Identification of novel signal of proton pump inhibitor-associated drug reaction with eosinophilia and systemic symptoms: a disproportionality analysis.

BACKGROUND: Proton pump inhibitors (PPIs) are commonly prescribed for treating upper gastrointestinal hemorrhage, eradicating Helicobacter pylori, and stress ulcer prophylaxis, among other digestive system diseases. Recent case reports provided limited evidence of a correlation between PPIs and drug reactions with eosinophilia and systemic symptoms (DRESS). However, there is currently no established association between PPIs and DRESS. AIM: This research aimed to identify the associations between PPIs and DRESS using the US Food and Drug Administration Adverse Events Reporting System (FAERS) database. METHOD: A retrospective investigation of DRESS associated with six PPIs used FAERS data from Q1 2004 to Q3 2023. Data mining algorithms were used to identify adverse events in the FAERS database that met the following criteria: (1) proportional reporting ratio (PRR) ≥ 2; (2) reporting odds ratio (ROR) > 1; (3) 95% confidence interval (CI) of ROR > 1; (4) Chi-square (χ2) ≥ 4 and case count ≥ 3. RESULTS: There were 495 reports of PPI-related DRESS, including pantoprazole (174, 35.2%), omeprazole (103, 20.8%), lansoprazole (103, 20.8%), esomeprazole (101, 20.4%), rabeprazole (8, 1.6%), and dexlansoprazole (6, 1.2%). The results indicated a significant association of three PPIs (pantoprazole, omeprazole, and lansoprazole) with DRESS. The sensitivity analysis demonstrated that only pantoprazole remained significantly associated with DRESS after 10 concomitant drugs had been removed (ROR: 3.00, PRR: 2.99, and information component [IC]: 1.57). CONCLUSION: This study identified the signals suggesting a potential association between DRESS and six PPIs. However, more investigation of epidemiological data is required to validate of these conclusions.

Abundance, spatial variation, and sources of rare earth elements in soils around ion-adsorbed rare earth mining areas.

Rare earth elements (REEs) concentrated in soils have attracted increasing attention about their impact on soil health as emerging contaminants. However, the sources of REEs enriched in soils are diverse and need to be further investigated. Here, surface soil samples were collected from southern Jiangxi Province, China. REEs contents and soil physicochemical properties were determined, and cerium (Ce) and europium (Eu) anomalies were calculated. Moreover, we established a model to further identify the main sources of REEs accumulation in the studied soils. Results show that the abundance of soil REEs reveals larger spatial variation, suggesting spatially heterogeneous distribution of REEs. The median content of light REEs in soils (154.5 mg kg-1) of the study area was higher than that of heavy REEs and yttrium (35.8 mg kg-1). In addition, most of the soil samples present negative Ce anomalies and all the soil samples present negative Eu anomalies implying the combined effect of weathering and potential exogenous inputs on soil REEs. Positive matrix factorization modeling reveals that soil REEs content is primarily influenced by soil parent materials. Potential anthropogenic sources include mining-related leachate, traffic exhaust, and industrial dust. These results demonstrate that the identification of sources of soil REEs is an important starting point for targeted REEs sources management and regulation of excessive and potentially harmful REEs levels in the soil.

Interactive influences of meteorological and socioeconomic factors on ecosystem service values in a river basin with different geomorphic features.

Ecosystem service value (ESV) is influenced by land use and land cover (LULC), and is closely related to natural conditions and human activities. However, the interactions between human and natural systems and ESV remain unclear, especially concerning widely discussed meteorological and socioeconomic factors. In this study, three periods of LULC patterns (2000, 2010, and 2020) in the Haihe River Basin, northern China, were collected to determine the relationship between changes in LULC and ESV over time. Natural and socioeconomic data associated with ESV were obtained and the structural equation model was used to decouple interactions between these factors. Results showed that the total value of regional ecosystem services has decreased as cultivated land shrunk and artificial surfaces increased over the past two decades. The ESV was significantly decreased in the middle of the basin. The direct effects of meteorological factors and socioeconomic factors on ESV were positive (0.094) and negative (-0.203), respectively. The indirect effect of socioeconomic factors on ESV through meteorological and LULC factors was 0.149. Structural equation modeling demonstrated that under the dominance of LULC, interactions between natural and socioeconomic factors affected ESV in a complex manner. These results implied that identifying the direct and indirect effects of economic development and human activities on ESV could guide and implement effective land management policies.

