Rivaroxaban-loaded SLNs with treatment potential of deep vein thrombosis: in-vitro, in-vivo, and toxicity evaluation.

OBJECTIVES: Rivaroxaban (RXB), a novel Xa inhibitor having groundbreaking therapeutic potential. However, this drug is associated with few limitations, including its pharmacokinetics related toxicities. Here, we developed RXB-loaded SLNs (RXB-SLNs) to improve its biopharmaceutical profile. Methods: High pressure homogenizer was used to prepare RXB-SLNs, followed by their particle characterization, Transmission electron microscopy (TEM), Dynamic light scattering (DSC), and Powder X-ray diffraction (PXRD) analysis. Beside this, in-vitro, ex-vivo, and in-vivo evaluation, prothrombin time assessment and toxicity was investigated. RESULTS: RXB-SLNs had their particle size in nano range (99.1 ± 5.50 nm) with excellent morphology and low polydispersity index (0.402 ± 0.02) and suitable zeta potential (-25.9 ± 1.4 mV). The incorporation efficiency was observed around 95.9 ± 3.9%. In-vitro release profiles of the RXB-SLNs exhibited enhanced dissolution (89 ± 9.91%) as compared to pure drug (11 ± 1.43%) after 24 h of the study. PK study demonstrated a seven times enhanced bioavailability of RXB-SLNs when compared with pure drug. Furthermore, RXB-SLNs exhibited an expressive anti-coagulant behavior in human and rat blood plasma. Also, the final formulation exhibited no toxicity after oral administration of the SLNs. CONCLUSIONS: All together, these studies revealed the capability of the SLNs for carrying the RXB with enhanced therapeutic efficacy and no toxicity, most importantly for the treatment of deep vein thrombosis.

Bibliometric analysis of the global research status and trends of the association between Vitamin D and infections from 2001 to 2021.

Objective: The objective of this study was the visualization of hot spots and evolving trends in research on the association between vitamin D and infections through the use of bibliometric analysis. Methods: Based on 3046 relevant articles collected in the Web of Science Core Collection for the period of 2001-2021, the data were processed using CiteSpace software. GraphPad software was used for some of the graphics. Results: A total of 3,046 literature were retrieved, with an average citation frequency of 27.89 times. The number of published papers in the direction of "Immunology" (453 articles, 14.9%) and "Infectious diseases" (312 articles, 10.2%) is much higher. The United States presents the highest publication count (890, 29.2%) and shows a strong leadership in this field. Country burst shows that since 2015, many developing countries and low-income countries have carried out enthusiastic research in this regard, including China, Pakistan, and Iran. As for institutions, the League of European Research Universities produces a larger proportion of articles (220, 7.2%). In terms of authors, Martineau AR and Camargo CA have the highest number of published articles, contributing 30 (0.99%) and 28 articles (0.92%), respectively. Major studies are supported by the United States Department of Health Human Services funding (394, 12.9%). According to the keyword co-occurrence diagram, the 10 most frequent keywords from 2001 to 2021 are "vitamin D", "infection", "d deficiency", "risk", "association", "expression", "disease", "d supplementation", "vitamin d deficiency", and "children". The top 10 cited articles in 2021 are all related to COVID-19, suggesting it is a hotspot in recent times. Conclusion: Research on the association between vitamin D and infection has grown rapidly since 2012 and is generally developing well. While developed Western countries continue to be leading roles in this field, research trends in developing countries are also very promising. It is demonstrated that the relationship between vitamin D and respiratory infections, especially respiratory viruses and the more recently COVID-19, has received a lot of attention in the last two decades, suggesting that this is the hotspot and frontier of research issue.

A study of the influence of lead pollution on the anticoagulant activity of Whitmania pigra based on pharmacodynamics and metabolomics research.

