Category Archives: Secrets

When Does a Drug Trial End?

By Justin Rivest

An eighteenth-century proprietary medicine vendor. Detail from “Le Charlatan, 1785.” Hand coloured etching and aquatint. Antoine Borel after J. Augustin L’Eveillé. Source: Wellcome Images.

The question I’d like to begin this post by asking is, When does a drug enter “normal use”? Is a trial a “provisional” phase, that reaches a definitive end, say when “proof” is found, or when the relevant authorities are convinced? Or in an age where drug monopolies were insecure and difficult to enforce, was the state of trial—l’épreuve—always ongoing?

This question first crossed my mind while preparing my contribution for the recent special issue of the Bulletin of the History of Medicine, “Testing drugs and trying cures,” edited by Elaine Leong and Alisha Rankin. My article focuses on the role of patient trials in granting monopoly privileges for proprietary drugs in eighteenth-century France. These royally-granted privileges were the distant ancestors of modern drug patents. They gave their inventors a legally enforceable monopoly over the drug in question by enabling them to fine counterfeiters.

Even after they were granted monopoly privileges, drug vendors continued, almost compulsively, to gather further evidence of the effectiveness of their drugs. This evidence often took the form of an attestation or certificat. These documents could take several forms: some were notarized statements, made by a patient declaring that he or she had been cured of this or that condition. Others were endorsements signed by an expert practitioner—a famous doctor, a representative of a local college or guild—who had personally witnessed the drug’s effects.

In this post, I will use the practice of what we might call “cure attestation collection” to question whether “trials” (épreuves) of a drug really had an end from the perspective of early modern drug monopolists.

The most important reason to continue gathering documentation of the effectiveness of their drug was to convince authorities to renew their privilege at a later date, as most monopoly privileges had fixed terms of three, ten, or fifteen years. But even within these term limits, they did not have perfect guarantees. Early modern drug monopolies were tenuous. Vendors knew that they might even have to re-submit both their drugs and their documentation for arbitrary re-examination by the authorities.

Even barring arbitrary re-examinations, the multi-generational duration of many early modern monopolies meant that they would be evaluated more than once by the authorities. The drug monopoly I studied in my article, the poudre fébrifuge of the Chevalier de Guiller, was particularly long-standing, extending across four generations. As a febrifuge, the drug was targeted at “intermittent fevers,” an important cause of mortality in the French army in this period. The drug was first awarded a monopoly privilege in 1713, at the end of the reign of Louis XIV. Its inheritors faced various challenges in exploiting it over the coming decades, but they consistently managed to get the privilege renewed. By the 1770s, in fact, the latest inheritors, the sisters Marie-Thérèse and Marie-Victoire de La Jutais, had accumulated a veritable archive of attestations in favour of their drug, spanning over sixty years.

Most of these documents were cure attestations and endorsements from patients, and prominent medical practitioners. A signed personal endorsement of the drug from the supervising practitioner was often the most important result of a hospital trial. Vendors who sold drugs in bulk to the state, especially to the military, could appeal to a special type of attestation. The La Jutais sisters, for instance, did not just rely on the documents that had been handed down to them through their family. They also went to government archives—much as historians do today—looking to collect documentation that might endorse their drug. They paid the navy office to make official copies of fifty-year-old correspondence concerning their drug so that they could submit it with their petition to renew their monopoly.

Monopolists were not, however, impartial researchers. The La Jutais sisters seem not to have collected any documentation which might cast their drug in a negative light—or at least, if they came across such evidence, they avoided disseminating it. Indeed, during my research I came across several documented cases of ambiguous or negative patient trial results of the poudre fébrifuge. In one 1714 trial involving “twenty or thirty” patients at a navy hospital, the drug was deemed to be too inconsistent in its effects and was dismissed as a violent purgative rather than a true febrifuge. It seems at least plausible that the La Jutais sisters’ archival searches might have drawn up this material as well. Nonetheless this report is notably absent from their petitions for monopoly renewal in the 1770s.

