Selective cyclooxygenase-2 (COX-2) inhibitors: importance and limitations

The discovery of an inducible form of cyclooxygenase (COX-2) requires a refinement of the theory that inhibition of cyclooxygenase activity explains both therapeutic effects and side-effects of non-steroidal anti-inflammatory drugs (NSAIDs). Selective COX-2 inhibitors have demonstrated in clinical trials a significantly better gastrointestinal tolerability than classical NSAIDs, for the same anti-inflammatory activity. Their tolerability in patients with active ulcer or with a recent history of ulcer as well as in patients suffering from cardiovascular or renal diseases has still to be investigated in detail. Their therapeutic potential in several new indications, including pre-term labour, colorectal cancer and Alzheimer's disease, is currently being investigated.     

Ulcerogenic influence of selective cyclooxygenase-2 inhibitors in the rat stomach with adjuvant-induced arthritis

Cyclooxygenase (COX)-2 inhibitors have been developed as new gastric sparing anti-inflammatory drugs. We previously reported that the ulcerogenic response to conventional nonselective COX inhibitors, such as indomethacin and aspirin, was markedly increased in arthritic rats. The ulcerogenic effect of selective COX-2 inhibitors in arthritic animals, however, remains unknown. The present study was designed to examine the influence of selective COX-2 inhibitors, such as rofecoxib and celecoxib, on gastric mucosal integrity in rats with adjuvant-induced arthritis. Arthritis was induced in male dark Agouti rats by injection of Freund's complete adjuvant into the right hind paw. Two weeks after the injection, the animals were fasted for 18 h, various COX inhibitors were administered orally, and the mucosa was examined for lesions 4 h later. Oral administration of indomethacin caused hemorrhagic gastric lesions in both normal and arthritic rats, although the severity of lesions was significantly greater in the latter group. In contrast, neither rofecoxib nor celecoxib caused any gastric damage in normal rats, but both drugs provoked hemorrhagic gastric lesions in arthritic rats. The expression of COX-2 mRNA and immuno-positive cells was observed in the gastric mucosa of arthritic but not normal rats. The gastric mucosal prostaglandin (PG) E(2) content was significantly elevated in arthritic rats in a rofecoxib-sensitive manner. In conclusion, COX-2 inhibitors produce gastric lesions in arthritic rats, similar to the nonselective COX-inhibitors. COX-2 is up-regulated in the stomach of arthritic rats, and PGs produced by COX-2 play a role in maintaining the integrity of the gastric mucosa.     

Update on the management of pain in arthritis and the use of cyclooxygenase-2 inhibitors

Chronic pain from arthritis continues to be one of the biggest causes of disability and loss of function in the United States today. This is still the case despite many new insights into the pathophysiology of pain, effective treatment approaches, and new, safer medications that can be used long-term. There are many different types of arthritic problems. New disease-modifying agents that are available for some of these types of arthritic diseases, such as rheumatoid arthritis, have the potential to have a substantial impact on improvement in the long-term prognosis. Despite this optimistic outlook, pain often is a significant problem and should be treated whenever it becomes a barrier to function. To complicate treatment for this condition, the most widely used group of medications is under new scrutiny because of concerns regarding long-term detrimental side effects. A complete understanding of the risk factors for NSAIDs, specifically cyclooxygenase-2 inhibitors, is still not available. But published data and new clinical guidelines still suggest that treatment for this large category of diseases can be effective and safe.     

