Publications by authors named "Yimin Cui"

166 Publications

Target Drug-Calibrated Anti-Xa Activity Assays and Expected Peak-Trough Levels in an Asian Population: A Multicenter Study.

Am J Cardiovasc Drugs 2021 Jun 18. Epub 2021 Jun 18.

Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China.

Background: For patients taking factor Xa (FXa) inhibitors who have life-threatening bleeding, emergency surgery, drug interactions, etc., a rapid and precise assay is needed to monitor for potential medication failure, to assess safety during periprocedural anticoagulation management, and to manage the care of chronically anticoagulated patients. Anti-factor Xa (anti-Xa) activity assays have been recommended in guidelines, but the evaluation of different calibrations of anti-Xa activity assays and the data on the recommended range are still limited, especially in the Asian population.

Methods: This is a nationwide multicenter methodology exploratory study in an Asian population, including nine hospitals from Beijing, Shanghai, Liaoning, Shandong, Jiangsu, Anhui, Henan, Chongqing, and Fujian. A total of 485 healthy volunteers and 219 patients taking rivaroxaban or apixaban (single dose) were enrolled in the study. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS) was employed to detect plasma rivaroxaban and apixaban. The prothrombin time (PT), activated partial thromboplastin time (APTT), and levels of anti-Xa activity were tested as pharmacodynamic parameters in plasma samples. We evaluated the correlation of anti-Xa activity and blood concentration via HPLC-MS, and then compared the two methods of target drug-calibrated and low-molecular-weight heparin (LMWH)-antithrombin-calibrated anti-Xa activity. Correlations between variables were examined using Pearson's correlation analysis. Logistic regression was applied to evaluate significant differences in anti-Xa activity and blood concentration, using models adjusted by baseline characteristics.

Results: The results suggested anti-Xa activity had better correlation with blood concentrations of apixaban and rivaroxaban than APTT and PT (p < 0.001). Target drug-calibrated anti-Xa activity had better correlation with HPLC-MS results at every dose level and blood collection time (p < 0.001). The expected concentrations (ng/mL) derived from rivaroxaban-calibrated assays of rivaroxaban 10 mg, 15 mg, and 20 mg were about 210, 330, and 270 at peak concentrations, and 28, 44, and 58, respectively, at the trough concentrations.

Conclusions: In this study, we confirm that target drug calibration of anti-Xa activity is a better quantitative detection method for oral direct FXa inhibitors than LMWH-calibrated anti-Xa activity in clinical practice, and expected peak-trough levels are recommended for the Asian population.
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http://dx.doi.org/10.1007/s40256-021-00479-5DOI Listing
June 2021

Acid Suppression Use Among Infants in One Tertiary Children's Hospital in China, 2015-2018: A Retrospective Observational Study.

Front Pediatr 2021 21;9:679203. Epub 2021 May 21.

Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University, Beijing, China.

Clinical guidelines emphasized that physicians should be cautious when prescribing acid suppressions to infants. Histamine-2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) are not approved for use in infants aged below 2 years in China. We investigated H2RA/PPI use in infants aged below 2 years hospitalized between 1st January 2015 and 31st December 2018 in a Chinese tertiary children's hospital. Our study observed that H2RAs/PPIs were frequently prescribed with a prevalence of 4.4% (7,158/162,192). The frequency of PPI use was over two-fold than that of H2RA use (71.9%, 5,148/7,158; 28.1%, 2,011/7,158). H2RAs/PPIs were commonly used to treat infants without digestive system diseases (57.5%, 4,118/7,158). Further studies are urgently needed to evaluate the effectiveness and safety of H2RAs/PPIs in infants.
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http://dx.doi.org/10.3389/fped.2021.679203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175967PMC
May 2021

Effect of More Intensive LDL-C-Lowering Therapy on Long-term Cardiovascular Outcomes in Early-Phase Acute Coronary Syndrome: A Systematic Review and Meta-analysis.

Clin Ther 2021 Jun 3. Epub 2021 Jun 3.

Clinical Research Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China. Electronic address:

Purpose: The effect of more intensive LDL-C-lowering therapy (ILLT) on long-term cardiovascular outcomes during the early phase of acute coronary syndromes (ACSs) remains uncertain. We aimed to explore the influence of more intensive LDL-C-lowering therapyduring the early disease phase on long-term cardiovascular events among patients with ACSs.

Methods: Randomized controlled trials that focused on the effect of more ILLT during early-phase ACSs on long-term major adverse cardiac events (MACEs) were searched in electronic databases (MEDLINE, Embase, and Cochrane Central Register of Controlled Trials databases) from database inception until November 23, 2019. The end points included the incidence of MACEs, myocardial infarction, stroke, revascularization, heart failure, and death events. Study risk of bias was assessed using the Cochrane Collaboration tools. Fixed- or random-effects models and meta-regression were performed to evaluate the association between baseline/proportional reduction of LDL-C levels during early-phase disease and the risk of end points using risk ratios with 95% CIs.

Findings: A total of 53,199 participants were involved from 19 studies. The risk of MACEs decreased by 17% (95% CI, 0.76-0.90; P = 0.0012) for more intensive versus control therapy but varied by baseline and proportional reduction of LDL-C levels during early disease phase. The risk reduction of MACEs for more intensive versus control therapy among different subgroups was 26% (95% CI, 0.57-0.95; P = 0.06) with a baseline level >130 mg/dL, 23% (95% CI, 0.63-0.94; P = 0.02) with a baseline level of 100 to 130 mg/dL, and 10% (95% CI, 0.83-0.99; P = 0.07) with a baseline level <100 mg/dL. A significant difference of risk reduction for MACEs existed between patients treated with statin plus ezetimibe versus statin alone in the subgroup with a baseline level >130 mg/dL and proportional reduction >50%. Patients treated with more intensive therapy benefited from reduced risk of myocardial infarction, stroke, revascularization, and heart failure compared with control therapy.

Implications: More ILLT during early disease phase could significantly reduce the risk of long-term cardiovascular outcome in patients with ACSs. This benefit was most pronounced in patients with higher baseline and larger reduction of LDL-C levels in MACEs.
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http://dx.doi.org/10.1016/j.clinthera.2021.04.019DOI Listing
June 2021

Kynurenine metabolism and metabolic syndrome in patients with schizophrenia.

J Psychiatr Res 2021 Jul 8;139:54-61. Epub 2021 May 8.

Peking University HuiLongGuan Clinical Medical School, Beijing HuiLongGuan Hospital, Beijing, 100096, PR China. Electronic address:

Accumulating evidence indicates that a dysregulated kynurenine (KYN) pathway (KP) metabolism may play an important role in the pathogenesis of both schizophrenia and metabolic syndrome (MS). However, the underlying mechanisms remain poorly understood. Here, we aimed to evaluate the potential roles of KP in the pathogenesis of MS in schizophrenia. A total of 160 schizophrenia patients and 70 healthy controls were enrolled in this study. KP metabolites were quantified, and MS scores were calculated, for comparisons between patients and controls. Associations among the indices were explored in both groups. Multiple linear regression analyses were performed to investigate the effects of KP metabolites on MS factors. We observed a significantly higher MS score, lower levels of all KP metabolites, and higher nicotinamide adenine dinucleotide (NAD)/quinolinic acid (QUNA) in patients than in controls (all p < 0.01). Partial correlation analyses revealed that, in the patient group, QUNA and QUNA/KYN correlated positively with MS score (r = 0.24 and 0.27, respectively, both p < 0.025), and NAD/QUNA correlated negatively with MS score (r = -0.25, p = 0.002). Results of multiple regression analyses showed significant QUNA × group interactions in the model representing QUNA effects on MS score (β = 0.25) and a significant QUNA/KYN × group interaction in the model representing QUNA/KYN effects on MS score (β = 0.23) (both p < 0.001). Among all factors contributing to MS in schizophrenia, an interactive effect of schizophrenia itself and dysregulated KP plays a contributory role. Conceivably, modulation of the KP could theoretically lead to treating schizophrenia and MS simultaneously.
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http://dx.doi.org/10.1016/j.jpsychires.2021.05.004DOI Listing
July 2021

A cross-sectional study of chemotherapy-related AKI.

