A fully validated LC­MS/MS method for quantifying bevacizumab in plasma samples from patients with NSCLC and its implications in therapeutic drug monitoring.

Given the increasing use of bevacizumab in combinatorial drug therapy for a multitude of different cancer types, there is a need for therapeutic drug monitoring to analyze the possible correlation between drug trough concentration, and therapeutic effect and adverse reactions. An ultra-performance liquid chromatography tandem-mass spectrometry method was then developed and validated to determine bevacizumab levels in human plasma samples. Chromatographic separation was achieved on a Shimadzu InertSustainBio C18 HP column, whereas subsequent mass spectrometric analysis was performed using a Shimadzu 8050CL triple quadrupole mass spectrometer equipped with an electro-spray ionization source in the positive ion mode. In total, three multiple reaction monitoring transitions of each of the surrogate peptides were chosen with 'FTFSLDTSK' applied as the quantification peptide whereas 'VLIYFTSSLHSGVPSR' and 'STAYLQMNSLR' were designated as the verification peptides using the Skyline software. This analytical method was then fully validated, with specificity, linearity, lower limit of quantitation, accuracy, precision, stability, matrix effect and recovery calculated. The linearity of this method was developed to be within the concentration range 5-400 µg/ml for bevacizumab in human plasma. Subsequently, eight patients with non-small cell lung cancer (NSCLC) were recruited and injected with bevacizumab over three periods of treatment to analyze their steady-state trough concentration and differences. To conclude, the results of the present study suggest that bevacizumab can be monitored in a therapeutic setting in patients with NSCLC.

RAE1 promotes gastric carcinogenesis and epithelial-mesenchymal transition.

AIMS: The purpose of this study was to explore the role of RAE1 in the invasion and metastasis of gastric cancer (GC) cells. MATERIALS AND METHODS: RAE1 expression in GC cells was determined by reverse-transcription polymerase chain reaction (qRT-PCR) and Western blotting (WB). Cell models featuring RAE1 gene silencing and overexpression were constructed by lentiviral transfection; The proliferation, migration, and invasion ability of cells were detected by cell counting, colony formation assay, would healing assay, and transwell invasion and migration test. WB analysis of ERK/MAPK signaling pathway (ERK1/2, p-ERK1/2, c-Myc) and EMT-related molecules (ZEB1, E-cadherin, N-cadherin, and Vimentin). RESULTS: The expression level of RAE1 in GC was notably higher than in adjacent tissues. Elevated RAE1 expression correlated with an unfavorable prognosis for GC patients. Knockdown of RAE1, as compared to the control group, resulted in a significant inhibition of proliferation, migration, and invasion abilities in GC cell lines. Furthermore, RAE1 knockdown led to a substantial decrease in the expression of N-cadherin, vimentin, ZEB1, p-ERK1/2, and c-Myc proteins, coupled with a marked increase in E-cadherin expression. The biological effects of RAE1 in GC cells were effectively reversed by the inhibition of the ERK/MAPK signaling pathway using SCH772984. Additionally, RAE1 knockdown demonstrated a suppressive effect on GC tumor size in vivo. Immunohistochemistry (IHC) results revealed significantly lower expression of Ki-67 in RAE1 knockout mice compared to the control group. CONCLUSIONS: RAE1 promotes GC cell migration and invasion through the ERK/MAPK pathway and is a potential therapeutic target for GC therapy.

A fully validated method for simultaneous determination of icotinib, osimertinib, gefitinib and O-desmethyl gefitinib in human plasma using UPLC-MS/MS for therapeutic drug monitoring.

