Generic placeholder image

Recent Advances in Inflammation & Allergy Drug Discovery

Editor-in-Chief

ISSN (Print): 2772-2708
ISSN (Online): 2772-2716

Mini-Review Article

Insights into Prospects of Novel NSAID Prodrugs in the Management of Gastrointestinal Toxicity: A Perspective Review

Author(s): Rajat Goyal, Sumeet Gupta*, Prabodh Sharma and Manu Sharma

Volume 18, Issue 1, 2024

Published on: 23 January, 2024

Page: [2 - 10] Pages: 9

DOI: 10.2174/0127722708278736231205055035

Price: $65

Abstract

Non-steroidal anti-inflammatory drugs (NSAIDs) have a long history in the healthcare system due to their therapeutic potential. These NSAIDs cause ulcerogenicity, stomach pains, gastrointestinal hemorrhage, mucosa bleeding, and pancreatitis when used moderately and consistently. With researchers, managing the aforementioned adverse effects therapeutically is getting increasingly difficult. One method for creating NSAID moieties with low penetration as well as ulcerogenic properties is the prodrug technique. During the oral consumption of NSAID-prodrugs, ulcerations, intestinal hemorrhage, and mucosa hemorrhage have significantly decreased. Considering this background, this review focussed on NSAID prodrugs as well as their justifications, the pathogenesis of NSAIDs inducing gastrointestinal toxicity, and the role of different antioxidants and spacer groups. Prodrug moieties have more advantages over parent medicines concerning both solubility and lipophilicity. In general, NSAID-class prodrugs can successfully treat both acute and long-term inflammation and aches without causing ulcerotoxicity and related gastrointestinal side effects, which reduces their burden from the pharmacoeconomic perspective.

