sign in sign up
<<
Home , Superoxide dismutase

BENHA VETERINARY MEDICAL JOURNAL, VOL. 36, NO. 1:382-392, March, 2019

Side effects of have been ameliorated with vitamin E Gamal El-Din A.M. Shams, Suhair A. Abd El-Latif, Haydi H. El Din Abdallah Pharmacology Department, Faculty of Veterinary Medicine, Zagazig University, Egypt

A B S T R A C T

The present study was designed to define the effects of daily administration of 100 mg vitamin E\kg on side effects in mice treated with dexibuprofen (7.2 mg/kg, P.O once daily) for 21 consecutive days and its scavenging capacity. Blood samples were collected from mice on 1st, 2nd, 14th, 21st days post –treatment and tissue samples were collected on 7th, 14th days post- treatment to assess the protective effects of vitamin E. The results indicated significant increase in antioxidant Glutathione , dismutase(SOD)& (CAT) together decrease the level of malondialdehyde besides diminished and in portal fibrosis and decrease in congestion of hepatic blood vessels and sinusoids caused by dexibuprofen administration as demonstrated by kidney histopathology Therefore, Vitamin E should be taken with dexibuprofen to decrease its side effects.

Key words Antioxidant activity, Dexibuprofen, Histopathology, Vitamin E. ) BVMJ-36(1): 382-392, 2019)

1. INTRODUCTION (http://www.bvmj.bu.edu.eg

Dexibuprofen is non-steroidal anti- between the two drugs was in the degree of inflammatory drug. It's the active recovery of platelet function. The effect of dextrorotatory enantiomer of . Most persisted for 24 h after the last dose ibuprofen formulations contain a racemic (remaining inhibition 50% respect to the mixture of both isomers (Hardikar, 2008). pretreatment value), whereas platelet Dexibuprofen is the single aggregation had returned to baseline pharmacologically effective enantiomer of pretreatment values within 24 hr. after Rac-ibuprofen. Rac–ibuprofen and dexibuprofen was stopped (Gonzalez et al., dexibuprofen differ in their physic-chemical 2007). properties, in terms of their pharmacological Dexibuprofen has an equal efficacy and properties and their metabolic Dexibuprofen comparable safety and tolerability with has proven at least comparable efficacy to in treatment of osteoarthritis. , and celecoxib and has Dexibuprofen shows excellent tolerability, shown a favorable tolerability (Kaehler et al., safety than other low–density lipoprotein like 2003). Antiplatelet effect of dexibuprofen diclofenac sodium, dexibuprofen has (maximal inhibition of aggregation was 48- stronger pain reducing effect than racemic 55% for adenosine diphosphate and 90-95% ibuprofen (Kumaresan, 2010). for collagen and arachidonic acid) was equal Dexibuprofen-antioxidant conjugates were to the effect of aspirin The main difference synthesized with the aim to reduce its

