Cyclooxygenase-2 Inhibitors

Cyclooxygenase (COX) catalyzes the initial step of arachidonic acid metabolism and prostaglandin production. COX activity has been found to be associated with two distinct isoenzymes, COX-1 and COX-2. COX-1 was hypothesized to be involved in the maintenance of physiologic functions such as gastric protection and hemostasis, whereas COX-2 was thought to be involved in pathophysiologic processes such as inflammation, pain, and fever. This compelling hypothesis led to the development of the currently available selective COX-2 inhibitors celecoxib, rofecoxib, and valdecoxib. These drugs have analgesic efficacy comparable with that of conventional nonsteroidal antiinflammatory drugs (NSAIDs). In addition, they have no antiplatelet activity at therapeutic dosages and may be associated with reduced gastrointestinal (GI) side effects compared with conventional NSAIDs such as ibuprofen. COX Expression and Function NSAIDs are a commonly used group of medications with a number of advantageous features (Table 1). NSAIDs were discovered to act by inhibition of the enzyme COX, which catalyzes the synthesis of prostaglandins from arachidonic acid (1–3). The COX gene was cloned by three separate research groups in 1988 (4–6), and two isoforms of COX have since been identified: COX-1 and COX-2 (7–14). The 2 isoforms have an approximate 60% amino acid homology, similar tertiary structures, and similar, but not identical, active sites (15–17).Table 1: Features of Conventional Nonsteroidal Antiinflammatory DrugsCOX-1 is expressed constitutively throughout the body (18–21) and is only slightly upregulated (two- to fourfold) in some cells in response to hormones or growth factors (22). It plays an essential role in homeostatic processes such as platelet aggregation, GI protection, and renal function. In contrast, COX-2 is expressed predominantly in inflammatory cells and is involved in the synthesis of prostaglandins mediating pathologic processes such as pain, inflammation, fever, and carcinogenesis (23–25). Expression of COX-2 may facilitate several oncogenic processes, including tumor invasion, angiogenesis, and metastasis (26–28). However, COX-2 has also been detected in the brain, testes, kidney, and trachea (29–32). COX-2 induction within the spinal cord may play an important role in central sensitization (33–38). Indeed, the acute antihyperalgesic action of NSAIDs has been shown to be mediated by the inhibition of constitutive spinal COX-2 (39). In response to inflammation and other stressors, COX-2 expression is markedly upregulated (10- to 20-fold) by a variety of mediators (40). These distinct expression patterns have led to the theory that COX-1-derived prostaglandins are largely responsible for physiologic (housekeeping) functions (41), whereas COX-2-derived prostaglandins mediate pathophysiologic and inflammatory processes, including pain (Fig. 1). Conventional NSAIDs inhibit both COX-1 and COX-2 (42–48). It was hypothesized that selective COX-2 inhibitors would have the advantages of conventional NSAIDs but would not interfere with GI protection or hemostasis (49,50). However, it may be overly simplistic to view the efficacy and safety of NSAIDs only in terms of their effects on prostaglandin synthesis (51). Physicochemical and pharmacokinetic factors may also be important (52–54).Figure 1: Cyclooxygenase (COX) pathways.It is interesting to note that the existence of a COX-3 enzyme has been postulated. In a rat carrageenan pleurisy model, there was a second increase in COX-2 protein at 48 h that produced antiinflammatory prostanoids (55). It was suggested that this protein, which was formed during the resolution phase of inflammation, may represent a third COX isoform, COX-3. COX-3 has been proposed as a possible site of action for acetaminophen (56–58). COX-2-Selective Drugs Celecoxib (Celebrex®; Pharmacia, Peapack, NJ; Pfizer, New York, NY) was approved by the Food and Drug Administration in December 1998 (56), rofecoxib (Vioxx®; Merck, Whitehouse Station, NJ) in May 1999, and valdecoxib (Bextra®; Pharmacia) in November 2001 (59) (Fig. 2). Parecoxib is an injectable prodrug of valdecoxib that has yet to be approved by the Food and Drug Administration (60,61).Figure 2: Structure of cyclooxygenase-2 inhibitors.Although the biochemical selectivity of COX-2 inhibitors may be analyzed in several different in vitro assays, the most relevant evaluate the drug-enzyme interaction in whole-blood assays (62,63). Thromboxane B2 generated in clotting whole blood is a validated measure for COX-1 activity, and prostaglandin E2 (PGE2) production after incubation of whole blood with lipopolysaccharide is a validated measure of COX-2 activity (64,65). Whole-blood assays have shown the following COX-2/COX-1 selectivity ratios: ibuprofen, 0.2; indomethacin, 0.4; meloxicam, 2.0; etodolac, 2.4; diclofenac, 3; celecoxib, 7.6; valdecoxib, 30; rofecoxib, 35; and etoricoxib, 106 (66,67). However, the clinical