Search

Vancomycin (VAN) has a narrow therapeutic window and variable pharmacokinetic properties, which require timely monitoring of plasma concentration to adjust the dosage for better effectiveness. A sensitive and quantitative immunochromatographic method was developed to detect VAN in plasma. The linear response range of the method to detect plasma VAN was 1.25–50 μg/mL. The intra‐ and inter‐assay coefficients were 4.68% and 8.81%, respectively, while the recovery was 89.10%–98.32%. The clinical comparative experiment results demonstrated a good correlation (r > 0.90) between the fluorescent immunochromatographic strip test and the mass spectrum. In this study, a simple, rapid, and high‐sensitivity immunochromatographic method was established for detecting VAN, which helped establish the basis for further application of monitoring plasma concentration. [ABSTRACT FROM AUTHOR]

Mitofusin‐2 (MFN2) is a transmembrane GTPase that regulates mitochondrial fusion and thereby modulates mitochondrial function. However, the role of MFN2 in lung adenocarcinoma remains controversial. Here, we investigated the effect of MFN2 regulation on mitochondria in lung adenocarcinoma. We found that MFN2 deficiency resulted in decreased UCP4 expression and mitochondrial dysfunction in A549 and H1975 cells. UCP4 overexpression restored ATP and intracellular calcium concentration, but not mtDNA copy number, mitochondrial membrane potential or reactive oxygen species level. Furthermore, mass spectrometry analysis identified 460 overlapping proteins after independent overexpression of MFN2 and UCP4; these proteins were significantly enriched in the cytoskeleton, energy production, and calponin homology (CH) domains. Moreover, the calcium signaling pathway was confirmed to be enriched in KEGG pathway analysis. We also found by protein–protein interaction network analysis that PINK1 may be a key regulator of MFN2‐ and UCP4‐mediated calcium homeostasis. Furthermore, PINK1 increased MFN2/UCP4‐mediated intracellular Ca2+ concentration in A549 and H1975 cells. Finally, we demonstrated that low expression levels of MFN2 and UCP4 in lung adenocarcinoma are associated with poor clinical prognosis. In conclusion, our data suggest not only a potential role of MFN2 and UCP4 in co‐regulating calcium homeostasis in lung adenocarcinoma but also their potential use as therapeutic targets in lung cancer. [ABSTRACT FROM AUTHOR]

Osimertinib is a highly selective third‐generation irreversible inhibitor of epidermal growth factor receptor mutant, which can be utilized to treat non‐small cell lung cancer. As the substrate of cytochrome P450 enzyme, it is mainly metabolized by the CYP3A enzyme in humans. Among the metabolites produced by osimertinib, AZ5104, and AZ7550, which are demethylated that is most vital. Nowadays, deuteration is a new design approach for several drugs. This popular strategy is deemed to improve the pharmacokinetic characteristics of the original drugs. Therefore, in this study the metabolism profiles of osimertinib and its deuterated compound (osimertinib‐d3) in liver microsomes and human recombinant cytochrome P450 isoenzymes and the pharmacokinetics in rats and humans were compared. After deuteration, its kinetic isotope effect greatly inhibited the metabolic pathway that produces AZ5104. The plasma concentration of the key metabolite AZ5104 of osimertinib‐d3 in rats and humans decreased significantly compared with that of the osimertinib. This phenomenon was consistent with the results of the metabolism studies in vitro. In addition, the in vivo results indicated that osimertinib‐d3 had higher systemic exposure (AUC) and peak concentration (Cmax) compared with the osimertinib in rats and human body. [ABSTRACT FROM AUTHOR]

