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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Synthesis and Biological Evaluation of Hydroxypropyl Ester of Mefenamic Acid as a Promising Prodrug

Author(s): Qais Jarrar*, Rami Ayoub, Said Moshawih, Yazun Jarrar and Jamal Jilani

Volume 20, Issue 2, 2023

Published on: 14 June, 2022

Page: [144 - 152] Pages: 9

DOI: 10.2174/1570180819666220330160134

Price: $65

Abstract

Background: The free carboxylic acid group in the mefenamic acid (MFA) structure plays a potential role in developing various neuromuscular side effects after MFA administration. In this study, the hydroxypropyl promoiety was added to the carboxylic acid group of MFA in an attempt to reduce the neuromuscular side effects of MFA and improve its therapeutic effects.

Methods: Hydroxypropylester of MFA (HPEMA) was synthesized and subjected to various in vivo investigations compared to MFA. The neuromuscular toxicity was conducted following high doses administration in mice and was evaluated at various measuring parameters, such as the percentage of catalepsy, clonic-tonic seizure, and death. In addition, the anti-inflammatory and anti-nociceptive effects of HPEMA were evaluated in the carrageenan-induced paw edema test and acetic acid-induced writhing test, respectively.

Results: The findings of this study reveal that the percentage of catalepsy, clonic-tonic seizure, and death is significantly lower in mice treated with HPEMA than in those treated with equimolar doses of MFA. In addition, treatment with HPEMA caused a comparable anti-inflammatory activity in the carrageenaninduced paw edema test and a significantly higher anti-nociceptive effect in the acetic acid-induced writhing test than the MFA treatment.

Conclusion: This study’s findings suggest that HPEMA is a promising prodrug for MFA.

Keywords: Mefenamic acid, seizure, CNS convulsion, prodrug, anti-nociceptive, hydroxypropyl ester.

