I have a new article out, published in 'Canadian Holmes', the magazine of the Bootmakers of Toronto, and edited by Mark Alberstat. This article arose from my intrigue at finding a small booklet of Sherlock Holmes stories published by 'Flint Laboratories'. As a pharmacologist and drug discovery person, I wanted to know more about the drug being advertised. Was there any actual connection between the drug and the canon? No, not really - it's not clear to me what the advertising pitch would have been.
I've become quite interested in Sherlock books published as an advertising ploy, and using Holmes/Watson in advertising medicines. I'm currently working on a follow-up article on another interesting advertising campaign.
As always, I'm posting the original submitted article here (like a scientific pre-print).
A Scandal in Pharmacopeia
Matthew D. Hall
The image of Sherlock Holmes has constantly been used to promote a wide range of products. Less common is the publication of stories from the Canon as the basis for an advertising strategy, or to act as promotional materials.
Yet this is exactly the approach taken by the pharmaceutical company Flint Laboratories in the 1970s. Using the publisher/printer The Benjamin Company (of Madison Avenue, New York), Flint Laboratories arranged for a collection of five stories to be published under the title "The Adventures of Sherlock Holmes and Doctor Watson". The stories selected were The Five Orange Pips, The Adventure of the Engineer's Thumb, The Adventure of the Blue Carbuncle, The Adventure of the Noble Bachelor, and The Red-Headed League.
The cover of the small orange volume (measuring only 4 by 5 1/2 inches) is dominated by a close shot of Sherlock Holmes wearing a deerstalker and with a calabash pipe held to his mouth, leaning in to Dr. Watson wearing a bowler hat. On the rear cover of the paperback orange volume is the logo and details of Flint Laboratories (Division of Travenol Laboratories, Morton Grove, Illinois). The publications are undated, but De Waal dates them at 1970 (Note 1), and the National Library of Medicine holds a copy of 'The Five Orange Pips' from this series and also cites 1970 (Note 2). Flint Laboratories published each of the five stories separately, with each identical in appearance, but containing a single story and the title of the story on the cover. One remarkable aspect of these Flint Laboratories publications is that nowhere do they name the author of the stories (Arthur Conan Doyle), and there is no acknowledgment of obtaining permission from the copyright holder to publish the stories.
What were Flint Laboratories advertising? Inside the front cover it is stated:
"Elementary, my dear Holmes, the drug of choice is... SYNTHROID® (sodium levothyroxine)."
"Quite, my dear Doctor. And investigation will prove no pure synthetic is more economical to your patients."
Presumably the booklets were distributed to physicians to influence prescribing behavior. There are a series of rules regarding the promotion and advertisement of prescription medications, imposed by regulators, and through attempts at self-regulation by professional bodies (Note 3). It is unlikely that a free booklet of Sherlock Holmes stories would concern regulators in the 1970s.
Synthroid is the brand (or trade name) for a medicine used to treat thyroid hormone deficiency (hypothyroidism) (Note 4). The active ingredient in the drug is sodium levothyroxine (also called L-thyroxine, or T4), a thyroid hormone produced by healthy humans in the thyroid gland. This article will refer to the medication by its generic name (thyroxine), as is standard practice in science, unless specifically describing the product produced by Flint Laboratories named Synthroid.
Thyroxine contains four iodine atoms (hence T4), and one of these is removed in the thyroid to produce the triiodothyronine (T3) that regulates nearly all biological process including growth and development, metabolism, body temperature, and heart rate. As such, Synthroid contains synthetic hormone identical to the natural hormone that is low in patients with hypothyroidism, and lifelong treatment is often curative as it supplements the low level of L-thyroxine in patients with hypothyroidism (an analogy may be made to using insulin to treat diabetes).
Thyroxine is an important medication: it is the treatment of choice for hypothyroidism and in 2022 the drug was the fourth-most prescribed in the US with more than 80 million prescriptions (Note 5).
