Aspirin Nonsteroidal Anti-inflammatory Drugs Research Articles

Aspirin and other non-steroidal anti-inflammatory drugs and depression, anxiety, and stress-related disorders following a cancer diagnosis: a nationwide register-based cohort study

BackgroundCancer patients have a highly increased risk of psychiatric disorders following diagnosis, compared with cancer-free individuals. Inflammation is involved in the development of both cancer and psychiatric disorders. The role of non-steroidal anti-inflammatory drugs (NSAIDs) in the subsequent risk of psychiatric disorders after cancer diagnosis is however unknown.MethodsWe performed a cohort study of all patients diagnosed with a first primary malignancy between July 2006 and December 2013 in Sweden. Cox proportional hazards models were used to assess the association of NSAID use during the year before cancer diagnosis with the risk of depression, anxiety, and stress-related disorders during the first year after cancer diagnosis.ResultsAmong 316,904 patients identified, 5613 patients received a diagnosis of depression, anxiety, or stress-related disorders during the year after cancer diagnosis. Compared with no use of NSAIDs, the use of aspirin alone was associated with a lower rate of depression, anxiety, and stress-related disorders (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81 to 0.97), whereas the use of non-aspirin NSAIDs alone was associated with a higher rate (HR, 1.24; 95% CI, 1.15 to 1.32), after adjustment for sociodemographic factors, comorbidity, indications for NSAID use, and cancer characteristics. The association of aspirin with reduced rate of depression, anxiety, and stress-related disorders was strongest for current use (HR, 0.84; 95% CI, 0.75 to 0.93), low-dose use (HR, 0.88; 95% CI, 0.80 to 0.98), long-term use (HR, 0.84; 95% CI, 0.76 to 0.94), and among patients with cardiovascular disease (HR, 0.81; 95% CI, 0.68 to 0.95) or breast cancer (HR, 0.74; 95% CI, 0.56 to 0.98).ConclusionPre-diagnostic use of aspirin was associated with a decreased risk of depression, anxiety, and stress-related disorders during the first year following cancer diagnosis.

Exploratory Genome-Wide Interaction Analysis of Nonsteroidal Anti-inflammatory Drugs and Predicted Gene Expression on Colorectal Cancer Risk.

Regular use of nonsteroidal anti-inflammatory drugs (NSAID) is associated with lower risk of colorectal cancer. Genome-wide interaction analysis on single variants (G × E) has identified several SNPs that may interact with NSAIDs to confer colorectal cancer risk, but variations in gene expression levels may also modify the effect of NSAID use. Therefore, we tested interactions between NSAID use and predicted gene expression levels in relation to colorectal cancer risk. Genetically predicted gene expressions were tested for interaction with NSAID use on colorectal cancer risk among 19,258 colorectal cancer cases and 18,597 controls from 21 observational studies. A Mixed Score Test for Interactions (MiSTi) approach was used to jointly assess G × E effects which are modeled via fixed interaction effects of the weighted burden within each gene set (burden) and residual G × E effects (variance). A false discovery rate (FDR) at 0.2 was applied to correct for multiple testing. Among the 4,840 genes tested, genetically predicted expression levels of four genes modified the effect of any NSAID use on colorectal cancer risk, including DPP10 (PG×E = 1.96 × 10-4), KRT16 (PG×E = 2.3 × 10-4), CD14 (PG×E = 9.38 × 10-4), and CYP27A1 (PG×E = 1.44 × 10-3). There was a significant interaction between expression level of RP11-89N17 and regular use of aspirin only on colorectal cancer risk (PG×E = 3.23 × 10-5). No interactions were observed between predicted gene expression and nonaspirin NSAID use at FDR < 0.2. By incorporating functional information, we discovered several novel genes that interacted with NSAID use. These findings provide preliminary support that could help understand the chemopreventive mechanisms of NSAIDs on colorectal cancer.

