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Ji-Ming-Shan (JMS) is a traditional prescription use for patients with rheumatism, tendons swelling, athlete's foot, diuresis and even gout. This study developed a rapid and sensitive method for the analysis of JMS chemical components in the Traditional Chinese medicine (TCM) prescription and in the serum samples of rats which were administered with the herbal extract. Two mass spectrometric approaches were used namely Ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-Q-TOF-MS) method for the major metabolites of the JMS extract while Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed for the detection of the JMS metabolites in the sera of rats. It was revealed that the major components in the JMS extract were identified to be narirutin and hesperidin. It was confirmed that 17 compounds were determined in JMS prescription extract and 16 metabolites resulting from the biotransformation of narirutin and hesperidin were identified in the serum samples. In silico analyses also revealed that the metabolite hersperidin-7-glucoside exhibited the best binding ability with respect to the Cyclooxygenase-2 (COX-2) enzyme target. This study showcased the possible biochemical mechanism involved in the therapeutic efficiency of JMS components and their biotransformation products. [ABSTRACT FROM AUTHOR]

An ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed for the simultaneous quantitation of doxorubicin (DOX) and sorafenib (SOR) in rat plasma. Chromatographic separation was performed using a reversed-phase column C 18 (1.7 μm, 1.0 × 100 mm Acquity UPLC BEH™). The gradient mobile phase system consisted of water containing 0.1% acetic acid (mobile phase A) and methanol (mobile phase B) with a flow rate of 0.40 mL/min over 8 min. Erlotinib (ERL) was used as an internal standard (IS). The quantitation of conversion of [M + H]+, which was the protonated precursor ion, to the corresponding product ions was performed using multiple reaction monitoring (MRM) with a mass-to-charge ratio (m / z) of 544 > 397.005 for DOX, 465.05 > 252.03 for SOR, and 394 > 278 for the IS. Different parameters were used to validate the method including accuracy, precision, linearity, and stability. The developed UPLC–MS/MS method was linear over the concentration ranges of 9–2000 ng/mL and 7–2000 ng/mL with LLOQ of 9 and 7 ng/mL for DOX and SOR, respectively. The intra-day and inter-day accuracy, expressed as % relative standard deviation (RSD%), was below 10% for both DOX and SOR in all QC samples that have drug concentrations above the LLOQ. The intra-day and inter-day precision, expressed as percent relative error (Er %), was within the limit of 15.0% for all concentrations above LLOQ. Four groups of Wistar rats (250–280 g) were used to conduct the pharmacokinetic study. Group I received a single intraperitoneal (IP) injection of DOX (5 mg/kg); Group II received a single oral dose of SOR (40 mg/kg), Group III received a combination of both drugs; and Group IV received sterile water for injection IP and 0.9% w/v sodium chloride solution orally to serve as a control. Non-compartmental analysis was used to calculate the different pharmacokinetic parameters. Data revealed that coadministration of DOX and SOR altered some of the pharmacokinetic parameters of both agents and resulted in an increase in the Cmax and AUC and reduction in the apparent clearance (CL/F). In conclusion, our newly developed method is sensitive, specific, and can reliably be used to simultaneously determine DOX and SOR concentrations in rat plasma. Moreover, the results of the pharmacokinetic study suggest that coadministration of DOX and SOR might cause an increase in exposure of both drugs. [ABSTRACT FROM AUTHOR]

Copyright of China Surfactant Detergent & Cosmetics (2097-2806) is the property of China Surfactant Detergent & Cosmetics Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of China Surfactant Detergent & Cosmetics (2097-2806) is the property of China Surfactant Detergent & Cosmetics Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Detergent & Cosmetics is the property of Detergent & Cosmetics Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Food & Machinery is the property of Food & Machinery Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

ObjectiveTo establish a high-performance liquid chromatography-tandem mass spectrometry （UPLC-MS/MS） method for the detection of 6 quinolones residues in milk tofu.MethodsThe milk tofu sample was extracted with 0.1 mmol/L EDTA-Mcllvaine buffer with 0.1 mL each of ferrocyanide and zinc acetate， purified by HLB Pro solid phase extraction column， and separated by Shim-pack FC-ODS （150 mm×20 mm， 3 μm）， gradient eluted by 10 mmol/L ammonium acetate （containing 0.1% formic acid）-methanol acetonitrile （40：60， V/V）， and detected in full scan （full MS） mode.ResultsThe results showed that the 6 quinolones had good linearity in the concentration range of 10-100 ng/mL， the correlation coefficient （R2） was all above 0.995， the limit of detection （LOD） was 0.5-1.5 μg/kg， the limit of quantification （LOQ） was 2-4 μg/kg， the recovery rate of spiked sample was 82.3%-101.6%， and the relative standard deviation was less than 10%.ConclusionThis method is highly sensitive， rapid and accurate， and suitable for rapid screening， quantitative and qualitative analysis of 6 quinolones in milk tofu.

ObjectiveAn ultra-high performance liquid chromatography-tandem mass spectrometric （UPLC-MS/MS） method was developed to quantitatively determine the six kinds of aflatoxins in dairy products by employing a novel graphene based adsorbent.MethodsThe samples were dissolved in water and extracted by acetonitrile. After concentrated with nitrogen， the extracts were re-dissolved in the mixture of acetonitrile and 0.1% formic acid （1∶1）， and purified by graphene adsorbent. The analytes were separated by UPLC， and detected with triple quadrupole mass spectrometer.ResultsThe linear range was 0.05-100 ng/mL with correlation coefficients （r） above 0.998. The recoveries of aflatoxins in spiked dairy product ranged from 91.0% to 118.5% with relative standard deviations of 2.39%-6.00%. The limits of quantitation were in the range of 0.01-0.05 μg/kg.ConclusionThis simple and sensitive method can be used for rapid determination of six kinds of aflatoxins in dairy products.

Abstract Background Pulmonary arterial hypertension is a common complication in patients with congenital heart disease. In the absence of early diagnosis and treatment, pediatric patients with PAH has a poor survival rate. Here, we explore serum biomarkers for distinguishing children with pulmonary arterial hypertension associated with congenital heart disease (PAH-CHD) from CHD. Methods Samples were analyzed by nuclear magnetic resonance spectroscopy-based metabolomics and 22 metabolites were further quantified by ultra-high-performance liquid chromatography–tandem mass spectroscopy. Results Serum levels of betaine, choline, S-Adenosyl methionine (SAM), acetylcholine, xanthosine, guanosine, inosine and guanine were significantly altered between CHD and PAH-CHD. Logistic regression analysis showed that combination of serum SAM, guanine and N-terminal pro-brain natriuretic peptide (NT-proBNP), yielded the predictive accuracy of 157 cases was 92.70% with area under the curve of the receiver operating characteristic curve value of 0.9455. Conclusion We demonstrated that a panel of serum SAM, guanine and NT-proBNP is potential serum biomarkers for screening PAH-CHD from CHD.

Abstract Backgrounds Insertion of Mg2+ into protoporphyrin IX (PPIX) to produce magnesium-protoporphyrin IX (Mg-PPIX) was the first step toward chlorophyll biosynthesis, which not only imparts plants green pigmentation but underpins photosynthesis. Plants that blocked the conversion of PPIX to Mg-PPIX displayed yellowish or albino-lethal phenotypes. However, the lack of systematic study of the detection method and the metabolic difference between species have caused the research on chloroplast retrograde signaling controversial for a long time. Results An advanced and sensitive UPLC-MS/MS strategy for determining PPIX and Mg-PPIX was established in two metabolic different plants, Arabidopsis thaliana (Columbia-0) and Camellia sinensis var. sinensis. Two metabolites could be extracted by 80% acetone (v/v) and 20% 0.1 M NH4OH (v/v) without hexane washing. Since the Mg-PPIX could be substantially de-metalized into PPIX in acidic conditions, analysis was carried out by UPLC-MS/MS with 0.1% ammonia (v/v) and 0.1% ammonium acetonitrile (v/v) as mobile phases using negative ion multiple reaction monitoring modes. Interestingly, it could be easier to monitor these two compounds in dehydrated samples rather than in fresh samples. Validation was performed in spiked samples and mean recoveries ranged from 70.5 to 916%, and the intra-day and inter-day variations were less than 7.5 and 10.9%, respectively. The limit of detection was 0.01 mg·kg− 1 and the limit of quantification was 0.05 mg·kg− 1. The contents of PPIX (1.67 ± 0.12 mg·kg− 1) and Mg-PPIX (3.37 ± 0.10 mg·kg− 1) in tea were significantly higher than in Arabidopsis (PPIX: 0.05 ± 0.02 mg·kg− 1; Mg-PPIX: 0.08 ± 0.01 mg·kg− 1) and they were only detected in the leaf. Conclusions Our study establishes a universal and reliable method for determining PPIX and Mg-PPIX in two plants using UPLC-MS/MS. This procedure will facilitate studying chlorophyll metabolism and natural chlorophyll production.

