Explore the vast range of titles available.

The major groups of antioxidant compounds (isoflavonoids, xanthones, hydroxycinnamic acids) in the rhizome methanol extracts of four Ukrainian Iris sp. (Iris pallida, Iris hungarica, Iris sibirica, and Iris variegata) were qualitatively and quantitatively analyzed using HPLC-DAD and UPLC-MS/MS. Gallic acid, caffeic acid, mangiferin, tectoridin, irigenin, iristectorigenin B, irisolidone, 5,6-dihydroxy-7,8,3′,5′-tetramethoxyisoflavone, irisolidone-7-O-β-d-glucopyranoside, germanaism B, and nigricin were recognized by comparing their UV/MS spectra, chromatographic retention time (tR) with those of standard reference compounds. I. hungarica and I. variegata showed the highest total amount of phenolic compounds. Germanaism B was the most abundant component in the rhizomes of I. variegata (7.089 ± 0.032 mg/g) and I. hungarica (6.285 ± 0.030 mg/g). The compound analyses showed good calibration curve linearity (r2 > 0.999) and low detection and quantifications limit. These results validated the method for its use in the simultaneous quantitative evaluation of phenolic compounds in the studied Iris sp. I. hungarica and I. variegata rhizomes exhibited antioxidant activity, as demonstrated by the HPLC-ABTS system and NRF2 expression assay and anti-inflammatory activity on respiratory burst in human neutrophils. Moreover, the extracts showed anti-allergic and cytotoxic effects against cancer cells. Anti-coronavirus 229E and lipid formation activities were also evaluated. In summary, potent antioxidant marker compounds were identified in the examined Iris sp.

Meng-Jie Wang,1 Yu-Hang Zhao,2 Chen Fan,3 Ying-Jie Wang,3 Xin-Qi Wang,3 Xiang-Jun Qiu,3 Rui-Le Shen1 1Department of Neurology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, 471003, People’s Republic of China; 2School of Medical Imaging, Hangzhou Medical College, Hangzhou, 310051, Zhejiang, People’s Republic of China; 3Department of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, Henan, People’s Republic of ChinaCorrespondence: Xiang-Jun QiuDepartment of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, Henan, People’s Republic of ChinaEmail lyxiangjun@126.comRui-Le ShenDepartment of Neurology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, Henan, People’s Republic of ChinaEmail yfyshenruile@126.comBackground: Upadacitinib, a novel selective Janus kinase 1 (JAK1) inhibitor, has been recently approved by the US FDA for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantitative analysis of upadacitinib in beagle dog plasma was developed and validated.Methods: Upadacitinib and fedratinib (internal standard, IS) were extracted with ethyl acetate under alkaline condition and then separated and detected. The chromatographic column was Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm), the mobile phase was acetonitrile and 0.1% formic acid in water with gradient elution procedure, and the flow rate was 0.40 mL/min. Under the positive ion mode, upadacitinib and IS were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 447.00 → 361.94 for upadacitinib and m/z 529.82 → 141.01 for IS.Results: In the concentration range of 1– 500 ng/mL, upadacitinib had good linearity, and the lower limit of quantification (LLOQ) was 1 ng/mL. The RSD of the intra- and inter-day precision was less than 10.03%, and the RE of accuracy was − 3.79% to 2.58%. The extraction recovery of upadacitinib was more than 80%, the matrix effect was around 100%, and upadacitinib was found to be stable.Conclusion: The novel optimized UPLC-MS/MS assay was an effective tool for the determination of upadacitinib and had been successfully applied to the pharmacokinetic study of upadacitinib in beagle dogs, and this method would also be used to study DDIs.Keywords: upadacitinib, UPLC-MS/MS, pharmacokinetic, beagle dog

