Data mining techniques for detecting signals of adverse drug reaction of cardiac therapy drugs based on Jinan adverse event reporting system database: a retrospective study.

OBJECTIVE: Cardiac therapy drugs are widely used in the treatment of heart disease. However, the concern regarding adverse events (AEs) of cardiac therapy drugs have been rising. This study aimed to analyse cardiac therapy drug-related AEs using the Jinan adverse event reporting system (JAERS) database mining and conduct a comprehensive evaluation to provide safe medication information for patients. DESIGN: Retrospective observational study. SETTING: In this study, cardiac therapy drug-related AEs were detected using the JAERS database from January 2000 to March 2022. METHODS: Reports of cardiac therapy drug-related AEs were extracted from JAERS database, and the basic information of patients, reports and common AEs were analysed. Four disproportionality analysis methods, proportional reporting ratio (PRR), reporting odds ratio (ROR), Bayesian Confidence Propagation Neural Network (BCPNN), Medicines and Healthcare products Regulatory Agency (MHRA), were used to detect cardiac therapy drug-related signals. We further checked whether the detected signals exist on drug labels in China and two developed countries, the USA and Japan. RESULTS: In total, 168 314 AEs were reported, of which 4788 were associated with cardiac therapy drugs. Using the PRR, ROR, MHRA and BCPNN method, we detected 52 signals, 52 signals, 33 signals and 43 signals, respectively. Among the 52 signals, 14 were not included on the drug labels of China. One (isosorbide mononitrate-head bilges) was not included on the drug labels of the three countries. CONCLUSION: We identified 14 new cardiac therapy drug signals that did not appear on drug labels in China and 1 new signal that did not appear on drug labels in 3 counties. A causal link between cardiac therapy drugs and AEs should be evaluated in further studies.

Knockdown of ANRIL aggravates H2O2-induced injury in PC-12 cells by targeting microRNA-125a.

Spinal cord injury (SCI) is a devastating and common neurological disorder which causes local oxidative damage. The study aimed to investigate the underlying role of ANRIL in H2O2-induced cell injury of rat PC-12 cells. Cell injury was evaluated on the basis of cell viability, migration, invasion and apoptosis. The effect of ANRIL on H2O2-induced cell injury was estimated after cell transfection. Then, the interaction between ANRIL and miR-125a was explored by qRT-PCR and estimation of cell injury. Predicted by TargetScan, the possible target gene of miR-125a was verified. After that, the effects of aberrantly expressed target gene on cell viability, migration, invasion and apoptosis as well as phosphorylation of key kinases involved in JAK/STAT and ERK/MAPK pathways were evaluated. Results revealed that H2O2-induced PC-12 cell injury could be aggravated by ANRIL suppression. ANRIL appeared to act as a sponge of miR-125a, and ANRIL suppression promoted H2O2-induced cell injury by up-regulation of miR-125a. MCL-1 was a target of miR-125a, and MCL-1 was negatively correlated with miR-125a. Subsequent experiments showed the effect of MCL-1 silence on H2O2-induced PC-12 cell injury was the same as ANIRL suppression. MCL-1 attenuated H2O2-induced PC-12 cell injury by activating JAK/STAT and ERK/MAPK pathways. These findings suggested that knockdown of ANRIL aggravates H2O2-induced injury in PC-12 cells by targeting miR-125a. This might provide novel insights in the role of ANRIL in pathogenesis of oxidative damage during SCI.

Comparison of local infiltration analgesia and sciatic nerve block for pain control after total knee arthroplasty: a systematic review and meta-analysis.