Objective: To detect eight kinds of insecticides in dairy products （pure milk, fermented milk, milk powder） rapidly. Methods: A high performance liquid chromatography-tandem mass spectrometry （HPLC-MS/MS） method based on dispersive solid phase extraction pre-treatment technology was established. The samples were extracted with acetonitrile-acetone solution （Vacetonitrile∶Vacetone=80∶20） in ultrasonic way, and the extraction solution was purified by Florisil, primary secondary amine and anhydrous MgSO4. After purification, the samples were analyzed by HPLC-MS/MS qualitatively and quantitatively in multi reaction monitoring （MRM） mode. Results: The correlation coefficient （r） of fenamiphos, imidacloprid, spinosad, dinotefuran, emamectin benzoate, methomyl, thiacloprid and oxamyl in the linear range of 2.00~100 μg/L was greater than 0.99, the limits of detection were 0.010~0.30 μg/kg, the recoveries of method were 82.6%~97.5%, and the relative standard deviations （RSDs） were 1.2%~4.6% （n=6）. Conclusion: The method is simple, rapid, sensitive and reproducible. It is suitable for the rapid screening of insecticides in dairy products.

The fruit of Acanthopanax senticosus (Rupr. and Maxim.) has been newly developed for the treatment of blood deficiency syndrome clinically, but the effective constituents are still unclear, restricting its quality control and the new medicinal development based on it. This study elucidated the efficacy of A. senticosus fruit (ASF) for treating blood deficiency syndrome and accurately characterize the constituents. Chinmedomics strategy was used to identify the metabolic biomarkers of the model and the overall effect of ASF was evaluated based on the biomarker when it showed intervention effects for blood deficiency syndrome. ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the components in the blood absorbed from A. senticosus fruit, and the components highly relevant to the biomarker are regarded as potential effective constituents for blood deficiency syndrome. Twenty-two of the 28 urine metabolites of blood deficiency syndrome were significantly regulated by A. senticosus fruit, 97 compounds included 20 prototype components, and 77 metabolites were found in vivo under the acting condition. The highly relevant constituents were isofraxidin, eleutheroside B, eleutheroside B1, eleutheroside E, and caffeic acid, which might be the effective constituents of A. senticosus fruit. It is a promising new medicinal resource that can be used for treating blood deficiency syndrome.

Abstract Newborn screening (NBS) for isovaleric acidemia (IVA) is performed by flow injection tandem mass spectrometry quantifying C5 carnitines (C5). Isovalerylcarnitine, however, is isomeric with pivaloylcarnitine which can be present in blood due to maternal use of pivaloylester‐containing antibiotics, available in Germany since late 2016. During a 36‐month period (January 19–December 21), all newborns screened in Hamburg with a C5 above cutoff (NeoGram®: 0.50 μmol/L or Neobase®2: 0.45 μmol/L) were included in the study. As a second‐tier test, a simple ultra performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) method was developed to differentiate the C5 isomers pivaloyl‐, 2‐methylbutyryl‐, isovaleryl‐, and valerylcarnitine. Out of 156 772 newborns tested, one turned out to have genetically proven IVA while 99 were false positive (C5: 0.5–8.2 μmol/L) due to the presence of pivaloylcarnitine. These cases have increased year by year and show local clusters. Retrospective analysis of another 39 cases from 287 206 neonates tested at the NBS center in Heidelberg with C5 elevation (0.9–10.6 μmol/L) but clinical and biochemical exclusion of IVA yielded evidence of pivaloylcarnitine in all cases. Inclusion of a second‐tier test into NBS significantly reduces the high and increasing false‐positive rate of IVA screening. This avoids further diagnostic steps, prevents unnecessary stress and anxiety of parents in a remarkably high number of cases. If Hamburg data of 2021 are extrapolated to all of Germany, one can assume around 800 (1‰) false‐positive cases in comparison to an average of two classic IVA cases per year. Unless licensing of pivaloylester‐containing drugs for use during pregnancy is reconsidered, a second‐tier test for C5 determination is indispensable.

Occurrence of multi-class antibiotics in edible fish species from the Saudi market was investigated. A fast and sensitive UPLC-MS/MS method for simultaneous determination of selected fluoroquinolones, sulfonamides and macrolides in fish muscle was developed and validated. Sample clean up was performed using solid-phase extraction on Oasis HLB cartridges. The greenness profile of the developed method was evaluated using three assessment tools: analytical Eco-scale assessment method, green analytical procedure index and analytical greenness metric. Detection limits ranged from 0.008 to 0.35 μg/kg. The recovery ranged from 80.1 % to 98.6 % with RSDs ≤ 12.1 %. The mean and maximum concentrations of the detected antibiotics in fish samples ranged between 0.28 and 19.15 and 3.50–112.00 µg/kg, respectively. Human antibiotics (clarithromycin and roxithromycin) were detected in 50 % and 27.5 % of the samples, respectively. The estimated daily intake for the detected antibiotics ranged from 0.10 to 6.61 ng/kg/ BW/day for Saudi adults. The health risk associated with fish consumption was evaluated. The results suggested that fish consumption may not pose a serious risk to consumers in Saudi Arabia. The developed method was fast, sensitive, cost-effective and environmentally friendly.

Context Aidi injection (ADI), a traditional Chinese medicine antitumor injection, is usually combined with doxorubicin (DOX) for the treatment of malignant tumours. The cardiotoxicity of DOX is ameliorated by ADI in the clinic. However, the relevant mechanism is unknown.Objective To investigate the effects of ADI on DOX-induced cardiotoxicity and its mechanism.Materials and methods ICR mice were randomly divided into six groups: control, ADI-L, ADI-H, DOX, DOX + ADI-L and DOX + ADI-H. DOX (i.p., 0.03 mg/10 g) was administered in the presence or absence of ADI (i.p., 0.1 or 0.2 mL/10 g) for two weeks. Heart pathology and levels of AST, LDH, CK, CK-MB and BNP were assessed. H9c2 cells were treated with DOX in the presence or absence of ADI (1, 4, 10%). Cell viability, caspase-3 activity, nuclear morphology, and CBR1 expression were then evaluated. DOX and doxorubicinol (DOXol) concentrations in heart, liver, kidneys, serum, and cells were analysed by UPLC-MS/MS.Results High-dose ADI significantly reduced DOX-induced pathological changes and the levels of AST, LDH, CK, CK-MB and BNP to normal. Combined treatment with ADI (1, 4, 10%) improved the cell viability, and IC50 increased from 68.51 μM (DOX alone) to 83.47, 176.9, and 310.8 μM, reduced caspase-3 activity by 39.17, 43.96, and 61.82%, respectively. High-dose ADI inhibited the expression of CBR1 protein by 32.3%, reduced DOXol levels in heart, serum and H9c2 cells by 59.8, 72.5 and 48.99%, respectively.Discussion and Conclusions ADI reduces DOX-induced cardiotoxicity by inhibiting CBR1 expression, which provides a scientific basis for the rational use of ADI.

建立超高效液相色谱-串联质谱法（UPLC-MS/MS）测定植物油中4种杂环胺(MeIQx、4，8-DiMeIQx、7,8-DiMeIQx、PhIP)的分析方法。样品经含1%氨水乙腈提取、乙腈饱和的正己烷脱脂后，利用PCX固相萃取柱进行净化。净化后的样品采用乙腈和10 mmol/L甲酸铵溶液作为流动相进行梯度洗脱，在正离子模式下以电喷雾电离串联质谱对杂环胺的定量离子和定性离子进行监测，并利用内标法进行定量。结果表明：4种杂环胺在0.5~100.0 ng/mL范围内线性关系良好，相关系数均大于0.99，方法检出限为0.01~0.04 μg/kg，定量限为0.03~0.13 μg/kg；在1.0、5.0、10.0 μg/kg的加标水平下，杂环胺的平均回收率在64.5%~96.5%之间，相对标准偏差在2.83%~8.52%之间。本方法快速、准确、灵敏，可应用于植物油中4种杂环胺的同时检测。 A method for determination of four heterocyclic aromatic amines(MeIQx, PhIP, 4,8-DiMeIQx and 7,8-DiMeIQx) in vegetables oils by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was established. The samples were extracted by acetonitrile containing 1% ammonium hydroxide, defatted by n-hexane saturated by acetonitrile, followed by the purification with PCX solid phase extraction column. Then the heterocyclic aromatic amines in the extracts were separated by a gradient elution of acetonitrile and 10 mmol/L ammonium formate aqueous solution, then quantitative and qualitative ion of heterocyclic aromatic amines were monitored by electrospray ionization tandem mass spectrometry in positive ion mode, and quantified by internal standard method. The results showed that all of the analytes showed good linearity in the range of 05-1000 ng/mL and the correlation coefficients (r2) were all above 0.99. The limits of detection for heterocyclic aromatic amines were 0.01-0.04 μg/kg, and the limits of quantification were 0.03-0.13 μg/kg. The average recoveries of heterocyclic aromatic amines at spiked levels of 1.0, 5.0, 10.0 μg/kg ranged from 64.5% to 96.5%, with the relative standard deviations of 2.83%-8.52%. The method is rapid, accurate and sensitive, and is suitable for the determination of four heterocyclic aromatic amines in vegetable oils.

