1 General Introduction: Features of Eighteenth-Century Pharmacology The foundations of modern pharmacology are generally thought to have been laid during the first half of the nineteenth century. In 1805, Friedrich Wilhelm Sertürner published his isolation of morphine from opium, i.e. the discovery of the first plant alkaloid. In 1821, François Magendie’s Formulaire pour la Préparation et l’Emploi de Plusieurs Nouveaux Médicamens , the first textbook on chemically pure drugs, came out. And in 1847, Rudolf Buchheim of the University of Dorpat created the first laboratory for experimental pharmacology. Improved methods of analytical chemistry and the emerging discipline of experimental physiology contributed considerably to the new pharmacological research. 1 Moreover, increasing use of clinical statistics led to the rise of modern therapeutics. In his Recherches sur les Effets de la Saignée (1835), the Paris hospital doctor Pierre Louis famously applied the “numerical method” to evaluate bloodletting and drug treatments for pneumonia and other inflammatory diseases. 2 Customary focus on these milestones in the history of pharmacology and therapeutics has resulted, however, in a relative lack of appreciation of important changes within the materia medica of the seventeenth and eighteenth centuries. Gernot Rath for example, in a by now classic paper on this subject, argued that the transformation of pharmacology from a part of therapeutics to an experimental science did not originate from materia medica itself, but was induced by the development of pathology and physiology. 3 The history of modern pharmacology was thus firmly linked with the nineteenth century, the age of the natural sciences in medicine. By contrast, this book attempts to show that experimental pharmacology was not a nineteenth-century, but essentially an eighteenth-century creation. It will demonstrate that the basic methodology of the field was developed through critical examinations of key drugs of the period, such as opium and Peruvian 1 Andreas-Holger Maehle - 9789004333291 Downloaded from Brill.com09/25/2021 04:33:25AM via free access Features of Eighteenth-Century Pharmacology bark, and of important proprietary medicines, such as Mrs Stephens’s remedy against bladder stones. It will also reveal that along with the methodological development an ethical awareness arose regarding the sacrifices and risks in animal and human testing. Finally, it will show that the evaluation of remedies was not confined to university medicine and learned scientific societies, but that many rank and file practitioners contributed to this enterprise as well. But how did it come about that certain drugs were put “on trial” in the first place? The historical preconditions for this step probably have to be sought in the challenges to Galenism, and its gradual transformation, during the seventeenth and eighteenth centuries. As Harold Cook has argued in general terms, the scientific revolution of the seventeenth century led to an emphasis on the curative part of medicine, at the cost of the Galenist preoccupations with health advice, diet, and regimen. 4 In other words, the focus of medical attention started to move away from the old art of prescribing for the individual patient according to his or her unique condition and circumstances, towards efficient, “specific” remedies for particular types of disease. It is consistent with this interpretation that highly effective medicines, such as opium and mercury preparations, and those used for specific illnesses, such as Peruvian bark (quinine) in fevers and lithontriptics in urinary stone disease, acquired a prominent position in therapeutics. 5 Iatrochemistry and its predecessor, Paracelsianism, played a major part in this process. Paracelsus (1493/94-1541) had introduced new mineral, “chemical” remedies: mercury, antimony, arsenic, iron, lead, copper, sulphur. After initial resistance Galenic medicine accommodated these substances, adding them to its vast collection of plant drugs and its remedies of animal origin. For example, the first official pharmacopoeia of the Royal College of Physicians of London, published in December 1618, included calomel (mercurous chloride), mineral acids, and iron preparations; and in its second edition, in 1650, salts of mercury were added. 6 In 1566 the Paris Parlement had banned antimony, following an initiative of the University’s conservative Medical Faculty. But in 1638 a recipe for an antimony preparation was included in the Paris Faculty’s official pharmacopoeia, and in 1666 the antimony ban was lifted. 7 As has recently been shown in detail by Laurence Brockliss and Colin Jones, Galenism in seventeenth-century France was “plastic” and eclectic enough to take up new therapeutic items and practices. 