Analyzing the correlation between quinolone-resistant Escherichia coli resistance rates and climate factors: A comprehensive analysis across 31 Chinese provinces.

BACKGROUND: The increasing problem of bacterial resistance, particularly with quinolone-resistant Escherichia coli (QnR eco) poses a serious global health issue. METHODS: We collected data on QnR eco resistance rates and detection frequencies from 2014 to 2021 via the China Antimicrobial Resistance Surveillance System, complemented by meteorological and socioeconomic data from the China Statistical Yearbook and the China Meteorological Data Service Centre (CMDC). Comprehensive nonparametric testing and multivariate regression models were used in the analysis. RESULT: Our analysis revealed significant regional differences in QnR eco resistance and detection rates across China. Along the Hu Huanyong Line, resistance rates varied markedly: 49.35 in the northwest, 54.40 on the line, and 52.30 in the southeast (P = 0.001). Detection rates also showed significant geographical variation, with notable differences between regions (P < 0.001). Climate types influenced these rates, with significant variability observed across different climates (P < 0.001). Our predictive model for resistance rates, integrating climate and healthcare factors, explained 64.1% of the variance (adjusted R-squared = 0.641). For detection rates, the model accounted for 19.2% of the variance, highlighting the impact of environmental and healthcare influences. CONCLUSION: The study found higher resistance rates in warmer, monsoon climates and areas with more public health facilities, but lower rates in cooler, mountainous, or continental climates with more rainfall. This highlights the strong impact of climate on antibiotic resistance. Meanwhile, the predictive model effectively forecasts these resistance rates using China's diverse climate data. This is crucial for public health strategies and helps policymakers and healthcare practitioners tailor their approaches to antibiotic resistance based on local environmental conditions. These insights emphasize the importance of considering regional climates in managing antibiotic resistance.

Metabolic activation of tyrosine kinase inhibitors: recent advance and further clinical practice.

At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.

Effects of Trough Concentration and Solute Carrier Polymorphisms on Imatinib Efficacy in Chinese Patients with Chronic Myeloid Leukemia.

PURPOSE: We investigated the relationship between imatinib trough concentrations and genetic polymorphisms with efficacy of imatinib in Chinese patients with chronic myeloid leukemia (CML). METHODS: There were 171 eligible patients. Peripheral blood samples were collected from 171 eligible patients between 21 and 27 hours after the last imatinib administration. Complete cytogenetic response (CCyR), major molecular response (MMR) and complete molecular response (CMR) were used as metrics for efficacy. Nine single nucleotide polymorphisms in 5 genes, SLC22A4 (917 T>C, -248 C>G and -538 C>G), SLC22A5 (-945 T>G and -1889 T>C), SLCO1A2 (-361 G>A), SLCO1B3 (334 T>G and 699 G>A) and ABCG2 (421C>A) were selected for genotyping. RESULTS: Patients with CCyR achieve higher trough concentrations than those without CCyR (1478.18±659.83 vs 984.89±454.06 ng mL-1, p<0.001). Patients with MMR and CMR achieve higher trough concentrations than those without MMR and CMR, respectively (1486.40±703.38 vs 1121.17±527.14 ng mL-1, p=0.007; 1528.00±709.98 vs 1112.67±518.35 ng mL-1, p=0.003, respectively). Carriers of A allele in SLCO1A2 -361G>A achieve higher CCyR and MMR rates (p=0.047, OR=4.320, 95% CI: 0.924-20.206; p=0.042, OR=2.825, 95% CI: 1.016-7.853, respectively). Both trough concentrations and SLCO1A2 -361G>A genotypes are independent factors affecting imatinib efficacy. The positive and negative predictive values for CCyR are 71.01% and 68.75%, respectively. The positive and negative predictive values for MMR are 62.86% and 69.70%, respectively. CONCLUSION: Imatinib trough concentrations and SLCO1A2 -361G>A genotypes are associated with imatinib efficacy in Chinese patients with CML.

Effects of licorice extracts on the pharmacokinetics of brucine in rats and its possible mechanism.

