Freed M I, Audet P R, Zariffa N, Krishna G G, Ilson B E, Everitt D E, Brown L E, Rizzo S M, Nichols A I, Jorkasky D K
Clinical Research Unit, SmithKline Beecham, Presbyterian Medical Center of Philadelphia, PA 19104.
J Clin Pharmacol. 1994 Nov;34(11):1098-108. doi: 10.1002/j.1552-4604.1994.tb01987.x.
Nonsteroidal antiinflammatory drugs differ with respect to their effects on prostaglandin metabolism in various tissues, a property that may be partly responsible for some of the differences in the pharmacologic activities and side-effect profiles that are associated with their use. The effects of nabumetone on urinary prostaglandin excretion have not been reported. Fourteen healthy females, age 21-43 years, were treated with nabumetone (NAB) 1000 mg daily, sulindac (SUL) 200 mg every 12 hours, and indomethacin (IND) 50 mg every 12 hours for 7 days in a randomized period-balanced crossover study. The effects of drug treatment on urinary prostaglandin excretion (PGE2, 6-keto-PGF1 alpha, PGF2 alpha, thromboxane [TX] B2) and platelet function (collagen-induced whole blood platelet aggregation [CIPA] and template bleeding time) were determined on day 1 and day 7. For each treatment regimen, mean baseline urinary PG excretion values were comparable for each prostanoid, but the pattern of excretion differed in response to each drug. Treatment with NAB significantly increased the urinary excretion rates of PGE2 and PGF2 alpha, but 6-keto-PGF1 alpha and TXB2 excretion were unchanged. IND treatment did not result in a significant change in PGE2 excretion but did significantly reduce urinary 6-keto-PGF1 alpha and TXB2 excretion rates. Reduced excretion of PGF2 alpha was observed on both study days during treatment with IND and SUL. SUL treatment also resulted in increased urinary PGE2 excretion while significantly reducing 6-keto-PGF1 alpha excretion on day 7. Significant differences were observed between the NAB and SUL regimens with respect to PGF2 alpha excretion and between the NAB and SUL regimens for PGE2, PGF2 alpha, 6-keto-PGF alpha 1 (on day 1 only) and TXB2 (on day 1 only). Neither NAB nor SUL caused inhibition of CIPA or bleeding time although platelet aggregation was inhibited during IND treatment. That NAB treatment was neither associated with alterations in platelet function nor decreases in the urinary excretion of the vasodilatory prostaglandins, PGE2 and 6-keto-PGF1 alpha, suggests that NAB possesses renal sparing properties.
非甾体抗炎药在对各种组织中前列腺素代谢的影响方面存在差异，这一特性可能部分解释了与其使用相关的药理活性和副作用谱的一些差异。萘丁美酮对尿前列腺素排泄的影响尚未见报道。在一项随机的周期平衡交叉研究中，14名年龄在21 - 43岁的健康女性，每日服用萘丁美酮（NAB）1000毫克、每12小时服用舒林酸（SUL）200毫克、每12小时服用吲哚美辛（IND）50毫克，持续7天。在第1天和第7天测定药物治疗对尿前列腺素排泄（前列腺素E2、6 - 酮 - 前列腺素F1α、前列腺素F2α、血栓素[TX]B2）和血小板功能（胶原诱导的全血血小板聚集[CIPA]和模板出血时间）的影响。对于每种治疗方案，每种前列腺素的平均基线尿前列腺素排泄值相当，但排泄模式因每种药物而异。NAB治疗显著增加了前列腺素E2和前列腺素F2α的尿排泄率，但6 - 酮 - 前列腺素F1α和TXB2排泄未改变。IND治疗未导致前列腺素E2排泄有显著变化，但确实显著降低了尿6 - 酮 - 前列腺素F1α和TXB2排泄率。在IND和SUL治疗期间的两个研究日都观察到前列腺素F2α排泄减少。SUL治疗还导致尿前列腺素E2排泄增加，同时在第7天显著降低6 - 酮 - 前列腺素F1α排泄。在前列腺素F2α排泄方面，NAB和SUL方案之间以及在前列腺素E2、前列腺素F2α、6 - 酮 - 前列腺素α1（仅在第1天）和TXB2（仅在第1天）的NAB和SUL方案之间观察到显著差异。NAB和SUL均未引起CIPA抑制或出血时间改变，尽管在IND治疗期间血小板聚集受到抑制。NAB治疗既不与血小板功能改变相关，也不导致血管舒张性前列腺素前列腺素E2和6 - 酮 - 前列腺素F1α的尿排泄减少，这表明NAB具有肾脏保护特性。
