ON THE DISCOVERY OF THE MYDRIATIC ACTION OF THE SOLANACEI. BY Professor of the History of Medicine and' ITarafSCWtegy in Dorpat, Russia. DR. RUD. ROBERT, REPRINTED FROM THE THERAPEUTIC GAZETTE, JULY, 1886. DETROIT, MICH. : GEORGE S. DAVIS, PUBLISHER. 1886. On the Discovery of the Mydriatic Action of the Solanaceae. THERE can be no doubt that the discovery of the mydriatic action of certain sola- nacese was a matter of great importance for therapeutic practice. Nevertheless, there ex- ists a singular uncertainty, if not confusion, as to the time of this discovery and as to the dis- coverer himself. In fact, there is not a single book published in German, French, or Eng- lish, in which I can find reliable data in regard to this matter.* In order to mend this defect, I beg leave to gather for a historical discussion all perti- nent material, which, as may be presumed, is no light task. The Greeks and Romans understood by mydriasis a condition of visual weakness, to- gether with a dilatation of the pupil. This definition can be found in Paulus iEgineta (iii. 22),f Celsus (vi. 6), and Isagoges ; and is * The statements of A. Hirsch in the History of Oph- thalmology (Graefe-Saemisch, Textbook of Ophthalmol- ogy, vol. vii. p. 235), appearing to be more trustworthy than those of other authors, have been adopted in the main in this paper. f This interesting passage is rendered by Adams as follows: When the pupil does not appear changed in color, but much wider than natural, and when it some- times wholly impairs the vision, and sometimes nearly so, and when every object appears smaller, the affection is called mydriasis. The cause of it is some redundant humor. 2 probably derived from the peculiar condition of visual weakness and pupillary dilatation in- variably to be found in glaucoma. Some few authors, as Aetius, designate improperly, also, other pathological conditions of the eye, such as phthisis bulbi, as mydriasis. In the pres- ently accepted meaning—i.e., dilatation of the pupils *—the word appears to have been first used by Caelius Aurelianus (Chron. ii., p. 344). The first mention of a mydriasis produced by preparations of solanaceaef we find in Galen’s third volume of Methodus Medendi (Edit. Kuhn, tom. x., Lipsise, 1825, p. 171). This author states in the second chapter of the quoted volume that grave visual interfer- ences and mydriasis may result by a too in- tensive local application of drugs containing mandragora or hyoscyamus. Dioscorides and Plinius Secundus do not appear to have known anything of this action, at least these writers never mention it, while mydriasis itself occurs in Pliny, who even mentions an artificial pro- duction of mydriasis by the seeds of anagal- lis. Galen, therefore, is unquestionably the first author who refers to the mydriatic action of two species of solanaceae. Still, his in every * The word pupil, with its present signification, was used by Cicero (De Natura Deorum, ii. 57), who derives it from pupula, a little doll. f The identification of the solanacese of the ancients is a difficult and as yet but partially-solved problem, vide Sprengel (Fed. Dioscorides de Mat. Med., Lipsise, 1829, pp. 602-605), Francis Adams (Paulus iEgineta, London, 1847, ii. pp. 218-19, and iii. p. 290), and Im- bert Gourbeyre (Recherches sur les Solanum des An- ciens, Paris, 1884). For our purposes it is of importance to know that all of the species in question have a mydri- atic action. 3 way correct statement appears to have been wholly forgotten, for no subsequent writer ever speaks of this action, which fifteen hun- dred years later had to be discovered anew.* In 1686, Dr. Ray, a famous English physi- cian, reported in his Historia Plantarum (vol. i. p. 680) that a lady coming under his obser- vation had placed upon a small ulcer beneath the eye a belladonna-leaf, and had afterwards been annoyed by an excessive dilatation of the pupil. Simultaneously the lady lost en- tirely the power of the pupil to react on light. The physician regarded this defect at first as a matter of accident, until a repetition of the belladonna application taught him that a dila- tation of the pupil and loss of reactive power for several days were the physiological effects of belladonna. But this second discovery also was again forgotten, although Ray’s work was largely read. Thus, Boerhave (1668-1738), however familiar with medical literature, says in his book De Morbis Nervorum (p. 371), express- ively that the juice of belladonna had no in- fluence upon the eye, while Van Swieten, in his commentary of Boerhave’s Aphorisms (vol. iii. p. 363), quotes Ray’s case. And quite independently