BACKGROUND AND AIMS: A few researches have reported the exposure-efficacy/toxicity relationships of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). On account of the large interpatient pharmacokinetic variability, therapeutic drug monitoring (TDM) seems promising for optimizing dosage regimen and improving treatment efficacy and safety. Therefore, a rapid and convenient ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the determination of icotinib, osimertinib, gefitinib and O-demesthyl gefitinib in human plasma for TDM. MATERIALS AND METHODS: Icotinib-D4 and osimertinib-13CD3 were used as the internal standards (ISs). The samples were prepared by protein precipitation using acetonitrile. Chromatographic separation was achieved on a 40 â„ƒ Shimadzu Shim-pack Scepter C18-120 column (2.1 ×50 mm, 3.0 µm, Japan) by a Shimadzu 30 A solvent management system. Detection was carried out using a Shimadzu LC-MS 8050CL triple quadrupole mass spectrometer coupled with an electrospray ionization source in positive mode. RESULTS: This analytical method was fully validated with selectivity, carry-over, linearity, lower limit of quantification, accuracy (from 92.68% to 106.62%) and precision (intra- and inter-day coefficients of variation ranged from 0.92% to 9.85%), matrix effect, extraction recovery, stability and dilution integrity. The calibration curves were developed to be within the concentration ranges of 200-4000 ng/mL for icotinib, 50-1000 ng/mL for osimertinib, gefitinib and O-desmethyl gefitinib in human plasma which meet the needs of routine TDM. CONCLUSIONS: The proposed method was used in 100 patients with non-small cell lung cancer for monitoring plasma concentration of the mentioned EGFR-TKIs. The trough concentrations of ICO were distributed between 226.42 ng/mL and 3853.36 ng/mL, peak concentrations were between 609.20 ng/mL and 2191.54 ng/mL. The trough concentrations of OSI were distributed between 110.48 ng/mL and 1183.13 ng/mL. The trough concentrations of GEF were distributed between 117.71 ng/mL and 582.74 ng/mL, while DeGEF was distributed from 76.21 ng/mL to 1939.83 ng/mL with two less than 20 ng/mL. The results of therapeutic drug monitoring aimed to investigate exposure-efficacy/toxicity relationship and improve the efficacy and safety of targeted therapies.

Severe adverse reaction induced by albendazole and praziquantel for cystic echinococcosis.

Albendazole and praziquantel have been used to treat various parasitic infections for many years. Studies have confirmed the efficacy in the treatment of cystic echinococcosis (CE). We reported the case of a 45-year-old Chinese patient with pulmonary CE. He experienced diarrhea, stomachache, increase bilirubin, hair loss and acute fatal pancytopenia 10 days after albendazole and praziquantel treatment. We performed a literature review of severe adverse reaction caused by albendazole and praziquantel. It showed that severe adverse reactions such as bone marrow suppression caused by albendazole or praziquantel are rare, but patients with a course of treatment exceeding 10 days or with liver diseases are more likely to experience. Clinicians should pay attention to monitoring the patient's gastrointestinal tract reaction and peripheral blood cells (PBCs). If the patient showed a progressive disease, the medication should be immediately stopped. Supportive treatments should be considered, such as the administration of granulocyte colony-stimulating factor (G-CSF) against neutropenia or antibiotics to prevent infection.

Impact of statin treatment and exposure on the risk of chronic allograft dysfunction in Chinese lung transplant recipients.

PURPOSE: Chronic lung allograft dysfunction (CLAD) was a common complication following lung transplantation that contributed to long-term morbidity and mortality. Statin therapy had been suggested to attenuate recipient inflammation and immune response, potentially reducing the risk and severity of CLAD. This study aimed to evaluate the impact of statin use and in vivo exposure on the incidence of CLAD in lung transplant recipients (LTRs), as well as their effects on immune cells and inflammatory factors. METHODS: A retrospective cohort study was conducted on patients who underwent lung transplantation between January 2017 and December 2020. The incidence of CLAD, as per the 2019 ISHLT criteria, was assessed as the clinical outcome. The plasma concentrations of statin were measured using a validated UPLC-MS/MS method, while inflammation marker levels were determined using ELISA kits. RESULTS: The statin group exhibited a significantly lower rate of CLAD (P = 0.002). Patients receiving statin therapy showed lower CD4+ T-cell counts, total T-lymphocyte counts, and IL-6 levels (P = 0.017, P = 0.048, and P = 0.038, respectively). Among the CLAD groups, the atorvastatin level (2.51 ± 1.31 ng/ml) was significantly lower than that in the non-CLAD group (OR = 1.438, 95%CI (1.007-2.053), P = 0.046). CONCLUSION: Statin therapy significantly reduced the incidence of CLAD, as well as immune cell counts and inflammatory cytokine levels in LTRs. Although the statin exposure was significantly lower in CLAD patients, it was not associated with the incidence of CLAD.

