Cyclo-Oxygenase Isoenzymes

Jouzeau, Jean‐Yves; Terlain, Bernard; Abid, Amr; Nédélec, Emmanuelle; Netter, Patrick

doi:10.2165/00003495-199753040-00003

Cited by 164 publications

(35 citation statements)

References 189 publications

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“…Initial studies reported on the renal sparing effects of predominantly selective COX-2 inhibitors [21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32]. The renal function was preserved in healthy volunteers and in patients with renal insufficiency during treatment with oxicam derivatives [26, 27, 28, 29].…”

Section: Discussionmentioning

confidence: 99%

“…Nabumetone has about 50 times selectivity for COX-2 inhibition in vitro [21], but its true COX-1 inhibitory potential in our settings has not been tested. Moreover, a rather significant role for the COX-2 isoenzyme itself in renal development and physiology has been recently identified [1].…”

Section: Discussionmentioning

confidence: 99%

“…By contrast, COX-2, induced during the inflammatory process and expressed primarily in inflammatory cells, is responsible for the production of local PGs that participate in the inflammatory response. It has been assumed that the use of selective COX-2 inhibition, acting predominantly in inflamed tissues, may result in negligible or no gastrointestinal or renal impairment [19, 20, 21]. Indeed, early clinical trials emphasize the safety of these agents, devoid of renal and gastrointestinal side-effects [20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32].…”

Section: Introductionmentioning

confidence: 99%

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Renal Effects of Nabumetone, a COX-2 Antagonist: Impairment of Function in Isolated Perfused Rat Kidneys Contrasts with Preserved Renal Function in vivo

Reichman¹,

Cohen²,

Goldfarb

et al. 2001

Nephron Exp Nephrol

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The constitutive cyclooxygenase (COX)-1 enzyme has been considered the physiologically important isoform for prostaglandin synthesis in the normal kidney. It has, therefore, been suggested that selective inhibitors of the ‘inducible’ isoform (COX-2) may be free from renal adverse effects. We studied the renal effects of the predominantly COX-2 antagonist nabumetone in isolated perfused kidneys. As compared with controls, kidneys removed after in vivo administration of oral nabumetone (15 mg/kg) disclosed altered renal function with reduced glomerular filtration rate, filtration fraction, and urine volume and enhanced hypoxic outer medullary tubular damage. By contrast, renal function and morphology were not affected in vivo by nabumetone or its active metabolite 6-methoxy-2-naphthylacetic acid. The latter agent (10–20 mg/kg i.v.) did not significantly alter renal microcirculation, as opposed to a selective substantial reduction in medullary blood flow noted with the nonselective COX inhibitor indomethacin (5 mg/kg i.v.). In a rat model of acute renal failure, induced by concomitant administration of radiocontrast, nitric oxide synthase, and COX inhibitors, the decline in kidney function and the extent of hypoxic medullary damage with oral nabumetone (80 mg/kg) were comparable to a control group, and significantly less than those induced by indomethacin. In rats subjected to daily oral nabumetone for 3 consecutive weeks, renal function and morphology were preserved as well. Both nabumetone and 6-methoxy-2-naphthylacetic acid reduced renal parenchymal prostaglandin E₂ to the same extent as indomethacin. It is concluded that while nabumetone adversely affects renal function and may intensify hypoxic medullary damage ex vivo, rat kidneys are not affected by this agent in vivo, both in acute and chronic studies. COX selectivity may not explain the renal safety of nabumetone.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Renal Effects of Nabumetone, a COX-2 Antagonist: Impairment of Function in Isolated Perfused Rat Kidneys Contrasts with Preserved Renal Function in vivo

Reichman¹,

Cohen²,

Goldfarb

et al. 2001

Nephron Exp Nephrol

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“…[5][6][7]36 However, when a va- riety of cells such as macrophages and endothelial cells were challenged with various inflammatory mediators, COX-2 expression was rapidly induced. Moreover, at sites of inflammation such as the rheumatoid synovium, COX-2 was dramatically up-regulated.…”

Section: The Homeostatic Vs Proinflammatory Theory Of Cox Actionsmentioning

confidence: 99%

Unresolved Issues in the Role of Cyclooxygenase-2 in Normal Physiologic Processes and Disease

Lipsky¹,

Brooks²,

Crofford³

et al. 2000

Arch Intern Med

143

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Originally suggested to function mainly in inflammatory situations, recent data have implied important roles for the cyclooxygenase-2 isoenzyme in reproductive biologic processes, renal and neurologic function, and the antithrombotic activities of endothelial cells. As cyclooxygenase-2-specific inhibitors have recently become available as analgesic and anti-inflammatory drugs, a comprehensive view of this rapidly evolving field is necessary to anticipate both the potential therapeutic benefits and toxic effects associated with these agents.

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“…Now, it is well known that the therapeutic utility of nonselective COX inhibitors is due to inhibition of COX-2, while their side effect profile (i.e., gastrointestinal irritation and bleeding) results from inhibition of COX-1. Clearly, the development of selective inhibitors of COX-2 is an attractive target, because such agents retain the anti-inflammatory, analgesic, and antipyretic properties of nonselective COX inhibitors, while reducing the risk of gastrointestinal side effects [7][8][9]. Until recently, much attention has been focused on the design of potent and selective COX-2 inhibitors, such as celecoxib, etoricoxib and valdecoxib.…”

Section: Introductionmentioning

confidence: 99%