The “selective archive” of positive attestations that the La Jutais sisters assembled helped them to renew their monopoly privilege in 1775. We can see from their case that early modern drug monopolists had good reasons to keep collecting cure attestations wherever they could get them. They had the effect of turning the drug’s everyday use into a form of legally acceptable evidence, making a successful trial out of every cure.

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Justin is a postdoctoral researcher at the University of Cambridge and his work focuses on early drug monopolies and the role of bulk drug producers and consumers in the early modern medical marketplace. He recently co-wrote a short piece in The New England Journal of Medicine with Alisha Rankin on this topic, as well as an article in the Canadian Journal of History on one particularly successful drug entrepreneur, Adrien Helvétius (1662-1727), who sold massive quantities of his drug against dysentery to the French state for use in the army and rural poor relief efforts. His research has shown that trials on patients played a critical role in licensing early drug monopolies as well as in helping entrepreneurs secure lucrative supply contracts with the state.

Anecdotes and Antidotes

By Alisha Rankin

How did early modern individuals test and try their recipes and cures? This question is at the heart of the special issue of the Bulletin of the History of Medicine, “Testing Drugs and Trying Cures in Medieval and Early Modern Europe,” in which I participated as both a co-editor and an author. My article, “On Anecdote and Antidotes: Poison Trials in Early Modern Europe,” examines the ways in which early modern practitioners tested a specific kind of cure: antidotes to poison. It contains some information I discussed in earlier posts on this blog – here and here – but adds many details and thoughts about testing in general. Most cures, I argue, tended to be tested in the course of regular clinical experience. A patient got sick; a practitioner tried a particular remedy, observed the results, and frequently shared anecdotes of success or failure. The scale of this kind of testing could be small or large, but in most cases it involved patients who were already sick.

Poison antidotes were a little different, because practitioners could actually create the condition of illness by giving poison to a test subject. In 1563, for example, the royal surgeon to Holy Roman Emperor Ferdinand I, Claudius Richardus, wrote a letter describing the marvellous virtues of bezoar stone. As avid Harry Potter readers will know, bezoar was an animal byproduct prized as a poison antidote and cure-all. Richardus recounted a series of marvellously successful tests he had conducted on bezoar at the Emperor’s behest. In two of them, patients received bezoar in the midst of a serious illness – the usual practice. In the other two, bezoar was tested in contrived trials on condemned criminals.[1]

Bezoar stones from the imperial Kunstkammer, Kunsthistorisches Museum Vienna. Photo by Alisha Rankin.

This second kind of test – which I call a poison trial – has a long history dating back to antiquity. Many ancient kings, most famously Mithridates VI of Pontos (135-63 BCE), used condemned criminals to test poison antidotes, from which he developed his famous antidote and cure-all, mithridatium. The Greco-Roman physician Galen reportedly tested theriac, a derivative of mithridatium, on roosters, and versions of this test appeared in the writings of several Arabic physicians, including Avicenna’s highly influential Canon of Medicine.[2] Medieval physicians repeated the description of Galen’s test as well. However, poison trials tended to be described as theoretical tests that one could conduct rather than as anecdotes about tests that had actually taken place, and they were mainly suggested as a means to test whether a batch of theriac was inferior, fraudulent, or old – not whether theriac actually worked. From the time of Galen, moreover, poison trials were conducted exclusively on animals, not humans. The dominant argument for the efficacy of these drugs remained anecdotal reports of their use on sick patients.

In the Renaissance, poison trials expanded significantly, as did their role in medical communication. From the 1520s, powerful rulers began to revive the gruesome tradition of using condemned criminals to test a variety of poison antidotes – not just theriac. In addition, these tests were reported and circulated as anecdotes rather than being described as theoretical suggestions. The first known example comes from Rome in August 1524, when Pope Clement VII directed his medical personnel to test an antidote oil created by the surgeon Gregorio Caravita. He granted the medics two Corsican criminals who had been condemned to death by beheading. Both prisoners were given a strong dose of the deadly herb wolfsbane (aconitum napellus). Caravita then anointed one prisoner with the oil. The other, a “savage spirit,” was given no antidote. The first man survived; the other died in much agony.

