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True but not Tested: Experimentation in the Apothecary’s Shop

By Valentina Pugliano

Testing and standardization are firmly entrenched in the pharmacological imagination of western biomedicine and its public. Before a new drug can be put on the market, the U.S. Food and Drug Administration demands five rounds of trials. Approximately 70% of new ‘recipes’ fails to pass the first round. Similarly, the European Medicines Agency maintains a database of adverse drug reactions (EudraVigilance) which, growing of one million entries yearly, is used to monitor all pharmaceuticals on sale across the European Economic Area. Meanwhile, the media seizes upon the perils of untested cures as if on morality tales, policing the boundaries of modern science from potential intrusion from the miraculous and the charlatanesque.

Yet, can the same be said of premodern drug manufacturing? Was a drug’s efficacy established by testing? And what did ‘testing’ recipes even mean in the sixteenth and seventeenth centuries? When these questions were suggested at Elaine Leong and Alisha Rankin’s Testing Drugs, Trying Cures Workshop in 2013, I began to look for answers among those early modern medical practitioners who most closely resemble the pharmaceutical industry of our times, combining the manufacturing of a Glaxo Smith-Kline and AstraZeneca with the retailing of Boots and Walgreens: apothecaries. [1]

Pharmacy shop, Tacuinum sanitatis, 16th century (BNF, MS Latin 9333, fol. 51v).

While not corporate giants, apothecaries thrived in every large hamlet and town of Italy, reaching spectacular numbers in metropolises like Rome, Naples, and Venice. Unlike free-lance alchemists and empirics, they belonged to the city’s official infrastructure of healthcare: they worked from a licensed shop, trained through formal apprenticeship and, like physicians and surgeons, belonged to a professional association or arte. This ‘trade brotherhood’ gave them bargaining powers but also subjected them to standardization rules and quality controls. As disgruntled masters testify from the archives, in severe cases of infraction the apothecary could see the remedies he had belaboured on for weeks thrown into the gutter or burnt to ashes.

So what did it mean to have ‘correct’ remedies that passed the test of shop inspections and satisfied “God and the public good”? As a historian of artisan knowledge I have learnt that infractions, those occasions when things go (deliberately) wrong, sometimes provide the best clue to understanding which methods of doing things were considered orthodox in the crafts. Apothecaries loved to speak of the abuses supposedly perpetrated by their colleagues. In Florence, for example, they conned customers by mixing expensive guaiac wood with the bark of mulberry trees. In Mantua and Padua, those with a fever and a bad stomach better beware the Lenitive Electuary, regularly adulterated with black sugar (instead of its fine white variety) and counterfeit tamarinds (mimicked by a paste made of old cassia and badly preserved dates ).[2]

Tamarinds

These complaints were not the only ones to be voiced, but they are telling. They are not motivated by protestations from patients, who are remarkably absent from the writings of early modern apothecaries. Nor are they driven by doubts about the method employed to make the remedy from a set of instructions. While household experimenters and professors of secrets were always seeking new formulas and ways to stabilise them, the corpus of remedies sold in sixteenth-century Italian pharmacies was fairly stable, and so were their recipes.

What these criticisms suggested, rather, was that medicinal ingredients possessed a purity, and that this purity had been tainted. The rogue apothecary had played around with the ‘honesty’ of simples, diluting their strength or altogether replacing the ‘sincere originals’ prescribed in the recipe with fraudulent alternatives (often from the kitchen pantry).

With this concern for authenticity in mind, I returned to the apothecaries’ writings, and especially to two bestselling pharmacopoeias, Girolamo Calestani of Parma’s Observations on the Antidotes and Medicaments Most Used in Italy (1562), and Giorgio Melichio of Venice’s Warnings on the Compound Remedies in Use in Pharmacy (1575). Leafing through these texts, I made a curious discovery. Repeatedly, key plant and mineral ingredients in their recipes were referred to according to their reputed truth or falsity: e.g. “true cinnamon”, “true rhaponticum”, “false stibium”, “false balsam”. Repeatedly, apothecaries stressed the importance of sourcing these authentic materials, while their absence was said to ruin the preparation.

