French Pharmacist Discovers Digit~line

CLAUDE-ADOLPHE NATIVELLE

Pharmacist Discovers Digitaline By Karl F. Meyer

C, N A TIVELLE

laude-Adolphe Nativelle-the laterto-be famed French pharmacistwas born in June 25, 1812, in Marche Saint-Jean (the old Paris marketplace of the Marais Quarter not far from Notre-Dame) into a severely impoverished family and was orphaned at the age of 13. His father sold a variety of goods in a butcher's shop, and to supplement this meager income in the depressed economy created by Napoleon's debacle in Russia, the boy peddled elixirs, ointments and medical herbs collected from the countryside by his mother. When he was baptized, the parents (prematurely) decided that Claude-Adolphe should become an apothecary. But misfortune struck, and two years after the birth of his second son, the father died in 1820. In a desperate attempt to provide for herself and her children, his mother increased her collecting of herbaceous plants of Paris such as Bicetre, Gentilley and Bourge-Ia-Reine. ClaudeAdolphe terminated his elementary education, and began to accompany her on these excursions. Gradually he built up an herbarium, prepared according to the methods of Jean-Jacques Rousseau (after reading and re-reading the "Lettres sur la Botanique"). By treating the paper on which he fixed the plants with a solution of alum, he prevented the ravages of insects and preserved the natural colors. His interest in medicinal plants was aroused when a pharmacist, to whom he regularly delivered wild flowers, called his attention to the curious foxglove from the Vosges region-a plant containing a drug which could cure invalids suffering from heart disease. Because of competition from charla-

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tans, however, herb-marketing was very difficult for the boy. Eventually the strain became too great for him and his mother, who was ailing with the symptoms of suffocation due to cardiac insufficiency. She died suddenly in 1825. In retrospect this sad experience probably spurred Claude-Adolphe to devote all his judgment, shrewdness and energy to extracting the "alkaloid" from foxglove. ' The two children were forced to leave their home, which was sold to meet accumulated debts. They were placed in an orphaq.age-Claude to , be taught the brush-making business; his brother to become a watchmaker. They passed what free time they had with a hatmaker, Monsieur Foisol, godfather of Claude. Impressed by th~ intelligence of his godson and recalling the wishes of his parents, he recommended Claude-Adolphe as apprentice to a pharmacist near Port SaintMartin. Unfortunately, this anticipated opportunity to learn pharmacology never materialized, for Claude-Adolphe was reprimanded by his patron for reading a book on medicine after he had finished his work as a bottlecleaner. M. Foisol then tried to teach Claude "la chapellerie," but soon realized that the boy had no aptitude for the manufacture of hats. Hence he relinquished him to the care and tutelage of a pharmacist friend, Guillerey, who maintained an apothecary shop in the Rue Montorgueil. Here, nearly 19 years old, Claude-Adolphe studied with zeal. He enlisted at the Ecole de Pharmacie de la Rue de l' Arbalete for a course of eight years, with the understanding that after completion of the studies, he

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

would undertake the final examination. Though inadequately housed and poorly paid, he developed into a good pharmacy student. , The period was not favorable for quiet study, however. The young student, like the entire population of Paris, became involved in the nerve-wracking activities of the Revolution of 1830 and the "choleramorbus" epidemic of 1832. But with his usual obstinate enthusiasm, Nativelle studied the achievements of illustrious chemists and pharmacists such as Pelletier and Caventou, who discovered alkaloids while investigating the new science of "basic chemistry," which, through the genius of men like Lavoisier and Pri'estley, had gradually replaced alchemy. In the first quarter of the 19th century, when many extraction experiments designed to isolate the active principles from plant drugs were in progress, Claude-Adolphe, approaching maturity, was eager to embark upon discoveries of his own. He appeared to be tormented, rarely associated with his patron or friends, and preferred to spend his evenings closeted in his room with his books. To' fulfill the conditions favorable to this mode of living, he had to change his employment twice. In the pharmacy of Seguin, Rue Sainte Honore, he found a place suitable for his scientific inquiries and work, but not amenable to his personality. Uncompromising in his contacts with others, he was by nature unable to cope with his employer or bear the opposition ' of his colleagues, who resented ' these exclusive evenings spent incarcerated in his room. Intensely engaged in exploring the still widely discussed subject of

isolating ~ctive substances from Cinchona bark, he decided to submit the results of his painstaking observations to the Academy of Science in the form of a communication. ' His employer stumbled upon this fact by chance, and the dial~gue which ensued emphasizes Nativelle's strong personality"What ~trange idea did you have, my boy,'? the pharmacist asked him with a smile completely devoid of benevolence-:"now you are writing to the Academy? "Can we know what you are telling the Academy of Science?"

This biography of C.A. Nativelle was one of the last works completed by Karl F. Meyer, MD, before his death last April. Meyer, a native of Switzerland, held degrees in medicine, zoology and veterinary medicine. The last 60 years of his career were spent at the University of California where he was director of the George Williams Hooper Foundation for Medical Research and was a professor of bacteriology and experimental pathology. Under his guidance, the university established the first school of public health west of the Mississippi. In the area of research, he is best known for his basic studies on botulism and ihe first isolation of the virus of western encephalitis. Meyer's work has been recognized with 17 honorary lectureships, 16 awards (including the Sedgwick Memorial Medal, the Lasker Award and the Walter Reed Medal) and nine honorary degrees.

