Anti-Inflammatory Drugs in the 21st Century

Abstract

Historically, anti-inflammatory drugs had their originsin the serendipitous discovery of certain plants and their extracts being applied for the relief of pain, fever and inflammation. When salicylates were discovered in the mid-19th century to be the active components of Willow Spp., thisenabled these compounds to be synthesized and from this,acetyl-salicylic acid or Aspirin trademark was developed.Likewise, the chemical advances of the 19th–20th centuries leadto development of the non-steroidal anti-inflammatory drugs(NSAIDs), most of which were initially organic acids, but laternon-acidic compounds were discovered. There were two periods ofNSAID drug discovery post-World War 2, the period up to the 1970’swhich was the pre-prostaglandin period and thereafter up to the latter part of the last century in which their effects on prostaglandin production formed part of the screening in thedrug-discovery process. Those drugs developed up to the 1980-late90’s were largely discovered empirically following screening for anti-inflammatory, analgesic and antipyretic activities inlaboratory animal models. Some were successfully developed thatshowed low incidence of gastro-intestinal (GI) side effects (theprincipal adverse reaction seen with NSAIDs) than seen with their predecessors (e.g. aspirin, indomethacin, phenylbutazone); the GIreactions being detected and screened out in animal assays. In the1990’s an important discovery was made from elegant molecular andcellular biological studies that there are two cyclo-oxygenase(COX) enzyme systems controlling the production of prostanoids [prostaglandins (PGs) and thromboxane (TxA₂) ]; COX-1that produces PGs and TxA₂ that regulategastrointestinal, renal, vascular and other physiological functions, and COX-2 that regulates production of PGs involved in inflammation, pain and fever. The stage was set in the 1990’s forthe discovery and development of drugs to selectively controlCOX-2 and spare the COX-1 that is central to physiological processes whose inhibition was considered a major factor indevelopment of adverse reactions, including those in the GI tract.At the turn of this century, there was enormous commercialdevelopment following the introduction of two new highly selectiveCOX-2 inhibitors, known as coxibs (celecoxib and rofecoxib) whichwere claimed to have low GI side effects. While found to have fulfilled these aims in part, an alarming turn of events tookplace in the late 2004 period when rofecoxib was withdrawn worldwide because of serious cardiovascular events and other coxibs were subsequently suspected to have this adverse reaction, although to a varying degree. Major efforts are currently underwayto discover why cardiovascular reactions took place with coxibs, identify safer coxibs, as well as elucidate the roles of COX-2 andCOX-1 in cardiovascular diseases and stroke in the hope that there may be some basis for developing newer agents (e.g. nitricoxide-donating NSAIDs) to control these conditions

The discovery of the COX isoforms led to establishing their importance in many non-arthritic or non-pain states where there isan inflammatory component to pathogenesis, including cancer, Alzheimer’s and other neurode generative diseases. The applications of NSAIDs and the coxibs in the prevention and treatment of theseconditions as well as aspirin and other analogues in the prevention of thrombo-embolic diseases now constitute one of the major therapeutic developments of the this century. Moreover, new anti-inflammatory drugs are being discovered and developed based ontheir effects on signal transduction and as anti-cytokine agents andthese drugs are now being heralded as the new therapies to controlthose diseases where cytokines and other non-prostaglandin components of chronic inflammatory and neurode generative diseasesare manifest. To a lesser extent safer application ofcorticosteroids and the applications of novel drug delivery systemsfor use with these drugs as well as with NSAIDs also represent newer technological developments of the 21st century. What started out asdrugs to control inflammation, pain and fever in the last two centuries now has exploded to reveal an enormous range and type of anti-inflammatory agents and discovery of new therapeutic targets totreat a whole range of conditions that were never hitherto envisaged