Even the use of substitutes began to be criticised. The practice of substituting one ingredient with another possessing similar qualities (quid pro quo), usually a local simple for an exotic import difficult to acquire, had been necessary since antiquity. Yet, the changing attitude to substitutions in the sixteenth century is summarised well by the Neapolitan physician Bartolomeo Maranta: “Substitutes are an abuse.” Never more so than for Theriac, the most celebrated antidote of Italian pharmacy and the toughest to prepare with over sixty ingredients. A Theriac with substitutes instead of true ingredients, Maranta declared, “will be itself in a certain way sick”.[4]

How should we interpret such appeal to the truthfulness of ingredients? At a superficial level, we can understand the apothecary wanting to reassure the public of the genuineness of his wares. After all, practitioners of pharmacy were often portrayed as profiteers and cheats. But, as I argue in my article “Pharmacy, Testing and the Language of Truth in Renaissance Italy,” something else had changed between the medieval period and the 1540s, when this terminology of trues and falses appears: Greek and Roman books on materia medica were reintroduced into western Europe. It is well known that the reappearance of Dioscorides’s On Medicinal Plants, Theophrastus’s On Plants and Pliny’s revised Natural History created as many problems as it solved for those who wished to implement their teachings. Many of the Mediterranean and Levantine simples described in them remained entirely unavailable during the sixteenth century, while many others were plagued by problems of identification and nomenclature.

My sense is that this ‘Language of Truth’ was an intervention into this state of affairs. It helped the apothecaries get a grip on which was which among rare ingredients, and reflected their aspiration, shared with many contemporaries, of restoring the wisdom of the ancients. It also showed the increasing influence on pharmacy of the contemporary botanical renaissance and the ethos of naturalists who, for the first time, put nature in the foreground, liberating flowers, trees, animals and rocks from the need to be useful.

Crucially, authenticity came to replace experimentation. As ingredients acquired more importance in the apothecary’s mind, the efficacy of the recipe began to be pegged to their presence and quality. Providing the remedy contained the true, correct ingredients its efficacy and fitness for human consumption would be guaranteed, with no need to involve test subjects or pursue the feedback of patients and colleagues. How much this ‘testing by truth’ differed from modern-day trials becomes clear when we turn to the contemporary idiom of the pharmaceutical industry: it is as if the apothecaries’ R&D stopped at the preclinical stage.

 

Notes:

[1] V. Pugliano, “Pharmacy, Testing and the Language of Truth”, Bulletin of the History of Medicine 92/2 (2017): 233-273. See also the other articles in the same issue of BHM.

[2] Ricettario Fiorentino dell’Arte dei Medici e Spetiali di Firenze (Florence, 1574), pp. 45, 74; Giovanni Antonio Lodetto, Dialogo degl’inganni d’alcuni malvagi speciali (Padua, 1572), pp. 21-22.

[3] Giorgio Melichio, Avvertimenti nelle compositioni per uso della spetiaria (Venice, 1601), pp. 27-28.

[4] Bartolomeo Maranta, Della Theriaca et Mithridato libri due (Naples, 1572), p. 33.

 

 

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.

‘This one is good’: Recipes, Testing and Lay Practitioners in Early German Print

By Tillmann Taape

Title illustration from Brunschwig’s Small book of distillation. © Wellcome Images

Having recently finished my doctoral thesis on the printed works of Hieronymus Brunschwig, which have previously featured on the Recipes Blog (here and here), I am delighted to contribute to this series of posts on testing and trying (for an overview, see our re-posted summary of the Testing Drugs and Trying Cures conference). What better opportunity to share how it all came together, and reflect on the role of recipes and testing in the narrative.

Hieronymus Brunschwig (c.1450–c.1530), a surgeon and apothecary from Strasbourg, wrote the first printed books on surgery and distillation. In my thesis, Hieronymus Brunschwig and the Making of Vernacular Medical Knowledge in Early German Print, I read these uncommonly practical and technical books alongside records from the Strasbourg archives, about the craft guilds and medical practice. This allows us to make sense of Brunschwig’s practical vernacular medicine in relation to local intellectual trends, different forms of healing, the local milieu of guilds and artisans, and early German print culture.

Brunschwig’s first book was the Cirurgia of 1497, the first surgical manual in print. This, of course, was an opportunity to codify and re-define surgery. Brunschwig revives the medieval tradition of what Michael McVaugh has termed rational surgery (i.e. a learned as well as a practical art), to educate trainee surgeons and to present their discipline as a respectable and useful trade. Emphasising the need for skilled hands as well as a working knowledge of the human body, Brunschwig defends surgery on two fronts: against learned physicians’ rhetoric of superiority, and against other craftsmen’s deep-seated anxieties about occupations which were in contact with sick and dead bodies.

