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Oxylipid Profile of Low-Dose Aspirin Exposure: A Pharmacometabolomics Study.

ABSTRACT: BACKGROUND:While aspirin is a well-established and generally effective anti-platelet agent, considerable inter-individual variation in drug response exists, for which mechanisms are not completely understood. Metabolomics allows for extensive measurement of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response. METHODS AND RESULTS:We used a mass-spectrometry-based metabolomics platform to investigate the changes in the serum oxylipid metabolome induced by an aspirin intervention (14 days, 81 mg/day) in healthy subjects (n=156). We observed a global decrease in serum oxylipids in response to aspirin (25 metabolites decreased out of 30 measured) regardless of sex. This decrease was concomitant with a significant decrease in serum linoleic acid levels (-19%, P=1.3×10(-5)), one of the main precursors for oxylipid synthesis. Interestingly, several linoleic acid-derived oxylipids were not significantly associated with arachidonic-induced ex vivo platelet aggregation, a widely accepted marker of aspirin response, but were significantly correlated with platelet reactivity in response to collagen. CONCLUSIONS:Together, these results suggest that linoleic acid-derived oxylipids may contribute to the non-COX1 mediated variability in response to aspirin. Pharmacometabolomics allowed for more comprehensive interrogation of mechanisms of action of low dose aspirin and of variation in aspirin response.

SUBMITTER: Ellero-Simatos S

PROVIDER: S-EPMC4845113 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Oxylipid Profile of Low-Dose Aspirin Exposure: A Pharmacometabolomics Study.

Ellero-Simatos Sandrine S Beitelshees Amber L AL Lewis Joshua P JP Yerges-Armstrong Laura M LM Georgiades Anastasia A Dane Adrie A Harms Amy C AC Strassburg Katrin K Guled Faisa F Hendriks Margriet M W B MM Horenstein Richard B RB Shuldiner Alan R AR Hankemeier Thomas T Kaddurah-Daouk Rima R

Journal of the American Heart Association 20151026 10

<h4>Background</h4>While aspirin is a well-established and generally effective anti-platelet agent, considerable inter-individual variation in drug response exists, for which mechanisms are not completely understood. Metabolomics allows for extensive measurement of small molecules in biological samples, enabling detailed mapping of pathways involved in drug response.<h4>Methods and results</h4>We used a mass-spectrometry-based metabolomics platform to investigate the changes in the serum oxylipi ...[more]

PMID: 26504148

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Project description:BackgroundLong-term daily use of aspirin has been associated with reduced cancer mortality. To explore this association, we compared tumour TNM characteristics among aspirin users with those among non-users.MethodsFrom the Swedish Cancer Register, we identified patients diagnosed with colorectal, lung, prostate and breast cancers between 2006 and 2009 and matched them to the Swedish Prescribed Drug Register to obtain information on low-dose aspirin use prior to diagnosis. Contingency table and logistic regression analyses were used to test for association and obtain odds ratios (ORs).ResultsWe identified 17,041 colorectal, 9766 lung, 29,770 prostate and 20,299 breast cancer patients. The proportion of low-dose aspirin users was ~26% among colorectal, lung and prostate cancer patients and ~14% among breast cancer patients. Adjusted for age, gender, education level and place of residence, low-dose aspirin use was associated with lower tumour extent (T) for colorectal and lung cancers (P<0.0001) but not for prostate and breast cancers. The adjusted OR of aspirin use for the T4 vs T1 categories was ~0.7 (95% confidence interval (CI) 0.6-0.8). For all cancers, we found no evidence of association of aspirin use with nodal involvement (N). Except for a borderline result in prostate cancer (OR ~0.9; 95% CI 0.8-1.0), aspirin use was associated with a lower rate of metastatic disease (ORs ~0.6-0.8). Among the histological subgroups of lung cancer, significant differences in tumour extent were observed most clearly within the adenocarcinoma subgroup (OR ~0.6, 95% CI 0.5-0.8), although numbers of other subtypes were more limited; and there was a significant reduction of ~20-30% in the odds of metastasis among the aspirin users across the subgroups.ConclusionUse of low-dose aspirin in the year prior to diagnosis was found to be associated with lower tumour extent and fewer metastatic disease for colorectal and lung cancers. For these cancers, the benefit of aspirin use appears to be during both early and late cancer progression.

Dataset Information

Oxylipid Profile of Low-Dose Aspirin Exposure: A Pharmacometabolomics Study.

Publications

Oxylipid Profile of Low-Dose Aspirin Exposure: A Pharmacometabolomics Study.

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