Vous êtes sur la page 1sur 14

21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

Author: Daniel H Solomon, MD, MPH


Section Editor: Daniel E Furst, MD
Deputy Editor: Paul L Romain, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jul 2018. | This topic last updated: Jul 27, 2018.

INTRODUCTION — The primary effect of the nonsteroidal antiinflammatory drugs (NSAIDs) is to inhibit
cyclooxygenase (COX or prostaglandin synthase [PGHS]), thereby impairing the ultimate transformation of
arachidonic acid to prostaglandins, prostacyclin, and thromboxanes (figure 1) [1]. The extent of enzyme
inhibition varies among the different NSAIDs, although there are no studies relating the degree of COX
inhibition with antiinflammatory efficacy in individual patients [2,3]. (See "NSAIDs: Pharmacology and
mechanism of action".)

Two related isoforms of the COX enzyme have been described [4,5]: COX-1 (PGHS-1) and COX-2 (PGHS-
2). They possess 60 percent homology in those amino acid sequences apparently conserved for catalysis of
arachidonic acid [6-10]. The most important differences between the two isoforms are the regulation and
expression of the enzymes in various tissues:

● COX-1 is expressed in most tissues, but variably. It is described as a "housekeeping" enzyme,


regulating normal cellular processes (such as gastric cytoprotection, vascular homeostasis, platelet
aggregation, and kidney function), and it is stimulated by hormones or growth factors.

● COX-2 is constitutively expressed in the brain, in the kidney, in bone, and probably in the female
reproductive system [11]. Its expression at other sites is increased during states of inflammation or,
experimentally, in response to mitogenic stimuli. As an example, growth factors, phorbol esters, and
interleukin (IL)-1 stimulate the expression of COX-2 in fibroblasts, while endotoxin serves the same
function in monocytes/macrophages [5,12].

● Both COX isoforms are regulated by physiologic stimuli, including shear stress in the vasculature [13]
and ovulation and implantation in the female reproductive tract of rodents [14]. In the human kidney, in
nonphysiologic states such as diabetic nephropathy, hypertension, bone fracture, and heart failure,
increased expression of COX-2 mRNA and protein has been noted [15]. The clinical relevance of this is
not yet clear.

Thus, differences in the extent to which a particular NSAID inhibits an isoform of COX may affect both its
activity and toxicity. It has been proposed that the perfect NSAID would inhibit the inducible COX-2 isoform
(thereby decreasing inflammation) without having any effect on the constitutive COX-1 isoform (thereby
minimizing toxicity). Such an agent would maximize effectiveness without inducing toxicity, particularly
gastroduodenal erosions. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity".)

Most traditional NSAIDs are nonselective inhibitors of both COX-1 and COX-2. Selective COX-2 inhibitors,
celecoxib, rofecoxib, and valdecoxib, received approval from the US Food and Drug Administration (FDA).
All three were approved for use in rheumatoid arthritis and osteoarthritis, while rofecoxib and celecoxib were
also approved for use in acute pain. Rofecoxib was withdrawn worldwide by the manufacturer due to an
increased risk of adverse cardiovascular events seen in a placebo-controlled trial. Valdecoxib was also
withdrawn from the United States and European Union markets in April 2005. (See "COX-2 selective
inhibitors: Adverse cardiovascular effects".)

Other selective COX-2 inhibitors that are being actively investigated include etoricoxib and lumiracoxib.
Parecoxib, a water soluble prodrug that is metabolized to valdecoxib [16,17], seems unlikely to be
commercially developed following the withdrawal of valdecoxib.
https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 1/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

The selective COX-2 inhibitors demonstrate at least a 200- to 300-fold selectivity for inhibition of COX-2
over COX-1 at the defined therapeutic doses (figure 2). They provide comparable analgesia to the
nonspecific NSAIDs among patients with rheumatoid arthritis and osteoarthritis and several benefits,
particularly a reduction in gastroduodenal toxicity (since COX-1 is involved in gastric cytoprotection).
However, the one remaining agent in this class, celecoxib, never received approval from the FDA to be
marketed as safer on the gastrointestinal system. Selective COX-2 inhibitors have not been approved for
use in children.

An overview of selective COX-2 inhibitors will be presented here. Their use in specific disorders is
discussed separately. (See appropriate topics).

BENEFITS — The principal benefit with the selective cyclooxygenase (COX)-2 inhibitors is the production
of comparable analgesia and antiinflammatory effects to the nonselective nonsteroidal antiinflammatory
drugs (NSAIDs), but with fewer symptomatic gastric and duodenal ulcers and a decrease in gastrointestinal
symptoms. An additional possible benefit is protection against the development of colon cancer; this has yet
to be clearly shown.

Analgesia and antiinflammatory activity — Celecoxib was approved based upon the results of five
clinical trials (some of which have been published only in preliminary form) involving more than 5200
patients with osteoarthritis or rheumatoid arthritis in which its efficacy and toxicity were compared with
nonselective NSAIDs and placebo [18-21]. One of the published studies included a total of 688 patients with
rheumatoid arthritis who completed a controlled trial comparing various doses of celecoxib with naproxen or
placebo for 12 weeks [18]. All doses of celecoxib and naproxen improved signs and symptoms of arthritis
compared with placebo. Similar results were found in a second study of 655 patients with rheumatoid
arthritis, which compared the efficacy and gastrointestinal toxicity of celecoxib versus diclofenac [19].

Celecoxib is also as efficacious as ketoprofen in ankylosing spondylitis [22]. (See "Assessment and
treatment of ankylosing spondylitis in adults".)

Rofecoxib had equivalent efficacy in patients with osteoarthritis to that of nonselective NSAIDs, such as
diclofenac and ibuprofen [23-25], and to that of the selective COX-2 inhibitor celecoxib [26]. Rofecoxib (12.5
mg daily) was both more efficacious and had a more rapid onset of action than nabumetone (500 mg twice
daily) [27]. Its efficacy was similar to that of naproxen for the treatment of rheumatoid arthritis [28]. However,
as noted above, rofecoxib was withdrawn worldwide by the manufacturer due to increased risk of adverse
cardiovascular events.