Whitmania pigra Whitman (leech, also called Shuizhi in China, abbreviated as SZ), which has been used as a traditional Chinese medicine in the treatment of blood stasis syndrome (BSS) for a long time, is vulnerable to lead pollution in aquaculture environments. SZ has good anticoagulant activity. However, there are few studies on the influence of lead pollution on it. Therefore, we carried out the following researches to explore the influence of lead pollution on the anticoagulant activity of SZ and its mechanism. Firstly, the acute blood stasis model of rats was established by subcutaneous injection of adrenaline hydrochloride and ice water bath. Then unpolluted SZ (UPS) and lead-polluted SZ (LPS) were extracted. Next, the blood stasis model rats were administrated by gavage and the rats in normal control (NC) group and blood stasis model (BM) group were given the same amount of normal saline. Finally, the blood of the rats was collected to detect the coagulation function and hemorheology indexes. The metabolomics of rat plasma was studied by ultra-high-performance liquid chromatography coupled with orbitrap mass spectrometry (UPLC-Orbitrap-MS) technology. Principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA) and Hierarchical clustering analysis (HCA) were used to perform metabolomics analysis. MetPA analysis was used to search for related metabolic pathways. The results of coagulation function and hemorheology showed that lead pollution could decrease the anticoagulant activity of SZ. The OPLS-DA score plots indicated that the plasma metabolites of rats in LPS group were close to BM group, while UPS group tended to be close to NC group both in the positive and negative ion mode. Hierarchical cluster analysis (HCA) suggested that UPS group and NC group were clustered into a branch, while LPS group and BM group were clustered into a branch. To sum up, lead pollution will reduce the anticoagulant activity of SZ. And lead pollution reduces the anticoagulant activity of SZ probably by influencing the metabolic pathways such as sphingolipid metabolism, amino acid metabolism and energy metabolism in rats.

Oral Anticoagulants for Nonvalvular Atrial Fibrillation in Patients With High Risk of Gastrointestinal Bleeding.

Importance: Many patients with nonvalvular atrial fibrillation (NVAF) are at a high risk of gastrointestinal (GI) bleeding due to conditions including older age; stage III to V chronic kidney disease (CKD); HAS-BLED (hypertension, kidney or liver disease, stroke history, prior bleeding, unstable international normalized ratio, age >65, drug or alcohol use) score of 3 or greater; corticosteroid, antiplatelet or nonsteroidal anti-inflammatory drug (NSAID) use; or GI conditions. Objective: To compare the risk of stroke and/or systemic embolism (SE) and major bleeding (MB) among patients with NVAF and high risk of GI bleeding who received non-vitamin K antagonist oral anticoagulants (NOACs) vs those who received warfarin. Design, Setting, and Participants: This retrospective cohort study included patients with NVAF who were 75 years and older; had stage III to V CKD; had an HAS-BLED score of 3 or greater; used corticosteroids, antiplatelets, or NSAIDs; or had GI conditions. Data were collected from the Centers for Medicare & Medicaid Services and 4 commercial insurance databases between January 1, 2012, and September 30, 2015. Data analysis was conducted from January 2012 to September 2015. Exposures: New prescription for apixaban, dabigatran, rivaroxaban, or warfarin between January 1, 2013, and September 30, 2015 (identification period). Main Outcomes and Measures: Six propensity score-matched cohorts were created to compare between study drugs. For the primary objective, Cox models were used to estimate stroke and/or SE and MB hazard ratios (HRs). Results: A total of 381 054 patients (187 489 [49.2%] women) with NVAF and at least 1 high-risk GI bleeding factor were identified (HAS-BLED score ≥3: 284 527 [74.7%]; aged ≥75 years: 252 835 [66.4%]; corticosteroid, antiplatelet, or NSAID therapy: 107 675 [28.3%]; prior GI bleeding conditions: 74 818 [19.6%]; and stage III-V CKD: 56 892 [14.9%]). All NOACs were associated with a lower risk of stroke and/or SE vs warfarin (apixaban: HR, 0.60; 95% CI, 0.52-0.68; dabigatran: HR, 0.75; 95% CI, 0.64-0.88; rivaroxaban: HR, 0.79; 95% CI, 0.73-0.86). Compared with warfarin, apixaban and dabigatran were associated with a lower risk of MB (apixaban: HR, 0.59; 95% CI, 0.56-0.63; dabigatran: HR, 0.78; 95% CI, 0.70-0.86), while rivaroxaban was associated with a higher risk (HR, 1.11; 95% CI, 1.05-1.16). Conclusions and Relevance: In this study of patients with NVAF and high risk of GI bleed, NOACs were associated with lower rates of stroke and/or SE, but NOACs had varying risks of MB compared with warfarin. These results may help inform treatment options in this patient population.