The detoxification effects of licorice are believed to be related to its pharmacokinetic (PK) interference. This paper aimed to evaluate the effects of licorice water extracts (LWE) on the pharmacokinetics of brucine. Rats were administered brucine and/or LWE. The pharmacokinetic behavior of brucine and bioactive components of licorice were quantified by HPLC-MS/MS. P-glycoprotein (P-gp) inhibitor verapamil, real time PCR, vesicular transport assay and everted gut sacs were employed to investigate its possible mechanism. We found LWE reduced the Cmax and AUC of oral brucine in a dose-dependent way. In contrast, the AUC values of intraperitoneal brucine showed no significant difference between LWE treated and untreated rats, which indicating the intestinal absorption of brucine was influenced by LWE. We found that high dose of LWE activated the transport activity of P-gp in vesicular transport assay, while the mRNA level of P-gp in the intestinal was not affected by licorice. Moreover, high dose of LWE decreased the intestinal absorption of brucine in the everted gut sacs model, which could over turned by verapamil. These results suggested that a single high dose of LWE could impair the intestine absorption of brucine, and its potential mechanism may be mediated by P-gp in intestine.

Simple and rapid UPLC-MS/MS method for quantification of entecavir in human plasma: Application to a bioequivalence study
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A simple and fast ultra-performance liquid chromatography-tandem mass spectrometry method was developed and validated to determine entecavir in human plasma with the stable isotopically labeled internal standard entecavir-13C215N. Samples (100 µL each) were pretreated by protein precipitation with methanol, and then separated on an ACQUITY UPLC BEH C18 analytical column (2.1 × 50 mm, 1.7 µm) with a simple isocratic elution. The detection was operated by a positive ionization electrospray mass spectrometry in multiple reaction monitoring mode. The method had a short chromatographic run time of 2 minutes, and obtained sharp peaks of entecavir and the internal standard. Good linearity was found within 0.1 - 20 ng/mL. The intra- and inter-day precision and accuracy met the acceptance criteria, and no matrix effect was observed. This method was successfully applied in a bioequivalence study of two kinds of entecavir tablets in healthy Chinese volunteers. And the results showed that no significant differences were found between the test and reference preparations in pharmacokinetic parameters (p > 0.05) by ANOVA. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax, AUC0-tlast, and AUC0-∞ fell within the bioequivalence acceptance criteria (80 - 125%). No significant difference was found in tmax between the two preparations. The two one-sided t-tests showed that these two products were bioequivalent.
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Association Between Vancomycin Blood Brain Barrier Penetration and Clinical Response in Postsurgical Meningitis.