Valdecoxib had approximately the same efficacy in treating patients with rheumatoid arthritis as naproxen;
American College of Rheumatology 20 percent (ACR20) response rates of about 50 percent were noted for
both agents from week 2 through week 12 compared with 30 to 36 percent for placebo [29]. Valdecoxib
doses of 10, 20, and 40 mg per day were equally efficacious. Likewise, valdecoxib appears to be equivalent
in efficacy to diclofenac as assessed in a study of 722 patients with RA who were randomly assigned to
valdecoxib (either 20 or 40 mg per day) or diclofenac (75 mg twice daily) [30]. However, like rofecoxib,
valdecoxib has been removed from the market due to an apparent increase in the risk of cardiovascular
events and allergic reactions associated with its use. (See "COX-2 selective inhibitors: Adverse
cardiovascular effects".)

Lumiracoxib is a highly selective COX-2 inhibitor that is efficacious at doses of 100 mg to 400 mg daily for
osteoarthritis [31,32]. It does not contain a sulfonamide or sulfone moiety. It is approved for use in the
United Kingdom.

Etoricoxib is another highly selective COX-2 inhibitor. In a randomized trial that compared etoricoxib (30 mg
daily) with ibuprofen (800 mg three times daily) and with placebo in 528 patients with osteoarthritis [33], a
beneficial effect of treatment was apparent by two weeks of treatment. Etoricoxib was significantly more
effective than placebo and similar to ibuprofen in the amount of pain relief and improvement in patient global
assessment. Drug-related adverse events were significantly more frequent in those receiving ibuprofen
https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 2/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

when compared with the placebo group, but there was no significant difference between the ibuprofen and
etoricoxib groups. Larger long-term studies are underway to address the cardiovascular safety of etoricoxib.

Reduction in gastroduodenal toxicity — Many clinical trials have confirmed the efficacy and relative
reduction in gastroduodenal toxicity of all of the selective COX-2 inhibitors when compared with
nonselective NSAIDs. Detailed information regarding these trials is presented elsewhere (see "COX-2
inhibitors and gastroduodenal toxicity: Major clinical trials"). The range of findings can be briefly summarized
by the following observations, which address the relative frequency of ulceration detected by surveillance
endoscopy and of adverse clinical gastrointestinal events:

● Representative of the results from surveillance endoscopy is a trial in which 688 patients with
rheumatoid arthritis were randomly assigned to various doses of celecoxib, naproxen, or placebo for 12
weeks [18]. All doses of celecoxib and naproxen improved signs and symptoms of arthritis compared
with placebo. The incidence of endoscopically determined gastroduodenal ulcers among patients taking
celecoxib was similar to that of those taking placebo (approximately 4 percent) and significantly lower
than that of those taking naproxen (26 percent) (figure 3). However, it is not clear that endoscopic
results are a surrogate for an endpoint that includes ulcer complications.

● Ulcer symptoms and complications were the focus of a prospective trial (CLASS study) involving 8059
patients that found celecoxib to be significantly associated with a reduced incidence of a combined
outcome (symptomatic ulcers and ulcer complications) compared with ibuprofen or diclofenac at six
months [20]. In addition, celecoxib was associated with a decrease in liver toxicity, hypertension, and
edema compared with the nonselective NSAIDS. At the final study endpoint (one year), there was no
statistically significant reduction in ulcers and their complications among patients taking celecoxib.
There was substantial patient dropout, making the final study time point difficult to interpret.

● In the subsequent Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen
or Naproxen (PRECISION) trial, subjects with osteoarthritis or rheumatoid arthritis using a proton pump
inhibitor were randomly allocated to receive celecoxib, ibuprofen, or naproxen [34,35]. Clinically
significant adverse gastrointestinal events (a composite outcome that included either symptomatic
ulcers or bleeding, obstruction, perforation events from the stomach downwards) were less common
with celecoxib, occurring, respectively, in 0.34, 0.74, and 0.66 percent of patients (hazard ratios [HR] for
celecoxib versus ibuprofen of 0.43, 95% CI 0.27-0.68; and for celecoxib versus naproxen of 0.51, 95%
CI 0.32-0.81).

● The effect of rofecoxib on adverse clinical gastrointestinal events (gastroduodenal perforation or


obstruction, upper gastrointestinal bleeding, and symptomatic gastroduodenal ulcers) was evaluated in
a trial (VIGOR study) of 8076 patients with rheumatoid arthritis who were randomly assigned to
rofecoxib or naproxen [28]. At a median follow-up of nine months, significantly fewer events occurred in
the rofecoxib group (2.1 versus 4.5 per 100 patient-years, relative risk [RR] 0.5, 95% CI 0.3-0.6).

A possible concern of selective COX-2 inhibition is the potential to delay healing of gastric erosions or
ulcers, an effect that has been observed in mouse models [36]. Although neither a clinically significant nor
statistically significant delay in healing of ulcers was observed in the clinical trials of celecoxib,
approximately 40 percent of the patients included in the trials were required to be free of ulcers prior to
study entry. In addition, studies on rofecoxib excluded patients with active peptic ulcer disease. Thus, it is
still unclear whether the COX-2 inhibitors may induce damage to the gastrointestinal tract, even though
there may be no effects on COX-1 activity in vivo at any therapeutic dose. Instead, the observed
gastrointestinal effects of the Selective COX-2 inhibitors may be due to the drug effect on healing of ulcers
induced through other pathologic effects. (See "NSAIDs (including aspirin): Pathogenesis of gastroduodenal
toxicity".)

Effect of low-dose aspirin — The potential gastroduodenal sparing effect with selective COX-2 agents
may be counterbalanced by toxicity from concurrent low-dose aspirin therapy for primary or secondary

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 3/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

prevention of cardiovascular or cerebrovascular disease. As an example, in the CLASS trial, similar rates of
ulcers and ulcer complications were noted among those receiving celecoxib plus low-dose aspirin as were
those among patients receiving a nonselective NSAID plus aspirin (2.02 and 2.12 percent, respectively)
[20]. However, in the PRECISION trial, where all subjects were using a proton pump inhibitor, even those
taking low-dose aspirin had fewer gastrointestinal events (eg, for celecoxib versus ibuprofen, HR 0.52, 95%
CI 0.29-0.94). Thus, if one decides to pursue use of an NSAID or selective COX-2 inhibitor in a patient
requiring concomitant aspirin therapy, then consideration should be given to using a proton pump inhibitor
prophylactically. (See "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and
"Aspirin in the primary prevention of cardiovascular disease and cancer", section on 'Bleeding'.)

An abrogation of the gastrointestinal sparing effect was seen when lumiracoxib was combined with low-dose
aspirin [37].

