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In non-valvular atrial fibrillation (NVAF) patients with chronic kidney disease (CKD), rivaroxaban was not inferior to warfarin in preventing stroke and systemic embolism. However, a comparative evaluation of the cost-effectiveness of rivaroxaban and warfarin therapies for NVAF patients at different renal function levels has not yet been reported, and this study aimed to estimate the cost-effectiveness of rivaroxaban compared with warfarin in Chinese NVAF patients with CKD.A Markov model was constructed to estimate quality-adjusted life years (QALYs) and lifetime costs associated with the use of rivaroxaban relative to warfarin in patients with NVAF at different estimated glomerular filtration rate (eGFR) levels as follows: 30 to50, 50 to80 and ≥80 mL/min. Input parameters were sourced from the clinical literature. Probabilistic sensitivity analyses were performed to assess model uncertainty.The incrementalQALYs with rivaroxaban was slightly increased by approximately 0.3 QALY as compared with that with warfarin in all the subgroups, resulting in an ICER of $9,736/QALY (eGFR, 30 to50 mL/min), $9,758/QALY (50 to80 mL/min) and $9,969/QALY (≥80 mL/min). The probabilistic sensitivity analysis suggested a chance of80% that the ICER would be lower than the willingness-to-pay threshold of three times the GDP of China in 2019 in all the subgroups. Results were consistent even under the assumption of anticoagulant discontinuation after major bleeding events. The model was most sensitive to event-free-related utility and survival rates.The existing evidence supports the cost-effectiveness of rivaroxaban therapy as an alternative anticoagulant to warfarin for patients with NVAF at different renal function levels.

Background: Liver injury commonly occurs in patients with COVID-19. There is limited data describing the course of liver injury occurrence in patients with different disease severity, and the causes and risk factors are unknown. We aim to investigate the incidence, characteristics, risk factors, and clinical outcomes of liver injury in patients with COVID-19.Methods: This retrospective observational study was conducted in three hospitals (Zhejiang, China). From January 19, 2020 to February 20, 2020, patients confirmed with COVID-19 (≥18 years) and without liver injury were enrolled and divided into non-critically ill and critically ill groups. The incidence and characteristics of liver injury were compared between the two groups. Demographics, clinical characteristics, treatments, and treatment outcomes between patients with or without liver injury were compared within each group. The multivariable logistic regression model was used to explore the risk factors for liver injury.Results: The mean age of 131 enrolled patients was 51.2 years (standard deviation [SD]: 16.1 years), and 70 (53.4%) patients were male. A total of 76 patients developed liver injury (mild, 40.5%; moderate, 15.3%; severe, 2.3%) with a median occurrence time of 10.0 days. Critically ill patients had higher and earlier occurrence (81.5 vs. 51.9%, 12.0 vs. 5.0 days; p < 0.001), greater injury severity (p < 0.001), and slower recovery (50.0 vs. 61.1%) of liver function than non-critically ill patients. Multivariable regression showed that the number of concomitant medications (odds ratio [OR]: 1.12, 95% confidence interval [CI]: 1.05–1.21) and the combination treatment of lopinavir/ritonavir and arbidol (OR: 3.58, 95% CI: 1.44–9.52) were risk factors for liver injury in non-critically ill patients. The metabolism of arbidol can be significantly inhibited by lopinavir/ritonavir in vitro (p < 0.005), which may be the underlying cause of drug-related liver injury. Liver injury was related to increased length of hospital stay (mean difference [MD]: 3.2, 95% CI: 1.3–5.2) and viral shedding duration (MD: 3.0, 95% CI: 1.0–4.9).Conclusions: Critically ill patients with COVID-19 suffered earlier occurrence, greater injury severity, and slower recovery from liver injury than non-critically ill patients. Drug factors were related to liver injury in non-critically ill patients. Liver injury was related to prolonged hospital stay and viral shedding duration in patients with COVID-19.Clinical Trial Registration: World Health Organization International Clinical Trials Registry Platform, ChiCTR2000030593. Registered March 8, 2020.

