Quadruple Mass Spectrometer Research Articles

Dual COF functionalized magnetic MXene composite for enhancing magnetic solid phase extraction of thiophene compounds from oilfield produced waters prior to GC-MS/MS analysis

In this study, a novel COFTABT@COFTATp modified magnetic MXene composite (CoFe2O4 @Ti3C2 @COFTABT@COFTATp) was synthesized by Schiff base reaction and irre-versible enol-keto tautomerization, and employed to establish a sensitive monitoring method for six thiophene compounds in oilfield produced water samples based on magnetic solid-phase extraction (MSPE) prior to gas chromatography coupled with a triple quadruple mass spectrometer (GC-MS/MS). The designed magnetic materials exhibited unexpected enrichment ability to target thiophene compounds and achieved good extraction efficiencies ranging from 83 % to 98 %. The developed MSPE/GC-MS/MS method exhibited good linearity in the range of 0.001–100 μg L−1, and obtained lower limits of detection ranging from 0.39 to 1.9 ng L−1. The spiked recoveries of thiophene compounds obtained in three oilfield produced water samples were over the range of 96.26 %−99.54 % with relative standard deviations (RSDs) less than 3.7 %. Notably, benzothiophene, 4-methyldibenzothiophene and 4,6-dimethyldibenzothiophene were detected in three oilfield-produced water samples. Furthermore, the material still kept favorable stability after six recycling experiments. The adsorption kinetics, adsorption isotherms as well as adsorption thermodynamics of thiophene compounds were investigated in detail to provide insight into the mechanisms. Overall, the present work contributed a promising strategy for designing and synthesizing new functionalized materials for the enrichment and detection of typical pollutants in the environment.

Comparative analysis of additive decomposition using one-dimensional and two–dimensional gas chromatography: Part II - Irgafos 168 and zinc stearate

Plastic production has experienced a significant increase in the last sixty years due to its cost-efficiency and adaptable characteristics, leading to the extensive use of additives to improve its performance and longevity. Due to the high demand for plastic, plastic waste production has increased, contaminating the environment and living beings by leaching additives, among other substances. Pyrolysis stands out among recycling techniques because it can handle mixed polymer waste feedstock. However, understanding the pyrolyzates distribution of additives is fundamental to assessing pyrolysis process of plastic waste. This study investigated the pyrolysis product distributions of two commonly used antioxidants, namely, Irgafos 168 and zinc stearate (ZnSt), using one-dimensional gas chromatography equipped with a quadruple mass spectrometer (GC–MS) and two-dimensional gas chromatography coupled to flame ionization detector and time–of–flight mass spectrometer (GC×GC–FID/TOF–MS). While GC separation technique provided limited information on product distribution, GC×GC offered enhanced resolution and identification of the decomposition products. In the pyrolysis of Irgafos 168 at 550 °C, GC identified 18 products, while GC×GC identified 198 products, representing an increase of approximately 11-fold. Similarly, for ZnSt, GC identified 67 products, while GC×GC identified 434 products, representing a 6-fold increase. GC×GC identified decomposition products from 15 different chemical classes for Irgafos 168 and 16 chemical classes for ZnSt, compared to 4 and 11 chemical classes identified by GC, respectively. Phenols and their derivatives were the major chemical class in the decomposition products of Irgafos 168 with a yield of 9.51 wt.%. In contrast, olefinic products were the dominant ones for ZnSt, with a yield of 9.73 wt.%. The major decomposition product of Irgafos 168 and ZnSt was 2‑tert‑butyl‑methylphenol (C11H16O) and C6 olefin (C6H12) with yields of 3.88 wt.%, and 1.13 wt.%, respectively. Utilizing the GC×GC separation method improved the ability to identify decomposition products, which can ultimately lead to a better understanding of antioxidant degradation that occurs during the pyrolysis process. GC×GC also provided thorough characterization of minor and co-eluted products along with major antioxidant degradation products. Additionally, the decomposition product distribution of Irgafos 168 and ZnSt was also compared with the primary antioxidants, Irganox 1010, Irganox 1076, and BHT, studied in part 1. The analysis indicated that the olefinic chemical class was the predominant one in Irganox 1010, Irganox 1076, and ZnSt, while ketones were the major chemical class in the decomposition of BHT and phenolics had the highest yield in Irgafos 168.

Serum INSL3 measured by LC-MS/MS in pubertal girls and in girls with precocious puberty during GnRH agonist treatment.

