{"id":49739,"date":"2021-03-05T19:48:34","date_gmt":"2021-03-05T18:48:34","guid":{"rendered":"https:\/\/blogs.bmj.com\/bmj\/?p=49739"},"modified":"2021-03-12T17:37:32","modified_gmt":"2021-03-12T16:37:32","slug":"jeffrey-aronson-when-i-use-a-word-n-of-1-studies-and-adverse-drug-reactions","status":"publish","type":"post","link":"https:\/\/blogs.bmj.com\/bmj\/2021\/03\/05\/jeffrey-aronson-when-i-use-a-word-n-of-1-studies-and-adverse-drug-reactions\/","title":{"rendered":"Jeffrey Aronson: When I Use a Word . . . N-of-1 studies and adverse drug reactions"},"content":{"rendered":"<p><span style=\"font-weight: 400\">Lovastatin is one of the words whose earliest citations in the <\/span><i><span style=\"font-weight: 400\">Oxford English Dictionary<\/span><\/i><span style=\"font-weight: 400\"> are from 1986 (Table 1).\u00a0<\/span><\/p>\n<p><b>Table 1.<\/b><span style=\"font-weight: 400\"> Biomedical words (n=17) in the <\/span><i><span style=\"font-weight: 400\">OED<\/span><\/i><span style=\"font-weight: 400\"> for which the earliest citations are from 1986 (out of a total of 150); I have found one antedating (23years)<\/span><br \/>\n<img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-49745\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021.jpg\" alt=\"\" width=\"467\" height=\"256\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021.jpg 467w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021-300x164.jpg 300w\" sizes=\"auto, (max-width: 467px) 100vw, 467px\" \/><br \/>\n<span style=\"font-weight: 400\">*Antedating: monomethylate (<\/span><a href=\"https:\/\/www.google.co.uk\/books\/edition\/Proceedings_of_the_Chemical_Society\/HKQqAQAAMAAJ?hl=en&amp;gbpv=1&amp;bsq=monomethylates&amp;dq=monomethylates&amp;printsec=frontcover\"><span style=\"font-weight: 400\">1963<\/span><\/a><span style=\"font-weight: 400\">); the verb to monomethylate is a back formation from an earlier word, the adjective monomethylated, which the <\/span><i><span style=\"font-weight: 400\">OED<\/span><\/i><span style=\"font-weight: 400\"> dates from 1880; however, it can also be antedated, at least to <\/span><a href=\"https:\/\/www.jstor.org\/stable\/113136\"><span style=\"font-weight: 400\">1872<\/span><\/a><span style=\"font-weight: 400\">; the adjective monomethyl can be antedated from 1868 to <\/span><a href=\"https:\/\/www.jstor.org\/stable\/112112\"><span style=\"font-weight: 400\">1865<\/span><\/a><span style=\"font-weight: 400\">; monomethylized (<\/span><a href=\"https:\/\/www.jstor.org\/stable\/108986\"><span style=\"font-weight: 400\">1867<\/span><\/a><span style=\"font-weight: 400\">) may be a hapax legomenon<\/span><\/p>\n<p><span style=\"font-weight: 400\">Lipid modifying statins were originally isolated from fungi. The first was discovered by two groups independently, one in Japan, who isolated it from <\/span><i><span style=\"font-weight: 400\">Penicillium citrinum<\/span><\/i><span style=\"font-weight: 400\"> and called it <\/span><a href=\"https:\/\/www.jstage.jst.go.jp\/article\/antibiotics1968\/29\/12\/29_12_1346\/_article\"><span style=\"font-weight: 400\">mevastatin<\/span><\/a><span style=\"font-weight: 400\">, and one in the UK, who isolated it from <\/span><i><span style=\"font-weight: 400\">Penicillium brevicompactum<\/span><\/i><span style=\"font-weight: 400\"> and therefore called it <\/span><a href=\"https:\/\/pubs.rsc.org\/en\/content\/articlepdf\/1976\/p1\/p19760001165\"><span style=\"font-weight: 400\">compactin<\/span><\/a><span style=\"font-weight: 400\">. It was never marketed, although \u201cmevastatin\u201d become the International Nonproprietary Name (INN). Lovastatin was also discovered by two groups: Endo, in Japan, isolated it from <\/span><i><span style=\"font-weight: 400\">Monascus ruber<\/span><\/i><span style=\"font-weight: 400\">, and therefore called it <\/span><a href=\"https:\/\/www.jstage.jst.go.jp\/article\/antibiotics1968\/32\/8\/32_8_852\/_article\"><span style=\"font-weight: 400\">monacolin<\/span><\/a><span style=\"font-weight: 400\">, while Alberts et al isolated it from <\/span><i><span style=\"font-weight: 400\">Aspergillus tereus<\/span><\/i><span style=\"font-weight: 400\"> and called it <\/span><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC349746\/\"><span style=\"font-weight: 400\">mevinolin<\/span><\/a><span style=\"font-weight: 400\">. Other later drugs, both semisynthetic and synthetic are listed in Tables 2 and 3.<\/span><\/p>\n<p><b>Table 2.<\/b><span style=\"font-weight: 400\"> Statins and their routes of metabolism<\/span><br \/>\n<img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-49746\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_2.jpg\" alt=\"\" width=\"706\" height=\"340\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_2.jpg 706w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_2-300x144.jpg 300w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_2-640x308.jpg 640w\" sizes=\"auto, (max-width: 706px) 100vw, 706px\" \/><br \/>\n<sup><b>a<\/b><\/sup><span style=\"font-weight: 400\">Only lovastatin and pravastatin are included as headwords; the dates for simvastatin and atorvastatin are from citations under other headwords [given in brackets]<\/span><br \/>\n<sup><b>b<\/b><\/sup><span style=\"font-weight: 400\">Failed owing to adverse reactions<\/span><\/p>\n<p><b>Table 3.