A surgeon treating an abdominal wound. Hieronymus Brunschwig, Dis ist das Buoch der Cirurgia (Strasbourg, 1497). © Wellcome Images.

The later books on distillation, published in 1500 and 1512, open up to a wider readership, including not only medical artisans such as surgeons or apothecaries, but also the ‘common man’ – a middling social layer of literate citizens, householders and other lay practitioners. This new kind of medical reader, as I have discussed in a previous post and elsewhere, is emblematised in the figure of the ‘striped layman’ which appears in numerous woodcut illustrations throughout Brunschwig’s works.

A conspicuously stripy student, from Brunschwig’s Cirurgia (1497). © Wellcome Images

Many of the recipes and instructions in the distillation books are adjusted for this type of reader. They start from scratch and are rich in technical details which are not found elsewhere in print or, to my knowledge, in manuscript. Although Brunschwig engages with complex ideas about the nature of matter and its manipulation, such as John of Rupescissa’s notion of a ‘quintessence’ in all things, he re-works them into manageable, pedestrian remedies. Rather than pursuing Rupescissa’s heavenly panacea, Brunschwig uses distillation to produce a type of middle-class quintessences: although earth-bound and imperfect, they were reliable and effective remedies in the hands of laypeople.

Detailed woodcut images of distillation apparatus and instructions for its use. Brunschwig, Liber de arte distillandi de simplicibus (Strasbourg, 1500). © Wellcome Images.

One overarching theme of my thesis is the artisan’s approach to understanding and manipulating nature. For a craftsman with no Latin, Brunschwig mined a surprising amount of knowledge from texts. But more importantly, I argue, he knew things through direct physical engagement with bodies, materials and technical processes. His books are full of instructions to probe wounds, check temperature by touch, inspect colour changes in the alembic, and smell or taste distilled remedies. His expertise was located as much in the body and its senses as in books.

Nonetheless, writing was a powerful tool for recording and communicating practical insights. From cautionary tales of exploding alembics to heroic accounts of successful cures, Brunschwig emphasises his own experience as a source of knowledge. The German term he uses for this type of knowledge, erfarung, is related to fahren, meaning ‘to travel’. In the early sixteenth century, it denoted a way of experiencing the world through one’s own senses, by moving through it or simply being in it in an active, attentive manner. Erfarung was compared, often unfavourably, to spiritual contemplation and introspection. Over time, however, doctors and students of nature such as Paracelsus came to see personal erfarung as the necessary labour of insight rather than a sinful distraction. The Book of Nature, they insisted, should be read with one’s feet. Brunschwig’s emphasis on his own and others’ erfarung was thus part of a larger vernacular culture of experiential knowledge, as well as learned debates about experientia which have often been the focus of historical accounts of a medical empiricism developing in the early modern period.

Recipes played a major part in Brunschwig’s codification of experiential medical knowledge. Some, as I have shown in a previous post, were presented in Latin pharmaceutical jargon likely unknown to laypeople. These recipes were closed to readers, who were meant to copy them out on a piece of paper and hand them to an apothecary who would manufacture the remedy according to his art and his experience. Although the great majority of recipes are in German, some of these are also presented as tried and tested, by Brunschwig himself or others, and do not call for ‘tweaking’ on the part of readers.

Other recipes, however, give alternative ingredients or leave the exact composition up to the practitioner’s judgment. Many recipes come without the author’s seal of approval, and their sheer number makes it seem unlikely that Brunschwig could have tested each one. Such ‘open’ recipes leave room for improvisation and testing. The ongoing work of erfarung runs on into readers’ own practice, and often spills out into the margins of Brunschwig’s printed books. In many surviving copies, early modern healers from different walks of life marked recipes with a magisterial probatum est, or a simple vernacular note such as ‘this one is good’.

In some of the earliest medical works in print, Brunschwig addresses a readership of lay healers and ‘common men’ which would come to represent a significant portion of the early German print market. Through his use of recipes embedded within a culture of erfarung, he involved his vernacular readers in a continued effort of empirical trying and testing.

Pursuing the themes of recipes and artisanal knowledge, I am delighted to be joining the Making and Knowing Project at Columbia University this summer, and look forward to sharing our work on making, testing, and trying, which has previously featured on this blog.

 

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).