with patient BMI.

Improvement of side-effects and treatment on the experimental colitis in mice of a resin microcapsule-loading hydrocortisone sodium succinate.

CONTEXT: Extensive or long-time use of corticosteroids often causes many toxic side-effects. The ion exchange resins and the coating material, Eudragit, can be used in combination to form a new oral delivery system to deliver corticosteroids. OBJECTIVES: The resin microcapsule (DRM) composed by Amberlite 717 and Eudragit S100 was used to target hydrocortisone (HC) to the colon in order to improve its treatment effect on ulcerative colitis (UC) and reduce its toxic side-effects. METHODS: Hydrocortisone sodium succinate (HSS) was sequentially encapsulated in Amberlite 717 and Eudragit S100 to prepare the HSS-loaded resin microcapsule (HSS-DRM). The scanning electron microscopy (SEM) was employed to investigate the morphology and structure of HSS-DRM. The in vitro release and in vivo studies of pharmacokinetics and intestinal drug residues in rat were used to study the colon-targeting of HSS-DRM. The mouse induced by 2,4,6-trinitrobenzenesulfonic acid was used to study the treatment of HSS-DRM on experimental colitis. RESULTS: SEM study showed good morphology and structure of HSS-DRM. In the in vitro release study, > 80% of HSS was released in the colon environment (pH 7.4). The in vivo studies showed good colon-targeting of HSS-DRM (Tmax = 0.97 h, Cmax = 118.28 µg/mL of HSS; Tmax = 2.16 h, Cmax = 64.47 µg/mL of HSS-DRM). Moreover, the HSS-DRM could reduce adverse reactions induced by HSS and had good therapeutic effects on the experimental colitis. CONCLUSIONS: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeting preparations.

Anti-inflammatory, analgesic and antioxidant activities of 3,4-oxo-isopropylidene-shikimic acid.

Context 3,4-Oxo-isopropylidene-shikimic acid (ISA) is an analog of shikimic acid (SA). SA is extracted from the dry fruit of Illicium verum Hook. f. (Magnoliaceae), which has been used for treating stomachaches, skin inflammation and rheumatic pain. Objective To investigate the anti-inflammatory, analgesic and antioxidant activities of ISA. Materials and methods Analgesic and anti-inflammatory activities of ISA were evaluated using writhing, hot plate, xylene-induced ear oedema, carrageenan-induced paw oedema and cotton pellets-induced granuloma test, meanwhile the prostaglandin E2 (PGE2) and malondialdehyde (MDA) levels were assessed in the oedema paw tissue. ISA (60, 120 and 240 mg/kg in mice model and 50, 120 and 200 mg/kg in rat model) was administered orally, 30 min before induction of inflammation/pain. Additionally, ISA was administered for 12 d in rats from the day of cotton pellet implantation. The active oxygen species scavenging potencies of ISA (10(-3)-10(-5) M) were evaluated by the electron spin resonance spin-trapping technique. Results ISA caused a reduction of inflammation induced by xylene (18.1-31.4%), carrageenan (7.8-51.0%) and cotton pellets (11.4-24.0%). Furthermore, ISA decreased the production of PGE2 and MDA in the rat paw tissue by 1.0-15.6% and 6.3-27.6%, respectively. ISA also reduced pain induced by acetic acid (15.6-48.9%) and hot plate (10.5-28.5%). Finally, ISA exhibited moderate antioxidant activity by scavenging the superoxide radical and hydroxyl radical with IC50 values of 0.214 and 0.450 µg/mL, respectively. Discussion and conclusion Our findings confirmed the anti-inflammatory, analgesic and antioxidant activities of ISA.

Pharmacokinetic/pharmacodynamic evaluation of linezolid for the treatment of staphylococcal infections in critically ill patients.

Several studies have demonstrated that the ideal therapeutic effect of linezolid cannot be achieved in critically ill patients with the recommended standard dosing regimen of 600 mg every 12 h (q12h). Moreover, the optimal strategy for successful treatment is still lacking. This study analysed factors influencing the efficacy of linezolid treatment and determined the target for successful treatment by logistic regression in 27 critically ill patients with staphylococcal infection who received linezolid 600 mg q12h. The results showed that only the 24-h area under the concentration-time curve to minimum inhibitory concentration (AUC24/MIC) ratio was significantly associated with staphylococcal eradication. Reaching 80% bacterial eradication required an AUC24/MIC of 120.5, defining the therapeutic target. Different dosing regimens were evaluated using Monte Carlo simulation to determine the optimal dosage strategy for linezolid. Although the probability of target attainment (PTA) was high (>99.9%) for the standard dosing regimen at MIC ≤ 1 mg/L, the PTA was almost 0 at MIC = 2 mg/L, thus the dosing regimen required adjustment. In addition, if the dosing regimen was adjusted to 600 mg every 8 h or 600 mg every 6 h, the major staphylococci (except for MRSA and MSSA) exhibited a cumulative fraction of response of >80%, showing a higher treatment success. These findings indicate that a strategy of high linezolid dosage may be needed to increase the probability of successful treatment at MIC > 1 mg/L. The role of therapeutic drug monitoring should be encouraged for optimising linezolid exposure in critically ill patients.