PURPOSE: This study investigated the association between vancomycin blood brain barrier penetration and clinical response in patients with postsurgical meningitis. METHODS: Adult patients with postsurgical meningitis were recruited. Eligible patients received vancomycin 500 mg every 6 h for at least 5 days. On day 3 or 4, cerebrospinal fluid (CSF) and simultaneous serum samples were obtained to determine CSF minimum concentrations (Cmin), serum Cmin and CSF to serum Cmin ratio. RESULTS: Twenty-two patients (14 men and 8 women; mean age of 52.6± 12.1 years) were recruited. The vancomycin Cmin was 3.63 ± 1.64 mg/L in CSF and 13.38 ± 5.36 mg/L in serum, with the CSF to serum Cmin ratio of 0.291 ± 0.118. The Cmin in serum and in CSF showed a significant correlation (p=0.005, r =0.575). The vancomycin CSF Cmin had a significant correlation with the decline of white blood cell counts (WBCs) in CSF (p=0.003, r =0.609). CSF Cmin, serum Cmin and CSF to serum Cmin ratio all showed no significant correlation with clinical response (p=0.335, 0.100, 0.679, respectively). CONCLUSIONS: There was a positive correlation between serum Cmin and CSF Cmin. However, only CSF Cmin is positively correlated with WBCs improvement in CSF. All other parameters such as serum Cmin, CSF Cmin and CSF to serum Cmin ratio had no correlation with clinical response. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Quantitative analysis of valsartan by two-dimensional liquid chromatography (2D-HPLC) and its application in a bioequivalence study in Chinese volunteers
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PURPOSE: To develop a sensitive, two-dimensional liquid chromatography (2D-LC) method for determination of valsartan, applied to investigate bioequivalence of two valsartan tablets in Chinese volunteers under fasting condition. METHODS: A full automatic 2D-HPLC system was used to quantify valsartan in human plasma. The analytes were extracted by protein precipitation, using telmisartan as internal standard. The analytical method was applied in a randomized, crossover bioequivalence study of valsartan tablets; the study enrolled 18 Chinese volunteers (12 were men and 6 were women). The subjects received a single 160-mg dose of test or reference preparation with 7-days of washout under fasting state. Plasma samples were collected, pharmacokinetic parameters were obtained and the bioequivalence was evaluated. RESULTS: The calibration range was 9.2 - 4213.8 ng×mL-1. Inter- and intraprecision was less than 7.0%, and accuracies ranged from 99.5 to 103.8%. The extraction recovery for valsartan varied between 89.3 and 97.8%, and the stability in all conditions was excellent. The 90% CI of AUC0→36h and Cmax were 96.5 - 109.4% and 94.2 - 108.6%, respectively. The relative bioavailability was 103.9 ± 15.7%. No gender difference was observed in pharmacokinetic parameters. CONCLUSIONS: A sensitive 2D-HPLC method was established for the estimation of valsartan in human plasma and successfully applied in a bioequivalence study of valsartan, which suggests that these two formulations can be assumed to be bioequivalent.
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Pharmacokinetics and relative bioavailability of a generic amisulpride tablet in healthy Chinese volunteers
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OBJECTIVE: To assess and compare the pharmacokinetic properties and bioavailability of a newly developed formulation of amisulpride with those of a conventional formulation in healthy Chinese volunteers under fasting state. MATERIALS AND METHODS: A single-dose, two-sequence crossover study was designed. 20 healthy subjects (14 males and 6 females) were randomized into two groups. A single oral dose of amisulpride (200 mg) was given after an overnight fast of 12 hours. Blood samples were taken at scheduled time spots and separated by a washout period of 14 days. Plasma concentration of amisulpride was measured by high-performance liquid chromatography-fluorescence detector (HPLC-FLD) method. RESULTS: The pharmacokinetic parameters of AUC0-tlast, AUC0-∞, and Cmax for the 20 subjects after a single oral dose of the trial preparation or the reference preparation were 4,767.2 and 4,856.3 ng×h×mL-1; 4,891.7 and 5,043.2 ng×h×mL-1; 584.7 and 586.3 ng×mL-1, respectively. The relative bioavailability was 98.9 ± 14.5%. No significant difference was found among the main pharmacokinetic parameters in the two preparations by ANOVA. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax and AUC0-tlast were 90.7 - 109.1% and 92.5 - 103.6%, respectively, meeting the predetermined criteria (80 - 125%) for bioequivalence. No serious adverse events were reported. CONCLUSION: The study demonstrated that the two preparations met the regulatory criteria for bioequivalence and both formulations were well tolerated.
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Pharmacokinetics and relative bioavailability of two allopurinol tablets in healthy Chinese volunteers
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OBJECTIVE: To evaluate the pharmacokinetics and relative bioavailability of two allopurinol tablets in healthy Chinese volunteers. METHODS: A single-center, randomized, cross-over, two-period study design was conducted in healthy male subjects who were identified as not carrying the HLA-B*58:01 allele. Under fasting conditions, a single oral dose of 300 mg test or reference tablets was given with a 1-week washout period. The blood samples were collected for up to 12 hours after the administration and the plasma concentrations of allopurinol were determined by high performance liquid chromatography. Subject interviews and physical examinations were done over regular intervals to monitor the adverse events. RESULTS: 18 subjects were enrolled in the study, and none dropped out. The main pharmacokinetic parameters of allopurinol test and reference preparations were as follows: AUC0-tlast was 6,725.1 ± 1,390.0 ng×h×mL-1 and 6,425.6 ± 1,257.6 ng×h×mL-1; AUC0-∞ was 7,069.1 ± 1,503.2 ng×h×mL-1 and 6,750.6 ± 1,347.7 ng×h×mL-1; tmax was 1.3 ± 0.8 hours and 1.3 ± 0.8 hours; Cmax was 2,203.7 ± 557.4 ng×mL-1 and 2,310.8 ± 662.8 ng×mL-1; and T1/2 was 2.0 ± 1.6 hours and 1.7 ± 0.7 hours. The relative bioavailability was 105.1 ± 12.6%. The 90% confidence intervals for the geometric mean ratios (test/reference) of Cmax, AUC0-tlast, and AUC0-∞ of both preparations fell within the bioequivalence acceptance criteria (80 - 125%). No adverse events were found or reported during the study. CONCLUSION: The test allopurinol preparations and the reference preparations are bioequivalent and both are well tolerated.
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Bioequivalence and food effect study of enteric-coated mesalazine tablets in healthy Chinese volunteers by HPLC-ESI-MS/MS.

