Antiinflamatórios não esteróides inibidores da ciclooxigenase-2 (COX-2): aspectos atuais

Carmen Luize Kummer; Tereza Cristina R. B. Coelho

doi:10.1590/S0034-70942002000400014

Review Article

Antiinflamatórios não esteróides inibidores da ciclooxigenase-2 (COX-2): aspectos atuais

Cycloxygenase-2 inhibitors nonsteroid anti-inflammatory drugs: current issues

Carmen Luize Kummer; Tereza Cristina R. B. Coelho

http://dx.doi.org/10.1590/S0034-70942002000400014 Braz J Anesthesiol, vol.52, n4, p.498-512, 2002

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Resumo

JUSTIFICATIVA E OBJETIVOS: Devido à alta incidência de efeitos colaterais relacionados aos antiinflamatórios não hormonais (AINES), a descoberta de duas isoformas da enzima ciclooxigenase, classificadas como: COX-1 ou constitutiva e COX-2 ou indutiva, formulou o paradigma que as propriedades antiinflamatórias dos AINES seriam mediadas através da inibição da enzima COX-2; já os efeitos colaterais, do bloqueio da COX-1. Entretanto, a isoforma COX-2 tem sido detectada constitutivamente em tecidos normais, levantando a dúvida sobre o quão realmente são seguros os inibidores específicos desta enzima. O objetivo desta revisão é relatar as mais recentes evidências clínicas e experimentais envolvendo a COX-2 e os compostos inibidores desta isoforma. CONTEÚDO: São exibidos os novos conceitos sobre as diferenças estruturais entre COX-1 e COX-2, a existência destas isoformas nos diversos tecidos, os resultados de experimentos em animais e humanos, além da observação clínica dos compostos inibidores específicos COX-2 (coxibs). Algumas prováveis novas indicações de antiinflamatórios não esteróides, principalmente coxibs, na demência de Alzheimer e em neoplasias são exemplificadas. CONCLUSÕES: Os coxibs representam importante avanço farmacológico no tratamento antiinflamatório, reduzindo a incidência de lesões gastrointestinais e apresentando possível indicação na prevenção de neoplasias e doenças neurológicas. No entanto, tais compostos apresentam efeitos colaterais indistinguíveis dos AINES convencionais e são drogas de alto custo. Como toda medicação de recente lançamento no arsenal médico, maiores avaliações são necessárias para o estabelecimento da real segurança destes compostos.

Palavras-chave

ANALGÉSICOS, ANALGÉSICOS

Abstract

BACKGROUND AND OBJECTIVES: Due to the high incidence of NSAID-related side-effects, the discovery of two cycloxygenase isoforms, classified as: COX-1 or constitutive and COX-2 or inductive, has formulated the paradigm that NSAIDs anti-inflammatory properties would be mediated by COX-2 inhibition, and side-effects, by COX-1 blockade. However, COX-2 has been constitutively detected in normal tissues raising the question of how really safe are specific inhibitors of such enzyme. This review aimed to report new clinical and experimental evidences involving COX-2 and its specific inhibitors. CONTENTS: New concepts on structural differences between COX-1 and COX-2, the existence of these isoforms in different organic tissues, and animal and human experiments are reported, in addition to clinical observations of specific COX-2 inhibitors (coxibs). Potential new therapeutic indications of NSAIDS, mainly coxibs, for Alzheimers disease and cancer are emphasized. CONCLUSIONS: Coxibs are an important pharmacological advance for anti-inflammatory treatment, decreasing the incidence of gastrointestinal adverse effects and probably playing a role in the prevention of cancer and neurological diseases. However, similar side-effects from conventional NSAIDs still exist, and also, coxibs are high-cost drugs. Like any new medication, further evaluations are needed to determine the actual safety profile of such compounds.

Keywords

ANALGESICS, ANALGESICS

References

Dubois R, Abramson S, Crofford L. Cyclooxigenase in biology and disease. Faseb J.. 1998;12:1063-1088.

Tilley Sl, Coffman TM, Koller BH. Mixed messages modulation of inflammation and immune responses by prostaglandins and thromboxanes. J Clin Invest. 2001;108:15-23.

Gottschalk A, Smith DS. New concepts in acute pain therapy: preemptive analgesia. Am Fam Physician. 2001;63:1979-1984.

Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature. 1971;231:232-235.

Dahl V, Aeder JC. Non-opioid postoperative analgesia. Acta Anaesthesiol Scand. 2000;44:1191-1203.

Yaksh TL, Dirig DM, Conway CM. The acute antihy- peralgesic action of nonsteroidal, anti-inflammatory drugs and release of spinal prostaglandin E2 is mediated by the inhibition of constitutive spinal cyclooxygenase-2 (COX-2) but not COX-1. J Neurosc. 2001;21:5847-5853.

