The in vivo assessment of nimesulide cyclooxygenase-2 selectivity

Shah, A. A.; Murray, FE; Fitzgerald, D J

doi:10.1093/rheumatology/38.suppl_1.19

Cited by 56 publications

(34 citation statements)

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“…We have shown previously that nimesulide is selective for COX-2 at the dose used in this study. 21,41 Nimesulide had no effect on gastric COX activity or systemic TXA 2 formation while it suppressed LPS-induced PGE 2 formation. 41 Selectivity was confirmed in the present study in that nimesulide had little effect on serum TXB 2 , an assay of COX-1 activity, whereas it markedly suppressed LPSinduced PGE 2 , an assay of COX-2 activity.…”

Section: Discussionmentioning

confidence: 95%

“…21,41 Nimesulide had no effect on gastric COX activity or systemic TXA 2 formation while it suppressed LPS-induced PGE 2 formation. 41 Selectivity was confirmed in the present study in that nimesulide had little effect on serum TXB 2 , an assay of COX-1 activity, whereas it markedly suppressed LPSinduced PGE 2 , an assay of COX-2 activity. 32 Nimesulide reduced the urinary excretion of 2,3-dinor-6-keto-PGF 1␣ in patients with atherosclerosis by nearly 50% before surgery and to a similar extent after surgery.…”

Section: Discussionmentioning

confidence: 95%

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Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

et al. 2000

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Background-The formation of prostacyclin (PGI 2 ), thromboxane (TX) A 2 , and isoprostanes is markedly enhanced in atherosclerosis. We examined the relative contribution of cyclooxygenase (COX)-1 and -2 to the generation of these eicosanoids in patients with atherosclerosis. Methods and Results-The study population consisted of 42 patients with atherosclerosis who were undergoing surgical revascularization. COX-2 mRNA was detected in areas of atherosclerosis but not in normal blood vessel walls, and there was evidence of COX-1 induction. The use of immunohistochemical studies localized the COX-2 to proliferating vascular smooth muscle cells and macrophages. Twenty-four patients who did not previously receive aspirin were randomized to receive either no treatment or nimesulide at 24 hours before surgery and then for 3 days. Eighteen patients who were receiving aspirin were continued on a protocol of either aspirin alone or a combination of aspirin and nimesulide. Urinary levels of 11-dehydro-TXB 2 and 2,3-dinor-6-keto-PGF 1␣ , metabolites of TXA 2 and PGI 2 , respectively, were elevated in patients with atherosclerosis compared with normal subjects (3211Ϯ533 versus 679Ϯ63 pg/mg creatinine, PϽ0.001; 594Ϯ156 versus 130Ϯ22 pg/mg creatinine, PϽ0.05, respectively), as was the level of the isoprostane 8-iso-PGF 2␣ . Nimesulide reduced 2,3-dinor-6-keto-PGF 1␣ excretion by 46Ϯ5% (378.3Ϯ103 to 167Ϯ37 pg/mg creatinine, PϽ0.01) preoperatively and blunted the increase after surgery. Nimesulide had no significant effect on 11-dehydro-TXB 2 before (2678Ϯ694 to 2110Ϯ282 pg/mg creatinine) or after surgery. The levels of both products were lower in patients who were taking aspirin, and no further reduction was seen with the addition of nimesulide. None of the treatments influenced urinary 8-iso-PGF 2␣ excretion. Conclusions-Both COX-1 and -2 are expressed and contribute to the increase in PGI 2 in patients with atherosclerosis, whereas TXA 2 is generated by COX-1. (Circulation. 2000;102:840-845.)

