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Pharmacokinetics, safety and bioequivalence of two formulations of progesterone soft capsule in healthy Chinese postmenopausal females: Impacts of a high-fat meal.
Qin, H, Zheng, L, Fang, Y, Liu, Y, Liu, A, Wu, J, Zhu, F, Chen, J, Fan, Y, Hu, W
Basic & clinical pharmacology & toxicology. 2022;(2):268-276
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Abstract
Progesterone is an important natural hormone regulating ovulation and menstruation. The present study aimed to investigate the pharmacokinetics and safety of two formulations of progesterone in Chinese postmenopausal females under fasting and fed conditions. The study adopted a single-dose, open-label, randomized, three-period bioequivalence design. A total of 96 subjects were enrolled and randomly assigned to the fasting cohort or fed cohort. A high-fat meal (890 kcal) was used in the fed study. The reference-scaled average bioequivalence method was used for bioequivalence evaluation. A high-fat meal led to a 22-fold higher peak concentration (Cmax ) and a 7-fold higher area under the curve (AUC) while time to reach Cmax and half-life was not significantly affected. The concentration-time curve displayed double peaks suggesting the existence of enterohepatic circulation. The test/reference geometric mean ratios for Cmax and AUC under fasting and fed conditions are all within the range of 80% to 125%. All adverse events (AEs) that occurred during the trial were mild and did not cause drop-out, though these AEs occurred more frequently under fed state. In conclusion, the two formulations of progesterone are bioequivalent in Chinese subjects under fasting and fed conditions. Drug label modification regarding food effects needs further discussion.
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Histologic Outcomes With Vedolizumab Versus Adalimumab in Ulcerative Colitis: Results From An Efficacy and Safety Study of Vedolizumab Intravenous Compared to Adalimumab Subcutaneous in Participants With Ulcerative Colitis (VARSITY).
Peyrin-Biroulet, L, Loftus, EV, Colombel, JF, Danese, S, Rogers, R, Bornstein, JD, Chen, J, Schreiber, S, Sands, BE, Lirio, RA
Gastroenterology. 2021;(4):1156-1167.e3
Abstract
BACKGROUND AND AIMS VARSITY (An Efficacy and Safety Study of Vedolizumab Intravenous [IV] Compared to Adalimumab Subcutaneous [SC] in Participants With Ulcerative Colitis) showed superior clinical remission and endoscopic improvement in ulcerative colitis with vedolizumab vs adalimumab. This analysis compared histologic outcomes. METHODS Patients in VARSITY were randomized 1:1 to maintenance with vedolizumab IV 300 mg every 8 weeks or adalimumab SC 40 mg every 2 weeks (both following standard induction). Geboes Index and Robarts Histopathology Index (RHI) scores were used to assess prespecified histologic exploratory end points of histologic remission (Geboes <2 or RHI ≤2) and minimal histologic disease activity (Geboes ≤3.1 or RHI ≤4) at weeks 14 and 52. RESULTS In total, 769 patients received vedolizumab (n = 383) or adalimumab (n = 386). Mean baseline histologic disease activity was similar between vedolizumab and adalimumab groups. Vedolizumab induced greater histologic remission than adalimumab at week 14 (Geboes: 16.7% vs 7.3%, Δ9.4% [95% confidence interval {CI}, 4.9%-13.9%], P < .0001; RHI: 25.6% vs 16.1%, Δ9.5% [95% CI, 3.8%-15.2%], P = .0011) and week 52 (Geboes: 29.2% vs 8.3%, Δ20.9% [95% CI, 15.6%-26.2%], P < .0001; RHI: 37.6% vs 19.9%, Δ17.6% [95% CI, 11.3%-23.8%], P < .0001) overall and in both anti-tumor necrosis factor (TNF)-naïve and -failure subgroups. Results were similar for minimal histologic disease activity. Histologic outcomes were generally better in anti-TNF-naïve vs -failure patients. At week 52, rates of mucosal healing (composite end point of histologic plus endoscopic improvement) were also higher with vedolizumab than adalimumab (Geboes: 25.6% vs 6.7%; RHI: 30.5% vs 14.5%). CONCLUSIONS Higher rates of histologic remission, minimal histologic disease activity, and combined histologic plus endoscopic outcomes were observed with vedolizumab than with adalimumab in ulcerative colitis in both anti-TNF-naïve and -failure subgroups. REGISTRATION ClinicalTrials.gov NCT02497469; EudraCT 2015-000939-33.