Clinical and Economic Outcomes Among Nonvalvular Atrial Fibrillation Patients With Coronary Artery Disease and/or Peripheral Artery Disease.

To address literature gaps on treatment with real-world evidence, this study compared effectiveness, safety, and cost outcomes in NVAF patients with coronary or peripheral artery disease (CAD, PAD) prescribed apixaban versus other oral anticoagulants. NVAF patients aged ≥65 years co-diagnosed with CAD/PAD initiating warfarin, apixaban, dabigatran, or rivaroxaban were selected from the US Medicare population (January 1, 2013 to September 30, 2015). Propensity score matching was used to match apixaban versus warfarin, dabigatran, and rivaroxaban cohorts. Cox models were used to evaluate the risk of stroke/systemic embolism (SE), major bleeding (MB), all-cause mortality, and a composite of stroke/myocardial infarction/all-cause mortality. Generalized linear and two-part models were used to compare stroke/SE, MB, and all-cause costs between cohorts. A total of 33,269 warfarin-apixaban, 9,335 dabigatran-apixaban, and 33,633 rivaroxaban-apixaban pairs were identified after matching. Compared with apixaban, stroke/SE risk was higher in warfarin (hazard ratio [HR]: 1.93; 95% confidence interval [CI]: 1.61 to 2.31), dabigatran (HR: 1.69; 95% CI: 1.18 to 2.43), and rivaroxaban (HR: 1.24; 95% CI: 1.01 to 1.51) patients. MB risk was higher in warfarin (HR: 1.67; 95% CI: 1.52 to 1.83), dabigatran (HR: 1.37; 95% CI: 1.13 to 1.68), and rivaroxaban (HR: 1.87; 95% CI: 1.71 to 2.05) patients vs apixaban. Stroke/SE- and MB-related medical costs per-patient per-month were higher in warfarin, dabigatran, and rivaroxaban patients versus apixaban. Total all-cause health care costs were higher in warfarin and rivaroxaban patients compared with apixaban patients. In conclusion, compared with apixaban, patients on dabigatran, rivaroxaban, or warfarin had a higher risk of stroke/SE, MB, and event-related costs.

FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation.

Cytosolic sensing of pathogens and damage by myeloid and barrier epithelial cells assembles large complexes called inflammasomes, which activate inflammatory caspases to process cytokines (IL-1ß) and gasdermin D (GSDMD). Cleaved GSDMD forms membrane pores, leading to cytokine release and inflammatory cell death (pyroptosis). Inhibiting GSDMD is an attractive strategy to curb inflammation. Here we identify disulfiram, a drug for treating alcohol addiction, as an inhibitor of pore formation by GSDMD but not other members of the GSDM family. Disulfiram blocks pyroptosis and cytokine release in cells and lipopolysaccharide-induced septic death in mice. At nanomolar concentration, disulfiram covalently modifies human/mouse Cys191/Cys192 in GSDMD to block pore formation. Disulfiram still allows IL-1ß and GSDMD processing, but abrogates pore formation, thereby preventing IL-1ß release and pyroptosis. The role of disulfiram in inhibiting GSDMD provides new therapeutic indications for repurposing this safe drug to counteract inflammation, which contributes to many human diseases.

Metabolomics-based study reveals the effect of lead (Pb) in the culture environment on Whitmania pigra.

