On the way toward designing next-generation nonsteroidal anti-inflammatory drugs: amtolmetin guacil
https://doi.org/10.14412/1996-7012-2014-2-83-89
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the main component of symptomatic treatment of patients with rheumatic disorders. The use of these drugs reduces the intensity of the most unpleasant symptoms and improves patients’ quality of life. Unfortunately, NSAID therapy is limited by the risk of dangerous gastric and cardiovascular complications. Researchers all over the world are involved in designing new drugs belonging to this family that would be characterized by increased safety. These drugs include coxibs (selective cyclooxygenase-2 (COX-2) inhibitors), combination drugs containing NSAIDs and gastroprotector agents (misoprostol, H2 blockers, proton pump inhibitors), COX2/LOG2 (lipoxygenase 2) inhibitors, and COX-inhibiting nitric oxide donors (CINODs). However, all these drugs proved to have serious drawbacks. Some of them are being actively used; launching of other drugs has been stopped at the stage of clinical trials; while the others were abandoned because of inadequate efficacy/tolerability ratio.
A new representative of improved NSAIDs, amtolmetin guacil (AMG), was synthesized from tolmetin, a nonselective NSAID. As opposed to tolmetin, AMG has a number of gastroprotective properties. The most important one is that it increases NO concentration in the mucous membrane of the gastrointestinal tract. The pharmacological features of AMG are discussed; the data obtained during pre-clinical and clinical trials are reported.
About the Author
A.E. Karateev
V.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, Moscow, Russia
References
1. Насонов ЕЛ. Анальгетическая терапия в ревматологии: путешествие между Сциллой и Харибдой. Клиническая фармакология и терапия. 2003;12(1):64–9. [Nasonov EL. Analgetic therapy in rheumatology: travel between Stsilla and Haribda. Klinicheskaya farmakologiya i terapiya. 2003;12(1):64–9. (In Russ.)]
2. Яхно НН, Кукушкин МЛ, редакторы. Боль (практическое руководство для врачей). Москва: Издательство РАМН; 2012. 512 c. [Yakhno NN, Kukushkin ML, editors. Bol' (prakticheskoe rukovodstvo dlya vrachei) [Pain (practical guidance for doctors)]. Moscow: Izdatel'stvo RAMN; 2012. 512 p.]
3. Lee Y. Effect and treatment of chronic pain in inflammatory arthritis. Curr Rheumatol Rep. 2013;15(1):300. DOI: 10.1007/s11926-012-0300-4.
4. Van de Laar M, Pergolizzi J, Mellinghoff H, et al. Pain treatment in arthritis-related pain: beyond NSAIDs.
5. Open Rheumatology J. 2012;6:320–30. DOI: 10.2174/1874312901206010320. Epub 2012 Dec 13.
6. Fiorucci S, Distrutti E. COXIBs, CINODs and H?S-releasing NSAIDs: current perspectives in the development of safer non steroidal anti-inflammatory drugs. Curr Med Chem. 2011;18(23):3494–505. DOI: http://dx.doi.org/10.2174/ 092986711796642508.
7. Hunt R, Harper S, Watson D, et al. The gastrointestinal safety of the COX-2 selective inhibitor etoricoxib assessed by both endoscopy and analysis of upper gastrointestinal events. Am J Gastroenterol. 2003;98(8):1725–33. DOI: http://dx.doi.org/10.1111/j.1572-0241.2003.07598.x.
8. Laine L, Curtis SP, Cryer B, et al. Assessment of upper gastrointestinal safety of etoricoxib and diclofenac in patients with osteoarthritis and rheumatoid arthritis in the Multinational Etoricoxib and Diclofenac Arthritis Long-term (MEDAL) programme: a randomised comparison. Lancet. 2007;369(9560):465–73. DOI: http://dx.doi.org/10.1016/S0140-6736(07)60234-7.
9. Silverstein F. New strategies for the prevention of serious upper GI complication from NSAIDs: lessons from the MUCOSA trial. New stand. Arthrisis Care Res (Hoboken). 1996;(5):2–6.
10. Acevedo E, Castaneda O, Ugaz M, et al. Tolerability profiles of rofecoxib (Vioxx) and Arthrotec. A comparison of six weeks treatment in patients with osteoarthritis. Scand J Rheumatol. 2001;30(1):19–24. DOI: http://dx.doi.org/10.1080/ 030097401750065274.
11. Roberts D, Miner P. Safety aspects and rational use of a naproxen + esomeprazole combination in the treatment of rheumatoid disease. Drug Healthc Patient Saf. 2011;3:1–8. DOI: 10.2147/DHPS.S7329. Epub 2011 Mar 3.
12. Gigante A, Tagarro I. Non-steroidal antiinflammatory drugs and gastroprotection with proton pump inhibitors: a focus on ketoprofen/omeprazole. Clin Drug Investig. 2012;32(4):221–33. DOI: 10.2165/11596670-000000000-00000.