// Dongsheng Hong 1, * , Ling Bi 2, * , Jun Zhou 1, * , Yinghui Tong 3 , Qingwei Zhao 1 , Jing Chen 4 and Xiaoyang Lu 1 1 Department of Pharmacy, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China 2 Department of Stomatology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China 3 Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, 310022, P.R. China 4 Department of Medical Oncology, The First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, 310003, P.R. China * These authors have contributed equally to this work Correspondence to: Jing Chen, email: angelcq@zju.edu.cn Xiaoyang Lu, email: lxy00711@126.com Keywords: breast cancer, aromatase inhibitors, menopausal symptoms, hot flashes, meta-analysis Received: January 02, 2017 Accepted: April 02, 2017 Published: April 18, 2017 ABSTRACT Aromatase inhibitors (AIs) are the standard of care for postmenopausal women with estrogen receptor-positive breast cancer. Here, we performed a meta-analysis to evaluate the occurrence of menopausal symptoms in breast cancer patients receiving the AI therapy. Patients treated with AIs had an increased risk of all-grade arthralgia (1.63 [95% CI: 1.34–1.98]) and insomnia (1.24 [95% CI: 1.14–1.34]). The overall incidence of hot flashes, fatigue, arthralgia, sweating, and insomnia in patients receiving AIs was 30.47% (95% CI: 25.51%–35.93%), 17.16% (95% CI: 14%–20.85%), 17.91% (95% CI: 11.29%–27.22%), 14.64% (95% CI: 11.46%–18.52%), and 16.52% (95% CI: 12.45%–21.6 %), respectively. Both arthralgia (RR = 0.34, 95% CI: 0.16–0.75) and sweating (RR = 11.02, 95% CI: 4.11–29.57) differed between patients with early- and advanced-stage breast cancer. Our findings indicates that AIs are associated with a significant risk of developing arthralgia and insomnia in breast cancer patients. Effective early detection and management of menopausal symptoms would likely lead to safer use of AIs in breast cancer patients.

Background Cardiovascular events (CVEs) was considered as one of the primary cause to reduce the quality of life in breast cancer patients with aromatase inhibitors (AIs) treatment, which has not been sufficiently addressed. The aim of this study was to assess the correlation between risk of CVEs and AIs in patients with breast cancer. Methods Included studies were obtained from the databases of Embase, Pubmed, Cochrane Library, Clinical Trials.gov, and reference lists. The main outcome measures were overall incidence, odds ratios (ORs), and 95% confidence intervals (CIs). Furthermore, the association and the risk differences among different tumor types, AIs,ages,or treatment regimens were conducted. Fixed-effect or random-effect models were applied in the statistical analyses according to the heterogeneity. Our analysis was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results Seventeen studies, which included 44,411 subjects, were included in our analyses. The overall incidence of CVEs in AIs group was 13.02% (95% CI: 8.15–20.17%) and almost all of the high-grade CVEs occurred in patients treated with AIs. The pooled ORs of CVEs was 0.9940 (95% CI: 0.8545–1.1562). Under sub-group analysis, the incidence of CVEs related to exemestane was higher than that of controls (OR = 1.1564, 95% CI: 1.0656–1.2549), but no statistical differences in risk of CVEs were found in other sub-group analysis. No evidence of publication bias was found for incidence of CVEs in our meta-analysis by a funnel plot. Conclusions These results suggest that patients with breast cancer treated with AIs do not have a significant risk of developing CVEs in comparison with the controls, and exemestane might not be considered as the alternative AI to the breast cancer patients from the perspective of CVEs. Further studies are recommended to investigate this association and the risk differences among different tumor types, AIs or treatment regimens.

Capecitabine, an oral prodrug of 5-fluorouracil, inhibits DNA synthesis and has received FDA approval for treatment of metastatic colorectal and breast cancers. Hand-foot syndrome (HFS) is a serious dose-limiting toxicity and the most frequently reported side effect of capecitabine. Because of the lack of knowledge about the causative mechanism of HFS, scarce information is available for effective treatment or prevention. Data are based on published literatures and reports available from the HFS development program database. The purpose of this Review is to provide information regarding definition, clinical manifestation, and the possible mechanisms of HFS induced by capecitabine. Ethnic variations in the clinical presentation of HFS warrant further attention. Several physiological and pharmacological mechanisms have been investigated, such as cyclooxygenase (COX) inflammatory-type reaction, accumulation of capecitabine metabolites, and enzymes and transporters involved in the metabolism and absorption. Although current studies describe the possible mechanisms of HFS induced by capecitabine, much remains to be determined. It appears from this scientific evidence that additional study is needed to determine the effect of skin-mediated metabolism in the possible mechanism of HFS induced by capecitabine.

