ANTI-INFLAMMATORY EFFECT OF SIMVASTATIN-ASPIRIN COMBINATION
Abstract
The aim of this study is to investigate the anti-inflammatory effects of simvastatin alone and in combination with aspirin, the most widely used analgesic, antipyretic and anti-inflammatory agent, and to evaluate the effect of using them in combination which may produce synergistic effect and lower the dose required for each agent. 72 Male Wistar albino rats suffering from air pouch granuloma were used. They were divided into 12 groups each comprising 6 rats, they received either simvastatin (20 mg/kg/day) or aspirin (25 mg/kg/day) or combined therapy (simvastatin & aspirin) for either 3 or 6 executive days. The control groups received the solvents only for the same periods. Biochemical markers of inflammation as serum tumor necrosis factor-α, interleukin-6 and interleukin-4 were measured by an Elisa method. Antioxidant activity was calorimetrically assessed by measuring serum nitric oxide concentration. Results indicated that treatment with simvastatin alone had no significant difference from treatment with aspirin alone which give solid ground for the predicted anti-inflammatory effects of simvastatin. Furthermore, our study demonstrated that treatment with the combined therapy reduced the extent of inflammation as compared to treatment with simvastatin alone or aspirin alone indicating that aspirin-simvastatin combination represents a synergistic combination concerning the immune response to the inflammatory challenge. The combination treatment with agents that inhibit different aspects of the signal transduction pathways will be transformational and have better efficacy with fewer side effects.
Keywords:
Simvastatin; tumor necrosis factor-α (TNF-α); interleukin-6 (IL-6); interleukin-4 (IL-4).DOI
https://doi.org/10.25004/IJPSDR.2011.030204References
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14. Girgis RE, Li D, Zhan X, Garcia JG, Tuder RM, Hassoun PM, Johns RA. Attenuation of Chronic Hypoxic Pulmonary Hypertension by Simvastatin. Am J Physiol Heart Circ Physiol. 2003; 285:H938-H45.
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31. Polte T, Schroder H. Cyclic AMP Mediates Endothelial Protection by Nitric Oxide. Biochem Biophys Res Commun. 1998; 251: 460-465.
32. Marx N, Duez H, Fruchart J, Staels B. Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells. Circ Res. 2004; 94: 1168-1178.
33. Yoo CG, Lee S, Lee C, Kim YW, Han SK, Shim YS. Effect of Acetylsalicylic Acid on Endogenous IkB Kinase Activity in Lung Epithelial Cells. Am J Physiol Lung Cell Mol Physiol. 2001; 280: L3-9.
34. Paul WE. Interleukin 4/B Cell Stimulatory Factor 1: One Lymphokine, Many Functions. FASEB J. 1987; 1: 456-1461.
35. Aktas O, Waiczies S, Smorodchenko A, Dorr J, Seeger B, Prozorovski T, Sallach S, Endres M, Brocke S, Nitsch R, Zipp F. Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells Through Atorvastatin. J Exp Med. 2003; 197: 725-733.
36. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchel DJ, Sobel RA, Steinman L, Zamil SS. The HMG-CoA Reductase Inhibitor, Atorvastatin, Promotes a Th2 Bias and Reverses Paralysis in Central Nervous System Autoimmune Disease. Nature 2002; 420: 78-84.
37. Saleem S, Dai Z, Coelho SN, Konieczny BT, Assmann KJ, Baddoura FK, Lakkis FG. IL-4 is an Endogenous Inhibitor of Neutrophil Influx and Subsequent Pathology in Acute Antibody-Mediated Inflammation. J Immunol. 1998; 160: 979-984.
2. Funk CD. Prostaglandins and Leukotrienes: Advances in Eicosanoid Biology. Science 2001; 294:1871-1875.
3. D’Acquisto F, May MJ, Ghosh S. Inhibition of Nuclear Factor kappa B (NF-B): An Emerging Theme in Anti-inflammatory Therapies. Mol Interven. 2002; 2:22-35.
4. Liao JK, Laufs U. Pleiotropic Effects of Statins. Annu Rev Pharmacol Toxicol. 2005; 45: 89-118.
5. Evans M., Roberts A, Davies S, Rees A. Medical Lipid-Regulating Therapy: Current Evidence, Ongoing Trials and Future Developments. Drugs. 2004; 64:1181-1196.
6. Wang CY, Liu P, Liao JK. Pleiotropic Effects of Statin Therapy: Molecular Mechanisms and Clinical Results. Trends Mol Med. 2008; 14:37-44.