Possible prevention of colon cancer — A number of studies have documented an association between
the use of aspirin and other NSAIDs and a reduced risk of colorectal adenomas; this reduction in risk
extends to colorectal cancer [38]. The evidence supporting these associations is provided elsewhere. (See
"NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

One possible mechanism by which aspirin NSAIDs may prevent colon cancer is the inhibition of COX-2.
Studies in human colon cancer have shown increased COX-2 expression when compared with the adjacent
colonic mucosa; similar observations have been made in experimental models of colon cancer [39-41].
COX-2 expression may also increase the metastatic potential of colon cancer cells and possibly influence
patient survival [42,43]. In one study, for example, COX-2 expression was determined in 76 patients with a
variety of stages of colorectal cancer [43]. Ten-year survival was significantly higher in patients with the
lowest levels of COX-2 staining (68 versus 35 percent).

These findings suggest that COX-2 activation may promote tumor growth. Consistent with this hypothesis is
a study in which human colon cancer cells that expressed high levels of COX-2 were implanted into nude
mice; treatment with a selective COX-2 inhibitor reduced tumor formation by 85 to 90 percent and inhibited
colony formation of cultured cells [40]. This benefit was not seen with tumor cells that lacked COX-2.

There may also be an interaction between COX-2 inhibition and the induction of apoptosis. In one report,
the ras mutation (found in 50 percent of colorectal carcinomas) made rat intestinal epithelial cells more
resistant to spontaneous apoptosis [44]. The ras-transformed cells also had increased expression of COX-
2. Administration of a COX-2 selective antagonist impaired the growth of these cells by both inhibition of cell
proliferation and the induction of apoptosis. However, in another study, a different COX-2 selective
antagonist induced apoptosis in a colorectal cancer cell line that lacked detectable COX-2 expression,
suggesting that COX-2 selective NSAIDs may induce apoptosis via mechanisms that do not involve COX-2,
or it may be the result of a combination of these effects [45].

A controlled trial involving 83 patients with familial adenomatous polyposis (FAP) suggested that one of the
COX-2 inhibitors (celecoxib 400 mg twice daily) was associated with a 28 percent reduction in rectal polyps.
These data led a US Food and Drug Administration (FDA) advisory panel to recommend the drug for
approval in patients with phenotypic expression of FAP (see "Clinical manifestations and diagnosis of
familial adenomatous polyposis"). The data from the selective COX-2 inhibitor non-familial adenomatous
polyp prevention trials APPROVe and APC are still awaited.

However, increased rates of cardiovascular events have been noted in some primary prevention trials that
utilized the selective COX-2 inhibitors celecoxib and rofecoxib. The cardiovascular risks associated with
COX-2 selective agents, including the results of the polyp prevention trials, are presented in detail
separately. (See "COX-2 selective inhibitors: Adverse cardiovascular effects".)

Lack of effect upon platelets — Generation of prostanoids by activated platelets plays an important role in
platelet function and in promoting vasoconstriction (see "Platelet biology", section on 'Eicosanoids and
arachidonate'). Since production of the potent prostanoid, thromboxane A2, is dependent upon COX-1,
https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 4/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

inhibition of COX-2 alone should produce little or no effect upon platelet function. This has been
substantiated in one study in which doses of celecoxib that were much larger than those used in clinical
practice were given to normal subjects for 10 days; platelet function was assessed with in vitro measures as
well as measurement of bleeding time [46]. Neither celecoxib at 600 mg twice daily (which is greater than
the usual maximum dose of 200 mg BID) nor placebo had any measurable effect on platelet function, while
naproxen 500 mg twice daily produced significant prolongation of the bleeding time and decreases in
platelet aggregation and adhesion.

Reduced risk of bleeding in anticoagulated patients — The lack of an inhibitory effect on platelet
function of the selective COX-2 inhibitors, as noted above, may be valuable when an antiinflammatory effect
is needed for a patient who is receiving ongoing anticoagulation. This was illustrated by a case-control study
of 1491 reported episodes of bleeding in patients who were anticoagulated with warfarin [47]. Cases were
patients who bled who reported use of an NSAID (selective COX-2 or not), and controls were warfarin-
treated patients who reported NSAID use but who did not bleed.

Cases more often used a nonselective NSAID than controls (96 versus 88 percent, respectively). The
adjusted odds ratio (OR) for bleeding was approximately threefold higher for those using nonselective
agents compared with use of COX-2 inhibitors (OR 3.07, 95% CI 1.18-8.03). Use of highly selective COX-2
inhibitors was infrequent, with most patients using somewhat selective agents (nabumetone and
meloxicam). (See 'Other relatively selective COX-2 inhibitors' below.)

Lack of bronchoconstriction — Unlike aspirin and some NSAIDs, selective COX-2 inhibitors appear to
have little risk of precipitating bronchospasm in patients with aspirin-induced asthma (see "NSAIDs
(including aspirin): Allergic and pseudoallergic reactions", section on 'Highly selective COX-2 inhibitors' and
"Aspirin-exacerbated respiratory disease"). However, despite the reassuring data from clinical trials, it
should be noted that the manufacturers' labeling for the coxibs in the United States includes a warning that
they should not be given to patients who have experienced asthma, urticaria, or allergic reactions after
taking aspirin or other NSAIDs.

TOXICITIES AND POSSIBLE TOXICITIES — Limited data are available concerning the toxicity associated
with cyclooxygenase (COX)-2 inhibitors outside the gastrointestinal tract [48]. In addition, the long-term
safety of this class of drugs has not been established.

Cardiovascular disease — A discussion of adverse cardiovascular effects that may occur with some
selective COX-2 inhibitors is presented in detail elsewhere. (See "COX-2 selective inhibitors: Adverse
cardiovascular effects".)

Acute renal failure — Multiple studies in vitro and in animals suggest that the COX-2 enzyme has a
significant role in renal development and function [49-53]. In mice, for example, deletion of the COX-2 gene
is associated with aberrant kidney development after birth, resulting in marked diffuse tubular cysts,
glomerular hypoplasia, interstitial fibrosis, and renal failure [49,54]. The enzyme is also constitutively
expressed and occasionally upregulated in the macula densa, cortical thick ascending limb, and cortical
collecting duct [50]. In rabbits, the functional effects of selective COX-2 inhibition include an enhanced
pressor effect of angiotensin-2 and decreased renal medullary blood flow, urine output, and sodium
excretion [55].