COX-2-selective inhibitors in the treatment of arthritis

Therapy with nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) has long been the cornerstone of pharmacologic management of patients with osteoarthritis (OA) and rheumatoid arthritis (RA). Many patients with OA or RA, however, are at increased risk of developing clinically significant adverse events associated with NSAID therapy, particularly upper gastrointestinal (GI) complications including symptomatic and complicated ulcers. The introduction of cyclooxygenase (COX)-2-selective inhibitors (coxibs) represents a major advance in the pharmacologic approach to the signs and symptoms of arthritis. In addition to the first two members of this class, celecoxib and rofecoxib, other coxibs have been introduced or are in development (valdecoxib, etoricoxib). In numerous clinical trials, coxibs have been shown to be as effective as nonselective NSAIDs in relieving pain and inflammation associated with OA and RA, and notably, with a significantly lower risk of NSAID-type adverse events. The use of coxibs to treat OA and RA is recommended as first-line therapy when symptoms of pain and inflammation are present in patients vulnerable to potential NSAID-associated GI toxicity.     

Coxibs: cyclooxygenase-2 inhibitors

The oxygenating enzyme cyclooxygenase (COX) catalysis the conversion of arachidonic acid to proinflammatory prostaglandins. For many years it was thought that COX is a single enzyme that is present constitutively in most tissues. But in the late 80ies COX activity was found to be increased in inflammatory states with cytokines and bacterial lipopolysaccharides as inducing agents. The expression of the induced COX is inhibited by glucocorticoids which is not the case with the COX known up to then. According to these findings COX exists in two forms, the aminoacid sequences of which are known. The expression of COX-1 is not or only poorly regulated, the prostaglandins produced by it are responsible for the protection of the gastric mucosa, maintenance of normal kidney function and platelet aggregation. COX-2, in contrast, is highly regulated, the prostaglandins produced by this isoenzyme are involved in inflammation, fever and pain but also in the regulation of kidney function. Conventional non-steroidal antiinflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2. The analgesic, antipyretic and antiinflammatory effects of these agents are accounted for by COX-2 inhibition, whereas the toxic effects on the stomach as well as the inhibition of platelet aggregation are attributed to COX-1 inhibition. In search for selective blockers of COX-2, celecoxib and rofecoxib were developed which have an analgetic and antirheumatic potency similar to that of conventional NSAIDs but are associated with significantly fewer adverse gastroduodenal events. The renal toxicity of the selective COX-2 inhibitors is not better than that of the non-selective NSAIDs.     

The cyclooxygenase-2 inhibitors: safety and effectiveness.

OBJECTIVE: To review the development of cyclooxygenase-2 (COX-2) inhibitors and discuss specific agents that are currently under investigation or have been marketed. DATA SOURCES: Primary literature on selective COX inhibitors was identified from a comprehensive MEDLINE, English-literature search from January 1966 through September 1998, with additional studies selected by review of the references. Abstracts from recent meetings and package insert literature from approved agents were also used as source material. Indexing terms included COX-2 inhibitors, meloxicam, celecoxib, rofecoxib, flosulide, SC-58635, and MK-966. STUDY SELECTION: Human clinical, pharmacokinetic, and dose-ranging trials performed in Europe and the US and randomized comparative trials were reviewed. DATA SYNTHESIS: With the discovery of at least two COX isoforms, a better understanding of the mechanism of action and gastrointestinal toxicity of nonsteroidal antiinflammatory drugs (NSAIDs) has been realized. While COX-1 is involved in physiologic maintenance, COX-2 seems to be involved in inflammation, mitogenesis, and specialized signal transductions. Selective COX-2 inhibitors may allow maximum antiinflammatory activity while improving the safety profile associated with NSAID therapy. Celecoxib and rofecoxib have been approved by the Food and Drug Administration for the treatment of osteo- and rheumatoid arthritis; meloxicam is undergoing Phase III clinical trials. Preliminary data indicate that the selective COX-2 inhibitors provide analgesic and antiinflammatory efficacy comparable with older NSAIDs, with fewer adverse gastrointestinal effects. CONCLUSIONS: Specific COX-2 inhibitors offer promising benefits over older NSAIDs with regard to gastrointestinal safety while maintaining analgesic and antiinflammatory efficacy. Further study is required to determine long-term efficacy and safety in clinical use.     

