BENHA VETERINARY MEDICAL JOURNAL, VOL. 36, NO. 1:382-392, March, 2019 Side effects of dexibuprofen 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 antioxidant 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 enzymes Glutathione peroxidase, dismutase superoxide dismutase(SOD)&catalase (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 ibuprofen. Most aspirin 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 celecoxib in treatment of osteoarthritis. diclofenac, naproxen 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% peroxidases (Sies., 1997). Defenses against human plasma and thus release free free radical 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 glutathione peroxidase selenium), catalase is more significant than the parent iron, and superoxide dismutase copper zinc dexibuprofen exhibited that synthesized manganese and proteins such as prodrugs formed stable complexes with the ceruloplasmin copper superoxide dismutase COX-2 protein 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 colitis 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- oxygen 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 antioxidants 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 propionic acid derivative 2004). dexibuprofen was the most potent antiplatelet Dexibuprofen was approved that it had drug, and its pharmacodynamics profile is nephrotoxicity-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 ‘oxidative stress’ 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 cytosol, 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.