CHRONIC INTERACTION BETWEEN METFORMIN AND MELOXICAM IN MICE

FALAH MUOSA KADHIM AL-REKABI

doi:10.22159/ajpcr.2019.v12i2.29947

Authors

FALAH MUOSA KADHIM AL-REKABI Department of Physiology, Biochemistry and Pharmacology College of Veterinary Medicine, University of Baghdad, Iraq.

DOI:

https://doi.org/10.22159/ajpcr.2019.v12i2.29947

Keywords:

Chronic, Interaction, Metformin, Meloxicam, Mice

Abstract

Objective: This study is performed for investigation the chronic interaction between metformin and meloxicam from toxicological view.

Methods: Lethal dose 50 after chronic exposure assessed in mice by up and down method. Their interaction analyzed by isobolographic analysis indicated that both medicines exhibited synergism. Assessment of the effects of repeated chronic dosing for 3 months of both medicines also performed on mice. Medicines in question administered orally as therapeutic doses of metformin 14 mg/kg. Body weight (BW) (G1), meloxicam 0.2 mg/kg.BW (G2), and combination of both medicines (G3) while G4 assigned control and dosed DW.

Results: Both G1 and G3 showed significant p˂0.05 decrease in blood glucose and serum cholesterol levels. Meloxicam group (G3) showed statistically significant p˂0.05 increase in triglycerides and alanine aminotransferase (ALT), and aspartate aminotransferase (AST), while group of combination showed statistically significant p≤0.05 decrease in both ALT and AST. Blood urea nitrogen, uric acid, and serum creatinine showed statistically significant p˂0.05 increase in group of meloxicam but decrease in G3 and no changes in G1. Histopathological changes included variable lesions in kidney such as swelling and necrosis in renal tubules of metformin group, cortical vacuolar degeneration in renal tubules, and deterioration of most glomeruli in G2, while G3 showed generalized cortical necrosis of renal tubules and interstitial nephritis. Liver lesions included central venous congestion (VC) and perivascular lymphocytic infiltration and marked necrosis in both groups of metformin and meloxicam, while there were severe VC and necrosis of hepatocytes in group of combination.

Conclusion: Metformin administration with meloxicam may have beneficial important through preventing many deleterious effects of meloxicam after long-standing administration, but adjusting dosing regimen study might be recommended.

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References

Bailey CJ, Day C. Metformin: Its botanical background. Pract Diabetes Int 2004;21:115-7.

Bailey CJ, Turner RC. Metformin. N Engl J Med 1996;334:574-9.

Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: An update. Ann Intern Med 2002;137:25-33.

Andújar-Plata P, Pi-Sunyer X, Laferrère B. Metformin effects revisited. Diabetes Res Clin Pract 2012;95:1-9.

Kala P, Jamuna RR, Kumar J. A comparative study of efficacy and safety among metformin with sitagliptin, metformin with voglibose, and metformin with glimepiride in patients with Type 2 diabetes mellitus. Asian J Pharm Clin Sci 2017;10:313-6.

Garber AJ, Duncan TG, Goodman AM, Mills DJ, Rohlf JL. Efficacy of metformin in Type II diabetes: Results of a double-blind, placebo-controlled, dose-response trial. Am J Med 1997;103:491-7.

Suzuki K, Yoshioka T, Wakui Y. Quantifying the effect of metformin 1000 mg/day in Japanese patients with Type 2 diabetes. Int J Clin Med 2014;5:894-901.

Liesel C, Jonathan P, Vishwanath S, Sanman A, Sadhna J. Effect of food on the absorption of metformin from sustained release metformin hydrochloride formulations in healthy Indian volunteers. Asian J Pharm Clin Sci Res 2013;6:95-9.

Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011;50:81-98.

Foretz M, Guigas B, Bertrand L, Pollak M, Viollet B. Metformin: From mechanisms of action to therapies. Cell Metab 2014;20:953-66.

He L, Wondisford FE. Metformin action: Concentrations matter. Cell Metab 2015;21:159-62.

Rojas LB, Gomes MB. Metformin: An old but still the best treatment for Type 2 diabetes. Diabetol Metab Syndr 2013;5:6.

Gionfriddo MR, Morey-Vargas O, Brito J, Leppin AL, Murad MH, Montori VM. Systematic reviews to ascertain the safety of diabetes medications topical collection on pharmacologic treatment of Type 2 diabetes. Curr Diabetes Rep 2014;14:478.

