High-dose ASA Research Articles

National Trends in Aspirin Use and Expenditures in the United States: Analysis of The Medical Expenditure Panel Survey 2000-2021.

Since its invention in 1897, aspirin (ASA) has been the most widely used and cost-effective antiplatelet agent to prevent and treat atherosclerotic cardiovascular disease (ASCVD). We aimed to study the trends and expenditures associated with ASA use in the USA. We conducted a serial cross-sectional analysis using the Medical Expenditure Panel Survey data from January 2000 to December 2021, focusing on adults aged ≥ 40years. Total and out-of-pocket expenditures associated with ASA were estimated to 2021 US dollars (USD). Trends, demographics, and predictors of ASA use among patients with and without ASCVD were also evaluated. A total of 53million adults were identified during the study period. The number of ASA users increased from 2.9million to 6.6million with increased female (36.7%-49.7%; ptrend = 0.02) and African American (13%-18.9%; ptrend = 0.03) representation amongst all ASA users during the survey period. The use of low-dose ASA increased, while high-dose ASA declined significantly. Only 50% of all ASA users had known ASCVD. The most prevalent ASA users among patients with ASCVD were those aged ≥ 70years, while patients without ASCVD, it was the 50-69 age group. The total annual expenditure on ASA averaged approximately 60million USD, with 27.3million USD out-of-pocket. Total and low-dose (81mg) ASA use has increased, while high-dose (325mg) ASA has declined. ASA use for primary prevention has risen among adults aged 50-69years, and patients ≥ 70years continue to use ASA without known ASCVD. Further studies are needed to understand the implications of increased ASA use, especially among those without ASCVD.

Thirty day low-dose versus regular-dose aspirin for venous thromboembolism prophylaxis in primary total joint arthroplasty.

The optimal dosing of aspirin (ASA) monotherapy for prophylaxis after total joint arthroplasty is debatable. The objective of this study was to compare two ASA regimens with regards to symptomatic deep venous thrombosis (DVT), pulmonary embolism (PE), bleeding, and infection 90days after primary total hip arthroplasty (THA) and total knee arthroplasty (TKA). We retrospectively identified 625 primary THA and TKA surgeries in 483 patients who received ASA for 4weeks post-op. 301 patients received 325mg once daily (QD) and 324 patients received 81mg twice daily (BID). Patients were excluded if they were minors, had a prior venous thromboembolism (VTE), had ASA allergy, or received other VTE prophylaxis drugs. There was a significant difference in rate of bleeding and suture reactions between the two groups. Bleeding was 7.6% for 325mg QD and 2.5% for 81mg BID (p = .0029 Χ2, p = .004 on multivariate logistic regression analysis). Suture reactions were 3.3% for 325mg QD and 1.2% for 81mg BID (p = .010 Χ2, p = .027 on multivariate logistic regression analysis). Rates of VTE, symptomatic DVT, and PE were not significantly different. The incidence of VTE was 2.7% for 325mg QD and 1.5% for 81mg BID (p = .4056). Symptomatic DVT rates were 1.6% for 325mg QD and 0.9% for 81mg BID (p = .4139). Deep infection was 1.0% for 325mg QD and 0.31% for 81mg BID (p = .3564). Low-dose ASA in patients with limited comorbidities undergoing primary THA and TKA is associated with significant lower rates of bleeding and suture reactions than high dose ASA. Low-dose ASA was not inferior to higher dose ASA for the prevention of VTE, wound complications, and infection 90days postoperatively.

Low-Dose Aspirin Administered for Venous Thromboembolism Prophylaxis Reduces the Incidence of Heterotopic Ossification in Total Joint Arthroplasty

BackgroundHeterotopic ossification (HO) is a common complication following total joint arthroplasty (TJA). However, the pathophysiology of HO is not entirely understood. Inflammation may play a significant role in the pathogenesis of HO as nonsteroidal anti-inflammatory drugs are effective in the prevention of HO. The purpose of this study is to examine if aspirin (ASA), when used as venous thromboembolism (VTE) prophylaxis, influenced the rate of HO formation following TJA. MethodsWe queried our longitudinally maintained database to identify all patients who underwent primary total hip arthroplasty (THA) or total knee arthroplasty (TKA) for osteoarthritis between January 2016 and June 2018 with at least 3-month radiographic follow-up. In total, 1238 THAs and 1051 TKAs were included for analysis. Radiographs were reviewed and HO formation graded according to the Brooker classification. Patient demographic and VTE prophylaxis data were collected and reviewed for accuracy. Univariate and multivariate analysis was performed to evaluate the effect of ASA on HO formation. ResultsThe overall rate of HO was 37.5% after THA and 17.4% after TKA. Patients receiving ASA were less likely to develop HO after THA (34.8% vs 45.5%; P < .001), as well as HO after TKA (13.4% vs 18.4%; P = .047) compared to patients receiving non-ASA VTE prophylaxis. The rate of HO formation trended to be lower, albeit not statistically significantly, in patients receiving low-dose ASA (81 mg) vs high-dose ASA (325 mg). ConclusionPatients undergoing primary TJA receiving ASA for VTE prophylaxis were less likely to develop HO compared to patients who were administered non-ASA VTE prophylaxis.