Souter AJ, Fredman B, White PF. Controversies in the perioperative use of nonsteroidal antiinflamatory drugs. Anesth Analg. 1994;79:1178-1190.

Perazella MA, Tray K. Selective cyclooxygenase-2 inhibitors: A pattern of nephrotoxicity similar to traditional nosteroidal anti-inflammatory drugs. Am J Med. 2001;111:64-67.

Brooks P, Emery E, Evans F. Interpreting the clinical significance of the diferential inhibition of cyclooxygenase-1 and cyclooxygenase-2. Rheumatology. 1999;38:779-788.

Marnett LJ, Rowlinson WS, Goodwin DC. Arachidonic acid oxygenation by COX-1 and COX-2. J Biol Chem. 1999;274:22903-22906.

Jones R. Nonsteroidal Anti-inflamatory drug prescribing: past, present and future. Am J Med. 2001;110:4s-7s.

Fitzgerald GA, Patrono C. The coxibs, selective inhibitor of cyclooxygenase-2. N Engl J Méd. 2001;345:433-442.

Harris RC, Breyer MD. Physiological regulation of cyclo- oxygenase-2 in the kidney. Am J Physiol Renal Physiol. 2001;281:F1-F11.

Schonbeck U, Sukhova GK, Graber P. Augmented expression of COX-2 in human atherosclerotic lesions. Am J Pathol. 1999;155:1281-1291.

Reddy ST, Herschman HR. Transcellular prostaglandin production following mast cell activation is mediated by proximal secretory phospholipase A2 and distal prostaglandin synthase-. J Biol Chem. 1996;271:186-191.

Lipsky PE. Unresolved issues in the role of cyclooxygenase-2 in normal physiologic processes and disease. Arch Intern Med. 2000;160:913-920.

Beejay V, Wolfe MM. Cyclooxygenase 2 selective inhibitors: panacea or flash in the pan?. Gastroenterology. 1999;117:1002-1005.

Willoughby DA, Moore AR, Colville-Nash PR. - COX-1, COX-2, and COX-3 and the future of chronic inflammatory disease. Lancet. 2000;355:646-648.

Pairet M, Van Ryn J. Experimental models used to investigate the diferential inhibition of cyclooxygenase-1 and cyclooxygenase-2 by non-steroidal anti-inflammatory drugs. Inflamm Res. 1998;47:s93-s101.

Whelton A. Renal aspects of treatment with conventional nonsteroidal anti-inflammatory drugs versus cyclooxygenase-2 specifec inhibitors. Am J Med. 2001;110:33s-42s.

Chan CC, Boyce S, Brideau C. Rofecoxib [VIOXX, MK-0966,4-(4´methylsulfonylphenyl)-3-phenyl-2-(5H)- furanone]: a potent and orally active cyclooxygenase-2 inhibitor-pharmacological and biochemical profiles. J Pharmacol Exp Ther. 1999;290:551-560.

Cannon Gw, Breedveld FC. Efficacy of cyclooxygenase-2 specific inhibitors. Am J Med. 2001;110:6s-12s.

Jain KK. Evaluation of intravenous parecoxib for the relief of acute post-surgical pain. Expert Opin Investig Drugs. 2000;9:2717-2723.

Cheer SM, Goa KL. Parecoxib (parecoxib sodium). Drugs. 2001;61:1133-1141.

Lee A, Cooper MG, Craig JC. Effects of nonsteroidal anti-inflammatory drugs on post-operative renal function in adults. Cochrane Database Syst Rev. 2000;4.

Harris CJ, Brater DC. - Renal effects of cyclooxygenase 2 selective inhibitors. Curr Opin Nephrol Hypertens. 2001;10:603-610.

Wang JL, Cheng HF, Harris RC. Cyclooxygenase inhibition decreases rennin content and lowers blood pressure in a model of renovascular hypertension. Hypertension. 1999;34:96-101.

Wolf K, Castrop H, Hartner A. Inhibition of the rennin-angiotensin system upregulates cyclooxygenase-2 expression in the macula densa. Hypertension. 1999;34:503-507.

Yang T, Schnermann JB, Briggs JP. Regulation of cyclo- oxygenase-2 expression in renal medulla by tonicity in vivo and in vitro. Am J Physiol Renal Physiol. 1999;277:F1-F9.

Hao CM, Yull F, Blackwell T. Dehydration activates an NF-kB-driven: COX-2 dependent survival mechanism in renal medullary intesticial cells. J Clin Invest. 2000;106:973-982.

Cowley A, Mattson D, Lu S. The renal medulla and hypertension. Hypertension. 1995;25:663-673.

Brater DC. Effects of nonsteroidal anti-inflammatory drugs on renal function: focus on cyclooxygenase-2 inhibition. Am J Med. 1999;107:65s-70s.

Komhoff M, Wang JL, Cheng HF. Cyclooxygenase-2 selective inhibitors impair glomerulogenesis and renal cortical development. Kidney Int. 2000;57:414-422.