of Ray’s observation, Evers reported in the Berliner Sammlung, 1773, vol. v. p. 565,f that he noticed in six * Ebn, Baithar, and Paulus vEgineta, know positively nothing of this action. f Gmelin states, in his General History of Vegetable Poisons (Nuremberg, 1777), p. 301, that already in 1765 he had noticed mydriasis as one of the symptoms of bel- ladonna-poisoning, but he does not appear to regard this symptom as characteristic, but rather as an incidental one, for, in reviewing all symptoms, he omits this one. 4 persons hebetude oculorum and dilatatio pupillae as symptoms of the belladonna in- toxication. Evers must accordingly be men- tioned as the third discoverer of the mydri- atic power of belladonna. Three years later the following case of poisoning occurred at Hamburg. A physician of repute, Dr. Rei- marus, had ordered in a drug-store belladonna. The nephew of the apothecary, Johannes An- dreas Daries (De Atropa Belladonna, Dissert. Inaug. Auctore Petro Joanne Andrea Daries. Lipsias, 1776. Reprinted in Ballinger’s Syl- loge, vol. ii. p. 58), who prepared the prescrip- tion from the fresh plant, had a drop of the juice of the berries, or of the herb, accidentally get into his right eye. Very soon after this accident he was troubled by mydriasis and considerable visual interferences. Reimarus, informed by letter of the druggist’s trouble, wrote that he was aware that the ingestion of large quantities of belladonna produced my- driasis, but that he was surprised to learn that the external application of the drug could likewise produce this result. This was, how- ever, Reimarus added, a very interesting mat- ter, and invited decidedly to therapeutic trials of the drug in cataract operations. But even before the arrival of this letter, Daries ascer- tained, by experiments on a cat, that the fresh juice of the herb and of the berries of bella- donna had actually a mydriatic power. Hence Daries is to be designated as the fourth dis- coverer of the mydriatic action of belladonna. About the same time, or a little later, Doe- derlein* observed in his practice a case recall- * Conrad Moench, Lehre von den Arzneimitteln, 5 ing that one of Ray mentioned above. A patient having placed a leaf of datura stra- monium upon an ulcer near the eye, was soon affected with a complete paralysis of the pupil. Doederlein interpreted this mydriasis very cor- rectly as the action of stramonium, and is ac- cordingly to be regarded as the fifth discov- erer of this action. Independently of him, Schiferli,* following the example of his pre- ceptor Loder, who appears to have found the belladonna action for himself, used and rec- ommended in 1796 an infusion of belladonna for cataract extraction. Loder is consequently the sixth discoverer of this action. After this time the specific action of bella- donna upon the eye became generally known in Germany and in other countries. Thus, we find it mentioned as something generally known in Tromsdorf’s Pharmaco- logical Dictionary (Hamburg and Leipzig, 1802, vol. i. p. 299) The action of hyoscya- mus was discovered by Himly in 1800 from botanical deductions, and was warmly recom- mended for ophthalmological purposes, f Ehl- ers,j; one of his pupils, translated the publi- Marburg, 1795, P- 337- Moench, by the way, was quite familiar with the publications of Ray and Daries. * Rud. Abraham Schiferli, Dissertatio de Cataracta, Jenae, 1796; and Theoretical Practical Treatise on Cat- aract, Jena and Leipzig, 1797, p. 85. He was military surgeon, later professor of surgery, and died as such in Bern in 1837. •j- Ophthalmolog. Beobachtungen und Untersuchun- gen, Bremen, vol. i. p. 1. X De la Paralysie de I’lris par Application locale de la Belladone, et de son Utility dans le Traite- ment de divers Maladies des Yeux, par Himly, trad, par Emil August Ehlers, Paris, 1802. 6 cation of Himly in question into French, but, either on purpose or by mistake, always wrote belladonna instead of hyoscyamus, inducing thus the French physicians to employ bella- donna therapeutically. In the second French edition, however, appearing 1803 in Altona, the word jusquiame is used instead of bella- donna. In England, Paget* recommended the belladonna application for cataract ex- traction. In lay circles, however, the mydriatic action of the solanacese was in the beginning of this century still wholly unknown, and was anew discovered by Runge, the discoverer of the aniline colors. This chemist makes, in his Chemischen Briefen,f the following interest- ing communication : “ln Jena I became soon acquainted with Dobereiner, and discussed with him my re- searches about vegetable