ON THE DISCOVERY OF THE MYDRIATIC ACTIONOF THE SOLANACEI.

BY

DR. RUD. ROBERT,Professor of the History of Medicine and' ITarafSCWtegy in Dorpat, Russia.

REPRINTED FROM THE THERAPEUTIC GAZETTE,JULY, 1886.

DETROIT, MICH.:

GEORGE S. DAVIS, PUBLISHER.1886.

On the Discovery of the MydriaticAction of the Solanaceae.

THERE can be no doubt that the discoveryof the mydriatic action of certain sola-

nacese was a matter of great importance fortherapeutic practice. Nevertheless, there ex-ists a singular uncertainty, if not confusion, asto the time of this discovery and as to the dis-coverer himself. In fact, there is not a singlebook published in German, French, or Eng-lish, in which I can find reliable data in regardto this matter.*

In order to mend this defect, I beg leaveto gather for a historical discussion all perti-nent material, which, as may be presumed, isno light task.

The Greeks and Romans understood bymydriasis a condition of visual weakness, to-gether with a dilatation of the pupil. Thisdefinition 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 trustworthythan those of other authors, have been adopted in themain in this paper.

f This interesting passage is rendered by Adams asfollows: When the pupil does not appear changed incolor, but much wider than natural, and when it some-times wholly impairs the vision, and sometimes nearlyso, and when every object appears smaller, the affectionis called mydriasis. The cause of it is some redundanthumor.

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probably derived from the peculiar conditionof visual weakness and pupillary dilatation in-variably to be found in glaucoma. Some fewauthors, as Aetius, designate improperly, also,other pathological conditions of the eye, suchas phthisis bulbi, as mydriasis. In the pres-ently accepted meaning—i.e., dilatation of thepupils *—the word appears to have been firstused by Caelius Aurelianus (Chron. ii., p. 344).

The first mention of a mydriasis producedby preparations of solanaceaef we find inGalen’s third volume of Methodus Medendi(Edit. Kuhn, tom. x., Lipsise, 1825, p. 171).This author states in the second chapter ofthe quoted volume that grave visual interfer-ences and mydriasis may result by a too in-tensive local application of drugs containingmandragora or hyoscyamus. Dioscorides andPlinius Secundus do not appear to have knownanything of this action, at least these writersnever mention it, while mydriasis itself occursin Pliny, who even mentions an artificial pro-duction of mydriasis by the seeds of anagal-lis. Galen, therefore, is unquestionably thefirst author who refers to the mydriatic actionof two species of solanaceae. Still, his in every

* The word pupil, with its present signification, wasused by Cicero (De Natura Deorum, ii. 57), who derivesit from pupula, a little doll.

f The identification of the solanacese of the ancientsis 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 importanceto know that all of the species in question have a mydri-atic action.

3way correct statement appears to have beenwholly forgotten, for no subsequent writerever 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 beneaththe eye a belladonna-leaf, and had afterwardsbeen annoyed by an excessive dilatation ofthe pupil. Simultaneously the lady lost en-tirely the power of the pupil to react on light.The physician regarded this defect at first asa matter of accident, until a repetition of thebelladonna application taught him that a dila-tation of the pupil and loss of reactive powerfor several days were the physiological effectsof belladonna.

But this second discovery also was againforgotten, although Ray’s work was largelyread. Thus, Boerhave (1668-1738), howeverfamiliar with medical literature, says in hisbook De Morbis Nervorum (p. 371), express-ively that the juice of belladonna had no in-fluence upon the eye, while Van Swieten, inhis commentary of Boerhave’s Aphorisms(vol. iii. p. 363), quotes Ray’s case. Andquite 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 positivelynothing of this action.f Gmelin states, in his General History of Vegetable

Poisons (Nuremberg, 1777), p. 301, that already in 1765he had noticed mydriasis as one of the symptoms of bel-ladonna-poisoning, but he does not appear to regard thissymptom as characteristic, but rather as an incidentalone, for, in reviewing all symptoms, he omits this one.