Metastasis-associated colon cancer 1 (MACC1) has been demonstrated to promote metastasis of several cancers via regulating epithelial-mesenchymal transition (EMT). However, its biological behavior in human malignant melanoma remains unclear. In this study, MACC1 downregulation was established in two melanoma cell lines (A375 and G361 cells) using RNA interference, as confirmed by quantitative real time PCR (qRT-PCR) and Western blot analysis. Subsequently, we investigated the effects of MACC1 silencing on cell mobility, migration and invasion using scratch wound and Transwell assays. Our results indicated that knockdown of MACC1 significantly suppressed cell migration and invasion ability of both melanoma cell lines. Moreover, downregulation of MACC1 upregulated E-cadherin, N-cadherin and Vimentin, as confirmed by qRT-PCR, Western blot and immunofluorescent Staining analysis. These findings suggest MACC1 might serve as a new molecular target for the treatment of melanoma by a novel mechanism underlying the metastasis of melanoma cells.

BACKGROUND Statins have been reported to exert anti-inflammatory effects, but the association between statins and acute lung injury (ALI) remains controversial. Thus, we performed a meta-analysis of all published randomized controlled trials (RCTs) aiming to summarize and evaluate the current evidence about the potential use of statins in ALI patients. METHOD We searched for articles that focused on the association between statins and ALI-related outcomes through electronic databases until December 10th, 2014. The inclusion of articles, quality appraisal of included studies, and data extraction were performed by two investigators. Eligible articles were analyzed by Review manager 5.2 and STATA 12.0 software. RESULTS Data from 1,778 patients in five randomized controlled clinical trials were analyzed. No differences in intensive care unit (ICU) mortality (RR=0.88, 95% CI=0.63-1.22, p=0.44), hospital mortality (RR=1.00, 95% CI=0.85-1.17, p=0.97) and mechanical ventilation duration (MD=-0.40, 95% CI=-1.52-0.71, p=0.48) were observed between the experimental and control groups. CONCLUSIONS According to large and high-quality published clinical trials as also summarized by the present meta-analysis, there is insufficient evidence to support the use of statins in ALI patients.

Therapies that targeted PD-1 have shown remarkable rates of durable clinical responses in patients with various tumor types. However, the extent and knowledge of pulmonary toxicities associated with PD-1 blockade, mainly manifested as pneumonitis, remains obscure. In this study, a total of 6360 subjects from 16 phase II/III clinical trials were pooled for meta-analysis to evaluate the overall incidence and risk of PD-1 inhibitors-related pneumonitis in cancer patients. The incidence of pneumonitis during anti-PD-1 immunotherapy was 2.92% (95%CI: 2.18–3.90%) for all-grade and 1.53% (95%CI: 1.15–2.04%) for high-grade pneumonitis. Compared with routine chemotherapy, PD-1 inhibitors were associated with a significant increased risk of pneumonitis. Moreover, among the types of tumor treated with PD-1 inhibitors, the melanoma patients have the lowest incidence of pneumonitis, while the non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) patients have the highest. Furthermore, no significant differences were detected in the incidences of all- and high-grade pneumonitis between high-dose and low-dose groups of PD-1 inhibitors. In conclusion, PD-1 inhibitors were probably associated with an increased risk of pneumonitis in a dose-independent manner, compared with routine chemotherapeutic agents. The frequency and severity of treatment-mediated pneumonitis was quite different in patients with various tumor types.