The peptide hormone Insulin-like Factor 3 (INSL3) is a biomarker of testicular Leydig cells in the male but is also expressed by the theca cells of the ovaries. With the advent of sensitive assays INSL3 can be quantified in female circulation, and we suggest that circulating INSL3 is a novel biomarker for pubertal development in girls. The aim of the study is to quantify INSL3 by LC-MS/MS in sera from normal girls during pubertal transition, and during gonadal suppression by GnRH agonist therapy in girls with central precocious puberty (CPP). The sensitivity of an established LC-MS/MS-based method for serum INSL3 was improved by switching to a state-of-the-art triple quadruple mass spectrometer (Altis Plus, Thermo). The limit of detection of the improved LC-MS/MS method for serum INSL3 was 0.01 ug/L (1.5 pM) and the inter-assay CV was < 12%. Serum INSL3 increased during the pubertal transition in healthy girls and changes correlated with the concomitant rise in other measured hormones. In some girls, but not all, INSL3, FSH, inhibin B and estradiol serum concentrations increased prior to first clinical signs of puberty. Serum INSL3 concentrations were increased at baseline in girls with CPP compared to prepubertal controls and decreased during treatment with GnRH agonist followed by a steep rise and normalization after cessation of treatment. The improved method allowed for quantification of INSL3 in longitudinally collected serum samples during pubertal transition in healthy girls as well as in girls with CPP before, during and after treatment with GnRH agonist. Future studies are needed to clarify if INSL3 in combination with other biomarkers enhances the predictive value of differentiating between premature thelarche and CPP.

Isolation and characterization of major degradants in dihydroergotamine injection

AbstractIn this study, we report the systematic approach for characterization of two major degradant impurities, which are not listed in any compendia and were formed during the stability studies of Dihydroergotamine mesylate injection (DHE). An ion-pair UPLC chromatographic method was developed to quantify the related substances present in the DHE injection drug product. The same was used to monitor the impurity profiling during its stability. The two unknown impurities were observed at RRT about 0.08 (Impurity-1) and RRT about 0.80 (Impurity-5) and found to be significantly increasing on stability. Forced degradation studies revealed the nature of the impurity and conditions required for enriching them. A Mass compatible HPLC method was developed to quantify only these two impurities using 25% ammonia and formic acid in water. Their mass numbers were identified using LC MS/MS with triple quadruple mass spectrometer coupled with a HPLC. These two impurities were then isolated from enriched products using preparative HPLC. These impurities were then characterized using Mass and NMR analysis along with Q-TOF elemental analysis.

Assessment of Iohexol Serum Clearance by LC-MS/MS with Isotopically Labeled Internal Standard.

Accurate measurement of the glomerular filtration rate (GFR) is essential for detecting renal insufficiency in living kidney donors. Iohexol is a "near-ideal" exogenous filtration marker for GFR measurement that has attracted increasing interest in clinical practice because it is non-toxic, non-radioactive, readily available, and easy to measure. In this chapter, we describe a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to measure iohexol in serum and to calculate GFR based on the rate of iohexol clearance. In this procedure, the contrast agent iohexol is administrated to the study subject in an outpatient setting, and three timed blood samples are collected. The serum proteins are precipitated, and the supernatant containing iohexol and the internal standard 2H5-iohexol is diluted prior to LC-MS/MS analysis. The LC-MS/MS method utilizes a Thermo Vanquish UHPLC coupled with TSQ Endura triple quadruple mass spectrometer, with a total run time of 2.5min. The LC-MS/MS method has demonstrated good analytical performances, and the workflow can be used to reliably measure GFR in apparently healthy individuals without impaired renal function, such as living kidney donors.

Accuracy-Based Glomerular Filtration Rate Assessment by Plasma Iohexol Clearance in Kidney Transplant Donors.

