Department of Pathology, University of Washington, Seattle, Washington, United States of America.
PLoS One. 2010 Feb 19;5(2):e9340. doi: 10.1371/journal.pone.0009340.
Results from prevention trials, including the Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT), have fueled discussion about the cardiovascular (CV) risks associated with non-steroidal anti-inflammatory drugs (NSAIDs). We tested the hypotheses that (i) adverse CV events reported among ADAPT participants (aged 70 years and older) are associated with increased ratio of urine 11-dehydrothromboxane B(2) (Tx-M) to 2'3-donor-6-keto-PGF1 (PGI-M) attributable to NSAID treatments; (ii) coincident use of aspirin (ASA) would attenuate NSAID-induced changes in Tx-M/PGI-M ratio; and (iii) use of NSAIDs and/or ASA would not alter urine or plasma concentrations of F(2)-isoprostanes (IsoPs), in vivo biomarkers of free radical damage. We quantified urine Tx-M and PGI-M, and urine and plasma F(2)-IsoPs from 315 ADAPT participants using stable isotope dilution assays with gas chromatography/mass spectrometry, and analyzed these data by randomized drug assignment and self-report compliance as well as ASA use. Adverse CV events were significantly associated with higher urine Tx-M/PGI-M ratio, which seemed to derive mainly from lowered PGI-M. Participants taking ASA alone had reduced urine Tx-M/PGI-M compared to no ASA or NSAID; however, participants taking NSAIDs plus ASA did not have reduced urine Tx-M/PGI-M ratio compared to NSAIDs alone. Neither NSAID nor ASA use altered plasma or urine F(2)-IsoPs. These data suggest a possible mechanism for the increased risk of CV events reported in ADAPT participants assigned to NSAIDs, and suggest that the changes in the Tx-M/PGI-M ratio was not substantively mitigated by coincident use of ASA in individuals 70 years or older.
结果来自预防试验，包括阿尔茨海默病抗炎预防试验（ADAPT），这激发了关于与非甾体抗炎药（NSAIDs）相关的心血管（CV）风险的讨论。我们检验了以下假设：（i）ADAPT 参与者（年龄在 70 岁及以上）报告的不良 CV 事件与 NSAID 治疗导致的尿液 11-脱氢血栓烷 B2（Tx-M）与 2'3-供体-6-酮-PGF1（PGI-M）比值升高有关；（ii）同时使用阿司匹林（ASA）会减轻 NSAID 引起的 Tx-M/PGI-M 比值变化；（iii）使用 NSAIDs 和/或 ASA 不会改变尿液或血浆中 F2-异前列腺素（IsoPs）的浓度，IsoPs 是自由基损伤的体内生物标志物。我们使用气相色谱/质谱的稳定同位素稀释分析测定了 315 名 ADAPT 参与者的尿液 Tx-M 和 PGI-M，以及尿液和血浆 F2-异前列腺素，并根据随机药物分配和自我报告的依从性以及 ASA 使用情况对这些数据进行了分析。不良 CV 事件与较高的尿液 Tx-M/PGI-M 比值显著相关，这似乎主要源于 PGI-M 降低。单独服用 ASA 的参与者的尿液 Tx-M/PGI-M 比值低于未服用 ASA 或 NSAIDs 的参与者；然而，与单独服用 NSAIDs 相比，同时服用 NSAIDs 和 ASA 的参与者的尿液 Tx-M/PGI-M 比值并没有降低。NSAIDs 或 ASA 的使用均未改变血浆或尿液 F2-异前列腺素。这些数据表明，ADAPT 参与者分配到 NSAIDs 后报告的 CV 事件风险增加可能存在一种机制，并表明在 70 岁或以上的个体中，同时使用 ASA 并不能实质性地减轻 Tx-M/PGI-M 比值的变化。