Abstract A19: Aspirin use and ovarian cancer risk by lymphocyte infiltration

Abstract Introduction: There is growing evidence to support a modest inverse association between daily aspirin use and ovarian cancer risk. We previously hypothesized that this association may differ by immune cell infiltration. In our prior study evaluating heterogeneity by tumor-associated macrophage (TAM) infiltration, aspirin use was associated with lower risk of ovarian cancer with high protumorigenic M2-type TAM infiltration, but not low M2-type TAM infiltration. The goal of the present study was to evaluate the hypothesis that the association between aspirin use and ovarian cancer risk also differs by infiltration with tumor-infiltrating lymphocytes (TILs). Methods: We included cases and matched controls from the Nurses’ Health Study (NHS), NHSII, and New England Case Control Study. Study participants self-reported aspirin use including regular use (≥1 x per week), duration of use, and number of tablets. A gynecologic pathologist (JLH), who was blinded to exposure status, reviewed hematoxylin and eosin stained tumor slides to quantify TILs for all cases (n=547). We used polytomous logistic regression, adjusted for ovarian cancer risk factors, to estimate odds ratios (OR) for aspirin use and ovarian cancer risk by TIL infiltration. Results: Overall, recent aspirin use was associated with lower risk of ovarian cancer compared with no regular aspirin use (OR=0.65, 95%CI=0.47-0.89). Recent aspirin use was associated with a lower risk of ovarian cancer exhibiting TIL infiltration (OR=0.38, 95%CI=0.26-0.56) but not with TIL-negative cancers (OR=1.00, 95%CI=0.71-1.41; p-heterogeneity &amp;lt;0.001). We observed similar results for aspirin duration and tablets. For duration, comparing ≥10 years of aspirin use to &amp;lt;1 year we observed a significantly lower risk of ovarian cancer with TILs (OR=0.47, 95%CI=0.41-0.71; p-trend=0.004), but a nonsignificant reduction for ovarian cancer without TILs (OR=0.86, 95%CI=0.59-1.26; p-trend=0.72; p-heterogeneity=0.03). Comparing ≥6 tablets to &amp;lt;1 tablet per week, there was evidence of a lower risk of ovarian cancer with TILs (OR=0.47, 95%CI=0.30-0.75; p-trend=0.001) but not without TILs (OR=1.02, 95%CI=0.70-1.48; p-trend=0.84; p-heterogeneity=0.003). Conclusions: Our results suggest that prediagnosis aspirin use may be an important modulator of immune cell infiltration in ovarian tumors, supporting an immunogenic mechanism for aspirin in ovarian carcinogenesis. Further work is under way to evaluate nonaspirin nonsteroidal anti-inflammatory drugs, and to consider which subsets of TAMs and TILs may be driving heterogeneity in the associations between anti-inflammatory drugs and ovarian cancer risk. Citation Format: Mollie E. Barnard, Britton Trabert, Jonathan L. Hecht, Ellen L. Goode, Naoko Sasamoto, Kathryn L. Terry, Shelley S. Tworoger. Aspirin use and ovarian cancer risk by lymphocyte infiltration [abstract]. In: Proceedings of the AACR Special Conference on Modernizing Population Sciences in the Digital Age; 2019 Feb 19-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(9 Suppl):Abstract nr A19.

UV Spectroscopic Method for Optimization and Determination of Glibenclamide in Bulk, Pharmaceutical Dosage Form and its Application for In Vitro Interaction Studies

A simple, easy and cost-efficient UV spectroscopic method was developed and validated for glibenclamide, the second generation of sulfonylureas, using 0.1 N NaOH as a solvent. The proposed method is linear (R2 > 0.999) with the range 5–25 µg mL−1, accurate (99.60%), precise (inter and intraday variation 0.241 and 0.019%, respectively) and robust (< 1%). The quantification and detection limit were 1.46 and 0.48 μg mL−1, respectively. The validated method was applied for in vitro interaction studies of glibenclamide (GLB) with commonly prescribed quinolones (ciprofloxacin, levofloxacin, moxifloxacin, and gemifloxacin) and nonsteroidal anti-inflammatory drugs (NSAIDs) (diclofenac sodium, ibuprofen, mefenamic acid, and aspirin) using UV spectrophotometer. The in vitro interaction studies were carried out in different artificially prepared physiological buffers at 37 °C for 2 h. Results showed raised level of glibenclamide when interacted with gemifloxacin (pH 7.4), levofloxacin (pH 9), ciprofloxacin (pH 4.5) and with moxifloxacin (pH 4.5, 7.4 and 9). Interaction with NSAIDs results in increased %availability of glibenclamide in the presence of diclofenac sodium, ibuprofen, and mefenamic acid at pH 4.5. The anticipated method can be successfully applied for the routine analysis and also for the interaction of glibenclamide with other drugs.

History of Nonsteroidal Anti-inflammatory Drug Use and Functional Outcomes After Spontaneous Intracerebral Hemorrhage.

