Immunomodulatory and hematological effects induced by diclofenac, ibuprofen or paracetamol toxicity in Swiss albino mice
Keywords:
Immunological and hematological studies, Diclofenac, Ibuprofen, Paracetamol, Toxicity
Abstract
Anti-inflammatory drugs (both COX-2 inhibitors and nonselective non-steroidal anti-inflammatory drugs = NSAIDs), paracetamol and opioid agents are associated with potentially different adverse events with varying degrees of efficacy. The present work was conducted to elucidate the haemato-immunological changes in mice when treated with diclofenac (Diclo), ibuprofen (Ibu) and paracetamol (Para). Mice were intraperitoneally administered with Diclo (7.4 mg/kg and 14.8 mg/kg), Ibu (60 mg/kg and 120 mg/kg) or Para (36.7 mg/kg and 73.4 mg/kg) daily for one month against saline-treated mice served as control. Diclo administration (14.8 mg/kg) caused decrease in RBCs count, Hb content and Hct%, depending on dose toxicity, while paracetamol and ibuprofen treatment showed increase in RBCs count, Hb content and Hct%. Additionally, all tested drugs induced activities of IgM and C-reactive protein in serum and caused perturbations in absolute and relative weight of immune related organs. Further, Diclo and Para treatments reduced levels of IgG in dose dependent manner however, Ibu administration enhanced activities of IgG that was reduced with increasing dose of Ibu. And activities of serum complement component C3 was diminished after administration of tested drugs activating alternative complement pathway. The implication of this research is that long use of diclofenac, ibuprofen or paracetamol may cause immunotoxic and hematotoxic effects in mice; and the dose plus the duration of treatment may augment their toxicity probably due to immune modulatory effects. Further studies are needed to assess the relevance between Diclo, Ibu or Para treatment and immunological and hematological perturbations.
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References
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2. Milsom I, Minic M, Dawood MY, Akin MD, Spann J, Niland NF, Squire RA. Comparison of the efficacy and safety of nonprescription doses of naproxen and naproxen sodium with ibuprofen, acetaminophen, and placebo in the treatment of primary dysmenorrhea: a pooled analysis of five studies. Clin Ther. 2002; 24:1384-1400.
3. Simmons DL, Botting RM, Hla T. Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition. Pharmacol Rev. 2004; 56: 387-437.
4. Shafi M, Garg UK, Saqib N, Baba OK, Farid BD, Wali A. Haemato-biochemical studies on diclofenac, ibuprofen and nimesulide induced toxicity in broilers. Nat Env Poll Tech. 2012; 11(4): 649-652.
5. Zarghi A, Arfaei S. Selective COX-2 inhibitors: a review of their structure-activity relationships. Iran J Pharmac Res. 2011; 10(4): 655-683.
6. Bushra R, Aslam N. An overview of clinical pharmacology of ibuprofen. Oman Med J. 2010; 25(3): 155-161.
7. Reynolds EF. Aspirin and similar analgesic and anti-inflammatory agents. In: Martindale. The Extra Pharmacopoeia, 28th edn., Pharmaceutical Press: London, 1982: 234-282.
8. Hörl WH. Non-steroidal Antiinflammatory Drugs and the kidney. Pharmaceuticals. 2010; 3: 2291-2321.
9. Bradbury F. How important is the role of the physician in the correct use of a drug? An observational cohort study in general practice. Int J Clin Pract Suppl. 2004; 144: 27-32.
10. Capone ML, Tacconelli S, Di-Francesco L, Sacchetti A, Sciulli MG, Patrignani P. Pharmacodynamic of cyclooxygenase inhibitors in humans. Prostaglandins Other Lipid Mediat. 2007; 82(1-4): 85-94.
11. Traversa G, Walker AM, Ippolito FM, Caffari B, Capurso L, Dezi A, et al. Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs. Epidemiol. 1995; 6(1): 49-54.
12. Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, et al. Present status and strategy of NSAIDs-induced small bowel injury. J Gastroenterol. 2009; 44(9): 879-888.
13. Bennett W, Henrich WL, Stoff JS. The renal effects of nonsteroidal anti-inflammatory drugs: Summary and recommendations. Am J Kidney Dis. 1996; 28: 56-62.
14. Aprioku JS and Uche FI. Renal Effects of non-steroidal antiinflammatory drugs in albino rats. Br J Pharm Res. 2013; 3(3): 314-325.
15. Fries JF. Assessing and understanding patient risk. Scand J Rheumatol. 1992; 92: 21-24.
16. Orinya OA, Adenkola AY, Ogbe RJ. Haematological and biochemical studies on the effect of diclofenac sodium on Wistar Rattus norvegicus. Int J Pharm Chem Biol Sci. 2016; 10(5): 2231-2242.
17. Boshra SA, Hussein MA. The protective role of colchicine on diclofenac sodium induced hepatorenal toxicity in albino rats model. Int J Pharm Sci Res. 2014; 5(12): 5136-5144.
18. Ahmad I, Qureshi TA, Khan FA, Mughal SAK, Sadique U, Shah Z, et al. Evaluation of biochemical effects of diclofenac sodium in goats. J Anim Plant Sci. 2012; 22(2): 1-4.
19. Oaks JL and Khan A. Diagnostic investigation of vulture mortality: the anti-inflammatory drug diclofenac is associated with visceral gout. J Ind Vet. 2004; 23: 152-158.
20. Bhogaraju A, Nazeer S, Al-Baghdadi Y, Rahman M, Wrestler F, Patel N. Diclofenac-associated hepatitis. J South Mediterian. 1999; 7: 711-713.
21. Aydin G, Gokcimen A, Oncu M, Clcek E, Karahan N, Golkalp O. Histopathologic changes in liver and renal tissues induced by different doses of diclofenac sodium in rats. Turk J Vet Anim Sci. 2003; 27: 1131-1140.
22. El-Maddawy ZKH, El-Ashmawy IM. Hepato-renal and haematological effects of diclofenac sodium in rats. Global J Pharmacol. 2013; 7(2): 123-132.
23. Anderson MD, Piper SE and Swan GE. Non-steroidal anti-inflammatory drug use in South Africa and possible effects on vultures. S Afr J Anim Sci. 2005; 101: 112-114.
24. Graham GG, Scott KF. Mechanism of action of paracetamol. Am J Ther. 2005; 12(1): 46-55.
25. Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF. The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings. Inflammopharmacology. 2013; 21(3): 201-232.
26. Smith HS. Potential analgesic mechanisms of acetaminophen. Pain Physician. 2009; 12: 269-280
27. Jóźwiak-Bebenista M, Nowak JZ. Paracetamol: mechanism of action, applications and safety concern. Acta Pol Pharm. 2014; 71(1): 11-23.
28. Chiam E, Weinberg L, Bellomo R. Paracetamol: a review with specific focus on the haemodynamic effects of intravenous administration. Heart Lung Vessel. 2015; 7(2): 121-132.
29. McGill MR, Williams CD, Xie Y, Ramachandran A, Jaeschke H. Acetaminophen-induced liver injury in rats and mice: comparison of protein adducts mitochondrial dysfunction, and oxidative stress in the mechanism of toxicity. Toxicol Appl Pharmacol. 2012; 264(3): 387-394.
30. Seham A, Abd E, Begonia M, Morales A, Sara K, Daniel LS, Lucy FD. Localisation of cyclooxygenase-3 in rat central nervous system. Univ Cambridge J Physiol. 2004; 555P: C156.
31. European community regulations. Diclofenac sodium, Safety Data Sheet, 2008.
32. Adams SS, Bough RG, Cliffe EE, Lessel B, Mills RF. Absorption, distribution and toxicity of ibuprofen. Toxicol Appl Pharmacol. 1969; 15(2): 310-330.