4persons hebetude oculorum and dilatatiopupillae 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 laterthe following case of poisoning occurred atHamburg. 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 JoanneAndrea 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 thejuice of the berries, or of the herb, accidentallyget into his right eye. Very soon after thisaccident he was troubled by mydriasis andconsiderable visual interferences. Reimarus,informed by letter of the druggist’s trouble,wrote that he was aware that the ingestion oflarge quantities of belladonna produced my-driasis, but that he was surprised to learn thatthe external application of the drug couldlikewise produce this result. This was, how-ever, Reimarus added, a very interesting mat-ter, and invited decidedly to therapeutic trialsof the drug in cataract operations. But evenbefore the arrival of this letter, Daries ascer-tained, by experiments on a cat, that the freshjuice of the herb and of the berries of bella-donna had actually a mydriatic power. HenceDaries 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,

5ing that one of Ray mentioned above. Apatient having placed a leaf of datura stra-monium upon an ulcer near the eye, was soonaffected 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 thebelladonna action for himself, used and rec-ommended in 1796 an infusion of belladonnafor cataract extraction. Loder is consequentlythe sixth discoverer of this action.

After this time the specific action of bella-donna upon the eye became generally knownin Germany and in other countries.

Thus, we find it mentioned as somethinggenerally 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 frombotanical 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 quitefamiliar 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 militarysurgeon, later professor of surgery, and died as such inBern in 1837.

•j- Ophthalmolog. Beobachtungen und Untersuchun-gen, Bremen, vol. i. p. 1.

X De la Paralysie de I’lris par Applicationlocale de la Belladone, et de son Utility dans le Traite-ment de divers Maladies des Yeux, par Himly, trad, parEmil August Ehlers, Paris, 1802.

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cation of Himly in question into French, but,either on purpose or by mistake, always wrotebelladonna instead of hyoscyamus, inducingthus the French physicians to employ bella-donna therapeutically. In the second Frenchedition, however, appearing 1803 in Altona,the word jusquiame is used instead of bella-donna. In England, Paget* recommendedthe belladonna application for cataract ex-traction.

In lay circles, however, the mydriatic actionof the solanacese was in the beginning of thiscentury still wholly unknown, and was anewdiscovered by Runge, the discoverer of theaniline colors. This chemist makes, in hisChemischen Briefen,f the following interest-ing communication :

“ln Jena I became soon acquainted withDobereiner, and discussed with him my re-searches about vegetable poisons, especiallythe solanaceag. Dobereiner appeared pleasedwith the methods instituted by me and theresults of my investigations ; he constantlystimulated me to new researches. About thistime 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 ofascertaining with certainty whether or not apoisoning with stramonium had occurred.Goethe had thereupon expressed the desireto 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.

7demonstration of his discovery. When Icrossed 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 myfantastic 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 ledinto the reception-room, and soon stood be-fore the poet. His lofty, handsome, and pow-erful presence made such an overwhelmingimpression upon me, that, all in a tremble, Ihanded him the cat, as if I wanted thus to de-fend myself. ‘Ah ! So,’ Goethe said, ‘that’swhat is going to be the future terror of thepoison-mixers. Just let me look.’ I thenturned the cat’s head so that the light struckboth eyes simultaneously, and the differencebetween the eyes could be readily seen. Goethewas greatly surprised. Alongside of the smallslit in one eye, the round great opening inthe other presented a very striking differ-ence. In consequence of a somewhat largedose, the entire iris had almost become in-visible, thus enhancing this singular aspect.‘ How did you obtain this effect ?’ askedGoethe. ‘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 youhave ascertained that the active toxic princi-

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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 thoseof an affiliated relation?’ ‘A friend of mine,Dr. Carl Heise, induced by the peculiar actionof the stated plants, has shown in an elaboratework that only the plants of the three ordersmentioned above affect the pupils in a my-driatic manner. He has tried the action ofinnumerable other plants on the eye, andfound them all to be inert save a few whichproduced the reverse of mydriasis, viz., a con-traction of the pupil, such as aconitum.’ ‘ Well,’Goethe said, ‘ there is a chance to discover theproper antidote for the toxic action of bella-donna. Try this, and apply both antagonis-tic plants either simultaneously or one afteranother to the eyes of a cat. Observe the re-sult. The matter is not without difficulties,but you will overcome these. But now, praytell me, how you came to this peculiar kindof organic chemistry ?’