A pharmacoeconomic evaluation of the pharmacotherapeutic options for painful diabetic neuropathy.

INTRODUCTION: Painful diabetic neuropathy (PDN) is a high incidence and severe complication of diabetes mellitus, significantly compromising patients' quality of life and causing tremendous economic burden. Considering drug costs becomes part of treatment decisions, with the growing choice of monotherapy or combination treatment strategies for PDN treatment. AREAS COVERED: This systematic review aims to identify the cost-effectiveness of pharmacotherapies in PDN, summarize key findings, and assess the quality of studies to inform healthcare resource allocation decisions and future research. Economic evaluations were identified by searching PubMed, Web of Science, Scopus and health technology assessment (HTA) databases, as well as screening reference lists of previously identified studies. Relevant data was extracted, and the CHEERS checklist was used to assess the quality of the studies. EXPERT OPINION: Collectively, the findings indicate that more pharmacoeconomics research is urgently needed to directly compare high-quality research for PDN combination medication/sequential treatment, and which is performed from a societal perspective. Simultaneously, to strengthen the reliability of the analysis, metrics such as adherence, incidence of adverse drug reactions, and pain levels utility value should be examined to verify the robustness of the basic results.

Effects of Avitinib on CYP450 Enzyme Activity in vitro and in vivo in Rats.

PURPOSE: Avitinib is the first third-generation epithelial growth factor receptor (EGFR) inhibitor independently developed in China and is mainly used for treating non-small cell lung cancer. However, pharmacokinetic details are limited. This study explored the in vivo and in vitro effects of avitinib on cytochrome CYP450 enzymes metabolic activity. METHODS: A rapid and sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for determining six probe substrates and their metabolites. Avitinib influence on activity levels of CYP isozymes was examined in vitro using human and rat liver microsomes (HLMs/RLMs). For in vivo studies, rats were pretreated with 30 mg/kg avitinib once daily for 7 days (avitinib multiple-doses group), 30 mg/kg avitinib on day 7 (avitinib single-dose group), or an equivalent amount of CMC-Na once daily for 7 days (control group), followed by intragastrical administration of the probe substrates (1 mg/kg tolbutamide and 10 mg/kg phenacetin, bupropion, chlorzoxazone, dextromethorphan, and midazolam). Plasma pharmacokinetics and IC50 values of the probe substrates were then compared. Pharmacokinetic parameters were determined using non-compartmental analysis implemented in a pharmacokinetic program. RESULTS: In vitro experiments revealed different inhibitory effects of avitinib on the six probe substrates with various IC50 values (bupropion, 6.39/22.64 µM; phenacetin, 15.79/48.36 µM; chlorzoxazone, 23.15/57.09 µM; midazolam, 27.64/59.6 µM; tolbutamide, 42.18/6.91 µM; dextromethorphan, 44.39/56.57 µM, in RLMs and HLMs respectively). In vivo analysis revealed significant differences (P <0.05) in distinct pharmacokinetic parameters (AUC(0-t), AUC (0-∞), Cmax, MRT(0-t), MRT (0-∞), and CLz/F) for the six probe substrates after avitinib pretreatment. CONCLUSION: A sensitive and reliable UPLC-MS/MS method was established to determine the concentration of six probe substrates in rat plasma. Avitinib had inhibitory effects on CYP450 enzymes, especially cyp2b1, cyp1a2 in RLMs, CYP2C9 in HLMs, and cyp1a2, cyp2b1, cyp2d1, and cyp2e1 in vivo. Our data recommend caution when avitinib was taken simultaneously with drugs metabolized by CYP450 enzymes.

HLA-A∗24:02 associated with lamotrigine-induced cutaneous adverse drug reactions: A systematic review and meta-analysis.