Preclinical and clinical studies have suggested a potential benefit from COX-2 inhibition on secondary injury activation after spontaneous intracerebral hemorrhage (ICH). The aim of this study was to investigate the effect of pre-admission NSAID use on functional recovery in spontaneous ICH patients. Consecutive adult ICH patients enrolled in the Intracerebral Hemorrhage Outcomes Project (2009-2018) with available 90-day follow-up data were included. Patients were categorized as NSAID (daily COX inhibitor use ≤ 7days prior to ICH) and non-NSAID users (no daily COX inhibitor use ≤ 7days prior to ICH). Primary outcome was the ordinal 90-day modified Rankin Scale (mRS) score. Outcomes were compared between cohorts using multivariable regression and propensity score-matched analyses. A secondary analysis excluding aspirin users was performed. The NSAID and non-NSAID cohorts comprised 228 and 361 patients, respectively. After 1:1 matching, the matched cohorts each comprised 140 patients. The 90-day mRS were comparable between the NSAID and non-NSAID cohorts in both the unmatched (aOR = 0.914 [0.626-1.336], p = 0.644) and matched (aOR = 0.650 [0.392-1.080], p = 0.097) analyses. The likelihood of recurrent ICH at 90days was also comparable between the NSAID and non-NSAID cohorts in both the unmatched (aOR = 0.845 [0.359-1.992], p = 0.701) and matched analyses (aOR = 0.732 [0.241-2.220], p = 0.581). In the secondary analysis, the non-aspirin NSAID and non-NSAID cohorts comprised 38 and 361 patients, respectively. After 1:1 matching, the matched cohorts each comprised 38 patients. The 90-day mRS were comparable between the non-aspirin NSAID and non-NSAID cohorts in both the unmatched (aOR = 0.615 [0.343-1.101], p = 0.102) and matched (aOR = 0.525 [0.219-1.254], p = 0.147) analyses. The likelihood of recurrent ICH at 90days was also comparable between the non-aspirin NSAID and non-NSAID cohorts in both the unmatched (aOR = 2.644 [0.258-27.091], p = 0.413) and matched (aOR = 2.586 [0.228-29.309], p = 0.443) analyses. After the exclusion of patients with DNR or withdrawal of care status, NSAID use was associated with lower mRS at 90days (aOR = 0.379 [0.212-0.679], p = 0.001), lower mRS at hospital discharge (aOR = 0.505 [0.278-0.919], p = 0.025) and lower 90-day mortality rates (aOR = 0.309 [0.108-0.877], p = 0.027). History of nonselective COX inhibition may affect functional outcomes in ICH patients. Pre-admission NSAID use did not appear to worsen the severity of presenting ICH or increase the risk of recurrent ICH. Additional clinical studies may be warranted to investigate the effects of pre-admission NSAID use on ICH outcomes.

Prescriber responsibility, predictors for initiation, and 20-year trends in use of non-aspirin non-steroidal anti-inflammatory drugs in patients with cardiovascular contraindications: a nationwide cohort study.

To examine whether prescription patterns complied with recommendations not to use non-steroidal anti-inflammatory drugs (NSAIDs) in patients with cardiovascular contraindications. Moreover, we examined predictors for initiation and prescriber responsibility. We used Danish medical databases to identify all patients with first-time cardiovascular disease during 1996-2017 (n = 628 834). We assessed standardized prevalence proportions, predictors from logistic regression, and prescriber identifiers. One-year prevalence of NSAID initiation increased 3.4% from 1996 (19.4%) to 2001 (22.7%) and declined by 2.7% thereafter until 2017 (13.5%). Trends were independent of age, sex, and disease subtype, although larger annual declines occurred for heart failure (3.9%) and ischaemic heart disease (3.5%) since 2002. One-year prevalence remained highest among patients with venous thromboembolism (16.6%) and angina (13.8%), and lowest for ST-segment elevation myocardial infarction (7.0%) and heart failure (8.8%). Initiators were predominantly prescribed ibuprofen (59%), diclofenac (23%), and etodolac (6%). Diclofenac and coxib use declined, while ibuprofen and naproxen use increased. Median prescribed pill dose of ibuprofen declined after 2008 from moderate/high (600 mg) to low (400 mg). Treatment duration declined for all NSAIDs, except celecoxib. Rheumatic, obesity, and pain-related conditions predicted NSAID initiation. General practitioners issued 86-91% of all NSAID prescriptions, followed by hospital prescribers (7.3-12%). Initiation of NSAIDs in patients with cardiovascular disease declined since 2002. Shorter treatment duration, declining COX-2 inhibition, and increasing use of naproxen and low-dose ibuprofen suggest adherence to guidelines when NSAIDs cannot be avoided. Still, NSAID use remained prevalent despite cardiovascular contraindications, warranting awareness of appropriateness of use among general practitioners in particular.

