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1 Studies in the Development of Experimental 1 STUDIES IN THE DEVELOPMENT OF EXPERIMENTAL PHARMACOLOGY IN THE EIGHTEENTH AND EARLY NINETEENTH CENTURIES A Thesis presented by MELVIN PETER EARLES for the degree of Doctor of Philosophy in the University of London. University College, October, 1961. London. 2 ABSTRACT General pharmacology in -the seventeenth and eighteenth centuries is considered (Parts 1 and 2). Reference is made to some criticisms of the contemporary materia medica and -to early attempts at a scientific investigation of drugs and poisons. The studies of vegetable drugs by Stoerk and Withering are discussed to illustrate the problems associated with pharmaco-dynamic studies in clinical practice. Part 3 describes the experiments with drugs arid poisons carried out in -the eighteenth century. Parti- cular reference is made to experimental studies of cherry laurel, arrow-poisons, viper venom and opium. The influence of this work on the history of experimental pharmacology is considered in a discussion concerning the recognition of animal experiments as a valid contribution to pharmacology and human medicine. In Part 4 the factors contributing to advances in posology are discussed with particular reference to experi- mental studies and to the isolation of active constituents of drugs. Part is concerned with the development of knowledge concerning the mode of action of drugs and poisons, in particular with the problem of the manner in 3 which a substance can affect an organ situated at a dis- tance from the site of administration. These sections of the thesis include a study of the work of some inves- tigators in the early nineteenth century with particular reference to some early researches by Fran9ois Magendie. 4 COITTENTS Page No. ACKNOWLEDGEMENTS 8 INTRODUCTI ON 9 1. DEVELOPMENTS IN PHABDIACOLOGY DURING TI1E SEVENTEENTH CENTURY 15 1. Materia ivfedica and Therapeutics 15 a. The origins of the inateria medica b. The influence of dogmatic medicine c. The study of the action of drugs in clinical practice. ii. Criticisms of the Materia Medica 27 iii. Development of Methods for the Investi- gation of Drugs and Poisons. 31 a. Determination of effects by refer- ence to morphological and sensory characters. b. The study of drugs and poisons by chemical analyciB. iv. Experimental Pharriacology in the Seventeenth Century. 38 v. Knowledge and Theories concerning the Mode of Action of Drugs and Poisons. 58 5 Page No. 2. GENERAL AND OFFICIAL PHARMACOLOGY IN THE EIGHTEENTH CENTURY 70 1. The Medical Systems 70 ii. Changes in the Official Materia Medlca 75 iii. Pharmacological Classifications 85 iv. Pharmacotherapeutic Studies of Hemlock, Digitalis and other Vegetable Poisons 89 3 ' EXPERIMENTS ON ANIMALS WITH DRUGS AND POISONS IN THE EIGHTEENTH CENTURY 110 i. Experiments by Stephen Hales with some 'common Liquors'. 110 ii. Experiments with Cherry-laurel Water 119 iii. Experiments with Arrow Poisons 135 iv. Experiments with Opium 157 a. Experimental studies on opium before 1750 b. The Whytt-Haller controversy con- cerning the action of opium c. Experiments by Alexander Monro with opium, camphor and alcohol v. Felice Fontana - Experiments in Pharma- cology and Toxicology, 1764-1781. 199 a. Studies of the viper venom. 6 Page No. b. Studies of' tiounas arrow poison c. Studies of' solutions prepared from cherry-laurel leaves d. Studies of opium vL Studies with Oputn, 1782-1800 279 vii The Recognition of the Place or Role of the Experimental Liethod in Pharmacology 305 4. DEVELOPMENTS IN KNO7LEDGE OF DOSE AND EPYECT 321 i. Standardization of Drugs and Poisons 326 ii. Scientific Studies relating to Dose 328 a. Studies of therapeutic doses b. The application of dose in experi- mental studies on drugs and poisons iii. Development of Knowledge concerning the Active Constituents of Drugs and Poisons 45 5. II0WLEDGE CONCERNING THE I'IODE OP ACTION OF DRUGS AND P015 ONS 368 BIBLIOGRAPHY 419 - 7 ILLUSTRATI ONS Plate I The elements, qualities & humours II Injection into the vein of a dog From Elsholz, Olysmatica Nova, 1667 III 7epfer's report of an experiment with nux vornica. Prom Cicutae .AQuatica, 1679 IV Linnean classification of medicines From Materia Medica, De Plantis, 1740 V Diagrams to illustrate the technique used by Fontana for injection into a vein. VI Sketch to illustrate Fontana's experiment of immersing the nerves of a frog in a solution of opium. VII Table of doses calculated by Cockburn. From Philosohioal Transactions, vol.28, 1708 VIII Bernard's modification of Magendie's experiment with the isolated limb. From Lecons de Physiologie Operatoire, 1879. Plates II, II, IV and VIII are by courtesy of the Welicornellistorical Medical Library. Plate VII is by courtesy of the Science Museum Library. 