In order to further grasp the contamination level of Alternaria toxins in red date, this study took commercially available red date and its products as the research objects, explored the extraction method of mycotoxins with QuChERS as the core and established ultra-high performance liquid chromatography-tandem mass spectrometry analysis technology for five kinds of Alternaria toxins in red dates, and analyzed the pollution level of Alternaria toxin in red jujube and its products. Results showed that the recovery of Alternaria toxins in solid samples by QuChERS method ranged from 74.89% to 98.04%, and in liquid samples by solid-phase extraction method ranged from 68.35% to 99.63% with the relative standard deviations less than 10%. After the determination of five Alternaria toxins in Jun-date from Aksu, Kashi and Hotan regions, two toxins, TeA and AOH, were detected. Among them, the TeA in Jun-date in Kashgar was the highest, reaching 5.12~10.76 μg/kg. Three Alternaria toxins, TeA, AOH and ALT, were detected in 11 kinds of products of red date, among which TeA in red date wine reached 127.08 μg/kg and AOH was detected only in amethyst date, with content ranging from 34.76 to 98.61 μg/kg. ALT was detected in freeze-dried red dates slices, fried red dates and amethyst date, with content ranging from 2.04 to 399.64 μg/kg. In this paper, a UPLC-MS/MS method was developed to meet the requirements for the determination of Alternaria toxins in date samples with different forms, it would provide a theoretical basis for the edible safety of red dates.

Background: Abnormally changed steroid hormones during pregnancy are closely related to the pathological process of gestational diabetes mellitus (GDM). Our aim was to systematically profile the metabolic alteration of circulating steroid hormones in GDM women and screen for risk factors. Methods: This study was a case-control study with data measured from 40 GDM women and 70 healthy pregnant women during their 24-28 gestational weeks. 36 kinds of steroid hormones, including 3 kinds of corticosteroids, 2 kinds of progestins, 5 kinds of androgens and 26 kinds of downstream estrogens in serum were systematically measured using a combined sensitive UPLC-MS/MS method. The flux of different metabolic pathways of steroid hormones was analyzed. Logistic regression and ROC curve model analyses were performed to identify potential steroid markers closely associated with GDM development. Results: Serum corticosteroids, progestins and almost all the estrogen metabolites via 16-pathway from parent estrogens were higher in GDM women compared with healthy controls. Most of the estrogen metabolites via 4-pathway and more than half of the metabolites via 2-pathway were not significantly different. 16a-hydroxyestrone (16OHE1), estrone-glucuronide/sulfate (E1-G/S) and the ratio of total 2-pathway estrogens to total estrogens were screened as three indicators closely related to the risk of GDM development. The adjusted odds ratios of GDM for the highest quartile compared with the lowest were 72.22 (95% CI 11.27-462.71, Ptrend <0.001) for 16OHE1 and 6.28 (95% CI 1.74-22.71, Ptrend <0.05) for E1-G/S. The ratio of 2-pathway estrogens to total estrogens was negatively associated with the risk of GDM. Conclusion: The whole metabolic flux from cholesterol to downstream steroid hormones increased in GDM condition. The most significant changes were observed in the 16-pathway metabolism of estrogens, rather than the 2- or 4-pathway or other types of steroid hormones. 16OHE1 may be a strong marker associated with the risk for GDM. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is now used in eye drops for the management of conjunctival malignant melanoma, intraepithelial neoplasia, and corneal and conjunctival squamous cell carcinoma. The previously used methods for 5-FU quantification in AqH were time-consuming and less sensitive. Herein, a highly perceptive bioanalytical UPLC–MS/MS method was developed for the quantitative determination of 5-FU in the aqueous humor (AqH) of rabbits using allopurinol as the internal standard (IS). The 5-FU and IS were well separated in an Acquity™ HILIC column. Acetonitrile and 10 mM of ammonium acetate at 95:5 (v/v) were isocratically pumped at a 0.3 mL/min flow rate with a total runtime of 2.5 min. AqH samples were processed with a liquid–liquid extraction method in ethyl acetate. The 5-FU and IS were identified in the negative mode with electrospray ionization. The parent to daughter ion transitions for the 5-FU and IS occurred at m/z 128.92→41.68 and 134.80→64.10, respectively, as quantified using the multiple reaction monitoring mode. The developed method was validated with the ICH-Harmonized Guideline for Bioanalytical Method Validation, and the parameters were within acceptable limits. The calibration curve was linear at the 10.5–2000 ng/mL concentration range, with a correlation coefficient (R2) of 0.9946, and the lower limit of detection was 3.55 ng/mL. The developed and validated method was rapid, sensitive, accurate and robustly able to quantify 5-FU in rabbit AqH. The method was effectively applied to establish the ocular pharmacokinetics of 5-FU following the topical instillation of 5-FU-containing preparations in rabbits. [ABSTRACT FROM AUTHOR]

In hepatocellular carcinoma treatment, sorafenib, oxaliplatin, 5-fluorouracil, capecitabine, lenvatinib, and donafenib are first-line drugs; regorafenib, apatinib, and cabozantinib are second-line drugs; and oxycodone, morphine, and fentanyl are commonly used analgesics. However, the high degree of interand intra-individual variability in the efficacy and toxicity of these drugs remains an urgent issue. Therapeutic drug monitoring (TDM) is the most reliable technical means for evaluating drug safety and efficacy. Therefore, we developed an ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for simultaneous TDM of three chemotherapy drugs (5-fluorouracil, oxaliplatin, and capecitabin), six targeted drugs (sorafenib, donafenib, apatinib, cabozantinib, regorafenib, and lenvatinib), and three analgesics (morphine, fentanyl, and oxycodone). We extracted 12 analytes and isotope internal standards (ISs) from plasma samples by magnetic solid phase extraction (mSPE) and separated them using a ZORBAX Eclipse Plus C18 column with water containing 0.1% formic acid and methanol containing 0.1% formic acid as the mobile phase. The analytical performance of our method in terms of sensitivity, linearity, specificity, carryover, precision, limit of quantification, matrix effect, accuracy, dilution integrity, extraction recovery, stability, and crosstalk of all the analytes under different conditions met all the criteria stipulated by the guidelines of the Chinese Pharmacopoeia and U.S. Food and Drug Administration. The response function was estimated at 10.0-10 000.0 ng/mL for sorafenib, donafenib, apatinib, cabozantinib, regorafenib, and lenvatinib, and 20.0-20 000.0 ng/mL for 5-fluorouracil, oxaliplatin, capecitabin, morphine, fentanyl, and oxycodone, with a correlation of > 0.9956 for all compounds. The precision and accuracy of all analytes were < 7.21% and 5.62%, respectively. Our study provides empirical support for a simple, reliable, specific, and suitable technique for clinical TDM and pharmacokinetics. [ABSTRACT FROM AUTHOR]

Modafinil has a strong and long-lasting awakening effect. Short-term use can improve cognitive and work efficiency. Therefore, it has been known to be abused by students and parents as a "smart drug." It is in the first category of psychotropic drugs and strictly controlled. To detect modafinil in rat plasma and study the differences in the pharmacokinetics of modafinil between oral and sublingual administration in rats, an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed. Rats were injected with modafinil by oral gavage and sublingual vein, respectively, blood was collected within a certain period, and the plasma was obtained by centrifugation. Midazolam was used as the internal standard, and the concentration of modafinil in the plasma was determined by UPLC-MS/MS, where a drug-time curve was created to calculate the pharmacokinetic parameters. The standard curve for modafinil ranged from 1 to 2000 ng mL−1 with good linearity. The intra-day accuracy of modafinil was between 86% and 104%, and the intra-day accuracy was between 90% and 103%. Intra-day precision (RSD%) was less than 15%, inter-day precision (RSD%) was less than 15%. The matrix effect was between 93% and 102%, and the recovery was greater than 91%. The UPLC-MS/MS method established in this work has good selectivity and high sensitivity, and the UPLC-MS/MS method was successfully applied to the pharmacokinetics of modafinil by oral gavage and sublingual injection in rats. The bioavailability of modafinil was calculated to be 55.8%. [ABSTRACT FROM AUTHOR]

