Pharmacokinetic profile and<i>in vitro</i>selective cyclooxygenase‐2 inhibition by nimesulide in the dog

Toutain, Pierre‐Louis; Cester, C. C.; Haak, T.; Metge, S.

doi:10.1046/j.1365-2885.2001.00303.x

Cited by 45 publications

(73 citation statements)

References 19 publications

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“…The data obtained in the whole blood assay are in keeping with the selectivity described in the literature for the respective compounds (28,43,48,50). It is significant to note that COX-2 inhibition was not observed with SC-560, whereas the selective COX-2 inhibitor nimesulide inhibited the COX-2 isoform.…”

Section: Discussionsupporting

confidence: 85%

“…The selectivity of the pharmacological interventions was assessed with the use of standard assays conducted on whole blood for COX inhibition (7,50) and suppression of ex vivo platelet aggregation in response to AA (12). The formation of TxB 2 in clotted whole blood was used to assess COX-1 inhibition, and PGE 2 production in LPS-treated heparinized whole blood was used to assess COX-2 inhibition.…”

Section: Discussionmentioning

confidence: 99%

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Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

Hong¹,

Huang²,

Barrett³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis. Am J Physiol Heart Circ Physiol 294: H145-H155, 2008. First published October 5, 2007 doi:10.1152/ajpheart.00646.2007.-This study was designed to determine the effect of inhibitors of cyclooxygenase (COX)-1, COX-2, and the nonselective COX inhibitor naproxen on coronary vasoactivity and thrombogenicity under baseline and lipopolysaccharide (LPS)-induced inflammatory conditions. We hypothesize that endothelial COX-1 is the primary COX isoform in the canine normal coronary artery, which mediates arachidonic acid (AA)-induced vasodilatation. However, COX-2 can be induced and overexpressed by inflammatory mediators and becomes the major local COX isoform responsible for the production of antithrombotic prostaglandins during systemic inflammation. The interventions included the selective COX-1 inhibitor SC-560 (0.3 mg/kg iv), the selective COX-2 inhibitor nimesulide (5 mg/kg iv), or the nonselective COX inhibitor naproxen (3 mg/kg iv). The selective prostacyclin (IP) receptor antagonist RO-3244794 (RO) was used as an investigational tool to delineate the role of prostacyclin (PGI 2) in modulating vascular reactivity. AA-induced vasodilatation of the left circumflex coronary artery was suppressed to a similar extent by each of the COX inhibitors and RO. The data suggest that AA-induced vasodilatation in the normal coronary artery is mediated by a single COX isoform, the constitutive endothelial COX-1, which is reported to be susceptible to COX-2 inhibitors. The effect of the COX inhibitors on thrombus formation was evaluated in a model of carotid artery thrombosis secondary to electrolytic-induced vessel wall injury. Pretreatment with LPS (0.5 mg/kg iv) induced a systemic inflammatory response and prolonged the time-to-occlusive thrombus formation, which was reduced in the LPS-treated animals by the administration of nimesulide. In contrast, neither SC-560 nor naproxen influenced the time to thrombosis in the animals pretreated with LPS. The data are of significance in view of reported adverse cardiovascular events observed in clinical trials involving the use of selective COX-2 inhibitors, thereby suggesting that the endothelial constitutive COX-1 and the inducible vascular COX-2 serve important functions in maintaining vascular homeostasis.inflammation; vascular reactivity CONVENTIONAL NONSELECTIVE anti-inflammatory drugs (NSAIDs), such as naproxen, ibuprofen, and aspirin, inhibit both cyclooxygenase (COX)-1 and COX-2. COX-1, the COX isoform expressed constitutively in platelets, mediates the synthesis of thromboxane A 2 (TxA 2 ), a prostaglandin known to activate platelets and cause vasoconstriction. The second isoform of COX, COX-2, with ϳ50% sequence homology to COX-1, is an inducible form of COX during inflammation (30, 46). Despite considerable study, the functionally important COX isoform or isoforms present in the normal vascular endothelium has been uncertain. On the basis of earlier studies that failed to demonstrate ...

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

Hong¹,

Huang²,

Barrett³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

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“…In vitro, COX2/COX1 IC 50 ratios have been reported to range from 0.76 to Ͻ0.0001, i.e. from a 1.3-to a 10,000-fold higher COX2 versus COX1 selectivity of nimesulide [see (13) for review (33)(34)(35)]. Ex vivo, plasma from volunteers who were given nimesulide produced a marked inhibition of COX2 activity with little effect on COX1 (36).…”