Dudhgaonkar SP, Tandan SK, Bhat AS, Jadhav SH, Kumar D. Synergistic anti-inflammatory interaction between meloxicam and aminoguanidine hydrochloride in carrageenan-induced acute inflammation in rats. Life Sci 2006;78:1044-8.

Mahaprabhu R, Bhandarkar AG, Jangir BL, Rahangadale SP, Kurkure NV. Ameliorative effect of ocimum sanctum on meloxicam induced toxicity in wistar rats. Toxicol Int 2011;18:130-6.

Weyna DR, Cheney ML, Shan N, Hanna M, Zaworotko MJ, Sava V, et al. Improving solubility and pharmacokinetics of meloxicam via multiple-component crystal formation. Mol Pharm 2012;9:2094-102.

Huskisson E, Narjes H, Bluhmki E. Efficacy and tolerance of meloxicam, a new NSAID, in daily oral doses of 15, 30 and 60 mg in comparison to 20 mg piroxicam in patients with rheumatoid arthritis. Scand J Rheumatol 1994;23:115.

Busch U, Schmid J, Heinzel G, Schmaus H, Baierl J, Huber C, et al. Pharmacokinetics of meloxicam in animals and the relevance to humans. Drug Metab Dispos 1998;26:576-84.

Stamm O, Latscha U, Janecek P, Campana A. Development of a special electrode for continuous subcutaneous pH measurement in the infant scalp. Am J Obstet Gynecol 1976;124:193-5.

Vane JR, Botting RM. Mechanism of action of aspirin-like drugs. Semin Arthritis Rheum 1997;26:2-10.

Mohammed M, Kassim J, Nizar A. Evaluation of the clinical use of metformin or pioglitazone in combination with meloxicam in patients with knee osteoarthritis; using knee injury and osteoarthritis outcome score. Iraqi J Pharm Sci 2017;23:13-23.

Kalariya NM, Shoeb M, Ansari NH, Srivastava SK, Ramana KV. Antidiabetic drug metformin suppresses endotoxin-induced uveitis in rats. Invest Ophthalmol Vis Sci 2012;53:3431-40.

Yuan H, Li L, Zheng W, Wan J, Ge P, Li H, et al. Antidiabetic drug metformin alleviates endotoxin-induced fulminant liver injury in mice. Int Immunopharmacol 2012;12:682-8.

Vozarova B, Weyer C, Lindsay RS, Pratley RE, Bogardus C, Tataranni PA, et al. High white blood cell count is associated with a worsening of insulin sensitivity and predicts the development of Type 2 diabetes. Diabetes 2002;51:455-61.

Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE, et al. The effects of salsalate on glycemic control in patients with Type 2 diabetes: A randomized trial. Ann Intern Med 2010;152:346-57.

Agrawal NK, Kant S. Targeting inflammation in diabetes: Newer therapeutic options. World J Diabetes 2014;5:697-710.

Matsunaga A, Kawamoto M, Shiraishi S, Yasuda T, Kajiyama S, Kurita S, et al. Intrathecally administered COX-2 but not COX-1 or COX-3 inhibitors attenuate streptozotocin-induced mechanical hyperalgesia in rats. Eur J Pharmacol 2007;554:12-7.

Dixon WJ. Efficient analysis of experimental observations. Annu Rev Pharmacol Toxicol 1980;20:441-62.

Tallarida RJ. Drug Synergism and Dose-effect Data Analysis. Boca Raton: CRC/Chapman-Hall; 2000.

Trinder P. Determination of glucose in blood using glucose oxidase with an alternative oxygen acceptor. Ann Clin Biochem 1969;6:24-7.

Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470-5.

Bucolo G, David H. Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem 1973;19:476-82.

Gella FJ, Olivella T, Cruz Pastor M, Arenas J, Moreno R, Durban R, et al. A simple procedure for the routine determination of aspartate aminotransferase and alanine aminotransferase with pyridoxal phosphate. Clin Chim Acta 1985;153:241-7.

Barham D, Trinder P. An improved colour reagent for the determination of blood glucose by the oxidase system. Analyst 1972;97:142-5.