13. Bello A. DUEXIS® (ibuprofen 800 mg, famotidine 26.6 mg): a new approach to gastroprotection for patients with chronic pain and inflammation who require treatment with a nonsteroidal anti-inflammatory drug. Ther Adv Musculoskelet Dis. 2012;4(5):327–39. DOI: http://dx.doi.org/10.1177/ 1759720X12444710.
14. Kulkarni SK, Singh VP. Licofelone: the answer to unmet needs in osteoarthritis therapy? Curr Rheumatol Rep. 2008 Jan;10(1):43–8.
15. Lanas A. Role of nitric oxide in the gastrointestinal tract. Arthritis Res Ther. 2008;10 Suppl 2:S4. DOI: 10.1186/ar2465.
16. Keeble J, Moore P. Pharmacology and potential therapeutic applications of nitric oxide-releasing non-steroidal anti-inflammatory and related nitric oxide-donating drugs. Br J Pharmacol. 2002;137(7):295–310.
17. Lanas A, Garcia-Rodriguez LA, Arroyo MT, et al. Effect of antisecretory drugs and nitrates on the risk of ulcer bleeding associated with nonsteroidal anti-inflammatory drugs, antiplatelet agents, and anticoagulants. Am J Gastroenterol. 2007;102(3):507–15. DOI: http://dx.doi.org/10.1111/j.1572-0241.2006.01062.x.
18. Lohmander LS, McKeith D, Svensson O, et al. A randomised, placebo controlled, comparative trial of the gastrointestinal safety and efficacy of AZD3582 versus naproxen in osteoarthritis. Ann Rheum Dis. 2005;64(3):449–56. DOI: http://dx.doi.org/10.1136/ard.2004.023572. Epub 2004 Sep 2.
19. Cordrey LJ. Tolmetin sodium, a new anti-arthritis drug: double-blind and long-term studies. J Am Geriatr Soc. 1976;24(10):440–6.
20. McEvoy GK, editor. AHFS Drug Information 2007. Tolmetin. Bethesda, MD: American Society of Health-System Pharmacists; 2007. P. 2118–22.
21. Coruzzi G, Coppelli G, Spaggiari S, et al. Gastroprotective effects of amtolmetin guacyl: a new non-steroidal anti-inflammatory drug that activates inducible aastric nitric oxide svnthase. Dig Liver Dis. 2002;34(6):403–10. DOI: http://dx.doi.org/10.1016/S1590-8658(02)80037-8.
22. Tubaro E, Belogi L, Mezzadri CM. The mechanism of action of amtolmetin guacyl, a new gastroprotective nonsteroidal antiinflammatory drug. Eur J Pharmacol. 2000;387(2):233–44. DOI: http://dx.doi.org/10.1016/S0014-2999(99)00791-8.
23. Morini G, Guaita E, Lazzaretti M, et al. Morphological features of rat gastric mucosa after acute and chronic treatment with amtolmetin guacyl: comparison with non-selective and COX-2-selective NSAIDs. Digestion. 2003;68(2–3):124–32. DOI: http://dx.doi.org/10.1159/000074726.
24. Riezzo G, Chiloiro M, Montanaro S. Protective effect of amtolmetin guacyl versus placebo diclofenac and misoprostol in healthy volunteers evaluated as gastric electrical activity in alcohol-induced stomach damage. Dig Dis Sci. 2001;46(8):1797–804. DOI: http://dx.doi.org/10.1023/A:1010686411837.
25. Tavella A, Ursini G. A clinical study on the anti-inflammatory activity and gastrointestinal tolerability of amtolmetin guacyl, a new NSAID, compared with diclofenac in aged patients with osteoarticular diseases. Clin Ter. 1997 Nov;148(11):543–8.
26. Marcolongo R, Frediani B, Biasi G, et al. A meta-analysis of the tolerability of amtolmetin guacil, a novel, effective nonsteroidal anti-inflammatory drug, compared with established agents. Clin Drug Invest. 1999;17(2):89–96. DOI: http://dx.doi.org/10.2165/00044011-199917020-00002.
27. Jajic Z, Malaise M, Nekam K, et al. Gastrointestinal safety of amtolmetin guacyl in comparison with celecoxib in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2005;23(6):809–18.
28. Belisari A, Mantovani L. Cost-Benefit Analysis of Amtolmetin-Guacil. Clin Drug Invest. 2001;21(1):47–58. DOI: http://dx.doi.org/10.2165/00044011-200121010-00007.
Review
For citations:
Karateev A. On the way toward designing next-generation nonsteroidal anti-inflammatory drugs: amtolmetin guacil. Sovremennaya Revmatologiya=Modern Rheumatology Journal. 2014;8(2):83-89. (In Russ.) https://doi.org/10.14412/1996-7012-2014-2-83-89
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