Eur J Clin Pharmacol 2021 May 15. Epub 2021 May 15.

Renal Division, Department of Medicine, Peking University First Hospital, and Institute of Nephrology, Peking University, Beijing, People's Republic of China.

Purpose: This study aims to detail the characteristics of chemotherapy-related acute kidney injury (CR-AKI) and investigate its effect on patient outcomes.

Methods: This is a multicenter cross-sectional study of cancer patients with CR-AKI screened from hospital-acquired adult AKI patients based on a nationwide AKI survey in China.

Results: Of the 3468 patients with hospital-acquired AKI, 258 cases of CR-AKI were identified. Of the patients, 20.1% (52/258) were ≥ 70 years old. Among the 258 CR-AKI cases, 61 (23.6%) reached AKI stage 3, and 75 (29.1%) reached AKI stage 2. The remaining 122 (47.3%) remained at AKI stage 1. A total of 413 chemotherapeutic agents were related to AKI, of which platinum compounds (24.5%, 101/413) were the most common. In-hospital mortality was 14.7% (38/258), and the rate of AKI non-recovery was 48.3% (100/207). AKI stage 3 (OR 2.930, 95% CI 1.156-7.427) and age ≥ 70 years (OR 3.138, 95% CI 1.309-7.519) were independent risk factors for in-hospital death. Compared to stage 2 or 3 AKI cases, a higher proportion of patients with stage 1 AKI did not recover their renal function (57.1% vs. 41.4% vs. 36.4%, P = 0.032). More AKI episodes were not recognized in patients with stage 1 AKI compared with the other two groups (82.8% vs. 60.0% vs. 36.1%, P < 0.001).

Conclusions: CR-AKI accounted for a noteworthy proportion of hospital-acquired AKI, and severe CR-AKI increased in-hospital mortality. Mild CR-AKI was more likely to be overlooked, and sustained kidney injury was common in this situation. Recognizing CR-AKI at an early stage and personalizing treatment should be emphasized in those undergoing chemotherapy.
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http://dx.doi.org/10.1007/s00228-021-03115-yDOI Listing
May 2021

MiR-205-5p suppresses angiogenesis in gastric cancer by downregulating the expression of VEGFA and FGF1.

Exp Cell Res 2021 Jul 4;404(2):112579. Epub 2021 May 4.

Department of General Surgery, Peking University First Hospital, Beijing, 100034, China. Electronic address:

Anti-angiogenic therapy represents one of the most promising treatment modalities for human cancers. However, the response to antiangiogenic therapy in gastric cancer (GC) remains dismal. To help identify new strategies for antiangiogenic therapy in GC, we evaluated miR-205-5p expression in GC tissues from TCGA database and our hospital, and its functions in angiogenesis were explored in vitro and in vivo. We investigated miR-205-5p expression and microvessel densities (MVDs) in GC tissues and liver metastases from patients. The function and mechanisms of miR-205-5p were examined in human cell lines and in xenograft mouse models. Associations between miR-205-5p expression and clinical characteristics were analyzed using either Pearson's χ test or Fisher's exact test. Differences in overall survival (OS) distributions were evaluated using the log-rank test. Differences in measurement data were compared using Student's t-test and one-way ANOVA. We found that miR-205-5p expression was downregulated in GC tissues and was negatively correlated with CD31 expression in both TCGA and our clinical samples. GC cell lines expressed low levels of miR-205-5p, and miR-205-5p upregulation significantly impaired the proliferation and angiogenesis of GC cells. Moreover, vascular endothelial growth factor A (VEGFA) and fibroblast growth factor 1 (FGF1) expression and activation of extracellular-related kinase (ERK) signaling were suppressed by miR-205-5p. MiR-205-5p inhibition promoted malignant phenotypes by enhancing VEGFA and FGF1 expression, as well as the activation of ERK signaling. Angiogenesis and ERK signaling were decreased in response to VEGFA and FGF1 downregulation induced by miR-205-5p overexpression. The dual-luciferase reporter assay showed that VEGFA and FGF1 were direct targets of miR-205-5p. Xenograft mouse models revealed that miR-205-5p suppressed tumor growth by inhibiting neovascularization. Altogether, these results demonstrate that miR-205-5p suppresses angiogenesis in GC by attenuating the expression of VEGFA and FGF1, indicating that upregulation of miR-205-5p may represent as an antiangiogenic therapy for GC.
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http://dx.doi.org/10.1016/j.yexcr.2021.112579DOI Listing
July 2021

Case report: Secondary sclerosing cholangitis induced by lapatinib and vinorelbine in a metastasis breast cancer patient.

Thorac Cancer 2021 Jun 6;12(12):1912-1916. Epub 2021 May 6.

Department of Pharmacy, Peking University First Hospital, Beijing, China.

Secondary sclerosing cholangitis (SSC) is a rare cholestatic liver disease that may have a severe clinical course. A 61-year-old woman with a history of metastasis breast cancer was admitted to our hospital for the second cycle of chemotherapy with lapatinib and vinorelbine. The patient had no reports of elevated liver function tests (LFTs) in the previous multiple chemotherapies or history of liver disease. However, the admission laboratory results showed severe cholestatic liver injury with the possibility of SSC by magnetic resonance cholangiopancreatography. Although chemotherapy was discontinued and patient was treated with hepatoprotective drugs, the LFTs did not improve and liver biopsy indicated mild injury of intrahepatic bile duct epithelium and hepatocyte. We added ursodeoxycholic acid and prednisolone to protect the liver, and laboratory data showed a response. To prevent the progression, lapatinib and vinorelbine were reintroduced and transient increases in alanine aminotransferase and γ-glutamyl transpeptidase were observed. With no evidence of viral or autoimmune liver disease, SSC induced by lapatinib and vinorelbine was diagnosed. This is the first case report of tyrosine kinase inhibitors and vinorelbine induced SSC and clinicians should be aware of the possibility of it. More case reports about this adverse drug reaction are needed to delineate optimal management.
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http://dx.doi.org/10.1111/1759-7714.13986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201538PMC
June 2021

Efficacy and Safety of Eculizumab for Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review and Meta-Analysis.

J Pediatr Hematol Oncol 2021 Apr 26. Epub 2021 Apr 26.

Departments of Pharmacy Pediatrics, Peking University First Hospital Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.

Background: Eculizumab is indicated for the treatment of paroxysmal nocturnal hemoglobinuria (PNH). This study aimed to evaluate the efficacy and safety of eculizumab in patients with PNH.

Methods: PubMed, EMBASE, The Cochrane Library, and ClinicalTrials.gov were searched for prospective interventional studies treating PNH with eculizumab. The primary outcome was the change in lactate dehydrogenase (LDH) levels, whereas secondary outcomes included the change in hemoglobin (Hb) levels, transfusion rates, and adverse drug events.