Graphical Abstract

[1]
Arora M, Choudhary S, Silakari O. In silico guided designing of 4-(1H-benzo[d]imidazol-2-yl)phenol-based mutual-prodrugs of NSAIDs: Synthesis and biological evaluation. SAR QSAR Environ Res 2020; 31(10): 761-84.
[http://dx.doi.org/10.1080/1062936X.2020.1810117] [PMID: 32867537]
[2]
Verma A, Das N, Dhanawat M, Shrivastava SK. Conjugation of some NSAIDs with 5-phenyl-2-aminothiazole for reduced ulcerogenicity. Thaiphesatchasan 2010; 34: 49-57.
[3]
Gliszczyńska A, Sánchez-López E. Dexibuprofen therapeutic advances: Prodrugs and nanotechnological formulations. Pharmaceutics 2021; 13(3): 414.
[http://dx.doi.org/10.3390/pharmaceutics13030414] [PMID: 33808908]
[4]
Dhaneshwar SS, Buchade RS, Vetal S, Gautam H, Tewari KM, Karandikar HM. Synthesis, release kinetics and pharmacological profile of chimeric aceclofenac prodrug. Pharma Chem 2011; 3(3): 354-63.
[5]
Bacchi S, Palumbo P, Sponta A, Coppolino MF. Clinical pharmacology of non-steroidal anti-inflammatory drugs: A review. Antiinflamm Antiallergy Agents Med Chem 2012; 11(1): 52-64.
[http://dx.doi.org/10.2174/187152312803476255]
[6]
Bindu S, Mazumder S, Bandyopadhyay U. Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochem Pharmacol 2020; 180: 114147.
[http://dx.doi.org/10.1016/j.bcp.2020.114147] [PMID: 32653589]
[7]
Madhukar M, Sawraj S, Sharma PD. Design, synthesis and evaluation of mutual prodrug of 4-biphenylacetic acid and quercetin tetramethyl ether (BPA–QTME) as gastrosparing NSAID. Eur J Med Chem 2010; 45(6): 2591-6.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.047] [PMID: 20227799]
[8]
Suthar SK, Sharma M. Recent developments in chimeric NSAIDs as safer anti-inflammatory agents. Med Res Rev 2015; 35(2): 341-407.
[http://dx.doi.org/10.1002/med.21331] [PMID: 25319808]
[9]
Hawkins C, Hanks GW. The gastroduodenal toxicity of nonsteroidal anti-inflammatory drugs: A review of the literature. J Pain Symptom Manage 2000; 20(2): 140-51.
[http://dx.doi.org/10.1016/S0885-3924(00)00175-5] [PMID: 10989252]
[10]
Musumba C, Pritchard DM, Pirmohamed M. Review article: Cellular and molecular mechanisms of NSAID induced peptic ulcers. Aliment Pharmacol Ther 2009; 30(6): 517-31.
[http://dx.doi.org/10.1111/j.1365-2036.2009.04086.x] [PMID: 19575764]
[11]
Shaheed DQ, Mubarak AKH. Aziz libeg AA, Abbas HK, ALRekabi MD, Hussein AH. Design and synthesis of new derivatives of Ketoprofen linked to natural antioxidants (Thymol, Menthol and Guaiacol) as possible mutual prodrugs. World J Pharm Res 2015; 4(1): 310-9.
[12]
Ahmed M, Azam F, Gbaj A, et al. Ester prodrugs of ketoprofen: Synthesis, in vitro stability, in vivo biological evaluation and in silico comparative docking studies against COX-1 and COX-2. Curr Drug Discov Technol 2016; 13(1): 41-57.
[http://dx.doi.org/10.2174/1570163813666160119092807] [PMID: 26785683]
[13]
Halen P, Murumkar P, Giridhar R, Yadav M. Prodrug designing of NSAIDs. Mini Rev Med Chem 2009; 9(1): 124-39.
[http://dx.doi.org/10.2174/138955709787001695] [PMID: 19149665]
[14]
Narsinghani T, Sharma R. Lead optimization on conventional non-steroidal anti-inflammatory drugs: An approach to reduce gastrointestinal toxicity. Chem Biol Drug Des 2014; 84(1): 1-23.
[http://dx.doi.org/10.1111/cbdd.12292] [PMID: 24460671]
[15]
Coruzzi G, Venturi N, Spaggiari S. Gastrointestinal safety of novel nonsteroidal antiinflammatory drugs: Selective COX-2 inhibitors and beyond. Acta Biomed 2007; 78(2): 96-110.