Vasoactive exposures and risk of amniotic band syndrome and terminal transverse limb deficiencies.

Amniotic band syndrome (ABS) includes limb deficiencies accompanied by fibrous strands originating from the amniotic lining. Terminal transverse limb deficiencies (TTLD) appear to be similar but lack fibrous strands. Both are hypothesized to result from vascular disruption. For ABS, limb deficiencies are considered secondary to amnion rupture. We explored an alternative possibility-that TTLD is the primary defect and ABS is secondary. Using data from the National Birth Defects Prevention Study, we expanded on a previous study. We examined smoking, alcohol, and medications categorized by indicated vasoactivity as markers of vascular disruption. Logistic regression models with Firth's penalized likelihood were used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs). Use of bronchodilators and aspirin appeared to increase the risk of ABS, while decongestants and nonaspirin NSAIDs increased the risk of TTLD. The risk of ABS was markedly increased in cases reporting combinations of vasoactive exposures, particularly alcohol and aspirin (aOR 3.7, 95% CI 1.6, 7.8), and alcohol and bronchodilators (aOR 3.4, 95% CI 1.4, 7.5). Increased risk of TTLD due to combinations of vasoactive exposures was only observed for smoking and decongestants (aOR 2.3, 95% CI 1.4, 3.6). Exposures associated with increased risk of ABS had no apparent association with TTLD, supporting previous evidence that these may be distinct phenotypes. ABS appears to be associated with combined exposures with vasodilation properties, such as alcohol and bronchodilators, while increased risk of TTLD may be associated with smoking and decongestants, both vasoconstrictive exposures.

Statin use and risk of acute diverticulitis

The goal of the study was to examine the association between statin use and the development of acute diverticulitis requiring hospital admission.Acute diverticulitis is a common and costly gastrointestinal disorder. Although the incidence is increasing its pathophysiology and modifiable risk factors are incompletely understood. Statins affect the inflammatory response and represent a potential risk reducing agent.A retrospective, population-based, case-control study was carried out on a cohort of adults, resident in Canterbury, New Zealand. All identified cases were admitted to hospital and had computed tomography confirmed diverticulitis. The positive control group comprised patients on non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and the negative control group were patients on selective serotonin reuptake inhibitors (SSRIs). Medicine exposure was obtained from the Pharmaceutical Management Agency of New Zealand. Subgroup analysis was done by age and for complicated and recurrent diverticulitis.During the study period, there were 381,792 adults resident in Canterbury. The annual incidence of diverticulitis requiring hospital presentation was 18.6 per 100,000 per year. Complicated disease was seen in 37.4% (158) of patients, and 14.7% (62) had recurrent disease. Statins were not found to affect the risk of developing acute diverticulitis, nor the risk of complicated or recurrent diverticulitis. Subgroup analysis suggested statin use was associated with a decreased risk of acute diverticulitis in the elderly (age >64 years). NSAIDs were associated with a decreased risk of acute diverticulitis (risk ratio = 0.65, confidence interval: 0.26–0.46, P < .01), as were SSRIs (risk ratio = 0.37, confidence interval: 0.26–0.54, P < .01).This population-based study does not support the hypothesis that statins have a preventative effect on the development of diverticulitis, including complicated disease. We also found a decreased risk of diverticulitis associated with NSAID and SSRI use.

Migraine treatment and healthcare costs: retrospective analysis of the China Health Insurance Research Association (CHIRA) database

BackgroundAdult migraine remains underdiagnosed and undertreated, despite significant negative effects on physical and emotional functioning. Information on prescribing patterns and treatment costs of migraine in China is limited.MethodsThis retrospective analysis of the China Health Insurance Research Association (CHIRA) medical insurance claims database in 2016 to 2017 evaluated treatment patterns, direct medical costs, and healthcare resource utilization among adults with migraine in mainland China.ResultsOf 108,375 patients with headache-related outpatient visits, 10,652 were adults with migraine (mean age 51.4 years, 55.4% female). Common comorbidities were major depressive disorder (4.1%), insomnia (3.8%), and anxiety (2.3%). Migraine patients were prescribed acute medication (26.4%), preventive medication (15.0%), and Chinese patent and herbal medicines (24.5% and 11.7%, respectively). Of patients prescribed acute medication, 68.8% received non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), 7.1% received opioids, while only 3.3% received triptans. Mean annual outpatient costs per patient were 46.5 United States dollars (USD), with mean (standard deviation) 1.8 (2.0) outpatient visits per year. Medication costs for traditional Chinese medicine (22.4 USD per patient) were higher than for Western medicine (13.5 USD).ConclusionAmong migraine patients in China, NSAIDs were commonly prescribed as acute medication, while utilization of migraine-specific triptans and preventive medications was low.