relevance of whole-blood assays has been questioned, and the relationship of COX-2 selectivity to patient outcome remains to be established (68–70). The currently available COX-2 inhibitors are chemically distinct compounds (Table 2). Celecoxib is a sulfonamide that is extensively distributed into tissues (volume of distribution is 400 L for the 200-mg dose) and is metabolized by the cytochrome P450 2C9/3A4 system. Indeed, interaction with other P450 inhibitors has been observed. Its half-life is 11 h. Rofecoxib, however, is a sulfone that is not as well distributed into tissues (volume of distribution is 86 L for the 25-mg dose) and is metabolized principally by cytosolic reduction. Cytochrome P450 plays only a minor role; thus, no important interaction with other P450 inhibitors has been observed. Its half-life is 17 h. These differences may result in variations in the degree of COX-2 versus COX-1 inhibition or in additional effects unrelated to COX-2 inhibition at the tissue level. This might also explain the differences in blood pressure increases and edema frequency reported by Whelton et al. (71).Table 2: Comparison of Currently Available Cyclooxygenase-2 InhibitorsInitial comparative trials with NSAIDs demonstrated the analgesic efficacy of selective COX-2 inhibition with a decreased incidence of GI side effects in patients with arthritis. These data and the high commercial value of the market, along with extensive marketing programs, have led to wide-ranging use for a number of indications (Table 3).Table 3: Indications and Dosage Recommendations for Cyclooxygenase-2 InhibitorsAnalgesic Efficacy Each trial has been assessed for quality by using a 1–5 scale (72) (Table 4). One point each was given if the report was described as randomized and double-blinded and if there was a description of withdrawals or dropouts. An additional point each was given if the method of randomization was described and adequate and if the method of blinding was adequate and appropriate.Table 4: Analgesic EfficacyTable 4: ContinuedTable 4: ContinuedOsteoarthritis. A 6-wk trial evaluated the efficacy of two doses of celecoxib (100 mg twice daily [BID] and 200 once daily [QD]) in patients with osteoarthritis (OA) of the knee in flare Celecoxib was with comparable for both of patients with of the knee that patients with celecoxib mg in pain with mg or In a of patients with of the et al. found celecoxib mg celecoxib 200 and mg to be In a 6-wk of patients with of the rofecoxib mg and mg were found to be and both were In of patients with of the or knee in were randomized to rofecoxib mg rofecoxib mg mg three daily or doses of rofecoxib and were and were et al. two in patients with of the knee or A 6-wk compared rofecoxib mg rofecoxib mg and mg and a compared rofecoxib mg rofecoxib mg and mg mg and mg demonstrated efficacy comparable with that of ibuprofen. rofecoxib doses and efficacy at rofecoxib doses and similar efficacy randomized of patients with of the and knee assessed the efficacy of rofecoxib mg rofecoxib mg and mg The three were In a 6-wk of patients with of the celecoxib 200 mg and rofecoxib mg were found to be and In patients with of the knee were to rofecoxib mg rofecoxib mg celecoxib 200 mg or acetaminophen for mg was acetaminophen celecoxib 200 mg or rofecoxib mg In a by et al. patients with of the knee were randomized to valdecoxib or mg valdecoxib mg mg or demonstrated analgesic efficacy that was that of at mg The were at mg mg and mg compared with doses of mg mg and mg were also as as mg et al. randomized patients with osteoarthritis of the knee to valdecoxib or mg or mg and mg and were and were In addition, the incidence of was in the group in valdecoxib In a of patients with of the were randomized to valdecoxib mg valdecoxib mg or mg mg and mg demonstrated similar and both were In a of patients with patients were randomized to celecoxib or 400 mg mg or dosages of celecoxib and were that celecoxib 200 mg was as as mg In a by et al. dosages of rofecoxib and mg were compared with in patients with in rofecoxib and mg clinical compared with mg not from A compared the efficacy and of daily doses of valdecoxib and mg with mg or in patients with doses of valdecoxib and similar efficacy and were However, demonstrated an incidence of pain, and compared with the doses of valdecoxib and mg COX-2 inhibitors are as the drugs of by the for to pain from both and of their efficacy and GI In a 6-wk of patients with celecoxib mg demonstrated efficacy compared with mg and both were to In a patients with were to celecoxib 400 or Celecoxib and were and patients demonstrated In a trial of patients with acute celecoxib 200 mg and mg were found to be of efficacy In patients with acute pain were randomized to celecoxib 200 mg or mg for both were found to be and the analgesic efficacy of a of rofecoxib celecoxib 200 or given h spinal given an of mg of after celecoxib mg and rofecoxib mg both rofecoxib and celecoxib produced