8 ACKNOWLEDGEMENTS I wish to express my gratitude to Professor D. McKie, Professor of History and Philosophy of Science, University College, for his encouragement and advice throughout the course of my work. Also to Professor H. 0. Schild, Professor of Pharmacology, University College, who has read my manuscript and advised on its technical content. I acknowledge the valuable assistance of Dr. Poynter and his staff of the Weilcome Historical Medical Library, Miss Lothian and Miss Jones of the Library of the Pharmaceutical Society, the librarians and staffs of the :Bri-tish Museum Reading Room, the British Museum Library (Natural History), the Patent Office Library, the Science Museum Library, the Library of University College, the Chelsea Public Library, the Library of the Royal Society of Medicine and the Library of the London Medical Society. Finally I wish to thank my wife, Yolande, for her assistance in checking the manuscript and for her patience at my frequent neglect of domestic duties during the course of this work. 9 INTRODUCTI ON A number of physicians in the seventeenth and eighteenth centuries, influenced by developments in experimental science, began to take a more critical view of the large collection of real and supposed remedies then in common use. The gradual rationalization of the materia medics that folloved, resulted in the simplifica- tion of the eighteenth-century pharniacopoelas and the deletion of superstitious and traditional remedies. Deletion, however, is a negative process and this rejec- tion of the inert, when once initiated by more rational modes of thought, required little more than experience and common sense to accomplish it. The study of the active materials on the other hand demanded more positive and objective methods of approach. In the late seventeenth century attempts were made to define and predict medicinal action by a study of the sensory, botanical and chemical characteristics of drugs. These methods, although achieving a limited success with some drugs, did not yield the results neces- sary to establish a reliable therapeutic or pharniaco- dynamic classification, and still less lead to a knowledge of the mode of action. The two principal sources of 10 information leading to such a knowledge are (i) objective experimentation on animals and (ii) clinical practice. In the eighteenth century the greater care and precision that developed in clinical practice gave rise, in a few cases, to &iore objective reporting of the effects of drugs, but this source did not contribute greatly to knowledge concerning pharrnacodynamic action. The best known examples are the studies by Anton Freiher: von Stoerk with hemlock, stramonium, aconi-te and coichicurn, and William Withering's study of digitalis. It must be remembered, however, that in these excellent studies the reporting of pharniacodynamic effects was secondary to the therapeutic purpose of the work which was directed to the relief of certain symptoms. Likewise many animal experiments carried out during this period were undertaken with therapy in mind. Here, how- ever, because the observations were made on healthy animals, -the results were more productive of a knowledge of the true pharmacological effects of the substances inves- tigated. In -this thesis a number of these animal experi- ments have been studied in order to show that, although they were primarily made for therapeutic, toxicological or physiological purposes, they were none the lees concerned with some problems of phartnacology and might, therefore, be rightly considered as part of the history of that subject. 11 It is necessary a-t -this poinl to give some consideration to what is meant by pharmacology since its exact meaning has changed over the years and even today is variably defined. The word is derived f•rom the Greek Pharmakon - a remedy. John Schroeder in his Pharmacopoeia Medico-chymica (Lugduni, 1649) used the term Pharmacologia and William Rowland in an English edition (London, 1669) translated this into Pharmacology. Rowland described pharmacology as "the Art of making Medicines" and later in Nathaniel Bailey's An Universal Etymological English Dictionary (London, 1721), it is defined as a "Treatise concerning the Art of Preparing Medicines". The word subsequently assumed a much wider meaning. Jonathon Pereira in his textbook on -the materia medica, first published in 1839, defined pharmacology as a branch of therapeutics devoted to a consideration of medicines. He divided the subject into pharmacogriosia, -the study of crude drugs, pharmacy, -the preparation and dispensing of medicines, and pharmaco-dynamics, which treats of the effects and uses of medicines. A number of modern medical and general dictionaries continue to define the word as "the science of the effects of drugs'1 but in Germany and in the English-speaking world this definition is no longer exact. In the latter half of 12 the nineteenth century Rudolf Buchheim and his pupil Oswald Schiniedeberg of the University of Dorpat freed pharmacology from traditional therapeutio so that sub- stances were grouped according to their chemical nature and phartuacodynainic action instead of their therapeutic effects. The modern pharmacology which has developed from this movement is, therefore, more accurately defined as the experimental investigation of the action of natural and synthetic substances on healthy animal tissues.
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