Advertisement

Inflammopharmacology

, Volume 24, Issue 4, pp 163–172 | Cite as

Evaluation of anti-inflammatory, analgesic activities, and side effects of some pyrazole derivatives

  • Souraya Domiati
  • Ahmed El-Mallah
  • Asser Ghoneim
  • Adnan Bekhit
  • Heba Abd El Razik
Original Article

Abstract

Background and purpose

Non-steroidal anti-inflammatory drugs are associated with several side effects, such as gastrointestinal mucosal damage, renal toxicity, and cardiovascular side effects. Aiming to find a novel analgesic/anti-inflammatory drug with minimal side effects, the present study was designed to screen and evaluate some newly synthesized pyrazole derivatives.

Method

Anti-inflammatory activity using carrageenan-induced rat paw edema and cotton-pellet-induced granuloma, COX-1/COX-2 selectivity using thin layer chromatography, and analgesic using hot plate and tail flick tests as well as ulcerogenic and renal side effects of the ten compounds were assessed.

Results and discussion

The results of the carrageenan-induced rat paw edema showed that the carboxyphenylhydrazone derivative (N9) was more potent than the chlorophenyl counterpart (N8) with a relative activity compared to celecoxib of 1.08 and −0.13, respectively, after 1 h. Even though this is true, N9 caused significant increase in the ulcer index, creatinine, and Blood Urea Nitrogen levels. The cotton granuloma test showed that the carboxyphenylhydrazone derivative (N7) was also more potent than its chlorophenyl counterpart (N6) with a relative activity compared to celecoxib of 1.13 and 0.86, respectively. Moreover, adding an acetyl not only increased the anti-inflammatory activity from a relative activity compared to celecoxib of 0.57–1.17 for the compounds X4 and N5, respectively, in the granuloma test, but also increased the selectivity toward COX-2 from 0.197 to 47.979.

Conclusion

As a conclusion, from the ten compounds analyzed, N5 and N7 showed promising results as anti-inflammatory/analgesic agents with low ulcerogenicity and nephrotoxicity and thus should be further analyzed to determine the ED50 and other side effects.

Keywords

Inflammation Non-steroidal anti-inflammatory drugs Pyrazole derivatives Cyclooxygenase 

Abbreviations

PG

Prostaglandin

COX

Cyclooxygenase

NSAIDs

Non-steroidal anti-inflammatory drugs

X1, X2, X3, X4, N1, N5, N6, N7, N8, N9

Products analyzed

BUN

Blood urea nitrogen

SPSS

Statistical Package for the Social Science

Notes

Compliance with ethical standards

Conflict of interest

The authors state no conflict of interest.

