{"id":47949,"date":"2020-07-03T16:21:57","date_gmt":"2020-07-03T15:21:57","guid":{"rendered":"https:\/\/blogs.bmj.com\/bmj\/?p=47949"},"modified":"2020-07-10T17:47:43","modified_gmt":"2020-07-10T16:47:43","slug":"jeffrey-aronson-when-i-use-a-word-ivermectin","status":"publish","type":"post","link":"https:\/\/blogs.bmj.com\/bmj\/2020\/07\/03\/jeffrey-aronson-when-i-use-a-word-ivermectin\/","title":{"rendered":"Jeffrey Aronson: When I Use a Word . . . Ivermectin"},"content":{"rendered":"<p><span style=\"font-weight: 400\">The Nobel Prize in Medicine or Physiology in 2015 was awarded for two pharmacological discoveries: Tu Youyou\u2019s discovery of the efficacy in malaria of <\/span><a href=\"http:\/\/blogs.bmj.com\/bmj\/2015\/10\/30\/jeffrey-aronson-when-i-use-a-word-a-twist-on-the-nobel-prize\"><span style=\"font-weight: 400\">qinghao<\/span><\/a><span style=\"font-weight: 400\">, <\/span><i><span style=\"font-weight: 400\">Artemisia annua<\/span><\/i><span style=\"font-weight: 400\">, the source of artemisinin-based treatments, and the discovery of the avermectin group of macrolide antimicrobial drugs by Satoshi \u014cmura and William C Campbell.<\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-47950 alignnone\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_3july_2020.jpg\" alt=\"\" width=\"682\" height=\"379\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_3july_2020.jpg 682w, https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_3july_2020-300x167.jpg 300w, https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_3july_2020-640x356.jpg 640w\" sizes=\"auto, (max-width: 682px) 100vw, 682px\" \/><\/p>\n<p><b>Figure 1.<\/b><span style=\"font-weight: 400\"> Two of the three Nobel Prize winners for medicine or physiology in 2015 (photo credits: Bengt Nyman &#8211; Own work, CC BY-SA 4.0; <\/span><a href=\"https:\/\/commons.wikimedia.org\/w\/index.php?curid=45489848\"><span style=\"font-weight: 400\">\u014cmura<\/span><\/a><span style=\"font-weight: 400\">; <\/span><a href=\"https:\/\/commons.wikimedia.org\/w\/index.php?curid=45490291\"><span style=\"font-weight: 400\">Campbell<\/span><\/a><span style=\"font-weight: 400\">)<\/span><\/p>\n<p><span style=\"font-weight: 400\">\u014cmura had isolated the actinomycete <\/span><i><span style=\"font-weight: 400\">Streptomyces avermitilis<\/span><\/i><span style=\"font-weight: 400\"> (previously NRRL 8165) at the Kitasato Institute, from a soil sample collected at Kawana, Ito City, in the Shizuoka Prefecture, Japan. He and his colleagues at the <\/span><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC352666\/\"><span style=\"font-weight: 400\">Kitasato Institute<\/span><\/a><span style=\"font-weight: 400\">, and others at <\/span><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC352667\/pdf\/aac00273-0052.pdf\"><span style=\"font-weight: 400\">Merck Sharp &amp; Dohme&#8217;s Research Laboratories<\/span><\/a><span style=\"font-weight: 400\"> in Rahway, New Jersey, to whom they sent their samples, extracted compounds from it and called them <\/span><a href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/PMC352666\/\"><span style=\"font-weight: 400\">avermectins<\/span><\/a><span style=\"font-weight: 400\">. One of them, abamectin was marketed as a treatment for equine parasites, and another, ivermectin, was marketed as Mectizan for human infections.\u00a0<\/span><\/p>\n<p><span style=\"font-weight: 400\">It was Campbell at the Merck Institute for Therapeutic Research who recognized the efficacy of ivermectin against the onchocerciasis parasite <\/span><i><span style=\"font-weight: 400\">Oncocerca cervicalis<\/span><\/i><span style=\"font-weight: 400\">, and this is now one of its main uses. It is also used for strongyloidiasis and scabies.