One Rare Warfarin Resistance Case and Possible Mechanism Exploration.

One 59-year-old female patient with deep venous thrombosis (DVT) and pulmonary embolism (PE) was treated with 6 mg warfarin once daily as an anticoagulant. Before taking warfarin, her international normalized ratio (INR) was 0.98. Two days after warfarin treatment, her INR did not change from baseline. Due to the high severity of the PE, the patient needed to reach her target range (INR goal = 2.5, range = 2~3) rapidly, so the dose of warfarin was increased from 6 mg daily to 27 mg daily. However, the patient's INR did not improve with the dose escalation, still maintaining an INR of 0.97-0.98. We drew a blood sample half an hour before administering 27 mg warfarin and detected single nucleotide polymorphism for the following genes, which were identified to be relevant with warfarin resistance: CYP2C9 rs1799853, rs1057910, VKORC1 rs9923231, rs61742245, rs7200749, rs55894764, CYP4F2 rs2108622, and GGCX rs2592551. The trough plasma concentration of warfarin was 196.2 ng/mL after 2 days of warfarin administration with 27 mg QD, which was much lower than the therapeutic drug concentration ranges of warfarin (500-3,000 ng/mL). The genotype results demonstrate that the CYP4F2gene has rs2108622 mutation which can explain some aspect of warfarin resistance. Further investigations are necessary to fully characterize other pharmacogenomics or pharmacodynamics determinants of warfarin dose-response in Chinese.

A combination of Beers and STOPP criteria better detects potentially inappropriate medications use among older hospitalized patients with chronic diseases and polypharmacy: a multicenter cross-sectional study.

BACKGROUND: Research on potentially inappropriate medications (PIM) and medication-related problems (MRP) among the Chinese population with chronic diseases and polypharmacy is insufficient. OBJECTIVES: This study aimed to investigate the prevalence of PIM and MRP among older Chinese hospitalized patients with chronic diseases and polypharmacy and analyze the associated factors. METHODS: A retrospective cross-sectional study was conducted in five tertiary hospitals in Beijing. Patients aged ≥ 65 years with at least one chronic disease and taking at least five or more medications were included. Data were extracted from the hospitals' electronic medical record systems. PIM was evaluated according to the 2015 Beers criteria and the 2014 Screening Tool of Older Persons' Prescriptions (STOPP) criteria. MRPs were assessed and classified according to the Helper-Strand classification system. The prevalence of PIM and MRP and related factors were analyzed. RESULTS: A total of 852 cases were included. The prevalence of PIM was 85.3% and 59.7% based on the Beers criteria and the STOPP criteria. A total of 456 MRPs occurred in 247 patients. The most prevalent MRP categories were dosages that were too low and unnecessary medication therapies. Hyperpolypharmacy (taking ≥ 10 drugs) (odds ratio OR 3.736, 95% confidence interval CI 1.541-9.058, P = 0.004) and suffering from coronary heart disease (OR 2.620, 95%CI 1.090-6.297, P = 0.031) were the influencing factors of inappropriate prescribing (the presence of either PIM or MRP in a patient). CONCLUSION: PIM and MRP were prevalent in older patients with chronic disease and polypharmacy in Chinese hospitals. More interventions are urgently needed to reduce PIM use and improve the quality of drug therapies.

Population Pharmacokinetics and Hemorrhagic Risk Analysis of Rivaroxaban in Elderly Chinese Patients With Nonvalvular Atrial Fibrillation.