Despite these findings in animals, the clinical trials with celecoxib and rofecoxib did not demonstrate
significant changes in renal function associated with treatment at the approved doses for osteoarthritis and
rheumatoid arthritis. However, these studies are limited since nonsteroidal antiinflammatory drugs (NSAIDs)
generally have little toxicity in the general population of patients with rheumatic diseases. The precipitation
of hemodynamically mediated acute renal failure is limited to selected patients in whom the secretion of
vasodilator prostaglandins is increased in an attempt to counteract the effect of increased renal
vasoconstrictors such as angiotensin II. Patients at risk include those with volume depletion, heart failure,

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 5/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

cirrhosis, intrinsic renal disease (eg, diabetic nephropathy), and hypercalcemia. (See "NSAIDs: Acute
kidney injury (acute renal failure)".)

There is evidence that selective COX-2 inhibitors adversely affect renal function in such at risk patients. As
examples [56-59]:

● In a review of the literature, acute renal failure and/or severe electrolyte disturbances (particularly
hyperkalemia and metabolic acidosis) were clearly precipitated by either celecoxib or rofecoxib [58].
Clinical characteristics shared by almost all 14 patients included older age and one or more risk factor
for NSAID-associated nephrotoxicity such as baseline renal insufficiency, volume depletion, diabetic
nephropathy, congestive heart failure, and/or concurrent use of medications that impair renal potassium
excretion. After discontinuation of selective COX-2 inhibitors and suspect agents in combination with
aggressive supportive therapy, renal function returned to baseline within two days to three weeks.
Acute hemodialysis was required in four patients.

● In another study, 60 older adult patients receiving a low-salt diet were administered rofecoxib (12.5 or
25 mg per day), indomethacin (50 mg three times per day) or placebo over five days [57]. Compared
with placebo, 12.5 mg per day of rofecoxib, 25 mg per day of rofecoxib, and indomethacin significantly
lowered the glomerular filtration rate by 8.4, 7.8, and 6.0 mL/minute per 1.73 m2, respectively. A
companion study of 15 similar patients found that a single dose of high amounts of rofecoxib (250 mg)
had significant and similarly detrimental effects on renal function as a single dose of indomethacin (75
mg) [57].

These observations suggest that selective COX-2 inhibitors should be avoided in patients with chronic
renal insufficiency, severe heart disease, volume depletion, and/or hepatic failure [57,60]. However, there is
evidence from the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or
Naproxen (PRECISION) trial that celecoxib may be associated with fewer renal events than ibuprofen
[34,35]. There were nearly 40 percent fewer renal events in adults using celecoxib compared with ibuprofen
(hazard ratio [HR] 0.61, 95% CI 0.44-0.85). The trend was similar when comparing celecoxib with naproxen,
but did not reach statistical significance (HR 0.79, 95% CI 0.56-1.12).

Discussions relating to acute interstitial nephritis and/or nephrotic syndrome occurring in association with
these agents are presented separately. (See "NSAIDs: Acute kidney injury (acute renal failure)" and
"Clinical manifestations and diagnosis of acute interstitial nephritis".)

Sulfonamide allergy — The molecular structures of celecoxib and valdecoxib include a sulfonamide
moiety, whereas rofecoxib contained a sulfone. The sulfur components are necessary for receptor binding,
but their varying structures have different potentials for causing allergic reactions.

Celecoxib — Cross-reactivity between antimicrobial sulfonamides (such as trimethoprim-


sulfamethoxazole) and celecoxib (a non-arylamine sulfonamide) has not been adequately analyzed,
although some studies suggest it is unlikely. The risk of allergic reactions to celecoxib, potential cross-
reactivity with antimicrobial sulfonamides, and the use of celecoxib in patients with a history of possible
antimicrobial sulfonamide hypersensitivity are discussed in more detail separately. (See "Sulfonamide
allergy in HIV-uninfected patients", section on 'Celecoxib'.)

The COX-2 selective agents, including celecoxib, are associated with higher rates of Stevens-Johnson
syndrome and toxic epidermal necrolysis [61]. (See "Stevens-Johnson syndrome and toxic epidermal
necrolysis: Pathogenesis, clinical manifestations, and diagnosis".)

Valdecoxib — Initial clinical trials of valdecoxib included patients with a history of sulfonamide allergy,
and there was no higher incidence of allergic reactions noted. As a result, sulfonamide allergy was initially
not considered a contraindication to the use of valdecoxib. However, postmarketing reports of serious
anaphylactoid reactions in sulfonamide allergic patients who received valdecoxib led to relabeling with a
caution against use of this agent in patients with an allergy to sulfonamide-containing antibiotics [62]. In

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 6/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

April 2005, the US Food and Drug Administration (FDA) recommended and the manufacturer agreed to a
withdrawal of valdecoxib from the United States and European Union markets.

Anaphylactoid reaction — Patients who have had anaphylactoid reactions to aspirin or nonselective
NSAIDs may be at risk for similar effects when challenged with COX-2 selective agents. This was illustrated
by one patient with well-documented anaphylactoid reactions to diclofenac-misoprostol who had a similar
reaction (shaking, flushing, and hypotension) when given rofecoxib [63]. Rapid resolution of symptoms and
hypotension followed subcutaneous epinephrine and intravenous administration of saline, diphenhydramine,
and methylprednisolone. (See "Anaphylaxis: Emergency treatment".)

Anaphylactoid reactions and angioedema have been reported in association with valdecoxib; serious skin
reactions have also been noted, including exfoliative dermatitis, toxic epidermal necrolysis, and the
Stevens-Johnson syndrome [64].

Aseptic meningitis — Postmarketing surveillance has identified at least five cases of aseptic meningitis in
patients treated with rofecoxib [65]. This uncommon side effect also occurs in patients treated with
nonselective NSAIDs. The incidence of aseptic meningitis in patients receiving rofecoxib is estimated to be
less than 2 percent. (See "Nonselective NSAIDs: Overview of adverse effects".)

Possible proinflammatory activity — Although a large body of evidence suggests that COX-2 is induced
in inflammation, the effect of COX-2 inhibition on inflammation is not completely understood:

● COX-2 knockout mice are as susceptible to inflammation as intact mice [49,66]. Paradoxically, COX-1
knockout mice show less gastric inflammation and ulceration after the administration of indomethacin
than intact mice even though their gastric prostaglandin E2 levels are reduced by 99 percent [67].

● COX-2 may have antiinflammatory properties. Using an animal model of inflammation and carrageenin-
induced pleurisy, one study showed that maximal COX-2 expression coincided with inflammatory
resolution and was associated with minimal prostaglandin E2 synthesis [68].