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

Cyclooxygenase-1 and -2–Dependent Prostacyclin Formation in Patients With Atherosclerosis

et al. 2000

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“…Next, injection of a bolus of the selective COX-2 inhibitor nimesulide (3 mg/kg body wt) or a 50 mM sodium carbonate vehicle (1 ml/kg body wt) was followed by a 15-min delay. Nimesulide has been previously shown to be selective for COX-2 (4,34) and to elicit alterations in renal function (26,30,31). The third and fourth 30-min urine samples were collected during COX-2 inhibition.…”

Section: Experimental Studiesmentioning

confidence: 99%

Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II

Green

Rodríguez

Navar

2010

American Journal of Physiology-Renal Physiology

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Green T, Rodriguez J, Navar LG. Augmented cyclooxygenase-2 effects on renal function during varying states of angiotensin II. Am J Physiol Renal Physiol 299: F954 -F962, 2010. First published July 28, 2010 doi:10.1152/ajprenal.00609.2009.-Nonsteroidal anti-inflammatory drug usage has long revealed renoprotective prostaglandin actions on the renal microvasculature during increased pressor hormone influence, but whether increased cyclooxygenase (COX)-2 expression supports prostaglandin vasodilatory influence by interfering with the actions of ANG II remains unresolved. Therefore, we tested the hypothesis that COX-2 inhibition causes hemodynamic and excretory effects that are increased in proportion to ANG II activity. In anesthetized Sprague-Dawley rats having augmented cortical COX-2 expression but different ANG II activity, we conducted renal clearance experiments during acute inhibition of COX-2 with nimesulide (NMSLD) and inhibition of COX-1 with SC-560. In one series of experiments, acute captopril [acute angiotensin-converting enzyme (ACE) inhibitor (aACEi)] was administered alone (n ϭ 13) or in combination with chronic captopril [chronic ACEi (cACEi)] pretreatment (n ϭ 19). In another series of experiments, rats were fed a normal-sodium [0.4% (NS), n ϭ 12] or a low-sodium [0.03% (LS), n ϭ 18] diet. NMSLD did not alter mean arterial blood pressure in any group but, in the LS and cACEi groups, decreased renal plasma flow (from 3.99 Ϯ 0.33 to 2.85 Ϯ 0.26 and from 4.30 Ϯ 0.19 to 3.22 Ϯ 0.21 ml·min Ϫ1 ·g Ϫ1 ), cortical blood flow (Ϫ12 Ϯ 8% and Ϫ13 Ϯ 4%), and glomerular filtration rate (from 0.88 Ϯ 0.04 to 0.65 Ϯ 0.05 and from 0.95 Ϯ 0.07 to 0.70 Ϯ 0.05 ml·min Ϫ1 ·g Ϫ1 ). In contrast, medullary blood flow (MBF) was significantly decreased by COX-2 inhibition in NS (Ϫ24 Ϯ 5%), LS (Ϫ27 Ϯ 8%), aACEi (Ϫ16 Ϯ 3.8%), and cACEi (Ϫ24 Ϯ 4.2%) groups. Absolute and fractional sodium excretion rates were unchanged by NMSLD, except in the LS group (0.75 Ϯ 0.05 eq/min and 0.43 Ϯ 0.15% and 0.51 Ϯ 0.06 eq/min and 0.26 Ϯ 0.10%). SC-560 did not augment the effects of NMSLD. These results demonstrate an augmented COX-2-mediated vasodilation that is not contingent on ANG II, in contrast to COX-2-mediated augmented sodium excretion, where ANG II activity is requisite. Furthermore, the COX-2 effects on MBF are not contingent on ANG II or changes in cortical microvascular responses. These results reflect COX-2 continual regulation of MBF and adaptive opposition to ANG II prohypertensinogenic effects on renal plasma flow, cortical blood flow, glomerular filtration rate, and absolute and fractional sodium excretion.angiotensin-converting enzyme inhibition; sodium restriction; medullary blood flow THE DYNAMIC PROSTAGLANDIN biosynthetic capacity in the kidney relies on the catalysis of the rate-limiting step by the cyclooxygenase (COX) isoforms COX-1 and COX-2 (25). Adaptive renal responses to reduced sodium intake involve augmented COX activity, along with activation of the renin-angiotensin system (RAS) (21,36,38,41). Interactions of th...

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“…При применении нимесулида в терапевтических кон-центрациях преобладает ингибиция лейкоцитарной ЦОГ 2, при этом влияние на тромбоцитарную ЦОГ 1 минимально, что подтверждается отсутствием значительного эффекта на гемостаз [15,[19][20][21]. Нимесулид способен не только подав-лять активность ЦОГ 2, но и уменьшать ее образование [22].…”

Section: гу институт ревматологии рамн москваunclassified