Testimonium de verissima ac admirabili virtute olei compositi contra pestem & omnia venena (Rome, 1524), BNF.

A second successful test was conducted on a Mantuan prisoner given arsenic. Soon thereafter, the medical personnel published a public service pamphlet describing these trials in detail.[3]

A shorter version of this anecdote also appeared in the famous herbal published by Italian physician Pietro Andrea Mattioli in 1544 (with a Latin version in 1554). Mattioli’s influence helped spread poison trials around Europe. From 1561-67, a number of contrived trials on condemned criminals took place under powerful princes, including Emperor Ferdinand I, King Charles IX of France, and Duke Cosimo II de’Medici. Significantly, royal physicians and surgeons spearheaded these poison trials, and they communicated the results in anecdotes that appeared both in private documents and printed books. Claudius Richardus’s bezoar trials were part of a series of such events.

These anecdotes demonstrated careful thought in how the trials were devised and conducted. They described the trials in in excruciating detail, including the number of times a prisoner had vomited and defecated as well as the hour at which these events had occurred. In some cases, physicians attempted to created conditions that would lead to a useful outcome. Richardus’s letter described how food was withheld from a prisoner before the test, “so that one could be more certain of the trial.” This step came in response to a previous case in which the physicians had trouble getting the poison to work. Finally, physicians took care in reporting and circulating their reports about the trials, clearly imbuing them with significance. A series of poison trials on dogs conducted in 1580 by a German prince circulated in both manuscript and print as a detailed Observatio, a report intended to be shared.

Poison trials represented only a miniscule part of drug testing in early modern Europe. Indeed, anecdotes about drugs used successfully on sick people helped drive the interest in new drugs from around the globe, as described in this post by R.A. Kashanipour. Nevertheless, the anecdotes about antidotes demonstrated significant developments in both testing practices and medical communication. To find out more, read my article!

 

[1] Richardus’s letter, to Archbishop Nicholas Olahus, was later published in Latin and German. Thomas Jordan, Pestis phaenomena (Frankfurt, 1576), 621–630; Johann Wittich, Bericht von der wunderbaren bezoardischen Steinen (Leipzig, 1592), 21.

[2] Galen’s poison trial appeared in the treatise On Theriac to Piso, which may be spurious. However, scholars in the Islamic world and Europe assumed it was authentic. See Robert Leigh, On Theriac to Piso, Attributed to Galen: A Critical Edition with Translation and Commentary (Leiden: Brill, 2016).

[3] The pamphlet was signed by the physician Paolo Giovio, the apothecary Tomasso Bigliotti, and the senator Pietro Borghese. Testimonium de verissima ac admirabili virtute olei compositi contra pestem & omnia venena (Rome, 1524).

Tales from the Archives: Testing Drugs and Trying Cures Workshop Summary

In September 2016, The Recipes Project celebrated its fourth birthday. We now have over 500 posts in our archives and over 120 pages for readers to sift through. That’s a lot of material! (And thank you so much to our contributors for sharing such a wealth of knowledge on recipes.) But with so much material on the site, it’s easy for earlier pieces to be forgotten. So, the editors have decided that, every now and then, we’ll pull something out of the archives to share with our readers anew.

Over the next few weeks, The Recipes Project will feature a selection of case studies from the current issue of the Bulletin of the History of Medicine on “‘Testing Drugs and Trying Cures”. This special issue grew out of a 2014 workshop held at Max Planck Institute for the History of Science in Berlin. We were very lucky to have two then graduate students Ashley Buchanan and Tillman Taape, join us for and grateful that they took the time to pen the post below. It seems fitting to begin this month on testing drugs and trying cures with a revisit to their post. Elaine (editor).

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By Ashley Buchanan and Tillman Taape

What did it mean to test a drug or try a cure in the early modern world? This was the central question for a group of scholars who gathered for a workshop at Max Planck Institute for the History of Science in Berlin, Germany.  Since recipes emerged as one of the key themes throughout the workshop, and because the conference’s location in Berlin made it difficult for scholars outside of Europe to attend, we thought we might share a brief summary of the “Testing Drugs and Trying Cures” papers, in the hopes that we could bring the workshop’s key ideas and discussions to a larger audience.  What emerged from an exhilarating two days of discussion and debate was the conclusion that historians of science and medicine should not privilege experiment and experimentation as fixed categories, but should understand the multiple ways in which physicians, apothecaries, artisans, institutions, and individuals in the early modern world tested, tried, investigated, experienced, modified, observed, and measured medicinal remedies and materiae medicae.