Investigation of the colon-targeting, improvement on the side-effects and therapy on the experimental colitis in mouse of a resin microcapsule loading dexamethasone sodium phosphate.

CONTEXT: Dexamethasone is the major drug in the treatment of ulcerative colitis (UC). However, the extensive or long-time use of dexamethasone causes many toxic side-effects. Ion exchange resins react with external-ions through their own functional groups and Eudragit S occurs degradation when pH > 7. These features make them suitable for oral delivery system. OBJECTIVE: Resin microcapsule (DRM) composed by 717 anion exchange resin and Eudragit S100 was used to target dexamethasone to the colon to improve its treatment effect on UC and reduce its toxic side-effects. RESULTS: Dexamethasone sodium phosphate (DXSP) was sequentially encapsulated in 717 anion-exchange resin and Eudragit S100 to prepare the DXSP-loaded resin microcapsule (DXSP-DRM). The in vitro release study and in vivo study of pharmacokinetics and the intestinal drug residues in rat demonstrated the good colon-targeting of DXSP-DRM. Moreover, the DXSP-DRM can reduce the toxic side-effects induced by DXSP and have good therapeutic effects on colitis mouse induced by 2,4,6-trinitrobenzenesulfonic acid. DISCUSSION: Dexamethasone can be targeted to the colon by DRM, thereby enhancing its treatment effect and reducing its toxic side effects. CONCLUSION: The resin microcapsule system has good colon-targeting and can be used in the development of colon-targeted preparations.

Efficacy and safety of voriconazole and CYP2C19 polymorphism for optimised dosage regimens in patients with invasive fungal infections.

The aim of this study was to determine an optimum voriconazole target concentration, to study the influence of CYP2C19 gene status on metabolism of voriconazole and to identify a dose-adjustment strategy for voriconazole according to CYP2C19 polymorphism in patients with invasive fungal infections. A total of 328 voriconazole trough plasma concentrations (C(min)) were collected and monitored from 144 patients. Information on efficacy and safety was obtained. Voriconazole therapy was effective in 81.9% of patients (118/144), and 12.5% (18/144) exhibited signs of hepatotoxicity. The relationships between voriconazole C(min) and clinical response and hepatotoxicity were explored using logistic regression, and a target clinical C(min) range of 1.5-4 mg/L was identified. Values of voriconazole C(min) and the ratio of C(min) to concentration of voriconazole-N-oxide (C(min)/C(N)) of poor metabolisers (PMs) were significantly higher than extensive metabolisers and intermediate metabolisers. Model-based simulations showed that PM patients could be safely and effectively treated with 200 mg twice daily orally or intravenously, and non-PM patients with 300 mg twice daily orally or 200mg twice daily intravenously. This study highlighted that voriconazole C(min) and C(min)/C(N) are strongly influenced by CYP2C19 polymorphism, and gene-adjusted dosing is important to achieve therapeutic levels that maximise therapeutic response and minimise hepatotoxicity.

Proteomic analysis of the proteins that are associated with the resistance to paclitaxel in human breast cancer cells.

Cancers frequently develop resistance to paclitaxel but the underlying molecular mechanisms remain to be determined. We have investigated the proteins that are associated with the paclitaxel resistance in human breast cancer MCF-7 cells using proteomic analysis. Paclitaxel resistant human breast cancer MCF-7 cells (MCF-7/P) were established by escalating the concentrations of paclitaxel to drug-sensitive MCF-7 cells (MCF-7/S). The global protein profiles of MCF-7/P and MCF-7/S were compared using two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS). Eleven proteins were upregulated while six proteins were downregulated in MCF-7/P cells. Western blot and real-time PCR analyses showed that the protein and mRNA levels of heterogeneous nuclear ribonucleoprotein (hnRNP C1/C2), SET nuclear oncogene (SET), aspartate aminotransferase (AAT), transgelin-2 (TAGLN2) were increased, while those of nucleoside-diphosphate kinase A (NDKA) were decreased in MCF-7/P cells. Accordingly, knockdown of TAGLN2 by siRNA sensitized MCF-7/P cells to paclitaxel and reduced the multidrug resistance (MDR). Our identification of differential proteins, particularly transgelin-2, provides new insights into the mechanism of MDR to paclitaxel and novel biological targets for breast cancer treatment.