Rivaroxaban is a popular direct factor Xa inhibitor used for anticoagulation therapy in patients with nonvalvular atrial fibrillation (NVAF). The aim of this study was to establish a population pharmacokinetic (PPK) model for rivaroxaban in elderly Chinese patients with nonvalvular atrial fibrillation, evaluate precision dosing regimens, and analyze hemorrhagic risk after rivaroxaban treatment. A 1-compartment population PK model with estimated glomerular filtration rate (eGFR), total bilirubin (TBIL), and ABCB1 rs1045642 as major covariates for apparent clearance was developed using the nonlinear mixed-effects model (NONMEM). A Monte Carlo simulation was performed to evaluate various dosing schemes and different levels of covariates for the target range of therapeutic drug-monitoring concentrations (Cmax,ss and Cmin,ss ). The exposure to rivaroxaban was simulated and assessed through hemorrhagic risk evaluation. The results showed that the average probability of target attainment (PTA) for optimal dosing regimens with different covariate levels for the targeted Cmax,ss and Cmin,ss were 29.35% to 31.3% and 64.91% to 65.8%, respectively. A dosage of 10 mg of rivaroxaban in elderly Chinese patients with normal renal and liver function was appropriate. The area under the concentration-time curve estimated over 24 hours with precision dosing at steady state (AUC24,ss ) was statistically significantly associated with an increased risk of bleeding events (OR 1.0006, 95%CI 1.0003 to 1.001, P < .0001), and the bleeding risk increased by 1.82-fold for every 1000 µg*h/L increase in AUC24,ss . A lower dose is recommended for elderly patients with renal impairment to avoid overexposure and bleeding events. The PPK model could inform individualized dosing for elderly Chinese patients with nonvalvular atrial fibrillation receiving rivaroxaban anticoagulation therapy.

Comparison of external system and implanted system in intrathecal therapy for refractory cancer pain in China: A retrospective study.

INTRODUCTION: Intrathecal therapy (ITT) via an implanted system was demonstrated for the treatment of refractory cancer pain for decades. Recently, the dissemination of ITT is enhanced in an external system way in Asia for a lower implantation cost. This study compares the efficacy, safety, and cost of the two ITT systems in refractory cancer pain patients in China. METHODS: One hundred and thirty-nine cancer pain patients who underwent implantation of the ITT system were included. One hundred and three patients received ITT via the external system (external group), while 36 patients received ITT via the implanted system (implanted group). A 1:2 propensity score matching procedure was used to yield a total of 89 patients for the final analysis. Medical records of included patients were retrospectively reviewed and pain scores, incidences of complications, and costs were compared. RESULTS: ITT via the external system provided pain relief as potent as ITT via the implanted system but was less time-consuming in the implantation phase (13 vs. 19 days, p < .01). Nausea/vomiting and urinary retention were the most frequent adverse events in both external and implanted groups (32.14%, 16.07% vs. 36.36%, 21.21%). No significant difference was found in the incidences of all kinds of complications. Compared to the implanted group, the external group cost less for the initial implantation (7268 vs. 26,275 US dollar [USD], p < .001) but had a significant higher maintenance cost (606.62 vs. 20.23 USD calculated monthly, p < .001). CONCLUSIONS: ITT via the external system is as effective and safe as that via the implanted system and has the advantage of being cheap in the upfront implantation but costs more during the maintenance process in China.

Effect of ABCB1 gene variants on rivaroxaban pharmacokinetic and hemorrhage events occurring in patients with non-valvular atrial fibrillation.

Hemorrhage events occur most frequently in anticoagulant therapy for non-valvular atrial fibrillation (NVAF). Rivaroxaban is used widely for routine anticoagulation care. Genetic polymorphisms are thought to contribute to the wide intraindividual variability seen in rivaroxaban metabolism and the anticoagulant response. The aim of this study was to evaluate the effect of drug transport related single-nucleotide polymorphisms (SNPs) on rivaroxaban metabolism and on the risk of a hemorrhage event. A total of 216 Chinese patients with NVAF were enrolled in the study. Rivaroxaban was used for anticoagulation therapy. Rivaroxaban plasma concentrations were detected using a validated ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Seven SNPs in four genes were genotyped using the Sanger dideoxy DNA sequencing method. Associations between genotype variants, the incidence of hemorrhage events, and the time of bleeding were analyzed. ABCB1 2677G (rs2032582) variation was highly associated with the dose-adjusted rivaroxaban peak concentration in plasma (Cmax /D) (p = 0.025, FDR = 0.042). The ABCB1 G allele carriers had a higher rivaroxaban Cmax /D than non-carriers. Logistic regression showed that rivaroxaban Cmax /D and ABCB1 genotype variants were associated with a higher incidence of hemorrhage events. No statistically significant difference was found between ABCB1 genotypes and the time of bleeding after anticoagulant therapy in 30 days. These results indicated that ABCB1 2677G (rs2032582) genetic variant affects the rivaroxaban Cmax /Dose and the incidence of hemorrhage events significantly.

