Evolution of nonsteroidal anti-inflammatory drugs (NSAIDs): cyclooxygenase (COX) inhibition and beyond
20 Sep 2008-Journal of Pharmacy and Pharmaceutical Sciences (J Pharm Pharm Sci)-Vol. 11, Iss: 2, pp 81
TL;DR: This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects.
Abstract: Purpose. NSAIDs constitute an important class of drugs with therapeutic applications that have spanned several centuries. Treatment of inflammatory conditions such as rheumatoid arthritis (RA) and osteoarthritis (OA) starting from the classic drug aspirin to the recent rise and fall of selective COX-2 inhibitors has provided an enthralling evolution. Efforts to discover an ultimate magic bullet to treat inflammation continues to be an important drug design challenge. This review traces the origins of NSAIDs, their mechanism of action at the molecular level such as cyclooxygenase (COX) inhibition, development of selective COX-2 inhibitors, their adverse cardiovascular effects, and some recent developments targeted to the design of effective anti-inflammatory agents with reduced side effects. Methods. Literature data is presented describing important discoveries pertaining to the sequential development of classical NSAIDs and then selective COX-2 inhibitors, their mechanism of action, the structural basis for COX inhibition, and recent discoveries. Results. A brief history of the development of NSAIDs and the market withdrawal of selective COX-2 inhibitors is explained, followed by the description of prostaglandin biosynthesis, COX isoforms, structure and function. The structural basis for COX-1 and COX-2 inhibition is described along with methods used to evaluate COX-1/COX-2 inhibition. This is followed by a section that encompasses the major chemical classes of selective COX-2 inhibitors. The final section describes briefly some of the recent advances toward developing effective anti-inflammatory agents such as nitric oxide donor NO-NSAIDs, dual COX/LOX inhibitors and anti-TNF therapy. Conclusions. A great deal of progress has been made toward developing novel anti-inflammatory agents. In spite of the tremendous advances in the last decade, the design and development of a safe, effective and economical therapy for treating inflammatory conditions still presents a major challenge.
Citations
More filters
TL;DR: The Methylation Effect in Medicinal Chemistry Eliezer J. Barreiro,* Arthur E. K€ummerle, and Carlos A. M. Fraga Laborat orio de Avaliac-~ao e Síntese de Subst̂ancias Bioativas (LASSBio), Faculdade de Farm acia, Universidade Federal do Rio de Janeiro, CCS, Cidade Universit aria.
Abstract: The Methylation Effect in Medicinal Chemistry Eliezer J. Barreiro,* Arthur E. K€ummerle, and Carlos A. M. Fraga Laborat orio de Avaliac-~ao e Síntese de Subst̂ancias Bioativas (LASSBio), Faculdade de Farm acia, Universidade Federal do Rio de Janeiro, CCS, Cidade Universit aria, CP 68.006, 21941-902 Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Farmacologia e Química Medicinal, Instituto de Cîencias Biom edicas, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil Programa de P os-Graduac-~ao em Química, Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universit aria, Ilha do Fund~ao, Rio de Janeiro, RJ, Brazil
572 citations
TL;DR: The GI toxicity of the NSAIDs is discussed, lower but still therapeutics doses of some NSAIDs may be cardioprotective and their renal and CV adverse effects are assessed.