BACKGROUND: Several studies demonstrated a connection between human leukocyte antigen (HLA)-B∗1502 and lamotrigine (LTG)-induced cutaneous adverse drug reactions (cADRs). The correlation between the HLA-A∗24:02 and LTG-cADRs remains controversial. To examine the associations between HLA-A∗24:02 and LTG-cADRs, we conducted a systematic review and meta-analysis. METHODS: We performed a comprehensive search of the literature in several electronic database systems including Cochrane Library, EMBASE and PubMed from inception to January 2020. Review Manager was used to compare the frequencies of HLA-A∗24:02 carriers between the subgroups. RESULTS: A total of 5 studies were eligible, including 197 LTD-cADRs, 396 LTD-tolerant controls, and 2068 population controls. Compared with the LTG-tolerant controls, there was a statistically significant association between the HLA-A∗24:02 allele and LTG-induced cADRs (odds ratios: 1.94, 95% confidence intervals 1.06-3.54; P = .03). Compared with the general population, the relationship between the HLA-A∗24:02 genotype and LTG-induced cADRs was statistically significant (summary odds ratios: 2.12, 95% confidence intervals 1.04-4.30; P = .04). CONCLUSIONS: HLA-A∗24:02 may be a risk factor for LTG-cADRs.

Influences of Corydalis decumbens on the Activities of CYP450 Enzymes in Rats with a Cocktail Approach.

Corydalis decumbens, a Traditional Chinese Medicine, has been widely used for the alternative and/or complementary therapy of hypertension, arrhythmias rheumatoid arthritis, sciatica, stroke, hemiplegia, paraplegia, and vascular embolism. The aim of this study was to determinate the potential effects of Corydalis decumbens on the five cytochrome P450 (CYP) enzyme activities (CYP1A2, CYP3A4, CYP2C9, CYP2C19, and CYP2D6) by cocktail approach. To evaluate whether concurrent use of Corydalis decumbens interferes with the effect of several prescription drugs, saline (control group) or Corydalis decumbens (XTW group) were administrated via gavage for 7 successive days. A probe cocktail solution (phenacetin, omeprazole, metoprolol, tolbutamide, and midazolam) was given 24 h after the last dose of saline or Corydalis decumbens. A specific and sensitive UHPLC-MS/MS method was validated for the determination of five substrates and their metabolites in control group and XTW group. Our results indicated that Corydalis decumbens could have inductive effects of CYP2C19 and inhibit the activities of CYP1A2 and CYP3A4. However, Corydalis decumbens had no significant influence on CYP2C9 and CYP2D6. The herb-drug interaction should require more attention by careful monitoring and appropriate drug dosing adjustments to the concurrent use of western medications which were metabolized by CYP1A2, CYP2C19, and CYP3A4 in human-Corydalis decumbens, Cytochrome P450, Cocktail, Pharmacokinetics, herb-drug interactions.

Influences of Anlotinib on Cytochrome P450 Enzymes in Rats Using a Cocktail Method.

The present study aimed to investigate the effect of anlotinib (AL3818) on pharmacokinetics of cytochrome P450 (CYP) enzymes (CYP1A2, CYP2C6, CYP2D1, CYP2D2, and CYP3A1/2) by using five cocktail probe drugs in vivo. After pretreatment for 7 days with anlotinib (treatment group) or saline (control group) by oral administration, probe drugs phenacetin, tolbutamide, omeprazole, metoprolol, and midazolam were administered to rats by oral administration. Blood samples were obtained at a series of time-points and the concentrations of five probe drugs in plasma were determined by a UHPLC-MS/MS method. The results showed that treatment with anlotinib had no significant effect on rat CYP1A2, CYP2D2, and CYP2C6. However, anlotinib had a significant inductive effect on CYP2D1 and CYP3A1/2. Therefore, caution is needed during the concomitant use of anlotinib with other drugs metabolized by CYP2D1 and CYP3A1/2 because of potential drug-anlotinib interactions.

Effect of CYP2C9 Genetic Polymorphism in a Chinese Population on the Metabolism of Mestranol in vitro.