High-Versus Low-Dose Aspirin in the Treatment of Kawasaki Disease

Research Article| April 01 2020 High-Versus Low-Dose Aspirin in the Treatment of Kawasaki Disease AAP Grand Rounds (2020) 43 (4): 44. https://doi.org/10.1542/gr.43-4-44 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation High-Versus Low-Dose Aspirin in the Treatment of Kawasaki Disease. AAP Grand Rounds April 2020; 43 (4): 44. https://doi.org/10.1542/gr.43-4-44 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search toolbar search search input Search input auto suggest filter your search All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: aspirin low dose, fever, immunoglobulins, intravenous, kawasaki's disease Source: Platt B, Belarski E, Manaloor J, et al. Comparison of risk of recrudescent fever in children with Kawasaki disease treated with intravenous immunoglobulin and low-dose vs high-dose aspirin. JAMA Netw Open. 2020; 3(1): e1918565; doi: https://doi.org/10.1001/jamanetworkopen.2019.18565Google Scholar Investigators from Indiana University, Indianapolis, IN, conducted a retrospective study to compare rates of recrudescent fever and coronary artery (CA) abnormalities in children treated with IV immunoglobulin (IVIG) and either low- or high-dose aspirin (ASA) for treatment of Kawasaki disease (KD). Study participants were children with KD treated within 10 days of symptom onset with 2 g/kg of IVIG and ASA at Riley’s Hospital for Children, Indianapolis, IN, between 2007 and 2018. Eligible children were identified using ICD-9 and ICD-10 codes; the medical records of eligible children were reviewed, and information was abstracted on demographics, symptoms before admission, clinical course during hospitalization and follow-up, echocardiography results, and dose of ASA. Initial ASA doses were categorized as low (<10 mg/kg/d) or high (>10 mg/kg/d). The primary outcome was recrudescent fever, defined as a rectal temperature >38.0°C or axillary temperature >37.5°C within 14 days of initial treatment that necessitated retreatment. Secondary outcomes were development of CA abnormalities and length of initial hospital stay. Outcomes in children treated with low- or high-dose ASA were compared using regression analyses after controlling for confounding variables. Subgroup analyses, limited to study patients with complete KD, also were conducted. Data were analyzed in 260 children with a median age of 2.5 years. There were 142 patients treated with low-dose ASA (median dose, 4.4 mg/kg/d), and 118 received high-dose ASA (median dose, 75.5 mg/kg/d). Most of the children in the low-dose group were treated before 2016, whereas most of those receiving high-dose ASA were treated after 2015. The 2 groups were similar for most other characteristics except that the percentage of children with incomplete KD was significantly higher among those in the high-dose group (44.1% vs 28.9% for those in the low-dose group; P = .01). Among those receiving low-dose ASA, the rate of recrudescent fever was 27.5% versus 26.0% in those receiving high-dose ASA. After adjusting for age <1 year and incomplete KD, the OR for recrudescent fever was 1.63 (95% CI, 0.89–2.97). Among the 167 study children with complete KD, the OR for recrudescent fever was 1.87 (95% CI, 0.82–4.23), when comparing the low- to high-dose groups. There was also no significant difference in rates of CA abnormalities between children in the low- and high-dose groups (7.4% and 9.4%, respectively; OR, 1.02; 95% CI, 0.55–1.87). The median length of hospital stay was 3 days for both groups (P = .27). The authors conclude that there was no difference in rates of recrudescent fever or CA abnormalities among children with KD treated with IVIG and either low- or high-dose ASA. Dr Spar has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.... You do not currently have access to this content.