OBJECTIVE: To establish a developed HPLC-ESI-MS/MS method for simultaneous determination of mesalazine (5-ASA) and its major metabolite N-Ac-5-ASA in human plasma and to investigate bioequivalence of two enteric-coated mesalazine tablets as well as the effect of high-fat food on the pharmacokinetics of 5-ASA and N-Ac-5-ASA. METHODS: In this open-label, randomized, crossover, two-states, four-period study, 20 healthy Chinese volunteers were randomized to receive a single oral dose of trial or reference preparation (2 × 250 mg) under fasting and fed state. Plasma samples were obtained at 0, 1, 2, 3, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 10, 12, 24, and 36 hours postdose and were measured by a developed HPLC-ESI-MS/MS method. Safety and tolerability were assessed throughout the study. RESULTS: The HPLC-ESI-MS/MS method required only 7.0 minutes run time and was successfully applied in analyzing ~ 2,000 samples. High-fat-food administration prolonged tmax of 5-ASA and N-Ac-5-ASA (p < 0.05), while AUC was not significantly affected by the meal (p > 0.05). The 90% confidence intervals (CIs) of the fed/fasting and trial/reference ratios of log-transformed Cmax and AUC were within 80-125%. The two one-sided t-tests showed that the trial and reference preparation were bioequivalent (p > 0.05). CONCLUSIONS: This developed HPLC-ESI-MS/MS method is suitable for massive biomedical analysis. Trial and reference preparations are bioequivalent under fasting and fed state. High-fat-food administration delays the absorption of mesalazine while total exposure is not affected. Dietary habits should always be taken into consideration when enteric-coated mesalazine tablets were prescribed to patients.

Pharmacokinetic properties and bioequivalence of spironolactone tablets in fasting and fed healthy Chinese male subjects.

BACKGROUND AND PURPOSE: Spironolactone is a potassium-sparing diuretic and is a competitive antagonist of aldosterone, which is widely used in the treatment of primary aldosteronism, essential hypertension, congestive cardiac failure, and various edematous states. The purpose of this study was to compare the pharmacokinetic properties and bioequivalence of the two formulations of spironolactone tablets in healthy Chinese male subjects under fasting and fed condition. METHODS: A total of 40 male subjects were enrolled in this randomized, open-label, two-period crossover study, subjects in 2 groups (20 individuals in each group) received a single 100-mg dose of test or reference spironolactone tablet formulations with a 2-week washout period under both fasting and fed condition. The plasma concentrations of canrenone, a major active metabolite of spironolactone, were quantified by a validated high performance liquid chromatography-tandem mass spectrometry method. The pharmacokinetic parameters including AUC0-tlast, AUC0-∞, tmax, and Cmax were employed to test bioequivalence. RESULTS: The relative bioavailability was 99.2 ± 11.6% and 97.6 ± 7.4% under fasting and fed condition, respectively. The 90% confidence intervals of the adjusted geometric mean ratio (test/reference) of Cmax, AUC0-tlast, and AUC0-∞ were 89.7-113.8%, 93.9-103.3%, and 90.0-103.0% in fasting study and 87.7-102.3%, 95.1-99.5%, and 94.1-98.9% in fed study, respectively. CONCLUSIONS: Based on pharmacokinetic parameters and the Chinese Food and Drug Administration's guidance and regulatory criteria for bioequivalence, the test and reference formulations of spironolactone were bioequivalent under both fasting and fed condition. Both formulations were generally well tolerated, with no adverse reaction reported.