Aspirin and other non-steroidal anti-inflammatory drugs for the prevention of dementia.

Aspirin and other non-steroidal anti-inflammatory drugs for the prevention of dementia.

Cardiovascular effects and safety of (non-aspirin) NSAIDs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective, widely used analgesics. For the past 2 decades, considerable attention has been focused on their cardiovascular safety. After early studies indicating an association between NSAID use and increased risks of heart failure and elevated blood pressure, subsequent studies found a link between NSAID use and an increased risk of thrombotic events. Selective cyclooxygenase 2 (COX2) inhibitors (also known as coxibs) have been associated with the greatest risk of adverse vascular effects but concern also relates to non-selective NSAIDs, especially those with strong COX2 inhibition such as diclofenac. Although NSAID use is discouraged in patients with cardiovascular disease, pain-relief medication is often required and, in the absence of analgesics that are at least as effective but safer, NSAIDs are frequently prescribed. Furthermore, non-prescription use of NSAIDs, even among people with underlying cardiovascular risks, is largely unsupervised and varies widely between countries. As concern mounts about the disadvantages of alternatives to NSAIDs (such as opioids) for pain management, the use of NSAIDs is likely to rise. Given that the pharmaceutical development pipeline lacks new analgesics, health-care professionals, patients and medicine regulatory authorities are focused on optimizing the safe use of NSAIDs. In this Review, we summarize the current evidence on the cardiovascular safety of NSAIDs and present an approach for their use in the context of holistic pain management.

Common medications and survival in women with ovarian cancer: A systematic review and meta-analysis

ObjectivesOvarian cancer is usually diagnosed at an advanced stage when five-year relative survival is <50%. Therefore, strategies to improve survival are required. Studies suggest associations between common chronic disease medications such as metformin, statins, beta-blockers, aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs) and improved cancer survival. We aimed to review the evidence for a possible relation between these medications and survival among women with ovarian cancer. MethodsWe conducted four systematic reviews and evaluated the risk of bias in the included studies. Where possible, we calculated pooled hazard ratios (pHR) and 95% confidence intervals (CI), excluding studies considered to have the potential for immortal time bias (ITB) which, in practice, was the major source of bias. ResultsWe identified 36 studies evaluating one or more of the medications (metformin n = 8, statins n = 12, beta-blockers n = 11, aspirin and/or NA-NSAIDs n = 9). We rated 21 studies as ITB-free. The meta-analysis of the ITB-free studies suggested improved survival in statin users compared to non-users (pHR: 0.76, 95%CI: 0.68–0.85), but no overall survival benefit associated with use of metformin, beta-blockers, aspirin or NA-NSAIDs. The pooled result of two studies did, however, suggest a possible association between perioperative beta-blocker use and improved survival. Studies considered to have potential ITB were more likely to report survival benefits associated with these medications. ConclusionStatin use is associated with better ovarian cancer survival but further study, preferably a clinical trial, is required. There are insufficient data to draw conclusions regarding metformin, beta-blockers, aspirin and NA-NSAIDs.

Nonsteroidal anti-inflammatory drugs but not aspirin are associated with a lower risk of post-colonoscopy colorectal cancer.

