scholarly journals Development of a LC–MS/MS method for the quantification of toxic payload DM1 cleaved from BT1718 in a Phase I study

Bioanalysis ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 101-113 ◽  
Author(s):  
Catherine Gowland ◽  
Philip Berry ◽  
Julie Errington ◽  
Phillip Jeffrey ◽  
Gavin Bennett ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Targeting ◽  
Plasma Proteins ◽  
Reduction Reaction ◽  
Type I ◽  
Reaction Products ◽  
Quadrupole Mass ◽  
Triple Quadrupole Mass Spectrometer ◽  
Novel Method ◽  
Membrane Type

Background: BT1718 is a novel bicyclic peptide anticancer drug targeting membrane type I matrix metalloproteinase to release its toxic payload DM1. A LC–MS/MS method was validated to quantify DM1 generated from BT1718 in a Phase I/IIa clinical trial. Materials & methods: Plasma samples underwent a reduction reaction to artificially cleave BT1718 into DM1 and its bicycle components. An alkylation step was carried out to stabilize the reaction products, and plasma proteins extracted using acetonitrile. LC–MS/MS analysis utilized a C18 column and Agilent 6460 triple quadrupole mass spectrometer (Agilent, Cheshire, UK). Results: The method was fully validated over a linear range of 200–50,000 ng/ml BT1718, with overall precision ≤10% and accuracy 89–102%. Conclusion: A novel method for quantifying DM1 yielded from BT1718 has been validated and is now being utilized clinically.

scholarly journals REMAXINT: a two-mode clustering-based method for statistical inference on two-way interaction

2021 ◽  
Author(s):  
Zaheer Ahmed ◽  
Alberto Cassese ◽  
Gerard van Breukelen ◽  
Jan Schepers
Keyword(s):  
Null Hypothesis ◽  
Type I Error ◽  
Type I ◽  
The Novel ◽  
Simulation Studies ◽  
Test Statistic ◽  
Clustering Model ◽  
Novel Method ◽  
Main Effects ◽  
Empirical Case Studies

AbstractWe present a novel method, REMAXINT, that captures the gist of two-way interaction in row by column (i.e., two-mode) data, with one observation per cell. REMAXINT is a probabilistic two-mode clustering model that yields two-mode partitions with maximal interaction between row and column clusters. For estimation of the parameters of REMAXINT, we maximize a conditional classification likelihood in which the random row (or column) main effects are conditioned out. For testing the null hypothesis of no interaction between row and column clusters, we propose a $$max-F$$ m a x - F test statistic and discuss its properties. We develop a Monte Carlo approach to obtain its sampling distribution under the null hypothesis. We evaluate the performance of the method through simulation studies. Specifically, for selected values of data size and (true) numbers of clusters, we obtain critical values of the $$max-F$$ m a x - F statistic, determine empirical Type I error rate of the proposed inferential procedure and study its power to reject the null hypothesis. Next, we show that the novel method is useful in a variety of applications by presenting two empirical case studies and end with some concluding remarks.

scholarly journals Multistage Fragmentation of Ion Trap Mass Spectrometry System and Pseudo-MS3of Triple Quadrupole Mass Spectrometry Characterize Certain (E)-3-(Dimethylamino)-1-arylprop-2-en-1-ones: A Comparative Study

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Ali S. Abdelhameed ◽  
Adnan A. Kadi ◽  
Hatem A. Abdel-Aziz ◽  
Rihab F. Angawi ◽  
Mohamed W. Attwa ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Mass Spectrometer ◽  
Ion Trap ◽  
Quadrupole Mass Spectrometer ◽  
Ion Trap Mass Spectrometry ◽  
Triple Quadrupole ◽  
Quadrupole Mass ◽  
Triple Quadrupole Mass Spectrometer ◽  
Fragment Ions ◽  
Mass Spectrometry System