An accurate measurement of the glomerular filtration rate (GFR) is essential for detecting renal insufficiency in living kidney donors. Iohexol is a "near-ideal" exogenous filtration marker for GFR measurements that has attracted increasing interest in clinical practice because it is non-toxic, non-radioactive, readily available, and easy to measure. In this study, we aimed to set up a laboratory test to conveniently assess the plasma clearance of iohexol in living kidney donors. A workflow was established in the institution's infusion clinic to administer iohexol and to collect three timed blood samples from renal transplant donors. Iohexol was thereafter measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The serum proteins were precipitated and the supernatant containing iohexol was diluted prior to the LC-MS/MS analysis. The LC-MS/MS method was developed on a Thermo Vanquish UHPLC coupled with a TSQ Endura triple quadruple mass spectrometer with a total run time of 2.5 min. The analytical performance of the method was assessed. The LC-MS/MS method demonstrated a good analytical performance. To calculate the iohexol clearance rate and the GFR, automated data integration and a result calculation were accomplished by using a custom Python script. Automated result reporting was achieved using a laboratory informatics system (LIS) vendor's direct media interface. We developed and implemented a laboratory test to assess the plasma clearance of iohexol. A workflow was established in the hospital to reliably measure the GFR in living kidney donors, with a potential to be further expanded into other areas where an accurate GFR measurement is needed.

Preparation, Features, and Efficiency of Nanocomposite Fertilisers Based on Glauconite and Ammonium Dihydrogen Phosphate.

This paper studies the chemical and mechanochemical preparation of glauconite with ammonium dihydrogen phosphate (ADP) nanocomposites with a ratio of 9:1 in the vol.% and wt.%, respectively. The methods include X-ray diffraction analysis, scanning electron microscope with energy-dispersive X-ray spectroscopy, transmission electron microscopy, infrared spectroscopy, and differential thermal analysis with a quadruple mass spectrometer. The manufactured nanocomposites keep the flaky glauconite structure. Some glauconite unit structures have been thickened due to minimal nitrogen (ammonium) intercalation into the interlayer space. The globular, granular, or pellet mineral particles of nanocomposites can be preserved via chemical techniques. Globular and micro-aggregate particles in nanocomposites comprise a thin film of adsorbed ADP. The two-step mechanochemical method makes it possible to slightly increase the proportion of adsorbed (up to 3.2%) and intercalated (up to 6.0%) nutrients versus chemical ways. Nanocomposites prepared via chemical methods consist of glauconite (90%), adsorbed (1.8-3.6%), and intercalated (3.0-3.7%) substances of ADP. Through the use of a potassium-containing clay mineral as an inhibitor, nitrogen, phosphorus, and potassium (NPK), nanocomposite fertilisers of controlled action were obtained. Targeted and controlled release of nutrients such as phosphate, ammonium, and potassium are expected due to various forms of nutrients on the surface, in the micropores, and in the interlayer space of glauconite. This is confirmed via the stepwise dynamics of the release of ammonium, nitrate, potassium, and phosphate from their created nanocomposites. These features of nanocomposites contribute to the stimulation of plant growth and development when fertilisers are applied to the soil.

Validated UPLC-MS/MS method for the determination of ivosidenib in rat plasma: Application to a pharmacokinetic study

AbstractIvosidenib (AG-120) is an unlisted, but estimated to be valid, oral inhibitor for isocitrate dehydrogenase 1 (IDH1) in the phase Ⅰ study of IDH1-mutated acute myeloid leukemia (AML) patients. This paper presents the investigation and validation of a rapid, effective, qualitative and quantitative determination method of ivosidenib in rat plasma by ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The samples were treated using acetonitrile precipitation to remove protein influence. Then, the supernatant was extracted to analyze plasma concentration traits. In the UPLC system, acetonitrile and water containing 0.1% formic acid were selected as a cosolvent mobile phase, applying a gradient elution to isolate compounds in a C18 column. Mass detections were performed on a triple quadruple mass spectrometer in positive ion mode. Electroshock characteristic fragment ionization was used for m/z 583.95→214.53 for ivosidenib for quantitative determination, m/z 583.95→186.6 for qualitative determination, and m/z 492.06→354.55 for IS. The selectivity, linearity, stability, accuracy and precision were verified by reaching the guideline criteria from European Medicine Agency (EMA) and the Food and Drug Administration (FDA). The calibration curve was linear over the concentration range of 2–2,000 ng mL−1 for ivosidenib in rat plasma with a lower limit of quantification (LLOQ) of at least 2 ng mL−1. Additionally, there was no distinct matrix effect or carry-over phenomenon. The method was successfully established and applied to separate ivosidenib from plasma, with the entire analytical process being performed within 3 min for each sample, which shows high-efficiency and convenience for further studies of ivosidenib.