382 Vit E protection against side effects of dexibuprofen gastrointestinal effects. The esters analogs of extracellular fluids are protected Overall, dexibuprofen were obtained by reacting its - these low molecular mass antioxidant COOH group with chloroacetyl derivatives. molecules add significantly to the defense The in vitro hydrolysis data confirmed that provided by the enzymes superoxide synthesized prodrugs were stable in stomach dismutase, catalase and glutathione while undergo significant hydrolysis in 80% (Sies., 1997). Defenses against human plasma and thus release free free damage include tocopherol dexibuprofen. The minimum reversion was vitamin E, ascorbic acid vitamin C beta- observed at pH 1.2 suggesting that prod rugs carotene, glutathione, uric acid, bilirubin, and are less irritating to stomach than several metalloenzymes including dexibuprofen The anti-inflammatory activity selenium), catalase is more significant than the parent , and superoxide dismutase dexibuprofen exhibited that synthesized and proteins such as prodrugs formed stable complexes with the copper superoxide dismutase COX-2 therefore concluded that the has powerful anti-inflammatory activity synthesized prodrugs have promising (Mcginness et al., 1978). For example, pharmacological activities with reduced superoxide dismutase is a highly effective gastrointestinal adverse effects than the experimental treatment of chronic parent drug (Ashraf et al., 2016). inflammation in treatment with Dexibuprofen is as effective and tolerable as superoxide dismutase decreases reactive ibuprofen. A dose of 5 mg kg-1 and 7 mg kg- species generation and oxidative 1 dexibuprofen in place of 10 mg kg-1 stress and thus inhibits endothelial activation. ibuprofen would be sufficient to control fever Therefore, such may be caused by URTI in children (Yoon et al., important new therapies for the treatment 2008). of inflammatory bowel disease (Seguí et al., The aryl derivative 2004). dexibuprofen was the most potent antiplatelet Dexibuprofen was approved that it had drug, and its pharmacodynamics profile is -hepatotoxicity in rats. similar to aspirin (De La Cruz et al., 2010). Therefore, this study aims to hepato-nephro- Non-steroidal anti-inflammatory drugs protective effects of vitamin E (100 mg/kg, including selective cyclo-oxygenase-2 COX- P.O. once daily) against dexibuprofen side 2 inhibitors COXIBs are commonly used to effects given for 21 days when vitamin E treat acute gout Published guidelines upon it co-administered with dexibuprofen. recommend their use to treat acute attacks, using maximum recommended doses for a 2. MATERIALS AND METHODS short time (Van Durme et al., 2014). In the lipid phase, tocopherols and carotenes 2.1 Drugs and chemicals R as well as oxy-carotenoids are of interest, as Dexibuprofen was obtained as SERACTIL are vitamin A and ubiquinols. In the aqueous 500 mg, tablets that was supplied by Gebro phase, there are ascorbate, glutathione and pharmaceutical industry). Dexibuprofen was other compounds imbalance between dissolved in normal saline. And given at a oxidants and antioxidants in favor of the dosage of 7,2mg/kg according to Pagets and oxidants, potentially leading to damage, is Barnes (1964) to convert the dose of human termed ‘’ Oxidants are to rat. Vitamin E (vitamin E capsule) it was formed as a normal product of aerobic supplied by Pharco Pharmaceutical CO metabolism but can be produced at elevated Alex., Egypt. Vitamin E dissolved in corn oil. rates under pathophysiological conditions. Antioxidant defense involves several 2.2 Animals strategies, both enzymatic and non- The present study was carried on 80 adult enzymatic. In addition to the , the male albino rats weighing 150-200g. nuclear and mitochondrial matrices and Animals were purchased from Laboratory