The population pharmacokinetics and dose optimization of polymyxin B in critically ill patients with or without extracorporeal membrane oxygenation.

WHAT IS KNOWN AND OBJECTIVE: The presence of extracorporeal membrane oxygenation (ECMO) is suggested to further exacerbate the pharmacokinetics (PK) alterations that occur during critical illness. The objectives of this study were to determine the population PK model of polymyxin B in critically ill patients with or without ECMO support investigated the influence of ECMO on PK variability and to identify an optimal dosing strategy. METHODS: Forty-four critically ill patients were enrolled, including eight patients with ECMO support. Eight serial serum samples were collected from each patient at steady state. The population PK was determined using NONMEM and Monte Carlo simulation was performed to evaluate the exposures of different dosing regimens. RESULTS: The PK analyses included 342 steady-state concentrations and a two-compartment model was optimal for polymyxin B PK data modelling. In the final model, creatinine clearance (CLCR ) was the significant covariate on CL (typical value 1.27 L/h; between-subject variability 15.1%) and ECMO did not show a significant impact on the polymyxin B PK. Additionally, we found that the PK parameter estimates of patients with and without ECMO support were mostly similar. Based on Monte Carlo simulations, the dose escalation of polymyxin B in patients with increased CLCR improved the probability of achieving required exposure. For patients with CLCR ≤ 120 ml/min, a dosage regimen of 100 mg every 12 h may represent the optimal regimen at an MIC of 1 mg/L. WHAT IS NEW AND CONCLUSION: The impact of ECMO on the polymyxin B PK is likely to be minimal. Our study showed a potential relationship between CLCR and polymyxin B CL, and the dose of polymyxin B should be adjusted in patients with increased CLCR .

Effects of Voriconazole Exposure on the Pharmacokinetics of Tacrolimus in Lung Transplantation Patients, Based on Therapeutic Drug Monitoring Data.

Tacrolimus and voriconazole are usually used simultaneously in lung transplantations. Voriconazole can increase tacrolimus concentrations by inhibiting the cytochrome P450 (CYP) enzyme, which poses a great challenge for dose adjustment. The aim of this study is to clarify the correlation between voriconazole exposure and tacrolimus trough concentrations (C0 ), and to establish a population pharmacokinetic model including voriconazole trough concentrations (VOZ) as a covariate for dose optimization. All data were retrospectively collected from lung transplantation patients who were subjected to therapeutic drug monitoring of tacrolimus and voriconazole. The correlation between C0 and VOZ or voriconazole daily doses was analyzed by Spearman's correlation. A total of 52 patients accounting for 351 pairs of tacrolimus and voriconazole trough concentrations were included. C0 and C0 /daily dose of tacrolimus (DD) had a significant correlation with VOZ (P < .01) rather than voriconazole daily doses. A linear one-compartment model with first-order absorption and elimination was used as the basic model for population pharmacokinetic analysis. Body weight (WT), DD, VOZ, and hematocrit (HCT) were included as covariates in the final model. With the increase in voriconazole concentrations, the apparent total clearance (clearance/bioavailability, CL/F) of tacrolimus decreased significantly. The simulation results showed that the highest proportion of C0 within the target range can only reach <50% when the optimal initial drug regimen was given. Therefore, both tacrolimus and voriconazole concentrations need to be continuously monitored during treatments in lung transplantation patients, and the tacrolimus dose can be optimized according to VOZ based on the established pharmacokinetic model.