#3804 ASSOCIATION BETWEEN PLASMA XOR AND OUTCOMES IN CKD PATIENTS

Abstract Background and Aims Plasma xanthine oxidoreductase (pXOR) is an enzyme plays a key role in uric acid (UA) production and produces reactive oxygen species (ROS), and it has been reported that pXOR activity is related with cardiovascular events in the general population. However, the relationship between pXOR activity and prognosis in patients with chronic kidney disease (CKD) remains unclear. Method We measured pXOR activity by Liquid chromatography tandem quadruple mass spectrometer (LC-TQMS method) in 415 outpatients with CKD, and compared demographic and laboratory data between two groups based on the median pXOR activity. Furthermore, we examined the association between pXOR activity and outcomes; renal replacement therapy (RRT), major adverse cardiovascular events (MACE), and all-cause mortality, using multivariate Cox proportional hazards model. Results Median age and eGFR were 71 years old and 21.6 ml/min/1.73 m2, respectively. Median pXOR activity is 3.33 pmol/h/ml and 26.3 pmol/h/ml in the lower and higher pXOR activity groups, respectively. eGFR was significantly lower and UA was significantly higher in the lower pXOR activity group compared with the higher pXOR group (eGFR, 18.9 vs 27.4, P, &amp;lt;0.001; UA, 5.7 vs 6.1, P, &amp;lt;0.001). During the follow-up period of 38 months, the incidence of each outcome including RRT, MACE, or all-cause mortality were significantly higher in the lower pXOR group (log rank test, P&amp;lt;0.001). Multivariate Cox proportional hazards analysis including eGFR and UA levels showed that lower pXOR activity was significantly associated with poor renal? outcome (HR, 1.4; 95% CI, 1.0-2.1; P, 0.038). Furthermore, in subgroup analysis with or without antihyperuricemic use, univariate Cox analysis showed similar association between pXOR and each outcome. Conclusion In patients with CKD, lower pXOR activity has a significantly higher risk of all outcome (RRT, MACE, and all-cause mortality).

Direct Fabrication and Characterization of Zirconia Thick Coatings on Zirconium Hydride as a Hydrogen Permeation Barrier

The present work attempted to produce thick zirconia coatings formed by micro-arc oxidation as a hydrogen permeation barrier on zirconium hydride alloy. A novel multiphase zirconia coating was achieved, exhibiting superior hydrogen permeation barrier performance. The growth dynamics, formation mechanism, and phase evolution behavior of thick zirconia coatings were explored, and the hydrogen permeation barrier performance was evaluated by means of vacuum dehydrogenation experiment. The hydrogen desorption quantity was monitored by analyzing pressure changes with a quadruple mass spectrometer (QMS). Experimental results show that the multiphase coatings were composed of monoclinic ZrO2 (m-ZrO2), tetragonal ZrO2 (t-ZrO2), and a trace of cubic ZrO2 (c-ZrO2). The coatings were generally divided into a dense and uniform inner, intermediate layer, and a porous top layer. The quantitative analysis indicates an increased amount of m-ZrO2 toward the coating surface and an increased amount of t-ZrO2 toward the oxide/metal interface. This novel multiphase thick zirconia coating can noticeably improve hydrogen permeation resistance, and the permeation reduction factor (PRF) value is improved by nearly 13 times compared with bare zirconium hydride. It is demonstrated that hydrogen desorption is retarded to some extent in the presence of thick zirconia coating. Hydrogen desorption of the sample with ceramic coating started at 660 °C, which was apparently higher than that of the sample without coating.

Simultaneous Quantitation of Anlotinib and Osimertinib by Isotope-Labeled UHPLC-MS/MS in Human Plasma: Application in NSCLC Patients.

Anlotinib and osimertinib are a class of tyrosine kinase inhibitors for the treatment of malignant tumor. The combination of anlotinib and osimertinib is currently used for treating non-small cell lung cancer (NSCLC) patients. This study aimed to develop a simple and rapid isotope-labeled UHPLC-MS/MS method for the simultaneous determination of anlotinib and osimertinib in human plasma. The analytes were extracted by protein precipitation with acetonitrile and were then separated on a Shim-pack GIST C18 column. The detection was performed on Shimadzu 8050 triple quadruple mass spectrometer in the positive electrospray ionization mode with multiple reaction monitoring. The precursor-to-product ion transitions were m/z 408.10→339.75, 500.25→72.20 and 413.50→344.50 for anlotinib, osimertinib and D5-anlotinib, respectively. Validation is based on US Food and Drug Administration guidelines. The linearity ranges were 0.5-100ng/mL for anlotinib and were 1-500ng/mL for osimertinib with the correlation coefficients (r 2) ≥ 0.99. Accuracy and precision, matrix effect, extraction recovery and stability of anlotinib and osimertinib were acceptable after validation. The UHPLC-MS/MS method was successfully validated and was applied to monitor the concentration of anlotinib and osimertinib in NSCLC patients.