Pharmacokinetics and penetration into synovial fluid of systemical and electroporation administered sinomenine to rabbits.

Sinomenine is an anti-rheumatoid arthritis (RA) drug derived from the Sinomenium acutum. The major site of RA treatment is within the synovial compartment. However, the pharmacokinetic and penetration into synovial fluid (SF) of sinomenine have not been reported. In our study, the pharmacokinetics and penetration into SF of systemic and electroporation administered sinomenine were investigated by microdialysis incorporated with HPLC-MS/MS. Sinomenine went into plasma and SF more rapidly with higher peak concentration (Cmax ) by intramuscular injection compared with oral administration. The area under the concentration-time graph (AUC0-∞ ) of intramuscularly injected sinomenine was 1,403,294.75 ± 125,534.567 ng min/mL in plasma and 456,116.37 ± 62,648.36 ng min/mL in SF, which were equivalent with those for an oral dose. These results indicated that equal amounts of sinomenine could penetrate into SF by the two administration routes, and the permeation ratios were approximately 1:3. The AUC0-∞ and Cmax were lower with electroporation compared with systemic administration, but the CSF /CPlasma (concentration of sinomenine in SF vs that of plasma) at 90, 120, 150, 180, 240 and 480 min by electroporation was 3- to 10-fold higher relative to systemic administration. This illustrated that sinomenine can be targeted into joints by electroporation, and electroporation is a potential technique for sinomenine's transdermal delivery.

Repeated haloperidol administration has no effect on vitamin D signaling but increase retinoid X receptors and Nur77 expression in rat prefrontal cortex.

Both vitamin D (VD) signaling and Nur77 are implicated in dopaminergic neurotransmission and dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease. Developmental vitamin D (DVD) deficiency rats exhibit schizophrenia-like behaviors and disturbance of dopamine system, which could be partly normalized by haloperidol treatment. By blocking dopamine D2 receptor, haloperidol induces Nur77 expression, suggesting a modulatory role of Nur77 in brain dopamine system. Rxr is the heterodimeric partner of both Nur77 and vitamin D receptor and also participates in homeostatic regulation of central dopamine neurotransmission. Although D2 antagonist-induced Nur77 expression has been reported by several studies, the change of its active partner Rxr remains elusive. Here, we studied the impact of 2 weeks administration of haloperidol on VD signaling and Nur77/Rxr expression in rat prefrontal cortex. It was found that haloperidol has no effect on local VD signaling, but could significantly increase Nur77, Rxrß, and Rxrγ expression, which indicated that Nur77/Rxr, but not vdr/Rxr, was implicated in dopamine-related neuroadaptation. Given that VD deficiency is commonly observed in schizophrenia patients, the renal metabolism of VD was also examined.

Lack of effect of continuous glycyrrhizin administration on the pharmacokinetics of the P-glycoprotein substrate talinolol in healthy volunteers.

