International J. of Healthcare and Biomedical Research, Volume: 04, Issue: 01, October 2015, Pages 26-31

Original article Zaltoprofen induced histological changes in kidneys of albino rats Dr. R. Shalini

Department of Anatomy, Dhanalakshmi Srinivasan Medical College and Hospital, Siruvachur, Perambalur, Tamil nadu- 621212. Corresponding author: Dr. R. Shalini

Abstract Introduction: Non steroidal anti inflammatory drugs (NSAIDs) are the most commonly prescribed medications. The newer NSAIDs continue to be nephrotoxic as conventional NSAIDs. Zaltoprofen is a NSAID used commonly as an analgesic in the treatment of painful disorders. Our aim was to determine the histological changes in the kidneys of Albino rats after varying periods of oral Zaltoprofen administration. Materials: 36 adult male Albino Wistar rats and the drug Zaltoprofen in a dose of 40mg/ kg body weight of Albino rats. 10% Dimethyl Sulphoxide was used as the solvent for the drug. Methodology: Groups A1, B1 and C1 - each comprising of 6 rats served as control groups and was treated with 10% Dimethyl sulphoxide, orally for 7, 14 and 21 days respectively. Groups A2, B2 and C2 - each comprising of 6 rats served as the experimental group and was treated with the drug Zaltoprofen dissolved in 10% Dimethyl Sulphoxide orally for 7, 14 and 21 days respectively. The rats were sacrificed 24 hours after the last dose of drug and their kidneys were collected. Results: The histological changes noted at the end of 7 days of Zaltoprofen administration was interstitial inflammation and tubular necrosis. At the end of 14 days, there was lymphocytic infiltration in the glomerulus and interstitium, congestion of blood vessels and tubular necrosis. At the end of 21 days, the histological changes noted were tubular necrosis and hypoplasia of glomerulus. Conclusion: Zaltoprofen should be used cautiously in patients with kidney diseases. Key words: NSAID, Zaltoprofen, kidneys, histology

Introduction: tubulointerstitial nephritis, glomerulonephritis, renal Non steroidal anti inflammatory drugs (NSAIDs) are papillary necrosis, chronic renal failure, salt and the most commonly prescribed medications. But water retention, hypertension, hyperkalemia and these agents also have unwanted effects on the hypereninaemic hypoaldosteronism(3). gastrointestinal tract, liver and kidneys (1). The serious Renal failure associated with the use of Celecoxib gastro intestinal side effects of NSAIDs have been and Rofecoxib, which are specific cycloxygenase 2 minimized by the advent of selective and specific inhibitors, have been reported (4). Nephrotoxicity with Cyclo oxygenase 2 inhibitors. Rofecoxib in paediatric cases have been reported (5). The newer NSAIDs continue to be nephrotoxic as the Zaltoprofen, chemically-2- (10, 11-dihydro-10- conventional NSAIDs (2). The common nephrotoxic oxodibenzo[b,f]thiepin-2-yl)propionic acid (6) is a effects of NSAIDs are acute tubular necrosis, acute potent NSAID with preferential Cycloxygenase -2

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International J. of Healthcare and Biomedical Research, Volume: 04, Issue: 01, October 2015, Pages 26-31

inhibition (7). It is used in the treatment of Rheumatoid 10%Dimethyl Sulphoxide, orally via an oro- Arthritis (8), Osteoarthritis (9) as well as to relieve pain gastric tube, for 7,14 and 21 days respectively. after surgery, injury and tooth extraction (10,11). After - Groups A2, B2 and C2 - each comprising of oral administration of Zaltoprofen to humans, 62% of 6 rats served as the experimental group and the dose is excreted as conjugates in the urine and were treated with the drug Zaltoprofen in a dose only 3% is excreted unchanged (12). Also the of 40mg/kg body weight/day (13) dissolved in involvement of liver microsome CYP2C9 and 10%Dimethyl Sulphoxide, orally via an oro- UGT2B7 in the metabolism of Zaltoprofen is gastric tube, for 7,14 and 21 days respectively. established (12). The present study aims to observe the Blood samples were collected from the tail vein of histologic changes in kidneys of albino rats treated the rats before they were sacrificed, for biochemical with varying periods of Zaltoprofen. analysis of Blood urea nitrogen (BUN) and Serum Materials and methods: Creatinine. The rats were sacrificed 24 hours after 36 adult male Albino Wistar rats, weighing 180- the last dose of the drug by cervical dislocation and 220gm were obtained from Animal house of Sri their kidneys were collected. The organs were Manakula Vinayagar Medical College and Hospital, preserved in 10% formalin, processed and stained Puducherry. The experimental protocol was approved with eosin and hematoxylin stains. The program Epi by the Institutional Animal ethics Committee info version 3.4.3 was used in the statistical following the guidelines of CPCSEA (Committee for evaluation of the biochemical results. Mean and the Purpose of Control and Supervision of standard deviation was calculated for each of the Experiments on Animals for laboratory animal groups. ‘F’ test was used to determine the ‘p’ value facility). for each of the parameters. A ‘p’ value < 0.05 was The drug Zaltoprofen, obtained from Ipca taken to be statistically significant. Pharmaceuticals, was diluted in 10% Dimethyl Results: Sulphoxide and given as 40mg/kg body weight/day On histological examination, the kidneys of the (13) orally to the experimental group rat. The rats were control group rats were normal (Figure 1). The acclimatized for a period of 7 days before starting the kidneys of the rats treated with the drug Zaltoprofen study. Standard environmental conditions such as for 7 days (A2 group) showed interstitial temperature (24+/-2C), humidity (60-70%) and 12 inflammation and tubular necrosis. There was hours of light / dark cycle were maintained. Food and lymphocytic infiltration in the interstitium (Figure 2). water were allowed ad libitum under strict hygienic Blood urea nitrogen and serum creatinine were not conditions. significantly increased in the experimental A2 group STUDY GROUPS: (Table 1). - Groups A1, B1 and C1 - each comprising of The histological changes observed in the kidneys of 6 rats served as the control groups and were the rats treated with Zaltoprofen for 14 days (B2 treated with isovolumetric quantities of group) were lymphocytic infiltration in the glomerulus and interstitium, congestion of blood