Abstract P4-07-03: The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa

Abstract Introduction HIV-positive women with breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We, therefore, investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa. Methods Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on women with stages I-III HR-positive breast cancer who were prescribed 20mg of adjuvant tamoxifen daily for ≥3 months during the study period. We collected venous blood once from each participant during a routine clinic visit and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level &amp;lt; 60ng/mL after 3 months of prescribed daily tamoxifen use. We compared socio-demographic, lifestyle factors, tamoxifen-related side effects, and concurrent medication use among women with and without HIV and developed multivariable logistic regression models of tamoxifen non-adherence. Results Among 369 participants, 78 (21.1%) were HIV-positive and 291 (78.9%) HIV-negative. After a median (interquartile range) time of 13.0 (6.2-25.2) months since tamoxifen initiation, the tamoxifen serum concentration ranged between 1.54 and 943.0ng/mL, with a median of 52.3ng/mL. In the full cohort, 208 women (56.4%) were non-adherent to tamoxifen; only 161 (43.6%) were adherent. Women &amp;lt; 40 years of age were less likely to adhere to tamoxifen than women &amp;gt;60 years (73.4% vs 52.6%, odds ratio (OR)=2.49, 95% confidence interval (CI)=1.26-4.94); likewise, HIV-positive women (70.5% vs 52.6%, OR=2.16, 95% CI=1.26-3.70) were less likely to adhere than HIV-negative women. In an adjusted model, only HIV was associated with non-adherence; HIV-positive women had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR=2.40, 95% CI=1.11-5.20). Conclusion Non-adherence to tamoxifen may limit the overall survival of women with HR-positive breast cancer; in our study, especially in HIV-positive women. Citation Format: Oluwatosin A Ayeni, Shingirai Chiwambutsa, Wenlong Carl Chen, Nyasha N. Kapungu, Comfort Kanji, Roslyn Thelingwani, Nivashni Murugan, Rophiwa Mathiba, Boitumelo Phakathi, Sarah Nietz, Duvern Ramiah, Daniel S. O’Neil, Judith S. Jacobson, Paul Ruff, Herbert Cubasch, Tobias Chirwa, Maureen Joffe, Collen Masimirembwa, Alfred I. Neugut. The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-03.

Thermal and mass spectrometer analysis (TG - DTG - MS) of different oAPI gravity crude oils from new oil fields in Turkey

In this research, thermal analysis and kinetics of four different crude oil samples (oAPI range of 21.1–34.1) from different new oil fields of Turkey were studied using thermogravimetry (TG-DTG) coupled with a quadruple mass spectrometer (MS). Mixtures of crude oils and limestone matrix are prepared to give a composition of 15 % wt. crude oil in the matrix and the ramped temperature experiments are performed at different heating rates (10, 20 and 30 °C/min) under air atmosphere. In TG-DTG analysis three different reaction regions were observed, known as low temperature oxidation (LTO), fuel deposition (FD), high temperature oxidation (HTO) and finally limestone decomposition, respectively. In MS analysis, combustion products of different crude oils on the basis of both relative intensities and relevancy was monitored simultaneously. Finally, two different model free kinetic methods known as Ozawa-Flynn-Wall (OFW) and Kissinger-Akahira-Sunose (KAS) were used to determine the activation energy of the crude oil samples. It was observed that the activation energy values are varied between 189.47 and 290.41 kJ/mol (OFW method) and 181.75–288.37 kJ/mol (KAS method) in HTO region, respectively.

