{"id":42984,"date":"2018-09-07T16:18:16","date_gmt":"2018-09-07T15:18:16","guid":{"rendered":"https:\/\/blogs.bmj.com\/bmj\/?p=42984"},"modified":"2018-09-20T17:47:16","modified_gmt":"2018-09-20T16:47:16","slug":"jeffrey-aronson-when-i-use-a-word-non-steroidal-anti-inflammatory-drugs-origin-of-the-term","status":"publish","type":"post","link":"https:\/\/blogs.bmj.com\/bmj\/2018\/09\/07\/jeffrey-aronson-when-i-use-a-word-non-steroidal-anti-inflammatory-drugs-origin-of-the-term\/","title":{"rendered":"Jeffrey Aronson: When I use a word . . . Non-steroidal anti-inflammatory drugs\u2014origin of the term"},"content":{"rendered":"

\"jeffrey_aronson\"<\/a>As I discussed <\/span>last week<\/span><\/a>, non-steroidal anti-inflammatory drugs (NSAIDs) form a heterogeneous group of compounds, primarily defined by being anti-inflammatory and secondarily by not being steroids.<\/span><\/p>\n

The word \u201c<\/span>steroid<\/span><\/a>\u201d, which means \u201clike a sterol\u201d, first appeared in a 1936 <\/span>paper<\/span><\/a> in the <\/span>Proceedings of the Royal Society of London<\/span><\/i>, by Callow & Young, who proposed the term \u201cas [a] generic name for the group of compounds comprising the sterols, bile acids, heart poisons, saponins and sex hormones\u201d. Authors soon started identifying other compounds by the fact that they were <\/span>not<\/span><\/i> steroids, initially using the term \u201cnon-steroid\u201d, as in \u201cnon-steroid alcohols\u201d (<\/span>1940<\/span><\/a>), \u201cnonsteroid substances\u201d (<\/span>1946<\/span><\/a>), \u201cnon-steroid estrogens\u201d (1948), and \u201cnon-steroid hormones\u201d (<\/span>1952<\/span><\/a>), and then using the term \u201cnon-steroidal\u201d, as in \u201cnonsteroidal microcrystals\u201d (<\/span>1956<\/span><\/a>; the earliest citation in the <\/span>Oxford English Dictionary<\/span><\/i>), \u201cnonsteroidal compounds\u201d (<\/span>1956<\/span><\/a>), and \u201cnonsteroidal chromogen\u201d (<\/span>1956<\/span><\/a>).<\/span><\/p>\n

In <\/span>1927<\/span><\/a> Hartman, MacArthur, and Hartman used an extract of bovine adrenal cortex to treat adrenalectomized cats; Frank Hartman and others called their extract \u201c<\/span>cortin<\/span><\/a>\u201d, regarding it as a single compound. <\/span>Wilbur Swingle and Joseph Pfiffner<\/span><\/a> called their extract \u201ccortical hormone\u201d, recognizing that it might contain more than one active substance, and with Leonard Rowntree and Carl Greene showed that it was effective in patients with Addison\u2019s disease. Later, different compounds were isolated from adrenal cortical extracts. The one that Edward Kendall called Compound B, now known as corticosterone, was used to treat \u201cwound shock\u201d in rats in\u00a0<\/span>1940<\/span><\/a> by Hans Selye and Christine Dosne. Compound E, cortisone, was used to treat rheumatoid arthritis in humans by Philip Hench and Edward Kendall in <\/span>1948<\/span><\/a>.<\/span><\/p>\n

Cortisone then started to be used widely in the treatment of inflammatory conditions, such as <\/span>rheumatoid arthritis<\/span><\/a>, <\/span>allergies<\/span><\/a>, <\/span>glomerulonephritis<\/span><\/a>, and <\/span>lupus erythematosus<\/span><\/a>. However, in 1951 reports of its many adverse effects, both acute and chronic, started to appear, including <\/span>Cushing\u2019s syndrome<\/span><\/a>, <\/span>adrenal suppression<\/span><\/a>, <\/span>acute toxic psychosis<\/span><\/a>, <\/span>infections<\/span><\/a>, <\/span>osteoporosis<\/span><\/a>, <\/span>hypertension<\/span><\/a>, <\/span>skin pigmentation<\/span><\/a>, and many more.<\/span><\/p>\n

Discussing the use of the term \u201cnon-steroidal anti-inflammatory drugs\u201d, <\/span>Buer<\/span><\/a> has described how he discovered a <\/span>paper<\/span><\/a> by Michael W Whitehouse, published in August 1963, listed in Pubmed, and titled \u201cA biochemical distinction between nonsteroid anti-inflammatory and analgesic drugs\u201d. Dr Whitehouse in turn pointed him to a presentation by Whitehouse and Lash to the First International Congress of Endocrinology in Copenhagen in 1960, in which they wrote \u201cWe have studied the effects of a number of glucocorticoids and also of some non-steroid anti-inflammatory agents upon the biogenesis of cartilage in tissue culture.\u201d Buer suggested that that was the first use of the term. Whitehouse and Last used the term again in a <\/span>paper<\/span><\/a> in Nature<\/em> in 1961, after which it started to become more widely used, although uptake did not really become widespread until the mid-1970s (Figure 1).<\/span><\/p>\n