Optimal tigecycline dosage regimen is urgently needed: results from a pharmacokinetic/pharmacodynamic analysis of tigecycline by Monte Carlo simulation.

BACKGROUND: The number of reported cases of resistance to tigecycline is increasing. The aim of this study was to evaluate the current standard tigecycline dosage regimen from a pharmacokinetic/pharmacodynamic (PK/PD) perspective. METHODS: Pharmacokinetic parameters and microbiological data were analyzed by Monte Carlo simulation in an evaluation of effectiveness. RESULTS: Tigecycline exhibits excellent in vitro antimicrobial activity, however the standard tigecycline dosing regimen fails to achieve the best outcome in vivo for the common drug-resistant strains, including Acinetobacter baumannii, Enterobacter spp, and Klebsiella pneumoniae. This may result in a lack of response to tigecycline therapy or to a further increase in the resistance rate. CONCLUSIONS: In the absence of new drugs on the horizon, rather than using a single fixed dosing regimen, tigecycline dosing needs to be optimized in order to achieve the desired successful clinical response and to prevent an escalation in drug resistance.

Establishment of paclitaxel-resistant breast cancer cell line and nude mice models, and underlying multidrug resistance mechanisms in vitro and in vivo.

BACKGROUND: Breast cancer is a common malignant tumor which affects health of women and multidrug resistance (MDR) is one of the main factors leading to failure of chemotherapy. This study was conducted to establish paclitaxel-resistant breast cancer cell line and nude mice models to explore underlying mechanisms of MDR. METHODS: The breast cancer drug-sensitive cell line MCF-7 (MCF-7/S) was exposed in stepwise escalating paclitaxel (TAX) to induce a resistant cell line MCF-7/TAX. Cell sensitivity to drugs and growth curves were measured by MTT assay. Changes of cell morphology and ultrastructure were examined by optical and electron microscopy. The cell cycle distribution was determined by flow cytometry. Furthermore, expression of proteins related to breast cancer occurrence and MDR was tested by immunocytochemistry. In Vivo, nude mice were injected with MCF-7/S and MCF-7/TAX cells and weights and tumor sizes were observed after paclitaxel treatment. In addition, proteins involved breast cancer and MDR were detected by immunohistochemistry. RESULTS: Compared to MCF-7/S, MCF-7/TAX cells had a higher resistance to paclitaxel, cross-resistance and prolonged doubling time. Moreover, MCF-7/TAX showed obvious alterations of ultrastructure. Estrogen receptor (ER) expression was low in drug resistant cells and tumors while expression of human epidermal growth factor receptor 2 (HER2) and Ki-67 was up-regulated. P-glycoprotein (P-gp), lung resistance-related protein (LRP) and glutathione-S-transferase-π (GST-π) involved in the MDR phenotype of resistant cells and tumors were all overexpressed. CONCLUSION: The underlying MDR mechanism of breast cancer may involve increased expression of P-gp, LRP and GST-π.

Ameliorative effects of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis and their mechanisms in rats.

The aim of the present study was to investigate the therapeutic effect and mechanism of 3,4-oxo-isopropylidene-shikimic acid (ISA) on 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats. (50, 100, 200 mg/kg) was administered for 14 days, 1 day after the induction of colitis by TNBS. The colonic injury and inflammation were assessed by macroscopic damage scores and myeloperoxidase (MPO) activity. Malondialdehyde (MDA) and nitric oxide (NO) levels, and superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities in plasma were measured with biochemical methods. Prostaglandin E2 (PGE2) level in colon was determined by radioimmunoassay. Expressions of inducible nitric oxide synthase (iNOS), cyclo-oxygenase-2 (COX-2), inhibitor kappa B-alpha (IκBα) and nuclear factor kappa B (NF-κB) p65 proteins in the colonic tissue were detected with immunohistochemistry. Enhanced colonic mucosal injury, inflammatory response and oxidative stress were observed in the animals clystered with TNBS, which was manifested as the significant increase in colon mucosal damage index, MPO activity, levels of MDA, NO and PGE2, as well as the expressions of iNOS, COX-2 and NF-κB p65 proteins in the colonic mucosa, and the significant decrease in expressions of IκBα proteins in the colonic mucosa. However, these parameters were found to be significantly ameliorated in rats treated with ISA at given doses, especially at 100 mg/kg and 200 mg/kg. Administration of ISA may have significant therapeutic effects on experimental colitis in rats, probably due to its mechanism of antioxidation, its inhibition of arachidonic acid metabolism and its modulation of the IκBα/NF-κB p65 expression.