Antiplatelet Therapy and Adverse Hematologic Events During Heart Mate II Support

Hematologic adverse events are common during continuous flow left ventricular assist device support; yet, their relation to antiplatelet therapy, including aspirin (ASA) dosing, is uncertain. A single-center retrospective review of all patients supported by a continuous flow left ventricular assist device (Heart Mate II) from June 2006 to November 2014 was conducted. Patients were categorized into 3 groups: (1) ASA 81 mg+dipyridamole 75 mg daily (n = 26) with a target international normalized ratio (INR) of 2 to 3 from June 2006 to August 2009; (2) ASA 81 mg daily (n = 18) from September 2009 to August 2011 with a target INR of 1.5 to 2; and (3) ASA 325 mg daily from September 2011 to November 2014 with a target INR of 2 to 3 (n = 70). Hemorrhagic and thrombotic outcomes were retrieved ≤ 365 days after implantation. Cumulative survival free from adverse events was calculated using Kaplan-Meier curves and Cox proportional hazard ratios were generated. Hemorrhagic events occurred in 6 patients on ASA 81 mg+dipyridamole (26%; 0.42 events per patient year; mean INR at event, 2.2), 4 patients on ASA 81 mg (22%; 0.38 events per patient year; mean INR at event, 2.0), and in 38 patients on ASA 325 mg (54%; 1.4 events per patient year; mean INR at event, 2.2); P = 0.004. Patients on ASA 325 mg had a higher adjusted hazard ratio of 2.9 (95% confidence interval, 1.2-7.0 versus ASA 81 mg+dipyridamole; P = 0.02) and 3.4 (95% confidence interval, 1.2-9.5 versus ASA 81 mg; P = 0.02) for hemorrhagic events. Thrombotic events rates were not different between groups. High-dose ASA in Heart Mate II patients treated concomitantly with warfarin is associated with an increased hazard of bleeding but does not reduce thrombotic events.

Abstract 148: The Optimal Duration Of Asa Treatment After Acute Phase Of Kawasaki Disease Based On Inflammatory Markers

Purpose: Outcomes of Kawasaki disease (KD) are determined by the development of cardiovascular complications. Low dose aspirin(ASA) treatment is used as antithrombotic effect after acute phase of KD for 6-8 weeks.There are no standardized inflammatory markers used as guidance for completing low dose ASA treatment. The optimal duration of low dose ASA treatment is not determined. The aim of this study is to decide the duration of low dose ASA treatment based on inflammatory markers. Methods : We enrolled 80 KD children admitted to the Chungnam National University Hospital,South Korea between Sep 2012 and May 2014. We reviewed the medical records for clinical characteristics, duration of fever, cardiovascular complications and laboratory data on admission. Inflammatory markers were measured every 7-14 days at OPD after immunoglobulin(IVIG) and high dose ASA treatment in acute phase. Low dose ASA was stopped when the level of inflammatory markers were down to the normal without any cardiovascular complications. Echocardiograms were performed at admission, discharge and prior to completion of ASA treatment when the inflammatory marker turned to normal. Results : 80 KD patients,(Complete, n=44; Incomplete, n=36). The incidence of cardiovascular complications was similar both two groups. No significant differences in the laboratory studies either complete or incomplete KD. The levels of inflammatory marker were normalize after the acute phase as 13.0±13.6 days for platelets, 13.8± 8.3 days for CRP, 14.4±9.6 days for d-dimer, and 24.1 ± 10.5 days for ESR. The levels of platelets and CRP were first normalized within 2 weeks, and that of ESR was last within 3-4 weeks. The duration of raised CRP levels showed significantly shorter in incomplete group compared to complete groups (p=0.02). No new coronary lesions were developed among patients who didn’t have the coronary lesions at subacute phase. Conclusion: The majority of the inflammatory marker levels were normalized within 2-3 weeks after acute phase of KD. There were no new cardiovascular complications when the duration of low dose ASA treatment was guided by level of the inflammatory markers. So, the optimal duration of low dose ASA treatment can be reduced to 3-4 weeks without development of coronary lesions.

Retraction Note to: Anti-Inflammatory Effects of Chronic Aspirin on Brain Arachidonic Acid Metabolites. Neurochem Res (2011) 36:139-45.

Pro-inflammatory and anti-inflammatory mediators derived from arachidonic acid (AA) modulate peripheral inflammation and its resolution. Aspirin (ASA) is a unique non-steroidal anti-inflammatory drug, which switches AA metabolism from prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) to lipoxin A4 (LXA4) and 15-epi-LXA4. However, it is unknown whether chronic therapeutic doses of ASA are anti-inflammatory in the brain. We hypothesized that ASA would dampen increases in brain concentrations of AA metabolites in a rat model of neuroinflammation, produced by a 6-day intracerebroventricular infusion of bacterial lipopolysaccharide (LPS). In rats infused with LPS (0.5 ng/h) and given ASA-free water to drink, concentrations in high-energy microwaved brain of PGE2, TXB2 and leukotriene B4 (LTB4) were elevated. In rats infused with artificial cerebrospinal fluid, 6 weeks of treatment with a low (10 mg/kg/day) or high (100 mg/kg/day) ASA dose in drinking water decreased brain PGE2, but increased LTB4, LXA4 and 15-epi-LXA4 concentrations. Both doses attenuated the LPS effects on PGE2, and TXB2. The increments in LXA4 and 15-epi-LXA4 caused by high-dose ASA were significantly greater in LPS-infused rats. The ability of ASA to increase anti-inflammatory LXA4 and 15-epi-LXA4 and reduce pro-inflammatory PGE2 and TXB2 suggests considering aspirin further for treating clinical neuroinflammation.