Results: Patients (n=235) from 6 studies were included in this meta-analysis. LDH and Hb levels and transfusion rates decreased significantly at 12, 26 weeks, 12, 15, and >15 months. The most frequent adverse events included nasopharyngitis (effect size [ES]: 0.53; 95% confidence intervals [CI]: 0.47 to 0.60; P=0.00), headache (ES: 0.47; 95% CI: 0.25 to 0.69; P=0.00), upper respiratory tract infection (ES: 0.37; 95% CI: 0.27 to 0.46; P=0.00), nausea (ES: 0.31; 95% CI: 0.24 to 0.38; P=0.00), fatigue, diarrhea, cough, pyrexia, abdominal pain, pain in extremities, and contusion.

Conclusion: Eculizumab is an effective and well-tolerated treatment for patients with PNH. It is effective at decreasing LDH levels and transfusion rates while increasing Hb levels. Further studies are needed to explore the safety of eculizumab.
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http://dx.doi.org/10.1097/MPH.0000000000002178DOI Listing
April 2021

Comparison of the Safety and Efficacy of Direct Oral Anticoagulants and Warfarin in Atrial Fibrillation or Venous Thromboembolism in Patients with Renal Impairment: Systematic Review, Meta-Analysis and Network Meta-Analysis.

Am J Cardiovasc Drugs 2021 Apr 4. Epub 2021 Apr 4.

Department of Pharmacy, Peking University First Hospital, No. 6 Dahongluohang Street, Xicheng District, Beijing, 100034, China.

Background: Due to the high risk of ischemic and arterial or venous bleeding events in atrial fibrillation (AF) or venous thromboembolism (VTE) patients with renal impairment (RI), selection of appropriate anticoagulant regimen is important. Therefore, we systematically reviewed and compared the safety and effects of oral anticoagulants in AF and VTE patients with RI.

Methods: Eligible articles were identified through a literature search in PubMed, Embase, ClinicalTrials.gov, and the Cochrane Library for studies published between January 2008 and November 2020. Network meta-analysis was conducted with STATA 14.0 to analyze the effects and safety of each drug with regard to different levels of renal function.

Results: 15 studies including 82,931 patients (76,957 with AF and 5974 with VTE) were analyzed. Compared with those of warfarin, the risk ratios of effect and safety outcomes of apixaban were 0.70 (95% confidence interval [CI] 0.60-0.82) and 0.56 (95% CI 0.42-0.76) in AF patients and 0.33 (95% CI 0.19-0.59) and 0.95 (95% CI 0.68-1.34) in VTE patients. Apixaban had the first or second highest probability of being ranked first with respect to surface under the cumulative ranking curve (SUCRA) scores in the prevention of major bleeding events, while in the prevention of ischemic events, rivaroxaban showed a higher SUCRA score (0.78-0.92) in mild RI patients and dabigatran showed a higher SUCRA value (0.90-0.99) in moderate RI patients.

Conclusions And Relevance: In the systematic review and meta-analysis, for AF or VTE patients with RI, direct oral anticoagulants performed comparably to or better than warfarin with regard to safety and effects. The network meta-analysis indicated that for patients with mild RI, apixaban might be safer for patients with a lower risk of ischemic events, while rivaroxaban might be suitable for patients with a lower risk of bleeding events. For patients with moderate RI, apixaban could reduce the risk of ischemic events without increasing the risk of bleeding events. For AF patients with severe RI, apixaban, rivaroxaban, and warfarin showed a similar effect. These results might provide suggestions for clinical arterial and venous thrombosis prevention.
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http://dx.doi.org/10.1007/s40256-021-00469-7DOI Listing
April 2021

The safety and efficacy of a novel method for treatment of HSIL.

Arch Gynecol Obstet 2021 Apr 3. Epub 2021 Apr 3.

Department of Obstetrics and Gynecology, Peking University First Hospital, Xicheng District, Beijing, 100034, China.

Purpose: To investigate the efficacy and safety of Nr-CWS on treatment of cervical HSIL.

Method: In this observational study, 16 patients were treated with Nr-CWS 1 time every 2 days for 6 times as one-course group (OC group), the other 184 patients were treated with Nr-CWS 1 time every 2 days for 12 times between 2 menstruations as two-course group (TC group). The medical information including age, HPV assay, vaginal-cervical cytology, and the pathological result of biopsy before and after treatment was collected. All patients were followed up at least twice after treatment. The LEEP was performed once the patients with persistent HR-HPV infection and/or abnormal TCT after the second follow-up.

Results: The cytology remission rate of cervical HSIL in OC and TC group was 100.0% and 87.8%, respectively, which were significant higher than the control (25.0%) with the P value of 2.00 × 10 and 2.06 × 10. Furthermore, HPV clearance rate was 87.5% and 70.2% in OC and TC group, respectively, which were significant higher than control (32.4%) with the P value of 2.74 × 10 and 2.18 × 10, respectively. Moreover, the more severe of cytology, the worse effect of HPV clearance for the HPV remission was 75.4%, 68.3%, 67.4%, 65.6% and 64.3% in the negative, LSIL, ASC-US, ASC-H, and HSIL group. 12 patients underwent LEEP after Nr-CWS treatment, 9 (75%) had persistent HSIL and 44.4% cases were found HSIL lesion in the cervical canal. There was no serious adverse reaction observed during treatment and follow-up, four patients were pregnant after treatment and no adverse pregnancy outcomes were observed.

Conclusion: Nr-CWS is an effective and safe drug for treatment of cervical HSIL for Chinese women, especially for cases without lesions in cervical canal.
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http://dx.doi.org/10.1007/s00404-021-06047-1DOI Listing
April 2021

Assessment of CPS + EG, Neo-Bioscore and Modified Neo-Bioscore in Breast Cancer Patients Treated With Preoperative Systemic Therapy: A Multicenter Cohort Study.

Front Oncol 2021 16;11:606477. Epub 2021 Mar 16.

Institute of Mental Health, Peking University, Beijing, China.

This study was to assess the prognosis stratification of the clinical-pathologic staging system incorporating estrogen receptor (ER)-negative disease, the nuclear grade 3 tumor pathology (CPS + EG), Neo-Bioscore, and a modified Neo-Bioscore system in breast cancer patients after preoperative systemic therapy (PST). A retrospective multicenter cohort study was conducted from 12 participating hospitals' databases from 2006 to 2015. Five-year disease free survival (DFS), disease specific survival (DSS), and overall survival (OS) were calculated using Kaplan-Meier Method. Area under the curve (AUC) of the three staging systems was compared. Wald test and maximum likelihood estimates in Cox proportional hazards model were used for multivariate analysis. A total of 1,077 patients were enrolled. The CPS + EG, Neo-Bioscore, and modified Neo-Bioscore could all stratify the DFS, DSS, and OS (all P < 0.001). While in the same stratum of Neo-Bioscore scores 2 and 3, the HER2-positive patients without trastuzumab therapy had much poorer DSS (P = 0.013 and P values < 0.01, respectively) as compared to HER2-positive patients with trastuzumab therapy and HER2-negative patients. Only the modified Neo-Bioscore had a significantly higher stratification of 5-year DSS than PS (AUC 0.79 . 0.65, P = 0.03). So, the modified Neo-Bioscore could circumvent the limitation of CPS + EG or Neo-Bioscore.

Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03437837.
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http://dx.doi.org/10.3389/fonc.2021.606477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009183PMC
March 2021

Effects of neuroactive metabolites of the tryptophan pathway on working memory and cortical thickness in schizophrenia.