<\/b><span style=\"font-weight: 400\"> Drug names ending in \u2013statin<\/span><br \/>\n<img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-49747\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_3.jpg\" alt=\"\" width=\"699\" height=\"575\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_3.jpg 699w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_3-300x247.jpg 300w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_3-640x526.jpg 640w\" sizes=\"auto, (max-width: 699px) 100vw, 699px\" \/><\/p>\n<p><span style=\"font-weight: 400\">The official suffix, or stem, as it is properly called, for the group of drugs we now call \u201cstatins\u201d is actually -vastatin. This distinguishes them from other drugs, with other pharmacological actions, whose names also end in -statin (Table 3). Drugs with names that end in \u2013stat, whose full stems are all longer, are listed in Table 4. In addition to these, a product called <\/span><a href=\"https:\/\/www.google.co.uk\/books\/edition\/Federal_Register\/hVDqKQy24G8C?hl=en&amp;gbpv=1&amp;dq=statin&amp;pg=PA39193&amp;printsec=frontcover\"><span style=\"font-weight: 400\">Dr Karrs Acne-Statin<\/span><\/a><span style=\"font-weight: 400\"><sup>\u00ae<\/sup><\/span><span style=\"font-weight: 400\">, containing 0.5% salicylic acid, was marketed in the 1970s. And <\/span><a href=\"https:\/\/statinja.gov.jm\/\"><span style=\"font-weight: 400\">STATIN<\/span><\/a><span style=\"font-weight: 400\">, the Statistical Institute of Jamaica, dates from 1984.<\/span><\/p>\n<p><b>Table 4.<\/b><span style=\"font-weight: 400\"> Drug names ending in \u2013stat<\/span><br \/>\n<img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-49748\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_4.jpg\" alt=\"\" width=\"613\" height=\"243\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_4.jpg 613w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_4-300x119.jpg 300w\" sizes=\"auto, (max-width: 613px) 100vw, 613px\" \/><\/p>\n<p><span style=\"font-weight: 400\">The word \u201cstatin\u201d, as shorthand for any HMG Co-A reductase inhibitor, first appeared, according to the <\/span><i><span style=\"font-weight: 400\">OED<\/span><\/i><span style=\"font-weight: 400\">, in 1987, and I have not found an antedating. The reason \u201cstatin\u201d also featured in the <\/span><a href=\"https:\/\/blogs.bmj.com\/bmj\/2021\/02\/26\/jeffrey-aronson-when-i-use-a-word-fertile-philology\"><span style=\"font-weight: 400\">1985 list<\/span><\/a><span style=\"font-weight: 400\"> is that the word was used to describe a <\/span><a href=\"https:\/\/rupress.org\/jcb\/article\/101\/5\/1695\/58471\/Rapid-disappearance-of-statin-a-nonproliferating\"><span style=\"font-weight: 400\">nuclear phosphoprotein<\/span><\/a><span style=\"font-weight: 400\"> found in non-replicating and senescent cells but not in replicating cells.<\/span><\/p>\n<p><span style=\"font-weight: 400\">The IndoEuropean root STA meant to stand or stay, a place where something stands or stays, and anything that stands firm. Its many linguistics ramifications are shown in Figure 1.<\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-49750\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_again.jpg\" alt=\"\" width=\"798\" height=\"762\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_again.jpg 798w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_again-300x286.jpg 300w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_again-768x733.jpg 768w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_again-640x611.jpg 640w\" sizes=\"auto, (max-width: 798px) 100vw, 798px\" \/><br \/>\n<b>Figure 1.<\/b><span style=\"font-weight: 400\"> The roots of English words with implications of standing, staying, or staying firm, from the IndoEuropean root STA; in the names of drugs the infix -stat-implies inhibition<\/span><\/p>\n<p><span style=\"font-weight: 400\">Drug names ending in -stat or -statin usually imply some inhibitory action, typically of an enzyme (see Table 3). The first drug to have this stem, nystatin, originally called fungicidin, is an exception; it was isolated in <\/span><a href=\"https:\/\/journals.sagepub.com\/doi\/pdf\/10.3181\/00379727-76-18397\"><span style=\"font-weight: 400\">1951<\/span><\/a><span style=\"font-weight: 400\"> from an actinomycete by Elizabeth L Hazen and Rachel Brown of the New York State Department of Health, and \u201cnystatin\u201d is a toponym.<\/span><\/p>\n<p><span style=\"font-weight: 400\">Coincidentally, this week we heard about the results of <a href=\"https:\/\/www.bmj.com\/content\/372\/bmj.n135\">a series of n-of-one studies<\/a> in 151 subjects who had reported severe muscle pain, without raised creatine kinase activity, while taking a statin. Each underwent six double-blind two month treatment periods with atorvastatin or placebo. There was no difference in their muscle symptoms between the two treatments.