A UPLC-MS/MS method was developed to determinate curdione in the mouse blood, and the pharmacokinetics of curdione in mice after intravenous (5 mg kg−1) and oral (20 mg kg−1) administration were studied. The HSS T3 column was used for separation, and column temperature was set at 40 °C. Multiple reaction monitoring (MRM) mode were used for determination of curdione. Blood samples were taken from the caudal vein of Institute of Cancer Research (ICR) mice after administration of curdione. It showed a good linear relationship in the range of 1–500 ng mL−1 (r > 0.998); the intra-day precision was <13%, the inter-day precision was <15%, and the accuracy was 90%–105%, the recovery was >77%, and the matrix effect was 97%–107%. The half-life was relatively short, and the bioavailability was 6.5%. The developed method was suitable for the pharmacokinetics of curdione in mice. [ABSTRACT FROM AUTHOR]

Simple Summary: This study aimed to evaluate the rate and amount of cyclosporine A in cats following oral administration using intravenous administration as a reference. Twenty-four healthy cats were selected and randomly divided into four groups in this study. All animals were adapted in a convenient environment during the whole experiment and no adverse effect was observed. Each animal was given a respective dose only once. Blood samples were collected at scheduled time points and analyzed by the established method. The pharmacokinetic parameters were calculated by professional software used in the whole pharma industry of drug development. As a result, the amount of cyclosporine A absorbed in vivo is from one-fifth to one-third, demonstrating that the medium dose has great potential to get into the body. Due to its common side effects always being associated with the amount of cyclosporine in the blood, it is necessary to monitor the concentration of cyclosporine clinically. Practically, doctors draw blood before or 2 h after taking medicine. In this study, we concluded that taking a blood sample after 4 h has more power to estimate the extent of absorption and will be better at preventing the occurrence of side effects in clinical use. This study aimed to evaluate the absolute bioavailability of cyclosporine in cats by investigating the pharmacokinetic profile after intravenous and oral administration, respectively. Twenty-four clinically healthy cats were enrolled in this study and randomly divided into four groups, namely the intravenous group (3 mg/kg), low oral group (3.5 mg/kg), medium oral group (7 mg/kg), and high oral group (14 mg/kg). Whole blood was obtained at the scheduled time points after a single dose administration and cyclosporine was determined using ultra-performance liquid chromatography–tandem mass spectrometry technology (UPLC-MS/MS). Pharmacokinetic parameters were calculated using the WinNonlin 8.3.4 software via compartmental and non-compartmental models. As a result, the bioavailability values for the low, medium, and high oral groups were 14.64%, 36.98%, and 13.53%, respectively. The nonlinear pharmacokinetic profile was observed in the range from 3.5 mg/kg to 14 mg/kg in cats following oral administration. Whole blood concentrations taken 4 h after oral administration were better correlated with the area under the blood concentration–time curve AUC0–24 with a high regression coefficient (R2 = 0.896). This concentration would be a greater predictor in the following therapeutic drug monitoring. No adverse effect was observed in the whole study process. [ABSTRACT FROM AUTHOR]

As the validated agent for the treatment of chronic myelogenous leukemia (CML), flumatinib is a novel oral tyrosine kinase inhibitor (TKI) with higher potency and selectivity for BCR-ABL1 kinase compared to imatinib. Many patients experience aspergillosis infection and they may start using isavuconazole, which is an inhibitor of CYP3A4. However, there is no study on their interaction in vitro and in vivo. In the present study, the concentrations of flumatinib and its major metabolite M1 were rapidly determined using an stable ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method. The halfmaximal inhibitory concentration (IC50) was 6.66 μM in human liver microsomes (HLM), while 0.62 μM in rat liver microsomes (RLM) and 2.90 μM in recombinant human CYP3A4 (rCYP3A4). Furthermore, the mechanisms of inhibition of flumatinib in human liver microsomes, rat liver microsomes and rCYP3A4 by isavuconazole were mixed. Moreover, ketoconazole, posaconazole, and isavuconazole showed more potent inhibitory effects than itraconazole, fluconazole, and voriconazole on HLM-mediated flumatinib metabolism. In pharmacokinetic experiments of rats, it was observed that isavuconazole could greatly change the pharmacokinetic parameters of flumatinib, including AUC(0-t), AUC(0-∞), Cmax and CLz/F, but had no effect on the metabolism of M1. According to the results of in vitro and in vivo studies, the metabolism of flumatinib was inhibited by isavuconazole, suggesting that isavuconazole may raise the plasma concentration of flumatinib. Thus, it is important to take special care of the interactions between flumatinib and isavuconazole in clinical applications. [ABSTRACT FROM AUTHOR]

A sensitive and rapid ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was hereby developed for the determination of seven components, namely, glycyrrhizic acid, glycyrrhetinic acid, dehydrotumulosic acid, isoliquiritin, liquiritin, atractylenolide III, and cinnamic acid, in the plasma of rats after the oral administration of Ling-Gui-Zhu-Gan decoction (LGZGD). Besides, this very method was methodologically validated for specificity, linearity, inter-day and intra-day precision, accuracy, matrix effect, extraction recovery, and stability. It was also successfully used for the first time to compare the pharmacokinetic characteristics of the seven components after oral administration of LGZGD to normal rats and non-alcoholic fatty liver disease (NAFLD) rats. The results indicated significant differences between the pharmacokinetic characteristics of normal and NAFLD rats. To further reveal the different pharmacokinetic behaviors, the expressions of enzymes and transporters in the liver of normal and NAFLD rats were detected using UPLC-MS/MS. In the NAFLD rats, UDP-glucuronosyltransferase 1-1 (UGT1A1) and nine transporters were significantly inhibited and a positive correlation was observed between them and the AUC of the major components. The present results indicate that the pharmacokinetic differences between the normal and NAFLD rats might be attributed to the significant lower expression levels of both the metabolic enzyme UGT1A1 and nine transporter proteins in the NAFLD rats than in the normal rats. Meanwhile, UGT1A1 and the nine transporter proteins might be used as potential biomarkers to assess the ameliorative effect of LGZGD on NAFLD, which could provide useful information to guide the clinical application of LGZGD. [ABSTRACT FROM AUTHOR]

Introduction: Thai herbal Benjakul formula (BKF) is a Thai traditional medicine for balancing and nourishing body elements in unhealthy persons. It is composed of five pungent plants, namely fruits of Piper retrofractum Vahl., roots of Piper sarmentosum Roxb., stems of Piper wallichii (Miq.) Hand.-Mazz., roots of Plumbago indica L., and rhizome of Zingiber officinale Roscoe. There was no efficient method for quantification of the bioactive constituents in BKF using UPLC-TQD/MS. Objective: The objective of the study was to establish a method for quantification of some constituents of BKF, namely pellitorine (PE), piperine (PI), piperlonguminine (PLM), plumbagin (PG), 6-gingerol (GI), and 6-shogaol (SG) using ultra-performance liquid chromatography coupled with a triple quadrupole mass spectrometer (UPLC-TQD/MS) and determine six bioactive constituents amount in Ayurved Siriraj® (AVS) and five brands of BKF randomly selected from the market. Materials and Methods: Six bioactive constituents were determined using UPLCTQD/MS. The chromatographic separation was performed on a Waters ACQUITY UPLC® HSS T3 column using gradient elution with water and methanol. The method was fully validated in terms of the limit of detection, the lower limit of quantification precision, and recovery. Results: The method was a good linearity (R2 > 0.995) in the range of 1-75 ng/mL for all six bioactive constituents. The precision, accuracy, and recovery are in an acceptable range. The maximum concentrations of PE, PI, PLM, PG, GI, and SG in all samples were 0.342 ± 0.009%, 1.396 ± 0.020%, 0.080 ± 0.001%, 0.055 ± 0.003%, 0.165 ± 0.003%, and 0.175 ± 0.003%, w/w, respectively. Conclusion: This is the first study for quantification of the six standards in BKF using UPLC-TQD/MS. This method is useful in the quality control of BKF and can be used routinely in the manufacturing unit. [ABSTRACT FROM AUTHOR]

