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

Abstract

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)

Beneficial effect of insulin-like growth factor-1 on hypoxemic renal dysfunction in the newborn rabbit

“…The RVR was significantly increased by a maximum of 92%, resulting in a significant time-dependent decrease in GFR, RBF and diuresis. We reported in the normoxemic newborn rabbit that infusion of saline solution had no significant effect on MAP and renal function over time, demonstrating the stability of the model [29]. Therefore, the further deterioration of hemodynamics and renal function observed here can be considered as a specific effect of hypoxemia.…”

“…We also previously demonstrated in the same model that the newborn's kidney is highly sensitive to cyclooxygenase 2 (COX2) inhibition and that PGs play a key role in the regulation of neonatal GFR [29], through a rapid increase of COX2 renal expression during the first two postnatal weeks [38,39]. Prostaglandin synthesis inhibition with indomethacin completely blocked the IGF-1-induced increase in GFR in vitro and in vivo [24,40,41].…”

“…These were artifacts in the neonatal animal experiments resulting from repeated blood sampling for PaO 2 monitoring. We previously demonstrated that these changes do not interfere with the physiologic stability of the neonatal model [29].…”

Nimesulide-induced acute biliary tract injury and renal failure in a kitten: a case report

“…Van Steenbergen et al (1998) stated that immunological and metabolic idiosyncratic reactions may be the pathogenic mechanisms of nimesulide-induced liver disease in humans. Renal adverse effects to these drugs are due to the inhibition of prostaglandin synthesis, an increase in renal vascular resistance with a concomitant decrease in diuresis, GFR, and renal blood flow acute reversible renal failure (Apostolou et al, 1997;Balasubramaniam, 2000;Prevot et al, 2004). Merlani et al (2001) has reported that the primary manifestation of nimesulide toxicity is jaundice.…”

OBE022, an Oral and Selective Prostaglandin F2α Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor

“…As expected, RVR increased in the indomethacin group and decreased in the OBE002 and vehicle group (Table S3); single animals in the OBE002 group had outliers in RVR which lead to discordant mean and median percentage differences (Table S3) and marked SEM values (Table S2). (Prévot et al, 2004).…”