similar analgesic effects in the h after rofecoxib demonstrated an analgesic that throughout the et al. the analgesic efficacy of rofecoxib mg or The of was given on the and a second was given the induction of given rofecoxib in the in the the group in the rofecoxib group pain of and blood on to the compared with the In a of patients rofecoxib or was given on after 2 to patients in the and groups and the rofecoxib group rofecoxib or mg was found to be to and similar to for of pain 2 to the rofecoxib mg group of patients used and reported pain on compared with the et al. patients knee were to rofecoxib mg h rofecoxib mg after the of or h The of rofecoxib mg a of and pain during compared with patients given rofecoxib mg after the of In a of patients patients were to celecoxib 200 or rofecoxib with NSAIDs reduced the to The NSAIDs also decreased the for analgesic In addition, rofecoxib was associated with a reduced to et al. the efficacy and of celecoxib versus in the of pain after were to celecoxib 200 or within h after the the with pain for h after the of the patients celecoxib 200 mg as or mg as the patients with to pain after comparable with doses of celecoxib and the patients in the celecoxib group and compared with patients in the patients no 2 daily doses of celecoxib 200 mg for the of their It be that of the are they have not compared dosages of the different COX-2 acute pain, rofecoxib mg be compared with celecoxib 400 mg by an additional 200 mg on the if The for an initial of celecoxib is to of In patients were to valdecoxib or mg or in the valdecoxib groups compared with and to the use of was in the valdecoxib mg and mg groups to the valdecoxib mg and In a of patients valdecoxib mg or valdecoxib mg was given to 2 h and the was spinal patients with valdecoxib or mg on and patient were in both valdecoxib groups compared with are data to a conventional NSAIDs and acetaminophen are In patients were to acetaminophen 2 celecoxib 200 or celecoxib 200 mg with acetaminophen 2 the of celecoxib and acetaminophen was that In a patients were to acetaminophen 2 rofecoxib or rofecoxib mg with acetaminophen 2 The of was given and a second of the was given the after with rofecoxib mg was acetaminophen 2 or In addition, rofecoxib reduced the for by patient and the quality of of the of antiplatelet COX-2 inhibitors may be throughout the an of This may be important the of pain has been shown to with the of pain and the of after In a by et al. patients were randomized to rofecoxib rofecoxib or h with patients rofecoxib mg during the pain on and h after The efficacy of COX-2 inhibitors has been well in the pain In patients were randomized to rofecoxib or 400 mg after was found to be on of analgesic and were not different in terms of analgesic of or analgesic but rofecoxib a of In rofecoxib mg was found to be as as 400 mg and to in the of pain The analgesic efficacy of a of rofecoxib mg was also compared with that of three doses of mg and The analgesic efficacy of rofecoxib mg was to that of mg and pain compared rofecoxib and with rofecoxib mg demonstrated with a and a of patients in the group compared with patients in the rofecoxib several have shown that rofecoxib mg is in the of pain In a of pain after the of two or patients were given celecoxib 200 rofecoxib or 400 mg after with celecoxib, rofecoxib analgesic effects on of analgesic including analgesic to of pain and of In addition, analgesic efficacy was similar to that of ibuprofen, was In patients to of two third were randomized to valdecoxib or mg or valdecoxib groups analgesic efficacy with mg efficacy and but the to mg not additional A similar compared a of valdecoxib or a of or The efficacy of valdecoxib mg was comparable to that of doses of valdecoxib a of action and a similar to that of A assessed patients of two or third of which was were to valdecoxib rofecoxib or valdecoxib mg a of pain and decreased pain compared with patients rofecoxib mg or The to pain was in the valdecoxib mg in the rofecoxib mg and h in the It be that such as and have been shown to inhibit by with COX-1 effects are also mediated by the of the effects of conventional NSAIDs may be a in analgesic In a of patients with were to rofecoxib or mg by mg h as or mg h as for to and mg analgesic efficacy and to In with to pain were to valdecoxib valdecoxib or active were to mg was as as and valdecoxib GI GI is of the most in It has been that patients are and each in the as a result of GI GI have shown a of in the or of patients NSAIDs and associated with the use of conventional NSAIDs may in of patients for to and in of patients for and in patients with NSAIDs in patients with a number or no factors and of patients may have no The of clinical GI in on their the associated with the and the protection by with or the incidence of and gastric may be for the incidence of The of prostaglandins are involved in the maintenance of GI and only COX-1 is in the GI the GI of NSAIDs has been proposed to