Xiaohai Chen,* Hualu Wu,* Haoxin Fu, Peiqi Wang, Lu Cao, Ruibin Li, Ruanjuan Zhan, Ren-Ai Xu Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Ruanjuan Zhan, Email zhanruanjuan@163.com Ren-Ai Xu, Email ysxurenai@hotmail.comBackground: Due to the high risk of invasive fungal disease (IFD) in acute myeloid leukemia (AML) patients, the antifungal drug posaconazole is often co-administered with venetoclax. As posaconazole is a potent inhibitor of CYP3A4, the standard dosing regimen may lead to the elevated plasma concentrations of venetoclax due to potential drug-drug interactions (DDIs). Therefore, therapeutic drug monitoring (TDM) is necessary to optimize the dosage.Methods: This study developed and validated a rapid and sensitive ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the simultaneous quantification of venetoclax and posaconazole in human plasma. Plasma samples were pretreated using acetonitrile precipitation. The chromatographic separation was achieved using an Acquity BEH C18 column with gradient elution. The mobile phase consisted of 0.1% formic acid in water and acetonitrile, with a flow rate of 0.4 mL/min.Results: The method demonstrated good sensitivity and linearity within the concentration ranges of 10– 15,000 ng/mL for venetoclax and 10– 10,000 ng/mL for posaconazole, respectively. Additionally, the method showed acceptable selectivity, intra-day precision, inter-day precision, accuracy, matrix effects (95.2% to 102.0% for venetoclax and 98.4% to 102.5% for posaconazole), extraction recovery (93.2% to 95.4% for venetoclax and 87.8% to 95.8% for posaconazole), and stability under various conditions. The trough concentrations of venetoclax were 9326.88 ± 12,169.05 ng/mL in patients treated with venetoclax alone, and 31,623.55 ± 28,453.67 ng/mL in patients treated with venetoclax in combination with posaconazole.Conclusion: A rapid and simple method was established and successfully applied to the simultaneous determination of the concentrations of venetoclax and posaconazole in AML patients, providing a basis for TDM and clinical pharmacokinetic analysis of these drugs in AML patients.Keywords: invasive fungal disease, acute myeloid leukemia, therapeutic drug monitoring, UPLC-MS/MS

Hailun Xia,1 Yuxin Shen,1,2 Xinhao Xu,1,2 Jun Wu,1,2 Guanyang Lin,1,2 Xiaoxiang Du1 1Department of Pharmacy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China; 2School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of ChinaCorrespondence: Guanyang Lin; Xiaoxiang Du, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People’s Republic of China, Email 13867702133@163.com; 16336596@qq.comPurpose: Zanubrutinib, a second-generation Bruton’s tyrosine kinase (BTK) inhibitor, has been demonstrated to treat multiple B-cell malignancies, which include Waldenström’s macroglobulinemia, chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma and mantle cell lymphoma (MCL). There have been very few studies of drug–drug interactions (DDI) between zanubrutinib and other medications.Methods: The current study validated a sensitive and reliable quantitative detection of zanubrutinib and posaconazole in rat plasma using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The plasma samples were prepared by protein precipitation with the addition of acetonitrile, using orelabrutinib and fluconazole as internal standards (IS). Fifteen male Sprague-Dawley (SD) rats were randomly and equally divided into three groups: posaconazole (40 mg/kg) administered orally alone, zanubrutinib (16 mg/kg) received orally alone, co-administered orally zanubrutinib (16 mg/kg) and posaconazole (40 mg/kg).Results: The methodology was validated, and the precision, stability, accuracy, matrix effect and extraction recovery were within the permissible values. This method was successfully applied to evaluate the potential DDI between zanubrutinib and posaconazole, and the results showed a significant 0.98-fold increase in both AUC0-t and AUC0-∞ of zanubrutinib when zanubrutinib was administered concomitantly with posaconazole. In addition, posaconazole significantly increased AUC0-t, AUC0-∞, Tmax, and Cmax of zanubrutinib by 2.31-, 4.78-, 2.93-, and 0.86-fold, respectively, while CLz/F significantly decreased by 83.5%.Conclusion: These data suggested that when zanubrutinib was co-administered with posaconazole, there are increased exposures to both zanubrutinib and posaconazole. The current results contributed to a better understanding of the metabolism and DDI of zanubrutinib and posaconazole, and it is necessary to further investigate and validate the results in humans.Keywords: zanubrutinib, drug–drug interaction, posaconazole, pharmacokinetics, UPLC-MS/MS