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International J. of Healthcare and Biomedical Research, Volume: 04, Issue: 01, October 2015, Pages 26-31

vessels and tubular necrosis (Figure 3). Blood urea nitrogen levels were significantly elevated in the B2 group with a ‘p’ value of 0.01 (Table 1). The histological changes observed in the kidneys of the rats treated with Zaltoprofen for 21 days (C2 group) were, congestion of blood vessels, extensive tubular necrosis and hypoplasia of the glomerulus (Figure 4 & 5). There was less of lymphocytic infiltration compared to A2 and B2 groups. Blood urea nitrogen levels were significantly elevated in the

C2 group with a ‘p’ value of 0.01 (Table 1). Figure 3: Kidney of B2 group rat. The thin arrow

indicates lymphocytic infiltration and thick arrow indicates tubular necrosis

Figure 4: Kidney of C2 group rat. The thin arrow

points to hypoplasia of glomerulus and the thick Figure 1: Kidney of control group rat arrow points to tubular necrosis.

Figure 2. Kidney of A2 group rat. The thin arrow indicates interstitial lymphocytic infiltration and thick arrow indicates tubular necrosis.

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Figure 5: Kidney of C2 group rat. The thin arrow points to dilated and congested blood vessel

TABLE 1: BIOCHEMICAL PARAMETERS

Group Group ‘p’ Group Group ‘p’ Group C1 Group ‘p’ value A1 A2 value B1 B2 value n= 6 C2 n= 6 n= 6 n= 6 n= 6 n= 6

Blood urea 14.84+/ 16.02+/ 0.399 14.81+/ 17.69+/ 0.010 14+/ -1.55 17.19 +/ 0.012 nitrogen mg/dl - 3.24 -2.8 -2.10 -1.14 -1.14 Mean+/- Std. deviation

Serum 0.71+/ - 0.73+/ - 0.685 0.85+/ - 0.93+/ - 0.101 0.63+/ - 0.68+/ - 0.427 Creatinine 0.09 0.08 0.05 0.1 0.05 0.16 mg/dl Mean+/- Std. deviation

Discussion: interstitial lymphocytic infiltration, congested and Nephrotoxicity has been associated with clinical use dilated blood vessels, tubular necrosis and hypoplasia of NSAIDs. The present study with varying periods of glomerulus. These histological changes have also of Zaltoprofen administration to Albino rats showed been reported with the use of other NSAIDs in that there was borderline increase in Blood urea Albino rats. Loh A H L, et al., (14) have reported that nitrogen. The histological changes observed were NSAID induced Renal Tubulo interstitial nephritis is

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due to immune mediated reactions, vascular epithelial cells, vacuolar degeneration and marked congestion is due to capillary or ischemic damage tubular atrophy with interstitial fibrosis. Ucheya R E, and glomerular injury is due to alterations in Renin- et al., (18), studied the histological changes in kidneys angiotensin system or Prostaglandin synthesis in of pregnant Sprague Dawley rats after administration humans. Ejaz P, et al., (15) have reported that chronic of Paracetamol. They observed shrunken glomerulus, administration of NSAIDs to patients with painful vascular congestion, haemorrhage and tubular disorders caused acute tubular necrosis and acute necrosis. Burell J H, et al., (19) observed renal papillary renal failure. Papillary necrosis has been incriminated necrosis in female Fischer 344 rats after treatment in the development of chronic renal failure secondary with Aspirin and Paracetamol. Necrosis of the to NSAIDs. Kitahara M, et al., (16) in their study have epithelium of the thin limbs of the loop of Henle, reported that selective cyclo oxygenase 2 inhibitors- cortical interstitial fibrosis and tubular atrophy were Rofecoxib and Celecoxib, impaired glomerular observed. capillary healing in experimental Glomerulonephritis Conclusion: in Albino rats. Jain N, et al., (17) studied the renal Zaltoprofen caused renal histologic changes similar histological effect in albino rats after oral Aspirin to other NSAIDs, hence they should be used administration. They observed damage in the tubular cautiously in patients with renal diseases.

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