Whitmania pigra, called Mahuang (MH) in Chinese, has been used as a traditional Chinese medicine for many years and is susceptible to Pb exposure in aquaculture environments. To understand the impact of Pb in the culture environment on MHs, we carried out a 50-day culture of MHs in environments with different levels of Pb pollution. Then, tissue samples of MHs reared in the different Pb-polluted environments were collected and analysed by UPLC-Q/TOF-MS. The results showed that the Pb residue in MHs increased with increasing Pb in the culture environment. There was no significant difference in MH Pb content (P < 0.05) between the low-Pb residue group (PbL) and the blank control group (BC), and those of the middle-Pb residue group (PbM) and the high-Pb residue group (PbH) were significantly different from that of the BC group. Metabolomics results showed significant changes in 24 metabolites in the PbL, PbM and PbH groups, some of which were dose-dependent. These metabolites were mainly lipids, nucleotides, and dipeptides, which are involved in metabolic pathways such as glycerophospholipid metabolism, sphingolipid metabolism, and nucleotide metabolism. Overall, the results proved that metabolomics can be an effective tool to understand the effects of Pb on the metabolic responses of MHs.

[Storage and ecological stoichiometry of soil carbon, nitrogen, and phosphorus under diffe-rent ecological restoration patterns in the alpine desertified grassland of northwestern Sichuan, China]. / 川西北高寒沙地不同生态治理模式下土壤碳氮磷储量及生态化学计量特征.

We analyzed carbon (C), nitrogen (N), and phosphorus (P) contents and their stoichiometric characteristics of sandy soil in four restoration patterns after 5 years restoration in the northwest Sichuan, China, including planting grass alone (PG), planting shrub alone (PS), shrub-grass intercrop (SG), and shrub-herb intercrop (SH). The untreated sand land was set as control (CK). The results showed that soil organic carbon (SOC), total nitrogen (TN), total phosphorus (TP), C/N, C/P, and N/P were increased under different restoration patterns, especially under shrub-grass intercrop (SG). In 0-10 cm and 10-20 cm soil layers, the contents of SOC and TN under SG were significantly higher than that under other patterns. In 0-40 cm soil layer, the SOC storage under SG was higher than that under PG, PS, SH, and CK by 13.4%, 15.6%, 17.1% and 43.2%, respectively. The available N, available P, available K, and water content were positively correlated to SOC, TN, and TP in 0-10 cm and 10-20 cm soil layers. Soil bulk density was negatively correlated to SOC, TN and TP. The alkaline N, available P, available K, and water content were significantly correlated to C/N and C/P in 10-20 cm soil layer. The contents and stoichiometry of soil C, N and P were affected by both ecological restoration measures and soil depth. The shrub-grass intercrop pattern was most beneficial to improve sandy soil environment quality in the study area.

[Diversity of fungi on surface of Pheretima].

Traditional Chinese medicines( TCMs) are easily contaminated by fungi during planting,harvesting,processing,transportation and storage. The 2015 version of Chinese Pharmacopoeia stipulates the detection of aflatoxin in Dilong. After reviewing the literature,it has been found that there are no domestic and foreign scholars who have studied the surface fungi of Dilong. Pheretima,known as Dilong in China,is a commonly used TCMs in animal. In this experiment,8 batches of Dilong were collected from retail pharmacies in Beijing. The fungi on the surface of Dilong were cultured by traditional plate method and the single strain was obtained by the top purification method. The fungal colony morphology,microstructure characteristics and DNA barcode were used to isolate and identify the fungi. At the same time,based on Illumina Hi Seq 2500 high-throughput sequencing platform,the diversity of fungi on the surface of Dilong was analyzed. The results showed that 287 strains of 9 species of fungi were isolated and identified by plate method. Combined with 3 kinds of identification method,eight of nine fungi could be identified,respectively,Aspergillus niger,Penicillium,Alternaria nees,A. flavus,and Penicillium oxalicum,Humicola sp.,Talaromyces purpurogenus and A. insuetus,1 kind of fungi was not identified yet. Among them,Penicillium and Aspergillus were the dominant genus. The results of high-throughput sequencing belonged to 2 boundaries,6 gates,19 classes,44 orders,98 families,127 genus and 121 species in different classification levels. Wallemia,Aspergillus and Cordyceps were the dominant genus,and the relative abundances are 63. 33%,15. 28%,and 10. 28%,respectively. Through the diversity study on the surface fungi of Dilong in Beijing retail pharmacies,it can provide a reference for its safe storage and clinical use.