Selective serotonin-reuptake inhibitors for the treatment of hot flashes

OBJECTIVE: To review the literature evaluating the use of selective serotonin-reuptake inhibitors (SSRIs) for the treatment of hot flashes. DATA SOURCES: Biomedical literature was accessed through MEDLINE (1966-June 2003), MD Consult, and references of reviewed articles. Key search terms used were hot flashes, vasomotor symptoms, antidepressants, and SSRIs. DATA SYNTHESIS: Recent evidence from the Women's Health Initiative precludes the use of traditional hormonal therapy in some women. Nonhormonal therapies are possible options, but conflicting evidence of efficacy exists. CONCLUSIONS: Although further studies are warranted, preliminary data suggest that SSRIs are generally modestly successful in reducing the frequency and severity of hot flashes.     

Cardiovascular risk of selective cyclooxygenase-2 inhibitors

Recently, cyclooxygenase-2 (COX-2) inhibitors (coxibs), a class of drugs intended to be painkillers, have created unprecedented controversy because of their cardiovascular risk profile. The controversy has affected the patients, health-care providers, the Food and Drug Administration, and the manufacturers of these agents alike. We summarize the mechanisms of actions of this class of agents, their cardiovascular risk as evident in multiple trials, the basis of their adverse risk profile, and our views on this issue.     

Nephrotoxic potential of selective cyclooxygenase-2 inhibitors

OBJECTIVE: To determine the relative nephrotoxic potential of cyclooxygenase (COX)-2 inhibitors. DATA SOURCES: A MEDLINE search (1996-February 2004) identified clinical trials evaluating the nephrotoxicity of COX-2 inhibitors versus traditional nonsteroidal antiinflammatory drugs (NSAIDs). Key search terms included cyclooxygenase inhibitors, nonsteroidal antiinflammatory agents, nephrotoxicity, and chemically induced. DATA SYNTHESIS: Three clinical trials determined that COX-2 inhibitors have similar adverse effects on the kidney when compared with nonselective NSAIDs, while 2 studies concluded that COX-2 inhibitors are less nephrotoxic than nonselective NSAIDs. All 5 trials utilized low numbers of subjects, short-term therapy, and surrogate markers of kidney damage. CONCLUSIONS: COX-2 inhibitors may not offer distinct advantages over nonselective NSAIDs with respect to kidney function. Longer trials in patients with comorbidities are warranted. These agents should be used cautiously or not at all in patients with predisposing conditions.     

Selective COX-2 inhibitors and the surgical patient.

The identification of COX-2 less than a decade ago has been followed by an unprecedented period of discovery and drug development (Golden & Abramson, 1999). Clinical studies thus far have established that the selective COX-2 inhibitors, celecoxib (Celebrex) and rofecoxib (Vioxx) are effective in the treatment of OA and RA, as are conventional NSAIDs. However, they do not cause the same adverse effects on the GI mucosa nor do they increase bleeding time as do conventional NSAIDs. Therefore, their use is not contraindicated in pre or postsurgical patients. Further investigation is underway to fully elucidate the role of COX-2 and to determine any additional benefits of selective COX-2 inhibition.     

Recent development of selective cyclooxygenase-2 inhibitors

Nonsteroidal anti-inflammatory drugs(NSAIDs) are clinically effective against the inflammatory symptoms of rheumatoid arthritis. Recent attention has been focused on selective cyclooxygenase(COX)-2 inhibitors, a type of NSAID that inhibits a subtype of COX. Because of the different actions of COX-1 and COX-2, selective COX-2 inhibitors were expected to reduce adverse reactions such as gastrointestinal disorders. Various clinical studies have confirmed that the efficacy of COX-2 inhibitors for RA is similar to that of conventional NSAIDs, but they cause fewer severe gastrointestinal disorders. The incidence of complications related to renal dysfunction, such as edema and hypertension, is not different. Patients using selective COX-2 inhibitors have recently been reported to show an increase in thrombotic complications such as myocardial infarction. Therefore, more data on adverse events should be collected in the future from large-scale clinical studies to further clarify the actual value of selective COX-2 inhibitors.     