383 Shams et al., (2019) BVMJ, 36(1): 382-392

Animal Farm, Faculty of Veterinary Determination of malondialdehyde (MDA), Medicine, Zagazig University. All animals glutathione peroxidase activity (GPX), were housed in polypropylene cages with superoxide dismutase activity, catalase wood–chip bedding and were maintained on activity (CAT) according to the method 12 hr./dark schedule in a temperature and described formerly (Aebi, 1984; Nishikimi et humidity-controlled room. All animals were al., 1972; Paglia and Valentine, 1967, given access to food and water ad libitum The respectively). animals were kept under observation for two weeks before using to ensure stabilization. 2.6 Renal and hepatic histopathological evaluation 2.3 Experimental design Kidney and liver tissues were fixed in 10% A parallel study design was adapted as4 neutral buffered formalin solutions for 24 groups The 1st group (control): rats in this hours. Then tissue processing and paraffin group were not medicated and received blocks preparation were done. Masson, normal saline, the 2nd group (Vitamin E) rats trichrome and hematoxylin-eosin stains were in this group received repeated oral doses of used to evaluate fibric areas and necro vitamin E (100 mg/kg B. WT.) for successive inflammation activity (Suvarna et al., 2013). 21 days as antioxidant, once daily Rats were classified into 4 groups each contain 20 rats 2.7 Statistical analysis The 3rd group (Dexibuprofen therapeutic Statistical analyses were carried out by the dose) rats in this group received repeated oral one-way analysis of variance (ANOVA) doses of dexibuprofen (7.2 mg/kg b. wt.) for (Tamhane and Dunlop, 2000). successive twenty won days, once daily. The 4th group (Dexibuprofen and Vitamin E (Dex. + Vit. E)) rats in this group received repeated 3. RESULTS oral doses of dexibuprofen (7.2 mg/kg b. wt.) for successive 21 days plus vitamin E (100 3.1. Effects of dexibuprofen, Vitamin E and mg/kg B. WT.) once daily for 21 days. their combination on antioxidant enzymes. Effect of combination between Dexibuprofen 2.4 Preparation of serum and tissue sample and Vitamin E on Determination of MDA At the end of experiment (24 hrs. after the last level in the 1st day, there was a decrease in dose) rats were scarified and blood samples amount of MDA (15.426 ± 0.958 nmol/ml) collected in a sterile Wasserman tube without st th compared with (20.56 + 0.994 nmol/ml) for anticoagulant from 5 rats\group at the 1 , 7 , th th st dexibuprofen group. On the 7 day resulted 14 , 21 days post treatment and allowed to on a decrease in the amount of MDA (10.14 clot for 30 minutes and serum was separated ± 0.123 nmol/ml) compared with (14.01 + by centrifugation at 3000 rpm for 15 minutes 0.123 nmol/ml) compared with (14.01 ± ,and the top yellow layers of serum were 0.751nmol/ml) for dexibuprofen group .on pipette off without distributing the white the 14th day resulted in a decrease in buffy layer. Serum was stored at 20°C in Determination of MDA conc. (8.366 ± 0.389 Eppendorf tubes till the time of the work for nmol/ml) compared with (10.49 ± 0.262 determination of serum level of antioxidant nmol/ml) for the dexibuprofen group. On the enzymes The liver and the kidney of each rats st th th 21 day , there was decrease in the level of were collected at 7 and 14 days post- MDA (7.47 ± 0.068 nmol/ml) compared with treatment. They were isolated and kept in (8.10 + 0.184 nmol/ml) for dexibuprofen 10% phosphate –buffered formalin for group as shown in table (1). histopathological evaluation. Effect of combination between Dexibuprofen and Vitamin E on GPX. On the 1st day 2.5 Biochemical markers of antioxidant resulted in an increase in GPX activity activity (91.59 ± 1.37 U/L) compared with (78.45 ±

384 Vit E protection against side effects of dexibuprofen

5.02 U/L) for dexibuprofen group. On the 7th activity (18.26 ± 0.524 U/ml) compared with day there is an increase in GPX activity (15.84± 0.776 U/ml) for dexibuprofen group. (103.76 ± 2.97 U/L) compared with (87.80c ± In the 21st day resulted in an increase in 3.37 U/L) for dexibuprofen group. On the superoxide dismutase activity (21.23 ± 0.484 14th day there is an increase in GPX activity U/ml) compared with (19.16 ± 0.626 U/ml) (110.07 ± 0.587 U/L) compared with (100.30 for dexibuprofen group. ± 3.17 U/L) for dexibuprofen group. On the Effect of combination between Dexibuprofen 21st day there is an increase in GPX activity and Vitamin E on CAT. In the 1st day there (117.59 ± 2.09 U/L) compared with (110.11± was an increase catalase activity (191.85 ± 0.25 U/L) for the dexibuprofen group. 1.64 U/L) compared with (175.55± 5.12 U/L) Effect of combination between Dexibuprofen for dexibuprofen group. In the 7th day a and Vitamin E on superoxide dismutase. In significant increase in catalase activity the 1st day resulted in a highly significant (204.06 ± 4.08 U/L) compared with (186.23± increase in superoxide dismutase activity 4.17 U/L) for dexibuprofen group. In the 14th (9.33 ± 0.674 U/ml) compared with (6.39 ± day resulted in an increase in catalase activity 0.472 U/ml) for dexibuprofen group. In the (214.07 ± 3.04 U/L) compared with (197.26± 7th day resulted in an increase in superoxide 4.44 U/L) for dexibuprofen group. In the 21st dismutase activity (15.00 ± 0.663 U/ml) day resulted in an increase in catalase activity compared with (9.92 ± 0.569 U/ml) for (227.39 ± 2.52 U/L) compared with (205.59 dexibuprofen group. In the 14th day resulted ± 3.10 U/L) for dexibuprofen group in an increase in superoxide dismutase