[PMID: 17933277]
[16]
Abdulhadi SL, Qasir AJ, Razzak NA. Synthesis of new conjugates of some NSAIDs with sulfonamide as possible mutual prodrugs using tyrosine spacer for colon targeted drug delivery. Iraqi J Pharm Sci 2013; 22(2): 22-9.
[http://dx.doi.org/10.31351/vol22iss2pp22-29]
[17]
Abdel-Tawab M, Zettl H, Schubert-Zsilavecz M. Nonsteroidal anti-inflammatory drugs: A critical review on current concepts applied to reduce gastrointestinal toxicity. Curr Med Chem 2009; 16(16): 2042-63.
[http://dx.doi.org/10.2174/092986709788682209] [PMID: 19519380]
[18]
Peesa JP, Yalavarthi PR, Rasheed A, Mandava VBR. A perspective review on role of novel NSAID prodrugs in the management of acute inflammation. J Acute Dis 2016; 5(5): 364-81.
[http://dx.doi.org/10.1016/j.joad.2016.08.002]
[19]
Haley RM, von Recum HA. Localized and targeted delivery of NSAIDs for treatment of inflammation: A review. Exp Biol Med 2019; 244(6): 433-44.
[http://dx.doi.org/10.1177/1535370218787770] [PMID: 29996674]
[20]
Santos J, Moreira V, Campos M, et al. Pharmacological evaluation and preliminary pharmacokinetics studies of a new diclofenac prodrug without gastric ulceration effect. Int J Mol Sci 2012; 13(12): 15305-20.
[http://dx.doi.org/10.3390/ijms131115305] [PMID: 23203127]
[21]
Redasani VK, Bari SB. Synthesis and evaluation of mutual prodrugs of ibuprofen with menthol, thymol and eugenol. Eur J Med Chem 2012; 56: 134-8.
[http://dx.doi.org/10.1016/j.ejmech.2012.08.030] [PMID: 22982120]
[22]
Nija B, Rasheed A, Kottaimuthu A. Development, characterization and pharmacological investigation of umbelliferone conjugates of NSAIDs. Iraqi J Pharm Sci 2021; 30(1)
[23]
Shah K, Gupta JK, Chauhan NS, Upmanyu N, Shrivastava SK, Mishra P. Prodrugs of NSAIDs: A review. Open Med Chem J 2017; 11(1): 146-95.
[http://dx.doi.org/10.2174/1874104501711010146] [PMID: 29387273]
[24]
Kulabaş N, Set İ, Aktay G. Identification of some novel amide conjugates as potent and gastric sparing antiinflammatory agents: In vitro, in vivo, in silico studies and drug safety evaluation. J Mol Struct 2023; 1285: 135521.
[http://dx.doi.org/10.1016/j.molstruc.2023.135521]
[25]
Jilani J, Idkaidek N, Alzoubi K. Synthesis, in vitro and in vivo evaluation of the N-ethoxycarbonylmorpholine ester of diclofenac as a prodrug. Pharmaceuticals 2014; 7(4): 453-63.
[http://dx.doi.org/10.3390/ph7040453] [PMID: 24736104]
[26]
Sinha M, Gautam L, Shukla PK, Kaur P, Sharma S, Singh TP. Current perspectives in NSAID-induced gastropathy. Mediators Inflamm 2013; 2013: 258209.
[27]
Mandal SK, Pati K, Bose A, et al. Various ester prodrugs of NSAIDs with low ulcerogenic activity. Int J Pharm Sci Rev Res 2019; 54: 45-9.
[28]
Bandgar BP, Sarangdhar RJ, Viswakarma S, Ahamed FA. Synthesis and biological evaluation of orally active prodrugs of indomethacin. J Med Chem 2011; 54(5): 1191-201.
[http://dx.doi.org/10.1021/jm101085j] [PMID: 21284386]
[29]
Markovic M, Ben-Shabat S, Dahan A. Computational simulations to guide enzyme-mediated prodrug activation. Int J Mol Sci 2020; 21(10): 3621.
[http://dx.doi.org/10.3390/ijms21103621] [PMID: 32443905]
[30]
Stella VJ. Prodrugs: My initial exploration and where it led. J Pharm Sci 2020; 109(12): 3514-23.
[http://dx.doi.org/10.1016/j.xphs.2020.09.037] [PMID: 33002466]
[31]
Chandiran S, Vyas S, Sharma N, Sharma M. Synthesis and evaluation of antioxidant-s-(+)-Ibuprofen hybrids as gastro sparing NSAIDs. Med Chem 2013; 9(7): 1006-16.