● Human T lymphocytes express the COX-2 isoenzyme where it may serve a role in both the early and
late events of T-cell activation, such as the production of interleukin (IL)-2, tumor necrosis factor (TNF)-
alpha, and interferon (IFN)-gamma [69].

Healing of musculoskeletal injury

Possible effect on fracture healing — A small increased risk of nonunion in patients with bone
fractures has been reported with the use of nonselective NSAIDs or COX-2 selective agents. However, a
causal relationship has not been proven, and the effect of these drugs on fracture healing in humans is
uncertain. At present, we would not avoid the use of these agents in patients with fractures, given the very
small absolute risk. This is discussed in more detail elsewhere. (See "Nonselective NSAIDs: Overview of
adverse effects", section on 'Possible effect on fracture healing'.)

Possible effect on tendon injury — Possible effects on tendon and ligament injury are discussed
elsewhere. (See "Nonselective NSAIDs: Overview of adverse effects", section on 'Possible effect on tendon
injury'.)

Effects on vision — Irreversible blindness, temporary loss of vision, chromatopsia, and other visual
abnormalities have occurred in patients taking selective COX-2 inhibitors. A postmarketing surveillance
program in New Zealand identified seven cases of visual disturbances in patients taking celecoxib or
rofecoxib; in the six cases where the outcome was known, vision recovered after the selective COX-2
inhibitor was stopped [70]. As of May 2003, reports to the World Health Organization's Collaborating Center
for International Drug Monitoring included 37 cases of blindness and 14 cases of temporary blindness
associated with use of selective COX-2 inhibitors. However, a possible association with temporary or
permanent visual loss was also noted with nonselective NSAIDs.

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 7/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

It is difficult, from postmarketing reports, to conclude that there is a clear causal relationship between use of
COX-2 inhibitors or NSAIDs and vision problems. Although the issue of causality deserves further study,
occurrence of otherwise unexplained loss of vision, blurred vision, color vision changes, or scotomata
should lead to discontinuation of an NSAID or selective COX-2 inhibitor.

Pregnancy and lactation — The safety of NSAIDs during pregnancy and lactation is discussed separately.
(See "Safety of antiinflammatory and immunosuppressive drugs in rheumatic diseases during pregnancy
and lactation", section on 'NSAIDs'.)

OTHER RELATIVELY SELECTIVE COX-2 INHIBITORS — Some older nonsteroidal antiinflammatory drug
(NSAIDs) are also relatively selective for the cyclooxygenase (COX)-2 receptor at low doses. Nabumetone,
for example, appears to be a more effective inhibitor of COX-2 than COX-1 in some experimental systems
[71]. Etodolac and meloxicam also inhibit the COX-2 isoform more than COX-1 (10 to 1 ratio) [72,73].

Nabumetone — Limited clinical data suggest that nabumetone may be less likely to induce gastric ulcers
than other NSAIDs. However, relative inhibition of COX-2 decreases and the risk of ulcer disease increases
when higher doses of nabumetone are used. In one report, for example, the administration of nabumetone
to healthy human volunteers at an adequate antiinflammatory dose inhibited COX-2 and COX-1 to the same
degree [71]. Use of an in vitro model showed that 6-MNA (the active metabolite of nabumetone) also
equally inhibited both COX isoforms in a whole blood system consisting of inducible mononuclear cells.
These results were supported by a second study that found that most NSAIDs did not spare COX-1 activity
at therapeutic concentrations [74]. Thus, rather than a selective effect on COX-2, the relative gastric
protection observed with nabumetone may be due to the neutral state of its prodrug formulation and the fact
that 6-MNA is not a powerful inhibitor of COX at low doses.

Meloxicam — Meloxicam, an NSAID with similar properties as etodolac, is approved by the US Food and
Drug Administration (FDA) for the treatment of osteoarthritis at a starting dose of 7.5 mg per day. This agent
has been available in Europe and elsewhere at doses of 7.5 and 15 mg once per day. As with etodolac,
meloxicam principally inhibits the activity of COX-2 at low doses, while it has more effects upon COX-1 at
higher doses. This loss of COX-2 selectivity with higher doses is mirrored in an increase in the rate of
serious gastrointestinal adverse events when a dose of 15 mg per day is compared with 7.5 mg per day
[75].

In general, this agent has similar effects when used clinically to those of the other NSAIDs. As an example,
a double-blind randomized trial of 774 patients with osteoarthritis compared various doses of meloxicam
(3.75 mg, 7.5 mg, and 15 mg per day) with diclofenac 50 mg twice daily and placebo [76]. The 7.5 and 15
mg per day doses of meloxicam and diclofenac were approximately equal in efficacy and superior to
placebo. Meloxicam was associated with more adverse events than placebo but fewer than diclofenac (58,
48, and 66 percent, respectively). Rates of serious adverse drug-related reactions were less than 3 percent
for patients receiving either diclofenac or meloxicam versus 1.3 percent for placebo. Mild adverse
gastrointestinal side effects occurred in 17, 17, and 19 percent of placebo, meloxicam 15 mg per day, and
diclofenac 50 mg twice daily treated patients, respectively.

Meloxicam is also more efficacious than placebo in patients with rheumatoid arthritis. A randomized trial
compared three different daily doses of meloxicam (7.5 mg, 15 mg, and 22.5 mg) with diclofenac 150 mg
per day and with placebo in 894 patients [77]. The 15 and 22.5 mg daily doses of meloxicam and diclofenac
had similar efficacy and were significantly superior to placebo. Elevation of liver enzymes was more
frequent with diclofenac than meloxicam or placebo, while gastrointestinal adverse event rates were similar
in the three groups. Greater than 0.3 mg/dL (26 micromol/L) increases in serum creatinine were more
frequent in the highest-dose meloxicam and diclofenac groups when compared with placebo (9.5, 8.5, and
3.4 percent, respectively).

CLINICAL ROLE — The need for a nonsteroidal antiinflammatory drug (NSAID; selective or nonselective),
as opposed to acetaminophen, should be assessed in any patient for whom prescription of a selective

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 8/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

cyclooxygenase (COX)-2 inhibitor is being considered. In the absence of clinically apparent inflammation,
an analgesic may be sufficient in some patients.