Table (1): The effect of Vitamin E (100 mg/kg, P.O. once daily), dexibuprofen (7.2 mg/kg, P.O. once daily), and their combination for 21 consecutive days on serum antioxidant markers activities of rats at 1st, 7th, 14th and 21st days of drugs withdrawal CAT SOD GPX MDA Time Groups (µ/L) (µ/ml) (µ/L) (nmol/ml) Control 241.39a ±3.49 22.54 a ± 1.69 112.93 a ± 1.92 7.04 c ± 0.141 Vitamin E 247.28 a± 5.12 23.90 a ± 2.05 111.40 a ± 3.30 6.75 c ± 0.506 1st Day Dexibuprofen 175.55 c± 2.96 6.39 b ± 0.472 78.45 c ± 5.02 20.56 a ± 0.994 Dex. + Vit. E: 191.85 b ± 1.64 9.33 b ± 0.674 91.59 b ± 1.37 15.42 b ± 0.958 Control 233.77 a ± 2.47 20.91 a ± 1.19 116.04 a ± 3.99 7.11 c ± 0.522 Vitamin E 235.01 a ± 4.91 22.58 a ± 0.854 113.51 a ± 1.457 7.52 c ± 0.343 7th Day Dexibuprofen 186.23 c ± 4.17 9.92 c ± 0.569 87.80 c ± 3.37 14.01 a ± 0.751 Dex. + Vit. E: 204.06 b ± 4.08 15.00 b ± 0.663 103.76 b ± 2.97 10.14 b ± 0.123 Control 228.78 b ± 8.22 20.04 a ± 0.626 116.04 a ± 3.99 7.05 b ± 0.533 Vitamin E 224.14 b ± 8.02 21.59 a ± 0.994 111.25 a ± 5.83 7.64 b ± 0.142 14th Day Dexibuprofen 197.26 a ± 4.44 15.84 b ± 0.776 100.30 b ± 3.17 10.49 a ± 0.262 Dex. + Vit. E: 214.07 ab ± 3.04 18.26 ab ± 0.524 110.07 a ± 0.587 8.36 b ± 0.389 Control 229.669 a ± 5.25 21.58 a ± 0.928 118.48 a ± 2.75 7.43a ± 0.076 Vitamin E 227.58 a ± 5.06 21.78 a ± 0.401 114.60 a ± 4.82 7.66 a ± 0.163 21st Day Dexibuprofen 205.59 b ± 3.10 19.16 a ± 0.626 110.11 a ± 3.25 8.10 a ± 0.184 Dex. + Vit. E: 227.39 a ± 2.52 21.23 a ± 0.484 117.59 a ± 2.09 7.47 a ± 0.068 Dex. + Vit. E: Dexibuprofen plus Vitamin E. (n = 5, mean ± SE). Means with different superscripts within the same column per one time point were significantly different at P< 0.05.

3.2. Histopathological Changes Liver section revealed moderate congestion 3.2.1. Dexibuprofen 7th day of hepatic blood vessels and sinusoids, portal