[http://dx.doi.org/10.2174/1573406411309070015] [PMID: 23061566]
[32]
Shah K, Shrivastava SK, Mishra P. Synthesis, kinetics and pharmacological evaluation of mefenamic acid mutual prodrug. Acta Pol Pharm 2013; 70(5): 905-11.
[PMID: 24147370]
[33]
Manon B, Sharma PD. Design, synthesis and evaluation of diclofenac-antioxidant mutual prodrugs as safer NSAIDs. Indian J Chem 2009; 48(9): 1279-87.
[34]
Arun Kumar, Vijay Juy, Juyal V. Design. synthesis and evaluation of chalcone derivatives as anti-inflammatory, antioxidant and antiulcer agents. Lett Drug Des Discov 2012; 9(5): 479-88.
[http://dx.doi.org/10.2174/157018012800389368]
[35]
Zhang YC, Chen PT, Guan HS, Li YX. Synthesis and pharmacological evaluation of novel conjugates of indomethacin with antioxidant activity. Chin J Chem 2005; 23(11): 1523-9.
[http://dx.doi.org/10.1002/cjoc.200591523]
[36]
Shah K, Shrivastava SK, Mishra P. Evaluation of mefenamic acid mutual prodrugs. Med Chem Res 2013; 22(1): 70-7.
[http://dx.doi.org/10.1007/s00044-012-0016-z]
[37]
Datar P, Shendge T. Design, synthesis and stability studies of mutual prodrugs of NSAID’s. ChemInform 2015.
[38]
Ali BT, Monther FM, Mohammed HM. Design, synthesis, and hydrolysis study of mutual prodrugs of NSAIDS with different antioxidants via glycolic acid spacer. Int J Comprehen Pharm 2012; 1(3): 3.
[39]
Sharma N. Synthesis, characterization & biological evaluation of mutual prodrugs of some selected NSAIDs conjugated with different antioxidant via different amino acids. Org Med Chem Int J 2017; 4(4): 1-5.
[40]
Shinu P, Sharma M, Gupta GL, et al. Computational design, synthesis, and pharmacological evaluation of naproxen-guaiacol chimera for gastro-sparing anti-inflammatory response by selective COX2 inhibition. Molecules 2022; 27(20): 6905.
[http://dx.doi.org/10.3390/molecules27206905] [PMID: 36296501]
[41]
Rasheed A, Lathika G, Raju YP, Mansoor KP, Azeem AK, Balan N. Synthesis and pharmacological evaluation of mutual prodrugs of aceclofenac with quercetin, vanillin and l-tryptophan as gastrosparing NSAIDS. Med Chem Res 2016; 25(1): 70-82.
[http://dx.doi.org/10.1007/s00044-015-1469-7]
[42]
Sharma SK, Karthikeyan C, Hari Narayana Moorthy NS, Jain DK, Trivedi P. Synthesis and evaluation of some amino acid conjugates of pirprofen. Biomed Prev Nutr 2013; 3(3): 241-6.
[http://dx.doi.org/10.1016/j.bionut.2012.10.005]
[43]
Mishra A, Agrawal S, Pathak K. Naproxen glycine conjugate-synthesis, pharmaceutical preformulation and pharmacodynamic evaluation. Drug Deliv 2012; 19(2): 102-11.
[http://dx.doi.org/10.3109/10717544.2011.649218] [PMID: 22239596]
[44]
Sawraj S, Bhardawaj TR, Sharma PD. Design, synthesis, and evaluation of novel indomethacin-antioxidant codrugs as gastrosparing NSAIDs. Med Chem Res 2012; 21(6): 834-43.
[http://dx.doi.org/10.1007/s00044-011-9589-1]
[45]
Mizushima Y. Basic and clinical studies of prodrugs of nonsteroidal anti-inflammatory drugs. Pharmacology 1982; 25(1): 39-45.
[http://dx.doi.org/10.1159/000137776] [PMID: 7111381]
[46]
Goldstein JL, Jungwirthová A, David J, et al. Clinical trial: endoscopic evaluation of naproxen etemesil, a naproxen prodrug, vs. naproxen-a proof-of-concept, randomized, double-blind, active-comparator study. Aliment Pharmacol Ther 2010; 32(9): 1091-101.
[http://dx.doi.org/10.1111/j.1365-2036.2010.04442.x] [PMID: 20804454]
[47]
Qandil A. Prodrugs of nonsteroidal anti-inflammatory drugs (NSAIDs), more than meets the eye: a critical review. Int J Mol Sci 2012; 13(12): 17244-74.