A sensitive liquid chromatographic-mass spectrometry method for the quantification of vincristine in whole blood collected with volumetric absorptive microsampling

Vincristine is a well-established cytotoxic drug. In paediatric populations blood collection via venipuncture is not always feasible. Volumetric absorptive microsampling (VAMS) is a less invasive method for blood collection. Furthermore, VAMS lacks the haematocrit effect on the recovery known with dried blood spots. Therefore, a liquid chromatography tandem-mass spectrometry method was developed and validated for the quantification of vincristine in whole blood collected with VAMS devices. Sample preparation consisted of solid-liquid extraction with 0.2% formic acid in water and acetonitrile. The final extract was injected on a C18 column (2.0 ×50 mm, 5 µm). Gradient elution was used and quantification was accomplished with a triple quadruple mass spectrometer operating in the positive mode. The validated concentration range was from 1 to 50 ng/mL with an intra- and inter-accuracy and precision of ± 10.3% and ≤ 7.3%, respectively. This method was able to successfully quantify vincristine concentrations in whole blood collected with VAMS from paediatric oncology patients. Vincristine concentrations in whole blood were non-linearly associated with plasma concentrations, which could be described with a saturable binding equilibrium model.

The impact of HIV on non-adherence for tamoxifen among women with breast cancer in South Africa.

Women living with HIV (WLWH) and breast cancer (BC) have worse overall survival than HIV-negative women with BC, and poor adherence to prescribed tamoxifen is known to contribute to poor survival. We therefore investigated the association of HIV infection with adherence to adjuvant tamoxifen among women with localized hormone receptor (HR)-positive breast cancer in South Africa. Among 4,097 women diagnosed with breast cancer at six hospitals in the prospective South African Breast Cancer and HIV Outcomes (SABCHO) cohort study between July 2015 and December 2020, we focused on black women with stages I-III HR-positive breast cancer who were prescribed 20mg of adjuvant tamoxifen daily. We collected venous blood once from each participant during a routine clinic visit, and analyzed concentrations of tamoxifen and its metabolites using a triple quadruple mass spectrometer. We defined non-adherence as a tamoxifen level < 60ng/mL after 3months of daily tamoxifen use. We compared tamoxifen-related side effects, and concurrent medication use among women with and without HIV and developed multivariable logistic regression models of tamoxifen non-adherence. Among 369 subjects, 78 (21.1%) were WLWH and 291 (78.9%) were HIV-negative. After a median (interquartile range) time of 13.0 (6.2-25.2) months since tamoxifen initiation, the tamoxifen serum concentration ranged between 1.54 and 943.0ng/mL and 208 (56.4%) women were non-adherent to tamoxifen. Women < 40years of age were more likely to be non-adherent than women > 60years (73.4% vs 52.6%, odds ratio (OR) = 2.49, 95% confidence interval (CI) = 1.26-4.94); likewise, WLWH (70.5% vs 52.6%, OR = 2.16, 95% CI = 1.26-3.70) than HIV-negative women. In an adjusted model WLWH had twice the odds of non-adherence to tamoxifen, compared to HIV-negative women (OR = 2.40, 95% CI = 1.11-5.20). High rates of non-adherence to adjuvant tamoxifen may limit the overall survival of black South African women with HR-positive breast cancer, especially among WLWH.

Comparative Study on the Isothermal Reduction Kinetics of Iron Oxide Pellet Fines with Carbon-Bearing Materials

The isothermal reduction of iron oxide pellet fines–carbon composites was investigated at temperatures of 900–1100 °C. The reduction reactions were monitored using the thermogravimetric (TG) technique. Alternatively, a Quadruple Mass Spectrometer (QMS) analyzed the CO and CO2 gases evolved from the reduction reactions. The effect of temperature, carbon source, and reaction time on the rate of reduction was extensively studied. The phase composition and the morphological structure of the reduced composites were identified by X-ray diffraction (XRD) and a scanning electron microscope (SEM). The results showed that the reduction rate was affected by the temperature and source of carbon. For all composite compacts, the reduction rate, as well as the conversion degree (α) increased with increasing temperature. Under the same temperature, the conversion degree and the reduction rate of composites were greater according to using the following carbon sources order: Activated charcoal &gt; charcoal &gt; coal. The reduction of the different composites was shown to occur stepwise from hematite to metallic iron. The reduction, either by activated charcoal or charcoal, is characterized by two behaviors. During the initial stage, the chemical reaction model (1 − α)−2 controls the reduction process whereas the final stage is controlled by gas diffusion [1 − (1 − α)1/2]2. In the case of reduction with coal, the reduction mechanism is regulated by the Avrami–Erofeev model [−ln (1−α)2] at the initial stage. The rate-controlling mechanism is the 3-D diffusion model (Z-L-T), namely [(1−α)−1/3−1]2 at the latter stage. The results indicated that using biomass carbon sources is favorable to replace fossil-origin carbon-bearing materials for the reduction of iron oxide pellet fines.

