Waterbury L David, Silliman David, Jolas Thierry
Pacific BioLabs, Hercules, CA 94070, USA.
Curr Med Res Opin. 2006 Jun;22(6):1133-40. doi: 10.1185/030079906X112471.
To compare the cyclooxygenase (COX) activity and anti-inflammatory effects of the nonsteroidal anti-inflammatory drugs (NSAIDs) ketorolac tromethamine (ketorolac) and bromfenac sodium (bromfenac).
Cyclooxygenase activity and selectivity was determined in vitro by measuring prostaglandin E(2) (PGE(2)) production following incubation of varying concentrations of NSAID with human recombinant COX-1 or COX-2 and arachidonic acid. Anti-inflammatory effects were evaluated in a rabbit model in which an ocular inflammatory response was induced by intravenous injection of 10 microg/kg lipopolysaccharide (LPS). In study animals, one eye was treated with 50 microL (+/-) ketorolac 0.4% (Acular LS) or bromfenac 0.09% (Xibrom) and the other eye with 50 microL buffered saline. In control animals, both eyes were treated with vehicle. All animals were treated twice: 2 hours and 1 hour before LPS.
PGE(2) production in vitro, measured by enzyme immunoassay; fluorescein isothiocyanate (FITC)-dextran leakage into the anterior chamber, measured by fluorophotometry; aqueous PGE(2) levels in vivo, measured by ELISA immunoassay.
Ketorolac was six times more active against COX-1 (IC(50) = 0.02 microM) than COX-2 (IC(50) = 0.12 microM) while bromfenac was approximately 32 times more active against COX-2 (IC(50) = 0.0066 microM) than COX-1 (IC(50) = 0.210 microM). In the animal model, both drugs resulted in nearly complete inhibition of FITC-dextran leakage and PGE(2) production in the anterior chamber of treated eyes. There was also a 79% inhibition (p < 0.001) of FITC-dextran leakage in the contralateral eyes of bromfenac-treated rabbits, and a 22.5% inhibition (not statistically significant) in the contralateral eyes of ketorolac-treated rabbits.
Ketorolac is relatively COX-1 selective while bromfenac is potently selective for COX-2 over COX-1. In the animal model, both ketorolac 0.4% and bromfenac 0.09% demonstrated maximal anti-inflammatory activity in treated eyes. Only bromfenac 0.09% had a significant effect on the contralateral eye, suggesting possible systemic absorption of this drug.
比较非甾体抗炎药酮咯酸氨丁三醇（酮咯酸）和溴芬酸钠（溴芬酸）的环氧化酶（COX）活性及抗炎作用。
通过将不同浓度的非甾体抗炎药与人重组COX-1或COX-2及花生四烯酸孵育后，测量前列腺素E2（PGE2）的生成，在体外测定COX活性和选择性。在兔模型中评估抗炎作用，该模型通过静脉注射10微克/千克脂多糖（LPS）诱导眼部炎症反应。在研究动物中，一只眼用50微升0.4%（±）酮咯酸（阿乐迈LS）或0.09%溴芬酸（希布伦）治疗，另一只眼用50微升缓冲盐水治疗。在对照动物中，双眼均用赋形剂治疗。所有动物均接受两次治疗：在注射LPS前2小时和1小时。
通过酶免疫测定法测量体外PGE2生成；通过荧光光度法测量异硫氰酸荧光素（FITC）-葡聚糖向前房的渗漏；通过ELISA免疫测定法测量体内房水PGE2水平。
酮咯酸对COX-1（IC50 = 0.02微摩尔）的活性比对COX-2（IC50 = 0.12微摩尔）高6倍，而溴芬酸对COX-2（IC50 = 0.0066微摩尔）的活性比对COX-1（IC50 = 0.210微摩尔）高约32倍。在动物模型中，两种药物均导致治疗眼的前房中FITC-葡聚糖渗漏和PGE2生成几乎完全受到抑制。在溴芬酸治疗的兔的对侧眼中，FITC-葡聚糖渗漏也有79%的抑制（p < 0.001），而在酮咯酸治疗的兔的对侧眼中有22.5%的抑制（无统计学意义）。
酮咯酸相对选择性作用于COX-1，而溴芬酸对COX-2的选择性远高于COX-1。在动物模型中，0.4%酮咯酸和0.09%溴芬酸在治疗眼中均表现出最大抗炎活性。只有0.09%溴芬酸对侧眼有显著作用，提示该药物可能有全身吸收。