385 Shams et al., (2019) BVMJ, 36(1): 382-392

(mild) biliary proliferation and round cells cortex and medulla were cystically dilated aggregation, focal disorganization of some sometime with hyaline casts inside some of hepatocytes with degenerative changes and them (Figure 2). early necrotic changes. In some sections, the portal triads showed moderate aggregation of 3.2.2. Dexibuprofen 14th day round cells and eosinophil's The same cells 3.2.2.1. Liver: Section showed moderate were also interstitially aggregated portal congestion of hepatic blood vessels, portal edema was also seen (Figure 1). (mild) biliary proliferation with fibroplasia The renal blood vessels were moderately and round cells infiltration, focal interstitial congested with a wide spread perivascular aggregation of round cells and focal edema The renal pelvis sections revealed centrilobular and periportal degenerative congested blood vessels, edema, changes of the hepatocytes mainly hydropic degenerative changes in the surrounding degeneration and fatty change beside some tubules and focal sloughing of the epithelium apoptotic changes in a few hepatocytes characteristic multifocal myxoid changes in the renal stroma at different location with 3.2.2.2. Kidney: Sections showed presence of bluish myxoid secretory characteristic congestion of the renal blood materials were seen The glomeruli were vessels and perivascular edema. Some of the sporadically shrinked or lobulated, renal tubules were degenerated (cloudy sometimes with massive periglomerular swelling and hydropic) with early necrotic round cells aggregates and epithelial crescent changes. Moderate number of the renal formation. Multifocal interstitial round cells tubules particularly in the medulla were aggregation were seen. Most of the renal cystically dilated. A few number of the tubules showed degenerative changes mainly glomeruli were shrinked or lobulated in hydropic, sometime with early necrotic addition to periglomerular round cells changes. Large number of the tubules in both infiltration (Figure 3).

Figure (1): Photomicrograph of Liver showing moderate congestion of hepatic blood vessels (stars), portal mild biliary proliferation (arrow) and round cells aggregation (curved arrow), focal disorganization of some hepatocytes (arrowhead). In some cases, the portal triads showing moderate aggregation of round cells (curved arrow) and eosinophil's (closed arrow). H &E X 100 (A, C ), 400 (B, D)

386 Vit E protection against side effects of dexibuprofen

Figure (2): Photomicrograph of kidney showing congestion of renal blood vessels with perivascular edema (yellow star), shrinked or lobulated glomeruli (yellow arrows), with massive periglomerular round cells aggregates (blue star) and epithelial crescent formation (red star). Multifocal interstitial round cells aggregations (green star) beside degenerative changes mainly hydropic (red curved arrow) in some renal tubular epithelium and cystically dilated renal tubules(red arrow) H & E X 100 (G, J), 400 (E, F, H, I)

3.2.3. Dexi-ibuprofen + Vitamin E 7thday tubules in both cortex and medulla were 3.2.3.1. Liver: Sections showed normal cystically dilated. hepatic parenchyma with residual portal fibrosis and biliary hyperplasia. Minute 3.2.4. Dexibuprofen + Vitamin E 14thday interstitial leucocytic aggregation and mild 3.2.4.1. Liver: Sections from liver showed focal centrilobular degenerative changes apparently normal hepatic parenchyma with mainly hydropic degeneration and fatty residual fibrosis in the portal area, mild change were seen. The Kupffer cells were biliary proliferation and scanty minute prominently enlarged. The hepatic blood interstitial leucocytic aggregations. The vessels and sinusoids were mildly congested fibrotic areas and the previously degenerated (Figure 4). or necrotic hepatocytes were ameliorated and appeared partially surrounded by 3.2.3.2. Kidney: Sections revealed apparently regenerating hepatocytes. normal nephron units in most parts of the kidney with preserved renal papillae and 3.2.4.2. Kidney: Sections Showed apparently renal pelvis, the latter in some cases revealed normal nephron units, renal papillae and mildly edematous stroma with healthy renal pelvis. Some of the cortical tubules normal lining epithelium. Some of the renal were mildly dilated.

387 Shams et al., (2019) BVMJ, 36(1): 382-392

Figure (3): Photomicrograph of kidney showing congestion of the renal blood vessels (star) with perivascular edema (curved arrow) beside degenerative and necrotic changes in some renal tubular epithelium (arrow), cystically dilated medullary renal tubules (arrow heads) in addition to periglomerular round cells infiltration (red star) H & E X 100 (A, D), 400 (B, C)

Figure (4): Photomicrograph of Liver showing congestion of hepatic blood vessels (curved arrow), residual portal fibrosis (star) and biliary hyperplasia (arrow heads), minute interstitial leukocytic aggregation (arrow) and mild focal centrilobular degenerative changes (circle) mainly hydropic (closed arrow) and fatty change (curved yellow arrow) with hypertrophied Kupffer cells (red arrow) H & E X 100 (A, C), 400 (B, D)