Comparison of the prevalence and nature of potentially inappropriate medication use in geriatric outpatients between tertiary and community healthcare settings: a multicenter cross-sectional study.

Background Geriatric outpatients with polypharmacy have a high risk of potentially inappropriate medication (PIM) use. Aim To identify differences in both prevalence and patterns of PIMs and drug-related problems (DRPs) in older outpatients who visited the tertiary hospitals (THs) and community health centers (CHCs) and analyze associated factors. Method A prospective cross-sectional study was conducted in five THs and five CHCs from September 2018 to November 2019 in Beijing, China. Data were collected from outpatients aged ≥ 65 years with chronic diseases and polypharmacy. PIMs were evaluated using the 2015 and 2019 Beers Criteria and the Screening Tool of Older Persons' Prescriptions (STOPP) criteria. DRPs were classified using the Helper-Strand DRP Classification. The prevalence and types of PIMs and DRPs were compared, and relevant factors were analyzed. Results The prevalence of PIMs based on the 2015 Beers Criteria was higher in patients from the THs, while PIMs based on the 2019 Beers Criteria did not show a significant difference. PIM prevalence based on STOPP Criteria and DRPs was higher in patients from CHCs. Visiting CHCs was an independent factor of PIMs based on the 2015 Beers Criteria (OR 0.774, 95% CI 0.604-0.992) and the STOPP Criteria (OR 2.427, 95% CI 1.883-3.128), and DRPs (OR 3.612, 95% CI 2.682-4.865). Conclusion Differences in PIM and DRP might be due to the patients and settings. Specific measures to improve the appropriateness of medications in both settings should be used.

The impact of cytochrome P450 3A5 genotype on early tacrolimus metabolism and clinical outcomes in lung transplant recipients.

Background Tacrolimus (Tac) is the cornerstone of immunosuppressant therapy after lung transplantation (LTx). It shows great inter-individual variability in pharmacokinetics, which could partly be explained by pharmacogenetic factors. Aim We aim to investigate the influence of cytochrome P450 3A5 (CYP3A5) genotypes on early post-LTx Tac metabolism and whether it is affected by concomitant use of azole antifungals. Also, we explored the association between CYP3A5 genotype and clinical outcomes. Method 90 recipients who underwent LTx from 2017 to 2019 were enrolled in the study. The effect of CYP3A5 genotype on Tac metabolism and interaction with azole antifungals were assessed during week 1-4 after transplantation. Associations between CYP3A5 genotype and the incidence of acute kidney injury (AKI), length of hospital stay and mortality were analyzed. ResultsCYP3A5*1 carriers had lower dose adjusted concentration (C/D) than CYP3A5*3/*3 group at all time points (p < 0.05). The dose ratio of CYP3A5*1 carriers to CYP3A5*3/*3 was between 1.3 and 2.4 when comparable concentrations were reached. Use of azole antifungals did not blunt the effect of CYP3A5 genotypes on Tac metabolism. Logistic regression showed Tac concentration ≥ 7.5 ng/mL at week 1 was associated with higher incidence of AKI. No statistically significant difference was found between CYP3A5 genotypes and the length of hospital stay. Kaplan-Meier analysis showed no statistically significant difference between 30-day or 1-year mortality and CYP3A5 genotype. Conclusion CYP3A5 genotype could affect Tac metabolism early after LTx. However, it had no influence on the incidence of AKI, length of hospital stay and mortality.

Effect of Continuing Nursing Education on the Quality of Nursing Management of Cancer Pain in China.

BACKGROUND: Limited knowledge and poor attitudes toward pain are major barriers to nursing management of cancer pain. This study investigated the effect of continuing nursing education (CNE) on the management of cancer pain. METHOD: Annual CNE was provided from 2016 to 2019, and evaluation of nursing management of cancer pain was conducted every 2 years. The effect of CNE was determined based on the evaluation results. RESULTS: After annual CNE, the participating hospitals showed significant improvement in nursing management of cancer pain. Annual CNE significantly increased subscores in all domains except the domain of initial pain assessment. In terms of hospital levels, nursing management of cancer pain was significantly improved only for tertiary A hospitals. CONCLUSION: Annual CNE significantly improved nursing management of cancer pain. [J Contin Educ Nurs. 2021;52(11):535-540.].