Evaluation of the ratio of the estimated area under the concentration-time curve to minimum inhibitory concentration (estimated AUIC) as a predictor of the outcome for tigecycline treatment for pneumonia due to multidrug-resistant bacteria in an intensive care unit.

OBJECTIVES: Based on pharmacokinetics/pharmacodynamics (PK/PD) and the minimum inhibitory concentration (MIC) of tigecycline (TGC), dose increases have been advocated to maximize the efficacy against pneumonia that is suspected to be due to multidrug-resistant (MDR) bacteria in an intensive care unit. This practice-based study explored the relationship between the predicted PK parameter, the ratio of the area under the concentration-time curve to the 24 h of dosing/minimum inhibitory concentration (AUC0-24/MIC or AUIC), and the clinical and microbiological outcomes in critically ill patients with pneumonia due to MDR bacteria. METHODS: We conducted a prospective cohort study of the treatment of pneumonia due to MDR bacteria in an intensive care unit. The study patients were recruited and assigned to either TGC standard dose (SD, 50 mg q12 h) or high dose (HD, 100 mg q12 h) for the treatment of pneumonia due to MDR bacteria depending on the doctors' decisions. The relationships between the PK/PD parameters and outcomes were examined. RESULTS: Over the study period, 105 patients were included in the study. Whereas C1/2, Cmin, MIC and AUC were dramatically higher in the HD group than in the SD group (all P < 0.05), the Cmax and AUIC had no difference in both groups (all P > 0.05). The patients in the HD group had a higher clinical cure rate than those in the SD group (P = 0.029), but the bacterial eradication rate and survival rate of the patients in the HD group were not better than those in SD group (P = 0.279 and 0.416, respectively). The Cmax, C1/2, Cmin and AUC in the cured group were higher than those in failure group (all P < 0.05). The MICs were dramatically higher in the failure group than those in cure group (P = 0.0001), which led to significantly lower AUICs (P = 0.0001). In the ROC analysis, the areas of Cmax, C1/2, Cmin, AUC, negative-MIC and AUIC under the ROC curve were 0.64, 0.69, 0.67, 0.66, 0.73 and 0.82, respectively. The sensitivity was ascertained to be 75% and the specificity was 89% when the AUIC cut-off value was considered to be 10.12. Moreover, the sensitivity was ascertained to be 63% and the specificity was 80% when the MIC cut-off value was considered to be 1.75 mg/L. CONCLUSIONS: The AUIC and MIC are associated with tigecycline treatment outcomes in pneumonia due to MDR bacteria, and aiming to achieve an individualized AUIC ≥ 10.12 when MIC < 1.75 mg/L could improve outcomes.

[Effect of lead pollution on anticoagulant effect of Whitmania pigra based on in vitro anticoagulation experiment].

Leech has a good anticoagulant activity and is one of the raw materials for treatment of many cardiovascular and cerebrovascular diseases. This study was based on in vitro anticoagulant experiments( APTT and PT) to investigate the effects of lead contamination on the anticoagulant effect of leech. At present,the Hirudo circulating in the market are dominated by Whitmania pigra,therefore Wh. pigra were cultivated under a different lead pollution for 50 days. Then,the effects of Wh. pigra extract,extracting from different cultivating environment,on activated partial thrombin time( APTT) and prothrombin time( PT) were determined by automatic coagulation instrument. The results showed that the Wh. pigra extract significantly prolonged the APTT compared with the saline group.The APTT of the lead-high residual Wh. pigra was shorter than that of the blank Wh. pigra. The Wh. pigra extracts from different treatment groups had little effect on PT. The results showed that the lead residue in the Wh. pigra increased with the increase of lead in the cultured soil,the lead residual of the Pb-H group was( 10. 66±2. 79) mg·kg~(-1),which exceeded the lead limit specified in the 2015 edition of the Chinese Pharmacopoeia. The results indicated that growth environment pollution is one of the important factors causing excessive lead in Wh. pigra. Lead pollution will reduce the anticoagulant effect of Wh. pigra and affect its clinical efficacy.