result largely from inhibition of COX-1 activity Indeed, selective COX-2 inhibitors GI side effects conventional NSAIDs inhibitors with or have high and other that are similar to of NSAIDs with GI A trial compared the GI effects of celecoxib and in patients with The incidence of was in patients randomized to celecoxib mg in celecoxib 200 mg and in celecoxib 400 mg In contrast, the incidence in patients mg was which was or In the Celecoxib patients were randomized to celecoxib 400 mg mg or mg use for was The was and the was and Celecoxib was to to or the was The use of may have been an important their in the the of patients to be as the was In this the incidence of and with celecoxib was similar to that with the of celecoxib was Celecoxib was to a incidence of and compared with but not with the celecoxib and groups may also to be Celecoxib was also associated with in or both compared with the other the use of However, have been the trial with to possible of of the and of of celecoxib A of data from trials with celecoxib demonstrated that it was associated with an incidence of GI of This was similar to the incidence in patients and was the incidence of in patients given conventional In in patients not NSAIDs have been reported in to be by the and data and in a by et al. et al. randomized trials that compared at of celecoxib with or In patients celecoxib, the of withdrawals was the incidence of by was and the incidence of of and was of patients that the incidence of detected by was reduced by in patients given celecoxib compared with other The was in not In the trial patients with were to rofecoxib mg or mg for a of of was not The incidence of clinical GI which and GI was as the The of important GI was decreased in the rofecoxib group compared with the group This a in of However, the incidence of was in the rofecoxib group in the group it was in versus were in the rofecoxib group the group of GI side effects versus However, there was no safety of rofecoxib of an of in the rofecoxib group compared with the as well as and The incidence of was in the rofecoxib group and in the group However, other comparative of rofecoxib and conventional NSAIDs have demonstrated of and GI and A compared the effects of valdecoxib mg mg or on the GI of were by to have no at the incidence of with valdecoxib was similar to that with versus and with In patients were randomized to valdecoxib mg valdecoxib mg mg or mg the incidence of was similar in the valdecoxib and groups and was in patients or and et al. compared the incidence of associated with the use of valdecoxib mg valdecoxib mg and mg given for to patients with and arthritis. The incidence of in the valdecoxib mg and valdecoxib mg groups was that in the group and It be however, that not with clinical In patients with were randomized to valdecoxib mg valdecoxib mg mg or mg The incidence of in the valdecoxib mg and valdecoxib mg groups was in the and groups and The Celecoxib Efficacy and in trial was a double-blinded trial to clinical A of patients were with celecoxib 200 or 400 or Celecoxib was associated with and compared with conventional and differences were associated with of compared with conventional In a of GI in patients given selective COX-2 inhibitors or to there was an of GI for of NSAIDs and rofecoxib The of has inhibitors for patients are at for GI of drugs such as or a with NSAIDs in patients was also if the is given at COX-2 is upregulated at sites of gastric and both COX inhibitors and inhibitors may in The clinical for is and hemostasis on the of to from prostaglandin not synthesis of in the platelet is mediated by conventional NSAIDs the of to COX-2 inhibitors have no on platelet at therapeutic dosages no on platelet or in doses of has also not with the antiplatelet effects of which with use of of rofecoxib has not in spinal or A found with COX-2 inhibitors However, such have been for from different with patient and use of In the the incidence of was in the group and in the rofecoxib The for this remains a of The not a group and was not to that of in the of patients in been for of patients in the the and have shown that patients with have a decreased incidence of compared with patients NSAIDs other However, protection which is the for patients Celecoxib not to be associated with an of the of with COX-2 inhibitors Conventional NSAIDs and edema and in patients are at enzyme inhibitors and whereas conventional inhibit the production of such prostaglandins and blood pressure The distribution and of renal COX-2 by a role for this enzyme in renal and in the renal effects of NSAIDs and effects of the selective COX-2 inhibitors are similar to conventional NSAIDs In a doses of celecoxib mg for and 400 mg for and mg were compared in a group of Celecoxib no on the whereas a but in Celecoxib and both a in renal production of and COX-2 may play of a role in and whereas COX-1 may play of a role in the maintenance of However, there is in the renal functions of two In patients with renal the use of a COX-2 be as is for conventional of celecoxib and rofecoxib in have evaluated the of renal as by These have a of (100 to during the of to of the to a renal of the by using homeostatic that are of renal In a 6-wk patients with or and were to celecoxib 200 mg or rofecoxib mg The incidence of blood pressure was in the rofecoxib group compared with the celecoxib group versus the blood pressure from was for rofecoxib compared with for increases in blood pressure are to be both and important of The incidence of edema was also in the rofecoxib group compared with the celecoxib group versus and COX-2 inhibitors be for the development of in a 6-wk Whelton et al. assessed the effects of celecoxib and rofecoxib on blood pressure and edema in patients of or with and patients in the rofecoxib compared with the celecoxib group blood pressure an value of at the increase in blood pressure in patients inhibitors or whereas or celecoxib or rofecoxib no increases in blood or edema associated with in a of patients in the rofecoxib group compared with the celecoxib group A of the found that use of rofecoxib at doses mg was associated with an incidence of increases of or may in to of patients and increases of or three or the of have been reported in of patients in clinical trials with These may or be with of including and and with have been reported with A patient with or or in an has be for of the development of a with COX-2 clinical and with or if COX-2 be It be that in the patients of compared with on and compounds during A by et al. found that patients to NSAIDs for after after for In a rat of et al. demonstrated a of if was given for after versus in et al. demonstrated that the of NSAIDs spinal This of patients that was to if was after compared with no use of it has been demonstrated that the COX-2 inhibitors not have effects on the of in the In this were to celecoxib or for after with and that of the and of the in the with celecoxib were This was not the in the were and this was different from the the was to be in of the of the with celecoxib, and of the the the and groups was A in has suggested that selective inhibition of COX-2 may or in a rat model, et al. that COX-2 inhibitors have an on in and These be to the use of COX-2 inhibitors in are no data from randomized trials in It has been suggested that prostaglandins may have a role in there is some for in the rat the effects of COX-2 inhibitors on have not been The incidence of sulfonamide in the is at be as to of two biochemical or The to sulfonamide is thought to be to the of a that is to the Celecoxib and valdecoxib to the group of medications and are in patients to Drug NSAIDs may the of inhibitors and the of and in some of may result in an increase in of celecoxib and valdecoxib of and COX-2 inhibitors increases the of GI the effects of the COX-2 However, the of COX-2 inhibitors and is associated with GI side effects of NSAIDs and mg once a for of by in patients to for arthritis. However, doses of rofecoxib have not Celecoxib and valdecoxib not have a on the of The of has led to a in of rofecoxib, and may by the currently available COX-2 inhibitors may increase and be in the of or may also increase with the of celecoxib, rofecoxib, and valdecoxib COX-2 inhibitors not be given to patients with a to the or to patients have or after or other of which is generated by to be an important in the of this However, COX-2 inhibitors have been given to such patients Celecoxib and valdecoxib not be given to patients have demonstrated to In the GI COX-2 or of COX-2 are expressed COX-2 expression has been found to increase to in of or by These that COX-2 might play an important role in the development of Indeed, in use of and other conventional NSAIDs that inhibit COX-1 and was associated with a in the for activity of NSAIDs in the of was demonstrated in a trial that evaluated the effects of in patients with this a patients with a in the number and of compared with patients with The of with COX-2 inhibitors on tumor growth was in et al. cells that high of COX-2 expression into cells into a was to the in a inhibition of tumor In with celecoxib a in the number of and of and that inhibitors tumor growth was also shown in a the a for In patients with were with celecoxib mg celecoxib 400 mg or patients celecoxib 400 mg demonstrated a in compared with COX-2 inhibitors represent a therapeutic development of their side compared with conventional NSAIDs are to be used for the of pain and inflammation, and several other COX-2 inhibitors are currently of and data The of reported that the of was reduced in the medications for 2 or have this A possible for this is a in inflammatory processes that may The use of drugs to the of is are also to the use of COX inhibitors in the of gastric and However, the use of COX-2 such as of their use to patients at for safety compared with conventional NSAIDs prostaglandin or and safety in patients also for platelet inhibition