Retrospective analysis on incidence and risk factors of early onset acute kidney injury after lung transplantation and its association with mortality.

OBJECTIVES: Acute kidney injury (AKI) is a common complication after lung transplantation (LTx) which is closely related to the poor prognosis of patients. We aimed to explore potential risk factors and outcomes associated with early post-operative AKI after LTx. METHODS: A retrospective study was conducted in 136 patients who underwent LTx at our institution from 2017 to 2019. AKI was defined according to the Kidney Disease: Improving Global Outcomes (KDIGO) guideline. Univariate and multivariate analyses were conducted to identify risk factors related to AKI. The primary outcome was the incidence of AKI after LTx. Secondary outcomes were associations between AKI and short-term clinical outcomes and mortality. RESULTS: Of the 136 patients analyzed, 110 developed AKI (80.9%). AKI was associated with higher baseline eGFR (odds ratio (OR) 1.01 (95% confidence interval (CI): 1.00-1.03)) and median tacrolimus (TAC) concentration (OR 1.15 (95% CI: 1.02-1.30)). Patients with AKI suffered longer mechanical ventilation days (p = .015) and ICU stay days (p = .011). AKI stage 2-3 patients had higher risk of 1-year mortality (HR 16.98 (95% CI: 2.25-128.45)) compared with no-AKI and stage 1 patients. CONCLUSIONS: Our results suggested early post-operative AKI may be associated with higher baseline eGFR and TAC concentrations. AKI stage 1 may have no influence on survival rate, whereas AKI stage 2-3 may be associated with increased mortality at 1-year.

Validation of a novel UPLC-HRMS method for human whole-blood cyclosporine and comparison with a CMIA immunoassay.

Therapeutic drug monitoring is an essential tool when managing the therapeutic use of immunosuppressant cyclosporine A (CsA) in cases with solid organ transplantation. In China, the concentration of CsA is primarily measured using immunoassays. However, existing literature recommends mass spectrometry as the current gold standard for the quantitation of CsA. In the present study, it was attempted to develop a novel application to determine CsA concentrations by using ultra-performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-HRMS). This technique was then compared with a commercially available chemiluminescent microparticle immunoassay (CMIA) and it was investigated how clinical factors may contribute to quantitation differences between the two methods. An UPLC-Orbitrap-MS method was developed to determine CsA concentrations and this method was validated using guidelines put forward by the Food and Drug Administration from the US. In total, 127 blood samples were acquired from patients undergoing kidney transplantation and analyzed by UPLC-HRMS and CMIA assays. The novel method provided sensitive, accurate and precise results. The mean CsA concentration measured by CMIA was significantly higher than that measured by UPLC-HRMS (85.70±48.99 vs. 67.06±34.56 ng/ml, P<0.0001). Passing Bablok analysis yielded a slope of 1.34 (95% CI: 1.22-1.47) and an intercept of -2.54 (95% CI: -10.29-5.52). A group of samples with a higher metabolic ratio (hydroxylated CsA/CsA>1) exhibited larger discrepancies, while a group of samples taken from patients with a longer post-transplantation time (>10 years) featured narrow 95% CIs from -15.32 to 65.69%, as determined by Bland-Altman analysis. In summary, a reliable, accurate and rapid UPLC-HRMS method for CsA analysis was successfully developed. The measurement of CsA by the CMIA assay in renal transplant patients should be further evaluated with a specific focus on positive bias.

An in vitro approach to simulate the process of 5-fluorouracil degradation with dihydropyrimidine dehydrogenase: the process in accordance to the first-order kinetic reaction.