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[1]
Haley, R.M.; von Recum, H.A. Localized and targeted delivery of NSAIDs for treatment of inflammation: A review. Exp. Biol. Med. (Maywood), 2019, 244(6), 433-444.
[http://dx.doi.org/10.1177/1535370218787770] [PMID: 29996674]
[2]
Green, G.A. Understanding NSAIDs: From aspirin to COX-2. Clin. Cornerstone, 2001, 3(5), 50-60.
[http://dx.doi.org/10.1016/S1098-3597(01)90069-9] [PMID: 11464731]
[3]
Conaghan, P.G. A turbulent decade for NSAIDs: Update on current concepts of classification, epidemiology, comparative efficacy, and toxicity. Rheumatol. Int., 2012, 32(6), 1491-1502.
[http://dx.doi.org/10.1007/s00296-011-2263-6] [PMID: 22193214]
[4]
Jarrar, Q.B.; Hakim, M.N.; Cheema, M.S.; Zakaria, Z.A. Comparative ultrastructural hepatic alterations induced by free and liposome-encapsulated mefenamic acid. Ultrastruct. Pathol., 2017, 41(5), 335-345.
[http://dx.doi.org/10.1080/01913123.2017.1349850] [PMID: 28829237]
[5]
Jarrar, Q.B.; Hakim, M.N.; Zakaria, Z.A.; Cheema, M.S.; Moshawih, S. Renal ultrastructural alterations induced by various preparations of mefenamic acid. Ultrastruct. Pathol., 2020, 44(1), 130-140.
[http://dx.doi.org/10.1080/01913123.2020.1717705] [PMID: 31967489]
[6]
Kamour, A.; Crichton, S.; Cooper, G.; Lupton, D.J.; Eddleston, M.; Vale, J.A.; Thompson, J.P.; Thomas, S.H. Central nervous system toxicity of mefenamic acid overdose compared with other NSAIDs: An analysis of cases reported to the United Kingdom National Poisons Information Service. Br. J. Clin. Pharmacol., 2017, 83(4), 855-862.
[http://dx.doi.org/10.1111/bcp.13169] [PMID: 27785820]
[7]
Robson, R.H.; Balali, M.; Critchley, J.; Proudfoot, A.T.; Prescott, L. Mefenamic acid poisoning and epilepsy. BMJ, 1979, 2(6202), 1438.
[http://dx.doi.org/10.1136/bmj.2.6202.1438-c] [PMID: 519499]
[8]
Council, N. R. Guide for the care and use of laboratory animals, 2010.
[9]
Jarrar, Q.B.; Hakim, M.N.; Manraj, C.; Zainul, Z. In vitro characterization and in vivo performance of mefenamic acid-sodium diethyldithiocarbamate based liposomes. Braz. J. Pharm. Sci., 2019, 55, e17870.
[http://dx.doi.org/10.1590/s2175-97902019000117870]
[10]
Ayoub, R.; Jarrar, Q.; Ali, D.; Moshawih, S.; Jarrar, Y.; Hakim, M.; Zakaria, Z. Synthesis of Novel Esters of Mefenamic Acid with Pronounced Anti-nociceptive Effects and a Proposed Activity on GABA, Opioid and Glutamate Receptors. Eur. J. Pharm. Sci., 2021, 163, 105865.
[http://dx.doi.org/10.1016/j.ejps.2021.105865] [PMID: 33979659]
[11]
Nishchal, B.S.; Rai, S.; Prabhu, M.N.; Ullal, S.D.; Rajeswari, S.; Gopalakrishna, H.N. Effect of Tribulus terrestris on haloperidol-induced catalepsy in mice. Indian J. Pharm. Sci., 2014, 76(6), 564-567.
[PMID: 25593394]
[12]
Pemminati, S.; Nair, V.; Dorababu, P.; Gopalakrishna, H.N.; Pai, M. Effect of ethanolic leaf extract of Ocimum sanctum on haloperidol-induced catalepsy in albino mice. Indian J. Pharmacol., 2007, 39(2), 87.
[http://dx.doi.org/10.4103/0253-7613.32526]
[13]
Shimada, T.; Yamagata, K. “Pentylenetetrazole-induced kindling mouse model,” JoVE. J. Vis. Exp., 2018, (136), e56573.
[PMID: 29985308]
[14]
Morris, C.J. Carrageenan-induced paw edema in the rat and mouse. Inflamm. Protoc, 2003, 115-121.
[http://dx.doi.org/10.1385/1-59259-374-7:115]
[15]
Young, H-Y.; Luo, Y-L.; Cheng, H-Y.; Hsieh, W-C.; Liao, J-C.; Peng, W-H. Analgesic and anti-inflammatory activities of [6]-gingerol. J. Ethnopharmacol., 2005, 96(1-2), 207-210.
[http://dx.doi.org/10.1016/j.jep.2004.09.009] [PMID: 15588672]
[16]
Leach, M.C.; Klaus, K.; Miller, A.L.; Scotto di Perrotolo, M.; Sotocinal, S.G.; Flecknell, P.A. The assessment of post-vasectomy pain in mice using behaviour and the Mouse Grimace Scale. PLoS One, 2012, 7(4), e35656.
[http://dx.doi.org/10.1371/journal.pone.0035656] [PMID: 22558191]
[17]
Miller, A.L.; Leach, M.C. The mouse grimace scale: A clinically useful tool? PLoS One, 2015, 10(9), e0136000.
[http://dx.doi.org/10.1371/journal.pone.0136000] [PMID: 26406227]
[18]
Noamesi, B.K.; Adebayo, G.I.; Bamgbose, S.O.A. Muscle relaxant properties of aqueous extract of Lippia multiflora. Planta Med., 1985, 51(3), 253-255.
[http://dx.doi.org/10.1055/s-2007-969471] [PMID: 4034750]
[19]
Vasileva, L.; Getova, D. Effects of Rhodiola rosea L. standardized extract on nociceptive reactions and locomotor activity. Trakia J. Sci., 2013, 12, 119-122.
[20]
Rautio, J.; Kumpulainen, H.; Heimbach, T.; Oliyai, R.; Oh, D.; Järvinen, T.; Savolainen, J. Prodrugs: Design and clinical applications. Nat. Rev. Drug Discov., 2008, 7(3), 255-270.
[http://dx.doi.org/10.1038/nrd2468] [PMID: 18219308]
[21]
Stella, V.J. Prodrugs as therapeutics; Taylor & Francis, 2004.
[http://dx.doi.org/10.1517/13543776.14.3.277]
[22]
Shanbhag, V.R.; Crider, A.M.; Gokhale, R.; Harpalani, A.; Dick, R.M. Ester and amide prodrugs of ibuprofen and naproxen: Synthesis, anti-inflammatory activity, and gastrointestinal toxicity. J. Pharm. Sci., 1992, 81(2), 149-154.
[http://dx.doi.org/10.1002/jps.2600810210] [PMID: 1545354]
[23]
Redasani, V.K.; Bari, S.B. Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol. Eur. J. Med. Chem., 2012, 56, 134-138.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.030] [PMID: 22982120]
[24]
Cimolai, N. The potential and promise of mefenamic acid. Expert Rev. Clin. Pharmacol., 2013, 6(3), 289-305.
[http://dx.doi.org/10.1586/ecp.13.15] [PMID: 23656341]
[25]
Patil, K.R.; Mahajan, U.B.; Unger, B.S.; Goyal, S.N.; Belemkar, S.; Surana, S.J.; Ojha, S.; Patil, C.R. Animal models of inflammation for screening of anti-inflammatory drugs: Implications for the discovery and development of phytopharmaceuticals. Int. J. Mol. Sci., 2019, 20(18), 4367.
[http://dx.doi.org/10.3390/ijms20184367] [PMID: 31491986]
[26]
Ness, T.J. Models of visceral nociception. ILAR J., 1999, 40(3), 119-128.
[http://dx.doi.org/10.1093/ilar.40.3.119] [PMID: 11406690]
[27]
Yam, M.F.; Loh, Y.C.; Oo, C.W.; Basir, R. Overview of neurological mechanism of pain profile used for animal “pain-like” behavioral study with proposed analgesic pathways. Int. J. Mol. Sci., 2020, 21(12), 4355.
[http://dx.doi.org/10.3390/ijms21124355] [PMID: 32575378]

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