As written forms of medical and pharmaceutical knowledge and practice, recipes played an important part in the testing of drugs and cures, and our discussion raised larger questions surrounding the nature and purpose of an early modern recipe.

705px-ScuolaMedicaMiniatura
A miniature depicting the Schola Medica Salernitana from a copy of Avicenna’s Canons.  From Wikimedia Commons.

Michael McVaugh’s paper opened the discussion by exploring how medieval physicians went about testing drugs. Learned doctors in the Middle Ages might appear helplessly hidebound, and inclined to follow ancient authorities over experimentation. In contrast, McVaugh showed how a group of Montpellier physicians in the fourteenth century established something of an experimental program. Medieval physicians, however, were not testing to find a cure, but to determine the quality, strength, and effectiveness of a drug as it pertained to a particular person’s complexion. McVaugh underscored an important difference in the purpose of medieval drug testing. Physicians tested not for universal effectiveness, but to determine the quality of a drug – was it hot, cold, moist, or dry.

Duclos-title-page
Title page of the Academy’s Observations sur les eaux minérales (1675). From http://cures.hypotheses.org/the-workshop/programme-2/bycroft-michael

Although it became clear in our roundtable discussion that we should be wary of labeling such practices as obvious precursors to the experimental philosophies of the Scientific Revolution, many of the papers showed that the importance of specific tests resonated throughout the early modern period. Evan Ragland’s paper, for example, traced the use of the phrase periculum facere (‘to make a trial’) in physicians’ writings on medicine, anatomy and chemistry. Similarly, Michael Bycroft showed that French physicians and chemical experts of the Académie des Sciences became increasingly interested in the exact composition of mineral waters. Contrived tests such as color indicators or the analysis of residues after evaporation increasingly became the touchstone of proper inquiry.

McVaugh, Ragland, and Bycroft’s papers all underscored the need to understand the specific nature and purpose of testing in each historical context. Continuing to emphasize the importance of historical context, Francesco Paulo de Ceglia’s paper showed just how different the purpose of testing could be in the context of seventeenth century blood miracles in the Kingdom of Naples. Catholics tested the liquefaction of the blood of their patron saint to explore the limits of nature. By discovering nature’s limits, you could then determine what was truly miraculous. Protestants, on the other hand, tested various materials and recipes to recreate the liquefaction of blood to cast doubt on the alleged miracle.

san-gennaro
Reliquary containing a glass ampoule of San Gennaro’s blood. From La Repubblica.

In the context of testing, drugs and cures are often under scrutiny in the form of recipes detailing their production and administration. While recipes emerged from many of the papers as very important forms of knowledge, it proved virtually impossible to define exactly what a recipe was. Recipes can be very short or very detailed, ranging from a mere list of ingredients to careful step-by-step instructions. If there is one thing recipes have in common, it is the need for testing, trying, modifying and adapting to different conditions. While constructing an all-encompassing definition of a recipe proved futile, all agreed that it was fruitful to understand recipes as an important genre in early modern science and medicine.

apotheke_enhausen_l
From http://www.gn.geschichte.uni-muenchen.de/aktuelles/archiv_2011/archiv_2013/science_and_medicine/index.html

For her investigation on the testing practices of Venetian apothecaries, Valentina Pugliano emphasized the difference between experiment and experience. Venetian apothecaries were less concerned with testing drugs (in a traditional sense) than they were with the experience or truthfulness of their ingredients. Testing by inspection, smell and taste was also important in this pharmaceutical context, to ensure that the ingredients were what the merchant had promised them to be, and not a cheap substitute with inferior properties. For Pugliano’s apothecaries, the important issue that required testing was the authenticity of the ingredients rather than the efficacy of the finished product; after all, most preparations had proved their worth since antiquity. Like McVaugh, Pugliano questioned traditional “Baconian” understandings of what it meant to experiment and test and argued for more nuanced notions of testing and trying, which included observing, measuring, evaluating, and experiencing.

