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Effect of Different Non-Steroidal Anti-Inflammatory Drugs, Aspirin

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Effect of Different Non-Steroidal Anti-Inflammatory Drugs, Aspirin Nutr Hosp. 2008;23(4):326-331 ISSN 0212-1611 • CODEN NUHOEQ S.V.R. 318 Original Effect of different non-steroidal anti-inflammatory drugs, aspirin, nimesulide and celecoxib on the disaccharide hydrolases and histoarchitecture of the rat intestinal brush border membrane N. Sood, N. Kaushal and S. N. Sanyal Department of Biophysics. Panjab University. Chandigarth-160014. India. Abstract EFECTO DE DIFERENTES FÁRMACOS ANTI-INFLAMATORIOS NO ESTEROIDEOS, Non-steroidal anti-inflammatory drugs (NSAIDs) are ASPIRINA, NIMESULIDA Y CELECOXIB, known to cause gastrointestinal damage. New anti- SOBRE LAS HIDROLASAS DE DISACÁRIDO inflammatory drugs have been developed in an attemptto Y LA HISTO-ARQUITECTURA DE LA improve their gastrointestinal side effect profile which MEMBRANA DEL BORDE EN CEPILLO however failed to do so. Therefore, the objective of the INTESTINAL DE LA RATA present studywas to compare the effect of three different NSAIDs, aspirin, nimesulide and celecoxib on the intesti- nal brush border membrane (BBM) marker enzymes and Resumen correlate these alterations to the histoarchtecture of the Es sabido que los fármacos anti-inflamatorios no esteroi- intestine using electron microscopic study. Female Wis- deos (AINE) causan daño gastrointestinal. Los nuevos tar rats were divided into four different groups viz: fármacos anti-inflamatorios se han desarrollado con la Group I (Control), Group II (aspirin treated), Group III esperanza de mejorar su perfil de efectos adversos gastroin- (nimesulide treated) and Group IV (celecoxib treated). testinales, lo que sin embargo no se ha logrado. Por lo tanto, The Group II, III and IV received the corresponding el objetivo de este estudio fue comparar el efecto de tres drugs dissolved in water orally at a dose of 40 mg/kg body AINE distintos, aspirina, nimesulida y celecoxib, sobre las weight, while the control received the vehicle only. After enzimas marcadoras de la membrana del borde en cepillo 28 days, all the treatment groups demonstrated signifi- (MBC), y correlacionar estas alteraciones con la histo-arqui- cant alterations in the activities of intestinal disaccharide tectura del intestino utilizando la microscopia electrónica. Se hydrolases and alkaline phosphatase in both the crude dividió a ratas hembra Wistar en cuatro grupos distintos: homogenates and BBM preparations as well. The histo- Grupo I (Control), Grupo II (tratado con aspirina), Grupo pathological observations also showed considerable chan- III (tratado con nimesulida) y Grupo IV (tratado con celeco- ges in the intestinal mucosa. It was suggested that xib). Los grupos II, III y IV recibieron por vía oral el fármaco NSAIDs like aspirin, nimesulide and celecoxib pose intes- correspondiente disuelto en agua, a una dosis de 40 mg/kg de tinal side effects due to initial changes in the enzymatic peso corporal, mientras que el grupo control sólo recibió el composition of the intestinal apical membranes. It was vehículo. Tras 28 días, todos los grupos de tratamiento mos- further concluded that newly discovered NSAIDs such as traron alteraciones significativas en las actividades de las celecoxib has better safety profiles but studies are still disacaridasas intestinales y la fosfatasa alcalina tanto en las required to comment decisively on the suitability of preparaciones homogéneas crudas como en las preparacio- various NSAIDs depending upon their cyclooxygenase nes de MBC. Las observaciones histopatológicas también enzyme specificity. mostraron cambios considerables en la mucosa intestinal. Se (Nutr Hosp. 2008;23:326-331) sugería que los AINE como la aspirina, nimesulida y celeco- Key words: Non-steroidal anti-inflammatory drugs. Mem- xib acarrean efectos adversos debidos a cambios intestinales brane disaccharidases. Intestinal brush border membrane. en la composición enzimática de las membranas intestinales apicales. Se concluye, además, que los nuevos AINE como el celecoxib poseen mejores perfiles de seguridad pero aún son necesarios estudios para poder opinar de forma decisiva Correspondence: S. N. Sanyal. sobre la idoneidad de los diversos AINE dependiendo de su Department of Biophysics. especificidad por la enzima ciclooxigenasa. Panjab University. Nutr Hosp. Chandigarh-160014, India. ( 2008;23:326-331) E-mail: [email protected] Palabras clave: Fármacos anti-inflamatorios no esteroi- Recibido: 5-VII-2007. deos. Disacaridasas de membrana. Membrana del borde en Aceptado: 6-IX-2007. cepillo intestinal. 326 Introduction Materials and methods Non-steroidal anti inflammatory drugs (NSAIDs) - Animals: The female Wistar rats (175-200 g) were the most tolerated and widely prescribed drugs in the procured from the Central Animal House of the Panjab treatment of inflammation and pain 33 act by inhibition University. The principles of animal care as laid down of the enzyme cyclooxygenase (Cox). But, these broad by the National Institute of Health (NIH publication ranges of beneficial effects attributed to them come at no. 23-85, revised in 1985) were strictly followed in the the cost of various side effects such as ulcers and other maintenance of the animals. Animals were acclimati- serious gastrointestinal (GI) complications. 