Cardiovascular effects of selective cyclooxygenase-2 inhibitors

Selective cyclooxygenase-2 inhibitors represent a significant advance in the management of inflammatory disorders. They have similar efficacy to nonselective 'conventional' nonsteroidal anti-inflammatory drugs, but a superior gastrointestinal safety profile. However, a significant caveat is the perceived potential of cyclooxygenase-2 inhibitors to cause adverse cardiovascular effects, an issue first raised by the Vioxx Gastrointestinal Outcomes Research (VIGOR) study of rofecoxib (Vioxx, Merck & Co. Inc.). Mechanisms by which cyclooxygenase-2 inhibitors may increase cardiovascular risk are selective inhibition of prostaglandin I2 over thromboxane A2 within the eicosanoid pathway, which promotes thrombosis, and inhibition of prostaglandins E2 and I2 within the kidney, which leads to sodium and water retention and blood pressure elevation. In spite of this, the cardiovascular findings from VIGOR are not firmly supported by observations from large cohort studies and other clinical trials of selective cyclooxygenase-2 inhibitors, including the Celecoxib Long-term Arthritis Safety Study. The two main theories that explain the VIGOR findings are that the comparator used (naproxen; Naprosyn, Roche) is cardioprotective and that very high doses of rofecoxib were used, but at present neither is backed by firm evidence. Indeed, there is now early evidence that selective cyclooxygenase-2 inhibition with celecoxib may even protect against the progression of cardiovascular disease, on the basis that cyclooxygenase-2 mediates key processes in atherothrombosis. Currently, it is not clear what the net cardiovascular effects of cyclooxygenase-2 inhibitors are. The data are inconsistent and at best, speculative. It may be also that celecoxib and rofecoxib differ in their cardiovascular effects. Clarification of these issues is of vital importance given the vast number of patients presently taking both types of cyclooxygenase-2 inhibitors. Therefore, what is clear in this situation is the urgent need for randomized clinical trials designed specifically to examine the impact of selective cyclooxygenase-2 inhibitors on cardiovascular risk.     

Cardiovascular effects of selective cyclooxygenase-2 inhibitors

Selective cyclooxygenase-2 inhibitors represent a significant advance in the management of inflammatory disorders. They have similar efficacy to nonselective ‘conventional’ nonsteroidal anti-inflammatory drugs, but a superior gastrointestinal safety profile. However, a significant caveat is the perceived potential of cyclooxygenase-2 inhibitors to cause adverse cardiovascular effects, an issue first raised by the Vioxx Gastrointestinal Outcomes Research (VIGOR) study of rofecoxib (Vioxx^®, Merck & Co. Inc.). Mechanisms by which cyclooxygenase-2 inhibitors may increase cardiovascular risk are selective inhibition of prostaglandin I₂ over thromboxane A₂ within the eicosanoid pathway, which promotes thrombosis, and inhibition of prostaglandins E₂ and I₂ within the kidney, which leads to sodium and water retention and blood pressure elevation. In spite of this, the cardiovascular findings from VIGOR are not firmly supported by observations from large cohort studies and other clinical trials of selective cyclooxygenase-2 inhibitors, including the Celecoxib Long-term Arthritis Safety Study. The two main theories that explain the VIGOR findings are that the comparator used (naproxen; Naprosyn^®, Roche) is cardioprotective and that very high doses of rofecoxib were used, but at present neither is backed by firm evidence. Indeed, there is now early evidence that selective cyclooxygenase-2 inhibition with celecoxib may even protect against the progression of cardiovascular disease, on the basis that cyclooxygenase-2 mediates key processes in atherothrombosis. Currently, it is not clear what the net cardiovascular effects of cyclooxygenase-2 inhibitors are. The data are inconsistent and at best, speculative. It may be also that celecoxib and rofecoxib differ in their cardiovascular effects. Clarification of these issues is of vital importance given the vast number of patients presently taking both types of cyclooxygenase-2 inhibitors. Therefore, what is clear in this situation is the urgent need for randomized clinical trials designed specifically to examine the impact of selective cyclooxygenase-2 inhibitors on cardiovascular risk.     