” Runge related : “In1810 I was—a pastor’s son, from the countrynear Hamburg—sent to Liibeck, and placedin the Rathsapotheke as an apprentice. Itwas a warlike time, and Napoleon preparedhis invasion of Russia. All men able to carryarms were mustered out, and, on account ofthe universal unwillingness to serve under thetyrant, it was a matter of difficulty to find asubstitute. Through recommendation of myuncle, I had received admission into severalaristocratic families, and the son of one ofthem became a friend of mine. One eveninghe came to the drug-store in great commo-tion, and told me his trouble, that the dayafter to-morrow he had to present himself for

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service, and that, being without physical de-fect, he probably would be taken. ‘ I wouldlike to mutilate my hand,’ he sighed, ‘ in ordernot to go into this ignominious war.’ ‘Thatis not necessary,’ I said. ‘ Confide in me. Ibelieve to be able to mutilate you for a shorttime with impunity. They will have to exemptyou from service.’ ‘What are you going todo with me ?’ ‘ I will make you blind fortwenty-four hours.’ ‘ How are you going todo that ?’ ‘ Listen to me. About eight weeksago I had to prepare a medicine, according toa doctor’s prescription, in which a decoctionof the juice of hyoscyamus was to be dissolvedin water. Preparing the medicine in a mor-tar, a drop accidentally got into my eye. Iexperienced nO pain, and did not observe anyalteration until sensations of light flashescaused me to go to the looking-glass. Howgreat was my astonishment when I saw thechange that had taken place in my eye. Theiris had almost wholly disappeared, and theeye looked precisely like that of a man suffer-ing from amaurosis. The power of vision wasalso greatly weakened, as I noticed when Iclosed the unaffected eye. I don’t knowwhy this state of things did not raise anyfears in me. After lasting a few days, theabnormal condition disappeared, the powerof 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 ofyour eyes, and it would be very queer if youwould not be discharged, even after a super-ficial examination.’ After making some easily-removed objections, my friend consented to

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this at that time very pardonable fraud, andthus saved his life, for of all men that wentfrom Liibeck to the war in Russia but few re-turned. His temporary blindness lasted thirty-six hours, passed away painlessly, withoutleaving behind any deleterious results.”

Thus far goes the report? of Runge, fromwhich we can distinctly see that he ob-tained the knowledge of the mydriatic actionof the solanacem by the same accident asDaries derived his knowledge. Runge isconsequently the seventh discoverer of thisaction. He tried even to practically utilizehis discovery at once ; for he recommendedin his dissertation (De Novo Methodo Vene-ficium Dijudicandi, Jense, 1819) in a case ofsuspected atropine intoxication to place adrop of the urine of the poisoned person intothe eye of a cat. The word atropine doesnot seem to have been known to Runge, forthe solanacea alkaloid, isolated approximatelyby him, he calls koromegyn (Greek, magnifierof pupil). This alkaloid was isolated in 1830properly by the apothecary Mein,* of Neustadt-Goders, and independently of him in 1832 byGeiger and Hesse,f while Liebig J determinedits chemical formula. The solution of thepure sulphate of atropine, instead of the ex-tract of belladonna, was at once used byGeiger § and Hesse for the purpose of dilatingthe pupil. The named chemists succeededsoon |1 after also in isolating hyoscyamine, theactive principle of hyoscyamus. They showedthat this alkaloid, like atropine, had a dis-

* Liebig’s Annalen, vol. vi. p. 67.f Ibid., vol. v. p. 38. J Ibid., vol. vi., 1833, P- 66.\ Ibid., p. 68. |( Ibid., vol. vii., 1839,p.271.

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tinctly mydriatic action even in a dilution ofi to 1000.

In the majority of books treating of thesehistorical facts, such as in Hirsch’s History ofOphthalmology, and in Hirsch’s Latest Dis-coveries of Materia Medica, Heidelberg andLeipzig, 1843, vol. ii. p. 160, we find the state-ment that the complete isolation of atropineand hyoscyamus occurred in the first half ofthe second decade of this century, and wasobtained by Brandes and Runge. This, how-ever, is wholly untrue.* For all those casesreferred only to purified extracts but not tochemically pure alkaloids. After the mydri-atic action of the solanacese alkaloids was posi-tively made out, and had become generallyknown, their physiological modus operandi hadto be determined.

Ernst Heinrich, as early as 1821, stated inhis famous paper, De Motor Iridis (p. 102),that belladonna paralyzes the nerves of themuscular sphincter iridis. This view wasconfirmed by the experiments of Biffi (1845),Cramer and Ruiter (1853), and is now heldexclusively by all ophthalmologists. Neverthe-less, this view is only partially correct, for themost recent students of pharmacology havedemonstrated that we have to deal here onlywith a paralysis of the peripheral ends of thenervus 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 Gebieteder 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.

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Fraser, of Edinburgh, discovered in 1861the only practically applicable medium ofpupillary contraction, viz., physostigmine orthe extract of Calabar bean. Pilocarpine, mus-carine, and nicotinelikewise contract thepupil,but this contraction is in intensity and extentfar inferior to that produced by physostigmine,and is of little practical importance.