Occurrence of toxigenic molds and mycotoxins on dried fruits is a worldwide problem, but limited information is available in China. A total of 220 dried fruits (raisins, dried apricots, dates and wolfberries) purchased from China were analyzed for 17 mycotoxins (i.e., Alternaria toxins, ochratoxin A (OTA), patulin (PAT) and trichothecenes) by UPLC-MS/MS, combined with a single-step cleanup. The result showed that at least one mycotoxin was detected in 142 samples (64.6%). The lowest incidence of contaminated samples was observed in dried apricots (48.2%), and the highest incidence in dried wolfberries (83.3%). The Alternaria toxins seemed to be the major problem in dried fruits, rather than OTA or PAT. Tenuazonic acid (TeA) was the predominant mycotoxin, in both frequency and concentration, ranging from 6.9 to 5665.3 μg kg−1, followed by tentoxin (TEN; 20.5%), and mycophenolic acid (MPA; 19.5%). Moreover, raisins are more likely to be contaminated with OTA than the other dried fruits. Penicillic acid (PA) was detected only in dried dates, and PAT was detected only in one apricot sample. In addition, our results also showed that the simultaneous presence of 2–4 mycotoxins was observed in 31.4% of dried fruits. TeA and TEN were the most frequent combination, detected in 29 (13.2%) samples, followed by TeA and MPA with a prevalence of 11.4%. Therefore, the results of this survey suggest the need for wider monitoring on the contamination of these mycotoxins, especially Alternaria toxins in agro-products, and indicate the importance of setting a maximum limit for Alternaria toxins in China.

Human milk extracellular vesicles (HMEVs), secreted by mammary epithelial cells, are enriched in bioactive molecules that support intestinal epithelial integrity. Among these, oxylipins, that is, lipid mediators derived from polyunsaturated fatty acids, are gaining interest for their immunomodulatory and neuroprotective functions in breastfed infants. However, current workflows for oxylipin profiling in HMEVs often lack sensitivity or breadth, limiting mechanistic insights. This study presents an optimised workflow for comprehensive oxylipin profiling in HMEVs. HMEVs were isolated via size‐exclusion chromatography and ultracentrifugation, followed by characterisation using attenuated total reflectance–Fourier transform infrared spectroscopy, Western blotting, Exoview immunocapture, tunable resistive pulse sensing and transmission electron microscopy. The influence of different pre‐analytical protocols on HMEV recovery was assessed. Cryolysis with liquid nitrogen was employed for vesicle lysis before targeted oxylipin quantification using ultra‐performance liquid chromatography–tandem mass spectrometry. The analysis of 10 human milk samples revealed 9,10‐DiHOME, 12,13‐DiHOME and 11,12‐EET as the most abundant oxylipins, with concentrations ranging from 0.5 to 3.7, 0.8 to 4.5 and 0.1 to 0.3 nM, respectively. This refined pipeline enables in‐depth oxylipin profiling in HMEVs and serves as a robust platform for future in vitro and in vivo investigations into EV‐mediated lipid signalling.

•We present a case report of an accidental poisonings with mitragynine and 7-hydroxymitragynine.•Toxicological findings are discussed.•An UPLC–MS/MS method for the quantitative determination of mitragynine and 7-hydroxymitragynine. An increasing number of drugs of abuse are sold word wide over the internet. Names like “legal highs”, “herbal highs” etc. give the impression that these are safe products, although the risk of fatal reactions might be substantial. Leaves from the plant Mitragyna speciosa, contain active compounds like mitragynine and 7-hydroxymitragynine. It has been reported that the potency of 7-hydroxymitragynine at the μ-opioid receptor is 30 times higher than that of mitragynine and 17 times higher than that of morphine. Case reports regarding poisoning with Kratom are reported, but the toxic or lethal ranges for the concentrations of the active substances have not been established, and concentrations of 7-hydroxymitragynine have not been reported previously. We present a case report where a middle aged man was found dead at home. The deceased had a history of drug abuse and mental illness for several years. At autopsy, there were no significant pathological findings. Post-mortem analysis of peripheral blood revealed: zopiclone 0.043mg/L, citalopram 0.36mg/L and lamotrigine 5.4mg/L, i.e. concentrations regularly seen after therapeutic ingestion of these drugs. Additionally mitragynine 1.06mg/L and 7-hydroxymitragynine 0.15mg/L were detected in blood and both also in urine. The high concentrations of mitragynine and 7-hydroxymitragynine indicate that the cause of death is intoxication by these substances; and the circumstances point toward the manner of death being accidental. We recommend that both mitragynine and 7-hydroxymitragynine are analyzed for in cases with suspected Kratom intoxication.