Fenebrutinib (GDC-0853; FNB) is an oral small molecule that was developed by Roche Pharmaceuticals to slow multiple sclerosis progression. FNB is a reversible bruton tyrosine kinase (BTK) inhibitor, which showed the maximum potency of BTK inhibitors in phase III clinical trials for multiple sclerosis. In the current study, a fast, specific, and sensitive UPLC-MS/MS method for FNB quantification in human liver microsomes (HLMs) was established with application to the evaluation of metabolic stability. The UPLC-MS/MS methodology was verified using the stated USFDA validation guidelines for bioanalytical methodologies that involve selectivity, linearity, accuracy and precision, carryover and extraction recovery, stability, and matrix effect. The FNB calibration curve displayed a linearity in the range from 1 ng/mL to 3000 ng/mL (y = 1.731x + 2.013; R2: 0.9954; RSD < 4.37%) in the HLMs matrix. The limit of quantification was 0.88 ng/mL, which verified the UPLC-MS/MS analytical method sensitivity. The intraday and interday precision and accuracy results of the developed UPLC-MS/MS method were −3.99–14.0% and 0.52–3.83%, respectively. FNB and savolitinib (SVB) (internal standard) were chromatographically separated utilizing an isocratic mobile phase system with a ZORBAX Eclipse plus-C18 (50 mm, 2.1 mm, and 1.8 μm) column. The metabolic stability parameters for FNB, involving high intrinsic clearance (58.21 mL/min/kg) and a short in vitro half-life (13.93 min), revealed the high extraction ratio of FNB. Reviewing the literature revealed that the current UPLC-MS/MS method is the first analytical method for FNB quantification in the HLMs matrix with application to the assessment of FNB metabolic stability. [ABSTRACT FROM AUTHOR]

TMAO is a new risk biomarker for cardiovascular disease. With trimethylammonium as its main chemical skeleton, TMAO is structurally similar to many endogenous metabolites, such as acetylcholine, carnitine, phosphorylcholine, etc. The mechanism of TMAO on the pathological process of CVD is still unclear. In this study, the quantitative analysis of plasma TMAO is conducted, and the contribution of Cathepsin B and NLRP3 inflammasome during the process of TMAO-induced endothelial injury was proposed and investigated at animal and cellular levels. Immunofluorescence assay was applied to represent the protein expression of Cathepsin B and NLRP3 inflammasome located at endothelial cells. The results showed that TMAO could disrupt endothelial cells permeability to induce endothelial injury, meanwhile, TMAO could increase NLRP3 inflammasome activation and promote the activity and expression of Cathepsin B in vitro and in vivo, whereas inhibition of NLRP3 inflammasome activation by MCC950 could protect the endothelial cells from TMAO associated endothelial injury via Cathepsin B. The study reveals that TMAO can cause endothelial injury via Cathepsin B-dependent NLRP3 inflammasome, and inhibition of Cathepsin B and NLRP3 inflammasome can reduce the TMAO-induced damage. The results provide new insight into the role of TMAO in CVD, which can be a potential therapeutic target for disease treatment and drug design. [ABSTRACT FROM AUTHOR]

As a non-traditional sample matrix, feather samples can be used to effectively monitor antibiotic addition and organismal residue levels in poultry feeding. Therefore, an ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method was developed to simultaneously determine the residue levels of 26 quinolones in poultry feathers. The feather samples were extracted by sonication with a 1% formic acid and acetonitrile mixture in a water bath at 50 °C for 30 min, purified by the adsorption of multiple matrix impurities, dried with nitrogen, redissolved, and analyzed by UPLC-MS/MS. The linearity, limit of detection (LOD), limit of quantification (LOQ), recovery and precision were calculated. The 26 antibiotics demonstrated good linearity in the linear range. The recoveries and coefficients of variation were 78.9–110% and <13.7% at standard spiked levels of 10, 100 and 200 μg/kg, respectively. The LOD and LOQ were 0.12–1.31 and 0.96–2.60 μg/kg, respectively. The method also successfully identified quinolone residues in 50 poultry feather samples. The results showed that quinolones can accumulate and stabilize for a certain period of time after transferring from the body to the feathers of poultry. [ABSTRACT FROM AUTHOR]

A new, simple and sensitive method for determining and confirming methylene blue and its analogues such as azure A, azure B, azure C, thionine, and new methylene blue in fish muscles have been developed. The method is based on acetonitrile extraction followed by extract purification using dispersive solid-phase extraction (dSPE) with basic aluminium oxide (ALN) and solid-phase extraction (SPE) using primary and secondary amines (PSA) sorbent in matrix adsorption mode. The separation and detection of the dyes in the fish extract are achieved within 5 min by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) using an octadecyl analytical column with a mixture of acetonitrile, methanol and 0.1% formic acid as a mobile phase in gradient elution. The developed method has been in-house validated according to European law. The method recovery for fish muscle was 98.3–103.1%, whereas the decision limit (CCα) was from 0.45 to 0.49 µg kg−1. [ABSTRACT FROM AUTHOR]

Antibiotics are among the most common medicine groups since they are used to treat infectious diseases, as nutritional supplements in livestock breeding, and for preservation in the food industry. Turkey is among the highest antibiotic consumers in the world. In the present study, the most popular 14 antibiotics available in Turkey were monitored in one hospital sewage and two urban wastewater treatment plant influents and effluents seasonally in Istanbul province, the largest metropolitan center in Turkey. The present research aimed to develop a robust analytical method to determine 14 antibiotics, including six chemical groups, in environmental matrices which are considered significant antibiotic pollution sources, namely hospital sewage and urban wastewater. Solid-phase extraction (SPE) and UPLC-MS/MS analysis parameters included optimized column temperature, eluent, mobile phase, and flow rate. Three SPE cartridges were employed in recovery studies. The antibiotic recovery rates varied between 40 and 100%, and all analytes were identified within 3 min with UPLC-MS/MS under optimal conditions. It was determined that method detection limits (MDLs) varied between 0.07 and 2.72 µg/L for the antibiotics. In all seasons, the highest beta-lactam group antibiotic concentrations were identified in hospital sewage. The season with the greatest variety of antibiotics in urban wastewater was spring. Clarithromycin and ciprofloxacin were the antibiotics determined at the highest concentration in the influent and effluent of the wastewater treatment plant in all seasons. This study showed that the most widely used beta-lactam group antibiotics were found in high amounts in hospital sewage wastewater but in low concentrations in the treatment plants, and hence, it is seen that the degradability of beta-lactam group antibiotics was high. The presence of clarithromycin, ciprofloxacin, lincomycin, levofloxacin, and trimethoprim antibiotics in hospital sewage in higher amounts and also in inlet and outlet of wastewater treatment plants proves that those are resistant antibiotics. [ABSTRACT FROM AUTHOR]

The presence of Bisphenol A (BPA), Bisphenol A Diglycidyl Ether (BADGE), and their derivatives in seventy-nine samples of food products available in Turkish stores was determined using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Among Bisphenol A and its analogues, BPA was the most detected migrant with 56.97%. Fish products had the highest level of BPA with 0.102 mg/kg although only three fish samples exceeded the Specific Migration Limit (SML) for BPA of 0.05 mg/kg of food. The BPF, BPS, and BPB in all analyzed foods ranged between 0–0.021, 0–0.036, and 0.072 mg/kg, respectively. BADGE derivates, BADGE·2H2O and cyclo-di-BADGE (CdB) were present in 57 and 52 samples with concentrations ranging between 0–0.354, and 0–1.056 mg/kg, respectively. All the analyzed traditional Turkish ready-to-eat meals and fish products were contaminated with BADGE·2H2O and CdB. The overall levels of BADGE and the derivates were below the specific migration limit. CdB was found at higher concentrations in traditional Turkish ready-to-eat meals, up to 1.056 mg/kg. The CdB concentration in most of the samples was above the highest figure with 0.05 mg/kg authorized by the German Federal Institute for Risk Assessment. The predominant chlorinated derivative was BADGE·H2O·HCl which was found in thirty-seven samples in the range of 0.007–0.061 mg/kg. [ABSTRACT FROM AUTHOR]

Malignant melanoma is an aggressive type of skin cancer characterised by high metastatic capacity and mortality rate. On the other hand, Epilobium parviflorum is known for its medicinal properties, including its anticancer potency. In this context, we aimed to (i) isolate various extracts of E. parviflorum, (ii) characterize their phytochemical content, and (iii) determine their cytotoxic potential in an in vitro model of human malignant melanoma. To these ends, we utilized various spectrophotometric and chromatographic (UPLC-MS/MS) approaches to document the higher content of the methanolic extract in polyphenols, soluble sugars, proteins, condensed tannins, and chlorophylls -a and -b as opposed to those of dichloromethane and petroleum. In addition, the cytotoxicity profiling of all extracts was assessed through a colorimetric-based Alamar Blue assay in human malignant melanoma (A375 and COLO-679) as well as non-tumorigenic immortalized keratinocyte (HaCaT) cells. Overall, the methanolic extract was shown to exert significant cytotoxicity, in a time- and concentration-dependent manner, as opposed to the other extracts. The observed cytotoxicity was confined only to human malignant melanoma cells, whereas non-tumorigenic keratinocyte cells remained relatively unaffected. Finally, the expression levels of various apoptotic genes were assessed by qRT-PCR, indicating the activation of both intrinsic and extrinsic apoptotic cascades. [ABSTRACT FROM AUTHOR]