A new approach was recently introduced to improve the structure elucidation power of tandem mass spectrometry simulating the MS3of ion trap mass spectrometry system overcoming the different drawbacks of the latter. The fact that collision induced dissociation in the triple quadrupole mass spectrometer system provides richer fragment ions compared to those achieved in the ion trap mass spectrometer system utilizing resonance excitation. Moreover, extracting comprehensive spectra in the ion trap needs multistage fragmentation, whereas similar fragment ions may be acquired from one stage product ion scan using the triple quadrupole mass spectrometer. The new strategy was proven to enhance the qualitative performance of tandem mass spectrometry for structural elucidation of different chemical entities. In the current study we are endeavoring to prove our hypothesis of the efficiency of the new pseudo-MS3technique via its comparison with the MS3mode of ion trap mass spectrometry system. Ten pharmacologically and synthetically important (E)-3-(dimethylamino)-1-arylprop-2-en-1-ones (enaminones4a–j) were chosen as model compounds for this study. This strategy permitted rigorous identification of all fragment ions using triple quadrupole mass spectrometer with sufficient specificity. It can be used to elucidate structures of different unknown components. The data presented in this paper provide clear evidence that our new pseudo-MS3may simulate the MS3of ion trap spectrometry system.

Drug screening method development for paper spray coupled to a triple quadrupole mass spectrometer

2017 ◽  
Vol 9 (34) ◽  
pp. 5037-5043 ◽  
Author(s):  
Rachel Jett ◽  
Christine Skaggs ◽  
Nicholas E. Manicke
Keyword(s):  
Mass Spectrometry ◽  
Drug Screening ◽  
Method Development ◽  
Screening Method ◽  
Direct Analysis ◽  
Triple Quadrupole ◽  
Analysis Method ◽  
Quadrupole Mass ◽  
Triple Quadrupole Mass Spectrometer ◽  
Paper Spray

Paper spray mass spectrometry is a direct analysis method in which compounds are extracted and ionized from biofluids dried on paper.

Pesticides Analysis in Beans by Gas Chromatography Couplet with Tandem Mass Spectrometry

2021 ◽  
Vol 6 (4) ◽  
Author(s):  
Mizutani G ◽  
◽  
Bustillos O ◽  
Keyword(s):  
Gas Chromatography ◽  
Analytical Method ◽  
Extraction Procedure ◽  
Quadrupole Mass ◽  
Triple Quadrupole Mass Spectrometer ◽  
Mineral Salts ◽  
Pesticides Residues ◽  
Solid Liquid ◽  
Validation Of Analytical Method ◽  
Iron And Calcium

Beans are part of the basic diet alimentation for Brazilian population, as they gather proteins, carbohydrates, vitamins, mineral salts, fibers, amino acids and essential nutrients such as iron and calcium, being a complete food that can be compared with the amount of protein that the meat has. Considering the beans world production, in development countries represent almost 50%, being that Myanmar, India and Brazil the top three position. The use of pesticides is widely spread in these countries to reduce agricultural losses due to pests that interfere with grain production. Therefore the risk that could be generated from foods pesticides residues makes their analyses of quantification mandatory. The purpose of this work was to develop an analytical method to quantitatively characterize fungicides pesticides residues, flutriafol, procymidone and tebuconazole that were used to angular spot control, anthracnose, rust and alternaria spot, white mold fungi, present in beans, by means of gas chromatography coupled with a triple quadrupole mass spectrometer. Samples of beans, Phaseolus vulgaris L, types white, black, string and Vigna angularis, type adzuki, had been bought in grains store and supermarkets at metropolitan São Paulo city. The validation of analytical method was explored for sensitivity, selectivity, precision. The extraction procedure was performed in two different forms, QuEChERS, and solid-liquid extraction with low temperature. Through this methodology, reached below the maximum limit allowed by Brazilian law 0.5mgkg-1 for procymidone and 0.1mgkg-1 for flutriafol and tebuconazole. Several samples of four types of beans were tested and all of them had procymidone identified and 7% of samples higher than the law limit.