Before thyroxine - from the late 1880s onwards, patients with hypothyroidism were treated with animal thyroid extracts (that contained L-thyroxine along with many other things) (Note 6). At the same time, proponents of the rejuventating effects of 'organotherapy' reported that injections of liquid extracts of dog or guinea pig glands or testicles had positive effects in older men (Note 7). These sensational experiments distracted from important work in the late 1880s and early 1990s showing that sheep's thyroid improved patients with hypothyroidism. The work led to the conclusion that a specific agent within thyroid material may be identified that can be given to humans as a treatment.
L-thyroxine was first discovered as a natural hormone from hog thyroid glands by Edwin Calvin Kendall (Mayo Clinic) in 1914, and it was first chemically synthesized and reported in 1927 in Britain. The ability to create pure chemical thyroxine identical to the natural hormone, and the creation of its salt in 1955, allowed for a tablet form to be developed to treat patients with hypothyroidism. It should be noted though that thyroid extract was also used by many even after L-thyroxine was available (Note 8).
The wording attributed to Watson and Holmes in the advertisement highlights the choice of Synthroid as the best, and there is a good reason for that advertising angle. Flint Laboratories were not the only manufacturer of thyroxine, but they were the major supplier, and were strongly positioning their product as the most reliable. At the time though (1970s and 1980s), no generic versions of thyroxine were available, because of a quirk in the history of drug regulation (Note 9). In 1962, the FDA created new requirements for the information a company would need to present to the FDA to seek approval of that drug- such as safety studies, and how much drug was absorbed. When these new requirements were created, the pharmacopeia of older existing drugs were 'grandfathered', meaning that the companies could continue manufacturing and selling their pre-1962 drugs without further modern evaluation, and there were still hundreds of such drugs in the 1970s. Fundamentally, Synthroid had never been approved in the modern sense, never satisfied modern drug approval standards, but were allowed to continue selling based on meeting the standard at the time the drug was introduced.
For a drug with a market as large as hypothyroidism, there was a strong push from generic manufacturers to be allowed a seat at the table, and here's where the age of the drug benefited Flint Laboratories. For any drug no longer protected by patents, a generic manufacturer may produce an equivalent product to the approved commercial material - that is the definition of generic - it is identical to the brand drug, works the same, and allows market competition. However, to demonstrate the equivalence of a new generic to the FDA, the manufacturer must show that the generic drug is absorbed the same way as the original commercial product (Synthroid). However, because Synthroid was so old, that data was never generated, and the FDA could not compel Flint Laboratories to do so! So Flint owned their market through a quirk of the system, and were not compelled to generate data that would erode their market dominance.
In the 1980s, Flint Laboratories received significant pressure to release data showing their product was superior ("no pure synthetic is more economical to your patients") and they paid a University of California San Francisco (UCSF) group to perform the experiments. The data produced by UCSF showed all thryoxine products were equivalent, but Flint Laboratories suppressed the data - and that was a scandal in pharmacopeia (Note 10). Legal wrangling ultimately allowed the data to see the light of day (SEVEN YEARS after it was submitted for publication), and in 1997 the FDA announced throxine was a "new drug" requiring modern standard testing, and generated independent data. During the dispute with UCSF, Flint Laboratories became part of Boots, but the purpose of the Sherlock Holmes Synthroid booklets was to reinforce to prescribers that their product was superior and others should not be used. More aggressive business practices followed, and this received significant press attention.
So important and widely used was Synthroid that Dorothy L. Sayers based the plot of a short story on the medicine. Sayers embraced toxicology in her stories, including in the Wimsey-less 'The Documents in the Case' written with Robert Eustace, where the chemical difference between the natural and synthetic forms of muscarine allow murder to be detected (Note 11). In the 1933 short story 'The Incredible Elopement of Lord Peter Wimsey', Wimsey hears of of a woman taken to Spain by her physician husband in order to remove her from here suspected paramour (Note 12). In Spain she becomes exceedingly unwell. A mutual acquaintance who visits Spain tells Wimsey “her face {was} white and puffy, the eyes vacant, the mouth drooling and a dry fringe of rusty hair clinging to a half-bald scalp.” These are the classic features of advanced hypothryoidism (called myxedema), and Wimsey recognizes this. He travels to Spain to remove the woman from her husband's brutality. As her doctor, the husband had withdrawn his wife's thyroxine medication, allowing her hypothyroidism to recur in a severe form.