Although nonsteroidal anti-inflammatory drugs (NSAIDs) reduce colorectal cancer (CRC) risk, their role in preventing post-colonoscopy CRC (PCCRC) remains undetermined. To investigate whether NSAIDs reduce PCCRC risk after a negative baseline colonoscopy METHODS: This is a retrospective cohort study based on a territory-wide healthcare database of Hong Kong. All patients (aged 40 or above) who underwent colonoscopies between 2005 and 2013 were identified. Exclusion criteria included CRC detected within 6months of index colonoscopy, prior CRC, inflammatory bowel disease and prior colectomy. The primary outcome was PCCRC-3y diagnosed between 6 and 36months after index colonoscopy. Sites of CRC were categorised as proximal (proximal to splenic flexure) and distal. The adjusted hazards ratio (aHR) of PCCRC-3y with NSAID and aspirin use (defined as cumulative use for ≥90days within 5years before index colonoscopy) was derived by propensity score (PS) regression adjustment of 22 covariates (including patient factors, concurrent medication use and endoscopy centre's performance). Of 187897 eligible patients, 21757 (11.6%) were NSAID users. 854 (0.45%) developed PCCRC-3y (proximal cancer: 147 [17.2%]). NSAIDs were associated with a lower PCCRC-3y risk (aHR: 0.54, 95% CI: 0.41-0.70), but not CRC that developed >3years (aHR: 0.78, 95% CI 0.56-1.09). The aHR was 0.48 (95% CI: 0.24-0.95) for proximal and 0.55 (95% CI: 0.40-0.74) for distal cancer. A duration- and frequency response relationship was observed (Ptrend <0.001). For aspirin, the aHR was 1.01 (95% CI: 0.80-1.28). Non-aspirin NSAIDs were associated with lower PCCRC risk after a negative baseline colonoscopy.

Current states of prevention of drug-induced gastroduodenal ulcer in real clinical practice: a cross-sectional study

Non-steroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin (LDA) are the most common causes of drug-induced gastroduodenal ulcer and We investigated preventive treatment with use of concomitant anti-ulcer drugs and the clinical features of gastroduodenal ulcer in cases treated with these drugs. Patients with gastroduodenal ulcer and patients with bleeding were classified into 3 groups: LDA, non-aspirin NSAIDs, and those taking neither aspirin nor NSAIDs. Chronological changes over the past 16 years (1st-5th period) were investigated. The status of prevention of ulcer and clinical features were examined. From January 2002 to December 2018, the ratio of all patients taking NSAIDs and LDA increased significantly until 3rd period (p<0.05), but then started to decrease in 4th period; and the percentage of all patients taking NSAIDs and LDA decreased significantly (p<0.05) until 5th period. Among the 292 patients with gastroduodenal ulcer and the 121 patients with a bleeding ulcer taking NSAIDs and LDA, 16 (5.5%) and 9 (7.4%), respectively, were receiving preventive treatment with concomitant anti-ulcer drugs. The percentages of patients taking LDA and other antiplatelet drugs in patients with bleeding gastroduodenal ulcer were significantly higher than those in patients with non-bleeding. In conclusion, although the percentages of patients with gastroduodenal ulcer taking NSAIDs or LDA have not recently increased in real-world practice, preventive treatment in these patients is still low. This low rate of prevention suggests the need to enlighten physicians about preventive treatment because drug withdrawal of LDA has a high risk of cardiovasculr and cerebrovascular events.

Associations of low-dose aspirin or other NSAID use with prostate cancer risk in the Danish Diet, Cancer and Health Study.

Epidemiologic studies suggest that use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce prostate cancer risk. We examined these associations overall and according to clinical and lifestyle parameters. We identified male participants in the Danish Diet, Cancer and Health Study (n = 26,339), holding information on anthropometric measures and lifestyle factors. From Danish nationwide registries and medical records, we retrieved complete prescription histories and prostate cancer occurrence and characteristics. Cox regression was used to estimate hazard ratios (HRs) for prostate cancer associated with low-dose aspirin or nonaspirin NSAID use, overall and by clinical characteristics, anthropometric measures, and lifestyle factors. We identified 1,927 prostate cancer cases during a median follow-up of 17.0years. Low-dose aspirin use was not associated with overall prostate cancer risk, but a reduced HR for nonaggressive prostate cancer (high use [≥ 1,825 tablets]: 0.79; 95% confidence interval (CI) 0.60-1.04) and an increased HR for aggressive disease (high use: 1.27; 95% CI 1.00-1.61) was observed with low-dose aspirin use. Long-term, high-intensity use (≥ 10years with ≥ 0.25 defined daily doses/day) of nonaspirin NSAIDs was associated with an increased HR for prostate cancer (1.35, 95% CI 0.99-1.84), confined to localized and nonaggressive disease. No consistent variation in HRs was seen in analyses stratified by height, body mass index, smoking, and alcohol use. Low-dose aspirin or other NSAID use was not associated with reduced prostate cancer risk, neither overall nor according to anthropometric measures, smoking, or alcohol use. The variation according to outcome characteristics warrants further investigation.