Association of Aspirin Dose and Vorapaxar Safety and Efficacy in Patients With Non–ST-Segment Elevation Acute Coronary Syndrome (from the TRACER Trial)

Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial compared vorapaxar and placebo in 12,944 high-risk patients with non-ST-segment elevation acute coronary syndrome. We explored aspirin (ASA) use and its association with outcomes. Kaplan-Meier event rates were compared in groups defined by ASA dose (low, medium, and high). Landmark analyses with covariate adjustment were performed for 0 to 30, 31 to 180, and 181 to 365 days. Of 12,515 participants, 7,523, 1,049, and 3,943 participants were treated with low-, medium-, and high-dose ASA at baseline, respectively. Participants enrolled in North America versus elsewhere were more often treated with a high dose at baseline (66% vs 19%) and discharge (60% vs 3%). Unadjusted cardiovascular death, myocardial infarction, stroke, hospitalization for ischemia, or urgent revascularization event rates tended to be higher with higher baseline ASA (18.45% low, 19.13% medium, and 20.27% high; p for trend = 0.15573). Unadjusted and adjusted hazard ratios (95% confidence intervals) for effect of vorapaxar on cardiovascular (unadjusted p for interaction = 0.065; adjusted p for interaction = 0.140) and bleeding (unadjusted p for interaction = 0.915; adjusted p for interaction = 0.954) outcomes were similar across groups. Landmark analyses showed similar safety and efficacy outcomes with vorapaxar and placebo by ASA dose at each time point except for 0 to 30 days, when vorapaxar tended to be worse for efficacy (hazard ratio 1.13, 95% confidence interval 0.89 to 1.44, p for interaction = 0.0157). In conclusion, most TRACER participants were treated with low-dose ASA, although a high dose was common in North America. High-dose participants tended to have higher rates of ischemic and bleeding outcomes. Although formal statistical testing did not reveal heterogeneity in vorapaxar's effect across dose subgroups, consistent trends support use of low-dose ASA with other antiplatelet therapies.

Frequency of the Use of Low- Versus High-Dose Aspirin in Dual Antiplatelet Therapy After Percutaneous Coronary Intervention (from the Dual Antiplatelet Therapy Study)

In randomized trials, low-dose (LD) and high-dose (HD) aspirin (ASA) are equally effective in reducing ischemic complications, but HD ASA is associated with an increased risk of bleeding in the setting of dual antiplatelet therapy after percutaneous coronary intervention (PCI). ASA dose after PCI varies across countries, but little is known about variation within the United States (US) and whether this variation can be explained by clinical characteristics of patients. We used enrollment data from the Dual Antiplatelet Therapy Study, a randomized trial designed to compare 12 versus 30months of dual antiplatelet therapy after PCI, to quantify the variation in ASA dosing after PCI in the US subjects and assess the extent to which dose variability was attributable to patient characteristics. Of the 23,336 patients enrolled in the US, 28.0% were prescribed LD ASA at discharge after PCI. Patient characteristics explained 1.6% of total variance in ASA dose, whereas the study site accounted for 45.9% of the unexplained variability. The median odds ratio comparing sites was 5.05 (95% confidence interval 4.29 to 5.85), which was greater than any individual predictor of ASA dose. In conclusion, LD ASA after PCI in the US was used in a minority of patients, and heterogeneity in its selection was mainly influenced by the site of enrollment rather than patient characteristics. As HD ASA may be associated with adverse events in the setting of dual antiplatelet therapy, reducing local practice variation in the dose of ASA may be a target for quality improvement.