Nantel F, Meadows E, Denis D. Immunolocalization of cyclooxygenase-2 in the macula densa of human elderly. FEBS letters. 1999;457:475-477.

Rocha JL, Férnandez-Alonso J. Acute tubulointersticial nephritis associated with the selective COX2 enzyme inhibitor, rofecoxib. Lancet. 2001;357:1946-1947.

Buttgereit F, Burmester GR, Simon LS. Gastrointestinal toxic side effects of nonsteroidal antiiflammatory drugs and cyclooxygenase-2 specific inhibitors. Am J Med. 2001;110:13s-19s.

Emery P. Cyclooxygenase-2: A major therapeutic advance?. Am J Med. 2001;110:42s-45s.

Eckmann L, Stenson C, Matsuda K. Induction of intestinal epithelial cells in the host secretory response to infection by invasive bacteria: bacterial entry induces epithelial prostaglandin H synthase-2 expression and prostaglandin E2 and F2α production. J Clin Invest. 1997;100:269-309.

Schnitzer TJ. Cyclooxygenase-2 specific inhibitors: Are they safe?. Am J Med. 2001;110:46s-49s.

Patrono C. Aspirin as an antiplatelet drug. N Eng J Med. 1994;330:1287-1294.

Rodriguez-Tellez M, Arguelles F, Herrerias JM. Antiiniflammatory agents less dangerous for gastointestinal tract. Current Pharm Des. 2001;7:951-976.

Yeomans ND. New data on healing of nonsteroidal anti-inflammatory drug associated ulcers and erosion: omeprazole NSAID steering committee. Am J Med. 1998;104:56s-61s.

O´Beirne JP, Cairns SR. Cholestatic hepatitis in association with celecoxib. Br Med J. 2001;323:23.

Maddrey WC, Maurath CJ, Verburg KM. The hepatic safety and tolerability of the novel cyclooxygenase inhibitor celecoxib. Am J Ther. 2000;7:153-158.

Carillo-Jimenez R, Nurnberger M. Celecoxib-induced acute pancreatitis and hepatitis. Arch Intern Med. 2000;170:553-554.

Knowles S, Shapiro L, Shear NH. Should celecoxib be contraindicated in patients who are allergic to sulfonamides?: Revisiting the meaning of "sulfa" allergy. Drug Saf. 2001;24:239-247.

Catella-Lawson F, Crofford LJ. Cyclooxygenase inhibition and thrombogenicity. Am J Med. 2001;110:28s-32s.

Wijeyaratne SM, Abbott CR, Homer-Vanniasinkam S. Differences in the detection of cyclo-oxygenase 1 and 2 proteins in symptomatic and asymptomatic carotid plaques. Br J Surg. 2001;88:951-957.

Hawkey CJ, Lanas AI. Doubt and certainty about NSAID in the year 2000: a multidisciplinary expert statement. Am J Med. 2001;110:79s-100s.

Lipsky PE. Recommendations for the clinical use of cyclooxygenase-2-specific inhibitors. Am J Med. 2001;110:3s-5s.

Boers M. NSAIDS and COX-2 inhibitors: competition between gastroprotection and cardioprotection. Lancet. 2001;357:1222-1223.

Karplus TM, Saag KG. Nonsteroidal anti-inflammatory drugs and cognitive function: have a beneficial or deleterious effect?. Drug Saf. 1998;19:427-433.

Norwitz ER, Robinson JN, Challis JR. The control of labor. N Engl J Med. 1999;341:660-666.

Sawdy R, Slater D, Fisk N. Use of a cycoloxygenase type -2 selective non-steroidal anti-inflammatory agent to preent preterm delivery. Lancet. 1997;350:265-266.

Peruzzi L, Glanogllo B, Porcellinni MG. Neonatal end-stage renal failure associated with maternal ingestion of COX-2 selective inhibitor nimesulide as tocolytic. Lancet. 1999;354(9190):1615.

Sjodahl R. Extent, mode and dose dependence of anticancer effects. Am J Med. 2001;110:66S-69S.

Myers C, Koki A, Pamukcu R. Proapoptotic anti-inflammatory drugs. Urology. 2001;57:73S-75S.

Khan KN, Masferrer Jl, Woerner BM. Enhanced cyclooxygenase-2 expression in sporadic and familial adenomatous polyposis of the human colon. Scan J Gastroenterol. 2001;36:865-869.

Steibach G, Lynch PM, Phillips R. Effect of celecoxib on colorectal polyposis (FAP). Am Gastroenterol. 1999;94:A440.

Antiinflamatórios não esteróides inibidores da ciclooxigenase-2 (COX-2): aspectos atuais

Cycloxygenase-2 inhibitors nonsteroid anti-inflammatory drugs: current issues

Carmen Luize Kummer; Tereza Cristina R. B. Coelho

Resumo

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Abstract

Keywords

References

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