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Nutritional assessment and risk factors associated to malnutrition in patients with esophageal cancer.
Cao, J, Xu, H, Li, W, Guo, Z, Lin, Y, Shi, Y, Hu, W, Ba, Y, Li, S, Li, Z, et al
Current problems in cancer. 2021;(1):100638
Abstract
INTRODUCTION Esophageal cancer is the fourth most common cause of cancer death in China. Patients with esophageal cancer are more likely to suffer from malnutrition. The purpose of this study is to assess nutritional status of patients with esophageal cancer from multiple perspectives and analyze the risk factors. METHODS A total of 1482 esophageal cancer patients were enrolled in the study. We investigated the Scored Patient Generated Subjective Global Assessment (PG-SGA) scores, NRS-2002 scores, Karnofsky performance status scores, anthropometric, and laboratory indicators of patients. Unconditional logistic regression analysis was applied to identify the risk factors of nutritional status. RESULTS PG-SGA (≥4) and NRS-2002 (≥3) showed the incidence of malnutrition were 76% and 50%, respectively. In the patients with PG-SGA score ≥4, the proportion of patients who did not receive any nutritional support was 60%. The incidence of malnutrition in females was significantly higher than that in males. Besides, abnormality rates of Red blood cell (P < 0.001), MAC (P = 0.037), and MAMC (P < 0.001) in males was significantly higher than that in females, while abnormality rates of TSF (P < 0.001) was lower than that in females. After adjusted with the other potential risk factors listed, unconditional logistic regression analysis indicated smoking (odds ratio: 2.868, 95% confidence interval: 1.660-4.954), drinking (OR: 1.726, 95% CI: 1.099-2.712), family history (OR: 1.840, 95% CI: 1.132-2.992), radiotherapy or chemotherapy (OR: 1.594, 95% CI: 1.065-2.387), and pathological stage (OR: 2.263, 95% CI: 1.084-4.726) might be the risk factors of nutritional status, while nutritional support can reduce the risk of malnutrition. CONCLUSION Effective nutritional risk assessment methods and nutritional intervention measures can be adopted according to the research data to improve quality of life of esophageal cancer patients.
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Gut Microbiota and Urine Metabonomics Alterations in Constitution after Chinese Medicine and Lifestyle Intervention.
Jing, Y, Han, S, Chen, J, Lai, Y, Cheng, J, Li, F, Xiao, Y, Jiang, P, Sun, X, Luo, R, et al
The American journal of Chinese medicine. 2021;(5):1165-1193
Abstract
Traditional Chinese Medicine Constitution (TCMC) divides human beings into balanced (ping-he) constitution (PH) and unbalanced constitution. Yang-deficiency (yang-xu) constitution (YAX) is one of the most common unbalanced constitutions in Chinese general population, and it causes susceptibility to particular diseases. However, unbalanced constitutions can be regulated by Chinese medicine and lifestyle intervention in clinical practice. Gui-fu-di-huang-wan (GFDHW) is a well-known Chinese medicine with yang-invigorating activity and is regarded as improving YAX. In this study, 60 healthy YAX students selected from a prospective population of 5185 were enrolled in a randomized clinical trial and completed the study. We compared the gut microbiota and urinary metabolome between individuals with PH and those with YAX before and after one-month-intervention. Compared with the control group, the health status of the intervention group improved significantly, the YAX symptom score was reduced, and the efficacy remained high at the one-year follow-up. The gut microbiota of the healthy PH exhibited greater diversity, and significantly higher species were identified. Compared to PH group, YAX individuals showed increased abundance of Bacteroidetes and Bacteroides, also had higher levels of gut microbial-derived urinary metabolites. After one-month-intervention, both GFDHW treatment and lifestyle intervention enriched the diversity and modulated the structure in YAX. The intervention group also partially restored the microbiome and metabolome to healthy PH-like levels. Further, a microbiota co-occurrence network analysis showed that the metabolites enriched in YAX were correlated with microbial community structure. Taken together, our results suggest that Chinese medicine combined with lifestyle intervention benefits YAX individuals. Gut microbiota/metabolite crosstalk might be involved in the Chinese medicine-mediated effects.