BACKGROUND: This meta-analysis aimed to perform a meta-analysis to evaluate the efficiency and safety between local infiltration analgesia (LIA) and sciatic nerve block (SNB) when combined with femoral nerve block (FNB) after total knee arthroplasty (TKA). METHODS: A systematic search was performed in MEDLINE (1966-2017.04), PubMed (1966-2017.04), Embase (1980-2017.04), ScienceDirect (1985-2017.04), and the Cochrane Library. Only high-quality studies were selected. Meta-analysis was performed using Stata 11.0 software. RESULTS: Four randomized controlled trials (RCTs) and two non-randomized controlled trials (non-RCTs), including 273 patients met the inclusion criteria. The present meta-analysis indicated that there were significant differences between groups in terms of visual analogue scale (VAS) score at 12 h (SMD = -0.303, 95% CI -0.543 to -0.064, P = 0.013), VAS score at 24 h (SMD = -0.395, 95% CI -0.636 to -0.154, P = 0.001), morphine equivalent consumption at 24 h (SMD = -0.395, 95% CI -0.636 to -0.154, P = 0.001), and incidence of nausea (RD = 0.233, 95% CI 0.107 to 0.360, P = 0.000) and vomiting (RD = 0.131, 95% CI 0.025 to 0.237, P = 0.015). CONCLUSION: FNB-combined SNB provides superior pain relief and less morphine consumption within the first 24 h compared FNB-combined LIA in total knee arthroplasty. In addition, there were fewer side effects associated with SNB. Because the sample size and the number of included studies were limited, a multicenter RCT is needed to identify the effects of the two kinds of methods and further work must include range of motion analyses and functional test.

Is combined topical with intravenous tranexamic acid superior than topical, intravenous tranexamic acid alone and control groups for blood loss controlling after total knee arthroplasty: A meta-analysis.

BACKGROUND: The purpose of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to evaluate the efficacy and safety of combined topical with intravenous tranexamic acid (TXA) versus topical, intravenous TXA alone or control for reducing blood loss after a total knee arthroplasty (TKA). METHODS: In May 2016, a systematic computer-based search was conducted in the PubMed, Embase, Cochrane Library, Web of Science, and Chinese Wanfang database. This systematic review and meta-analysis were performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement criteria. Only patients prepared for primary TKA that administration combined topical with intravenous TXA with topical TXA, intravenous (IV) TXA, or control group for reducing blood loss were included. Eligible criteria were published RCTs about combined topical with intravenous TXA with topical alone or intravenous alone. The primary endpoint was the total blood loss and need for transfusion. The complications of deep venous thrombosis (DVT) were also compiled to assess the safety of combined topical TXA with intravenous TXA. Relative risks (RRs) with 95% CIs were estimated for dichotomous outcomes, and mean differences (MDs) with 95% CIs for continuous outcomes. The Cochrane risk of bias tool was used to appraise a risk of bias. Stata 12.0 software was used for meta-analysis. RESULTS: Fifteen studies involving 1495 patients met the inclusion criteria. The pooled meta-analysis indicated that combined topical TXA with intravenous TXA can reduce the total blood loss compared with placebo with a mean of 458.66 mL and the difference is statistically significant (MD = -458.66, 95% CI: -655.40 to 261.91, P < 0.001). Compared with intravenous TXA, combined administrated TXA can decrease the total blood loss, and the difference is statistically significant (MD = -554.03, 95% CI: -1066.21 to -41.85, P = 0.034). Compared with the topical administration TXA, the pooled meta-analysis indicated that combined TXA can decrease the amount of total blood loss with mean 107.65 mL with statistically significant(MD = -107.65, 95% CI: -525.55 to -239.9141.85, P = 0.001). The pooled results indicated that combined topical with intravenous TXA can decrease the need for transfusion (RR = 0.34, 95% CI: 0.23-0.50, P < 0.001). There is no significant difference between combined topical with intravenous TXA with topical or intravenous TXA (P > 0.05) in terms of need for transfusion and the occurrence of DVT. CONCLUSION: Compared with topical, intravenous TXA alone or control group, combined topical with TXA, can decrease the total blood loss and subsequent need for transfusion without increasing the occurrence of DVT. The dose and timing to administration TXA is different, and more randomized controlled trials are warranted to clarify the optimal dosing and time to administration TXA.

Discovery of 2-(6-(5-Chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999): A Highly Selective Mechanism-Based Myeloperoxidase Inhibitor for the Treatment of Cardiovascular Diseases.

Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders including vasculitis and cardiovascular and Parkinson's diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.

Efficient asymmetric synthesis of silanediol precursors from 1,5-dihydrosiloles.

Dihydrosiloles are easily prepared from 1,3-dienes and dichlorosilanes, even on kilogram scale. Asymmetric hydroboration of a 3-alkyl-1,5-dihydrosilole, prepared from a 2-alkyl-1,3-diene, followed by treatment with aqueous HF results in Peterson fragmentation, forming optically active 3-alkyl-4-fluorosilyl-1-butenes. The fluorosilanes are stable to moisture but very reactive toward nucleophiles. In addition, they can be converted to nucleophilic silyllithium reagents.