Effects of selective COX-2 inhibition on prostanoids and platelet physiology in young healthy volunteers
Effects of selective COX-2 inhibition on prostanoids and platelet physiology in young healthy volunteers
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DOI：
10.1111/j.1538-7836.2007.02782.x
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发表时间：
2007-12-01
影响因子：
10.4
通讯作者：
Nuesing, R. M.
中科院分区：
文献类型：
--
作者：
Graff, J.;Skarke, C.;Nuesing, R. M.
研究背景：环氧化酶-2（考克斯-2）的选择性抑制剂昔布类是一种有效的抗炎镇痛药物。最近，这些药物与心肌梗死和动脉粥样硬化血栓事件的风险增加有关。血栓素-前列环素失衡的假说已被首选来解释这些不必要的影响。方法：我们研究了服用罗非昔布（25 mg q.d.）14天的效果，塞来昔布（200 mg b.i.d.），萘普生（500 mg b.i.d.）在年轻健康志愿者（中位年龄25-30岁，每组n = 10）中进行的随机、盲法、安慰剂对照研究中，我们评估了前列腺素代谢产物（PGE-M，TXB 2，6-keto-PGF（1 α），11-dehydro-TXB 2，2，3-dinor-TXB 2和dinor-6-keto-PGF（1 α））的排泄，血小板活化标志物（CD 62 P，PAC-1，纤维蛋白原）的表达，血小板-白细胞形成，内源性凝血酶潜力，血小板cAMP含量和血浆血栓调节蛋白水平。结果：纳曲林抑制前列腺素E-M、前列环素代谢产物和血栓素代谢产物的生物合成，并抑制血栓调节蛋白的水平。相反，两种昔布仅对PGE-M、6-keto-PGF（1 α）和dinor-6-keto-PGF（1 α）有抑制作用，而TXB 2、2，3-dinor-TXB 2和11-dehydro-TXB 2排泄不受影响。没有一种昔布对血小板活化标志物的表达、cAMP生成、血小板-白细胞形成或血栓调节蛋白血浆水平产生显著影响。有趣的是，花生四烯酸或胶原刺激后，昔布治疗后，血小板聚集过程中TXB 2的释放增强。结论：昔布对健康青年人全身PGE（2）和PGI（2）的合成有抑制作用。血小板功能和血小板聚集标志物的表达不受影响;然而，昔布可刺激活化血小板释放TXB 2。血管舒张性PGE（2）和PGI（2）的减少与血栓素A（2）的增加一起可能导致昔布的副作用。
Background: Selective inhibitors of cyclooxygenase-2 (COX-2) called coxibs, are effective anti-inflammatory and analgesic drugs. Recently, these drugs were associated with an increased risk for myocardial infarction and atherothrombotic events. The hypothesis of thromboxane-prostacyclin imbalance has been preferred to explain these unwanted effects. Methods: We studied the effects of 14 days intake of rofecoxib (25 mg q.d.), celecoxib (200 mg b.i.d.), naproxen (500 mg b.i.d.) and placebo in a randomized, blinded, placebo-controlled study in young healthy volunteers (median age 25-30 years, each group n = 10). We assessed prostanoid metabolite excretion (PGE-M, TXB2, 6-keto-PGF(1 alpha), 11-dehydro-TXB2, 2,3-dinor-TXB2, and dinor-6-keto-PGF(1 alpha)), the expression of platelet activation markers (CD62P, PAC-1, fibrinogen), platelet-leukocyte formation, the endogenous thrombin potential, platelet cAMP content and plasma thrombomodulin level. Results: Naproxen suppressed biosynthesis of PGE-M, prostacyclin metabolites and thromboxane metabolites and thrombomodulin levels. In contrast, both coxibs had an inhibitory effect only on PGE-M, 6-keto-PGF(1 alpha), and on dinor-6-keto-PGF(1 alpha), whereas TXB2, 2,3-dinor-TXB2 and 11-dehydro-TXB2 excretion were unaffected. None of the coxibs exerted significant effects on the expression of platelet activation markers, cAMP generation, platelet-leukocyte formation, or on thrombomodulin plasma levels. Interestingly, platelet TXB2 release during aggregation was enhanced after coxib treatment following arachidonic acid or collagen stimulation. Conclusion: In young healthy volunteers coxibs inhibit systemic PGE(2) and PGI(2) synthesis. Platelet function and expression of platelet aggregation markers are not affected; however, coxibs can stimulate TXB2 release from activated platelets. Combined decrease in vasodilatory PGE(2) and PGI(2) together with increased TXA(2) in proaggregatory conditions may contribute to coxib side effects.