"I am studying quinquina." "Fine: quinquina, quinine. The laurels won by Messrs. Pelletier and Caventou (and their success) ' have turned your head." "My head is very solid, M. Seguin." "Somewhat hard, perhaps, M. Nativelle. I need good students here, not 'petits savants', not unimportant scholars."

One February evening in 1836, after this conversation, Nativelle left Seguin and entered the pharmacy of Quesneville, Quartler de la Monnaie. But he had too little time for his own research there; he 'soon transferred to the pharmacy ot Pierre Deleschamps in April 1837. There the patron gave him an ' abandoned corn~r of his laboratory, where he ' continued his studies on quinine. ' In' 1840 he 'returned to Quesneville as a senior student, and after taking his later 'term examination in 1841, was granted his diploma as a pharmacist on the basis of hi~ thesis on the isolation of a resin from the jalap root 1 (Ipomoea purgi). However, instead of directing an ~pothecary laboratory, Claude-Adolphe continued his work on Cinchona and accepted an assignment to South America for the purpose of developing newer methods of collecting and shipping the medicinal bark to Europe'. In 1843 Nativelle arrived at the seaport of Cartagena, Colombia. Impressed by the hospitality of the inhabitants and the exuberance of the forest vegetation, he explored the Cordillera Mountains with his caravans to an altitude of 2,500 meters. Influenced by the humidity of the climate as well as an apparent incompatibility with his companions, he returned alone to France. Aside from specimens and samples of plants, he brought back a Gaucho cape, whi~h he wore constantly until the end of his life and which lent a certain bravado to his personage. Upon his r~turn from Colombia, Claude Nativelle ceased to study quinine and , instead concentrated his efforts on isolating from foxglove leaves the cardiotonic activities which could have saved his mother's life. The medicinal

worth of digitalis had already been established. Later this potent cardiac agent was to suffer an eclipse during the period when its mode of action was not yet fully understood. But the main difficulty was that its active principle had not yet been isolated in pure form. To stimulate research on digitalis, La Societe de Pharmacie de Paris offered a prize of 500 francs in 1835 for the best answer to the question-"Does there exist in Digitalis purpurea one or more proximate principles to which the medical properties of this plant may be attributed ?" 2 Five years later, when still no purified principle had been obtained, the Societe doubled the prize money. In 1841 E. Homolle and Theodore A. Quevenne prepared from the leaves of the foxglove a partly crystalline material, which was quite active biologically. 3 On August 31, 1844, the Academy of Pharmacy on the Rue l' Arbalete received a treatise on "The active principle of Digitalis purpurea."According to the rules of the Societe, work requiring examination was submitted anonymously and ended with the axiom "Tempus omnia revelat" ("time reveals everything"). Accompanying the description of the procedures were samples of the "purest digitaline" yet produced. Nativelle, who had sent the letter, thought he had solved the problem proposed by the Societe. , When, to his keen disappointment, his rival (Dr. E. Homolle, a physician-not a chemist) was awarded the prize, he passionately protested the verdict and attempted to prove that he alone was the discoverer of digitaline. The scientific journals of the period vividly reflect the vehemence of the controversy between the competitofsHomolle and Quevenne with their supporters, and Natiyelle with his. The latter accused a member of the jury presenting the award-the eminent M. Quevenne, chief pharmacist of l' Hopit~l de la Charite, who had begun his work on digitalis in 1837-of making unjustifiably favorable statements in his report on the work of Dr. Homolle. These war-like disputations lasted for nearly 30 years ~nd served as a stiIIlulus

to the ultimate discovery of the active element in digitalis. 4 Certainly, Nativelle's preparations were far from pure, and the levels of their physiological activitIes (minutely studied in'France and Belgium) were lower than the "authorized" digitalis compounds in use at that time. Now Nativelle the investigator replaced Nativelle the pharmacist. Lea ving his apothecary in the care of his students, he locked himself up in two modestly ' equipped laboratories, the first on the old Rue de Berri, and the other 011 the Boulevard de Port-Royal. No details of those feverish years of arduous work are known. The obstinate 'chemist tried innumerable procedures conceived in his vivid imaginati'on and guided by his solid underst~nding of scientiic methods. By 1870, the long span between the amorphous digitaline of 1844 to the crystalline preparation had been bridged. It was obtained from the residue of digitalis after exhaustive extraction with water. The solvent was 50 percent alcohol. This extract was treated with lead acetate, followed by filtration with sodium phosphate and concentration, and emerging as yellow crystals, which were subsequently decolorized by treatment with charcoal and then recrystallized with chloroform. He named this 'substance "digitaline cristalis~e."5.6 The final step in eliminating the last traces of "digitinine" had been accomplished when the 1870 FrancoPrussian War interrupted Nativelle's studies, and our chemist l?ecame an ambulance man. At the end of 1871,he commenced the composition of a last decisive memoir on digitalis. The Academy of Medicine had announced cOplpetition for the Or fila Prize, reserved for the investigator who isolated the active principle of digitalis. A Commission was formed consisting of Dr. Wurtz, dean of the Faculty of Medicine; the famous >dermatologist Devergie; Jules Cloquet, professor of clinical surgery; the great cheririst Jules Renault, and the highly esteemed pharmacist Buignet as rapporteur. Trusting their own ' competence, they examined both physically and chemic~lly Vol. NS14, No.7, July 1974

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