A patient who requires an antiinflammatory agent for a well-established indication (eg, rheumatoid arthritis)
and who is at high risk for gastroduodenal damage (ie, has one or more risk factors for developing NSAID-
associated gastroduodenal ulcer and complications, such as a prior history of ulcer disease or
gastrointestinal bleeding; age >65; and concomitant use of aspirin, warfarin, clopidogrel, or glucocorticoids)
may be treated with a selective COX-2 inhibitor or a nonselective NSAID plus a gastroprotective agent (ie, a
proton pump inhibitor or misoprostol). (See "NSAIDs (including aspirin): Primary prevention of
gastroduodenal toxicity" and "NSAIDs (including aspirin): Secondary prevention of gastroduodenal toxicity".)

However, patients with known cardiovascular disease (a prior cardiovascular event or obstructive coronary
artery disease on angiography) should not receive an NSAID, selective or nonselective. (See "Nonselective
NSAIDs: Adverse cardiovascular effects" and "COX-2 selective inhibitors: Adverse cardiovascular effects".)

Celecoxib at 100 to 200 mg once per day appears to be the safest dose. Higher doses are clearly
associated with an increased cardiovascular risk and should be avoided, especially in patients with known
cardiovascular risk factors [78]. However, the 400 mg twice-daily dose is reserved for patients with familial
colonic adenomatous polyposis, and this dose has been shown to decrease both the incidence and size of
these polyps. (See "NSAIDs (including aspirin): Role in prevention of colorectal cancer".)

For patients beginning treatment with an NSAID or a selective COX-2 inhibitor who require use of low-dose
aspirin for another indication (most often for known ischemic cardiovascular disease), the lowest effective
dose of aspirin should be used (typically 81 mg daily for cardiovascular prevention), and concomitant use of
a proton pump inhibitor may be necessary to mitigate the risk conferred by aspirin use alone. (See "NSAIDs
(including aspirin): Primary prevention of gastroduodenal toxicity".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics”
and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th
grade reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer short, easy-to-
read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail
these topics to your patients. (You can also locate patient education articles on a variety of subjects by
searching on “patient info” and the keyword(s) of interest.)

● Beyond the Basics topic (see "Patient education: Nonsteroidal antiinflammatory drugs (NSAIDs)
(Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● For patients who require chronic use of nonsteroidal antiinflammatory drugs (NSAIDs), one must first
consider their risk of NSAID-related gastroduodenal toxicity. Risk factors for NSAID-related
gastroduodenal toxicity include age >65 years, use of an anticoagulant (aspirin, warfarin, low molecular
weight heparin, direct thrombin inhibitors, factor Xa inhibitors, and clopidogrel), prior gastrointestinal
bleed, active peptic ulcer disease, and concomitant use of oral glucocorticoids. If any of these risk
factors are present, then one should reconsider whether NSAID therapy is advised and consider other
analgesic options (acetaminophen, low-potency opioids, joint protection with a cane or brace,
musculoskeletal injections, or orthopedic interventions). If NSAID therapy is being considered in a
patient with risk factors for NSAID-related gastroduodenal toxicity, there are three safer options: an
NSAID with a proton pump inhibitor, an NSAID with misoprostol, or a selective cyclooxygenase

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_ty… 9/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

(COX)-2 inhibitor (with or without a proton pump inhibitor). (See "NSAIDs (including aspirin): Primary
prevention of gastroduodenal toxicity".)

● Patients with known coronary heart disease or cerebrovascular disease who require concomitant
therapy with low-dose aspirin should only receive a COX-2-selective NSAID or a nonselective NSAID
after full disclosure of their possible cardiovascular risks. Patients receiving low-dose aspirin may
require prophylaxis to prevent gastroduodenal damage. (See "COX-2 selective inhibitors: Adverse
cardiovascular effects" and "Nonselective NSAIDs: Adverse cardiovascular effects".)

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat
New Biol 1971; 231:232.
2. Brooks PM, Day RO. Nonsteroidal antiinflammatory drugs--differences and similarities. N Engl J Med
1991; 324:1716.
3. Abramson SB, Weissmann G. The mechanisms of action of nonsteroidal antiinflammatory drugs.
Arthritis Rheum 1989; 32:1.
4. Meade EA, Smith WL, DeWitt DL. Differential inhibition of prostaglandin endoperoxide synthase
(cyclooxygenase) isozymes by aspirin and other non-steroidal anti-inflammatory drugs. J Biol Chem
1993; 268:6610.
5. DeWitt DL, Meade EA, Smith WL. PGH synthase isoenzyme selectivity: the potential for safer
nonsteroidal antiinflammatory drugs. Am J Med 1993; 95:40S.
6. DeWitt DL, el-Harith EA, Kraemer SA, et al. The aspirin and heme-binding sites of ovine and murine
prostaglandin endoperoxide synthases. J Biol Chem 1990; 265:5192.
7. Shimokawa T, Smith WL. Prostaglandin endoperoxide synthase. The aspirin acetylation region. J Biol
Chem 1992; 267:12387.
8. Shimokawa T, Smith WL. Essential histidines of prostaglandin endoperoxide synthase. His-309 is
involved in heme binding. J Biol Chem 1991; 266:6168.
9. Shimokawa T, Kulmacz RJ, DeWitt DL, Smith WL. Tyrosine 385 of prostaglandin endoperoxide
synthase is required for cyclooxygenase catalysis. J Biol Chem 1990; 265:20073.
10. Toh H. Prostaglandin endoperoxide synthase contains an EGF-like domain. FEBS Lett 1989; 258:317.
11. Dubois RN, Abramson SB, Crofford L, et al. Cyclooxygenase in biology and disease. FASEB J 1998;
12:1063.
12. Lee SH, Soyoola E, Chanmugam P, et al. Selective expression of mitogen-inducible cyclooxygenase
in macrophages stimulated with lipopolysaccharide. J Biol Chem 1992; 267:25934.
13. Doroudi R, Gan LM, Selin Sjögren L, Jern S. Effects of shear stress on eicosanoid gene expression
and metabolite production in vascular endothelium as studied in a novel biomechanical perfusion
model. Biochem Biophys Res Commun 2000; 269:257.
14. Lim H, Paria BC, Das SK, et al. Multiple female reproductive failures in cyclooxygenase 2-deficient
mice. Cell 1997; 91:197.
15. Khan KN, Stanfield KM, Harris RK, Baron DA. Expression of cyclooxygenase-2 in the macula densa of
human kidney in hypertension, congestive heart failure, and diabetic nephropathy. Ren Fail 2001;
23:321.
16. Cheer SM, Goa KL. Parecoxib (parecoxib sodium). Drugs 2001; 61:1133.