4. DISCUSION Imbalance between oxidants and antioxidants in favor of the oxidants, potentially leading to

388 Vit E protection against side effects of dexibuprofen damage ,is termed (oxidative stress) (Sies, E. The group of eight compounds that include 1997). The oxidative stress is thought to four tocopherols and four tocotrienols. All contribute to the initiation and progression of eight feature achromane double ring, with a atherosclerosis. Free radicals catalyze lipid hydroxyl group that can donate a hydrogen peroxidation so can cause damage to cellular atom to reduce free radicals, and a and intracellular structures, so administration hydrophobic side chain which allow of anti-oxidants prevent oxidation of fatty penetration into biological membranes. The acid in the cell (Droke and Loerch, 1989). antioxidant activity of vitamin E during the Vitamin E act as a peroxyl radical scavenger, peroxidation of unsaturated lipids has been disabling the production of damaging free reviewed based on its reaction products. radicals in tissues, by reacting with them to Vitamin E used in a dose (100 mg/kg, P.O. form a tocopherol radical, which will then be once daily) for 21 days to clarify the hepatic reduced by a hydrogen donor (such as nephroprotective effects on rats. We found a vitamin C) and thus return to its reduced state significant changes in antioxidants markers (Traber et al., 2011) Vitamin E is thought to (SOD, CAT, GPX and MDA levels. have a role in preventing atherosclerosis by Histopathological results in liver at 7th day for inhibiting the oxidation of low–density dexibuprofen showed moderate congestion lipoprotein (Fuller et al., 1998). of hepatic blood vessels and sinusoids, mild Vitamin E is a potent naturally occurring biliary proliferation and round cells lipid soluble antioxidant possesses the ability aggregation. On the 14th day showed to directly quench free radicals and function moderate congestion of hepatic blood as a membrane stabilizer. It protects critical vessels, mild biliary proliferation with cellular structures against the damage from fibroplasias and round cells infiltration. On oxygen free radicals and reactive products of 7th day for Dexibuprofen + Vitamin E showed lipid peroxidation (Goldfarb et al., 1996). normal hepatic parenchyma with residual Superoxide dismutase as an that portal fibrosis and biliary hyperplasia Kidney alternately catalyzes the dismutation of the for Dexibuprofen only on 7th day showed the superoxide radical into either ordinary renal pelvis revealed congested blood molecular oxygen or was vessels, edema, degenerative changes in the defined by (Hayyan et al., 2016). Catalase is surrounding tubules and focal sloughing of a common enzyme found in nearly all living the epithelium. On 14th day showed organisms exposed to oxygen (such as characteristic congestion of the renal blood ,plants, and animals). It catalyzes the vessels and perivascular edema. In the 7th day decomposition of hydrogen peroxide to water for Dexibuprofen + Vitamin E the kidney and oxygen (Chelikani et al., 2004). Vitamin sections showed revealed apparently normal E can protect against acute Liver necrosis nephron units in most parts of kidney with induced by carbon tetrachloride (Maurizio et preserved renal papillae and renal pelvis. On al., 1992). Vitamin E is known to act by the 14th day kidney sections showed breaking the antioxidant chain that prevent apparently normal nephron units, renal ROS–produced cell membrane damage papillae and renal pelvis. (Factor et al., 2000). Vitamin E is well accepted as nature's most In the present study it was observed that effective lipid–soluble, chain-breaking vitamin E administration to rats produced an antioxidant, protecting cell membrane from appreciable improvement in the peroxidative damage (Kaehler et al., 2003). histopathological changes that occur in Antioxidant Vitamin E retard hepatic fibrosis kidney and liver which associated with in biliary obstructed rats (Parola et al., 1992). administration of Dexibuprofen, also Vitamin E is known to act by breaking the Vitamin E normalized levels of MDA, antioxidant chain that prevent ROS-produced catalase, glutathione peroxidase and cell membrane. It decreases lipid superoxide dismutase The possible pathway peroxidation and protects against liver injury. can be explained through structure of vitamin It decrease liver fibrosis, tumor necrosis