23, 25 Due to zed for a period of one week prior to any treatment. the use of NSAIDs at a large scale, these GI toxicities They were fed with standard pellet diet and water ad account for the most prevalent drug-associated health libitum. This diet constitutes crude protein 24%, other risks. These side effects are due to the non-specific extract 4%, crude fibre 4%, ash 8%, calcium 1%, inhibition of the two isoforms Cox-1 and Cox-2 that are phosphorus 6% and nitrogen-free extract 50%, vitamin the constitutive and inducible forms of the enzyme, B12 , thiamine, riboflavin, pentotothenic acid, niacin, prostaglandin synthase. Cox-2 is responsible for pyridoxine, choline chloride and folic acid. The mine- inflammation whereas Cox-1 is required for normal ral content of this diet was determined earlier by neu- homeostasis. 7 Since the discovery of these two iso- tron activation method 19 and it was found not to be defi- enzymes and their characterization established search cient in any mineral. for new NSAIDs with varying Cox-2 specific inhibi- The animals were randomly segregated into four tion and thus different levels of GI tolerability have groups. Group I served as control, Group II was admi- gained pace. nistered aspirin (40 mg/kg) 24 orally, Group III nimesu- Selective Cox-2 inhibitors (such as celecoxib) exhi- lide (40 mg/kg) 27 and Group IV celecoxib (40 mg/kg) 27 bit 100-1000 fold selectivity for Cox-2 with minimum orally for 28 days. The drugs were dissolved in water side effects as compared to the other relatively classical and the controls were administered equal amount of it NSAIDs such as nimesulide and aspirin. 10, 12 Numerous as vehicle. The dosage was chosen so as to compare the reports suggest that both aspirin and nimesulide pose toxic effects of the equal but clinically safer concentra- dose-related GI toxicities. 21, 22 Although celecoxib a tions of these drugs. In this regard, it is important to recent and widely prescribed NSAID is considered note that NSAID-induced gastric mucosal lesions are safer, it is also found to be associated with a number of time and dose dependent. 9 On the 29 th day after over- side effects such as gastroenteritis, hemorrhoids, dysp- night fasting, animals were sacrificed under an over- hagia etc. 20, 28 dose of ether anaesthesia. In order to avoid diurnal Therefore, studies are still warranted to evaluate the variation in the different parameters, animals were safety profile of various NSAIDs belonging to diffe- sacrificed uniformly around 8.00 am throughout the rent classes, so as to comment decisively on the desira- study. Intestine was removed, divided into duodenum, bility of these drugs which can help in better manage- jejunum, ileum and colon, washed with pre-cooled ment of the patients suffering from inflammatory physiological saline, weighed separately and a 10% conditions. homogenate of different segments prepared. A small It has been hypothesized that these drugs may aliquot used for enzyme estimations and rest is used for cause intestinal toxicity by initial local alterations in the preparation of BBM as described. the enzymatic composition of brush border mem- Preparation of Intestinal Brush Border Membrane: brane (BBM) lining the GI tract upto different levels. Intestinal BBM was isolated by the method of Schmitz Membrane bound proteins are important constituents et al. 26 A known weight of each portion of the intestine of the BBM, as they contain disaccharidases viz: was minced and 10% (w/v) homogenate was prepared sucrase, lactase and maltase and also binds the alka- in chilled 1mM Tris-50 mM mannitol buffer (pH-7.4) line phosphatase, dipeptidases, enterokinases etc. 13, 14 in a motor driven homogenizer at 4 0C. The homoge- Moreover, it also contains the transport proteins as nate was filtered through two layers of cheese cloth. To + + well as the Na /K ATPase responsible for maintai- the filtrate, anhydrous CaCl 2 was added with constant ning Na + ion gradient required for active inward trans- stirring on a magnetic stirrer to a final concentration of port of products of digestion such as glucose and 10 mM and left for 10-15 minutes in cold. Later it was amino acids. 6, 30 centrifuged at 2,000 × g for 10 minutes at 4 0C. The The present study was designed to compare the supernatant was recentrifuged at 42,000 xg for 20 effects of three different NSAIDs viz: aspirin, nimesu- minutes. The pellet obtained was suspended in 20 vol. lide and celecoxib (which represent different classes of of 50 mM sodium maleate buffer (pH 6.5-6.8) and Cox inhibitors) on the enzyme composition (intestinal recentrifuged at 42,000xg for 20 minutes. The final BBM associated disaccharidases and alkaline phosp- pellet was suspended in 50 mM sodium maleate buffer hatase) of the brush border membranes. The study was (pH 6.5-6.8) containing 0.02% sodium azide.
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