PURPOSE: To investigate the effects of repeated glycyrrhizin ingestion on the oral pharmacokinetics of talinolol, a probe drug for P-glycoprotein (P-gp) activity in humans. METHODS: Fourteen healthy adult male subjects were enrolled in a two-phase randomized crossover-design study. In each phase the volunteers received placebo or compound glycyrrhizin tablets (75 mg glycyrrhizin three times daily) for 6 days. On the seventh day, a single oral dose of 100 mg talinolol was administered, and blood samples were obtained to determine plasma talinolol concentrations, measured in plasma by high-performance liquid chromatography with an ultraviolet detector. Non-compartmental analysis was used to characterize talinolol plasma concentration-time profiles. All pharmacokinetics parameters were calculated using DAS ver. 2.1 software, and statistical analyses were performed with SPSS ver. 13.0 software. Analysis of variance was used to check the difference of the means of the pharmacokinetic parameters between the two treatments at a significance level of 0.05. RESULTS: All treatments were well tolerated during the study period. The geometric mean ± standard deviation of the AUC(0-∞) for talinolol treated by glycyrrhizin and talinolol treated by placebo was 2,218.3 ± 724.3 and 1,988.2 ± 649.2 ng·h/mL, respectively. The 90 % confidence intervals for the ratio of adjusted geometric means (glycyrrhizin:placebo) for AUC(0-∞) and C (max) fell wholly within the interval [80, 125]. Six days of glycyrrhizin treatment resulted in no significant alterations in the pharmacokinetic parameters (AUC(0-∞), AUC(0-24), C (max), t (max), t (½)) for talinolol. CONCLUSIONS: Continuous glycyrrhizin administration had no induction effect on the expression of P-gp in our trial. Further research is needed to study the direct inhibition effect of glycyrrhizin on the function of P-gp with the simultaneous administration of both glycyrrhizin and P-gp substrate.

HPLC-DAD method for comprehensive quality control of Semen Strychni.

CONTEXT: Semen Strychni is the seed of Strychnos nux-vomica L. (Loganiaceae). Its quality control procedure remains an issue since previous reports only focused on Strychnos alkaloids. To the best of our knowledge, chlorogenic acid (a phenolic acid) and loganin (an iridoid glycoside) are selected for the first time as marker constituents of quality control for Semen Strychni because of their bioactive activity correlating with therapeutic effects. OBJECTIVE: This study aimed to develop a simple and comprehensive quantity control method for Semen Strychni. MATERIALS AND METHODS: The optimal ultrasonic extraction procedure was carried out for 45 min using 50% aqueous methanol with 1% formic acid. The satisfactory chromatographic separation was achieved on an Ultimate LP-C18 column with gradient elution using acetonitrile and water containing 30 mmol/L ammonium acetate and 1% formic acid. The high performance liquid chromatography method with diode array detector was validated for linearity, limit of detection and quantification (LOQ), precision, repeatability, accuracy and stability. RESULTS: All the calibration curves showed good linearity (r(2) ≥ 0.999). The LOQ values for chlorogenic acid, loganin, strychnine, brucine, strychnine N-oxide and brucine N-oxide were 0.54, 0.83, 0.48, 0.50, 0.52 and 0.54 µg/mL, respectively. The method was reproducible with good accuracy in the range 95.6-104.4% and relative standard deviation (RSD) values less than 4.55%. The method was then applied to determine the components of the seed coat, seed leaf, endosperm and whole seed of Semen Strychni. CONCLUSION: This newly established method is validated as a simple and practical tool for authentication and quality control of Semen Strychni.

Metabolomic analysis of biochemical changes in the plasma and urine of first-episode neuroleptic-naïve schizophrenia patients after treatment with risperidone.