33. European community regulations. Acetaminophen Safety Data Sheet, 2008.
34. Arce S, Nawar, HF, Muehlinghaus G, Russell MW, Connell TD. In vitro induction of immunoglobulin A (IgA)-and IgM-secreting plasma blasts by cholera toxin depends on T-cell help and is mediated by CD154 up-regulation and inhibition of gamma interferon synthesis. Infect Immun. 2007; 75(3): 1413-1423.
35. Keggan A, Freer H, Rollins A, Wagner B. Production of seven monoclonal equine immunoglobulins isotyped by multiplex analysis. Vet Immunol Immunopathol. 2013; 153(3): 187-193.
36. Aniagu SO, Nwinyi FC, Akumka DD, Ajoku GA, Dzarma S, Izebe KS, et al. Toxicity studies in rats fed nature cure bitters. Afr J Biotechnol. 2005; 4(1): 72-78.
37. Tukmechi A, Rezaee J, Nejati V, Sheikhzadeh N. Effect of acute and chronic toxicity of paraquat on immune system and growth performance in rainbow trout, Oncorhynchus mykiss. Aqua Res. 2014; 45(11): 1737-1743.
38. Gilman A, Goodman L, Gilman A. The Pharmacological basis of therapeutics. 6th edn Macmillian Pub. Co. Inc. New York. 1990.
39. Ripamonti CI, Bandieri E, Roila F. Management of cancer pain: ESMO Clinical Practice Guidelines. Ann Oncol. 2011; 22(6): 69-77.
40. Raffa RB, Stone DJ, Tallarida RJ. Unexpected and pronounced antinociceptive synergy between spinal acetaminophen (paracetamol) and phentolamine. Eur J Pharmacol. 2001; 412(2): R1-2.
41. Moore K, Dalley A, Agur, AMR. Clinically orientated anatomy. 4th edn. Lippincott Williams and Williams, Philadelphia. 1999: 263-271.
42. Descotes J. Pseudo-allergic drug reactions. Clin Res Pract Drug Reg Affairs. 1986; 4(1): 75-84.
43. Oyedeji KO, Bolarinwa AF, Jeniran SS. Effect of paracetamol (acetaminophen) on haematological and reproductive parameters in male albino rats. Res J Pharmacol. 2013; 7(2): 21-25.
44. Nirogi R, Goyal VK, Jana S, Pandey SK, Gothi A. What suits best for organ weight analysis: review of relationship between organ weight and body/brain weight for rodent toxicity studies. Int J Pharm Sci Res. 2014; 5(4): 1525-1532.
45. Bailey SA, Zidell RH, Perry RW. Relationships between organ weight and body/brain weight in the rat: What is the best analytical endpoint? Toxicol Pathol. 2004; 32(4): 448-466.
46. Thanagari BS, Fefar DT, Prajapati KS, Jivani BM, Thakor KB, Patel JH. Haemato-biochemical alterations induced by diclofenac sodium toxicity in Swiss albino mice. Vet World. 2012; 5: 417-419.
47. El-Maddawy ZKH, El-Ashmawy IM. Hepato-renal and haematological effects of diclofenac sodium in rats. Global J Pharmacol. 2013; 7(2): 123-132.
48. Orinya OA, Adenkola, AY, Ogbe RJ. Haematological and biochemical studies on the effect of diclofenac sodium on Wistar Rattus norvegicus. Int J Biol Chem Sci. 2016; 10(5): 2231-2242.
49. Aprioku JS, Nwidu LL, Amadi CN. Evaluation of toxicological profile of ibuprofen in Wistar albino rats. Am J Biomed Sci. 2014; 6(1): 32-40.
50. Al-Saady MAJ, Abdul-Latif A, Al-Shemmery HN. Pharmacological effects of diclofenac sodium on some haematological parameters of male rabbits. Med J Babyl. 2011; 8(3): 441-452.