Transl Psychiatry 2021 Apr 1;11(1):198. Epub 2021 Apr 1.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

A number of tryptophan metabolites known to be neuroactive have been examined for their potential associations with cognitive deficits in schizophrenia. Among these metabolites, kynurenic acid (KYNA), 5-hydroxyindole (5-HI), and quinolinic acid (QUIN) are documented in their diverse effects on α-7 nicotinic acetylcholine receptor (α7nAChR) and/or N-methyl-D-aspartate receptor (NMDAR), two of the receptor types thought to contribute to cognitive impairment in schizophrenia. In this study, serum levels of KYNA, 5-HI, and QUIN were measured in 195 patients with schizophrenia and in 70 healthy controls using liquid chromatography-tandem mass spectrometry; cognitive performance in MATRICS Consensus Cognitive Battery and cortical thickness measured by magnetic resonance imaging were obtained. Patients with schizophrenia had significantly lower serum KYNA (p < 0.001) and QUIN (p = 0.02) levels, and increased 5-HI/KYNA (p < 0.001) and QUIN/KYNA ratios (p < 0.001) compared with healthy controls. Multiple linear regression showed that working memory was positively correlated with serum 5-HI levels (t = 2.10, p = 0.04), but inversely correlated with KYNA concentrations (t = -2.01, p = 0.05) in patients. Patients with high 5-HI and low KYNA had better working memory than other subgroups (p = 0.01). Higher 5-HI levels were associated with thicker left lateral orbitofrontal cortex (t = 3.71, p = 2.94 × 10) in patients. The different effects of 5-HI and KYNA on working memory may appear consistent with their opposite receptor level mechanisms. Our findings appear to provide a new insight into the dynamic roles of tryptophan pathway metabolites on cognition, which may benefit novel therapeutic development that targets cognitive impairment in schizophrenia.
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http://dx.doi.org/10.1038/s41398-021-01311-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016899PMC
April 2021

Effects of microRNA-181b-5p on cognitive deficits in first-episode patients with schizophrenia: Mediated by BCL-2.

J Psychiatr Res 2021 04 14;136:358-365. Epub 2021 Feb 14.

Institute of Biomedicine and Translational Medicine, Department of Physiology, Faculty of Medicine, University of Tartu, Tartu, Estonia.

MicroRNA (miR)-181b-5p is considered to be involved in the pathogenesis of schizophrenia, and one of its regulatory target genes BCL-2 (B-cell lymphoma 2) is suggested to associate with cognition of schizophrenia. Cognitive deficit is a core trait of schizophrenia. However, it remains unclear whether miR-181b-5p affects cognition and its possible pathway in schizophrenia. We hypothesized that miR-181b-5p affects cognition by targeting BCL-2 mRNA and downregulating BCL-2 protein expression in schizophrenia patients. In this study, first-episode patients with schizophrenia (FEPS, n = 123) and age- and gender-matched healthy controls (HCs, n = 50) were enrolled in Chinese populations. Expression levels of miR-181b-5p and BCL-2 mRNA in peripheral whole blood were measured with quantitative real-time PCR (Q-PCR) and BCL-2 protein in plasma were measured with Enzyme Linked Immunosorbent Assay (ELISA). Psychopathology was assessed with the Positive and Negative Syndrome Scale (PANSS), cognitive function was evaluated using the MATRICS Consensus Cognitive Battery (MCCB). Peripheral blood miR-181b-5p expression level was significantly upregulated (p = 0.001) whereas BCL-2 mRNA and BCL-2 protein levels were significantly downregulated (p = 0.002, p = 0.023 respectively) in the FEPS compared with those in the HCs. The miR-181b-5p level was negatively (p = 0.005), whereas the BCL-2 mRNA level was positively (p < 0.001), correlated with working memory in FEPS. Mediating effect analysis showed that the effect of miR-181b-5p on working memory in the FEPS was exerted via targeting BCL-2 mRNA. MiR-181b-5p in combination with BCL-2 mRNA might be suggested as potential biomarker for schizophrenia in our discovery sample. In conclusion, overexpressed miR-181b-5p may affect cognitive function in patients with schizophrenia.
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http://dx.doi.org/10.1016/j.jpsychires.2021.02.003DOI Listing
April 2021

Dalfampridine in the treatment of multiple sclerosis: a meta-analysis of randomised controlled trials.

Orphanet J Rare Dis 2021 02 15;16(1):87. Epub 2021 Feb 15.

Department of Pharmacy, Peking University First Hospital, 6 Dahongluochang Street, Xicheng District, Beijing, 100034, China.

Background: Multiple sclerosis (MS) is a chronic illness involving the central nervous system (CNS) that is characterised by inflammation, demyelination, and degenerative changes. Dalfampridine is one of the available treatments for MS symptoms and comorbidities. This meta-analysis aimed to assess the safety and benefits of dalfampridine versus placebo in MS by summarising data deriving from previously published clinical randomised controlled studies (RCTs).

Results: A total of 9 RCTs were included in this meta-analysis, involving 1691 participants. There were significant differences between dalfampridine and placebo in terms of decreased 12-item Multiple Sclerosis Walking Scale score (weighted mean difference [WMD] =  - 3.68, 95% confidence interval [CI] [- 5.55, - 1.80], p = 0.0001), improved response to the timed 25-foot walk test (relative risk [RR] = 2.57, 95% CI [1.04, 6.33], p = 0.04), increased 6-min walk test (WMD = 18.40, 95% CI [1.30, 35.51], p = 0.03), increased 9-Hole Peg Test score (WMD = 1.33, 95% CI [0.60, 2.05], p = 0.0004), and increased Symbol Digit Modalities Test score (WMD = 4.47, 95% CI [3.91, 5.02], p < 0.00001). Significant differences in the incidence of side effects were also observed (RR = 1.12, 95% CI [1.04, 1.21], p = 0.002).

Conclusion: Dalfampridine exerts positive effects on walking ability, finger dexterity, and cognitive function. Treatment should be administered under the guidance of a physician or pharmacist given the higher incidence of adverse events.
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http://dx.doi.org/10.1186/s13023-021-01694-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885571PMC
February 2021

Influence of gene polymorphisms on the pharmacokinetics of aripiprazole in healthy Chinese subjects.

Pharmacogenomics 2021 03 15;22(4):213-223. Epub 2021 Feb 15.

GCP Center, West China Hospital, Sichuan University, Chengdu 610041, China.

Pharmacogenetics study was added into 2 bioequivalence trials of aripiprazole. The correlation between polymorphisms and aripiprazole pharmacokinetics (PK) was analyzed. A total of 140 subjects were included. A total of 26 gene alleles were detected. The plasma concentration of aripiprazole was measured by liquid chromatography-tandem mass spectrometry. was used to analyze the correlation between polymorphisms and aripiprazole PK parameters. All of the four PK parameters were significantly influenced by and . t and area under the concentration-time curve exhibited significant difference between extensive metabolizers and intermediate metabolizers. Aripiprazole PK was greatly influenced by . Attention should be paid to the possible dose adjustment for intermediate metabolizer population when the drug is used in Chinese patients.
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http://dx.doi.org/10.2217/pgs-2020-0134DOI Listing
March 2021

The microRNA-195 - BDNF pathway and cognitive deficits in schizophrenia patients with minimal antipsychotic medication exposure.