Wimsey himself perfectly summarized hypothyroidism and the benefit of thyroxine when wrapping up the case:
"Alice Wetherall is one of those unfortunate people who suffer from congenital thyroid deficiency. You know the thyroid gland in your throat — the one that stokes the engine and keeps the old brain going. In some people, the thing doesn’t work properly, and they turn out cretinous imbeciles. Their bodies don’t grow, and their minds don’t work. But feed ’em the stuff, and they come absolutely all right — cheery and handsome and intelligent and lively as crickets. Only, don’t you see, you have to keep feeding it to ’em, otherwise, they just go back to an imbecile condition."
Did the Sherlock Holmes promotional booklets influence doctors? It seems unlikely. Was there a Sherlockian in the Flint Laboratories marketing division? Where were the booklets distributed? Print numbers do not appear to be available, but only a very small number of copies have been sighted through book vendors, or in library catalogs. Being cheaply made, and passed out freely, they were likely discarded readily.
Perhaps the biggest question that any Sherlockian reader will be asking is why the five stories were selected from among the canon. There are no plot elements in the five stories that relate to treatment of patients. On the other hand, The Adventure of the Creeping Man (published 1927) is connected to the history of Synthroid. In the story, Holmes is called in to examine the case of the 61-year-old Professor Presbury, whose behavior has changed since a foreign trip and following his engagement to a much younger woman. Holmes observes Presbury's odd primate-like behavior first-hand, when Presbury moves about on all fours, climbs the outside of his home, and provokes the family dog to the point that it attacks him. Holmes examines the treatment that Presbury has been taking, and finds that it is extracted from a primate (the langur). While not explicitly stated, it is implied that in seeking youthful energy to match his impending bride, he was being treated with an extract of primate gland or possibly testicle.
In the case of Presbury, rather than using animal gland extracts to treat hypothryoidism, he was seeking to turn "himself into a younger man". Given the element of terror and the Jekyll & Hyde analogy in the story, it is perhaps understandable that Flint excluded the story from its promotional plans. Still, it seems like an opportunity lost for a perfect intersection between the canon and pharmacology, and these booklets may be the only example of the stories from the canon being used to promote a pharmaceutical product.
References
Note 1. Ronald Burt De Waal, The Universal Sherlock Holmes, Third Edition, Toronto: Metropolitan Toronto Reference Library, 1994.
Note 2. Retrieved from National Library of Medicine catalog www.ncbi.nlm.nih.gov , NLM catalog 9918843281306676.
Note 3. David Grande, Limiting the Influence of Pharmaceutical Industry Gifts on Physicians: Self-Regulation or Government Intervention?, J Gen Intern Med, 2009, 79-83
Note 4. George J. Kahaly, 70 Years of Levothyroxine, Springer, 2021
Note 5. Retrieved from www.singlecare.com/blog/news/prescription-drug-statistics/
Note 6. George J. Kahaly, Therapeutic Use of Levothyroxine: A Historical Perspective, in 70 Years of Levothyroxine, Springer, 2021
Note 7. Phillipe L. Salvais, The case of Professor Presbury: a literary digression on the controversial birth of endocrinology, J Med Biogr, 1998, 149-151
Note 8. Stefan Slater, The discovery of thyroid replacement therapy. Part 3: A complete transformation, J Roy Soc Med, 2011, 100-106
Note 9. Editorial, Thyroid Storm, J Am Med Assoc, 1997, 1238-1243
Note 10. Jacqui Wise, Research suppressed for seven years by drug company, Br Med J, 1997, 1145
Note 11. Dorothy L. Sayers and Robert Eustace, 1930, Ernest Benn
Note 12. Dorothy L. Sayers, The Incredible Elopement of Lord Peter Wimsey, in Hangman's Holiday, 1933, Gollancz