The global population is aging, and intervention strategies for anti-aging and the prevention of aging-related diseases have become a topic actively explored today. Nicotinamide adenine dinucleotide (NAD+) is an important molecule in the metabolic process, and its content in tissues and cells decreases with age. The supplementation of nicotinamide mononucleotide (NMN), an important intermediate and precursor of NAD+, has increased NAD+ levels, and its safety has been demonstrated in rodents and human studies. However, the high content of NMN in natural plants has not been fully explored as herbal medicines for drug development. Here, we identified that the leaf of Cinnamomum verum J. Presl (C. verum) was the highest NMN content among the Plant Extract Library (PEL) with food experience, using ultra-performance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS). To validate this result, the extraction and quantitative analysis of bark, leaf, root, and stem of fresh C. verum was conducted. The results revealed that the bark had the highest NMN content in C. verum (0.471 mg/100 g). Our study shed light on the prospects of developing natural plants in the context of NMN as drugs for anti-aging and prevention of aging-related diseases. The future should focus on the development and application of C. verum pharmaceutical formulations.

This study aimed to elucidate the clinical diagnostic value of plasma catecholamines and their metabolites for pheochromocytoma and paraganglioma (PPGL)‐induced secondary hypertension using ultraperformance liquid chromatography‐mass spectrometry (UPLC‐MS/MS). The study population included 155 patients with PPGL that were divided into the PPGL with hypertension ( n  = 79) and a PPGL without hypertension ( n  = 76) groups, and 90 healthy volunteers and 90 patients with primary hypertension as the control groups. UPLC‐MS/MS was performed to detect plasma levels of catecholamines and their metabolites, including dopamine, vanillylmandelic acid (VMA), norepinephrine, metanephrine, and normetanephrine. Receiver operating characteristic curves were generated to analyze the diagnostic value of the plasma levels of catecholamines and their metabolites in PPGL‐induced secondary hypertension. Patients in the primary hypertension and PPGL without hypertension groups had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal group (all p  < .05). On the other hand, patients in the PPGL with hypertension group had higher levels of dopamine, VMA, norepinephrine, metanephrine, and normetanephrine than patients in the normal, primary hypertension, and PPGL without hypertension groups (all p  < .05). Collectively, our findings showed that dopamine, VMA, norepinephrine, metanephrine, and normetanephrine are all effective biomarkers for the diagnosis of PPGL and PPGL‐induced secondary hypertension.

Aim: In China, warfarin is usually prescribed with Chuanxiong Rhizoma for treating thromboembolism diseases. However, the reason for their combination is still being determined. The present study explored the pharmacokinetics interactions of warfarin, Chuanxiong Rhizoma, and gut microbiota in the rat model of middle cerebral artery occlusion (MCAO). Methods: A total of 48 rats were randomly divided into six groups: MCAO rats orally administered warfarin (W group), pseudo germ-free MCAO rats orally administered warfarin (W-f group), MCAO rats co-administered Chuanxiong Rhizoma and warfarin (C + W group), pseudo germ-free MCAO rats co-administered Chuanxiong Rhizoma and warfarin (C + W-f group), MCAO rats co-administered warfarin and senkyunolide I (S + W group); pseudo germ-free MCAO rats co-administered warfarin and senkyunolide I (S + W-f group). After treatment, all animals’ blood and stool samples were collected at different time points. The stool samples were used for 16S rRNA sequencing analysis. Ultra-performance liquid chromatography coupled to tandem mass spectrometry (UPLC-MS/MS) method was established to quantify warfarin, internal standards, and the main bioactive components of Chuanxiong in blood samples. The main pharmacokinetics parameters of warfarin were calculated by DAS 2.1.1 software. Results: The relative abundance of Allobaculum and Dubosiella in the pseudo germ-free groups (W-f, C + W-f, S + W-f) was lower than that in the other three groups (W, C + W, S + W). The relative abundance of Lactobacillus in the W-f group was higher than that of the W group, while the relative abundance of Akkermansia decreased. The relative abundance of Ruminococcaceae _UCG-014 and Ruminococcaceae _NK4A214_group in the S + W-f group was lower than in the S + W group. Compared to the W group, the AUC 0-t and C max of warfarin in the W-f group increased significantly to 51.26% and 34.58%, respectively. The AUC 0-t and C max in the C + W group promoted 71.20% and 65.75% more than the W group. Compared to the W group, the AUC 0-t and C max increased to 64.98% and 64.39% in the S + W group. Conclusion: Chuanxiong Rhizoma and senkyunolide I (the most abundant metabolites of Chuanxiong Rhizoma aqueous extract) might affect the pharmacokinetics features of warfarin in MCAO rats through, at least partly, gut microbiota.