Effectiveness and Safety of Oral Anticoagulants Among Nonvalvular Atrial Fibrillation Patients.

Background and Purpose- This ARISTOPHANES study (Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients) used multiple data sources to compare stroke/systemic embolism (SE) and major bleeding (MB) among a large number of nonvalvular atrial fibrillation patients on non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. Methods- A retrospective observational study of nonvalvular atrial fibrillation patients initiating apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, to September 30, 2015, was conducted pooling Centers for Medicare and Medicaid Services Medicare data and 4 US commercial claims databases. After 1:1 NOAC-warfarin and NOAC-NOAC propensity score matching in each database, the resulting patient records were pooled. Cox models were used to evaluate the risk of stroke/SE and MB across matched cohorts. Results- A total of 285 292 patients were included in the 6 matched cohorts: 57 929 apixaban-warfarin, 26 838 dabigatran-warfarin, 83 007 rivaroxaban-warfarin, 27 096 apixaban-dabigatran, 62 619 apixaban-rivaroxaban, and 27 538 dabigatran-rivaroxaban patient pairs. Apixaban (hazard ratio [HR], 0.61; 95% CI, 0.54-0.69), dabigatran (HR, 0.80; 95% CI, 0.68-0.94), and rivaroxaban (HR, 0.75; 95% CI, 0.69-0.82) were associated with lower rates of stroke/SE compared with warfarin. Apixaban (HR, 0.58; 95% CI, 0.54-0.62) and dabigatran (HR, 0.73; 95% CI, 0.66-0.81) had lower rates of MB, and rivaroxaban (HR, 1.07; 95% CI, 1.02-1.13) had a higher rate of MB compared with warfarin. Differences exist in rates of stroke/SE and MB across NOACs. Conclusions- In this largest observational study to date on NOACs and warfarin, the NOACs had lower rates of stroke/SE and variable comparative rates of MB versus warfarin. The findings from this study may help inform the discussion on benefit and risk in the shared decision-making process for stroke prevention between healthcare providers and nonvalvular atrial fibrillation patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT03087487.

Effectiveness and Safety of Anticoagulants in Adults with Non-valvular Atrial Fibrillation and Concomitant Coronary/Peripheral Artery Disease.

BACKGROUND: Direct oral anticoagulants (DOAC) are at least non-inferior to warfarin in efficacy and safety among patients with nonvalvular atrial fibrillation. Limited evidence is available regarding outcomes for nonvalvular atrial fibrillation patients with coronary/peripheral artery disease. METHODS: Non-valvular atrial fibrillation patients aged ≥65 years diagnosed with coronary/peripheral artery disease in the US Medicare population, newly initiating DOACs (apixaban, rivaroxaban, dabigatran) or warfarin were selected from January 1, 2013 to September 30, 2015. Propensity score matching was used to compare DOACs vs warfarin. Cox proportional hazards models were used to estimate the risk of stroke/systemic embolism, major bleeding, and composite of stroke/myocardial infarction/all-cause mortality. RESULTS: There were 15,527 apixaban-warfarin, 6,962 dabigatran-warfarin, and 25,903 rivaroxaban-warfarin-matched pairs, with a mean follow-up of 5-6 months. Compared with warfarin, apixaban was associated with lower rates of stroke/systemic embolism (hazard ratio [HR] 0.48; 95% confidence interval [CI], 0.37-0.62), major bleeding (HR 0.66; 95% CI, 0.58-0.75), and stroke/myocardial infarction/all-cause mortality (HR 0.63; 95% CI, 0.58-0.69); dabigatran and rivaroxaban were associated with lower rates of stroke/myocardial infarction/all-cause mortality (HR 0.79; 95% CI, 0.70-0.90 and HR 0.87; 95% CI, 0.81-0.92, respectively). Rivaroxaban was associated with a lower rate of stroke/systemic embolism (HR 0.72; 95% CI, 0.60-0.89) and a higher rate of major bleeding (HR 1.14; 95% CI, 1.05-1.23) vs warfarin. CONCLUSIONS: All DOACs were associated with lower stroke/myocardial infarction/all-cause mortality rates compared with warfarin; differences were observed in rates of stroke/systemic embolism and major bleeding. Findings from this observational analysis provide important insights about oral anticoagulation therapy among non-valvular atrial fibrillation patients with coronary/peripheral artery disease and may help physicians in the decision-making process when treating this high-risk group of patients.