Capmatinib (CMB) is an orally bioavailable mesenchymal–epithelial transition (MET) inhibitor approved by the US-FDA to treat metastatic non-small cell lung cancer (NSCLC) patients, with MET exon 14 skipping mutation. The current study aimed to establish a specific, rapid, and sensitive ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) analytical method for quantifying CMB in human liver microsomes (HLMs), with therapeutic implications for assessing metabolic stability. Validation of the UPLC-MS/MS analytical method in the HLMs was performed using selectivity, sensitivity, linearity, accuracy, precision, extraction recovery, stability, and matrix effects according to the guidelines for bio-analytical method validation of the US-FDA. CMB was ionized by positive electrospray ionization (ESI) as the ionization source and analysed using multiple reaction monitoring (MRM) as the mass analyser mode. CMB and pemigatinib (PMT) were resolved on the C18 column, with an isocratic mobile phase. The CMB calibration curve showed linearity in the concentration range of 1–3000 ng/mL. The intra- and inter-day accuracy and precision were −7.67–4.48% and 0.46–6.99%, respectively. The lower limit of quantification (LLOQ) of 0.94 ng/mL confirmed the sensitivity of the UPLC-MS/MS analytical method. The intrinsic clearance (Clint) and in vitro half-life (t1/2) of CMB were 61.85 mL/min/kg and 13.11 min, respectively. CMB showed a high extraction ratio. The present study is the first to develop, establish, and standardize UPLC-MS/MS for the purpose of quantifying and evaluating the metabolic stability of CMB. [ABSTRACT FROM AUTHOR]

Gongjindan (GJD) is a traditional Korean medicine consisting of four herbal medicines and two animal-derived medicines, and is taken as a tonic in Republic of Korea. In this study, the goal was to develop and validate a simultaneous analytical method to quantify eight compounds in commercially available GJD samples using high-performance liquid chromatography (HPLC), ultra-performance liquid chromatography with tandem mass spectrometry (UPLC–MS/MS), and gas chromatography with tandem mass spectrometry (GC–MS/MS) systems. In HPLC and UPLC–MS/MS, seven components (gallic acid, 5-(hydroxymethyl)furfural, morroniside, loganin, nodakenin, decursin, and decursinol angelate) were separated and quantified using a distilled water–acetonitrile mobile phase system on a Capcell Pak UG80 C18 column and an Acquity UPLC BEH C18 column, respectively. Muscone was quantified using GC–MS/MS. The developed assays were validated by evaluating the linearity, limit of detection, limit of quantitation, recovery, and precision. In the regression equations of all compounds, the coefficient of determination was ≥0.9917, showing good linearity. The recovery was 93.70–108.17%, and the relative standard deviation values in the precision test were all <1.50%. Using the developed analysis methods, GJD samples were determined to contain the eight target compounds in concentrations from non-detected to 10.75 mg/g. The analytical assays developed and validated in this study can be used to obtain data for the quality control of commercially available GJDs and for the further expansion of efficacy and clinical studies. [ABSTRACT FROM AUTHOR]

Gabapentin (GAB) is a cyclohexane acetic acid, structurally related to the neurotransmitter gamma-aminobutyric acid (GABA), and considered the principal inhibitory neurotransmitter in the central nervous system (CNS) of mammals. An ultra-performance liquid chromatography–tandem mass spectrophotometry (UPLC-MS/MS) method for assessing pregabalin (PRE) in human plasma, was developed and validated, via PRE usage as an internal standard. The plasma underwent protein precipitation using methanol, prior to analysis. Chromatographic separation was completed using a mobile phase of methanol: 0.1% formic acid solution, (65:35, v/v), at a flow rate of 0.2 mL/min, with an isocratic approach, on an Agilent Eclipse plus column (50 × 2.1 mm and 1.8 μm), in 1.6 min of running time. An Agilent triple quadrupole was used for mass analysis, to detect the ion transitions for GAB and PER, respectively, at m/z of 172.1 → 154.1 and 160.10 → 142.10. The calibration curve, over the linear range of 0.050–10.0 μg/mL, showed a high correlation coefficient, r = 0.9993. The limits of detection and quantitation were 13.37 ng/mL and 40.52 ng/mL, respectively, based on the standard deviation and slope equation. The results for intra- and inter-day measurement accuracy and precision were in acceptable ranges. The method was extended into the assessment of oral administrations of GAB at different doses, of one 600 mg/tablet and two capsules (each one of them has 300 mg of GAB), to volunteers who were used in pharmacokinetics and bioequivalent studies. The AGREE assessment tool was used to visualize the proposed method's greenness degree, which revealed a high AGREE rating score, supporting the accepted method's greenness profile. [ABSTRACT FROM AUTHOR]

Introduction: Osteonecrosis of the femoral head (ONFH) is a disorder that causes a collapse of the femoral head, requiring subsequent total hip replacement. However, the pathogenesis of ONFH remains largely unclear. Herein, exosome metabolomics analyses were conducted to explore the pathophysiology of ONFH. Objectives: This study aimed to conduct metabolic profiling of bone-derived exosomes of ONFH. Methods: 30 ONFH patients and 30 femoral neck fracture (FNF) patients were included in this study. Exosomes were harvested from the femoral head by using ultracentrifugation. Ultraperformance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) was performed in combination with multivariate statistical analysis to reveal and provided new insight into identify the global metabolic profile of ONFH. Results: The results of transmission electron microscope (TEM), nanoparticle tracking analysis (NTA), and Western blots indicated that the microvesicles isolated from the femoral head were exosomes. Several compounds were identified, including lipids and lipid-like molecules, amino acids, peptides, organooxygen compounds. 44 differential metabolites were screened between ONFH and FNF patients. The up-and down-regulation of Riboflavin metabolism, Pantothenate and CoA biosynthesis, Glycerophospholipid metabolism, and Sphingolipid metabolism were associated with ONFH pathophysiology. Conclusion: Our results suggest that metabolomics has huge prospects for elucidating pathophysiology of ONFH. [ABSTRACT FROM AUTHOR]

Alkylphenol ethoxylates (APEOs) represent a non-ionic surfactant widely used as adjuvants in pesticide formulation, which is considered to cause an endocrine-disrupting effect. In the current study, we established a detection method for the APEOs residue in tea based on solid-phase extraction (SPE) for the simultaneous analysis of nonylphenol ethoxylates (NPEOs) and octylphenol ethoxylates (OPEOs) by UPLC–MS/MS. In the spiked concentrations from 0.024 to 125.38 μg/kg for 36 monomers of APEOs (nEO = 3–20), the recoveries of APEOs range from 70.3–110.7% with RSD ≤ 16.9%, except for OPEO20 (61.8%) and NPEO20 (62.9%). The LOQs of OPEOs and NPEOs are 0.024–6.27 and 0.16–5.01 μg/kg, respectively. OPEOs and NPEOs are detected in 50 marketed tea samples with a total concentration of 0.057–12.94 and 0.30–215.89 µg/kg, respectively. The detection rate and the range of the monomers of NPEOs are generally higher than those of OPEOs. The current study provides a theoretical basis for the rational use of APEOs as adjuvants in commercial pesticide production. [ABSTRACT FROM AUTHOR]

Panax ginseng (P. ginseng), the dried root and rhizome of P. ginseng C. A. Meyer, is widely used in many fields as dietary supplements and medicine. To characterize the chemical constituents in P. ginseng cultivated in different growth environments, a UPLC-TOF-MS method was established for qualitative analysis. Four hundred and eight ginsenosides, including 81 new compounds, were characterized in P. ginseng from different regions. Among the detected compounds, 361 ginsenosides were recognized in P. ginseng cultivated in the region of Monsoon Climate of Medium Latitudes, possessing the largest amount of ginsenosides in all samples. Furthermore, 41 ginsenosides in 12 batches of P. ginsengs were quantified with a UPLC-MRM-MS method, and P. ginsengs from different regions were distinguished via chemometric analysis. This study showed that the different environments have a greater influence on P. ginseng, which laid a foundation for further quality control of the herb. [ABSTRACT FROM AUTHOR]