[http://dx.doi.org/10.3390/ijms131217244] [PMID: 23247285]
[48]
Fodey TL, Barnes P, Crooks SRH. Production of antisera to phenylbutazone and oxyphenylbutazone for use in immunochemical detection assays. Food Agric Immunol 2016; 27(2): 288-300.
[http://dx.doi.org/10.1080/09540105.2015.1086979]
[49]
Andrews FM, Reinemeyer CR, Longhofer SL. Effects of top-dress formulations of suxibuzone and phenylbutazone on development of gastric ulcers in horses. Vet Ther 2009; 10(3): 113-20.
[PMID: 20037965]
[50]
Mehta V, Johnston A, Cheung R, Bello A, Langford RM. Intravenous parecoxib rapidly leads to COX-2 inhibitory concentration of valdecoxib in the central nervous system. Clin Pharmacol Ther 2008; 83(3): 430-5.
[http://dx.doi.org/10.1038/sj.clpt.6100304] [PMID: 17687276]
[51]
Teagarden DL, Nema S. Case study: Parecoxib: A prodrug of valdecoxib. Prodrugs. Biotechnology: Pharmaceutical Aspects 2007; V(Part 1): 1335-46.
[http://dx.doi.org/10.1007/978-0-387-49785-3_51]
[52]
Gaynes B, Onyekwuluje A. Topical ophthalmic NSAIDs: A discussion with focus on nepafenac ophthalmic suspension. Clin Ophthalmol 2008; 2(2): 355-68.
[http://dx.doi.org/10.2147/OPTH.S1067] [PMID: 19668727]
[53]
Walters T, Raizman M, Ernest P, Gayton J, Lehmann R. In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. J Cataract Refract Surg 2007; 33(9): 1539-45.
[http://dx.doi.org/10.1016/j.jcrs.2007.05.015] [PMID: 17720067]
[54]
Day EA, Ford RJ, Smith BK, et al. Salsalate reduces atherosclerosis through AMPKβ1 in mice. Mol Metab 2021; 53: 101321.
[http://dx.doi.org/10.1016/j.molmet.2021.101321] [PMID: 34425254]
[55]
Jung TW, Youn BS, Choi HY, et al. Salsalate and adiponectin ameliorate hepatic steatosis by inhibition of the hepatokine fetuin-A. Biochem Pharmacol 2013; 86(7): 960-9.
[http://dx.doi.org/10.1016/j.bcp.2013.07.034] [PMID: 23948064]
[56]
Sehajpal S, Prasad DN, Singh RK. Prodrugs of non-steroidal anti-inflammatory drugs (NSAIDs): A long march towards synthesis of safer NSAIDs. Mini Rev Med Chem 2018; 18(14): 1199-219.
[http://dx.doi.org/10.2174/1389557518666180330112416] [PMID: 29600762]
[57]
Chen W, Zhong Y, Feng N, Guo Z, Wang S, Xing D. New horizons in the roles and associations of COX-2 and novel natural inhibitors in cardiovascular diseases. Mol Med 2021; 27(1): 123.
[http://dx.doi.org/10.1186/s10020-021-00358-4] [PMID: 34592918]
[58]
He Y, Qin M, Li M, Zhi D, Tian B, Qin F. Comparison of in vivo pharmacokinetic behaviors of R‐ and S‐flurbiprofen after intravenous injection of flurbiprofen axetil. Chirality 2023; 35(4): 247-55.
[http://dx.doi.org/10.1002/chir.23531] [PMID: 36759185]
[59]
Kotera A. Efficacy of flurbiprofen axetil for preventing postanesthetic shivering in patients undergoing gynecologic laparotomy surgeries. JA Clin Rep 2020; 6(1): 96.
[http://dx.doi.org/10.1186/s40981-020-00403-x] [PMID: 33289050]
[60]
Wu H, Chen Z, Sun G, et al. Intravenous flurbiprofen axetil can increase analgesic effect in refractory cancer pain. J Exp Clin Cancer Res 2009; 28(1): 33.
[http://dx.doi.org/10.1186/1756-9966-28-33] [PMID: 19267934]
[61]
Sánchez J, Martínez L, García-Barbal J, Roser R, Bartlett A, Sagarra R. The influence of gastric emptying on droxicam pharmacokinetics. J Clin Pharmacol 1989; 29(8): 739-45.
[http://dx.doi.org/10.1002/j.1552-4604.1989.tb03409.x] [PMID: 2778095]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy