NSAIDs clinical trials

The first two selective COX-2 inhibitors to be marketed and subjected to in depth clinical trials were celecoxib and rofecoxib. Both compounds are as effective as standard NSAIDs in rheumatoid arthritis, osteoarthritis and for pain following orthopaedic or dental surgery. Gastrointestinal side effects were far fewer than with comparator diugs and in fact were no... 

Clinical trial evidence supports many NSAID medications in the acute treatment of migraines with and without aura.30 The currently marketed cyclooxygenase-2 (COX-2) selective... 

Elucidation of the activities of individual COX isoforms led to the development of drugs that selectively inhibit the inducible form of the enzyme, COX-2. Thus COX-2 inhibitors were expected to minimize NSAID gastrointestinal toxicity and antiplatelet effects (see Fig. 55-3).19 A common misconception is that COX-2 inhibitors are more effective than nonselective NSAIDs in relieving pain and inflammation. In clinical trials, patients experienced similar levels of pain relief with COX-2 inhibitors and nonselective NSAIDs. 

Pain and joint function have been evaluated frequently in clinical trials administering hyaluronan to patients with OA. Results are conflicting, with some suggesting dramatic improvements and others indicating no effect. In one controlled trial, hyaluronan injections relieved pain to a similar extent as oral NSAIDs.29 Hyaluronan provides greater pain relief for a longer time than intraarticular corticosteroids, but corticosteroids work more rapidly.29... 

Pfizer s tenidap (CP-66,248) (157), another enolic compound, was also more potent (500-fold) toward CO over 5-LO inhibition in human ISN (0.032 /iM and 18 /iM, respectively) [379-381]. Efficacy in rheumatoid arthritis clinical trials has been reported [380,382] in patients, serum levels of acute phase proteins and synovial fluid levels of IL-1 were reduced by tenidap, in contrast to the lack of this effect with NSAIDs. Besides CO/5-LO inhibition, a variety of in vitro activities have been reported, including a number of effects on monocyte functions and differentiation [379], inhibition of neutrophil degranulation [382], inhibition of the activation of neutrophil collagenase [383], inhibition of leukocyte-endothelial cell adhesion [384], and inhibition of LTB4-induced neutrophil chemotaxis [385]. Al-... 

Timegadine (168) is an atypical basic NSAID which has shown efficacy in arthritis clinical trials [426,427]. It is a potent CO inhibitor in a variety of tissues, and also inhibited the production of 12-HETE from platelet ho-... 

Selective COX-2 inhibitors have also been shown to prevent early and late forms of colorectal neoplasia in rat models. Reddy et al. showed that administration of celecoxib inhibited aberrant colonic crypt foci (ACF) induction and multiplicity by about 40-49% in an azoxymethane-induced ACF rat model (81). Later the same investigators also showed that dietary administration of celecoxib can inhibit both the incidence and multiplicity of colon tumors by about 93 % and 97 %, respectively in the same rat model (82). Other researchers reported similar results with the Min mouse model (52). There is little data on human clinical trials with selective COX-2 inhibitors for colorectal tumor prevention. Recently Steinbach et al. conducted a double-blind, placebo-controlled study with 77 patients with FAP, and reported that treatment with celecoxib, a selective COX-2 inhibitor, for 6 mo led to a significant reduction (28%) in the number of colorectal polyps in these patients (50). Collectively, COX-2 nonspecific or specific NSAIDs appear to have chemopreventive activity against colorectal cancer development. Selective... 

Based on the bio-molecular pathogenesis, novel therapeutic agents have been developed since 1998 for the treatment of DMARDs refractory autoimmune diseases. These biological-DMARDs include infliximab, etanercept, adalimumab, rituximab and abatacept. The biological-DMARDs anti TNF-a were first approved for therapy of refractory RA, followed by Crohn s disease, AS, and PsA. Scores of other biological DMARDs in Phase I, II, and III clinical trials in autoimmune diseases indicate that the number of these biological agents may ultimately become equal to the number of NSAIDs introduced over the last 50 years. 

Celecoxib (Celebrex) and rofecoxib (Vioxx) are highly selective COX-2 inhibitors. Because of this, they produce less erosion of the GI mucosa and cause less inhibition of platelet aggregation than do the nonselective COX inhibitors. Short-term (6 months-to a year) clinical trials have shown that celecoxib and rofecoxib produce less GI toxicity than nonselective NSAIDs. However, serious GI bleeding and ulceration have occurred in patients taking these drugs, and long-term prospective studies of their safety have yet to be completed. Like the nonselective NSAIDs, the selective COX-2 inhibitors can produce renal side effects such as hypertension and edema. 