BACKGROUND: Mestranol is a widely used estrogen, which is converted into its active metabolite ethinyl estradiol by cytochrome P450 (CYP) 2C9. To comprehensively examine the enzymatic activity of reported CYP2C9 variants in Chinese individuals in response to mestranol, wild-type CYP2C9*1 and 35 allelic variants were highly expressed in Sf21 insect cell microsomes and used for the detection of their enzymatic values in vitro. These results showed that the majority of tested variants exhibited decreased clearance values compared to wild type, except for CYP2C9*40 and *36. METHOD: Insect microsomes expressing the 36 CYP2C9 variants were incubated with 0.25-8 µmol/l mestranol for 30 min at 37°C. Then, the production of the metabolite of mestranol, ethinyl estradiol, was analyzed using high-performance liquid chromatography. RESULTS: Most CYP-catalyzed reactions were sufficiently described by classical Michaelis-Menten kinetic parameters (e.g., Km and Vmax), while 9 variants exhibited atypical or non-Michaelis-Menten kinetic values, which were largely due to the self-inhibitory effect in response to mestranol. CONCLUSION: This is the first report of these rare alleles for mestranol metabolism, which provides fundamental data for further clinical studies on CYP2C9 alleles for mestranol metabolism.

Determination and pharmacokinetic study of pirfenidone in rat plasma by UPLC-MS/MS.

A rapid, sensitive and selective ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of pirfenidone in rat plasma. Sample preparation was accomplished through a simple one-step deproteinization procedure with 0.2 mL of acetonitrile to a 0.1 mL plasma sample. Plasma samples were separated by UPLC on an Acquity UPLC BEH C18 column using a mobile phase consisting of acetonitrile-0.1% formic acid in water with gradient elution. The total run time was 3.0 min and the elution of pirfenidone was at 1.39 min. The detection was performed on a triple quadrupole tandem mass spectrometer in the multiple reaction-monitoring (MRM) mode using the respective transitions m/z 186.2→92.1 for pirfenidone and m/z 237.1→194.2 for carbamazepine (IS), respectively. The calibration curve was linear over the range of 5-2000 ng/mL with a lower limit of quantitation (LLOQ) of 5 ng/mL. Mean recovery of pirfenidone in plasma was in the range of 80.4-84.3%. Intra-day and inter-day precision were both <12.1%. This method was successfully applied in pharmacokinetic study after oral administration of 10.0mg/kg pirfenidone in rats.

The effect of apigenin on pharmacokinetics of imatinib and its metabolite N-desmethyl imatinib in rats.

The purpose of this study was to determine the effect of apigenin on the pharmacokinetics of imatinib and N-desmethyl imatinib in rats. Healthy male SD rats were randomly divided into four groups: A group (the control group), B group (the long-term administration of 165 mg/kg apigenin for 15 days), C group (a single dose of 165 mg/kg apigenin), and D group (a single dose of 252 mg/kg apigenin). The serum concentrations of imatinib and N-desmethyl imatinib were measured by HPLC, and pharmacokinetic parameters were calculated using DAS 3.0 software. The parameters of AUC(0-t), AUC(0-∞), Tmax, V(z)/F, and CL(z)/F for imatinib in group B were different from those in group A (P < 0.05). Besides, MRT(0-t) and MRT(0-∞) in groups C and D differed distinctly from those in group A as well. The parameters of AUC(0-t) and Cmax for N-desmethyl imatinib in group C were significantly lower than those in group A (P < 0.05); however, compared with groups B and D, the magnitude of effect was modest. Those results indicated that apigenin in the short-term study inhibited the metabolism of imatinib and its metabolite N-desmethyl imatinib, while in the long-term study the metabolism could be accelerated.

The effect of glycyrrhetinic acid on pharmacokinetics of cortisone and its metabolite cortisol in rats.