Fossati P, Prencipe L, Berti G. Use of 3,5-dichloro-2- hydroxybenzenesulfonic acid/4-aminophenazone chromogenic system in direct enzymic assay of uric acid in serum and urine. Clin Chem 1980;26:227-31.

Talke H, Schubert G. Enzymatic substance determination in blood and sermi-optical test after Warburb. Clin Wkly 1965;43:174-5.

Gutman I, Bergmeyer HU. Methods of Enzymatic Analysis. 2nd ed. New York: Academic Press; 1974.

Weber JA, van Zanten AP. Interferences in current methods for measurements of creatinine. Clin Chem 1991;37:695-700.

Peake M, Whiting M. Measurement of serum creatinine – current status and future goals. Clin Biochem Rev 2006;27:173-84.

AL-Rekabi FMK, Asker SJ, Shwaish MM. Acute and subchronic interaction between metformin and meloxicam in mice. J Pharm Tech 2018;11:2336-44.

Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia 2008;51:1552-3.

Madiraju AK, Erion DM, Rahimi Y, Zhang XM, Braddock DT, Albright RA, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014;510:542-6.

Buse JB, DeFronzo RA, Rosenstock J, Kim T, Burns C, Skare S, et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: Results from short-term pharmacokinetic and 12- week dose-ranging studies. Diabetes Care 2016;39:198-205.

de Jongh S, Ose L, Szamosi T, Gagné C, Lambert M, Scott R, et al. Efficacy and safety of statin therapy in children with familial hypercholesterolemia: A randomized, double-blind, placebo-controlled trial with simvastatin. Circulation 2002;106:2231-7.

Rubins HB. Triglycerides and coronary heart disease: Implications of recent clinical trials. J Cardiovasc Risk 2000;7:339-45.

Forrester JS. Triglycerides: Risk factor or fellow traveler? Curr Opin Cardiol 2001;16:261-4.

Tenner SS. Acute pancreatitis. In: Feldman M, Friedman L, Brandt L, editors. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease.9th ed.St. Louis, MO: Saunders; 2010.

Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks F, Murad MH, et al. Evaluation and treatment of hypertriglyceridemia: An endocrine society clinical practice guideline. J Clin Endocrinol Metab 2012;97:2969-89.

Trivedi CD, Pitchumoni CS. Drug-induced pancreatitis: An update. J Clin Gastroenterol 2005;39:709-16.

Nitsche CJ, Jamieson N, Lerch MM, Mayerle JV. Drug induced pancreatitis. Best Pract Res Clin Gastroenterol 2010;24:143-55.

Rostom A, Goldkind L, Laine L. Nonsteroidal anti-inflammatory drugs and hepatic toxicity: A systematic review of randomized controlled trials in arthritis patients. Clin Gastroenterol Hepatol 2005;3:489-98.

Murray MD, Brater DC. Renal toxicity of the nonsteroidal anti-inflammatory drugs. Annu Rev Pharmacol Toxicol 1993;33:435-65.

Eng L. Action of Diclofenac and Meloxicam on Nephrotoxic Cell Death. Thesis (BSc. Hons). Singapore: National University of Singapore; 2008.

Hoshino T, Tabuchi K, Hara A. Effects of NSAIDs on the inner ear: Possible involvement in cochlear protection. Pharmaceuticals (Basel) 2010;3:1286-95.

Al-Rekabi F, Abbas D, Hadi N. Effects of subchronic exposure to meloxicam on some hematological, biochemical and liver histopathological parameters in rats. Iraqi J Vet Sci 2009;23:249-54.

Vane JR, Bakhle YS, Botting RM. Cyclooxygenases 1 and 2. Annu Rev Pharmacol Toxicol 1998;38:97-120.

Khan KN, Venturini CM, Bunch RT, Brassard JA, Koki AT, Morris DL, et al. Interspecies differences in renal localization of cyclooxygenase isoforms: Implications in nonsteroidal antiinflammatory drug-related nephrotoxicity. Toxicol Pathol 1998;26:612-20.

Schnellmann R. Toxic responses of the kidney. In: Klaassen CD, editor. Casarett and Doull’s Toxicology: The Basic Science of Poisons. New York, NY: McGraw-Hill; 2001. p. 583-608.

Yanto TA, Huang I, Kosasih FN, Lugito NPH. Nightmare and abnormal dreams: Rare side effects of metformin? Case Rep Endocrinol 2018;2018:7809305.