Editorial [Hot Topic: Anti-Inflammatory Therapy (Guest Editor: Dr. Subhash P. Khanapure)]

Significant advances for treating the signs and symptoms of inflammatory disease have been made in the last decade. Most of the existing anti-inflammatory drugs are effective, but not without adverse effects. Various strategies have been employed to overcome the major problem of the gastrointestinal (GI) toxicity that may accompany the long-term use of the traditional nonsteroidal anti-inflammatory drugs (NSAIDs). Among the most high-profile of these strategies in recent years has been the development of cyclooxygenase-2 (COX-2) selective inhibitors. The discovery of COX-2 identified an enzyme that is specifically upregulated during inflammation to produce proinflammatory prostaglandins (PGs). Selective COX-2 inhibition was thus embraced by many pharmaceutical companies as a major therapeutic and commercial goal predicated upon the “COX-2 hypothesis”: selective COX-2 inhibition should obviate the GI toxicity of nonselective NSAIDs by blocking selectively pro-inflammatory PG synthesis at inflammatory sites without interfering with gastroprotective PG production by cyclooxygenase-1 (COX-1) in the GI tract. Over the last fifteen years, remarkable accomplishments have been made on the synthesis of structurally diverse COXIBs, the identification of COXIBs with attractive preclinical profiles, and COXIB clinical development and marketing. As anti-inflammatory medicines, COXIBs proved just as effective as classical NSAIDs, but with reduced GI side-effects and notably better GI tolerability. By 2001, COXIBs had established a virtually unprecedented record in the pharmaceutical industry for global sales growth, sustained by an aggressive marketing program focused on COXIB GI safety. Since highly selective COX-2 inhibitors attenuate production of prostacyclin (PGI2), an important anti-thrombotic eicosanoid, theoretical concerns were voiced as early as 1999-2001 about their potential to precipitate cardiovascular events. In September, 2004, Merck voluntarily withdrew rofecoxib from the market in the face of clinical data from the APPROVe trial showing that subjects who had taken 25 mg rofecoxib/day for more than 18 months had a four-fold greater incidence of serious thromboembolic events and a doubling of the myocardial infarction rate vs. the placebo group. Subsequent reports provided compelling clinical evidence that structurally diverse COXIBs carry an enhanced cardiovascular risk that is likely a dosedependent class effect, especially for patients already at moderate-to-high risk of cardiovascular disease. Although in February, 2005, an FDA panel reviewed the cardiovascular safety of COXIBs and voted to allow their continued use, in April of that year the FDA requested withdrawal of valdecoxib (and its intravenously administered prodrug, parecoxib) from the market due to a cluster of cardiovascular events in treated patients undergoing coronary bypass graft surgery. The COXIB trajectory as a parabola spanning almost a decade stands as one of the biggest disappointments in the pharmaceutical industry and invites new thinking and approaches. In this issue, recent developments in anti-inflammatory drug development as well as possible future strategies have been reviewed. The status of currently available COX-2 inhibitor “Celecoxib” and its safety are presented in detail in the first contribution. Gajraj gives an outstanding in-depth overview of COX-2 inhibitors celecoxib and parecoxib as valuable options for postoperative pain management. Kulkarni and Singh describe “Licofelone a novel dual acting COX/5-LOX inhibitor” in the second contribution and give an up-to-date overview that covers our contemporary understanding of pathogenic mechanisms in inflammatory conditions, NSAID-induced adverse GI effects, and the rationale for the development of “Licofelone” (a dual 5-LOX/COX inhibitor) with data on its in vivo efficacy, pharmacodynamic activity, clinical studies, and comparison with COX-2 selective and nonselective inhibitors. The third contribution describes the development of dual acting anti-inflammatory drugs and the rationale for the development of dual acting drugs. Leone, Ottani and Bertolini gave an interesting overview of this topic, which also includes 5-LO expression and implication of 5-LO derived leukotrienes (LTs) in atherosclerosis and cardiovascular inflammation, an area that is currently receiving considerable attention. As alternatives to highly-selective COX-2 inhibitors, COX inhibiting nitric oxide (NO) donating drugs (CINODs) (previously termed “NO-NSAIDs”) have attracted interest. Nitroalkoxy esters of traditional NSAIDs are pro-drugs that are hydrolyzed to the parent NSAID and the nitroalkoxy ester. The nitroalkoxy ester can produce NO, presumably by physiological routes of reductive organic nitrate metabolism.......