Transl Psychiatry 2021 Feb 8;11(1):117. Epub 2021 Feb 8.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Cognitive impairment is a core characteristic of schizophrenia, but its underlying neural mechanisms remain poorly understood. Reduced brain-derived neurotrophic factor (BDNF), a protein critical for neural plasticity and synaptic signaling, is one of the few molecules consistently associated with cognitive deficits in schizophrenia although the etiological pathway leading to BDNF reduction in schizophrenia is unclear. We examined microRNA-195 (miR-195), a known modulator of BDNF protein expression, as a potential mechanistic component. One-hundred and eighteen first-episode patients with schizophrenia either antipsychotic medication-naïve or within two weeks of antipsychotic medication exposure and forty-seven age- and sex-matched healthy controls were enrolled. MiR-195 and BDNF mRNA and BDNF protein levels in peripheral blood were tested. Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). MiR-195 was significantly higher (p = 0.01) whereas BDNF mRNA (p < 0.001) and protein (p = 0.016) levels were significantly lower in patients compared with controls. Higher miR-195 expression was significantly correlated to lower BDNF protein levels in patients (partial r = -0.28, p = 0.003) and lower BDNF protein levels were significantly associated with poorer overall cognitive performance by MCCB and also in speed of processing, working memory, and attention/vigilance domains composite score (p = 0.002-0.004). The subgroup of patients with high miR-195 and low BDNF protein showed the lowest level of cognitive functions, and miR-195 showed significant mediation effects on cognitive functions through BDNF protein. Elevated miR-195 may play a role in regulating BDNF protein expression thereby influencing cognitive impairments in schizophrenia, suggesting that development of cognition enhancing treatment for schizophrenia may consider a micro-RNA based strategy.
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http://dx.doi.org/10.1038/s41398-021-01240-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870897PMC
February 2021

N-methyl-D-aspartate Receptor Antibody and White Matter Deficits in Schizophrenia Treatment-Resistance.

Schizophr Bull 2021 Jan 30. Epub 2021 Jan 30.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.

Insufficient or lack of response to antipsychotic medications in some patients with schizophrenia is a major challenge in psychiatry, but the underlying mechanisms remain unclear. Two seemingly unrelated observations, cerebral white matter and N-methyl-D-aspartate receptor (NMDAR) hypofunction, have been linked to treatment-resistant schizophrenia (TRS). As NMDARs are critical to axonal myelination and signal transduction, we hypothesized that NMDAR antibody (Ab), when present in schizophrenia, may impair NMDAR functions and white matter microstructures, contributing to TRS. In this study, 50 patients with TRS, 45 patients with nontreatment-resistant schizophrenia (NTRS), 53 patients with schizophrenia at treatment initiation schizophrenia (TIS), and 90 healthy controls were enrolled. Serum NMDAR Ab levels and white matter diffusion tensor imaging fractional anisotropy (FA) were assessed. The white matter specificity effects by NMDAR Ab were assessed by comparing with effects on cortical and subcortical gray matter. Serum NMDAR Ab levels of the TRS were significantly higher than those of the NTRS (P = .035). In patients with TRS, higher NMDAR Ab levels were significantly associated with reduced whole-brain average FA (r = -.37; P = .026), with the strongest effect at the genu of corpus callosum (r = -.50; P = .0021, significant after correction for multiple comparisons). Conversely, there was no significant correlation between whole-brain or regional cortical thickness or any subcortical gray matter structural volume and NMDAR Ab levels in TRS. Our finding highlights a potential NMDAR mechanism on white matter microstructure impairment in schizophrenia that may contribute to their treatment resistance to antipsychotic medications.
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http://dx.doi.org/10.1093/schbul/sbab003DOI Listing
January 2021

Allostatic Load Effects on Cortical and Cognitive Deficits in Essentially Normotensive, Normoweight Patients with Schizophrenia.

Schizophr Bull 2021 Jan 27. Epub 2021 Jan 27.

Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD.

Reduced cortical gray matter integrity and cognitive abilities are among core deficits in schizophrenia. We hypothesized that higher allostatic load (AL) that accounts for exposure to chronic stress is a contributor to structural and cognitive deficits in schizophrenia. One hundred and sixty-seven schizophrenia patients who were on average with normal weight, normal systolic, and diastolic blood pressure and 72 healthy controls were enrolled in the study. Group differences in subclinical cardiovascular, metabolic, immune, and neuroendocrine biological markers as indexed by AL and contribution of AL components to the structural and cognitive deficits in schizophrenia were explored. Compared with controls, schizophrenia patients who were normotensive, normoweight, and had low total cholesterol levels still had significantly higher AL mainly due to lower high-density lipoprotein cholesterol and higher heart rate, waist-hip ratio, hemoglobinA1c, hypersensitive C-reactive protein, and overnight-urine cortisol levels. Patients also had decreased whole-brain mean cortical thickness, and lower cognition assessed by the MATRICS consensus cognitive battery. AL was inversely correlated with mean cortical thickness and cognition in schizophrenia, while none of these relationships existed in controls. Mediation analyses showed the effect of AL on cognitive deficits in schizophrenia was significantly mediated by cortical thinning, and the most significant mediating cortical area was the left superior frontal gyrus. Cortical thickness may act as a mediator between AL and cognitive deficits in schizophrenia. Early intervention strategies to reduce cortical thinning and cognitive dysfunction in schizophrenia should target specific aspects of their high AL in addition to weight gain, hypertension and high cholesterol levels.
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http://dx.doi.org/10.1093/schbul/sbaa196DOI Listing
January 2021

Effects of CYP2D6, CYP3A5, and ABCB1 gene polymorphisms on the pharmacokinetics of two risperidone long-acting injection microsphere formulations.

Prog Neuropsychopharmacol Biol Psychiatry 2021 Jul 2;109:110241. Epub 2021 Jan 2.

Department of Pharmacy, Peking University First Hospital, Beijing, China. Electronic address:

Background: LY03004, a novel investigational risperidone long-acting injection (LAI) microsphere formulation, can release risperidone more quickly after injection than Risperdal Consta®. This study aimed to investigate the effects of genetic polymorphisms on the pharmacokinetics of LY03004 compared with those on Risperdal Consta®.

Methods: A total of 100 Chinese patients with stable schizophrenia were randomly assigned to the LY03004 or Risperdal Consta® treatment group. Each patient received five biweekly intramuscular injections of 25 mg risperidone long-acting injection microspheres. A total of 34 blood samples before and after injections from Day 1 to Day 113 were collected from each patient, and polymorphic alleles of cytochrome P450 enzymes CYP2D6 (*4, *10, *14), CYP3A5 (*3), and ABCB1 (C1236 > T, G2677T/A, and C3435T) were analyzed using Sanger sequencing and polymerase chain reaction-restriction fragment length polymorphism.

Results: The risperidone C, C, AUC, and the ratio of risperidone to 9-hydroxyrisperidone (9-OH-R) in CYP2D6 intermediate metabolizers (IMs) were significantly different compared with those in normal metabolizers (NMs) in both the LY03004 and Risperdal Consta® groups (P < 0.05). However, 9-OH-R was not significantly different between IMs and NMs (P > 0.05). The AUC of the active moiety (risperidone plus 9-OH-R) was 6.51 ± 3.34 in NMs and 7.00 ± 1.81 in IMs (P = 0.071) in the LY03004 group and 6.07 ± 2.31 and 7.95 ± 3.42 (P = 0.053) in NMs and IMs, respectively, in the Risperdal Consta® group. In the LY03004 group, the C of risperidone in carriers of the ABCB1-C3435T TT variant was significantly lower than that in CC and CT carriers (TT 7.76 ± 4.23 ng/mL, CT 11.6 ± 8.27 ng/mL, CC 14.3 ± 7.66 ng/ml; P = 0.045), but no significant differences were found in the active moiety. In the Risperdal Consta® group, C3435T TT carriers had significantly lower C of the active moiety (TT 5.09 ± 4.38 ng/mL, CT 11.4 ± 8.42 ng/mL, CC 14.3 ± 6.43 ng/mL; P = 0.007). Furthermore, C of the active moiety was significantly different among all ABCB1-G2677T/A genotypes (P < 0.05).