poisons, especially the solanaceag. Dobereiner appeared pleased with the methods instituted by me and the results of my investigations ; he constantly stimulated me to new researches. About this time I met Goethe, at the instigation of Dober- einer, who had told the poet that by experi- ments upon cats I had found a method of ascertaining with certainty whether or not a poisoning with stramonium had occurred. Goethe had thereupon expressed the desire to meet the young chemist, and to see the * London Med. and Phys. Journal, 1801, vi. p. 352; cf. Edinburgh Med. and Surg. Journal, 1813, ix. p. 279. f This book is wholly unobtainable in the book mar- ket. A brief abstract of it appeared in the Pharmac. Handdsblatt, 1885, p. 23. 7 demonstration of his discovery. When I crossed the market square in the afternoon, dressed with a borrowed frock coat and stove- pipe hat, and carrying the cat under my arm, I created a universal sensation. The boys, who were loitering about the place, at the cry ‘Doctor Poison !’ suddenly came towards me, and surrounded me. To those joking at my fantastic appearance I said, * Let me in peace. I am attending to some important business. I am going to Goethe.’ I was instantly re- leased. Coming to Goethe’s house, I was led into the reception-room, and soon stood be- fore the poet. His lofty, handsome, and pow- erful presence made such an overwhelming impression upon me, that, all in a tremble, I handed him the cat, as if I wanted thus to de- fend myself. ‘Ah ! So,’ Goethe said, ‘that’s what is going to be the future terror of the poison-mixers. Just let me look.’ I then turned the cat’s head so that the light struck both eyes simultaneously, and the difference between the eyes could be readily seen. Goethe was greatly surprised. Alongside of the small slit in one eye, the round great opening in the other presented a very striking differ- ence. In consequence of a somewhat large dose, the entire iris had almost become in- visible, thus enhancing this singular aspect. ‘ How did you obtain this effect ?’ asked Goethe. ‘With hyoscyaraus, your excel- lency,’ I answered. ‘I have placed the un- mixed juice of the pounded herb in the eye, therefore the action is so strong.’ ‘ Dober- einer told me,’ said Goethe, ‘ that both bella- donna and stramonium act alike, and that you have ascertained that the active toxic princi- 8 pie is contained in the plant in all of its parts, from the root to the blossom, fruit, and seed. How is it with other plants, especially those of an affiliated relation?’ ‘A friend of mine, Dr. Carl Heise, induced by the peculiar action of the stated plants, has shown in an elaborate work that only the plants of the three orders mentioned above affect the pupils in a my- driatic manner. He has tried the action of innumerable other plants on the eye, and found them all to be inert save a few which produced the reverse of mydriasis, viz., a con- traction of the pupil, such as aconitum. ’ ‘ Well,’ Goethe said, ‘ there is a chance to discover the proper antidote for the toxic action of bella- donna. Try this, and apply both antagonis- tic plants either simultaneously or one after another to the eyes of a cat. Observe the re- sult. The matter is not without difficulties, but you will overcome these. But now, pray tell me, how you came to this peculiar kind of organic chemistry ?’ ” Runge related : “In 1810 I was—a pastor’s son, from the country near Hamburg—sent to Liibeck, and placed in the Rathsapotheke as an apprentice. It was a warlike time, and Napoleon prepared his invasion of Russia. All men able to carry arms were mustered out, and, on account of the universal unwillingness to serve under the tyrant, it was a matter of difficulty to find a substitute. Through recommendation of my uncle, I had received admission into several aristocratic families, and the son of one of them became a friend of mine. One evening he came to the drug-store in great commo- tion, and told me his trouble, that the day after to-morrow he had to present himself for 9 service, and that, being without physical de- fect, he probably would be taken. ‘ I would like to mutilate my hand,’ he sighed, ‘ in order not to go into this ignominious war.’ ‘That is not necessary,’ I said. ‘ Confide in me. I believe to be able to mutilate you for a short time with impunity. They will have to exempt you from service.’ ‘What are you going to do with me ?’ ‘ I will make you blind for twenty-four hours.’ ‘ How are you going to do that ?’ ‘ Listen to me. About eight weeks ago I had to prepare a medicine, according to a doctor’s prescription, in which a decoction of the juice of hyoscyamus was to be dissolved in water. Preparing the medicine in a mor- tar, a drop accidentally got into my eye. I experienced nO pain, and did not observe any alteration until sensations of light flashes caused me to go to the looking-glass. How great was my astonishment when I saw the change that had taken place in my eye. The iris had almost wholly disappeared, and the eye looked precisely like that of a man suffer- ing from amaurosis. The power of vision was also greatly weakened, as I noticed when I closed the unaffected eye. I don’t know why this state of things did not raise any fears in me. After lasting a few days, the abnormal condition disappeared, the power of vision returned, and also the normal pro- portions of the iris, so that both pupils ap- peared again of equal size. And behold ! such an affection I will produce in both of your eyes, and it would be very queer if you would not be discharged, even after a super- ficial examination.’ After making some easily- removed objections, my friend consented to 10 this at that time very pardonable fraud, and thus saved his life, for of all men that went from Liibeck to the war in Russia but few re- turned. His temporary blindness lasted thirty- six hours, passed away painlessly, without leaving behind any deleterious results.” Thus far goes the report? of Runge, from which we can distinctly see that he ob- tained the knowledge of the mydriatic action of the solanacem by the same accident as Daries derived his knowledge. Runge is consequently the seventh discoverer of this action. He tried even to practically utilize his discovery at once ; for he recommended in his dissertation (De Novo Methodo Vene- ficium Dijudicandi, Jense, 1819) in a case of suspected atropine intoxication to place a drop of the urine of the poisoned person into the eye of a cat. The word atropine does not seem to have been known to Runge, for the solanacea alkaloid, isolated approximately by him, he calls koromegyn (Greek, magnifier of pupil). This alkaloid was isolated in 1830 properly by the apothecary Mein,* of Neustadt- Goders, and independently of him in 1832 by Geiger and Hesse,f while Liebig J determined its chemical formula. The solution of the pure sulphate of atropine, instead of the ex- tract of belladonna, was at once used by Geiger § and Hesse for the purpose of dilating the pupil. The named chemists succeeded soon |1 after also in isolating hyoscyamine, the active principle of hyoscyamus. They showed that this alkaloid, like atropine, had a dis- * Liebig’s Annalen, vol. vi. p. 67. f Ibid., vol. v. p. 38. \ Ibid., p. 68. J Ibid., vol. vi., 1833, P- 66. |( Ibid., vol. vii., 1839, p. 271. 11 tinctly mydriatic action even in a dilution of i to 1000. In the majority of books treating of these historical facts, such as in Hirsch’s History of Ophthalmology, and in Hirsch’s Latest Dis- coveries of Materia Medica, Heidelberg and Leipzig, 1843, vol. ii. p. 160, we find the state- ment that the complete isolation of atropine and hyoscyamus occurred in the first half of the second decade of this century, and was obtained by Brandes and Runge. This, how- ever, is wholly untrue.* For all those cases referred only to purified extracts but not to chemically pure alkaloids. After the mydri- atic action of the solanacese alkaloids was posi- tively made out, and had become generally known, their physiological modus operandi had to be determined. Ernst Heinrich, as early as 1821, stated in his famous paper, De Motor Iridis (p. 102), that belladonna paralyzes the nerves of the muscular sphincter iridis. This view was confirmed by the experiments of Biffi (1845), Cramer and Ruiter (1853), and is now held exclusively by all ophthalmologists. Neverthe- less, this view is only partially correct, for the most recent students of pharmacology have demonstrated that we have to deal here only with a paralysis of the peripheral ends of the nervus oculo-motorius, while the nervus sym- pathicus supplying the musculus dilator re- mains absolutely unaffected. * Equally erroneous is the statement that Reisinger (Bayerisch’s Annalen; Abhandlungen aus den Gebiete der Chirurgie, Sulzbach, 1827; also Salzburger Med. Chir. Zeitung, 1825, No. 14, p. 237, and No. 15, p. 253) in 1824 had used the pure alkaloids of solanacese. 12 Fraser, of Edinburgh, discovered in 1861 the only practically applicable medium of pupillary contraction, viz., physostigmine or the extract of Calabar bean. Pilocarpine, mus- carine, and nicotine likewise contract the pupil, but this contraction is in intensity and extent far inferior to that produced by physostigmine, and is of little practical importance.