title: Ibuprofen: from invention to an OTC therapeutic mainstay.
abstract: The discovery of ibuprofen's anti-inflammatory activity by Dr (now Professor) Stewart Adams and colleagues (Boots Pure Chemical Company Ltd, Nottingham, UK) 50 years ago represented a milestone in the development of anti-inflammatory analgesics. Subsequent clinical studies were the basis for ibuprofen being widely accepted for treating painful conditions at high anti-rheumatic doses (≤ 2400 mg/d), with lower doses (≤ 1200 mg/d for ≤ 10 days) for mild-moderate acute pain (e.g. dental pain, headache, dysmenorrhoea, respiratory symptoms and acute injury). The early observations have since been verified in studies comparing ibuprofen with newer cyclo-oxygenase-2 selective inhibitors ('coxibs'), paracetamol and other non-steroidal anti-inflammatory drugs (NSAIDs). The use of the low-dose, non-prescription, over-the-counter (OTC) drug was based on marketing approval in 1983 (UK) and 1984 (USA); and it is now available in over 80 countries. The relative safety of OTC ibuprofen has been supported by large-scale controlled studies. It has the same low gastro-intestinal (GI) effects as paracetamol (acetaminophen) and fewer GI effects than aspirin. Ibuprofen is a racemate. Its physicochemical properties and the short plasma-elimination half-life of the R(-) isomer, together with its limited ability to inhibit cyclo-oxygenase-1 (COX-1) and thus prostaglandin (PG) synthesis, compared with that of S(+)-ibuprofen, are responsible for the relatively low GI toxicity. The R(-) isomer is then converted in the body to the S(+) isomer after absorption in the GI tract. Ex vivo inhibition of COX-1 (thromboxane A(2)) and COX-2 (PGE(2)) at the plasma concentrations of S(+)-ibuprofen corresponding to those found in the plasma following ingestion of 400 mg ibuprofen in dental and other inflammatory pain models provides evidence of the anti-inflammatory mechanism at OTC dosages. R(-)-ibuprofen has effects on leucocytes, suggesting that ibuprofen has anti-leucocyte effects, which underlie its anti-inflammatory actions. Future developments include novel gastro-tolerant forms for 'at risk' patients, and uses in the prevention of neuro-inflammatory states and cancers.
authors.affiliation: Biomedical Research Centre, Sheffield Hallam University, Sheffield, UK. k.d.rainsford@shu.ac.uk
authors.forename: K D
authors.initials: KD
authors.lastname: Rainsford
mesh_terms: D059787:Acute Pain / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D000284:Administration, Oral; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D001682:Biological Availability; D002986:Clinical Trials as Topic; D051546:Cyclooxygenase 2 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000145:classification / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017277:Drug Approval; D016903:Drug Monitoring / Q000379:methods; D006207:Half-Life; D006801:Humans; D007052:Ibuprofen / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism; D008954:Models, Biological; D004366:Nonprescription Drugs; D010147:Pain Measurement; D060735:Pharmacovigilance
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D004366:Nonprescription Drugs; D051546:Cyclooxygenase 2; D007052:Ibuprofen