The purpose of this paper is to study pharmacokinetics of cortisone (E) and its metabolite cortisol (F) in rats after administration of glycyrrhetinic acid (GA) and cortisone. Healthy male SD rats were randomized to be given 20 mg/kg E or E combined with 10 mg/kg GA. Blood samples were collected at 5, 10, 20, 40, 60, 90, 120, 150, 180, and 240 min after administration. The serum concentrations of E and F were determined by HLPC and pharmacokinetic parameters were calculated using DASver2.0 software. The parameters of AUC((0-t)), AUC((0-∞)), and C(max) for E in the group of E + GA were significantly higher than those in the group of E (P < 0.01); the half-time (t(1/2ß)) was extended compared to E (P < 0.05) and CL/F was dropped obviously (P < 0.01). The rise in AUC((0-t)), AUC((0-∞)), and C(max) for cortisol in the group of E + GA was significantly compared to the group of E (P < 0.01). CL/F was lower than E (P < 0.01) and the half-time (t(1/2ß)) was slightly extended. In this study, we find that GA restrains the metabolism of E and F and thus increases AUC, t(1/2ß), and C(max) of E and F, which may be related to its inhibition effect on 11ß-hydroxysteroid dehydrogenase (11ß-HSD).

[Toxicokinetics of paraquat in rabbits].

OBJECTIVE: to develop a high performance liquid chromatography method (HPLC) for the determination of paraquat in rabbit plasma and study its toxicokinetics in rabbits. METHODS: twelve rabbits were randomly divided into 2 groups with giving oral and intravenous administration of paraquat at a single dose of 60 mg/kg and 6 mg/kg respectively. The plasma paraquat concentrations were determined by HPLC and calculated by DAS pharmacokinetics program. RESULTS: the linear range of paraquat in plasma was 0.05 ∼ 50.00 mg/L (r = 0.9998). The relative recoveries of the assay were 99.41% ∼ 102.32%. The absolute recoveries of the assay were 83.72% ∼ 90.48%. Both the intra-day and inter-day validations were less than 10%. For oral administration, the toxicokinetics parameters of paraquat were as follows: Cmax (14.46 ± 2.35) mg/L, Tmax (1.63 ± 0.31) h, AUC(0-t) (177.61 ± 14.62) mg × h/L, AUC(0-∞) (182.24 ± 14.54) mg × h/L, While for intravenous administration, the toxicokinetics parameters of paraquat: Cmax (35.13 ± 5.53) mg/L, Tmax 0.05 h, AUC(0-t) (121.74 ± 12.30) mg × h/L, AUC(0-∞) (125.12 ± 12.17) mg × h/L, The difference of these parameters between the two groups had statistical significance (P < 0.05). The oral bioavailability was (14.66 ± 1.55)%. CONCLUSION: the oral bioavailability of paraquat is relatively low. The biological half life of paraquat is relatively long and there is no significant difference between oral administration and intravenous on biological half life. This method is simple, sensitive and accurate. It can be used for the investigation of paraquat in rabbits.

[Effects of forest cutting on greenhouse gas emissions from Larix gmelini-Sphagnum swamps in Lesser Xing' an Mountains of Heilongjiang, China].

By using static chamber and gas chromatography methods, this paper studied the effects of clear cutting and selective cutting on the CO2, CH4, and N2O emissions from Larix gmelini-Sphagnum swamp in Lesser Xing' an Mountains. Dramatic changes in the seasonal dynamics of CH4 and N2O emissions were detected in different treatment sites. Control site absorbed CH4 in summer and emitted CH4 in autumn, and absorbed N2O in both summer and autumn; selective cutting site emitted CH4 and N2O mainly in summer; and clear cutting site emitted CH4 in summer and autumn, and absorbed N2O in summer but emitted it in autumn. Cutting pattern had less effects on the seasonal dynamics of CO2 emission. Both on the clear cutting site and on the selective cutting site, the CO2 emission was in order of summer > spring > autumn. Forest cutting altered the source and sink functions of the sites. Control site functioned as a source of CO2 and a weak sink of CH4 or N2O, while forest cutting sites had a decrease of CO2 emission by 25%, and became a weak source of N2O and a weak or strong source of CH4. Compared with that of control site, the Global Warming Potential (GWP) of selective cutting site and clear cutting site was reduced by 24.5% and increased by 3.2%, respectively.