Detection of platelet sensitivity to inhibitors of COX-1, P2Y1, and P2Y12 using a whole blood microfluidic flow assay

Microfluidic devices recreate the hemodynamic conditions of thrombosis. Whole blood inhibited with PPACK was treated ex vivo with inhibitors and perfused over collagen for 300 s (wall shear rate=200 s(-1)) using a microfluidic flow assay. Platelet accumulation was measured in the presence of COX-1 inhibitor (aspirin, ASA), P2Y₁ inhibitor (MRS 2179), P2Y₁₂ inhibitor (2MeSAMP) or combined P2Y1 and P2Y₁₂ inhibitors. High dose ASA (500 μM), 2MeSAMP (100 μM), MRS 2179 (10 μM), or combined 2MeSAMP and MRS 2179 decreased total platelet accumulation by 27.5%, 75.6%, 77.7%, and 87.9% (p<0.01), respectively. ASA reduced secondary aggregation rate between 150 and 300 s without effect on primary deposition rate on collagen from 60 to 150 s. In contrast, 2MeSAMP and MRS 2179 acted earlier and reduced primary deposition to collagen between 60 and 105 s and secondary aggregation between 105 and 300 s. R(COX) and R(P2Y) (defined as a ratio of secondary aggregation rate to primary deposition rate) demonstrated 9 of 10 subjects had R(COX)<1 or R(P2Y)<1 following ASA or 2MeSAMP addition, while 6 of 10 subjects had R(P2Y)<1 following MRS 2179 addition. Combined MRS 2179 and 2MeSAMP inhibited primary platelet deposition rate and platelet secondary aggregation beyond that of each individual inhibitor. Receiver-Operator Characteristic area under the curve (AUC) indicated the robustness of R(COX) and R(P2Y) to detect inhibition of secondary platelet aggregation by ASA, 2MeSAMP, and MRS 2179 (AUC of 0.874 0.966, and 0.889, respectively). Microfluidic devices can detect platelet sensitivity to antiplatelet agents. The R-value can serve as a self-normalized metric of platelet function for a single blood sample.

High-Dose Acetylsalicylic Acid Is Superior to Low-Dose as Well as to Clopidogrel in Preventing Lipopolysaccharide-Induced Lung Injury in Mice

Use of aspirin (acetylsalicylic acid [ASA]) was found to improve outcome in animal models of acute lung injury (ALI) or its more severe form, acute respiratory distress syndrome. In patients with acute respiratory distress syndrome, data indicating a protective effect of ASA are less convincing. We hypothesize that ASA in a high dose is superior to low-dose ASA in preventing lung injury. Also, the effect on lung injury of inhibiting platelet activation by clopidogrel was investigated. Acute lung injury was induced by intranasal instillation of 10 μg lipopolysaccharide (LPS). Before LPS, BALB/c mice were pretreated with either high dose of ASA (100 μg/g intraperitoneally, low-dose ASA (12.5 μg/g i.p), clopidogrel (50 μg/g i.p), or clopidogrel in combination with low dose of ASA. Controls received vehicle or LPS without intervention. Five hours after LPS, bronchoalveolar lavage fluid (BALF) and plasma were obtained. All treatment regimens reduced neutrophil influx in the BALF compared with LPS controls (high-dose ASA 75% ± 2% [mean ± SD], low-dose ASA 86% ± 3%, clopidogrel 82% ± 1%, and low-dose ASA-clopidogrel 82% ± 3% vs. LPS control 88% ± 2%; P ≤ 0.05). High-dose ASA reduced BALF levels of protein compared with LPS controls (median [interquartile range], 0.2 [15] vs. 75 [20] pg/mL; P < 0.01), to a greater extent than after low-dose ASA (48 [32] pg/mL), clopidogrel (37 [23] pg/mL), or low-dose ASA-clopidogrel (57 [8] pg/mL). High-dose ASA is superior to low-dose ASA, clopidogrel, and to a combination of clopidogrel and low-dose ASA in attenuating LPS-induced lung injury in mice, suggesting high-dose ASA to be the antiplatelet therapy of choice in further research on preventing ALI.

The Effects of the Antiplatelet Agents, Aspirin and Naproxen, on Pharmacokinetics and Pharmacodynamics of the Anticoagulant Edoxaban, a Direct Factor Xa Inhibitor

Edoxaban is an oral factor Xa (FXa) inhibitor in clinical development for stroke prevention in patients with atrial fibrillation, an elderly population that frequently receives aspirin (ASA) and/or nonsteroidal anti-inflammatory drugs for concurrent illnesses. Three studies were conducted to evaluate the pharmacokinetic and pharmacodynamic interactions of edoxaban 60 mg coadministered with low-dose (100 mg) ASA, high-dose (325 mg) ASA, or naproxen (500 mg) in healthy subjects (n = 126). Template bleeding times (BT) were measured. Mean baseline (predose) BT for the 3 studies ranged from 4.72 to 6.13 minutes. Edoxaban administered alone increased BT by 21%-35% (4 hours post dose) from baseline. Concomitant administration of edoxaban with high-dose ASA, low-dose ASA, or naproxen increased BT approximately 2-fold showing an additive effect greater than either agent administered alone. Edoxaban pharmacokinetics were not affected by concomitant low-dose ASA or naproxen, but high-dose ASA increased systemic exposure of edoxaban by approximately 30%. The effects of edoxaban on prothrombin time, activated partial thromboplastin time, international normalized ratio, anti-FXa, and intrinsic FXa activity were not influenced by administration with ASA or naproxen. Inhibition of platelet aggregation by high-dose ASA, low-dose ASA, or naproxen was not affected by edoxaban. Concomitant administration of edoxaban and ASA or naproxen was well tolerated.