In order to establish a rapid and effective method for the quantitative determination of microcystins (MC-LR, MC-YR and MC-RR) in bivalves such as mussels, by taking the mussels as the research object and optimizing the factors such as the extracting solvent, the concentration of extracting solvent, and dilution ratio, etc., a method for the determination of three microcystins (MC-LR, MC-YR and MC-RR) in mussels was established by using the direct dilution combined with ultra-high performance liquid chromatography-tandem mass spectrometry. The results showed that : the determination method of three toxins in mussels was as follows : after being extracted with 90% methanol aqueous solution, the extract fluid was diluted with 0.5% acetic acid methanol solution, and the diluent was directly determined by ultra-high performance liquid chromatography-tandem mass spectrometry. The limit of detection (LOD) was 5 µg ⋅ kg-1 and the limit of quantification (LOQ) was 15 µg ⋅ kg-1. The mixed standard substance of 15, 30, and 150 µg ⋅ kg-1 microcystins was added to mussels for the spiked recovery test, and the recovery rates of three microcystins (MC-LR, MC-RR and MC-YR) were 89.4%-91.8%, 77.1%-106.3%, and 75.8%-102.3%, respectively. The relative standard deviations were 3.5%-13.5%, 5.6%-9.2%, and 4.5%-8.1% (n= 6), respectively. The determination method was simple and fast, with low cost and strong operability, which could meet the technical requirements of the current batch quantitative detection of three microcystins in mussels. [ABSTRACT FROM AUTHOR]

Background: Intraventricular hemorrhage (IVH) is a major cause of morbidity and mortality in preterm neonates. It is essential to obtain new biomarkers for its early diagnosis. This can mainly occur by understanding its pathophysiology and mechanism of occurrence. Objective: To investigate the metabolic changes (blood amino acids and carnitine concentrations) associated with IVH in preterm neonates, and the ability to discover new biomarkers for early diagnosis of such disease that enable early intervention. Patients and Methods: This study was conducted on twenty preterm infants with IVH in the period from July 2019 to July 2020. Preterm infants were evaluated for IVH according to Velisavljev-Fillpovie with head US scans performed within 24 h after birth, on the 3rd day of life and thereafter weekly till discharge in survivors (Cases). Twenty preterm infants were chosen as a control group matching with the case group in gestational age, gender, and birth weight. Results: There was significant rise of alanine, aspartate, glutamate, and ornithine amino acids in IVH group than control in day 1 (P value < 0.05) in addition to glycine, valine, and proline in day 3. Alanine amino acid > 112.5 µmol/L showed the highest accuracy 80%, sensitivity 70% and specificity 90% for diagnosis of IVH in premature neonates among all tested amino acids in day 1with significant rise in C3:C2 at cut off point 0.095 (p= 0.001) and C6 cut off point 0.08 (P=0.001) and acylcarnitine cut off point >0.045 µmol/L (P=0.002) for diagnosis of IVH. Conclusion: Preterm neonates with IVH showed significant changes in amino acids and carnitines that might guide us to new biomarkers for early diagnosis and intervention. [ABSTRACT FROM AUTHOR]

In this study, the metabolites in insect tea and hawk tea were analyzed by ultra-high performance liquid chromatography–triple quadrupole mass spectrometry. We found 49 metabolites in insect tea and hawk tea that can be used as key active components in traditional Chinese medicine, as well as 98 metabolites that can be used as active components of pharmaceutical preparations for the treatment of cancers, hypertension, cardiovascular diseases, etc. Comparative analysis found that insect tea and hawk tea had significant differences in their metabolic profiles. Insect tea contains more metabolites beneficial to human health than hawk tea; insect tea also has higher antioxidant activity in vitro than hawk tea. The results of this study will contribute to the development of new health foods using insect tea. [ABSTRACT FROM AUTHOR]

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As set in the maximum residue limit regulations of the European Commission, this study aimed to obtain the residual parameters in milk with optimized UPLC-MS/MS conditions and to determine the conclusive drug withdrawal period to ensure food safety. In this research, an ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to study cefquinome sulfate's residue elimination in milk and to calculate cefquinome's withdrawal period. Twelve healthy cows free of endometritis were selected for the experiment. Before using the drug, the vaginal orifice and perineum of each cow was disinfected. One dose of intrauterine perfusion was used for each cow, followed by an additional dose after 72 h. Before administration and 12 h, 18 h, 24 h, 36 h, 42 h, 48 h, 60 h, 66 h, 72 h, 84 h, 90 h, and 96 h after the last dose, milk (10 mL) was gathered from each cow's teat and pooled. For the measurement of cefquinome concentrations in milk, UPLC-MS/MS was performed. A calibration curve was generated using linear regression as follows: Y = 250.86X − 102.29, with a correlation coefficient of 0.9996; the limits of detection and the limits of quantitation were 0.1 μg·kg−1 and 0.2 μg·kg−1, respectively. The average recovery of cefquinome was 88.60 ± 16.33% at 0.2 μg·kg−1, 100.95 ± 2.54% at 10 μg·kg−1, and 97.29 ± 1.77% at 50 μg·kg−1. For 5 consecutive days at the three spiking levels, the intra and inter-day relative standard deviations (RSD) were 1.28%–13.73% and 1.81%–18.44%, respectively; the residual amount of cefquinome was less than the maximum residue limit of 20 μg·kg−1, 36 h after administration; and the residual amount was less than the limit of detection (0.1 μg·kg−1) 48 h after administration. The withdrawal time of cefquinome in cow's milk was 39.8 h, as calculated using WTM1.4 software. In terms of clinical practical use, the withdrawal period of milk was temporarily set at 48 h after the administration of the cefquinome sulfate uterus injection to cows, in accordance with the recommended dose and course. [ABSTRACT FROM AUTHOR]

Aluminum (Al) affects the yield of forest trees in acidic soils. The oil tea plant (Camellia drupifera Lour.) has high Al tolerance, with abundant phenolic compounds in its leaves, especially flavonoid compounds. The role of these flavonoids in the Al resistance of oil tea plants is unclear. In this metabolomic study of C. drupifera under Al stress, ultra-pressure liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS) was utilized to identify metabolites, while principal component analysis, cluster analysis, and orthogonal partial least squares discriminant analysis were applied to analyze the data on the flavonoid metabolites. The leaf morphology of C. drupifera revealed significant damage by excess aluminum ions under each treatment compared with the control group. Under Al stress at 2 mmol/L (GZ2) and 4 mmol/L (GZ4), the total flavonoid content in C. drupifera leaves reached 24.37 and 35.64 mg/g, respectively, which are significantly higher than the levels measured in the control group (CK) (p < 0.01). In addition, we identified 25 upregulated and 5 downregulated metabolites in the GZ2 vs. CK comparison and 31 upregulated and 7 downregulated flavonoid metabolites in GZ4 vs. CK. The results demonstrate that different levels of Al stress had a significant influence on the metabolite profile of C. drupifera. It was found that the abundance of the 24 differential flavonoid metabolites was gradually elevated with increasing concentrations of Al stress, including catechin, epicatechin, naringenin-7-glucoside, astilbin, taxifolin, miquelianin, quercitrin, and quercimeritrin. Moreover, the most significant increase in antioxidant activity (about 30%) was observed in C. drupifera precultured in leaf extracts containing 7.5 and 15 μg/mL of active flavonoids. The qRT-PCR results showed that the expression levels of key genes involved in the synthesis of flavonoids were consistent with the accumulation trends of flavonoids under different concentrations of Al. Therefore, our results demonstrate the key role of flavonoid compounds in the oil tea plant C. drupifera in response to Al stress, which suggests that flavonoid metabolites in C. drupifera, as well as other aluminum-tolerant plants, may help with detoxifying aluminum. [ABSTRACT FROM AUTHOR]