Epigenetics/epigenomics and prevention by curcumin of early stages of inflammatory-driven colon cancer.

Colorectal cancer (CRC) is associated with significant morbidity and mortality in the US and worldwide. CRC is the second most common cancer-related death in both men and women globally. Chronic inflammation has been identified as one of the major risk factors of CRC. It may drive genetic and epigenetic/epigenomic alterations, such as DNA methylation, histone modification, and non-coding RNA regulation. Current prevention modalities for CRC are limited and some treatment regimens such as use the nonsteroidal anti-inflammatory drug aspirin may have severe side effects, namely gastrointestinal ulceration and bleeding. Therefore, there is an urgent need of developing alternative strategies. Recently, increasing evidence suggests that several dietary cancer chemopreventive phytochemicals possess anti-inflammation and antioxidative stress activities, and may prevent cancers including CRC. Curcumin (CUR) is the yellow pigment that is found in the rhizomes of turmeric (Curcuma longa). Many studies have demonstrated that CUR exhibit strong anticancer, antioxidative stress, and anti-inflammatory activities by regulating signaling pathways, such as nuclear factor erythroid-2-related factor 2, nuclear factor-κB, and epigenetics/epigenomics pathways of histones modifications, and DNA methylation. In this review, we will discuss the latest evidence in epigenetics/epigenomics alterations by CUR in CRC and their potential contribution in the prevention of CRC.

Analgesic use at ovulation and implantation and human fertility

Studies investigating the effects of pain-relieving medication use on conceiving a pregnancy have shown conflicting results. Furthermore, no previous study has examined medication use around ovulation or implantation and the associations with the probability of conception, fecundability. The objective of the study was to explore the association between fecundability and analgesic use in 3 different menstrual cycle windows (preovulation, periovulation, and implantation) as well as across the entire menstrual cycle. We analyzed data from a prospective cohort study of women between 30 and 44 years of age who were trying to conceive naturally from 2008 through 2015. Using daily diaries, medication usage was classified as acetaminophen, aspirin, or nonaspirin nonsteroidal antiinflammatory drug during 4 time periods of interest (preovulatory, periovulatory, and implantation) as well as the overall nonmenstrual bleeding days of the cycle. Menstrual cycles during the prospective attempt to become pregnant were enumerated using daily diary menstrual bleeding information. Conception was defined as a positive home pregnancy test. Discrete time fecundability models were used to estimate the fecundability ratio and 95% confidence interval in each of the 4 time windows of interest and for each pain reliever (aspirin use, nonaspirin nonsteroidal antiinflammatory drug use, acetaminophen) compared with no medication use after adjustment for several covariates including age, race, education, body mass index, alcohol and caffeine use, frequency of intercourse, and a history of migraines or uterine fibroids. Medication use was infrequent in the 858 women and 2366 cycles in this analysis. Use of nonaspirin nonsteroidal antiinflammatory drugs or acetaminophen was not associated with fecundability in any of the time windows of interest. Although the sample size was small, aspirin use during the implantation window was associated with increased fecundability (adjusted fecundability ratio [confidence interval]: 2.05 [1.23-3.41]). This association remained when limiting the analysis to cycles with minimal missing data or when adjusting for gravidity. None of the other medications were associated with fecundability. Aspirin use around implantation was associated with increased fecundability. These results expand previous literature to suggest the following: (1) implantation may be an important target for the effects of aspirin on conception and (2) aspirin may be beneficial, regardless of pregnancy loss history. These observations should be tested with a clinical trial.

Aspirin enhances cisplatin sensitivity of resistant non-small cell lung carcinoma stem-like cells by targeting mTOR-Akt axis to repress migration