The management of pain in arthritis and the use of cyclooxygenase-2 inhibitors: New paradigms and insights

Chronic pain from arthritis has been one of the biggest causes of disability and loss of function in the United States. This is still the case despite many new insights into the pathophysiology of pain, effective treatment approaches, and new safer medications that can be used for long-term use. There are many different types of arthritic problems. New diseasemodifying agents that are available for some of these types of arthritic diseases such as rheumatoid arthritis have the potential to have a substantial impact on improvement in the long-term prognosis. Despite this optimistic outlook, pain often is a significant problem and should be treated whenever it becomes a barrier to function.     

Hemicrania continua responds to cyclooxygenase-2 inhibitors

BACKGROUND: Hemicrania continua is a primary headache disorder defined by its absolute responsiveness to indomethacin. We report the treatment response to two cyclooxygenase-2 inhibitors, celecoxib and rofecoxib, in a series of patients with hemicrania continua. METHODS: Fourteen patients were treated, 9 with rofecoxib and 5 with celecoxib. RESULTS: Three patients in each group had a complete response to treatment. CONCLUSION: The cyclooxygenase-2 inhibitors may represent an alternative to indomethacin in the treatment of hemicrania continua. Their mechanism of action for this potential indication is unknown.     

Effect of cyclooxygenase-2 inhibitors on blood pressure

OBJECTIVE: To evaluate the effect of cyclooxygenase-2 selective inhibitors (CSIs) on blood pressure. DATA SOURCES: Clinical literature accessed through MEDLINE (1966-May 2002). Key search terms included COX-2 selective inhibitors; anti-inflammatory agents, nonsteroidal; celecoxib; rofecoxib; and hypertension. DATA SYNTHESIS: Data from prospective studies on the effects of CSIs on blood pressure are conflicting. Several studies have reported increased blood pressure as an adverse effect of CSIs. CONCLUSIONS: Additional studies are needed to evaluate the effects of CSIs on blood pressure. CSIs should be used with caution in hypertensive patients and blood pressure monitored closely if a CSI is indicated.     

Outcomes studies of the gastrointestinal safety of cyclooxygenase-2 inhibitors

Short-term endoscopic studies of the highly selective cyclooxygenase-2 (COX-2) inhibitors (coxibs) rofecoxib and celecoxib have shown that these agents are well tolerated and have efficacy equivalent to nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) with fewer adverse effects on the upper gastrointestinal (GI) tract. These studies are limited, however, as the detection of endoscopic lesions is not well correlated with symptomatic ulcers and ulcer complications. Outcomes studies of the GI safety are, therefore, essential to understanding how coxibs are likely to perform in a clinical practice setting. Four large outcomes studies (Vioxx Gastrointestinal Outcomes Research, VIGOR; Assessment of Difference Between Vioxx and Naproxen to Ascertain Gastrointestinal Tolerability and Effectiveness trial, ADVANTAGE; Celecoxib Long-term Arthritis Safety Study, CLASS; and the Successive Celecoxib Efficacy and Safety Studies, SUCCESS) examined the GI safety of rofecoxib and celecoxib in over 39,000 patients with osteoarthritis or rheumatoid arthritis. Results of these studies showed that patients taking a supratherapeutic dose of rofecoxib or celecoxib had significantly lower rates of GI-related adverse events than those taking a nonselective NSAID (naproxen, ibuprofen, or diclofenac). Reduced risk of upper GI events was seen in patients with multiple risk factors and in patients using low-dose aspirin and corticosteroids concomitantly with a coxib. Results of large outcomes studies provide support for the COX-2 hypothesis and demonstrate the long-term safety and tolerability of coxibs.