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_… 10/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

17. Stoltz RR, Harris SI, Kuss ME, et al. Upper GI mucosal effects of parecoxib sodium in healthy elderly
subjects. Am J Gastroenterol 2002; 97:65.
18. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of
celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA 1999; 282:1921.
19. Emery P, Zeidler H, Kvien TK, et al. Celecoxib versus diclofenac in long-term management of
rheumatoid arthritis: randomised double-blind comparison. Lancet 1999; 354:2106.
20. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-
inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized
controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 2000; 284:1247.
21. Bensen WG, Fiechtner JJ, McMillen JI, et al. Treatment of osteoarthritis with celecoxib, a
cyclooxygenase-2 inhibitor: a randomized controlled trial. Mayo Clin Proc 1999; 74:1095.
22. Dougados M, Béhier JM, Jolchine I, et al. Efficacy of celecoxib, a cyclooxygenase 2-specific inhibitor,
in the treatment of ankylosing spondylitis: a six-week controlled study with comparison against placebo
and against a conventional nonsteroidal antiinflammatory drug. Arthritis Rheum 2001; 44:180.
23. Saag K, van der Heijde D, Fisher C, et al. Rofecoxib, a new cyclooxygenase 2 inhibitor, shows
sustained efficacy, comparable with other nonsteroidal anti-inflammatory drugs: a 6-week and a 1-year
trial in patients with osteoarthritis. Osteoarthritis Studies Group. Arch Fam Med 2000; 9:1124.
24. Cannon GW, Caldwell JR, Holt P, et al. Rofecoxib, a specific inhibitor of cyclooxygenase 2, with clinical
efficacy comparable with that of diclofenac sodium: results of a one-year, randomized, clinical trial in
patients with osteoarthritis of the knee and hip. Rofecoxib Phase III Protocol 035 Study Group. Arthritis
Rheum 2000; 43:978.
25. Day R, Morrison B, Luza A, et al. A randomized trial of the efficacy and tolerability of the COX-2
inhibitor rofecoxib vs ibuprofen in patients with osteoarthritis. Rofecoxib/Ibuprofen Comparator Study
Group. Arch Intern Med 2000; 160:1781.
26. Gibofsky A, Williams GW, McKenna F, Fort JG. Comparing the efficacy of cyclooxygenase 2-specific
inhibitors in treating osteoarthritis: appropriate trial design considerations and results of a randomized,
placebo-controlled trial. Arthritis Rheum 2003; 48:3102.
27. Kivitz AJ, Greenwald MW, Cohen SB, et al. Efficacy and safety of rofecoxib 12.5 mg versus
nabumetone 1,000 mg in patients with osteoarthritis of the knee: a randomized controlled trial. J Am
Geriatr Soc 2004; 52:666.
28. Bombardier C, Laine L, Reicin A, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and
naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 2000; 343:1520.
29. Bensen W, Weaver A, Espinoza L, et al. Efficacy and safety of valdecoxib in treating the signs and
symptoms of rheumatoid arthritis: a randomized, controlled comparison with placebo and naproxen.
Rheumatology (Oxford) 2002; 41:1008.
30. Pavelka K, Recker DP, Verburg KM. Valdecoxib is as effective as diclofenac in the management of
rheumatoid arthritis with a lower incidence of gastroduodenal ulcers: results of a 26-week trial.
Rheumatology (Oxford) 2003; 42:1207.
31. Tannenbaum H, Berenbaum F, Reginster JY, et al. Lumiracoxib is effective in the treatment of
osteoarthritis of the knee: a 13 week, randomised, double blind study versus placebo and celecoxib.
Ann Rheum Dis 2004; 63:1419.
32. Schnitzer TJ, Beier J, Geusens P, et al. Efficacy and safety of four doses of lumiracoxib versus
diclofenac in patients with knee or hip primary osteoarthritis: a phase II, four-week, multicenter,
randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2004; 51:549.
33. Wiesenhutter CW, Boice JA, Ko A, et al. Evaluation of the comparative efficacy of etoricoxib and
ibuprofen for treatment of patients with osteoarthritis: A randomized, double-blind, placebo-controlled
trial. Mayo Clin Proc 2005; 80:470.
https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_t… 11/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

34. Nissen SE, Yeomans ND, Solomon DH, et al. Cardiovascular safety of celecoxib, naproxen, or
ibuprofen for arthritis. N Engl J Med 2016; 375:2519.
35. Yeomans ND, Graham DY, Husni ME, et al. Randomised clinical trial: gastrointestinal events in arthritis
patients treated with celecoxib, ibuprofen or naproxen in the PRECISION trial. Aliment Pharmacol
Ther 2018; 47:1453.
36. Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions
and its inhibition by the specific antagonist delays healing in mice. Gastroenterology 1997; 112:387.
37. Schnitzer TJ, Burmester GR, Mysler E, et al. Comparison of lumiracoxib with naproxen and ibuprofen
in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer
complications: randomised controlled trial. Lancet 2004; 364:665.
38. Giovannucci E, Egan KM, Hunter DJ, et al. Aspirin and the risk of colorectal cancer in women. N Engl
J Med 1995; 333:609.
39. Eberhart CE, Coffey RJ, Radhika A, et al. Up-regulation of cyclooxygenase 2 gene expression in
human colorectal adenomas and adenocarcinomas. Gastroenterology 1994; 107:1183.
40. Sheng H, Shao J, Kirkland SC, et al. Inhibition of human colon cancer cell growth by selective
inhibition of cyclooxygenase-2. J Clin Invest 1997; 99:2254.
41. DuBois RN, Radhika A, Reddy BS, Entingh AJ. Increased cyclooxygenase-2 levels in carcinogen-
induced rat colonic tumors. Gastroenterology 1996; 110:1259.
42. Tsujii M, Kawano S, DuBois RN. Cyclooxygenase-2 expression in human colon cancer cells increases
metastatic potential. Proc Natl Acad Sci U S A 1997; 94:3336.
43. Sheehan KM, Sheahan K, O'Donoghue DP, et al. The relationship between cyclooxygenase-2
expression and colorectal cancer. JAMA 1999; 282:1254.
44. Sheng GG, Shao J, Sheng H, et al. A selective cyclooxygenase 2 inhibitor suppresses the growth of
H-ras-transformed rat intestinal epithelial cells. Gastroenterology 1997; 113:1883.
45. Elder DJ, Halton DE, Hague A, Paraskeva C. Induction of apoptotic cell death in human colorectal
carcinoma cell lines by a cyclooxygenase-2 (COX-2)-selective nonsteroidal anti-inflammatory drug:
independence from COX-2 protein expression. Clin Cancer Res 1997; 3:1679.
46. Leese PT, Hubbard RC, Karim A, et al. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on
platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol 2000; 40:124.
47. Knijff-Dutmer EA, Van der Palen J, Schut G, Van de Laar MA. The influence of cyclo-oxygenase
specificity of non-steroidal anti-inflammatory drugs on bleeding complications in concomitant
coumarine users. QJM 2003; 96:513.
48. Lipsky PE, Brooks P, Crofford LJ, et al. Unresolved issues in the role of cyclooxygenase-2 in normal
physiologic processes and disease. Arch Intern Med 2000; 160:913.
49. Morham SG, Langenbach R, Loftin CD, et al. Prostaglandin synthase 2 gene disruption causes severe
renal pathology in the mouse. Cell 1995; 83:473.
50. Ferguson S, Hébert RL, Laneuville O. NS-398 upregulates constitutive cyclooxygenase-2 expression
in the M-1 cortical collecting duct cell line. J Am Soc Nephrol 1999; 10:2261.
51. Kömhoff M, Wang JL, Cheng HF, et al. Cyclooxygenase-2-selective inhibitors impair glomerulogenesis
and renal cortical development. Kidney Int 2000; 57:414.
52. Harris RC. Cyclooxygenase-2 in the kidney. J Am Soc Nephrol 2000; 11:2387.
53. Khan KN, Paulson SK, Verburg KM, et al. Pharmacology of cyclooxygenase-2 inhibition in the kidney.
Kidney Int 2002; 61:1210.
54. Norwood VF, Morham SG, Smithies O. Postnatal development and progression of renal dysplasia in
cyclooxygenase-2 null mice. Kidney Int 2000; 58:2291.