Traditional Chinese herbal medicines have attracted considerable attention in many countries with treatment of several end-stage liver diseases.The present study investigated the protective effects of baicalin on hepatotoxicity and hepatic fibrosis and explored the role of transforming growth factor β1 (TGFβ1) and peroxisome proliferator activated receptors γ (PPARγ) on the rat liver injury model.The rat liver injury model was introduced by subcutaneous injection of carbon tetrachloride (CCl(4)) for 8 weeks. At week 5, rats were treated with baicalin of different doses or silymarin. Detection of biochemical indicators, histological analysis, and enzyme-linked immunosorbent assays were employed to evaluate severity of liver inflammation, and western blotting and RT-PCR assay were performed to evaluate TGFβ1 and PPARγ pathway related proteins and gene expression.The administration of baicalin could significantly improve histological changes of CCl(4) treated rat livers and return biochemical indicators for liver injury to nearly baseline level. In addition, the increased expression of TGFβ1 was markedly suppressed by baicalin, and decreased expression of PPARγ was also dramatically elevated by baicalin as well. The hepatoprotective effects of baicalin may be conferred by elevating the level of PPARγ contributing to down-regulation of TGFβ1 signaling pathway and suppression of hepatic stellate cell activation.The studies demonstrated that baicalin is a potent and promising antifibrotic drug in the treatment of hepatic fibrosis.

Background The prognostic role of inflammation indices, such as the neutrophil-to-lymphocyte ratio (NLR) in gastric cancer (GC) remains controversial. We conducted a meta-analysis to determine the predictable value of NLR in the clinical outcome of GC patients. Methods We searched Embase, PubMed and the Cochrane Library database for relevant randomised controlled trials. Statistical analyses were conducted to calculate the hazard ratio (HR) and 95% confidence intervals of overall survival (OS) and progression-free survival (PFS) using either random-effect or fixed-effect models according to the heterogeneity of the included studies. An analysis was carried out based on data from nine studies to evaluate the association between NLR and OS in patients with GC. Results Our analysis indicated that elevated pre-treatment NLR predicted poorer OS (HR: 2.16, 95% CI: 1.86 to 2.51, P

Qingwei Zhao,1 Dongsheng Hong,1 Dongsheng Zheng,1 Yao Xiao,2 Baohua Wu11Department of Pharmacy, First Affiliated Hospital of College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2College of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, People’s Republic of ChinaBackground: Sitagliptin is an important drug used for diabetes treatment and is used as a monotherapy in diabetic patients. However, there are also reported cases of diarrhea with sitagliptin use. Unfortunately, data concerning the relationship of diarrhea with sitagliptin use in various conditions have yet to be identified. Therefore, the overall incidence and risk of diarrhea with sitagliptin use have not been well defined. Methods: We conducted searches on Embase, PubMed, and the Cochrane Library databases for relevant randomized controlled trials. Registered relevant trials at the clinical trials registration website were also searched. Statistical analyses were conducted to calculate the overall incidence, odds ratios, and 95% confidence intervals (CI) by using either random-effects or fixed-effect models according to the heterogeneity of the included studies. Results: A total of 8,891 subjects with diabetes from 30 randomized clinical trials were included in the meta-analysis. The overall incidence of sitagliptin-associated diarrhea was 4.48% (95% CI: 3.59%–5.58%). Compared with the controls, the use of sitagliptin was not associated with a significantly increased risk of diarrhea with an odds ratio of 1.10 (95% CI: 0.78%–1.55%; P=0.58). No evidence of publication bias was observed. Conclusion: Our study has shown that there is no difference in diarrhea risk between sitagliptin and controlled therapies. Moreover, sitagliptin is not a medicine that potentially increases the risk of diabetic diarrhea. More studies are recommended to further investigate this association.Keywords: dipeptidyl peptidase-4 inhibitors, adverse reaction, odds ratio, incidence, subgroup analysis, data analysis

Supplemental Digital Content is available in the text, Gefitinib is a selective tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR) used to treat adults with EGFR mutation-positive non-small-cell lung cancer (NSCLC). Clinical benefits of gefitinib administration in NSCLC patients have been observed in clinical practice, but the extent of the pulmonary toxicity of gefitinib in patients with advanced NSCLC remains unclear. The aim of this systematic review was to evaluate the overall incidence and risk of gefitinib-related pulmonary toxicity in advanced NSCLC patients. Relevant trials were identified from the databases of Pubmed, Embase, Cochrane Library, and the clinicaltrials.gov of the U.S. National Institutes of Health. The outcomes included the overall incidence, odds ratios (ORs), and 95% confidence intervals (CIs). Fixed-effects models were used in the statistical analyses according to the heterogeneity of the included studies. According to the data from the included trials, the overall incidence of high-grade hemoptysis, pneumonia, pneumonitis, and interstitial lung disease (ILD) was 0.49% (95% CI: 0.24%–0.99%), 2.33% (95% CI: 1.47%–3.66%), 2.24% (95% CI: 1.34%–3.72%), and 1.43% (95% CI: 0.98%–2.09%), respectively. The pooled ORs of high-grade hemoptysis, pneumonia, pneumonitis, and ILD were 1.73 (95% CI: 0.46–6.52; P = 0.42), 0.99 (95% CI: 0.66–1.49; P = 0.95), 4.70 (95% CI: 1.48–14.95; P = 0.0087), and 2.64 (95% CI: 1.22–5.69; P = 0.01), respectively. Gefitinib was associated with a significantly increased risk of high-grade/fatal ILD and pneumonitis compared with the controls, whereas the risk of other high-grade pulmonary events (pneumonia and hemoptysis) was not significant. Careful surveillance of gefitinib-related pulmonary toxicity is critical for the safe use of this drug.