Conclusion: The pharmacokinetics of risperidone and the ratio of risperidone to 9-OH-R were highly dependent on CYP2D6 activity. However, there was no significant effect in 9-OH-R. A future study involving a larger sample is required to verify whether CYP2D6 IMs have lower risperidone active moiety clearance than CYP2D6 NMs for LAI formulations. In addition, the risperidone active moiety was eliminated faster in ABCB1-G2677T/A and C3435T TT carriers receiving Risperdal Consta®.
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http://dx.doi.org/10.1016/j.pnpbp.2020.110241DOI Listing
July 2021

Plasma Magnesium Concentrations and Risk of Incident Cancer in Adults with Hypertension: A Nested Case-Control Study.

Ann Nutr Metab 2020 3;76(5):304-312. Epub 2020 Dec 3.

Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing, China.

Objective: The association between plasma magnesium and risk of incident cancer remains inconclusive in previous studies. We aimed to investigate the prospective relationship of baseline plasma magnesium concentrations with the risk of incident cancer and to examine possible effect modifiers.

Methods: A nested case-control study with 228 incident cancer cases and 228 matched controls was conducted using data from the China Stroke Primary Prevention Trial (CSPPT), a randomized, double-blind, controlled trial, conducted from May 2008 to August 2013. Study outcomes included incident cancer and its subtypes.

Results: When plasma magnesium concentrations were assessed as quartiles, a significantly higher incident risk of total cancer was found in participants in quartile 1 (<0.76 mmol/L; odds ratio [OR] = 2.70; 95% CI: 1.33-5.49) and quartile 4 (≥0.89 mmol/L; OR = 2.05; 95% CI: 1.12-3.76), compared with those in quartile 3 (0.83 to <0.89 mmol/L). In cancer site-specific analyses, similar trends were found for gastrointestinal cancer, esophageal cancer, gastric cancer, breast cancer, lung cancer, and other cancers. Furthermore, none of the variables, including age, sex, current smoking status, current alcohol intake, BMI, systolic blood pressure, and total cholesterol levels at baseline significantly modified the association between plasma magnesium and cancer risk.

Conclusions: Both low and high plasma magnesium concentrations were significantly associated with an increased incident risk of cancer, compared with the reference concentrations of 0.83 to <0.89 mmol/L among hypertensive adults.
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http://dx.doi.org/10.1159/000510214DOI Listing
December 2020

Randomised, double-blind, multicentre, phase Ⅰ/Ⅱ dose escalation and expansion trial of GR1501 in patients with plaque psoriasis: study protocol.

BMJ Open 2020 11 24;10(11):e039067. Epub 2020 Nov 24.

Department of Pharmacy, Peking University People's Hospital, Beijing, China

Introduction: Psoriasis is a life-long, immune-mediated disease that greatly reduces the quality of life of patients. Plaque psoriasis is the most common form of psoriasis. Treatment options for plaque psoriasis with good tolerance and sufficient response remain profoundly limited. Based on mechanistic findings that suggest the key pathogenic role of interleukin (IL)-17 in plaque psoriasis, we hypothesise that GR1501, a new monoclonal antibody (IL-17A targeted), will be an efficacious treatment for plaque psoriasis. This phase I/II trial aims to evaluate the safety, tolerability, pharmacokinetics, immunogenicity and preliminary efficacy of GR1501.

Methods And Analysis: A multicentre, randomised, double-blind, phase I/II dose escalation and expansion trial will be conducted at four hospitals in China. In total, 226 patients with plaque psoriasis will be enrolled in the study, with 46 cases in the dose-escalation stage and 180 cases randomised to GR1501 or the placebo in a 3:1 ratio in the expansion cohort. The primary outcomes are safety and tolerability; the secondary outcomes include pharmacokinetics, immunogenicity and efficacy.

Ethics And Dissemination: The study is in accordance with the Declaration of Helsinki, and the ethics approvals of the protocol have been obtained from the ethics committees of all participating centres, including Peking University People's Hospital, Chinese PLA General Hospital, The First Affiliated Hospital, College of Medicine, Zhejiang University and the Second Xiangya Hospital of Central South University. The findings of the study will be presented in published journals or at scientific conferences or meetings.

Trial Registration Number: ChiCTR1800017956.
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http://dx.doi.org/10.1136/bmjopen-2020-039067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689088PMC
November 2020

Anti-FXa-IIa activity test in Asian and its potential role for drug adherence evaluation in patients with direct oral anticoagulants: a nationwide multi-center synchronization study.

Cardiovasc Diagn Ther 2020 Oct;10(5):1293-1302

Department of Pharmacy, Peking University First Hospital, Beijing, China.

Background: The data of anti-FXa-IIa activity detection in Asian population is insufficient, and its potential role for drug adherence evaluation in patients with direct oral anticoagulants (DOACs) remains unclear. This study carried out multi-center anti-FXa-IIa activity detection in Asian, aiming to explore its applicability in Asian population and find its role in adherence evaluation.

Methods: We assessed patients' self-reported adherence using the Morisky, Green, and Levine Adherence Scale (MGLS) from six hospitals. Plasma samples were collected for peak and trough concentration determination, and anti-FXa-IIa chromogenic assay was conducted using rivaroxaban/dabigatran calibrators and controls. Multivariate logistic regression models, covariate adjustment and spearman's two-tailed test were conducted in the data analysis. This study had been registered in clinical trials (NCT03666962).

Results: In total, 271 patients taking rivaroxaban (n=149) or dabigatran (n=122) were enrolled. Among the 271 patients assessed by MGLS questionnaire, 188 persons (69.4%) showed high adherence, 77 persons (28.4%) was in intermediate adherence group, and only 6 patients (2.2%) had low adherence. Patients are more adherent dosed once daily of rivaroxaban compared to twice daily of dabigatran: 75.6% 63.6%. Anti-FXa-IIa activity had good linear correlation with routine coagulation indexes (P<0.001), but no significant association was found between drug adherence and anti-FXa-IIa activity (P>0.05).

Conclusions: This study confirms that anti-FXa-IIa activity detection based on target drug calibrations can be used as an effective index for pharmacodynamic evaluation in Asian population, but had limited value in drug adherence evaluation for DOACs. As the limited samples, these findings could serve as a hypothesis-generating effort, and should be validated in further studies with larger sample sizes.
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http://dx.doi.org/10.21037/cdt-20-564DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666955PMC
October 2020

Photodetection and Safety of 5-Aminolevulinic Acid-Induced Porphyrin in Patients With Cervical Intraepithelial Neoplasia.

Lasers Surg Med 2021 Jul 8;53(5):654-663. Epub 2020 Nov 8.

Department of Obstetrics and Gynecology, Peking University First Hospital, Beijing, 100034, China.

Background And Objectives: 5-Aminolevulinic acid (5-ALA) is a porphyrin-based photosensitizer and has been used for photodynamic therapy of cervical intraepithelial neoplasia (CIN). In this study, photodetection and safety of 5-ALA-induced porphyrin in CIN tissues were assessed.