7. McCarey DW, McInnes IB, Madhok R. Hampson R, Scherbakova O, Ford I, Capell HA, Sattar N. Trial of Atorvastatin in Rheumatoid arthritis (TARA): Double-Blind, Randomized Placebo-Controlled Trial. Lancet 2004; 363:2015-2021.
8. Vane JR, Botting RM. The Mechanism of Action of Aspirin. Thromb Res. 2003; 110:255-258.
9. Turnbull CM, Marcarino P, Sheldrake TA, Lazzarato L, Cena C, Fruttero R, Gasco A, Fox S, Megson IL, Rossi AG. A Novel Hybrid Aspirin-NO-Releasing Compound Inhibits TNF-Alpha Release from LPS-Activated Human Monocytes and Macrophages. J Inflamm. 2008; 5:12.
10. Mitchell JA, Warner TD. Cyclo-oxygenase-2 Pharmacology, Physiology, Biochemistry and Relevance to NSAID Therapy. Br J Pharmacol. 1999; 128:1121-1132.
11. Sedgwick AD, Sin YM, Edwards JC, Willoughby DA. Increased Inflammatory Reactivity in Newly Formed Lining Tissue. J Pathol. 1983; 141:483-495.
12. Diomede L, Abani D, Sottocorno M, Donati MB, Bianchi M, Fruscella P, Salmona M. In vivo Anti-inflammatory Effect of Statins is Mediated by Nonsterol Mevalonate Products. Arterioscler Thromb Vasc Biol. 2001; 21:1327-1332.
13. Conforti A, Bellavite P, Bertani S, Chiarotti F, Menniti-Ippolito F, Raschetti R. Rat Models of Acute Inflammation: A Randomized Controlled Study on the Effects of Homeopathic Remedies. BMC Complement Altern Med. 2007; 7:1-10.
14. Girgis RE, Li D, Zhan X, Garcia JG, Tuder RM, Hassoun PM, Johns RA. Attenuation of Chronic Hypoxic Pulmonary Hypertension by Simvastatin. Am J Physiol Heart Circ Physiol. 2003; 285:H938-H45.
15. Endres M, Laufs U, Huang Z, Nakamura T, Huang P, Moskowitz MA, Liao JK. Stroke Protection by 3-Hydroxy-3-methylglutaryl (HMG)-CoA Reductase Inhibitors Mediated by Endothelial Nitric Oxide Synthase. Proc Nat Accad Sci. 1998; 95:8880-8885.
16. Shinmura K, Kodani E, Xuan Y, Buddhadeb D, Tang X, Bolli R. Effect of Aspirin on Late Preconditioning Against Myocardial Stunning in Conscious Rabbits. J Am Coll Cardiol. 2003; 41:1183-1194.
17. Zheng L, Howell SJ, Hatala DA, Huang K, Kern TS. Salicylate-Based Anti-inflammatory Drugs Inhibit the Early Lesion of Diabetic Retinopathy. Diabetes 2007; 56:337-345.
18. Montgomery HC, Dymock JF. The Determination of Nitrite in Water. Analyst 1961; 86:414-416.
19. Beutler B, Cerami A. Cachectin (Tumor Necrosis Factor): A Macrophage Hormone Governing Cellular Metabolism and Inflammatory Response. Endocr Rev 1988; 9:57-66.
20. Cerdan, C, Martin Y, Brailly H, Courcoul M, Flavetta S, Costello R, Mawas C, Birg F, Olive D. IL-1 Alpha is Produced by T Lymphocytes Activated via the CD2 Plus CD28 Pathways. J Immunol. 1991; 146:560-564.
21. Cayphas S, Van Damme J, Vink A, Simpson RJ, Billiau A, Van Snick J. Identification of an Interleukin HPI-Like Plasmacytoma Growth Factor Produced by L Cells in Response to Viral Infection. J Immunol. 1987, 2965-2969.
22. Hirano T, Kishimoto T. Vol. 139. Interleukin-6 in: Handbook of Experimental Pharmacology. Peptide Growth Factors and Their Receptors, Sporn MB & Roberts AB (Eds.). Springer-Verlag, Berlin, 1990, pp: 633-665.
23. Brown M, Hu-Li J, Paul WE. IL-4/B Cell Stimulatory Factor-1 Stimulates T Cell Growth by an IL-2 Independent Mechanism. J Immunol. 1988; 141:504-511.