Image_Samir
Title page of Johannes Christophorus Homann’s Dissertatio inauguralis medica de medicinae cum geosophia nexu quam auspice deo prpitio (Hala Madgeburica, Hendelius, 1725). From http://cures.hypotheses.org/the-workshop/programme-2/boumediene-samir

With early modern Europeans’ increasing forays into the New World, however, more and more materiae medicae were found which were absent from ancient medical writings. Pliny and Dioscorides were silent on such substances as guaiacum wood, Peruvian bark or New World balsam, so their medicinal properties had to be newly investigated. Antonio Barrera-Osorio and Samir Boumediene’s papers added America, or the New World, into the discussion. Both emphasized the role of new drugs and materia medica in the rise of European experimental practices. New drugs and new medicinal recipes required new ways of testing.

Antonio Barrera-Osorio’s paper argued for an empirical culture in the Spanish empire, which was well suited to respond to these challenges. He showed how his protagonists gathered information about New World remedies from natives or travellers and experimented with ways of preparing them. Some of these drugs and recipes were deemed so important for the economy and health of the empire that the Spanish crown ordered tests in hospitals all over Castile. Samir Boumediene’s paper elaborated on the issue of making workable recipes for newly discovered drugs. Once more, taste and smell were important assays, but drugs such as guaiacum and Peruvian bark were also tested on a larger scale. Dispensing them to the poor inmates of charitable hospitals (as happened in France and Germany) helped to determine their effect, and to establish recipes, which indicated how to adjust the treatment in individual cases.

books
Andreas Cleyer, Specimen Medicinae Sinicae (Frankfurt, 1682). From http://cures.hypotheses.org/the-workshop/programme-2/hanson-marta-and-pomata-gianna

Gianna Pomata and Marta Hanson’s paper showed how recipes also functioned as vehicles of knowledge between different cultures. Recipes, as either formula or prescription, were both found in European and Chinese medical cultures. According to Pomata and Hanson, it was the familiar genre of the recipe that facilitated the transmission of Chinese pharmacology to Europe in the second half of the seventeenth century. Similarly, Carla Nappi argued that the Manchu medicinal recipes of the Qing court were spaces of encounter and medical translation in the early modern world. Pomata, Hanson, and Nappi demonstrated how the recipe served as the common ground between European and Chinese medicine and made the translation of Chinese pulse medicine and the transmission of Chinese materia medica possible in the seventeenth and eighteenth centuries.

Although recipes are difficult to characterize as a genre, it is clear that they are fascinating objects of historical study. More often than not, they are fluid rather than fixed forms of knowledge, requiring adaptation at every turn. They bring together ingredients, practices and often practitioners from all over the world, and themselves have a tendency to aggregate into larger collections. As written manifestations of gestures and processes, they play an important part in testing, assessing and modifying drugs and cures.

Consumers of the Exotic: summary of a workshop in Cambridge, April 5-6, 2017

By Emma Spary and Justin Rivest

By Reede tot Drakestein, Hendrik van,1637?-1691 [Public domain], via Wikimedia Commons
The project “Selling the Exotic in Paris and Versailles, 1670-1730”, running in the Faculty of History at the University of Cambridge, and funded by Leverhulme Research Grant 2014-289, held its planned workshop in April this year. Its theme, “Consumers of the Exotic: European commerce and the consumption of exotic materia medica, 1670-1730”, brought together a group of international scholars working on these questions in a broad variety of European contexts.