Curcumin has extensive cardioprotective effects against diabetic cardiovascular complications, cardiac hypertrophy and myocardial infarction (MI), but the molecular mechanism behind such cardioprotective effects remains still unclear. To explore the mechanism of MI, a rat model of coronary artery ligation was used to assess the cardioprotective effects of curcumin. Microarray technology was employed to detect the gene expression in the heart of MI rats treated with curcumin. Semiquantitative RT-PCR was then performed to verify the microarray result. Our results showed that curcumin could improve heart function, diminish infarct size and reverse the abnormal changes in the activities of serum lactate dehydrogenase and creatine kinase MB in rats after MI. A total of 179 genes were found to be significantly differentially expressed between sham-operated rats and coronary artery-ligated rats. Cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesions and colorectal cancer pathway may be involved in the cardioprotective effects of curcumin.

Tumor necrosis factor (TNF) is an important and pleiotropic cytokine which is also involved in the pathogenesis of inflammation in rheumatoid arthritis (RA), and RA treated with anti-TNF agents with a subsequent increase in hypertension risk is also observed in clinical trials. However, it is confusing that to what extent treatment with anti-TNF agents for RA might be associated with increasing risk of hypertension. The aim of this study was to investigate the overall incidence and risk of hypertension in RA patients who receive anti-TNF agents. The databases of Embase, PubMed, the Cochrane Library, and clinical trial registration Web site were searched for relevant trials. Statistical analyses were conducted to calculate the overall incidence, odds ratios, and 95% confidence intervals (CI) by using either random-effects or fixed-effect models according to the heterogeneity of the included studies. A total of 6321 subjects with RA from 11 randomized clinical trials (RCTs) were included in the meta-analysis. The overall incidence of hypertension associated with anti-TNF agent was 3.25% (95% CI: 1.51%–6.89%). The use of anti-TNF agent significantly increased the risk of developing hypertension (OR = 1.8896, 95% CI: 1.35–2.65). Sensitivity analysis showed that the OR between anti-TNF therapy and controls is not significantly influenced by omitting any single study. No evidence of publication bias was observed. Anti-TNF therapy is associated with a significantly increased risk of developing hypertension in patients with RA. Physicians should be aware of this risk and provide continuing monitoring in patients receiving these therapies.

Background Anakinra is the first interleukin-1 inhibitor to be used in clinical practice, and recent evidence showed that interleukin-1 plays a pivotal role in the pathogenesis of adult-onset Still disease (AoSD). However, data concerning efficacy with anakinra use in different clinical trials has not been evaluated, and the overall remission of AoSD with anakinra treatment has not been well defined. Methods We conducted a search on Embase, PubMed, and the Cochrane Library for relevant trials. Statistical analyses were conducted to calculate the overall remission rates, odds ratios (OR), and 95% confidence intervals (CI), by using either random effects or fixed effect models according to the heterogeneity. Results Of the 273 articles that were identified, 265 were excluded. Eight studies were eligible for inclusion. The overall remission rate and complete remission rate of anakinra in AoSD patients were 81.66% (95% CI: 69.51%–89.69%) and 66.75% (95% CI: 59.94%–75.3%), respectively. Compared with the controls, the use of anakinra was associated with a significant remission in AoSD, with an OR of 0.16 (95% CI: 0.06–0.44, P=0.0005). There were also significant reductions of the dosage of corticosteroid (mean difference =21.19) (95% CI: 13.2–29.18, P