389 Shams et al., (2019) BVMJ, 36(1): 382-392 factors, inflammation and hepatic porphyrin Molecular Dynamic Simulation (Bradford et al., 2003). The increased level of Studies of Dexibuprofen-Antioxidant antioxidants enzymes CAT, GPX, and Mutual Prodrugs. Int. J. Mol. Sci.; 21; superoxide dismutase resulted from 17 (12). administration of vitamin E might Beytut E, Erisir M, Ahsakal M. (2003): normalized the lipid peroxidation reaction Effects of additional, Vitamin E and and related biochemical changes which in selenium supply on antioxidative turn protects the cells from the increase risk defense mechanisms in the kidney of of peroxidative damage as result of rats treated with high dose of administration of cytotoxic drugs was glucocorticoid. Cell Biochem. Fun.; reported by (Beytut et al., 2003). 22: 59 – 65. Dexibuprofen can produce several adverse Bradford A, Atkinson J, Fuller N, and Rand effects as oxidative damage, it produce a RP. (2003): The effect of vitamin E on significant lipid peroxidation (Khan et al., the structure membrane lipid 2014). assemblies .J. Lipid Res.; 44: 1940 – Oxygen free radicals probably derived via 1945. action of , the decrease in Burak Cimen MY, Ozlem B, G, Eskandari, super oxide dismutase activity and depletion Gunsahsahin, Canan, Erdogan, Ugar of mucosal glutathione contribute to the Atik. (2003): Drug and Chemical pathogenesis of dexibuprofen induced Toxicology; 26 (3): 169 - 176. ulceration (Burak Cimen et al., 2003). Chandrasekaran, K. (2010): S + ibuprofen Oxygen free radicals probably derived via the (dexibuprofen): the superior non- action of xanthine oxidase during use of non- steroidal anti-inflammatory agents for steroidal anti-inflammatory drug that lead to development of pharmaceuticals decrease in superoxide dismutase activity and International Journal of Current depletion of mucosal glutathione (Ivillegas et Pharmaceutical Research 2 (3). al., 2000). Chelikani P, Fita I and , Loewen PC. (2004): Diversity of structures and properties among . Cellular and 5. CONCULOISONS Molecular Life Sciences; 61 (2): 192 – 208. It could be concluded that Dexibuprofen has De La Cruz JP, Reyes JJ, Ruiz-Moreno MI, hepatic and renal disturbance in rats; Vit. E Lopez-Villodres JA, Jebrouni N, has a protective effect against renal and Gonzalez-Correa J. (2010): hepatic disturbance, which may attribute to Differences in the In Vitro Antiplatelet decrease the harmful effects of Dexibuprofen Effect of Dexibuprofen, Ibuprofen, and by inhibiting free radical formation and by in Human Blood. restoration of the antioxidant systems. The Cardiovascular Anesthesiology: combination of vitamin E and Dexibuprofen Research Reports; 111 (6): 1341 – showed better results than Dexibuprofen 1346. alone. Droke E, Loerch S. (1989): Effect of parental selenium and vitamin E on performance health and humoral 6. REFERANCES response of stress new to feed lot environment. J. Anim. Sci.; 6150 -159. Aebi H. (1984): Colourimetrical Factor V, Laskowska D, Jensen M, Woitach determination of Catalase activity. J, Popescu N, Thorgeirsson S, (2000): Methods Enzymol, 105: 121 – 126. Vitamin E reduces chromosomal Ashraf Z, A, Rasool R, H M, Ahsan H, Afzal damage and inhibit hepatic tumor S, Afzal K, C H ,and Kim SJ. (2016): formation in a transgenic mouse Synthesis, Bio evaluation and