Our goal at the workshop was to produce a comparative picture of the ways in which exotic plant materials were processed, bought and consumed in Europe. Why did European consumers buy—and more significantly ingest—exotic plant materials? What did exoticism mean to them? While recent work has focused on colonial bioprospecting and the appropriation of indigenous knowledge, our aim was to investigate demand within Europe itself, exploring divergences and similarities across contexts. The choice of a restricted timespan—the decades around 1700—provided a baseline for comparison of drug production, sales and consumption in different cultures. Alexandra Cook (University of Hong Kong) kicked off the programme with a study of a proprietary drug, Garcin’s “Maduran pills”, sold around Europe in the early eighteenth century by an entrepreneur whose Protestant faith led to a complex intellectual and commercial itinerary. Cook argued that exotic ingredients were not necessarily a selling point for eighteenth-century patients. Harun Küçük (University of Pennsylvania) provoked us to think about the complexity of defining the exotic, and the importance of a multi-perspectival view of the history of drugs: Ottoman healers associated New World exotica like cinchona bark and ipecacuanha root with French medicine, since these substances often reached them via French commercial and intellectual networks. Continuing the global theme, Samir Boumediene explored the place of drugs in the missionary activities of the Society of Jesus. The decades around 1700 represented a decline in the relative importance of Jesuits in the global drug trade, as new players came to disrupt their initial privileged position.

Šebestián Kroupa (University of Cambridge) offered a counterpoint to the workshop’s focus on European consumption by exploring the supply of European drugs to transplanted European populations—Manila in the Philippines. European drugs were in fact imported in large volumes to this “exotic” locale; little attention was paid to the pursuit of plant substances that might be commodified in the metropole, an exception being the Saint Ignatius bean. Victoria Pickering explored the diverse trajectories, contacts, and exchanges that were necessary to assemble the massive collection of exotic plant substances of Sir Hans Sloane.

Moving to early modern Russia, Clare Griffin suggested that its unique geographical connections—in the form of a land route between Europe and the Far East—led commentators to represent distant substances and peoples as subject to incorporation into the Empire, rather than “exotic” in the sense of “foreign”, as the case of rhubarb showed. Paula De Vos concluded the first day with an account of Palacios’ prominent 1706 pharmacopoeia. Early modern Western pharmacy was indebted, for its materia medica, to the Indo-Mediterranean world rather than the continent of Europe. The slow appropriation of new drugs spread outwards from this Indo-Mediterranean core to the Silk Roads, the Indian Ocean, and eventually the Atlantic world.

On day 2, Laia Portet explored the architecture of exoticism in printed French materia medica. Where familiar European plants tended to be classified alphabetically, unfamiliar exotics were classified by parts (roots, barks, leaves) since this was the form in which they entered the European marketplace. Emma Spary used a case history of an exotic aromatic, cinnamon, to point up the disjuncture between textual, material and empirical knowledge of drugs, a conundrum for medical experts, market regulators and individual consumers. Hjalmar Fors provocatively suggested that for early modern Europeans, “the exotic” primarily evoked traded material goods, including spices and drugs, rather than foreign peoples or distant geographies. Lack of knowledge about the places of origin of drugs was critical to a substance remaining “exotic” in European eyes.

Justin Rivest spoke of the encounter between political power, the emerging state and the large-scale administration of drugs in France, looking at how personal trialling of drugs by successive ministers of war led to a centrally administered programme of dispensing exotic drugs like tobacco, quinquina and ipecacuanha to French troops. In a very different take on the end-user, Wouter Klein introduced us to the uses of print culture as a research tool for relating newspaper advertising and ships’ cargoes of drugs in the Dutch republic after 1700.

Several common themes emerged from the papers. It seemed that “colonial bioprospecting” had its limits as a way of understanding European engagement with non-European materia medica. Most substances discussed did not reach Europe thanks to state intervention, but rather were trafficked by a heterogenous set of actors: missionaries, trading company officials, entrepreneurial merchants and court physicians. Many papers also showed that “exoticism” was not necessarily inherently desirable. A drug’s value was established through consensus-building over time. Furthermore, “exoticism” was a relative, context-specific category, subject to change, not solely a feature of geographic origin, or of a core-periphery relation between European metropoles and their colonies. The papers demonstrated that exoticism was also, perhaps largely, a product of degrees of familiarity and unfamiliarity, which varied widely across different European contexts. In sum, rather than being inherently valuable objects of appropriation, exotic drugs were socially constructed goods.