Background and Purpose: Plasma triglyceride (TG) levels increase as gestation proceeds, and abnormal elevation of TG increases the risk of pregnancy complications. The current study explored the mechanisms involved in hypertriglyceridaemia during pregnancy. Experimental Approach: Lipid profile and expression levels of key genes involved in liver TG metabolism in non‐pregnant and pregnant mice were studied. The effects of pregnancy‐related hormones on key genes and the underlying mechanisms were uncovered in vitro and in vivo. Key Results: Plasma and hepatic TG levels were elevated, while hepatic fatty acid translocase (FAT/CD36) was up‐regulated in pregnant mice. Corticosterone and cortisol (endogenous glucocorticoids that are elevated during pregnancy), but not oestradiol or progesterone, significantly up‐regulated CD36 in hepatocytes, and this was abolished after knockdown of the glucocorticoid receptor (GR) using a siRNA or in the presence of GR antagonists, RU486 and AL082D06. The luciferase reporter gene and chromatin immunoprecipitation assay further revealed that corticosterone/cortisol promoted the direct binding of GR to the CD36 promoter and up‐regulated its transcription. Chronic corticosterone exposure induced liver lipid accumulation and increased plasma TG levels in mice, which were attenuated by RU486 via inhibition of the GR‐CD36 pathway. Conclusions and Implications: Increased corticosterone/cortisol induces liver lipid accumulation and hypertriglyceridaemia during pregnancy by accelerating fatty acid uptake into hepatocytes via activation of GR and its target gene, CD36. Our results may be useful for the prevention of severe hypertriglyceridaemia and associated pregnancy complications. [ABSTRACT FROM AUTHOR]

Background: An increasing number of cases of invasive pulmonary aspergillosis (IPA) complicating influenza have been described. We performed a meta‐analysis to estimate the incidence, risk factors and outcomes of IPA in patients with influenza. Methods: A systematic search was conducted in the PubMed, EMBASE and Cochrane Library databases from their inception to 31 August 2021 for eligible studies. Data on the incidence and risk factors of and mortality due to IPA in influenza patients were pooled using a random‐effects model. Sensitivity analyses restricted to severe influenza requiring intensive care unit (ICU) support and multiple subgroup analyses were performed. Results: Fourteen studies involving 6024 hospitalised patients with influenza were included. IPA was estimated to occur in 10% of influenza patients, with a mortality rate of 52%. Similar incidence (11%) and mortality (54%) estimates for IPA were observed in the sensitivity analysis including severe cases requiring ICU support. Subgroup analysis by geographical location showed a similar IPA rate between European (10%) and non‐European (11%) studies. The IPA rate in the subset of nine studies using the modified AspICU criteria was 13%. Most subgroup analyses showed ≥50% mortality in IPA patients. Several predictors for IPA susceptibility were identified, including male sex, smoking history, chronic lung disease, influenza A (H1N1), severe conditions requiring supportive therapy, corticosteroid use before admission, solid organ transplant and haematological malignancy. Conclusions: The IPA is common in individuals with severe influenza, and the prognosis is particularly poor. Influenza patients, especially those with high‐risk factors, should be thoroughly screened for IPA. [ABSTRACT FROM AUTHOR]