51. Samuel SA, Francis AO, Ayomide O, Onyinyechi UO. Effects of paracetamol-induced liver damage on some hematological parameters: red blood cell (RBC) count, white blood cell (WBC) count, and packed cell volume (PCV) in wistar rats of either sex. Indo Am J Pharm Res. 2015; 5(7): 2593-2599.
52. Dwivedi V, Mishra J, Shrivastava A. Efficacy study of livartho against paracetamol induced hepatotoxicity in adult Sprague Dawley rats. J Drug Metab Toxicol. 2015; 5: 175-181.
53. Adeneye AA, Ajagbonna OP, Adeleke TI, Bellow SP. Hematological evaluation of methanol seed extract of citrus. J Ethnopharmacol. 2006; 105: 374-379.
54. Inigues M, Punzon C, Fresno M. Induction of cyclooxygenase-2 on activated T lymphocytes: regulation of T cell activation by cyclooxygenase-2 inhibitors. J Immunol. 1999; 163: 111-119.
55. Paccani SR, Boncristiano M, Ulivieri C, D'Elios MM, Del Prete G, Baldari CT. Nonsteroidal anti-inflammatory drugs suppress T-cell activation by inhibiting p38 MAPK induction. J Biol Chem. 2002; 277: 1509-1513.
56. Hartel C, von Puttkamer J, Gallner F, Strunk T, Schultz C. Dose-dependent immunomodulatory effects of acetylsalicylic acid and indomethacin in human whole blood: potential role of cyclooxygenase-2 inhibition. Scand J Immunol. 2004; 60: 412-420.
57. Ryan EP, Pollock SJ, Murant TI, Bernstein SH, Felgar RE, Phipps RP. Activated human B lymphocytes express cyclooxygenase-2 and cyclooxygenase inhibitors attenuate antibody production. J Immunol. 2005; 174: 2619-2626.
58. Bernard MP, Phipps RP. CpG oligodeoxynucleotides induce cyclooxygenase-2 in human B lymphocytes: implications for adjuvant activity and antibody production. Clin Immunol. 2007; 125: 138-148.
59. Bancos S, Bernard MP, Topham, DJ, Phipps RP. Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells. Cell Immunol. 2009; 258(1): 18-28.
60. Salama A, Kroll H, Wittmann G, Mueller‐Eckhardt C. Diclofenac‐induced immune haemolytic anaemia: simultaneous occurrence of red blood cell autoantibodies and drug‐dependent antibodies. Brit J Haematol. 1996; 95(4): 640-644.
61. Meyer O, Hoffmann T, Aslan T, Ahrens N, Kiesewetter H, Salama A. Diclofenac‐induced antibodies against RBCs and platelets: two case reports and a concise review. Transfusion. 2003; 43(3): 345-349.
62. Rutkowski MJ, Sughrue ME, Kane AJ, Ahn BJ, Fang S, Parsa AT. The complement cascade as a mediator of tissue growth and regeneration. Inflamm Res. 2010; 59(11): 897-905.
63. Prohászka Z, Singh M, Nagy K, Kiss E, Lakos G, Duba J, Füst G. Heat shock protein 70 is a potent activator of the human complement system. Cell Stress Chaperones. 2002; 7(1): 17-22.
64. Navratil JS, Liu CC, Ahearn JM. Apoptosis and autoimmunity. Immunol Res. 2006; 36: 3-12.
65. Markiewski MM, DeAngelis RA, Strey CW, Foukas PG, Gerard C, Gerard N, Lambris JD. The regulation of liver cell survival by complement. J Immunol. 2009; 182(9): 5412-5418.
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Published
2017-12-31
How to Cite
(1)
Gomaa, S. Immunomodulatory and Hematological Effects Induced by Diclofenac, Ibuprofen or Paracetamol Toxicity in Swiss Albino Mice. European Journal of Biological Research 2017, 7, 348-359.
Section
Research Articles
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
