Medicinal effects of barks of some plants incl. willow known to several cultures for centuries;
Rev.Edmund Stone (UK) used willow bark in fever of malaria;
Salicin the bitter glycoside active ingredient of willow bark isolated in 1829 by Leroux who also demonstrated its antipyretic effect.
Sodium salicylate derived from salicin 1st used in RhF & fevers 1875;
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Acetanilide the parent member of para-aminophenol gp introduced into medicine in 1886 as antifebrin after its antipyretic activities accidentally discovered;
paracetamol (acetaminophen) 1st introduced 1887 & used in combination with other analgesics until realised in 1949 that it was the active metabolite of both acetanilide & phenacetin & thus gained popularity;
Aspirin clearly shown to be gastrotoxic in 1938.
Phenylbutazone the most important of the pyrazolone gp, introduced in 1949 but serum sickness/marrow suppression/hepatitis/nephritis;;
Other pyrazolones: antipyrine (phenazone), amidopyrine used 19thCent.
The fenamates' (mefenamic acid,etc) biological activities discovered in 1950's but did not gain widespread acceptance mainly due to diarrhoea.
No clear Rx advantage over other NSAID's but used in 1° dysmenorrhoea;
Indomethacin was the 1st of allied NSAID's to be widely used - introduced 1963 then sulindac & since then many more have been synthesised;
Tolmetin introduced in 1976 (US) as better tolerated than aspirin;
Propionic acid derivatives (ibuprofen, naproxen) are usually better tolerated than aspirin or indomethacin;
Piroxicam (Feldene) an oxicam derivative
Diclofenac (Voltaren) the 1st of the phenylacetic acid derivative as NSAID;
COX-2 gene discovered in 1990-91.
Ketorolac trometamol (Toradol) introduced 1992 (Aust) as periph. acting PG synthetase inhibitor developed specially for its analgesic properties as a 30mg IM replacement for pethidine 50-100mg or morphine 6-12mg IM;
In 1996-98, some existing NSAIDs shown to be COX-2 preferential (meloxicam, nimesulide)
New drugs designed to be COX-2 “selective”:
2003, reports of hypertensive crises & deaths when NSAIDs given in post partum period to women with PH pre-eclampsia or premature delivery. Advised to carefully watch BP in such pts if must use NSAIDs
2004: Vioxx (rofecoxib) withdrawn as long term Rx shown to increase risk of thrombotic events such as AMI and stroke. TGA places new restrictions on COX-2 inhibitors in Australia including avoidance in patients with high risk of cardiovascular events such as PH AMI, and the maximal long term dose of Celebrex (celecoxib) reduced to 200mg/d for other patients.
2005: Pfizer believes that the restrictions to Celebrex should apply to all NSAIDs not just COX-2 inhibitors.
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