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) are used chronically to reduce pain and inflammation in patients with arthritic conditions, and also acutely as analgesics by many patients Both therapeutic and adverse effects of NSAIDs are due to inhibition of cyclooxygenase (COX) enzyme NSAIDs are classified as non-selective and COX-2-selective inhibitors (COXIBS) based on their extent of selectivity for COX inhibition However, regardless of their COX selectivity, reports are still appearing on the GI side effect of NSAIDs particularly on the lower gastrointestinal (GI) tract and the harmful role of their controlled release formulations In addition, previously unpublished data stored in the sponsor’s files, question the GI sparing properties of rofecoxib, a COXIB that has been withdrawn due to cardiovascular (CV) side effects Presently, the major side effects of NSAIDs are the GI complications, renal disturbances and CV events There is a tendency to believe that all NSAIDs are associated with renal and CV side effects, a belief that is not supported by solid evidence Indeed, lower but still therapeutics doses of some NSAIDs may be cardioprotective In this review, we briefly discuss the GI toxicity of the NSAIDs and assess their renal and CV adverse effects in more detail This article is open to POST-PUBLICATION REVIEW Registered readers (see “For Readers”) may comment by clicking on ABSTRACT on the issue’s contents page
556 citations
TL;DR: DTINet is introduced, whose performance is enhanced in the face of noisy, incomplete and high-dimensional biological data by learning low-dimensional vector representations, which accurately explains the topological properties of individual nodes in the heterogeneous network.
Abstract: The emergence of large-scale genomic, chemical and pharmacological data provides new opportunities for drug discovery and repositioning. In this work, we develop a computational pipeline, called DTINet, to predict novel drug-target interactions from a constructed heterogeneous network, which integrates diverse drug-related information. DTINet focuses on learning a low-dimensional vector representation of features, which accurately explains the topological properties of individual nodes in the heterogeneous network, and then makes prediction based on these representations via a vector space projection scheme. DTINet achieves substantial performance improvement over other state-of-the-art methods for drug-target interaction prediction. Moreover, we experimentally validate the novel interactions between three drugs and the cyclooxygenase proteins predicted by DTINet, and demonstrate the new potential applications of these identified cyclooxygenase inhibitors in preventing inflammatory diseases. These results indicate that DTINet can provide a practically useful tool for integrating heterogeneous information to predict new drug-target interactions and repurpose existing drugs.Network-based data integration for drug-target prediction is a promising avenue for drug repositioning, but performance is wanting. Here, the authors introduce DTINet, whose performance is enhanced in the face of noisy, incomplete and high-dimensional biological data by learning low-dimensional vector representations.
502 citations
TL;DR: The present review provides a comprehensive insight of the existing knowledge and recent developments on NSAID-induced organ damage while reiterating on the emerging instances of NSAID drug repurposing along with pharmacophore modification aimed at safer usage of NSAIDs where toxic effects are tamed without compromising the clinical benefits.
493 citations
Cites methods from "Evolution of nonsteroidal anti-infl..."
...preferentially selective towards PGHS-2 [29-32]....
[...]
...The inhibitory 214 ratio is based on the PGHS-1 IC50/ PGHS-2 IC50 [29, 31-32]....
[...]
TL;DR: While strategies and guidelines aimed at reducing NSAID-associated complications exist, there is a need for evidence-based algorithms combining cardiovascular and gastrointestinal factors that can be used to aid treatment decisions at an individual patient level.
Abstract: Non-steroidal anti-inflammatory drugs (NSAIDs) represent a diverse class of drugs and are among the most commonly used analgesics for arthritic pain worldwide, though long-term use is associated with a spectrum of adverse effects. The introduction of cyclooxygenase-2-selective NSAIDs early in the last decade offered an alternative to traditional NSAIDs with similar efficacy and improved gastrointestinal tolerability; however, emerging concerns about cardiovascular safety resulted in the withdrawal of two agents (rofecoxib and valdecoxib) in the mid-2000s and, subsequently, in an overall reduction in NSAID use. It is now understood that all NSAIDs are associated with some varying degree of gastrointestinal and cardiovascular risk. Guidelines still recommend their use, but little is known of how patients use these agents. While strategies and guidelines aimed at reducing NSAID-associated complications exist, there is a need for evidence-based algorithms combining cardiovascular and gastrointestinal factors that can be used to aid treatment decisions at an individual patient level.
314 citations
Cites background from "Evolution of nonsteroidal anti-infl..."
...COX-2-mediated production of pro-aggregatory thromboxane in platelets and anti-aggregatory prostaglandin I2 in endothelial cells [18, 75, 76]....
[...]
...tract, and pro-aggregatory thromboxane A2 in the platelets [17, 18]....