Effects of cytochrome P450 2B6 and constitutive androstane receptor genetic variation on Efavirenz plasma concentrations among HIV patients in Kenya.

The effects of genetic variation of cytochrome P450 2B6 (CYP2B6) and constitutive androstane receptor (CAR) on efavirenz (EFV) plasma concentration was evaluated among 312 HIV patients in Nairobi Kenya. The EFV plasma concentration at steady-state were determined using ultra-high-performance liquid chromatography with a tandem quadruple mass spectrometer (LC-MS/MS). Thirteen CYP2B6 (329G>T, 341T>C, 444 G>T/C, 15582C>T, 516G>T, 548T>G, 637T>C, 785A>G, 18492C>T, 835G>C, 1459C>T and 21563C>T) and one CAR (540C>T) single nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction. HIV drug resistance mutations were detected using an in-house genotypic assay. The EFV concentration of patients ranged from 4 ng/mL to 332697 ng/mL (median 2739.5 ng/mL, IQR 1878-4891.5 ng/mL). Overall, 22% patients had EFV concentrations beyond therapeutic range of 1000-4000 ng/mL (4.5%% < 1000 ng/mL and 31.7% > 4000 ng/mL). Five SNPs (15582C>T, 516G>T, 785A>G, 983T>C and 21563C>T) were associated with higher EFV plasma concentration while 18492C>T with lower EFV plasma concentration (p<0.05). Strong linkage disequilibrium (LD) was observed for 15582C>T, 516G>T, 785A>G, 18492C>T, 983T>C, 21563C>T, 1459C>T and CAR 540C>T. Sixteen haplotypes were observed and CTGCTTCC, CTGCTTCT, TTGCTTCT and CGACCCCT were associated with high EFV plasma concentration. In multivariate analysis, factors significantly associated with EFV plasma concentration included; the presence of skin rash (β = 1379, 95% confidence interval (CI) = 3216.9-3416.3; p < 0.039), T allele of CYP2B6 516G>T (β = 1868.9, 95% CI 3216.9-3416.3; p < 0.018), the C allele of CYP2B6 983T>C (β = 2638.3, 95% CI = 1348-3929; p < 0.0001), T allele of CYP2B6 21563C>T (β = 1737, 95% CI = 972.2-2681.9; p < 0.0001) and the presence of 5 to 7 numbers of SNPs per patient (β = 570, 95% CI = 362-778; p < 0.0001) and HIV viral load ≤1000 cells/mL (β = -4199.3, 95% CI = -7914.9 --483.6; p = 0.027). About 36.2% of the patients had EFV plasma concentrations beyond therapeutic window, posing high risk of treatment failure or toxicity. The SNPs of CYP2B6 516G>T, CYP2B6 983T>C, 21563C>T, presence of higher numbers of SNPs per patient and haplotypes CTGCTTCC, CTGCTTCT, TTGCTTCT and CGACCCCT could efficiently serves as genetic markers for EFV plasma concentration and could guide personalization of EFV based ART treatment in Kenya.

UPLC-MS/MS method for the determination of voriconazole plasma concentration from pediatric patients with hematologic tumors: An application toward personalized therapy.

Untreated invasive fungal infection is one of the important risk factors affecting the prognosis of pediatric patients with hematologic tumors. Voriconazole (VOR) is the first-line antifungal drug for the treatment of Aspergillus infections. In order to reduce the risk of adverse drug reactions while producing an ideal antifungal effect, therapeutic drug monitoring was performed to maintain the VOR plasma concentration in a range of 1,000-5,500 ng/ml. In the present study, a reliable, accurate, sensitive and quick ultra-high performance liquid chromatograph-tandem mass spectrometry (UPLC-MS/MS) method was developed for the determination of the VOR level. Protein precipitation was performed using acetonitrile, and then the chromatographic separation was carried out by UPLC using a C18 column with the gradient mobile phases comprising 0.1% methanoic acid in acetonitrile (A) and 0.1% methanoic acid in water (B). In the selective reaction monitor mode, the mass spectrometric detection was carried out using an TSQ Endura triple quadruple mass spectrometer. The performance of this UPLC-MS/MS method was validated as per the National Medical Products Administration for Bioanalytical Method Validation. Additionally, the plasma concentrations of VOR in pediatric patients with hematologic tumors were detected using this method, and the analyzed results were used for personalized therapy.