<\/span><\/p>\n<p><a href=\"https:\/\/blogs.bmj.com\/bmj\/2020\/06\/19\/jeffrey-aronson-when-i-use-a-word-withdrawn\"><span style=\"font-weight: 400\">Two weeks ago<\/span><\/a><span style=\"font-weight: 400\">, in discussing articles that were retracted after publication, I quoted some comments on <a href=\"https:\/\/www.reddit.com\/r\/COVID19\/comments\/g4zuzw\/usefulness_of_ivermectin_in_covid19_illness\/#bottom-comments\">a discussion website<\/a> that had greeted a preprint that described apparently strikingly beneficial effects of ivermectin in covid-19. They illustrated the types of often uncritical responses that work of that sort attracts. This one particularly caught my attention:\u00a0<\/span><\/p>\n<table>\n<tbody>\n<tr style=\"border: 1px solid black\">\n<td style=\"border: 1px solid black\">\n<ul>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">I may have missed it, but what is the proposed mechanism?<\/span><\/li>\n<\/ul>\n<p><span style=\"font-weight: 400\">\u25cb<\/span> <span style=\"font-weight: 400\">It&#8217;s somewhat common, we still don&#8217;t know a definitive mechanism of action for Tylenol. There are many other medications with unknown MoA. Am a pharmacist.\u00a0<\/span><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p><span style=\"font-weight: 400\">It is disappointing that a pharmacist should appear insouciant about the fact that an apparently dramatic piece of clinical evidence should not be supported by mechanistic evidence. Now it is true that in the <\/span><a href=\"https:\/\/www.cebm.net\/2016\/05\/ocebm-levels-of-evidence\/\"><span style=\"font-weight: 400\">Oxford Levels of Evidence<\/span><\/a><span style=\"font-weight: 400\"> mechanistic reasoning is regarded as the lowest form of life in the evidence menagerie. However, as I have pointed out <\/span><a href=\"https:\/\/books.google.co.uk\/books?id=Ue7RDwAAQBAJ&amp;printsec=frontcover#v=onepage&amp;q&amp;f=false\"><span style=\"font-weight: 400\">elsewhere<\/span><\/a><span style=\"font-weight: 400\">, with detailed reasons, this is a category error. Mechanistic reasoning is not itself evidence, although it should be backed up by strong evidence if it is going to be convincing. It is also true that there are treatments that we use regularly whose mechanism of action is unknown. Nevertheless, when faced with a myriad of choices for a new acute disease, a supporting mechanism can be a guide.<\/span><\/p>\n<p><span style=\"font-weight: 400\">The mechanism of action of ivermectin in parasitic infections is thought to be inhibition of anion flux through a glutamate-controlled chloride channel present in the parasites, killing them by neurotoxicity. But the channel is not found in humans. Nor in viruses. Mechanisms, however, can always be conjured up. Here\u2019s one from the same thread of comments:<\/span><\/p>\n<table>\n<tbody>\n<tr style=\"border: 1px solid black\">\n<td style=\"border: 1px solid black\">\n<ul>\n<li style=\"font-weight: 400\"><span style=\"font-weight: 400\">Importin (IMP) \u03b1\/\u03b21 30 is a heterodimer that binds to the SARS-CoV-2 cargo protein and moves it into the nucleus which reduces the host cell antiviral response. Ivermectin destabilizes the Imp\u03b1\/\u03b21 heterodimer, prevents it from viral protein binding and thus from entering the nucleus.<\/span><\/li>\n<\/ul>\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n<p><span style=\"font-weight: 400\">This<\/span><span style=\"font-weight: 400\">, perhaps convincing sounding mechanism, based on some in vitro evidence in other viruses, has been dusted off, with apparent authority, to explain the action of ivermectin in covid-19. But we have no evidence that this proposed mechanism is at all relevant (Figure 2). In fact, it can\u2019t be relevant, because (spoiler alert) SARS-CoV-2 doesn\u2019t enter the nucleus to replicate; it replicates in the cytoplasm.