Partial or complete deficiency in the dihydropyrimidine dehydrogenase (DPD) has been observed in 3%-5% and 0.1% of the general population, respectively. It causes severe toxicity in the context of 5-fluorouracil (5-FU) therapy. However, the current tests for determination of DPD deficiency have limitations in routine clinical usage. Therefore, an in vitro approach for simulating 5-FU degradation was established by mixing 5-FU with blank whole blood matrix in this study. The effects of initial 5-FU concentrations and temperatures on DPD activities were investigated as well. The degradation process followed the first-order kinetic reaction (r2 > 0.98). The degradation rates were determined by temperature and individually different. The DPD inhibitor, gimeracil, could block this degradation, which indicated that DPD was the main factor. The degradation process of 5-FU in patients' whole blood in vitro was consistent with it after mixing 5-FU with blank whole blood matrix. In conclusion, mixing 5-FU with blank matrix can simulate the process of 5-FU degradation with DPD.

Estimation of the area under concentration-time curve of polymyxin B based on limited sampling concentrations in Chinese patients with severe pneumonia.

AIMS: The efficacy and toxicity of polymyxin B (PB) are closely related to its pharmacokinetic/pharmacodynamic (PK/PD) index area under the concentration-time curve (AUC) to minimum inhibitory concentration (MIC) ratio. The purpose of this study was to obtain PK data for PB in Chinese severe pneumonia patients and establish appropriate blood sampling time points for the PB therapeutic drug monitoring (TDM). SUBJECT AND METHOD: After treatment with at least four doses of PB (50 IU, q12h), the blood samples were collected immediately after the end of infusion (C0) and 1.5, 2, 4, 6, 8, and 12 h (C1.5, C2, C4, C6, C8, C12) after PB administration. The PB blood plasma concentrations were determined using an ultra-performance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS). All 42 patients were randomly divided into modeling (n = 24) and validation (n = 18) groups. The relationship between AUCss,24h and PB plasma concentration at each time point in modeling group was analyzed using limited sampling strategy and a PK method based on one-compartment with correction model. RESULTS: C6 scheme was found to provide the most accurate prediction of AUCss,24h values (r2 = 0.984) with the target value of 1.9-4.2 µg/ml at steady state to reach the 50-100 µg h/ml criteria of AUCss,24h. C0 with target value of 1.0-2.8 µg/ml can be considered an alternative sampling scheme (r2 = 0.900) but prediction deviation may exist. C0 and Cmax sampling scheme also demonstrated good predicting ability of AUC values using PK model. CONCLUSION: This study provides a clear plan for the implementation of TDM of PB, which is useful for optimizing the dosing regimen and individualizing treatment in severe pneumonia patients.

Impact of Continuing Medical Education for Physicians on the Quality of Cancer Pain Treatment in China.

CONTEXT: The management of cancer pain has gained attention in China since the proposal of the three-step analgesic ladder in 1986 and has been further improved after the Chinese Ministry of Health launched the campaign for "Good Pain Management Ward" in 2011. The Beijing Pain Management Center for Quality Control and Improvement was formed with the intent to improve the quality of pain management by various means such as providing continuing medical education (CME) and conducting evaluation in Beijing, the capital of China. OBJECTIVES: The objective of this study was to investigate the impact of CME on cancer pain treatment in hospitals in Beijing, China. METHODS: The Beijing Pain Management Center for Quality Control and Improvement carried out annual CME on cancer pain treatment for physicians in Beijing in February from 2016 to 2019. The quality of cancer pain treatment in these hospitals was evaluated in August 2015, 2017 and 2019 by using an evaluation instrument containing eight domains. The evaluation results were retrospectively reviewed to assess the impact of CME. RESULTS: After annual CME for four successive years, a significant increase in evaluation scores for cancer pain treatment was observed in the participating hospitals. The increased trend varied widely both among the levels of hospitals (secondary and two tiers of tertiary hospitals) and among evaluation domains. These hospitals scored lowest in domains related to opioid tolerance, ongoing care, and risk of nonsteroidal anti-inflammatory drugs in the last evaluation. CONCLUSION: CME significantly improved the quality of cancer pain treatment in the participating hospitals. Thus, standard CME courses may be adopted to improve the quality of cancer pain treatment by other regions in China and other countries.