Aims: The association of renal function and linezolid‐induced thrombocytopaenia (LIT) remains controversial. We performed a meta‐analysis to determine whether impaired renal function is associated with an increased LIT risk. Methods: We conducted a systematic search of PubMed, EMBASE and the Cochrane Library from inception to February 2021 for eligible studies evaluating the relationship between renal function and LIT. Indicators of renal function included renal impairment (RI), severe RI, haemodialysis status, creatinine clearance rate (Ccr) and estimated glomerular filtration rate (eGFR). Unadjusted and adjusted estimates and 95% confidence intervals (CIs) were calculated separately using a random‐effect model. Results: A total of 24 studies with 3580 patients were included in the meta‐analysis. RI patients had an increased LIT risk compared to non‐RI patients in both the unadjusted (OR 3.54; 95% CI 2.27, 5.54; I2 = 77.7%) and adjusted analyses (OR 2.51; 95% CI 1.82, 3.45; I2 = 17.9%). This association persisted in the subset of studies involving only patients receiving a fixed conventional dose (600 mg every 12 h) and other subgroup analyses by ethnicity, sample size and study quality. Moreover, the LIT risk was significantly higher in patients with severe RI and haemodialysis than in patients without severe RI and haemodialysis. The eGFR and Ccr were significantly lower in LIT patients than in non‐LIT patients. Conclusions: Impaired renal function is associated with an increased risk of LIT. A reduced linezolid dose may be considered in RI patients at a low risk of treatment failure, ideally guided by therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Background and Purpose: Entecavir (ETV), a first-line antiviral drug against hepatitis B virus (HBV), has the possibility to be used to prevent mother-to-child transmission. The aim of present study was to clarify the mechanism of ETV uptake into hepatocytes and evaluate the alteration of ETV's hepatic distribution during pregnancy.Experimental Approach: The roles of equilibrative nucleotide transporter (ENT) 1 and organic anion transporter (OAT) 2 in ETV accumulation and anti-HBV efficacy were studied in human ENT1 or OAT2 overexpressed cell models and HepG2.2.15 cells, respectively; meanwhile, the liver-to-plasma ETV concentration ratios in non-pregnant and pregnant mice were measured to evaluate the effect of pregnancy on ETV hepatic distribution.Key Results: ETV was shown to be a substrate of ENT1 and OAT2. An ENT1 inhibitor significantly decreased the efficacy of ETV in HepG2.2.15 cells, while overexpression of OAT2 increased susceptibility of HBV to ETV. The liver-to-plasma ETV concentration ratios in pregnant mice were sharply reduced; whereas, the absolute concentration of ETV in the liver did not obviously alter in pregnancy. Although oestradiol and progesterone showed a concentration-dependent inhibition on ETV accumulation both in hepatic cell lines and in primary human hepatocytes, a physiologically relevant concentration of oestradiol and progesterone did not affect antiviral activity of ETV.Conclusions and Implications: OAT2 and ENT1 are the main transporters involved in the hepatic uptake and anti-HBV efficacy of ETV. The concentration of ETV in the liver was not obviously altered during pregnancy, which indicates that dosage adjustment in pregnancy is not necessary. [ABSTRACT FROM AUTHOR]

Ibrutinib is a small molecule drug that targets Bruton's tyrosine kinase in B‐cell malignancies and is highly efficient at killing mantle cell lymphoma and chronic lymphocytic leukemia. However, the anti‐cancer activity of ibrutinib against solid tumors, such as non‐small cell lung cancer (NSCLC), remains low. To improve the cytotoxicity of ibrutinib towards lung cancer, we synthesized a series of ibrutinib derivatives, of which Ibr‐7 exhibited superior anti‐cancer activity to ibrutinib, especially against epithelial growth factor receptor (EGFR) wild‐type NSCLC cell lines. Ibr‐7 was observed to dramatically suppress the mammalian target of Rapamycin complex 1 (mTORC1)/S6 signaling pathway, which is only slightly affected by ibrutinib, thus accounting for the superior anti‐cancer activity of Ibr‐7 towards NSCLC. Ibr‐7 was shown to overcome the elevation of Mcl‐1 caused by ABT‐199 mono‐treatment, and thus exhibited a significant synergistic effect when combined with ABT‐199. In conclusion, we used a molecular substitution method to generate a novel ibrutinib derivative, termed Ibr‐7, which exhibits enhanced anti‐cancer activity against NSCLC cells as compared with the parental compound. Ibr‐7 exhibits antitumor activity against EGFR wild‐type and mutant NSCLC cells via inhibition of the mTOR‐S6 pathway; the parent compound of Ibr‐7, ibrutinib, does not affect this pathway. The anti‐proliferation effect of Ibr‐7 against freshly cultured primary lung cancer cells was greater than that of ibrutinib and AZD‐9291, irrespective of pathological patterns or EGFR mutation status. [ABSTRACT FROM AUTHOR]