Long-term aspirin pretreatment in the prevention of cerulein-induced acute pancreatitis in rats

To investigate the effects of long term pretreatment with low-, medium- and high-dose aspirin (acetylsalicylic acid, ASA) on a model of acute pancreatitis (AP) induced in rats. Forty male Wistar rats were used. Three experimental groups, each consisting of eight animals, received low- (5 mg/kg per day), medium- (150 mg/kg per day) and high-dose (350 mg/kg per day) ASA in supplemented pellet chow for 100 d. Eight animals, serving as the AP-control group, and another eight, serving as reference value (RV) group, were fed with standard pellet chow for the same period. After pretreatment, AP was induced in the experimental animals by intraperitoneal administration of cerulein (2 × 50 μg/kg), while the RV group received saline in the same way. Twelve hours after the second injection, the animals were sacrificed. Pancreatic tissue and plasma samples were collected. One part of the collected pancreatic tissues was used for histopathological evaluation, and the remaining portion was homogenized. Cytokine levels [tumor necrosis factor, interleukin (IL)-1β, IL-6], hemogram parameters, biochemical parameters (amylase and lipase), nuclear factor-κB, aspirin triggered lipoxins and parameters related to the antioxidant system (malondialdehyde, nitric oxide, hemeoxygenase-1, catalase and superoxide dismutase) were measured. Cerulein administration induced mild pancreatitis, characterized by interstitial edema (total histopathological score of 5.88 ± 0.44 vs 0.25 ± 0.16, P < 0.001). Subsequent pancreatic tissue damage resulted in an increase in amylase (2829.71 ± 772.48 vs 984.57 ± 49.22 U/L, P = 0.001) and lipase (110.14 ± 75.84 U/L vs 4.71 ± 0.78 U/L, P < 0.001) in plasma, and leucocytes (6.89 ± 0.48 vs 4.36 ± 0.23, P = 0.001) in peripheral blood. Cytokines, IL-1β (18.81 ± 2.55 pg/μg vs 6.65 ± 0.24 pg/μg, P = 0.002) and IL-6 (14.62 ± 1.98 pg/μg vs 9.09 ± 1.36 pg/μg, P = 0.04) in pancreatic tissue also increased. Aspirin pretreatment reduced the increase in the aforementioned parameters to a certain degree and partially improved the histopathological alterations caused by cerulein. No evidence of side effects related to chronic ASA administration (e.g., inflammation or bleeding) was observed in the gastrointestinal tract in macroscopic and histopathological examination. Long term ASA pretreatment could prevent and/or ameliorate certain hematological, serological and histological alterations caused by cerulein-induced AP.

Anti-inflammatory effects of chronic aspirin on brain arachidonic acid metabolites.

Pro-inflammatory and anti-inflammatory mediators derived from arachidonic acid (AA) modulate peripheral inflammation and its resolution. Aspirin (ASA) is a unique non-steroidal anti-inflammatory drug, which switches AA metabolism from prostaglandin E₂ (PGE₂) and thromboxane B₂ (TXB₂) to lipoxin A₄ (LXA₄) and 15-epi-LXA₄. However, it is unknown whether chronic therapeutic doses of ASA are anti-inflammatory in the brain. We hypothesized that ASA would dampen increases in brain concentrations of AA metabolites in a rat model of neuroinflammation, produced by a 6-day intracerebroventricular infusion of bacterial lipopolysaccharide (LPS). In rats infused with LPS (0.5 ng/h) and given ASA-free water to drink, concentrations in high-energy microwaved brain of PGE₂, TXB₂ and leukotriene B₄ (LTB₄) were elevated. In rats infused with artificial cerebrospinal fluid, 6 weeks of treatment with a low (10 mg/kg/day) or high (100 mg/kg/day) ASA dose in drinking water decreased brain PGE₂, but increased LTB₄, LXA₄ and 15-epi-LXA₄ concentrations. Both doses attenuated the LPS effects on PGE₂, and TXB₂. The increments in LXA₄ and 15-epi-LXA₄ caused by high-dose ASA were significantly greater in LPS-infused rats. The ability of ASA to increase anti-inflammatory LXA₄ and 15-epi-LXA₄ and reduce pro-inflammatory PGE₂ and TXB₂ suggests considering aspirin further for treating clinical neuroinflammation.