Early findings propose that impaired neurotransmission in the brain plays a key role in the pathophysiology of schizophrenia. Recent advances in understanding its multiple etiologies and pathogenetic mechanisms provide more speculative hypotheses focused on even broader somatic systems. Using a targeted tandem mass spectrometry (MS/MS)-based metabolomic platform, we compared metabolic signatures consisting of monoamine and amino acid neurotransmitter (NT) metabolites in plasma/urine simultaneously between first-episode neuroleptic-naïve schizophrenia patients (FENNS) and healthy controls before and after a 6-week risperidone monotherapy, which suggest that the patient NT profiles are restoring during treatment. To detect and identify potential biomarkers associated with schizophrenia and risperidone treatment, we also performed a combined ultraperformance liquid chromatography-mass spectrometry (UPLC-MS) and 1H nuclear magnetic resonance (NMR)-based metabolomic profiling of the same samples, indicating a further deviation of the patients' global metabolic profile from that of controls. The NTs and their metabolites together with the 32 identified biomarkers underpin that metabolic pathways including NT metabolism, amino acid metabolism, glucose metabolism, lipid metabolism, energy metabolism, antioxidant defense system, bowel microflora and endocrine system are disturbed in FENNS. Among them, pregnanediol, citrate and α-ketoglutarate (α-KG) were significantly associated with symptomatology of schizophrenia after Bonferroni correction and may be useful biomarkers for monitoring therapeutic efficacy. These findings promise to yield valuable insights into the pathophysiology of schizophrenia and may advance the approach to treatment, diagnosis and disease prevention of schizophrenia and related syndromes.

Effects of Astragalus polysaccharides on P-glycoprotein efflux pump function and protein expression in H22 hepatoma cells in vitro.

BACKGROUND: Astragalus polysaccharides (APS) are active constituents of Astragalus membranaceus. They have been widely studied, especially with respect to their immunopotentiating properties, their ability to counteract the side effects of chemotherapeutic drugs, and their anticancer properties. However, the mechanism by which APS inhibit cancer and the issue of whether that mechanism involves the reversal of multidrug resistance (MDR) is not completely clear. The present paper describes an investigation of the effects of APS on P-glycoprotein function and expression in H22 hepatoma cell lines resistant to Adriamycin (H22/ADM). METHODS: H22/ADM cell lines were treated with different concentrations of APS and/or the most common chemotherapy drugs, such as Cyclophosphamid, Adriamycin, 5-Fluorouracil, Cisplatin, Etoposide, and Vincristine. Chemotherapeutic drug sensitivity, P-glycoprotein function and expression, and MDR1 mRNA expression were detected using MTT assay, flow cytometry, Western blotting, and quantitative RT-PCR. RESULTS: When used alone, APS had no anti-tumor activity in H22/ADM cells in vitro. However, it can increase the cytotoxicity of certain chemotherapy drugs, such as Cyclophosphamid, Adriamycin, 5-Fluorouracil, Cisplatin, Etoposide, and Vincristine, in H22/ADM cells. It acts in a dose-dependent manner. Compared to a blank control group, APS increased intracellular Rhodamine-123 retention and decreased P-glycoprotein efflux function in a dose-dependent manner. These factors were assessed 24 h, 48 h, and 72 h after administration. APS down regulated P-glycoprotein and MDR1 mRNA expression in a concentration-dependent manner within a final range of 0.8-500 mg/L and in a time-dependent manner from 24-72 h. CONCLUSION: APS can enhance the chemosensitivity of H22/ADM cells. This may involve the downregulation of MDR1 mRNA expression, inhibition of P-GP efflux pump function, or both, which would decrease the expression of the MDR1 protein.

Abnormal plasma monoamine metabolism in schizophrenia and its correlation with clinical responses to risperidone treatment.

Abnormalities in plasma monoamine metabolism reflect partly the illness of schizophrenia and sometimes the symptoms. Such studies have been repeatedly reported but have rarely taken both metabolites and parent amines or inter-amine activity ratios into account. In this study, the monoamines, their metabolites, turnovers and between-metabolite ratios in plasma were measured longitudinally in 32 schizophrenic patients treated with risperidone for 6 weeks, to examine possible biochemical alterations in schizophrenia, and to examine the association between treatment responses and psychopathology assessed according to the Positive and Negative Syndrome Scale (PANSS). The results showed lower level of plasma 3,4-dihydroxyphenylacetic acid (DOPAC) in relapsed versus first-episode schizophrenic patients, higher norepinephrine (NE) turnover rate (TR) in undifferentiated in comparison to paranoid schizophrenic patients and relatively higher metabolic activity of dopamine (DA) to serotonin (5-HT) in first-episode versus relapsed schizophrenic patients. Risperidone treatment induced a decrement of plasma DA levels and increments of plasma DOPAC and DA TR in the total group of schizophrenic patients. The turnover rate of 5-HT was was reduced in undifferentiated and relapsed subgroups of schizophrenic patients. The linkages between 5-HT TR, DA/NE relative activity and clinical symptomatology were also identified. These findings are consistent with an involvement of these systems in the pathogenesis of schizophrenia as well as in the responses to treatment, and the usefulness of certain biochemical indices as markers for subgrouping.