Netoglitazone is an insulin sensitizer currently in Phase II clinical trials. It is able to modulate both PPAR-a and PPAR-y subtypes of peroxisome proliferator-activated receptor (Phase ll). Metaglidasen (MBX-102) is the (—)-enantiomer of the NSAID halofenate. This selective PPAR-y nuclear receptor agonist is being evaluated (Phase II) as an insulin sensitizer. It is structurally different from the currently marketed glitazones (Figure 8.84). ... 

Within the last 10, years several new compounds were launched in the field of non-steroidal antiinflammatory drugs (NSAIDs) with a clear focus on cyclooxygenase type 2 selective compounds. In the field of opioids on the other hand no new drugs have passed phase III clinical trials. In this field innovation has been achieved through new pharmaceutical formulations of known drugs such as transdermal systems, e.g. buprenorphine patch, transmucosal systems, e.g. fentanyl lollipop, or rectal delivery systems containing e.g. morphine. These were developed in order to reduce opioid side effects, but also to overcome pharmacokinetical limitations, in particular to prolong compliance and duration of action. 

The efficacy of flurbiprofen at dosages of 200-400 mg/d is comparable to that of aspirin and other NSAIDs in clinical trials for patients with rheumatoid arthritis, ankylosing spondylitis, gout, and osteoarthritis. It is also available in a topical ophthalmic formulation for inhibition of intraoperative miosis. Flurbiprofen intravenously has been found to be effective for perioperative analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat. 

These findings from special renal studies and the clinical trial data indicate that inhibition of Cox-2 does not eliminate the renal effects of NSAIDs because Cox-2-derived prostanoids are involved in normal renal function. However, the kidney contains considerably more Cox-1 than Cox-2, and the localization of the two isoforms is different It is not yet known whether the Cox-2 inhibitors will be safer in subgroups of patients prone to develop acute renal failure with NSAIDs, such as those patients with severe volume depletion, congestive heart failure, or hepatic cirrhosis with ascites (Bosch-Marce et al., 1999). Also, it is not known whether rare events, such as interstitial nephritis or papillary necrosis, will occur with long-term use of Cox-2 inhibitors, although studies in animals suggest that such events may be related to Cox-1 inhibition, since only Cox-1 is found in the papilla. Therefore, Cox-2 inhibitors may not produce these serious adverse effects (Khan etal., 1998). 

Many studies evaluated the use of topical NSAIDs in preventing CME after cataract extraction. Studies found consistent benefits in prevention of CME with administration of 0.5% ketorolac tromethamine, 0.03% flurbiprofen, and 0.1% diclofenac. A meta-analysis of 16 randomized clinical trials evaluating topical NSAIDs for prevention of CME found that NSAID use was beneficial in reducing the incidence of both angiographically evident and clinically relevant CME. 

Figure 7 y-Secretase inhibitor (LY-4S0,139) and NSAID-like modulator (fi-Flurbiprofen) in clinical trials for Alzheimer s disease. 

Clinical trial evidence in general appears to support the theory that COX-2 selective inhibitors are as effective as, but have fewer adverse effects than, non-COX-2 selective compounds for example meloxicam is better tolerated than diclofenac or piroxicam. The relative risk of serious gastrointestinal effects (bleeding peptic ulcers) due to rofecoxib (COX-2 selective) was 0.51 compared with conventional NSAIDs. COX-2 selective drugs are yet associated with significant dyspeptic symptoms (indigestion, heartburn), and these effects may result from inhibition of the (protective) constitutively expressed COX-2 in the stomach. 

The currently available NSAIDs exhibit a variety of molecular structures and it is usual to classify these drugs by their chemical class. Clinical trials in rheumatoid arthritis and osteoarthritis, however, rarely find substantial differences in response to average doses of NSAIDs whatever their structure, and this no doubt reflects their common mode of action. Some 60% of patients will respond to any NSAID and many of the remainder will respond to a drug from another group. A structural classification is nevertheless used here as it provides a logical framework furthermore, specific toxicity profiles tend also to relate to chemical group (see below). Summary data on NSAIDs licenced in the UK are given in Table 15.2. 

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