Anti-inflammatory effect of 3,4-oxo-isopropylidene-shikimic acid on acetic acid-induced colitis in rats.

The present work was done to investigate the possible effects of 3,4-oxo-isopropylidene-shikimic acid (ISA) on acetic acid (AA)-induced colitis in rats. Colitis was induced by intracolonic injection of 6 % AA. Several parameters, including macroscopic score and biochemical parameters, were determined to assess the degree of protection. Biochemical parameters such as myeloperoxidase (MPO) activity, malondialdehyde (MDA) and nitric oxide (NO) levels, and superoxide dismutase (SOD) and inducible NO synthase (NOS) activities were measured following standard assay procedures. The study showed that treatment of rats for 6 days with ISA (100 and 200 mg/kg) was able to give complete protection against AA-induced colitis. Moreover, biochemical changes were reversed and brought toward control. These results suggest a beneficial effect of ISA against experimental colitis and the possible mechanism of the protective effects may be partly due to an antioxidant action.

Protective effects of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis induced by trinitrobenzenesulfonic acid in rats.

BACKGROUND: 3,4-Oxo-isopropylidene-shikimic acid (ISA) is a derivative of shikimic acid (SA). SA is extracted from Illicium verum Hook.fil., which has been used in traditional Chinese medicine and used for treating vomiting, stomach aches, insomnia, skin inflammation, and rheumatic pain. AIMS: To investigate the effects and the protective mechanism of 3,4-oxo-isopropylidene-shikimic acid on experimental colitis model induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats. METHODS: Colitis in rats was induced by colonic administration with TNBS. ISA (50, 100, and 200 mg/kg) was administered for 12 days to experimental colitis rats. The inflammatory degree was assessed by macroscopic damage score, colon weight/length ratios (mg/cm), and myeloperoxidase (MPO) activity. Malondialdehyde (MDA), glutathione (GSH), and nitric oxide (NO) levels, and superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), inducible nitric oxide synthase (iNOS) activities were measured with biochemical methods. RESULTS: ISA significantly ameliorated macroscopic damage, reduced colon weight/length ratios and the activity of MPO, depressed MDA and NO levels and iNOS activity, and enhanced GSH level, and GSH-Px and SOD activities in the colon tissues of experimental colitis in a dose-dependent manner. Moreover, the effect of ISA (200 mg/kg) was as effective as sulfasalazine (500 mg/kg). CONCLUSIONS: The findings of this study demonstrate the protective effect of ISA on experimental colitis, probably due to an antioxidant action.

Clinical pharmacokinetic/pharmacodynamic profile of linezolid in severely ill intensive care unit patients.

Severely ill Intensive Care Unit (ICU) patients have an increased risk of developing multiresistant Gram-positive infections, largely due to the inappropriate use of antimicrobials. In this study, the pharmacokinetic/pharmacodynamic (PK/PD) profile of linezolid, an antibiotic against Gram-positive infections, was characterised in eight critically ill patients admitted to the ICU. Remarkable variation amongst patients in the PK parameters of linezolid was observed, including a 5-7-fold difference in peak serum concentration (C(max)) (mean±standard deviation 15.70±6.58 mg/L) and 12-h area under the serum concentration-time curve (AUC(0-12)) (96.73±56.45 mg h/L), although the minimum inhibitory concentration (MIC) was similar amongst patients. In particular, variation amongst patients was found in the ratio of AUC(0-24)/MIC (range 31.66-216.82, mean 96.73) and the percentage of time that the serum concentration exceeded the MIC (T>MIC) (range 53.4-100%), two parameters used to predict linezolid efficacy. These variations highlight the importance of individual monitoring of linezolid PK/PD properties in critically ill patients. Furthermore, it was observed that regardless of AUC(0-24)/MIC and T>MIC values, the clinical and microbiological responses of patients were primarily affected by the individual's pathophysiological condition. In summary, these findings point to highly variable PK/PD properties of linezolid in severely ill patients, providing the rationale for targeting linezolid dosage to each individual patient's specific properties. An optimal dosage regimen based on individual PK/PD properties and pathophysiological conditions will help reduce the occurrence of resistance in Gram-positive bacteria.