NO-Donating Aspirin and Aspirin Partially Inhibit Age-Related Atherosclerosis but Not Radiation-Induced Atherosclerosis in ApoE Null Mice

BackgroundWe previously showed that irradiation to the carotid arteries of ApoE−/− mice accelerated the development of macrophage-rich, inflammatory atherosclerotic lesions, prone to intra-plaque hemorrhage. In this study we investigated the potential of anti-inflammatory and anti-coagulant intervention strategies to inhibit age-related and radiation-induced atherosclerosis.Methodology/Principal FindingsApoE−/− mice were given 0 or 14 Gy to the neck and the carotid arteries and aortic arches were harvested at 4 or 30 weeks after irradiation. Nitric oxide releasing aspirin (NCX 4016, 60 mg/kg/day) or aspirin (ASA, 30 or 300 mg/kg/day) were given continuously in the chow. High dose ASA effectively blocked platelet aggregation, while the low dose ASA or NCX 4016 had no significant effect on platelet aggregation. High dose ASA, but not NCX 4016, inhibited endothelial cell expression of VCAM-1 and thrombomodulin in the carotid arteries at 4 weeks after irradiation; eNOS and ICAM-1 levels were unchanged. After 30 weeks of follow-up, NCX 4016 significantly reduced the total number of lesions and the number of initial macrophage-rich lesions in the carotid arteries of unirradiated mice, but these effects were not seen in the brachiocephalic artery of the aortic arch (BCA). In contrast, high dose ASA lead to a decrease in the number of initial lesions in the BCA, but not in the carotid artery. Both high dose ASA and NCX 4016 reduced the collagen content of advanced lesions and increased the total plaque burden in the BCA of unirradiated mice. At 30 weeks after irradiation, neither NCX 4016 nor ASA significantly influenced the number or distribution of lesions, but high dose ASA lead to formation of collagen-rich “stable” advanced lesions in carotid arteries. The total plaque area of the irradiated BCA was increased after ASA, but the plaque burden was very low compared with the carotid artery.Conclusions/SignificanceThe development and characteristics of radiation-induced atherosclerosis varied between different arteries but could not be circumvented by anti-inflammatory and anti-coagulant therapies. This implicates other underlying mechanistic pathways compared to age-related atherosclerosis.

Methotrexate Drug Interactions in the Treatment of Rheumatoid Arthritis: A Systematic Review

Patients with rheumatoid arthritis (RA) often have comorbidities that require multiple medications. Several of these medications may alter the efficacy or increase the toxicity of methotrexate (MTX). The purpose of our study was to determine which drugs used in combination with MTX (excluding disease modifying antirheumatic drugs, folic and folinic acid, corticosteroids, and biologic agents) enhance side effects or toxicity of MTX or lower its efficacy. A systematic literature search was performed with Medline, Embase, Cochrane Register and Database, and abstracts from the 2006/2007 annual congresses of the American College of Rheumatology and the European League Against Rheumatism. A manual search of the citation lists of retrieved publications was performed. Of the 1172 articles identified, 67 were included: 21 pharmacokinetics studies, 5 observational studies, and 78 case reports. Most medications do not significantly affect the pharmacokinetics profile of MTX. Among the clinical studies, cytopenia and elevation of liver enzymes were the main reported toxicities. The use of trimethoprim-sulfamethoxazole (TMP-SMX) was mentioned as a risk factor for developing cytopenia in one observational study and in 17 case reports. Thirty case reports of cytopenia were attributed to the use of concomitant nonsteroidal antiinflammatory drugs, including acetylsalicylic acid. Two studies described mild abnormalities of liver enzymes with the use of isoniazid, and one study with the use of high-dose ASA. Based on the published literature, MTX has limited drug interactions, with the exception of TMP-SMX and high-dose ASA, which can exacerbate toxicity of MTX. The clinical significance of these interactions has not been substantiated by extensive clinical observations.