Section: Discussionmentioning

confidence: 99%

Nimesulide, a Cyclooxygenase-2 Preferential Inhibitor, Impairs Renal Function in the Newborn Rabbit

et al. 2004

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Tocolysis with nonsteroidal anti-inflammatory drugs (NSAIDs) has been widely accepted for several years. Recently, the use of the cyclooxygenase-2 (COX2) preferential NSAID nimesulide has been proposed. However, data reporting neonatal acute renal failure or irreversible end-stage renal failure after maternal ingestion of nimesulide question the safety of this drug for the fetus and the neonate. Therefore, this study was designed to define the renal effects of nimesulide in newborn rabbits. Experiments were performed in 28 newborn rabbits. Renal function and hemodynamic parameters were measured using inulin and para-aminohippuric acid clearances as markers of GFR and renal blood flow, respectively. After a control period, nimesulide 2, 20, or 200 g/kg was given as an i.v. bolus, followed by a 0.05, 0.5, or 5 g · kg Ϫ1 · min Ϫ1 infusion. Nimesulide administration induced a significant dose-dependent increase in renal vascular resistance (29, 37, and 92%, respectively), with a concomitant decrease in diuresis (Ϫ5, Ϫ23, and Ϫ44%), GFR (Ϫ12, Ϫ23, and Ϫ47%), and renal blood flow (Ϫ23, Ϫ23, and Ϫ48%). These results are in contrast with recent reports claiming that selective COX2 inhibition could be safer for the kidney than nonselective NSAIDs. These experiments confirm that prostaglandins, by maintaining renal vasodilation, play a key role in the delicate balance regulating neonatal GFR. We conclude that COX2-selective/preferential inhibitors thus should be prescribed with the same caution as nonselective NSAIDs during pregnancy and in the neonatal period. Because of the role of prostaglandins (PGs) in the genesis of labor (term or preterm), nonselective nonsteroidal antiinflammatory drugs (NSAIDs) have been used as tocolytic drugs for several decades. Meanwhile, the use of NSAIDs during pregnancy to treat toxemia, polyhydramnios, or preterm labor and in the immediate postnatal period to induce closure of a symptomatic patent ductus arteriosus is increasing (1-4). However, side effects that affect mainly the cerebral, mesenteric, and renal microcirculations have been reported in fetuses and neonates (5-10), and NSAID-associated pulmonary hypoperfusion and persistence of fetal circulation may also compromise the newborn renal function (4, 11).It has been claimed that selective cyclooxygenase-2 (COX2) inhibitors could have the same curative effects as nonselective NSAIDs without the deleterious side effects attributed to COX1 inhibition. Therefore, the use of the COX2-preferential NSAID nimesulide (12, 13) has been proposed for tocolysis in humans (14). In a case report, Sawdy et al. (14) found no effect of nimesulide administered from the 16th to the 34th week of gestation on the renal and ductal functions of the fetus. Doppler flow indices for the ductus arteriosus and amniotic fluid index remained normal, and the infant was born with no congenital abnormalities and an uncomplicated neonatal course (14). However, recent data reporting severe oligohydramnios (15)

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“…Additional doses were given at 6, 12, 24, 36 and 48 h after stroke. This treatment schedule and dosage range were based on the pharmacokinetic profile of nimesulide [71] and on our previous experience with this compound in a model of global cerebral ischemia [9,12]. We also performed an experiment in which nimesulide was given as a single dose.…”

Section: Evaluation Of Nimesulide's Effects On Ischemic Damage 231mentioning

confidence: 99%

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

et al. 2004

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Results from several studies indicate that cyclooxygenase-2 (COX-2) is involved ischemic brain injury. The purpose of this study was to evaluate the neuroprotective effects of the selective COX-2 inhibitor nimesulide on cerebral infarction and neurological deficits in a standardized model of transient focal cerebral ischemia in rats. Three doses of nimesulide (3, 6 and 12 mg/kg; i.p.) or vehicle were administered immediately after stroke and additional doses were given at 6, 12, 24, 36 and 48 h after ischemia. In other set of experiments, the effect of nimesulide was studied in a situation in which its first administration was delayed for 3 to 24 h after ischemia.Total, cortical and subcortical infarct volumes and functional outcome (assessed by neurological deficit score and rotarod performance) were determined 3 days after ischemia. The effect of nimesulide on prostaglandin E 2 (PGE 2 ) levels in the injured brain was also investigated.Nimesulide dose-dependently reduced infarct volume and improved functional recovery when compared to vehicle. Of interest is the finding that neuroprotection conferred by nimesulide (reduction of infarct size and neurological deficits and improvement of rotarod performance) was also observed when treatment was delayed until 24 h after ischemia. Further, administration of nimesulide in a delayed treatment paradigm completely abolished PGE 2 accumulation in the postischemic brain, suggesting that COX-2 inhibition is a promising therapeutic strategy for cerebral ischemia to target the late-occurring inflammatory events which amplify initial damage. Theme: Disorders of the nervous systemTopic: Ischemia

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Pharmacokinetic profile andin vitroselective cyclooxygenase‐2 inhibition by nimesulide in the dog

Cited by 45 publications

References 19 publications

Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

Effects of cyclooxygenase inhibition on canine coronary artery blood flow and thrombosis

Nimesulide, a Cyclooxygenase-2 Preferential Inhibitor, Impairs Renal Function in the Newborn Rabbit

Wide therapeutic time window for nimesulide neuroprotection in a model of transient focal cerebral ischemia in the rat

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