A sensitive and validated LC-MS/MS method for high-throughput determination of pomalidomide in human plasma and pharmacokinetic studies

Pomalidomide is an immunomodulatory agent (IMiD) that has been approved by the US Food and Drug Administration (FDA) for clinical treatment of patients with multiple myeloma. In this work, we developed a sensitive and validated LC-MS/MS method for high-throughput determination of pomalidomide over the range of 1.006–100.6 ng/mL (R2 = 0.9991) in human plasma and pharmacokinetic studies. A liquid-liquid extraction method using ethyl acetate was applied to extract pomalidomide and afatinib (as an internal standard, IS) from human plasma. Chromatographic separation was performed on a Hedera ODS column (150 mm × 2.1 mm, 5 µm) with security guard C18 column (4 mm × 2.0 mm) at 40 °C. Methanol and 10 mmol/L aqueous solution of ammonium acetate containing 0.1% formic acid were used as a gradient elution mobile phase, and the flow rate was 0.4 mL/min. A triple quadruple tandem mass spectrometer using multiplex reaction monitoring mode (MRM) with electrospray ionization (ESI) positive ionization was employed. The precursor to product ion transitions for the quantitative analysis of pomalidomide and the IS were m/z 274.2→163.1 and m/z 486.1 → 371.1, respectively. This established method has been validated according to regulatory guideline, and the results were all within the acceptance criteria. The validated LC-MS/MS method was successfully applied to analyze samples obtained from clinical pharmacokinetics study after oral administration of pomalidomide (4 mg) capsules in human.

Development & validation of LC–MS/MS assay for 5-amino-1-methyl quinolinium in rat plasma: Application to pharmacokinetic and oral bioavailability studies

5-Amino-1-methyl quinolinium (5-AMQ) is a potent Nicotinamide N-methyl transferase (NNMT) inhibitor. NNMT is an enzyme that catalyzes the N-methylation of the endogenous substrate nicotinamide, as well as exogenous xenobiotics. NNMT is fundamental to cellular metabolism; NNMT is overexpressed in select tissues (e.g., adipose tissue, skeletal muscle, etc.) in pathophysiological conditions, making it a clinically relevant target for drug development in several chronic diseases including obesity and diabetes. The objective of this study was to develop and validate a simple, sensitive, and reproducible liquid chromatography-tandem mass spectrometry (LC–MS/MS) method for the quantification of 5-AMQ in rat plasma and urine samples. 5-AMQ was extracted from plasma and urine by protein precipitation. Chromatographic separation was achieved using an ACE® Excel™ C18 column (2 μm, 50 × 2.1 mm) with a binary gradient solvent system comprising of water (A) and acetonitrile (B) containing 0.1 % formic acid as the mobile phase. Analysis was performed using an API 4000 QTRAP hybrid triple quadruple mass spectrometer and multiple reaction monitoring (MRM) in positive mode at m/z transitions of 159.100 → 90.00 and 162.200 → 117.200 for 5-AMQ and the internal standard, respectively. The standard curves of 5-AMQ in rat urine and plasma samples were linear in the concentration range of 10–2500 ng/mL. The intra-day and inter-day precisions and accuracies for 5-AMQ at four concentration levels in rat plasma and urine samples were found to be within the 15 % FDA acceptance range. Similarly, the accuracy and precision of 5-AMQ quantification in samples diluted up to 20-fold using blank plasma were within the 15 % acceptable range. Furthermore, the extraction recoveries and matrix effects at three concentration levels of rat plasma samples ranged from 99.5 %–110.6 % and -6.1 %–14.1 %, respectively. 5-AMQ was stable in rat plasma samples subjected to standard storage, preparation, and handling conditions, with less than 15 % variation noted at two concentration levels. The validated, sensitive, and reproducible LC–MS/MS method for 5-AMQ in rat plasma and urine samples was effectively applied to a pharmacokinetic study in rats with IV and oral administration of 5-AMQ. 5-AMQ displayed substantial plasma exposures via IV and oral route, with a mean maximum plasma concentration of 2252 ng/mL after oral administration, mean area under the curve (AUC0-∞) of 3708 h.ng/mL and 14431 h.ng/mL for the IV and oral groups, respectively, mean terminal elimination half-life of 3.80 ± 1.10 h and 6.90 ± 1.20 h respectively after intravenous and oral dose, and a good oral bioavailability (F % = 38.4).