Study Design/materials And Methods: A total of 42 patients for whom colposcopy or loop electrosurgical excision procedure (LEEP) was planned were administered 10%, 20%, or 30% 5-ALA locally on the surface of the cervix for 1.5-18 hours. At different times after application, the fluorescence intensity of 5-ALA-induced porphyrin on CIN and non-CIN lesions of the cervix was detected.

Results: Fluorescence intensity was correlated with drug concentration and application time. With 20% 5-ALA, the porphyrin fluorescence intensity increased over time, reaching a peak after 6 hours of application intervals in CIN. There was no significant difference in fluorescence intensity between CIN lesions and chronic cervicitis (benign tissue) or among CIN lesions of different severities. Three adverse events were considered related to the drug; however, these had no significant correlation with the drug concentration or application time.

Conclusions: 5-ALA at 10%-30% concentration is safe in patients with CIN. For further treatment, we recommend the application of 20% 5-ALA, 6 hours before photodynamic therapy in CIN.

Clinical Trial Registration: This study was registered at http://www.chinadrugtrials.org.cn (registration number: CTR20130326) in accordance with the requirements of the National Medical Products Administration in China. Considering that there is no English version of the above website, we made a retrospective registration on http://www.chictr.org.cn (registration number ChiCTR1800016755) in 2018. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.
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http://dx.doi.org/10.1002/lsm.23338DOI Listing
July 2021

Genotype-guided antiplatelet treatment versus conventional therapy: A systematic review and meta-analysis.

Br J Clin Pharmacol 2021 May 29;87(5):2199-2215. Epub 2020 Dec 29.

Department of Pharmacy, Peking University First Hospital, Beijing, China.

Aim: This meta-analysis was carried out to explore if a personalized antiplatelet strategy based on genotyping is superior to conventional therapy.

Methods: PubMed, Web of Science, EMBASE and the Cochrane Library were searched from the inception of each database to 5 May 2020. Studies reporting endpoints in genotype-guided treatment group and conventional treatment group were included. The endpoint results were presented as the risk ratio (RR), with 95% confidence interval (CI).

Results: A total of 10 561 patients from 16 studies (eight randomized controlled trials [RCT] and eight cohort studies) were included in the meta-analysis. The rates of major adverse cardiovascular events (MACE), stent thrombosis and myocardial infarction (MI) were significantly lower in the genotype-guided group than in the conventional treatment group (RR 0.56, 95% CI 0.44-0.73, P < .0001; RR 0.40, 95% CI 0.24-0.67, P = .0005; RR 0.45, 95% CI 0.35-0.58, P < .00001, respectively). A significant difference was found between the two groups in major bleeding (RR 0.73, 95% CI 0.55-0.98, P = .04), which was not robust after sensitivity analysis.

Conclusion: Genotype-guided antiplatelet treatment could decrease the risk of MACE, stent thrombosis and MI in patients with coronary artery disease or undergoing percutaneous coronary intervention, without increasing the risk of bleeding over a long follow-up period. The decreased risk of efficacy outcomes was more obvious in cohort studies. Well-organized RCTs and clinical trials are required to verify the benefit of genotype-guided therapy.
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http://dx.doi.org/10.1111/bcp.14637DOI Listing
May 2021

Immature defense mechanisms mediate the relationship between childhood trauma and onset of bipolar disorder.

J Affect Disord 2021 01 15;278:672-677. Epub 2020 Oct 15.

Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, PR China. Electronic address:

Background: Accumulating evidence has converged to suggest that childhood trauma may contribute to bipolar disorder (BD). This study aimed to investigate the patterns of childhood trauma among patients with bipolar I (BD-I) and bipolar II (BD-II) disorders, according to DSM-IV and in contrast with healthy volunteers. We also explored whether the relationship between childhood trauma and onset of bipolar disorder is mediated by immature defense mechanisms.

Methods: Participants were patients with BD-I (n=44) and BD-II (n = 42), and healthy controls (HCs, n = 43). Childhood traumatic experiences and defense mechanisms were assessed by the Childhood Trauma Questionnaire (CTQ) and the Defense Style Questionnaire (DSQ), respectively.

Results: BD patients experienced more severe childhood trauma than HCs. Physical neglect sub-score and total score of the CTQ had both direct and indirect effects on the diagnosis of BD-I, and an immature defense style mediated the indirect effects. The diagnosis of BD-II was mainly related to the physical neglect and emotional abuse subs-core and total score of the CTQ, as mediated by the immature defense mechanisms. BD-I and BD-II significantly differed in the emotional abuse sub-score of the CTQ.

Conclusions: Physical neglect sub-score and total score of the CTQ were associated with the diagnosis of BD (both BD-I and BD-II), as mediated by an immature defense style. Furthermore, emotional abuse might be an important risk factor for BD-II compared to BD-I. These findings may inform risk reduction and psychosocial intervention strategies to prevent and treat patients with bipolar disorders.
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http://dx.doi.org/10.1016/j.jad.2020.10.029DOI Listing
January 2021

Pharmacokinetic-Pharmacodynamic Analysis' Role in Design of Phase ⅠClinical Trials of Anticoagulant Agents: A Systematic Review.

Expert Rev Clin Pharmacol 2020 Nov 27;13(11):1191-1202. Epub 2020 Oct 27.

Department of Pharmacy, Peking University First Hospital , Beijing, People's Republic of China.

Introduction: There remains an unmet need for better anticoagulants. The phase I clinical trial is of great significance in the development of anticoagulants, and the design is special. This system review aims to provide insights for the design of future phase I clinical trials of anticoagulants.

Areas Covered: We searched the database PubMed and ClinicalTrail.gov website, to collate the phase I clinical trial of anticoagulants in healthy people. The study protocol, inclusion-exclusion criteria, safety, and pharmacodynamic indexes were reviewed.

Expert Opinion: New anticoagulants under development focused on inhibiting one or more than one serine proteases within the coagulation cascade. Agents targeting intrinsic factors are in the pipeline of the drug development. The enrollment eligibility criteria have more restrictions on laboratory tests, medical history, or medication history related to bleeding and coagulation; more precautions were taken to assess and minimize the risk of hemorrhagic events. Pharmacodynamics markers were evaluated as a surrogate marker of anticoagulation potency to guide further dose selection in drug's development. In future, the positive control study can be applied in phase I studies of new anticoagulants with appropriate pharmacodynamics markers, which can provide more favorable information on making 'go/no' decision in drug development.
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http://dx.doi.org/10.1080/17512433.2020.1831914DOI Listing
November 2020

Pharmacokinetic-Pharmacodynamic Analysis' Role in Design of Phase ⅠClinical Trials of Anticoagulant Agents: A Systematic Review.

Expert Rev Clin Pharmacol 2020 Nov 27;13(11):1191-1202. Epub 2020 Oct 27.

Department of Pharmacy, Peking University First Hospital , Beijing, People's Republic of China.

Introduction: There remains an unmet need for better anticoagulants. The phase I clinical trial is of great significance in the development of anticoagulants, and the design is special. This system review aims to provide insights for the design of future phase I clinical trials of anticoagulants.

Areas Covered: We searched the database PubMed and ClinicalTrail.gov website, to collate the phase I clinical trial of anticoagulants in healthy people. The study protocol, inclusion-exclusion criteria, safety, and pharmacodynamic indexes were reviewed.