References

  1. Abouzeit-Har MS, Verimer T, Long JP (1982) Effect of long term estrogen and lithium treatment on restraint induced gastric erosion in intact and ovariectomized rats. Pharmazie 37(8):593–595PubMedGoogle Scholar
  2. Abu-Ghefreh AA, Masocha W (2010) Enhancement of antinociception by coadminstration of minocycline and a non-steroidal anti-inflammatory drug indomethacin in naïve mice and murine models of LPS-induced thermal hyperalgesia and monoarthritis. Musculoskele Disord 11:276. doi: 10.1186/1471-2474-11-276 CrossRefGoogle Scholar
  3. Ayoub S, Flower R, Seed M (eds) (2010) Cyclooxygenases: methods and protocols. Methods in molecular biology. chapter 8, vol. 644, Springer. doi:  10.1007/978-1-59745-364-6_8
  4. Bailey PJ, Sturm A, Lopez-Ramos B (1981) A biochemical and morphological study of the cotton pellet granuloma in the rat: effects of dexamethasone and indomethacin. Inflammation: mechanisms and treatment. Springer, 4: 345-346. doi: 10.1007/978-94-010-9423-8_50Google Scholar
  5. Bannon AW, Malmberg AB (2007) Models of nociception: hot-plate, tail-flick, and formalin tests in rodents. Curr Protoc Neurosci 10:1002. doi: 10.1002/0471142301.ns0809s41 Google Scholar
  6. Barkin RL (2012) Topical nonsteroidal anti-inflammatory drugs: the importance of drug, delivery, and theurapeutic outcome. Am J Ther. doi: 10.1097/MJT.0b013e3182459abd (Published ahead of print) PubMedGoogle Scholar
  7. Grosser T, Smyth E, FitzGerald GA (2011) Anti-inflammatory, antipyretic and analgesic agents; pharmacotherapy of gout. In: Brunton LL, Chabner BA, Knollmann BC (eds) Goodman & Gilman’s the pharmacological basis of therapeutics, 12th edn. Mc GrawHill, California, Chapter 34. ISBN 978-0-07-162442-8Google Scholar
  8. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM (2011) Pharmacotherapy: a pathophysiologic approach, 8th edn. Chapter 100, p 102. ISBN 978-0-07-170354-3Google Scholar
  9. Dunn M (1987) The role of arachidonic acid metabolites in renal homeostasis. Drugs 33(1):56–66CrossRefPubMedGoogle Scholar
  10. Ferguson S, Hebert RL, Laneuville O (1999) NS-398 upregulates constitutive cyclooxygenase-2 expression in the M-1 cortical collecting duct cell line. J Am Soc Nephrol 10(11):2261–2271PubMedGoogle Scholar
  11. Franklin KBJ, Abbott FV (1989) Techniques for assessing the effects of drugs on nociceptive responses. Psychopharmacology 13:145–216. doi: 10.1385/0-89603-129-2:145 CrossRefGoogle Scholar
  12. Guha P, Dey A, Sarkar B, Dhyani MV, Chattopadhyay S, Bandyopadhyay SK (2009) Improved antiulcer and anticancer properties of a trans-resveratrol analog in mice. J Pharmacol Exp Ther. doi: 10.1124/jpet.108.145334 PubMedGoogle Scholar
  13. Gupta JK, Upmanyu N, Patnaik AK, Mazumder AM (2010) Evaluation of antiulcer activity of leucas lavandulifolia on mucosal lesion in rat. Asian J Pharm Clin Res 3(2):118Google Scholar
  14. Harirforoosh S, Jamali F (2005) Effect of nonsteroidal anti-inflammatory drugs with varying extent of COX-2/COX-1 selectivity on urinary sodium and potassium excretion in the rat. Can J Physiol 94(6):2504–2510. doi: 10.1139/y04-129 Google Scholar
  15. Le Bars D, Gozariu M, Cadden SW (2001) Animal models of nociception. Pharmacol Rev 53(4):597–652PubMedGoogle Scholar
  16. Jackson LM, Wu KC, Mahida YR, Jenkins D, Hawkey CJ (2000) Cyclooxygenase (COX) 1 and 2 in normal, inflamed, and ulcerated human gastric mucosa. Gut 47(6):762–770. doi: 10.1136/gut.47.6.762 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Johnsen SP, Larsson H, Tarone RE, McLaughlin JK, Nørgård B, Friis S, Sørensen HT (2005) Risk of hospitalization for myocardial infarction among users of rofecoxib, celecoxib, and other NSAIDs: a population-based case-control study. Arch Intern Med 165:978. doi: 10.1001/archinte.165.9.978 CrossRefPubMedGoogle Scholar
  18. Khan KN, Paulson SK, Verburg KM, Lefkowith JB, Maziasz TJ (2002) Pharmacology of cyclooxygenase-2 inhibition in the kidney. Kidney Int 61:1209–1210CrossRefGoogle Scholar
  19. Kumar V, Abbas AK, Fausto N, Aster JC (2010) Acute and chronic inflammation. In: Robbins, Cotrans (eds) Pathologic basis of disease. 8th ed. Saunders, Elservier Inc, Chapter 2: 43–78. ISBN 978-1416031215Google Scholar