390 Vit E protection against side effects of dexibuprofen

model. Med Sci. 2000; 97: 2196 – Mcginness JE, Proctor PH, Demopoulos HB, 2201. Hokanson JA, Kirkpatrick DS, (1978): Fuller CJ, Huet BA, Jilal I. (1998): Effects of Amelioration of cis-platinum increasing doses of alpha –tocopherol nephrotoxicity by orgotein (superoxide in providing protection of low- density dismutase)". Physiological Chemistry lipoprotein from oxidation Am J. and Physics.; 10 (3): 267 – 77. Cardiol.; 81 (2): 231 – 3. Nishikimi M, Roa NA, Yogik. (1972): Goldfarb AH, Mclntosh MK, Boyer BT. Measurement of superoxide dismutase. (1996): Vitamin E attenuates Bioch. Btoph. Res. Commun.; 46: 849 myocardial oxidative stress induced by – 85. DHEA in rested and exercised rats. J. Paget GE, Barnes JM. (1964): Evaluation of Appl. Physiol.; 80: 486 – 490. drug activities: pharmacometric, Gonzalez C, Jose A, Arrebola Maria, Laurence and Bacharach, Vol1, Monsalud MD, Martin-Salido E, Academic press, New York. Pp 133 - Munoz-Marin, Javier MD, Cuesta FS, 166. De La Cruz JP. (2007): Effects of Paglia DE, Valentine WN. (1967): Studies on Dexibuprofen on Platelet Function in quantitative and qualitative Humans: Comparison with Low-dose characterization of erythrocyte Aspirin. Anesthesiology; 106 (2): 218 glutathione peroxidase. J. Lab. Clin. – 225. Med.; 70 (1): 158 – 169. Hardikar MS (2008): Chiral non-steroidal Parola M, Leonarduzzi G, Biasi F, Albano E, anti-inflammatory drugs--a review. J Biocca ME, Poli GA, Dianzani MU. Indian Med Assoc. 106 (9): 615–8, (1992): Vitamin E dietary 622, 624. supplementation protects against Hayyan M, Hashim MA, Al Nashef IM. carbon tetrachloride-induced chronic (2016): Superoxide : Generation liver damage and cirrhosis. and Chemical Implications. Chem. Hepatology; 16: 1014 – 1021. Rev.; 116 (5): 3029 – 3085. Seguí J, Gironella M, Sans M, Granell S, Gil Ivillegas M, Martin C, Lacasa V, Motilva C, F, Gimeno M, Coronel P, Piqué Jm, Alorcon de la Lastra. (2000): Effects of Panés J. (2004): Superoxide dismutase on oxygen radical ameliorates TNBS-induced colitis by generation in rat gastric mucosa reducing oxidative stress, adhesion inflammation. Research; 49 (7): 361 - molecule expression, and leukocyte 366. recruitment into the inflamed Kaehler ST, Phleps W, Hesse E. (2003): intestine. J Leukoc Biol.;76(3):537-44. Dexibuprofen: pharmacology, Sies H. (1997): Oxidative stress: oxidants and therapeutic uses and safety. antioxidants. experimental physiology. Inflammopharmacology; 11 (4-5-6): J.; 82 (2): 291 – 295. 371 - 383 Suvarna Kim S, Christopher Layton and Khan, AblMehry, Rampal, Satyavan. (2014): Bancroft John D. (2013): Bancroft "s Journal of American Association for Theory and Practice of laboratory Animal Science, 53: 399 - Histopathological Techniques, 7th Ed. 405. Traber MG, Stevens JF, Stevens. Maurizio P, Gabriella L, Fiorella B, (2011): Free Radical Biology and Emanuele A, Maria E, Giuseppe P, Medicine – Vitamins C and E: Mario P. (1992): Vitamin E dietary Beneficial effects from a mechanistic supplementation protects against perspective. Free Radical Biology and carbon tetrachloride –induced chronic Medicine; 51 (5): 1000 – 13. liver damage and cirrhosis. Van Durme CM, Wechalekar Hepatology.; (16): 4 – 6. MD, Buchbinder R, Schlesinger N, Van Der Heijde D, Landewé RB.

391 Shams et al., (2019) BVMJ, 36(1): 382-392

(2014): Non-steroidal anti- compared with ibuprofen in febrile inflammatory drugs for acute gout. children caused by upper respiratory Cochrane Database Syst Rev.; 16 (9): tract infection. British Journal of CD010120. Clinical Pharmacology; 66 (6): 854 – Yoon JS, Oh JW, Lee KY, Lee HS, Koh YY, 860. Kim JT, Kang JH, Lee J.S. (2008): The effects and safety of dexibuprofen

392