8 This applied also to drugs from the New World, such as ipecacuanha, guaiac, and Peruvian bark. For instance, by the mid-1680s the latter had become 2 Andreas-Holger Maehle - 9789004333291 Downloaded from Brill.com09/25/2021 04:33:25AM via free access Features of Eighteenth-Century Pharmacology fully acceptable to the Paris Faculty. 9 The London Pharmacopoeia included the bark in 1677. 10 Enlargement of the pharmacopoeias through new “chemical” and “exotic” drugs did not mean, however, that Galenic pharmacology was profoundly changed. It continued to be based on the four Aristotelian primary qualities (hot, cold, wet, dry), and Galenic therapy still aimed at the correction of imbalances of the Hippocratic four humours (blood, phlegm, yellow bile, black bile). But attention was drawn to “problem drugs” whose natural properties and therapeutic effects were hard to reconcile with Galenic doctrine. This was particularly true for Peruvian bark, which had been introduced to Europe in the 1630s. It tasted bitter and should therefore have been classified as a hot medicine, and yet it removed the heat of fevers. It did not seem to evacuate the so-called peccant humour (materia peccans ), and yet it was obviously effective. Similar difficulties emerged for opium, although it had been used since antiquity. Experimental investigation of these drugs was the response of many seventeenth- and eighteenth-century medical men, and accordingly their efforts in this area constitute a major theme of this book. The iatrochemical doctrines, as taught by Thomas Willis (1621- 75) in Oxford and Franciscus de le Boë (1614-72) in Leyden, provided a basis for such pharmacological explorations. 11 First of all, the general concept that bodily processes could be understood chemically as internal “fermentations” evoked a chemical (not merely qualitative) interpretation of drug action. More specifically, the iatrochemical idea of disease as an imbalance in the body’s acids and alkalis led to the notion that remedies acted through their acid or alkaline properties, based on the classical principle of contraria contrariis. The testing of substances for their acidity, respectively alkalinity, through their colour reaction with syrup of violets was introduced by Robert Boyle in 1664 and soon became a standard method.12 Moreover, the assumption that certain chemical constituents in a drug must be responsible for its efficacy stimulated considerable work in chemical analysis, both “by fire” (destructive distillation) and by testing reactions with other substances (precipitation, solubility, colour changes). Finally, within the iatrochemical paradigm of an effervescence of acids with alkalis it made sense to visualize the action of drugs on body fluids. Pharmacological in vitro experiments, especially on blood, were frequently carried out in the late seventeenth and early eighteenth centuries.13 3 Andreas-Holger Maehle - 9789004333291 Downloaded from Brill.com09/25/2021 04:33:25AM via free access Features of Eighteenth-Century Pharmacology Also iatromechanics, the rival concept to iatrochemistry towards the end of the seventeenth century, was conducive to pharmacological research. The corpuscular chemistry of Boyle provided the theoretical framework for explanations of the action of drugs and poisons by their content of specially shaped particles. 14 A protagonist of this line of reasoning was the Swiss physician Johann Jakob Wepfer (1620-95), who is commonly regarded as the pioneer of experimental toxicology. 15 Vivisecting orally poisoned animals, he traced the lesions in their gastrointestinal tract. These were then explained with sharp particles or “spikes”, hidden in toxic plants, such as water hemlock, aconite and strychnos nux-vomica, or in corrosive mineral poisons, such as mercury sublimate (mercuric chloride). Yet, this corpuscular toxicology did not signify a complete departure from Galenic pharmacological doctrine. In the terminology of the latter, Wepfer characterized those “sharp” poisons also as “hot” or “warm”. Neither was the corpuscular interpretation incompatible with iatrochemical ideas. Wepfer was sceptical about the “fight” between acids and alkalis, because it could not be observed in the stomachs of vivisected animals. But he integrated the concept of the archeus, i.e. the vital principle introduced by Paracelsus and elaborated by the early iatrochemist Jean Baptiste van Helmont (1579-1644). In Wepfer’s toxicology it was a personified archeus or, as he called him, Praeses systematis nervosi (“president of the nervous system”) who, enraged by the sharp poisons, tried to expel them and caused violent symptoms, such as convulsions and vomiting. 16 Iatromechanical concepts were likewise applied in the pharmacological