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Comparative analysis of volatile compounds in thirty nine melon cultivars by headspace solid-phase microextraction and gas chromatography-mass spectrometry.
Shi, J, Wu, H, Xiong, M, Chen, Y, Chen, J, Zhou, B, Wang, H, Li, L, Fu, X, Bie, Z, et al
Food chemistry. 2020;:126342
Abstract
The types and amounts of volatiles in the fruits of 39 melon cultivars were determined. We identified 146 volatiles, including 55 esters, 23 aldehydes, 30 alcohols, 15 ketones, 6 acids and 17 others. Ethyl acetate, (Z)-6-nonenal and 3,6-(E,Z)-nonadien-1-ol were the most three abundant volatiles (average content > 50 µg/kg FW). Aroma profiles showed significant differences among cultivars. Zhongtian49 and Zhongtian20 had the most abundant aroma components (76) and Jinguniang exhibited the least (23). One non-climacteric inodorus cultivar (Xizhoumi25) had the highest content of total volatiles (1840 µg/kg FW). Principal component analysis clustered the 39 melon cultivars into five groups. This work describes the comparative diversity of melon fruit volatiles for a large number of cultivars. Furthermore, this study could support the selection of cultivars with a flavor that suits the public and also future breeding work towards the genetic improvement of melon flavor.
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Application of a Backpropagation Artificial Neural Network in Predicting Plasma Concentration and Pharmacokinetic Parameters of Oral Single-Dose Rosuvastatin in Healthy Subjects.
Xu, Y, Lou, H, Chen, J, Jiang, B, Yang, D, Hu, Y, Ruan, Z
Clinical pharmacology in drug development. 2020;(7):867-875
Abstract
A backpropagation artificial neural network (BPANN) model was established for the prediction of the plasma concentration and pharmacokinetic parameters of rosuvastatin (RVST) in healthy subjects. The data (demographic characteristics and results of clinical laboratory tests) were collected from 4 bioequivalence studies using reference 10-mg RVST calcium tablets. After the data were cleaned using extreme gradient boosting, 13 important factors were extracted to construct the BPANN model. The model was fully validated, and mean impact values (MIVs) were calculated. The model was used to predict the plasma concentration and pharmacokinetic parameters of oral single-dose RVST in healthy subjects under fasting and fed conditions. The predicted and measured values were compared in order to evaluate the accuracy of prediction. The constructed model performed well in validation. The top 3 factors ranked by MIV related to RVST concentration are fasting/fed, time, and creatinine clearance. The time-concentration profiles of the measured and predicted data agreed well. There were no significant differences (P > .05) in the area under the concentration-time curve from 0 to the last measurable concentration (AUC0-t ) and extrapolated to infinity (AUC0-∞ ), half-time of elimination, peak concentration, and time to peak concentration of the measured data and data predicted by BPANN. The BPANN model has an accurate prediction ability and can be used to predict RVST concentration and pharmacokinetic parameters in healthy subjects.
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Observational and Genetic Associations of Body Mass Index and Hepatobiliary Diseases in a Relatively Lean Chinese Population.