FIRST-IN-HUMAN PHASE I RESULTS SHOW SAFETY, TOLERABILITY AND BRAIN PENETRANCE OF ORY-2001, AN EPIGENETIC DRUG TARGETING LSD1 AND MAO-B

2017 ◽  
Vol 13 (7) ◽  
pp. P1573-P1574 ◽  
Author(s):  
Tamara Maes ◽  
Cesar Molinero ◽  
Rosa M. Antonijoan ◽  
Juan Manuel Ferrero-Cafiero ◽  
Joan Martínez-Colomer ◽  
...  
Keyword(s):  
Phase I ◽  
Drug Targeting ◽  
Mao B ◽  
Epigenetic Drug

scholarly journals UHPLC-QQQ-MS/MS assay for quantification of dianthrones as potential toxic markers of Polygonum multiflorum Thunb: Application to the standardization of TCMs with endogenous toxicity

2021 ◽  
Author(s):  
Jian-Bo Yang ◽  
Yun-Fei Song ◽  
Yue Liu ◽  
Hui-Yu Gao ◽  
Qi Wang ◽  
...  
Keyword(s):  
High Performance ◽  
Multiple Reaction Monitoring ◽  
Internal Standard ◽  
Triple Quadrupole ◽  
Quadrupole Mass ◽  
Polygonum Multiflorum ◽  
Triple Quadrupole Mass Spectrometer ◽  
Benefit Risk Assessment ◽  
Heparg Cells

Abstract Background: The raw and processed roots of Polygonum multiflorum Thunb (PM) are commonly used in clinical practice to treat diverse diseases; however, the reports of hepatotoxicity induced by Polygoni Multiflori Radix (PMR) and Polygoni Multiflori Radix Praeparata (PMRP) have emerged worldwide. Thus, it is necessary for researcher to explore the methods to improve its quality standards and further ensure its quality and treatment effect.Methods: In the present study, an ultra-high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UHPLC-QQQ- MS/MS) method has been optimized and validated for the determination of dianthrones in PMR and PMRP, using bianthronyl as the internal standard. Chromatographic separation with a gradient mobile phase (A: acetonitrile and B: water containing 0.1% formic acid (v/v)) at a flow rate of 0.25 mL/min was achieved on a Waters Acquilty UPLC BEH b) C18 column (2.1 mm × 50 mm, 1.7 µm). A triple quadrupole mass spectrometer (TQMS) was operated in negative ionization mode with multiple reaction monitoring for the quantitative analysis of six dianthrones. Meanwhile, compounds 5 and 6 were further evaluated for cytotoxicity of HepaRG cells by CCK8 assay.Results: The UHPLC-QQQ-MS/MS method was first developed to simultaneous determination of six dianthrones in PMR and PMRP, namely polygonumnolides C1–C4 (1–4), trans-emodin dianthrones (5), and cis-emodin dianthrones (6). The contents of 1~6 in 90 batches of PMR were in the range of 0.027-19.04, 0.022-13.86, 0.073 -15.53, 0.034 -23.35, 0.38-83.67 and 0.29 -67.00 µg/g, respectively. The contents of 1~6 in 86 batches of commercial PMRP were in the range of 0.020-13.03, 0.051-8.94, 0.022-7.23, 0.030 -12.75, 0.098-28.54 and 0.14-27.79 µg/g, respectively. The six dianthrones were almost completely gone after reasonable processing for 24 h. Meanwhile, compounds 5 and 6 showed the inhibitory activity against HepaRG cells with the IC50 values of 10.98 and 15.45 μM, respectively. Furthermore, a systematic five-step strategy to realize the standardization of TCMs with endogenous toxicity is proposed for the first time, involving the establishment of determination methods, determination of the toxic markers, the standardization of processing method, the development of limit standards and benefit-risk assessment.Conclusion: The results of cytotoxicity evaluation of dianthrone indicated that trans-emodin dianthrones (5) and cis-emodin dianthrones (6) could be selected as the toxic markers of PMRP. Taking PMR and PMRP for example, we hope this study provided insight into the standardization and internationalization of endogenous toxic TCMs, with the main purpose of improving public health by scientifically using TCMs to treat diverse complex diseases in future.

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