24. Lee JD, Swisher SG, Minehart EH, McBride WH, Economou JS. Interleukin 4 Downregulates Interleukin 6 Production in Human Peripheral Blood Mononuclear Cells. J Leukocyte Biol. 1990; 47: 475-479.
25. Makay B, Makay O, Yenisey C, Icoz G, Ozgen G. Unsal E, Akyildiz M, Yetkin E. The Interaction of Oxidative Stress Response with Cytokines in the Thyrotoxic Rat: Is There a Link?. Mediat Inflamm. 2009: 1-7.
26. Tapia G, Fernandez V, Varela P, Cornejo P, Guerrero J, Videla LA. Thyroid Hormone-Induced Oxidative Stress Triggers Nuclear Factor-κB Activation and Cytokine Gene Expression in Rat Liver. Free Radic Biol Med. 2003; 35: 257-265.
27. Peng HB, Libby P, Liao JK. Induction and Stabilization of IκB-α by Nitric Oxide Mediates Inhibition of NF-κB. J Biol Chem. 1995; 270: 14214-14219.
28. Laufs U, Liao JK. Post-Transcriptional Regulation of Endothelial Nitric Oxide Synthase mRNA Stability by Rho GTPase. J Biol Chem. 1998; 273: 24266-242671.
29. Birnbaum Y, Ye Y, Lin Y, Freeberg SY, Nishi SP, Martinez JD, Huang MH, Uretsky BF, Perez-Polo JR. Augmentation of Myocardial Production of 15-Epi-Lipoxin-a4 by Pioglitazone and Atorvastatin in the Rat. Circulation 2006; 114: 929-935.
30. Polte T, Abate A, Dennery PA, Schroder H. Heme Oxygenase-1 is a cGMP-Inducible Endothelial Protein and Mediates the Cytoprotective Action of Nitric Oxide. Arterioscler Thromb Vasc Biol. 2000, 20: 1209-1215.
31. Polte T, Schroder H. Cyclic AMP Mediates Endothelial Protection by Nitric Oxide. Biochem Biophys Res Commun. 1998; 251: 460-465.
32. Marx N, Duez H, Fruchart J, Staels B. Peroxisome Proliferator-Activated Receptors and Atherogenesis: Regulators of Gene Expression in Vascular Cells. Circ Res. 2004; 94: 1168-1178.
33. Yoo CG, Lee S, Lee C, Kim YW, Han SK, Shim YS. Effect of Acetylsalicylic Acid on Endogenous IkB Kinase Activity in Lung Epithelial Cells. Am J Physiol Lung Cell Mol Physiol. 2001; 280: L3-9.
34. Paul WE. Interleukin 4/B Cell Stimulatory Factor 1: One Lymphokine, Many Functions. FASEB J. 1987; 1: 456-1461.
35. Aktas O, Waiczies S, Smorodchenko A, Dorr J, Seeger B, Prozorovski T, Sallach S, Endres M, Brocke S, Nitsch R, Zipp F. Treatment of Relapsing Paralysis in Experimental Encephalomyelitis by Targeting Th1 Cells Through Atorvastatin. J Exp Med. 2003; 197: 725-733.
36. Youssef S, Stuve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchel DJ, Sobel RA, Steinman L, Zamil SS. The HMG-CoA Reductase Inhibitor, Atorvastatin, Promotes a Th2 Bias and Reverses Paralysis in Central Nervous System Autoimmune Disease. Nature 2002; 420: 78-84.
37. Saleem S, Dai Z, Coelho SN, Konieczny BT, Assmann KJ, Baddoura FK, Lakkis FG. IL-4 is an Endogenous Inhibitor of Neutrophil Influx and Subsequent Pathology in Acute Antibody-Mediated Inflammation. J Immunol. 1998; 160: 979-984.
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01-04-2011
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“ANTI-INFLAMMATORY EFFECT OF SIMVASTATIN-ASPIRIN COMBINATION”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 3, no. 2, Apr. 2011, pp. 89-96, https://doi.org/10.25004/IJPSDR.2011.030204.
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How to Cite
“ANTI-INFLAMMATORY EFFECT OF SIMVASTATIN-ASPIRIN COMBINATION”. International Journal of Pharmaceutical Sciences and Drug Research, vol. 3, no. 2, Apr. 2011, pp. 89-96, https://doi.org/10.25004/IJPSDR.2011.030204.