[...]
References
More filters
TL;DR: Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.
Abstract: Experiments with guinea-pig lung suggest that some of the therapeutic effects of sodium salicylate and aspirin-like drugs are due to inhibition of the synthesis of prostaglandins.
8,204 citations
Additional excerpts
...novel anti-inflammatory therapies (2)....
[...]
University Health Network1, University of Southern California2, Merck & Co.3, National Autonomous University of Mexico4, University of Texas Health Science Center at Houston5, University of New South Wales6, Federal University of São Paulo7, Nottingham University Hospitals NHS Trust8, University of Maryland, Baltimore9, Northwestern University10
TL;DR: In patients with rheumatoid arthritis, treatment with rofecoxib, a selective inhibitor of cyclooxygenase-2, is associated with significantly fewer clinically important upper gastrointestinal events than treatment with naproxen, a nonselective inhibitor.
Abstract: Background Each year, clinical upper gastrointestinal events occur in 2 to 4 percent of patients who are taking nonselective nonsteroidal antiinflammatory drugs (NSAIDs). We assessed whether rofecoxib, a selective inhibitor of cyclooxygenase-2, would be associated with a lower incidence of clinically important upper gastrointestinal events than is the nonselective NSAID naproxen among patients with rheumatoid arthritis. Methods We randomly assigned 8076 patients who were at least 50 years of age (or at least 40 years of age and receiving long-term glucocorticoid therapy) and who had rheumatoid arthritis to receive either 50 mg of rofecoxib daily or 500 mg of naproxen twice daily. The primary end point was confirmed clinical upper gastrointestinal events (gastroduodenal perforation or obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers). Results Rofecoxib and naproxen had similar efficacy against rheumatoid arthritis. During a median follow-up of 9.0 months, 2.1 confirmed ga...
3,816 citations
"Evolution of nonsteroidal anti-infl..." refers background in this paper
...for celecoxib and the TARGET trial for lumiracoxib did not indicate an increased risk of cardiovascular events (47-49)....
[...]
...Clinical trials indicate short term GI safety benefits occur with selective COX-2 inhibitors compared to traditional NSAID therapy (47-49)....
[...]
TL;DR: In this study, celecoxib, at dosages greater than those indicated clinically, was associated with a lower incidence of symptomatic ulcers and ulcer complications combined, as well as other clinically important toxic effects, compared with NSAIDs at standard dosages.
Abstract: ContextConventional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated
with a spectrum of toxic effects, notably gastrointestinal (GI) effects, because
of inhibition of cyclooxygenase (COX)-1. Whether COX-2–specific inhibitors
are associated with fewer clinical GI toxic effects is unknown.ObjectiveTo determine whether celecoxib, a COX-2–specific inhibitor, is
associated with a lower incidence of significant upper GI toxic effects and
other adverse effects compared with conventional NSAIDs.DesignThe Celecoxib Long-term Arthritis Safety Study (CLASS), a double-blind,
randomized controlled trial conducted from September 1998 to March 2000.SettingThree hundred eighty-six clinical sites in the United States and Canada.ParticipantsA total of 8059 patients (≥18 years old) with osteoarthritis (OA)
or rheumatoid arthritis (RA) were enrolled in the study, and 7968 received
at least 1 dose of study drug. A total of 4573 patients (57%) received treatment
for 6 months.InterventionsPatients were randomly assigned to receive celecoxib, 400 mg twice per
day (2 and 4 times the maximum RA and OA dosages, respectively; n = 3987);
ibuprofen, 800 mg 3 times per day (n = 1985); or diclofenac, 75 mg twice per
day (n = 1996). Aspirin use for cardiovascular prophylaxis (≤325 mg/d)
was permitted.Main Outcome MeasuresIncidence of prospectively defined symptomatic upper GI ulcers and ulcer
complications (bleeding, perforation, and obstruction) and other adverse effects
during the 6-month treatment period.ResultsFor all patients, the annualized incidence rates of upper GI ulcer complications
alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 0.76%
vs 1.45% (P = .09) and 2.08% vs 3.54% (P = .02), respectively. For patients not taking aspirin, the annualized
incidence rates of upper GI ulcer complications alone and combined with symptomatic
ulcers for celecoxib vs NSAIDs were 0.44% vs 1.27% (P
= .04) and 1.40% vs 2.91% (P = .02). For patients
taking aspirin, the annualized incidence rates of upper GI ulcer complications
alone and combined with symptomatic ulcers for celecoxib vs NSAIDs were 2.01%
vs 2.12% (P = .92) and 4.70% vs 6.00% (P = .49). Fewer celecoxib-treated patients than NSAID-treated patients
experienced chronic GI blood loss, GI intolerance, hepatotoxicity, or renal
toxicity. No difference was noted in the incidence of cardiovascular events
between celecoxib and NSAIDs, irrespective of aspirin use.ConclusionsIn this study, celecoxib, at dosages greater than those indicated clinically,
was associated with a lower incidence of symptomatic ulcers and ulcer complications
combined, as well as other clinically important toxic effects, compared with
NSAIDs at standard dosages. The decrease in upper GI toxicity was strongest
among patients not taking aspirin concomitantly.
3,213 citations
"Evolution of nonsteroidal anti-infl..." refers background in this paper
...for celecoxib and the TARGET trial for lumiracoxib did not indicate an increased risk of cardiovascular events (47-49)....
[...]
...Clinical trials indicate short term GI safety benefits occur with selective COX-2 inhibitors compared to traditional NSAID therapy (47-49)....
[...]
TL;DR: This review examines how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors.
Abstract: ▪ Abstract The prostaglandin endoperoxide H synthases-1 and 2 (PGHS-1 and PGHS-2; also cyclooxygenases-1 and 2, COX-1 and COX-2) catalyze the committed step in prostaglandin synthesis. PGHS-1 and 2 are of particular interest because they are the major targets of nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin, ibuprofen, and the new COX-2 inhibitors. Inhibition of the PGHSs with NSAIDs acutely reduces inflammation, pain, and fever, and long-term use of these drugs reduces fatal thrombotic events, as well as the development of colon cancer and Alzheimer's disease. In this review, we examine how the structures of these enzymes relate mechanistically to cyclooxygenase and peroxidase catalysis, and how differences in the structure of PGHS-2 confer on this isozyme differential sensitivity to COX-2 inhibitors. We further examine the evidence for independent signaling by PGHS-1 and PGHS-2, and the complex mechanisms for regulation of PGHS-2 gene expression.
2,780 citations
"Evolution of nonsteroidal anti-infl..." refers background in this paper
...N-glycosylation of the COX isoforms is required for enzyme folding and activity (27)....
[...]
...of PG’s, thromboxanes (TxA) and other eicosanoids (11, 26, 27)....
[...]
...These products act as secondary messengers by interacting with prostanoid G-protein coupled receptors and other receptors (27)....
[...]
...In response to a wide variety of stimuli, free AA is released which is subsequently converted via COX, lipoxygenase (LOX) and cytochrome P450 enzyme catalysis to various lipid mediators known collectively as eicosanoids (27)....
[...]
TL;DR: The discovery ofCOX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1, which may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.
Abstract: Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer’s disease.
2,729 citations
"Evolution of nonsteroidal anti-infl..." refers background or methods in this paper
...Selective COX-2 inhibitors have been extensively studied in the treatment and prevention of a variety of cancers (10, 62)....
[...]
...Studies using animal models of renal diseases, and patients with congestive heart failure, liver cirrhosis or renal insufficiency have shown that PGE2 was primarily responsible for maintaining normal kidney function (10)....
[...]
...This discovery led to the hypothesis that anti-inflammatory prostaglandins (PGs) were produced through constitutive expression of COX-1, whereas the proinflammatory PGs were produced via induction of the COX-2 isoform (9-10)....
[...]