Comparison of effectiveness and safety of treatment with apixaban vs. other oral anticoagulants among elderly nonvalvular atrial fibrillation patients.

OBJECTIVE: To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) of elderly (≥65 years of age) nonvalvular atrial fibrillation (NVAF) patients initiating apixaban vs. rivaroxaban, dabigatran, or warfarin. METHODS: NVAF patients with Medicare Advantage coverage in the US initiating oral anticoagulants (OACs, index event) were identified from the Humana database (1 January 2013-30 September 2015) and grouped into cohorts depending on OAC initiated. Propensity score matching (PSM), 1:1, was conducted among patients treated with apixaban vs. each other OAC, separately. Rates of S/SE and MB were evaluated in the follow-up. Cox regressions were used to compare the risk of S/SE and MB between apixaban and each of the other OACs during the follow-up. RESULTS: The matched pairs of apixaban vs. rivaroxaban (n = 13,620), apixaban vs. dabigatran (n = 4654), and apixaban vs. warfarin (n = 14,214) were well balanced for key patient characteristics. Adjusted risks for S/SE (hazard ratio [HR] vs. rivaroxaban: 0.72, p = .003; vs. warfarin: 0.65, p < .001) and MB (HR vs. rivaroxaban: 0.49, p < .001; vs. warfarin: 0.53, p < .001) were significantly lower during the follow-up for patients treated with apixaban vs. rivaroxaban and warfarin. Adjusted risks for S/SE (HR: 0.78, p = .27) and MB (HR: 0.82, p = .23) of NVAF patients treated with apixaban vs. dabigatran trended to be lower, but did not reach statistical significance. CONCLUSIONS: In the real-world setting after controlling for differences in patient characteristics, apixaban is associated with significantly lower risk of S/SE and MB than rivaroxaban and warfarin, and a trend towards better outcomes vs. dabigatran among elderly NVAF patients in the US.

Nitrosative stress and nitrated proteins in trichloroethene-mediated autoimmunity.

Exposure to trichloroethene (TCE), a ubiquitous environmental contaminant, has been linked to a variety of autoimmune diseases (ADs) including SLE, scleroderma and hepatitis. Mechanisms involved in the pathogenesis of ADs are largely unknown. Earlier studies from our laboratory in MRL+/+ mice suggested the contribution of oxidative/nitrosative stress in TCE-induced autoimmunity, and N-acetylcysteine (NAC) supplementation provided protection by attenuating oxidative stress. This study was undertaken to further evaluate the contribution of nitrosative stress in TCE-mediated autoimmunity and to identify proteins susceptible to nitrosative stress. Groups of female MRL +/+ mice were given TCE, NAC or TCE + NAC for 6 weeks (TCE, 10 mmol/kg, i.p., every 4th day; NAC, ∼ 250 mg/kg/day via drinking water). TCE exposure led to significant increases in serum anti-nuclear and anti-histone antibodies together with significant induction of iNOS and increased formation of nitrotyrosine (NT) in sera and livers. Proteomic analysis identified 14 additional nitrated proteins in the livers of TCE-treated mice. Furthermore, TCE exposure led to decreased GSH levels and increased activation of NF-κB. Remarkably, NAC supplementation not only ameliorated TCE-induced nitrosative stress as evident from decreased iNOS, NT, nitrated proteins, NF-κB p65 activation and increased GSH levels, but also the markers of autoimmunity, as evident from decreased levels of autoantibodies in the sera. These findings provide support to the role of nitrosative stress in TCE-mediated autoimmune response and identify specific nitrated proteins which could have autoimmune potential. Attenuation of TCE-induced autoimmunity in mice by NAC provides an approach for designing therapeutic strategies.