Determination of dansylated monoamine and amino acid neurotransmitters and their metabolites in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry.

The determination of neurotransmitters (NTs) and their metabolites facilitates better understanding of complex neurobiology in the central nervous system disorders and has expanding uses in many other fields. We present a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS) method for the quantification of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), norepinephrine (NE), vanillymandelic acid (VMA), 3-methoxy-4-hydroxy phenylglycol (MHPG), 5-hydroxytryptamine (5-HT), 5-hydroxyindole-3-acetic acid (5-HIAA), glutamate (Glu), and gamma-aminobutyric acid (GABA). The NTs and their metabolites were dansylated and analyzed by an LC gradient on a C18 column on-line with a tandem mass spectrometer. This method exhibited excellent linearity for all of the analytes with regression coefficients higher than 0.99. The lower limit of quantification (LLOQ) values for DA, DOPAC, HVA, NE, VMA, MHPG, 5-HT, 5-HIAA, Glu, and GABA were 0.57, 0.37, 0.35, 0.40, 0.35, 0.91, 0.27, 0.43, 0.65, and 1.62 pmol/ml, respectively. The precision results were expressed as coefficients of variation (CVs), ranging from 1.5% to 13.6% for intraassay and from 2.9% to 13.7% for the interassay. This novel LC-ESI/MS/MS approach is precise, highly sensitive, specific, and sufficiently simple. It can provide an alternative method for the quantification of the NTs and their metabolites in human plasma.

Effects of Differential Food Patterns on the Pharmacokinetics of Enteric-Coated Mesalazine Tablets in the Same Cohort of Healthy Chinese Volunteers.

This study aimed to simultaneously determine mesalazine (5-ASA) and its major metabolite N-Ac-5-ASA in the plasma and to evaluate the impact of different food patterns on the relative bioavailability and pharmacokinetics of a single oral dose of 5-ASA in healthy subjects. In this single-dose, open-label, 3-period, 3-treatment crossover study, the subjects received a single, oral dose of 500-mg enteric-coated mesalazine tablet together with either a low-fat or a high-fat breakfast or under fasting condition (reference). The pharmacokinetic parameters were determined by noncompartmental methods and analyzed with a linear mixed-effect model. The geometric least squares mean ratio for the area under the plasma concentration-time curve from zero to infinity of N-Ac-5-ASA was 1.05 (90% confidence interval [CI], 0.70-1.58) for high-fat/fasted condition and 1.06 (90%CI, 0.82-1.36) for low-fat/fasted condition. The least squares mean ratio of 5-ASA was 0.86 (90%CI, 0.65-1.14) for high-fat/fasted condition and 0.78 (90%CI, 0.60-1.02) for low-fat/fasted condition. All P values were >.05. The mean maximum plasma concentration and the time to reach the maximum plasma concentration of N-Ac-5-ASA were 2084 ng/mL, 8 hours; 2639 ng/mL, 11 hours, and 2409 ng/mL, 9 hours for fasted, high-fat, and low-fat, respectively. The values of 5-ASA were 1950 ng/mL, 7 hours; 2869 ng/mL, 9 hours; and 2837 ng/mL, 8 hours for fasted, high-fat, and low-fat condition. 5-ASA was well tolerated under all 3 conditions. Food delayed the absorption of 5-ASA, especially a high-fat meal. Therefore, enteric-coated mesalazine tablets should be taken before meals to avoid causing patients slow response and any effect of food on its efficacy.