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_… 12/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

55. Qi Z, Hao CM, Langenbach RI, et al. Opposite effects of cyclooxygenase-1 and -2 activity on the
pressor response to angiotensin II. J Clin Invest 2002; 110:61.
56. Perazella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis 2000; 35:937.
57. Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in
elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med 2000; 133:1.
58. Perazella MA, Tray K. Selective cyclooxygenase-2 inhibitors: a pattern of nephrotoxicity similar to
traditional nonsteroidal anti-inflammatory drugs. Am J Med 2001; 111:64.
59. Braden GL, O'Shea MH, Mulhern JG, Germain MJ. Acute renal failure and hyperkalaemia associated
with cyclooxygenase-2 inhibitors. Nephrol Dial Transplant 2004; 19:1149.
60. Dunn MJ. Are COX-2 selective inhibitors nephrotoxic? Am J Kidney Dis 2000; 35:976.
61. La Grenade L, Lee L, Weaver J, et al. Comparison of reporting of Stevens-Johnson syndrome and
toxic epidermal necrolysis in association with selective COX-2 inhibitors. Drug Saf 2005; 28:917.
62. New treatment for hemophilia. FDA Consum 2003; 37:5.
63. Schellenberg RR, Isserow SH. Anaphylactoid reaction to a cyclooxygenase-2 inhibitor in a patient who
had a reaction to a cyclooxygenase-1 inhibitor. N Engl J Med 2001; 345:1856.
64. "The Pink Sheet" FDC Reports. Chevy Chase, MD 2002; 64(45):19.
65. Bonnel RA, Villalba ML, Karwoski CB, Beitz J. Aseptic meningitis associated with rofecoxib. Arch
Intern Med 2002; 162:713.
66. Dinchuk JE, Car BD, Focht RJ, et al. Renal abnormalities and an altered inflammatory response in
mice lacking cyclooxygenase II. Nature 1995; 378:406.
67. Langenbach R, Morham SG, Tiano HF, et al. Prostaglandin synthase 1 gene disruption in mice
reduces arachidonic acid-induced inflammation and indomethacin-induced gastric ulceration. Cell
1995; 83:483.
68. Gilroy DW, Colville-Nash PR, Willis D, et al. Inducible cyclooxygenase may have anti-inflammatory
properties. Nat Med 1999; 5:698.
69. Iñiguez MA, Punzón C, Fresno M. Induction of cyclooxygenase-2 on activated T lymphocytes:
regulation of T cell activation by cyclooxygenase-2 inhibitors. J Immunol 1999; 163:111.
70. Coulter DM, Clark DW, Savage RL. Celecoxib, rofecoxib, and acute temporary visual impairment. BMJ
2003; 327:1214.
71. Roth SH. NSAID gastropathy. A new understanding. Arch Intern Med 1996; 156:1623.
72. Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the
cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp
Ther 1994; 271:1705.
73. Glaser K, Sung ML, O'Neill K, et al. Etodolac selectively inhibits human prostaglandin G/H synthase 2
(PGHS-2) versus human PGHS-1. Eur J Pharmacol 1995; 281:107.
74. Cryer B, Feldman M. Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal
anti-inflammatory drugs. Am J Med 1998; 104:413.
75. Singh G, Lanes S, Triadafilopoulos G. Risk of serious upper gastrointestinal and cardiovascular
thromboembolic complications with meloxicam. Am J Med 2004; 117:100.
76. Yocum D, Fleischmann R, Dalgin P, et al. Safety and efficacy of meloxicam in the treatment of
osteoarthritis: a 12-week, double-blind, multiple-dose, placebo-controlled trial. The Meloxicam
Osteoarthritis Investigators. Arch Intern Med 2000; 160:2947.
77. Furst DE, Kolba KS, Fleischmann R, et al. Dose response and safety study of meloxicam up to 22.5
mg daily in rheumatoid arthritis: a 12 week multicenter, double blind, dose response study versus
placebo and diclofenac. J Rheumatol 2002; 29:436.

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_… 13/14
21/8/2018 Overview of selective COX-2 inhibitors - UpToDate

78. Solomon SD, Wittes J, Finn PV, et al. Cardiovascular risk of celecoxib in 6 randomized placebo-
controlled trials: the cross trial safety analysis. Circulation 2008; 117:2104.

Topic 7992 Version 18.0

https://www.uptodate.com/contents/overview-of-selective-cox-2-inhibitors?search=coxibs&source=search_result&selectedTitle=1~150&usage_… 14/14