Exacerbation of Celecoxib-Induced Renal Injury by Concomitant Administration of Misoprostol in Rats

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) can produce adverse effects by inhibiting prostaglandin (PG) synthesis. A PGE1 analogue, misoprostol, is often utilized to alleviate NSAID-related gastrointestinal side effects. This study examined the effect of misoprostol on celecoxib renal toxicity. Additionally, the effects of these drugs on cardiovascular parameters were evaluated. Four randomized rat groups were orally gavaged for 9 days, two groups receiving vehicle and two groups receiving misoprostol (100 µg/kg) twice daily. Celecoxib (40 mg/kg) was co-administered once daily to one vehicle and one misoprostol group from days 3 to 9. Urine and blood samples were collected and blood pressure parameters were measured during the study period. Hearts and kidneys were harvested on final day. Day 2 urinary electrolyte samples revealed significant reductions in sodium excretion in misoprostol (0.12±0.05 µmol/min/100 g) and misoprostol+celecoxib groups (0.07±0.02 µmol/min/100 g). At day 3, all treatment groups showed significantly reduced sodium excretion. Potassium excretion diminished significantly in vehicle+celecoxib and misoprostol+celecoxib groups from day 3 onward. Urinary kidney injury molecule-1 levels were significantly increased in vehicle+celecoxib (0.65±0.02 vs. 0.35±0.07 ng/mL, p = 0.0002) and misoprostol+celecoxib (0.61±0.06 vs. 0.37±0.06 ng/mL, p = 0.0015) groups when compared to baseline; while plasma levels of cardiac troponin I increased significantly in vehicle+celecoxib (p = 0.0040) and misoprostol+misoprostol (p = 0.0078) groups when compared to vehicle+vehicle. Blood pressure parameters increased significantly in all misoprostol treated groups. Significant elevation in diastolic (p = 0.0071) and mean blood pressure (p = 0.0153) was noted in misoprostol+celecoxib compared to vehicle+celecoxib. All treatments produced significant tubular dilatation/necrosis compared to control. No significant myocardial changes were noticed; however, three animals presented with pericarditis. Kidney, heart, and plasma celecoxib levels revealed no significant change between vehicle+celecoxib and misoprostol+celecoxib. Concomitant misoprostol administration did not prevent celecoxib renal toxicity, and instead exacerbated renal side effects. Misoprostol did not alter plasma or tissue celecoxib concentrations suggesting no pharmacokinetic interaction between celecoxib and misoprostol.

Histomorphological effect of celecoxib on cellular diameter of proximal convoluted tubules of kidney with protective effect of lycopene in albino rats; an experimental study.

“…4 The similar findings was observed in celecoxib induced oxidative injury to the renal tissue in wistar rats and necrosis of tubular cells with shortening of the microvilli in rats when treated by celecoxib, which produces the free radicals due to inhibition of anti-oxidative enzymes and cause the oxidative injury to the renal tissue. 15,26 The present study also showed that the lycopene markedly ameliorated the celecoxib induced oxidative damage to the renal tissue and prevented the damaging effect of celecoxib similar to control group. This was due to the anti-oxidative property of the lycopene which prevented the oxidative injury to the kidney and increased the antioxidative enzymes which protect the cell from necrotic and apoptotic changes.…”

“…It enhances immunity by maintaining structural and functional integrity of immune cells. 15 Microscopic examination of celecoxib treated renal tissues of group-B animals showed disrupted architecture of renal parenchyma. Proximal tubules with ill-defined microvilli at the luminal surface of epithelium, vacuolation and ballooning of cells were noticed.…”

“…11,12,13 Celecoxib reduces glomerular filtration rate (GFR) and raise blood pressure. 14,15 Carotenoids are the pigmented fat soluble dietary antioxidant, present in fruits like watermelon, grape fruit and tomato which we generally use in our diet. 16,17,18 Lycopene is an acyclic carotenoid, gives red color pigment to the fruits and vegetable.…”

Pain Control of Medical Abortion with Misoprostol in the First Trimester of Pregnancy

“…The study's results indicated that medical abortion caused pain that can be managed effectively by NSAIDs that their usage among previous medical abortion protocols was in accociation with disagreements due to probable interventions with misoprostol's function [15][16][17][18], were ignored and it doesn't seem they have significant difference for the management of medical abortion pain.…”

Marketed nonsteroidal anti-inflammatory agents, antihypertensives, and human immunodeficiency virus protease inhibitors: as-yet-unused weapons of the oncologists’ arsenal

“…Although coxibs seem promising anticancer agents, gastrointestinal side effects (ranging from irritation of the gastrointestinal mucosa to gastrointestinal bleeding), renal toxicity, and cardiovascular complications (thrombotic events, myocardial infraction, and ischemic episodes) raised serious concerns about the safety of this class of drugs, which is still a point of controversy, culminating in the withdrawal of distinct coxibs from the market. 43 , 55 – 61 Consequently, there is much skepticism regarding the applicability of coxibs in the field of oncology.…”