Gastric cancer is the fourth most common cancer in the world. The clinical applications of both chemotherapy and targeted drugs are limited because of the complexity of gastric cancer. In this study, sulforhodamine B, colony formation assay, 4',6-diamidino-2-phenylindole (DAPI) stain, flow cytometry were used to determine the in vitro cytotoxicity, apoptosis and mitochondrial membrane potential of gastric cancer AGS and HGC-27 cells before and after treatment. Real-time PCR and Western blot were used to analyse the mRNA transcription and protein expression respectively. Confocal microscopy was used to determine the localization of target protein within the cells. Treatment with the combination of ABT-737 and 2,5-dimethyl-celecoxib ( DMC) showed strong synergistic effect in both AGS and HGC-27 cells. Moreover, DMC would not influence the intracellular prostaglandin E2 (PGE2) level, thus lacking the toxicity profile of celecoxib. Interestingly, given the significant synergistic effect, combination treatment did not affect the protein expression of BH-3 proteins including Puma, Noxa and Bim. In combination treatment, cell apoptosis was found independent of caspase-3 activation. The translocation of apoptosis-inducing factor (AIF) from mitochondrion to nuclear was responsible for the induced apoptosis in the combination treatment. Taken together, this study provided a novel combination treatment regimen for gastric cancer. Furthermore, the existence of caspase-independent apoptotic pathway induced by treatment of ABT-737 was not yet seen until combined with DMC, which shed light on an alternative mechanism involved in Bcl-2 inhibitor-induced apoptosis. [ABSTRACT FROM AUTHOR]

The quantification of intracranial gefitinib (GEF) exposure is limited owing to the sensitivity of analytical equipment. Although mass spectrometry (MS) is the preferred method because of its high sensitivity, the equipment is not available in many laboratories, especially in developing Asian countries. In this paper, we developed a highly sensitive high performance liquid chromatography-diode array detector (HPLC-DAD) method for the assay of GEF in human cerebrospinal fluid (CSF) and plasma. GEF was extracted from CSF and plasma by solid-phase extraction and liquid-liquid extraction, respectively. The chromatographic separation was performed on a C18 column with gradient elution of 0.1% triethylamine solution and acetonitrile, then finally detected at 344 nm. This method was validated and proved to be highly sensitive with a lower limit of quantitation value of 0.11 ng/mL in CSF and 11 ng/mL in plasma. The blood-brain barrier penetration ratio of GEF ranged from 1.48 to 2.41%. This method provides a reliable MS-independent solution for the quantitation of GEF in patients' CSF and plasma. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Serum fibrinogen converted to insoluble fibrin by activated thrombin, plays an important role in the coagulation system. Increased fibrinogen considerably influences cancer cell growth, progression and metastasis. In nonsmall cell lung cancer (NSCLC), however, the association between serum fibrinogen concentration and prognosis has not been fully examined. We enlisted 567 operable NSCLC patients in our study. Preoperative serum fibrinogen was measured by the Clauss method. The association of serum fibrinogen concentration with clinical pathological factors and patient outcome was evaluated. Survival analysis indicated that serum fibrinogen was an independent prognostic factor in operable NSCLC. Patients with hyperfibrinogenemia had an elevated risk of disease progression and death compared to patients with normal fibrinogen levels. The hazard ratio was 1.49 (95% confidence interval [CI] 1.07-2.05) for disease progression and 1.64 (95% CI 1.06-2.53) for death. The trend linking increasing fibrinogen levels with risk was also statistically significant for both outcomes ( p < 0.05). These analyses were adjusted for patient age, sex, smoking behavior, disease stage, tumor grade and histology. Kaplan-Meier survival curves showed similar results. Preoperative serum fibrinogen is a novel independent prognostic biomarker in operable NSCLC. [ABSTRACT FROM AUTHOR]