IntroductionCinnamomum osmophloeum Kanehira (C. osmophloeum), a broad-leaved tree species of Taiwan, contains phenolic acids, flavonoids, and phenylpropanoids such as cinnamaldehyde and cinnamic acid in leaves. Many reports have shown that the cinnamon leaf extract possesses anti-inflammatory, hypoglycemic, hypolipidemic and neuroprotective functions. This study aims to analyze bioactive compounds in C. osmophloeum (cinnamon leaves) by UPLC-MS/MS and prepare hydrosol, cinnamon leaf extract and cinnamon leaf nanoemulsion for comparison in improving Parkinson’s disease (PD) in rats.MethodsAfter extraction and determination of total phenolic and total flavonoid contents, cinnamaldehyde and the other bioactive compounds were analyzed in cinnamon leaves and hydrosol by UPLC-MS/MS. Cinnamon leaf nanoemulsion was prepared by mixing a suitable proportion of cinnamon leaf extract, soybean oil, lecithin, Tween 80 and deionized water, followed by characterization of particle size and polydispersity index by dynamic light scattering analyzer, particle size and shape by transmission electron microscope, encapsulation efficiency, as well as storage and heating stability. Fifty-six male Sprague-Dawley rats aged 8 weeks were divided into seven groups with group 1 as control (sunflower oil) and group 2 as induction (2 mg/kg bw rotenone in sunflower oil plus 10 mL/kg bw saline), while the other groups including rotenone injection (2 mg/kg bw) followed by high-dose of 60 mg/kg bw (group 3) or low-dose of 20 mg/kg bw (group 4) for tube feeding of cinnamon leaf extract or cinnamon leaf nanoemulsion at the same doses (groups 5 and 6) every day for 5 weeks as well as group 7 with rotenone plus hydrosol containing 0.5 g cinnamon leaf powder at a dose of 10 mL/kg bw. Biochemical analysis of brain tissue (striatum and midbrain) was done to determine dopamine, α-synuclein, tyrosine hydroxylase, superoxide dismutase, catalase, glutathione peroxidase and malondialdehyde contents by using commercial kits, while catalepsy performed by bar test.Results and discussionAn extraction solvent of 80% ethanol was found to be the most optimal with a high yield of 15 bioactive compounds being obtained following UPLC analysis. A triple quadrupole tandem mass spectrometer with electrospray ionization mode was used for identification and quantitation, with cinnamaldehyde present at the highest amount (17985.2 µg/g). The cinnamon leaf nanoemulsion was successfully prepared with the mean particle size, zeta potential, polydispersity index and encapsulation efficiency being 30.1 nm, -43.1 mV, 0.149 and 91.6%, respectively. A high stability of cinnamon leaf nanoemulsion was shown over a 90-day storage period at 4 and heating at 100 for 2 h. Animal experiments revealed that the treatments of cinnamon leaf extract, nanoemulsion and hydrosol increased the dopamine contents from 17.08% to 49.39% and tyrosine hydroxylase levels from 17.07% to 25.59%, while reduced the α-synuclein levels from 17.56% to 15.95% in the striatum of rats. Additionally, in the midbrain of rats, an elevation of activities of superoxide dismutase (6.69-16.82%), catalase (8.56-16.94%), and glutathione peroxidase (2.09-16.94%) was shown, while the malondialdehyde content declined by 15.47-22.47%. Comparatively, the high-dose nanoemulsion exerted the most pronounced effect in improving PD in rats and may be a promising candidate for the development of health food or botanic drug.

N- Demethylsinomenine (NDSM), the in vivo demethylated metabolite of sinomenine, has exhibited antinociceptive efficacy against various pain models and may become a novel drug candidate for pain management. However, no reported analytical method for quantification of N- Demethylsinomenine in a biological matrix is currently available, and the pharmacokinetic properties of N- Demethylsinomenine are unknown. In the present study, an ultra-high performance liquid chromatography with tandem mass spectrometry (UPLC-MS/MS) method for quantification of N- Demethylsinomenine in rat plasma was developed and utilized to examine the preclinical pharmacokinetic profiles of N- Demethylsinomenine. The liquid-liquid extraction using ethyl acetate as the extractant was selected to treat rat plasma samples. The mixture of 25% aqueous phase (0.35% acetic acid-10 mM ammonium acetate buffer) and 75% organic phase (acetonitrile) was chosen as the mobile phases flowing on a ZORBAX C18 column to perform the chromatographic separation. After a 6-min rapid elution, NDSM and its internal standard (IS), metronidazole, were separated successfully. The ion pairs of 316/239 and 172/128 were captured for detecting N- Demethylsinomenine and IS, respectively, using multiple reaction monitoring (MRM) under a positive electrospray ionization (ESI) mode in this mass spectrometry analysis. The standard curve met linear requirements within the concentration range from 3 to 1000 ng/mL, and the lower limit of quantification (LLOQ) was 3 ng/mL. The method was evaluated regarding precision, accuracy, recovery, matrix effect, and stability, and all the results met the criteria presented in the guidelines for validation of biological analysis method. Then the pharmacokinetic profiles of N- Demethylsinomenine in rat plasma were characterized using this validated UPLC-MS/MS method. N- Demethylsinomenine exhibited the feature of linear pharmacokinetics after intravenous (i.v.) or intragastric (i.g.) administration in rats. After i. v. bolus at three dosage levels (0.5, 1, and 2 mg/kg), N- Demethylsinomenine showed the profiles of rapid elimination with mean half-life (T1/2Z) of 1.55–1.73 h, and extensive tissue distribution with volume of distribution (VZ) of 5.62–8.07 L/kg. After i. g. administration at three dosage levels (10, 20, and 40 mg/kg), N- Demethylsinomenine showed the consistent peak time (Tmax) of 3 h and the mean absolute bioavailability of N- Demethylsinomenine was 30.46%. These pharmacokinetics findings will aid in future drug development decisions of N- Demethylsinomenine as a potential candidate for pain analgesia.

Honey is well-known as a food product that is rich in active ingredients and is very popular among consumers. Free amino acids (FAAs) are one of the important nutritional components of honey, which can be used not only as a nutritional indicator of honey but also as an indicator of plant source identification. In this study, the contents of 20 FAAs in seven types of honey from 11 provinces in China were examined for the first time. The 20 FAAs were analyzed by ultra-performance liquid chromatography-mass spectrometry/mass spectrometry (UPLC-MS/MS). By analyzing 93 honey samples from seven types of honey, the FAAs were found to range from 394.4 mg/kg (linden honey) to 1771.7 mg/kg (chaste honey). Proline ranged from 274.55 to 572.48 mg/kg, and methionine was only present in some of the linden honey, chaste honey, acacia honey, and rape honey. Evaluated by amino acid principal component analysis, multifloral grassland honey had the highest overall evaluation score, acacia and jujube honey were the most similar, while chaste honey was the least similar to the other types of honey. In addition, DNA was extracted from 174 Xinjiang grassland honey samples and different plant leaves for PCR and sequencing to identify the species of nectar plants. As a result, 12 families and 25 species of honey plants were identified. The results confirmed the diversity of FAAs in dissimilar types and sources of honey. This study provides a reference for expanding honey quality standards and verifying the authenticity of honey.

Bopyeo-tang (BPT), comprising six medicinal plants, has been used for the treatment of respiratory diseases such as pulmonary fibrosis and chronic obstructive pulmonary disease. In this study, we developed and validated a quantitative method for the quality assessment of BPT using ultra-performance liquid chromatography with tandem mass spectrometry (UPLC–MS/MS). Eighteen marker compounds were separated on an Acquity UPLC BEH C18 reversed-phase column (2.1 mm × 100 mm, 1.7 μm) via gradient elution with a 0.1% aqueous formic acid–acetonitrile mobile phase. The multiple-reaction monitoring mode was used to improve analysis speed and accuracy. The coefficients of determination, limits of detection, and limits of quantitation of the 18 marker compounds were 0.9991–0.9996, 0.36–24.45 μg/L, and 1.07–73.35 μg/L, respectively. The recovery was 85.19–110.25%, and the relative standard deviation of precision was ≤9.01%. When applied to a typical BPT sample, the method revealed a range of concentrations from below the quantitative limit (one compound only) to a maximum of 3.20 mg/freeze-dried g. This method will be used for quality control of BPT preparations.

Bopyeo-tang (BPT) is composed of six medicinal herbs (Morus alba L., Rehmannia glutinosa (Gaertn.) DC., Panax ginseng C.A.Mey., Aster tataricus L.f., Astragalus propinquus Schischkin, and Schisandra chinensis (Turcz.) Baill.) and has been used for the treatment of lung diseases. This study focused on establishing an analytical method that can simultaneously quantify nine target compounds (i.e., hydroxymethylfurfural, mulberroside A, chlorogenic acid, calycosin-7-O-glucoside, 3,5-dicaffeoylquinic acid, quercetin, kaempferol, schizandrin, and gomisin A) from a BPT sample using high-performance liquid chromatography with a photodiode array detector (HPLC–PDA) and ultra-performance liquid chromatography with tandem mass spectrometry (UPLC–MS/MS). The separation of compounds in both analyses was performed on a C18 reversed-phase column using the gradient elution of water–acetonitrile as the mobile phase. In particular, the multiple reaction monitoring mode was applied for quick and accurate detection in UPLC–MS/MS analysis. As a result of analyzing the two methods, HPLC–PDA and UPLC–MS/MS, the coefficient of determination of the regression equation for each compound was ≥0.9952, and recovery was 85.99−106.40% (relative standard deviation (RSD) < 9.58%). Precision testing of the nine compounds was verified (RSD < 10.0%). The application of these analytical assays under optimized conditions for quantitative analysis of the BPT sample gave 0.01–4.70 mg/g. Therefore, these two assays could be used successfully to gather basic data for clinical research and the quality control of BPT.