Pang, Y, Kartsonaki, C, Lv, J, Millwood, IY, Yu, C, Guo, Y, Chen, Y, Bian, Z, Yang, L, Chen, J, et al
JAMA network open. 2020;(10):e2018721
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Abstract
IMPORTANCE There is some support for the existence of genetic associations between adiposity and certain hepatobiliary diseases in Western populations. However, there is little evidence of such genetic associations in China, where the causes of these diseases may differ from those in Western populations and the mean body mass index (BMI) is much lower. OBJECTIVES To compare the observational associations of BMI with hepatobiliary diseases and liver biomarkers with the genetic associations between BMI and these factors and to assess whether the genetic associations of BMI with liver diseases differed by hepatitis B virus infection status. DESIGN, SETTING, AND PARTICIPANTS This cohort study used data from the prospective China Kadoorie Biobank, including 473 938 adults aged 30 to 79 years without hepatobiliary diseases at baseline from 10 diverse areas in China from June 25, 2004, to July 15, 2008. A random sample of 75 736 participants with genotyping data was included in the Mendelian randomization analysis. Follow-up was completed January 1, 2017 (median [interquartile range] length of follow-up, 10.2 [9.2-11.1] years). Data were analyzed from January to October 2019. EXPOSURES Measured BMI obtained during the baseline survey and genetically instrumented BMI derived using 92 single-nucleotide variations. MAIN OUTCOMES AND MEASURES Incident cases of hepatobiliary diseases, liver enzymes, fatty liver index, and fibrosis score. RESULTS Among 473 938 individuals (276 041 [58.2%] women), the mean (SD) age was 52 (10.9) years and mean (SD) BMI was 23.8 (3.4). Baseline BMI was associated with higher risks of chronic liver disease (adjusted risk ratio per 1-SD increase, 1.14; 95% CI, 1.11 to 1.17) and gallbladder disease (adjusted risk ratio per 1-SD increase, 1.29; 95% CI, 1.27 to 1.31), with heterogeneity by disease subtype (P < .001). Genetically instrumented BMI was associated with higher risks of chronic liver disease (risk ratio per 1-SD increase, 1.55; 95% CI, 1.08 to 2.24) and gallbladder disease (risk ratio per 1-SD increase, 1.40; 95% CI, 1.11 to 1.76), with no heterogeneity between subtypes. A meta-analysis of the genetic associations in China Kadoorie Biobank and those calculated in UK Biobank gave a risk ratio of 1.55 (95% CI, 1.30 to 1.84) for chronic liver disease and 1.42 (95% CI, 1.22 to 1.64) for gallbladder disease. In the China Kadoorie Biobank study, there were positive genetic associations of BMI with liver enzymes, steatosis, and fibrosis scores, consistent with observational associations. The genetic associations of BMI with liver diseases and biomarkers did not differ by hepatitis B virus infection status. CONCLUSIONS AND RELEVANCE In this cohort study of a relatively lean Chinese population, there were positive genetic associations of BMI with hepatobiliary diseases. These results suggest that maintaining a healthy weight through diet and physical activity may help prevent hepatobiliary diseases.
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Effects of Sustained-Release Beraprost in Patients With Primary Glomerular Disease or Nephrosclerosis: CASSIOPEIR Study Results.
Nakamoto, H, Yu, XQ, Kim, S, Origasa, H, Zheng, H, Chen, J, Joo, KW, Sritippayawan, S, Chen, Q, Chen, HC, et al
Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy. 2020;(1):42-55
Abstract
TRK-100STP, a sustained-release preparation of the orally active prostacyclin analogue beraprost sodium, targets renal hypoxia. This study aimed to show the superiority of TRK-100STP over placebos in patients with chronic kidney disease (with either primary glomerular disease or nephrosclerosis) to determine the recommended dose. CASSIOPEIR (Chronic Renal Failure Asian Study with Oral PGI2 Derivative for Evaluating Improvement of Renal Function) was a randomized, double-blind, placebo-controlled study conducted at 160 sites in seven Asia-Pacific countries and regions. Eligible patients (n = 892) were randomized to TRK-100STP 120, 240 μg, or placebo for a treatment period of up to 4 years. The primary efficacy endpoint was time to first occurrence of a renal composite: doubling of serum creatinine or occurrence of end-stage renal disease. No significant differences were observed in composite endpoints between TRK-100STP and placebo (P = 0.5674). Hazard ratios (95% CI) in the TRK-100STP 120 and 240 μg vs. placebo groups were 0.98 (0.78, 1.22) and 0.91 (0.72, 1.14), respectively. The overall incidence of adverse events and adverse drug reactions was comparable between treatment arms.
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Comparison of the preventive efficacy of rosuvastatin versus atorvastatin in post-contrast acute kidney injury in patients with ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention.