Aspirin therapy: An attempt to explain the events of prothrombotic complications after treatment discontinuation

Aspirin remains the most widely used drug for prevention of vascular events. Recent observational epidemiological evidence has raised the concern that aspirin withdrawal for treatment non-compliance, surgery or side effects can carry an increased thrombotic risk. The delay to the thrombotic event was between 7 to 30 days in most reports and most frequently 7 to 10 days. The mechanism underlying this effect remains poorly understood. Using an in vivo model of laser-induced thrombosis, aspirin injected in one single dose of 100 mg/kg bw has also shown a prothrombotic activity in the rat 8 to 10 days after injection in the normal rat. The hypothesis was made that minimal concentrations of aspirin or ultra-low dose aspirin (ULDA) could induce this effect. ULDA showed prothrombotic properties in the same model of induced thrombosis that were very similar to those described after aspirin withdrawal, but the effect was observed only one hour after aspirin administration. This prothrombotic effect of ULDA is very similar to the effect observed after COX 2 selective inhibition with NS 398. The administration of both the selective COX 2 inhibitor and ULDA did not produce further changes. High-dose ASA counterbalances the lack of COX 2 with an antithrombotic effect. No effect of residual ASA was observed in COX 2 -/- mice, thus confirming the existence of a COX 2 inhibition pathway. COX 2 inhibition produced by residual ASA is the probable cause of ischaemic accidents and drug-eluting stents thrombosis a few days after ASA withdrawal.

Is it time to ban alcohol advertising?

Children and adolescents are particularly vulnerable to the harmful effects of alcohol, with heavy drinking risking impaired brain development and future alcohol dependence. Advertisements increase expectancies about alcohol, leading to a greater likelihood of drinking. A systematic review of 13 longitudinal studies of over 38,000 young people found convincing evidence of an impact of media exposure and alcohol advertising on subsequent alcohol use, including initiation of drinking and heavier drinking among existing drinkers. All European countries, with the exception of the UK, have a ban on one or more types of advertising. Since self-regulation is reported as failing to prevent marketing which has an impact on younger people, and since advertising commonly crosses country borders, there is an argument to approximate advertising rules across Europe banning alcohol advertising targeted at young people, a highly cost-effective measure to reduce harmful alcohol use, and one supported by European citizens and case law.

Aspirin augments 15-epi-lipoxin A 4 production by lipopolysaccharide, but blocks the pioglitazone and atorvastatin induction of 15-epi-lipoxin A 4 in the rat heart

Aspirin (ASA) inhibits cycloxygenase-1 and modifies cycloxygenase-2 (COX2) by acetylation at Ser 530, leading to a shift from production of PGH 2, the precursor of prostaglandin, to 15- R-HETE which is converted by 5-lipoxygenase to 15-epi-lipoxin A 4 (15-epi-LXA4), a potent anti-inflammatory mediator. Both atorvastatin (ATV) and pioglitazone (PIO) increase COX2 expression. ATV activates COX2 by S-nitrosylation at Cys 526 to produce 15-epi-LXA4 and 6-keto-PGF 1α (the stable metabolite of PGI 2). We assessed the effect of ASA on the myocardial production of 15-epi-LXA4 and PGI 2 after induction by lipopolysaccharide (LPS) or PIO + ATV. Sprague–Dawley rats were pretreated with: control; ASA 10 mg/kg; ASA 50 mg/kg; LPS alone; LPS + ASA 10 mg/kg; LPS + ASA 50 mg/kg; LPS + ASA 200 mg/kg; PIO (10 mg/kg/d) + ATV (10 mg/kg/d); PIO + ATV + ASA 10 mg/kg; PIO + ATV + ASA 50 mg/kg; PIO + ATV + ASA 50 mg/kg + 1400 W, a specific iNOS inhibitor; or PIO + ATV + 1400 W. ASA alone had no effect on myocardial 15-epi-LXA4. LPS increased 15-epi-LXA4 and 6-keto-PGF 1α levels. ASA (50 mg/kg and 200 mg/kg, but not 10 mg/kg) augmented the LPS effect on 15-epi-LXA4 but attenuated the effect on 6-keto-PGF 1α. PIO + ATV increased 15-epi-LXA4 and 6-keto-PGF 1α levels. ASA and 1400 W attenuated the effects of PIO + ATV on 15-epi-LXA4 and 6-keto-PGF 1α. However, when both ASA and 1400 W were administered with PIO + ATV, there was a marked increase in 15-epi-LXA4, whereas the production of 6-keto-PGF 1α was attenuated. In conclusion, COX2 acetylation by ASA shifts enzyme from producing 6-keto-PGF 1α to 15-epi-LXA4. In contrast, S-nitrosylation by PIO + ASA augments the production of both 15-epi-LXA4 and 6-keto-PGF 1α. However, when COX2 is both acetylated and S-nitrosylated, it is inactivated. We suggest potential adverse interactions among statins, thiazolidinediones, and high-dose ASA.

The antithrombotic profile of aspirin. Aspirin resistance, or simply failure?

The antithrombotic profile of aspirin. Aspirin resistance, or simply failure?