<\/span><\/p>\n<p><span style=\"font-weight: 400\">If ivermectin is at all effective, an action on an importin of any kind isn\u2019t the mechanism. Most of the time when we choose a drug to test, we seem to be entering a dark covid-19 tunnel. Is ivermectin the light at the end of the tunnel, or is it, as so often seems to be the case, just the light of a train coming in the other direction?<\/span><\/p>\n<p><span style=\"font-weight: 400\">As ever, we are reduced to mouthing the same old trite truism, that we must wait for the results of well designed trials, preferably double-masked and placebo-controlled.<\/span><\/p>\n<p><img loading=\"lazy\" decoding=\"async\" class=\" wp-image-47952 alignnone\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_3july2020_2.jpg\" alt=\"\" width=\"684\" height=\"560\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_3july2020_2.jpg 544w, https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_3july2020_2-300x246.jpg 300w\" sizes=\"auto, (max-width: 684px) 100vw, 684px\" \/><\/p>\n<p><b>Figure 2.<\/b><span style=\"font-weight: 400\"> Different types of mechanistic evidence and the Greek origins of the names I have given them; for a satisfactory explanation of the action of any investigative compound we need three types of evidence before we should be thinking about a clinical trial in covid-19:\u00a0<\/span><br \/>\n<span style=\"font-weight: 400\">(a) evidence that the mechanism exists in SAR-CoV-2 (evidence <\/span><i><span style=\"font-weight: 400\">for<\/span><\/i><span style=\"font-weight: 400\"> the mechanism or ontic evidence)\u00a0<\/span><br \/>\n<span style=\"font-weight: 400\">(b) evidence about how the mechanism would work and how the drug would affect it (anagnoristic evidence), and, optionally,<\/span><br \/>\n<span style=\"font-weight: 400\">(c) evidence that the mechanism is likely to be relevant to the clinical problem (evidence <\/span><i><span style=\"font-weight: 400\">from<\/span><\/i><span style=\"font-weight: 400\"> the mechanism, polychrestic evidence)<\/span><br \/>\n<span style=\"font-weight: 400\">Absence of (a) and (b) should make us think twice about doing a clinical trial <\/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\/06\/12\/jeffrey-aronson-when-i-use-a-word-benefits-harms-and-three-tales-of-retractions\/\"><img loading=\"lazy\" decoding=\"async\" class=\"size-full wp-image-47961 alignnone\" src=\"https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_july2020.jpg\" alt=\"\" width=\"698\" height=\"1566\" srcset=\"https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_july2020.jpg 698w, https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_july2020-134x300.jpg 134w, https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_july2020-456x1024.jpg 456w, https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_july2020-685x1536.jpg 685w, https:\/\/blogs.bmj.com\/bmj\/files\/2020\/07\/aronson_july2020-640x1436.jpg 640w\" sizes=\"auto, (max-width: 698px) 100vw, 698px\" \/><\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>The Nobel Prize in Medicine or Physiology in 2015 was awarded for two pharmacological discoveries: Tu Youyou\u2019s discovery of the efficacy in malaria of qinghao, Artemisia annua, the source of [&#8230;]<\/p>\n<p><a class=\"btn btn-secondary understrap-read-more-link\" href=\"https:\/\/blogs.bmj.com\/bmj\/2020\/07\/03\/jeffrey-aronson-when-i-use-a-word-ivermectin\/\">More&#8230;<\/a><\/p>\n","protected":false},"author":1,"featured_media":38359,"comment_status":"open","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[5762],"tags":[],"class_list":["post-47949","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 v27.4 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Jeffrey Aronson: When I Use a Word . . . 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