\"\"<\/p>\n

Figure 1.<\/b> The numbers of papers since 1963 containing the term \u201cnon-steroid\/al anti-inflammatory\u201d, with and without hyphens, as a textword (source Pubmed); the small dip in 2006-8 came soon after the withdrawal of rofecoxib and may have reflected doubts about the use of non-steroidal anti-inflammatory drugs at that time<\/span><\/p>\n

Now, databases like Pubmed cover papers published in bioscience journals, but not other publications, such as textbooks and advertisements. During <\/span>research<\/span><\/a> with my colleagues Richard Green and Peter Haddad into how medicinal products were advertised in the 1950s to 1980s, I came across advertisements for a product called Biosone GA. Biosone was first advertised in The BMJ<\/em> on 9 June 1956 and then again on 23 and 30 June, 1 and 29 September, and 27 October, always as \u201ca new anti-inflammatory and anti-pruritic agent\u201d (Figure 2).<\/span><\/p>\n

\"\"<\/p>\n

Figure 2.<\/b> An advert for Biosone G.A. in The BMJ<\/em> on 9 June 1956.<\/span><\/p>\n

Then, on 21 September 1957, the advertisement was changed. This time it proclaimed that Biosone was \u201ca new non-steroidal anti-inflammatory agent\u201d (Figure 3). Similar adverts appeared on 10 October 1957 and 11 January 1958. There may be earlier examples still, but I haven\u2019t found any. A search in Google Books suggests that there may also be an instance in a <\/span>1955 issue<\/span><\/a> of the <\/span>Journal of the South African Veterinary Medical Association<\/span><\/i>, but I have not been able to locate a copy of that.<\/span><\/p>\n

\"\"<\/p>\n

Figure 3.<\/b> An advertisement for \u201ca new non-steroidal anti-inflammatory agent\u201d in The BMJ<\/em> on 21 September 1957; this instance antedates the earliest citation given in the <\/span>Oxford English Dictionary<\/span><\/i>, from <\/span>1963<\/span><\/a>, describing flufenamic acid, and Whitehouse\u2019s first use of the term in 1960<\/span><\/p>\n

This evidence suggests to me that the term \u201cnon-steroidal anti-inflammatory drug<\/span>\u201d may have been introduced in advertising by Biorex Laboratories Ltd, in response to the increasingly recognized adverse effects of corticosteroids in the early 1950s. It is clear from the examples cited above, that the term \u201cnonsteroid\/al\u201d was already being widely used, and the term \u201canti-inflammatory\u201d has a pedigree going back to the 18<\/span>th<\/span> century. The active ingredient in Biosone GA was glycyrrhetinic acid, which has aldosterone like activity and has been <\/span>used<\/span><\/a> to treat Addison\u2019s disease; its derivative carbenoxolone, previously used to treat peptic ulceration, has given way to more modern treatments. In the earlier adverts for Biosone GA, the manufacturers stressed the structural similarity between glycyrrhetinic acid and hydrocortisone (Figure 2). Later, however, they contrasted the two compounds, instead of pointing to their similarity. Dropping the illustration of the structure of hydrocortisone and adding the term \u201cnon-steroidal\u201d would have stressed their assertion that \u201cno systemic or local reactions have been reported\u201d, implying \u201ccompared with steroids like hydrocortisone\u201d.<\/span><\/p>\n

The abbreviation \u201cNSAID[s]\u201d probably first appeared in <\/span>1973<\/span><\/a>, although earlier examples may yet be found.<\/span><\/p>\n

Incidentally, glycyrrhetinic acid is no longer used. <\/span>Biosone<\/span><\/a> is the name of a product containing hydrocortisone.<\/span><\/p>\n

Jeffrey Aronson<\/strong>\u00a0is a clinical pharmacologist, working in the Centre for Evidence Based Medicine in Oxford’s Nuffield Department of Primary Care Health Sciences. He is also president emeritus of the British Pharmacological Society.<\/em><\/p>\n

Competing interests:<\/strong>\u00a0None declared.<\/p>\n","protected":false},"excerpt":{"rendered":"

As I discussed last week, non-steroidal anti-inflammatory drugs (NSAIDs) form a heterogeneous group of compounds, primarily defined by being anti-inflammatory and secondarily by not being steroids. The word \u201csteroid\u201d, which […]<\/p>\n

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