Conventional chemotherapeutic regimens are unable to prevent metastasis of non-small cell lung carcinoma (NSCLC) thereby leaving cancer incurable. Cancer stem cells (CSCs) are considered to be the origin of this therapeutic limitation. In the present study we report that the migration potential of NSCLCs is linked to its CSC content. While cisplatin alone fails to inhibit the migration of CSC-enriched NSCLC spheroids, in a combination with non-steroidal anti inflammatory drug (NSAID) aspirin retards the same. A search for the underlying mechanism revealed that aspirin pre-treatment abrogates p300 binding both at TATA-box and initiator (INR) regions of mTOR promoter of CSCs, thereby impeding RNA polymerase II binding at those sites and repressing mTOR gene transcription. As a consequence of mTOR down-regulation, Akt is deactivated via dephosphorylation at Ser473 residue thereby activating Gsk3β that in turn causes destabilization of Snail and β-catenin, thus reverting epithelial to mesenchymal transition (EMT). However, alone aspirin fails to hinder migration since it does not inhibit the Integrin/Fak pathway, which is highly activated in NSCLC stem cells. On the other hand, in aspirin pre-treated CSCs, cisplatin stalls migration by hindering the integrin pathway. These results signify the efficacy of aspirin in sensitizing NSCLC stem cells towards the anti-migration effect of cisplatin. Cumulatively, our findings raise the possibility that aspirin might emerge as a promising drug in combinatorial therapy with the existing chemotherapeutic agents that fail to impede migration of NSCLC stem cells otherwise. This may consequently lead to the advancement of remedial outcome for the metastatic NSCLCs.

Risk of Multiple System Atrophy and the Use of Anti-Inflammatory Drugs: A Danish Register-Based Case-Control Study

Introduction: Multiple system atrophy (MSA) is a rare rapidly progressive atypical Parkinson disorder presenting clinically with parkinsonism and/or a cerebellar syndrome in combination with dysautonomia. Severe neuroinflammation develops along with hallmark neuropathological changes, and as in Parkinson’s disease, intake of anti-inflammatory medication has been hypothesized to be protective for development of disease. We aimed to investigate if use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, or statins were associated with a reduced risk of MSA. Methods: We performed a register-based case-control study in MSA (n = 155) cases and population controls (n= 7,750) matched on age, gender, and place of residency by risk-set sampling. Pharmacological exposure prior to diagnosis was assessed in 2 categories (user vs. nonuser, cumulated dose in tertiles [T1-T3]). In an unconditional logistic regression model, adjusted for age, gender, residency, and chronic obstructive pulmonary disease (COPD), we estimated ORs and 95% CIs. Results: Data suggested a trend towards non-aspirin NSAID use to be associated with a decreased risk of MSA (OR 0.72 [95% CI 0.49–1.06]) compared to nonusers, decreasing dose-dependently (T2 OR 0.77 [95% CI 0.43–1.38]; T3 OR 0.55 [95% CI 0.29–1.06]). However, data were based on small numbers. Use of statins and low-dose aspirin was not associated with a decreased risk of MSA. Results were lagged 5 years from index date to address reverse causation. Conclusion: A trend toward use of non-aspirin NSAID and an associated reduced risk of MSA was observed in this study. However, our analyses had limited statistical precision, and further studies including larger sample sizes and longer exposure periods are needed.

First report of a glycosaminoglycan-xylopyranan from the buccinid gastropod mollusk Babylonia spirata attenuating proinflammatory 5-lipoxygenase.

A previously undescribed xylated glycosaminoglycan characterized as β-D-Xylop(1→3)-(⋯→4)-GlcpA(1→3)-GlcpNAc(1→⋯) was purified from the buccinid gastropod Babylonia spirata and was evaluated for pharmacological properties using different in vitro models. The glycosaminoglycan-xylopyranan displayed prospective free radical quenching activities (IC50 <0.7mg/ml), whereas it exhibited potentially greater attenuation against the inductive proinflammatory enzyme 5-lipoxygenase (5-LOX, IC50 0.36mg/ml) than the synthetic nonsteroidal anti-inflammatory drug aspirin (0.42). Gel permeation chromatography analysis specified the average molecular mass of the purified polysaccharide to be 231.88kDa. The linkage sites, anomeric configuration, and the sequence of sugar residues of the purified xylated glycosaminoglycan were attributed by the inter-residue correlation obtained via two-dimensional nuclear resonance spectroscopic techniques. The results specified that the studied compound was composed of GlcpA(1→3)-GlcpNAc (1→⋯) disaccharide repeating unit in the glycosaminoglycanbackbone, with the xylose residues branching as C-3 substituents of the GlcpA. . PRACTICAL APPLICATIONS: The edible marine buccinid mollusk Babylonia spirata is a gastropod species of economic significance in the coastal regions of peninsular India. A previously unreported xylated glycosaminoglycan with a β-D-Xylop(1→3)-(⋯→4)-GlcpA(1→3)-GlcpNAc(1→⋯) framework was isolated to homogenity and was found to possess potential antioxidant and 5-lipoxygenase attenuation activities. The isolated metabolite mightbe anticipated as potential naturally-derived bioactive constituent in functional food and pharmaceutical applications.