Expert Opinion: New anticoagulants under development focused on inhibiting one or more than one serine proteases within the coagulation cascade. Agents targeting intrinsic factors are in the pipeline of the drug development. The enrollment eligibility criteria have more restrictions on laboratory tests, medical history, or medication history related to bleeding and coagulation; more precautions were taken to assess and minimize the risk of hemorrhagic events. Pharmacodynamics markers were evaluated as a surrogate marker of anticoagulation potency to guide further dose selection in drug's development. In future, the positive control study can be applied in phase I studies of new anticoagulants with appropriate pharmacodynamics markers, which can provide more favorable information on making 'go/no' decision in drug development.
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http://dx.doi.org/10.1080/17512433.2020.1831914DOI Listing
November 2020

Efficacy and safety of azathioprine for neuromyelitis optica spectrum disorders: A meta-analysis of real-world studies.

Mult Scler Relat Disord 2020 Nov 3;46:102484. Epub 2020 Sep 3.

Department of Pharmacy, Peking University First Hospital, Beijing, China; College of Pharmacy, Peking University, Beijing, China. Electronic address:

Objective: This study aimed to perform a meta-analysis of the efficacy and safety of azathioprine (AZA) for neuromyelitis optica spectrum disorders (NMOSD), considering the potential predictive factors related to patient response to AZA in this disease.

Methods: We performed a systematic online query in PubMed, EMBASE, The Cochrane Library, ClinicalTrials.gov, China National Knowledge Infrastructure, WANFANG DATA, and CQVIP DATA. The available studies on the use of AZA in NMOSD patients were included.

Results: We analyzed a total of 21 studies including 1016 patients. Results demonstrated that AZA significantly decreased annual relapse rate (ARR) by 1.164 (95% confidence intervals (CI), -1.396 to -0.932; p < 0.001). Subgroup analysis showed that AZA significantly decreased ARR in both low-dose group (effect size (ES): -1.545) and moderate-dose group (ES: -2.026). AZA therapy also resulted in a significant reduction of 1.117 (95% CI: -1.668 to -0.566; p < 0.001) in expanded disability status scale (EDSS) score. AZA did not affect EDSS score in the low-dose subgroup (ES: -0.535; p = 0.209) or the moderate-dose subgroup (ES: -0.709; p = 0.064). During AZA therapy, 47% of patients did not experience any relapses (95% CI, 39% to 54%). In addition, 13% of patients developed leukopenia, 11% had elevated liver enzyme levels, 8% experienced nausea or vomiting, 5% developed pancytopenia and 6% died during follow-up.

Conclusion: AZA is effective in reducing relapse and improving patients' neurological function. However, liver function monitoring and routine blood monitoring remain necessary. Within the safe upper limit, a higher dose of AZA may be associated with a better efficacy for NMOSD.
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http://dx.doi.org/10.1016/j.msard.2020.102484DOI Listing
November 2020

Safety, Efficacy, Pharmacokinetic and Pharmacodynamic evaluation of YF-H-2015005 for mobilizing Hematopoietic stem cells in Non-Hodgkin's Lymphoma Patients.

J Cancer 2020 25;11(19):5635-5640. Epub 2020 Jul 25.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, No.52 Fucheng Road, Haidian District, Beijing 100142, China.

Targeting the interaction between SDF1 and CXCR4 may provide an opportunity to intervene in the hematopoietic stem cell mobilization process. The present study aimed to investigate the safety, efficacy, pharmacokinetic and pharmacodynamic profiles of YF-H-2015005, a CXCR4 antagonist, for the mobilization of hematopoietic stem cells (HSCs). A total of 15 patients with non-Hodgkin's lymphoma (NHL) eligible for autologous hematopoietic stem cell transplantation were enrolled. All patients achieved a partial or complete remission after the first- or second-line therapy. Granulocyte colony stimulating factor (G-CSF) was given in the morning for 8 consecutive days, and 0.24 mg/kg YF-H-2015005 was subcutaneously administered in the evening of the 4 day of G-CSF treatment for up to four days. Apheresis was performed 9-10 hours following each dose of YF-H-2015005. Results: YF-H-2015005 was rapidly absorbed and eliminated, with T and t of 0.5 and 5.04 ± 1.00 hours, respectively. Moreover, the mean peripheral blood CD34 cell counts were elevated by 2.0- to 2.9-fold from 2 to 24 hours, and reached the maximum level of 76.5 ± 53.9 cells/kg at 10 hours after YF-H-2015005 treatment. Fourteen (93%) out of 15 NHL patients achieved a minimum target of ≥2×10/kg CD34 cells. Furthermore, there was no grades 3-4 treatment-related adverse event observed among these patients. Conclusion: YF-H-2015005 can serve as a safe, effective agent in combination with G-CSF for CD34 hematopoietic progenitor cell mobilization in NHL patients.
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http://dx.doi.org/10.7150/jca.48748DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7477452PMC
July 2020

Different Coagulation Indicators in Predicting Clinical Outcomes for Patients With Direct Oral Anticoagulants: A Systematic Review and Meta-analysis.

Clin Ther 2020 10 6;42(10):2066-2081.e9. Epub 2020 Sep 6.

Department of Pharmacy, Peking University First Hospital, Beijing, China; School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China. Electronic address:

Purpose: There are many anticoagulant test indexes available for direct oral anticoagulants (DOACs), but how to select the appropriate index and the index cutoff values are still controversial. This is the first study, to our knowledge, to assess the association of different coagulation indicators with clinical outcomes among DOACs using a meta-analysis of observational studies.

Methods: A medical literature search was conducted using PubMed, Web of Science, EMBASE, ClinicalTrials.gov, and the Cochrane Library from inception to February 2020. Studies that reported relationships between coagulation indexes and clinical outcomes or the diagnostic value of coagulation assays were included in the analysis.

Findings: A total of 17 articles (7 meta-analyses and 10 systematic reviews) from 8904 citations were included in the analysis. In the analysis of bleeding events with coagulation indexes for DOACs, for peak prothrombin time level (cutoff value of 19-25 s), the pooled results found a sensitivity of 0.61 (95% CI, 0.44-0.75) and a specificity of 0.71 (95% CI, 0.49-0.86). For rivaroxaban, the trough anti-factor Xa concentration (AXA-C) (cutoff value of 400-500 ng/mL) had a sensitivity of 0.53 (95% CI, 0.16-0.87) and a specificity of 0.87 (95% CI, 0.71-0.94), with a diagnostic odds ratio of 7 (95% CI, 2-32). For apixaban, trough AXA-C had a sensitivity of 0.85 (95% CI, 0.60-0.96) and a specificity of 0.83 (95% CI, 0.52-0.95). The AUC of the AXA-C peak was higher than that of the trough AXA-C for apixaban, with a higher sensitivity and specificity. Compared with trough concentration of anti-factor IIa for dabigatran, the peak concentration had a higher specificity (98%) at the cutoff value of 484 ng/mL. In the analysis of thromboembolic events with coagulation indexes for DOACs, peak and trough prothrombin time values were not typically correlated with subsequent symptomatic venous thromboembolism, without a sensitivity or specificity higher than 90%. Trough AXA-C had a sensitivity of 100% and but a low specificity (<50%) for rivaroxaban-apixaban. Trough AXA-C had a sensitivity of 100% and a specificity of 32% with a cutoff value of 108 ng/mL for dabigatran.

Implication: Peak prothrombin time (19-25 s) and AXA-C had a better predictive value on bleeding outcomes for rivaroxaban and apixaban, whereas peak concentration of anti-factor IIa activity can be an indicator for dabigatran. Coagulation indexes might not be a good indicator of thromboembolic events of DOACs. Because the limited studies focused on association of coagulation indicators and clinical outcomes, more studies are needed to verify this in the future.
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http://dx.doi.org/10.1016/j.clinthera.2020.08.001DOI Listing
October 2020