<\/span><\/p>\n<p><span style=\"font-weight: 400\">I believe that n-of-one studies of this kind originated in psychology experiments. For example, a <\/span><a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/13989163\/\"><span style=\"font-weight: 400\">paper<\/span><\/a><span style=\"font-weight: 400\"> published in 1963 described the results of a study in a single individual who was asked to choose between pairs of words with similar or different meanings. \u201cA significant negative relationship was found between reaction-time and perceived distance between the word-pairs. In spite of the elegance of demonstrating the relationship with an N of one, it seemed to us desirable to conduct a more extensive investigation of this problem [using more subjects] &#8230;\u201d The numbers of publications that have featured the term &#8220;n-of-one&#8221; or \u201cn-of-1\u201din their titles since 1973 are shown in Figure 2. The numbers are small, although they have increased markedly in the past six years or so.<\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"alignnone size-full wp-image-49751\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_6.jpg\" alt=\"\" width=\"640\" height=\"380\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_6.jpg 640w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_6-300x178.jpg 300w\" sizes=\"auto, (max-width: 640px) 100vw, 640px\" \/><br \/>\n<b>Figure 2. <\/b><span style=\"font-weight: 400\">Numbers of publications with \u201cn-of-one\u201d or \u201cn-of-1\u201d in the title (source PubMed)<\/span><\/p>\n<p><span style=\"font-weight: 400\">Adverse drug reactions are often poorly characterized in formal clinical trials, and first notice, particularly of rare but important adverse reactions, often comes from anecdotal reports. Statins can undoubtedly cause muscle damage, associated with a single-nucleotide polymorphism in a gene, <\/span><a href=\"https:\/\/www.nejm.org\/doi\/pdf\/10.1056\/NEJMoa0801936?articleTools=true\"><span style=\"font-weight: 400\">SLCO1B1<\/span><\/a><span style=\"font-weight: 400\">, which encodes an organic anion-transporter, OATP1B1, responsible for uptake of statins by skeletal muscle. However, such damage is rare. It has been said that muscle symptoms, as opposed to damage, are much more common, but it has not hitherto been entirely clear to what extent the symptoms are due to a nocebo effect.<\/span><\/p>\n<p><span style=\"font-weight: 400\">N-of-one studies cannot be used to study any suspected adverse drug reaction. The reaction has to be one that is reversible during a relatively short time, with a clearly measurable endpoint. And a suitable placebo formulation has to be available, limiting the design in clinical practice. But double-blind, randomized, n-of-one studies can be powerful. Ones in which I have been <\/span><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC1027572\/pdf\/jnnpsyc00137-0070.pdf\"><span style=\"font-weight: 400\">involved<\/span><\/a><span style=\"font-weight: 400\"> have been very informative.<\/span><\/p>\n<p><span style=\"font-weight: 400\">We should do more n-of-one studies.<\/span><\/p>\n<p style=\"text-align: left\"><span style=\"font-weight: 400\"><em><strong>Jeffrey Aronson<\/strong>\u00a0is a clinical pharmacologist, working in the Centre for Evidence Based Medicine in Oxford&#8217;s Nuffield Department of Primary Care Health Sciences. He is also president emeritus of the British Pharmacological Society.<\/em><\/span><\/p>\n<p style=\"text-align: left\"><strong>Competing interests:<\/strong> None declared.<\/p>\n<p><a href=\"https:\/\/blogs.bmj.com\/bmj\/2020\/01\/31\/jeffrey-aronson-when-i-use-a-word-coronas\"><img loading=\"lazy\" decoding=\"async\" class=\"alignnone wp-image-49753 size-full\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_integer.jpg\" alt=\"\" width=\"702\" height=\"1457\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_integer.jpg 702w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_integer-145x300.jpg 145w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_integer-493x1024.jpg 493w, https:\/\/blogs.bmj.com\/bmj\/files\/2021\/03\/aronson_5_march_2021_5_integer-640x1328.jpg 640w\" sizes=\"auto, (max-width: 702px) 100vw, 702px\" \/><\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>Lovastatin is one of the words whose earliest citations in the Oxford English Dictionary are from 1986 (Table 1).\u00a0 Table 1. Biomedical words (n=17) in the OED for which the [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/blogs.bmj.com\/bmj\/2021\/03\/05\/jeffrey-aronson-when-i-use-a-word-n-of-1-studies-and-adverse-drug-reactions\/\">More&#8230;<\/a><\/p>\n","protected":false},"author":419,"featured_media":38359,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[5762],"tags":[],"class_list":["post-49739","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-jeff-aronsons-words"],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.6 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Jeffrey Aronson: When I Use a Word . . . 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