  20. Laudanno OM, Esnarriaga JM, Cesolari JA, Maglione CB, Aramberry LJ, Sambrano JS et al (2000) Celecoxib versus indomethacin and gastric lesions in rats. Medicina 60(2):221–224PubMedGoogle Scholar
  21. Lerma EV (2012) Blood urea nitrogen (BUN). http://emedicine.medscape.com/article/2073979-overview
  22. Maddila S, Sampath SGCH, Lavanya P (2012) Synthesis and anti-inflammatory activity of some new 1,3,4-thiadiazoles containing pyrazole and pyrrole nucleus. J Saudi Chem Soc. doi: 10.1016/j.jscs.2012.11.007 Google Scholar
  23. Mohy El-Din MM, Senbel AM, Bistawroos AA, El-Mallah AA, Nour El-Din NA, Bekhit AA et al (2010) A novel COX-2 inhibitor pyrazole derivative proven effective as an anti-inflammatory and analgesic drug. Basic Clin Pharmacol Toxicol 108:263–273. doi: 10.1111/j.1742-7843.2010.00648.x CrossRefPubMedGoogle Scholar
  24. Schnellmann RG (2001) Toxic responses of the kidney. In: Klaassen CD (ed) Casarett, Doull’s Toxicology: the basic science of poisons, chap 14, 6th edn. McGraw Hill, pp 491–514Google Scholar
  25. Szallasi A, Bíró T (eds) (2012) TRP channels in drug discovery. Methods in pharmacology and toxicology, vol 2, chapter 25. ISBN 978-1-62703-095-3Google Scholar
  26. Tan PV, Nditafon NG, Yewah MP, Dimo T, Ayafor FJ (1996) Eremomastax speciosa: effects of leaf aqueous extract on ulcer formation and gastric secretion in rats. J Ethnopharmacol 54:139–142CrossRefPubMedGoogle Scholar
  27. Tassorelli C, Greco R, Sandrini G, Nappi G (2003) Central components of the analgesic/antihyperalgesic effect of nimesulide: studies in animal models of pain and hyperalgesia. Drugs 63(1):9–22CrossRefPubMedGoogle Scholar
  28. Thore SN, Gupta SV, Baheti KG (2012) Novel ethyl-5-amino-3-methylthio-1H-pyrazole-4-carboxylates: synthesis and pharmacological activity. J Saudi Chem Soc 06 (011). ahead of printGoogle Scholar
  29. Toby L, Derek AW, Derek WG (2002) Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol 2:787–795CrossRefGoogle Scholar
  30. Vane J, Botting R (1987) Inflammation and the mechanism of action of anti-inflammatory drugs. FASEB J 1(2):89–96PubMedGoogle Scholar
  31. Vittalrao AM, Shanbhag T, Bairy MK, Shenoy S (2011) Evaluation of antiinflammatory and analgesic activities of alcoholic extract of kaempferia galanga in rats. Indian J Physiol Pharmacol 55(1):13–24PubMedGoogle Scholar
  32. Vogel HG (2008) Drug discovery and evaluation: pharmacologic assays, 3rd ed. SpringerGoogle Scholar
  33. Wakitani K, Nanayama T, Masaki M, Matsushita M (1998) Profile of JTE-522 as a human cyclooxygenase-2 inhibitor. Jpn J Pharmacol 78(3):365–371. doi: 10.1254/jjp.78.365 CrossRefPubMedGoogle Scholar
  34. Wallace JL, McKnight W, Reuter BK, Vergnolle N (2000) NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology 119(3):706–714. doi: 10.1053/gast.2000.16510 CrossRefPubMedGoogle Scholar
  35. Whelton A (1999) Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med 106:13S. doi: 10.1016/S0002-9343(99)00113-8 CrossRefPubMedGoogle Scholar
  36. Whelton A, Hamilton CW (1991) Nonsteroidal anti-inflammatory drugs: effect on kidney function. J Clin Pharmacol 31(7):588–598. doi: 10.1002/j.1552-4604.1991.tb03743.x CrossRefPubMedGoogle Scholar
  37. Whiteley PE, Dalrymple SA (1998) Models of inflammation: measuring gastrointestinal ulceration in the rat. Curr Protoc Pharmacol, 10.2.1–10.2.4. doi:  10.1002/0471141755.ph1002s00
  38. Winyard PG, Morris CJ (2003) Carrageenan-Induced Edema in the Rat and Mouse. In: Winyard PG, Willoughby DA (eds) Methods in Molecular Biology: Inflammation Protocols, vol 225. Humana Press, New Jersey, p 115. ISBN 0-89603-970-6Google Scholar
  39. Xie W (2010) Assessment of pain in animals. Animal models of pain. Springer Protoc 49:1–21. doi: 10.1007/978-1-60761-880-5_1 Google Scholar

Copyright information

© Springer International Publishing 2016

Authors and Affiliations

  1. 1.Department of Pharmacology and Therapeutics, Faculty of PharmacyBeirut Arab UniversityBeirutLebanon
  2. 2.Department of Pharmacology, Faculty of PharmacyPharos UniversityAlexandriaEgypt
  3. 3.Department of Pharmacology and Toxicology, Faculty of PharmacyDamanhur UniversityDamanhurEgypt
  4. 4.Department of Pharmaceutical Chemistry, Faculty of PharmacyAlexandria UniversityAlexandriaEgypt

Personalised recommendations