Dai, Y, Huang, J, Zeng, L, Huang, Z, Duan, C, Shao, S, Chen, H, Xue, L, Chen, J, Tan, N, et al
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2020;:110336
Abstract
Statins have been shown to reduce the risk of post-contrast acute kidney injury (PC-AKI) in patients undergoing percutaneous coronary intervention (PCI). However, the preventive effect of rosuvastatin versus atorvastatin on PC-AKI in patients with ST-segment elevation myocardial infarction (STEMI) undergoing PCI remains unclear. Patients with STEMI undergoing PCI between January 2010 and May 2016 were consecutively enrolled. A total of 1300 included patients were divided into two groups according to the statin type (atorvastatin: n = 1040; rosuvastatin: n = 260). The primary endpoint was PC-AKI defined as an absolute increase of ≥ 0.5 mg/dL in the level of serum creatinine or an increase of ≥ 25 % over baseline within 48-72 h after contrast media exposure. In total, 245 (18.8 %) patients developed PC-AKI. The atorvastatin and rosuvastatin groups had similar rates of PC-AKI (19.1 % vs. 17.7 %, p = 0.595), in-hospital mortality (4.1 % vs. 3.8 %, p = 0.833), and major adverse clinical events (MACE). Multivariate logistic regression analysis revealed that rosuvastatin treatment had an effect similar to atorvastatin regarding PC-AKI (odds ratio [OR] = 0.97, 95 % confidence interval [CI], 0.66-1.43, p = 0.874). Propensity score analyses and subgroup analysis demonstrated similar results for PC-AKI. Kaplan-Meier survival curves and Cox proportional regression showed that the atorvastatin and rosuvastatin groups had no differences regarding follow-up mortality. Rosuvastatin exerted a similar preventive effect against PC-AKI and showed similar levels of in-hospital and follow-up all-cause mortality and in-hospital MACE compared with atorvastatin in patients with STEMI undergoing PCI.
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Elective nodal irradiation versus involved-field irradiation in patients with esophageal cancer receiving neoadjuvant chemoradiotherapy: a network meta-analysis.
Liu, T, Ding, S, Dang, J, Wang, H, Chen, J, Li, G
Radiation oncology (London, England). 2019;(1):176
Abstract
BACKGROUND To assess the comparative efficacy and safety of elective nodal irradiation (ENI) and involved-field irradiation (IFI) in patients with esophageal cancer (EC) receiving neoadjuvant chemoradiotherapy plus surgery (nCRTS). MATERIAL AND METHODS PubMed, Embase, Cochrane Library, Web of Science and major meetings were searched for randomized controlled trials (RCTs) that compared at least two of the following treatment regimens: nCRTS, neoadjuvant chemotherapy plus surgery (nCTS), and surgery (S) alone. Overall survival (OS) was the primary outcomes of interest, reported as hazard ratio (HR) and 95% confidence intervals (CIs). A Bayesian network meta-analysis was performed to compare all regimens simultaneously. RESULTS Twenty-nine RCTs with a total of 5212 patients were included in the meta-analysis. Both nCRTS adopting ENI (nCRTS-ENI) (HR = 0.63, 95% CI: 0.48-0.83) and nCRTS adopting IFI (nCRTS-IFI) (HR = 0.75, 95% CI: 0.66-0.86) significantly improved OS compared to S alone. No significant differences in OS, locoregional recurrence, distant metastases, R0 resection and postoperative mortality were observed between nCRTS-ENI and nCRTS-IFI. In subgroup analyses, nCRTS-IFI showed a significant OS advantage over nCTS (HR = 0.78, 95% CI: 0.63-0.96) and S alone (HR = 0.50, 95% CI: 0.38-0.68) for esophagus squamous cell carcinoma (ESCC), but nCRTS-ENI did not; nCRTS-ENI using three-dimensional radiotherapy (3D-RT) resulted in an improved OS compared to that with 2D-RT (HR = 0.58, 95% CI: 0.34-0.99). Based on treatment ranking in term of OS, nCRTS-IFI (0.90) and nCRTS-ENI (0.96) was ranked the most effective treatment for ESCC and esophagus adenocarcinoma (EAC), respectively. CONCLUSION Either adopting ENI or IFI, nCRTS is likely to be the optimal treatment for resectable EC, and nCRTS-IFI and nCRTS-ENI seem to be more effective for patients with ESCC and EAC, respectively. Future head to head comparison trials are needed to confirm these findings.