Part 30

ALKALOIDS.

The alkaloids extracted from vegetables are the ideal quintessences which the alchemical pharmacists of the sixteenth and seventeenth centuries sought so eagerly to obtain. Their characteristic property is that they are basic, that is, that definite salts can be formed from them by combination with acids. They all contain nitrogen, and have an alkaline reaction.

Of all the popular vegetable drugs opium was the one more than any other tortured to yield up its essence. The early laudanums and extracts of opium aimed at this result, and preparations, such as the Magisterium Opii of Ludovici of Weimar (born about 1625, and author of “Dissertations on Pharmacy”), were used in the belief that the quintessence had been in some degree secured. Robert Boyle experimented with opium with the object of extracting its essential principle. The process he adopted was first to treat the drug with calcined tartar (salt of tartar), and then extract with spirit of wine. By this means he obtained a solution which would be principally one of morphine.

In 1803 a French manufacturing chemist, working on an idea suggested by Vauquelin, produced a crystallisable salt which was at first supposed to be the active ingredient of opium. Experiments on animals seemed to confirm this opinion, and the salt of opium, or “sel narcotique de Derosne,” was believed to have solved the long-standing problem. The product was described in the “Annales de Chimie” of February, 1804. It was the substance now known as narcotine. Sertürner regarded it as meconate of morphium, a misapprehension which was corrected by Robiquet.

In December, 1804, Seguin, a chemist who had been a demonstrator under Fourcroy, and who subsequently got into trouble with Napoleon’s Government on charges of having enriched himself out of drug supplies to the Republican armies, read a paper to the Institute in which he described a process which would yield morphine. For some unexplained reason that paper was not published until 1814. Meanwhile Friedrich Wilhelm Adam Sertürner, a pharmacist of Eimbeck, in Hanover, had been working on Derosne’s salt, and had investigated more accurately than anyone before him the composition of opium. His first report was published in 1806, and in that he announced the discovery of “opium-säure” (opium acid), but in 1816 he named this product “meconic acid,” and explained how it was combined with an alkaline base which he called “Morphium.” He described this as analogous to ammonia, and prepared several salts from it. He came near to losing his life in the course of his experiments as, misled by the comparative harmlessness of Derosne’s salt, he had ventured on dangerous doses of his own product. Consequently he was able to determine very accurately the therapeutics of morphine at the same time that he announced its discovery.

“I flatter myself,” wrote Sertürner in 1816, “that chemists and physicians will find that my observations have explained to a considerable extent the constitution of opium, and that I have enriched chemistry with a new acid (meconic) and with a new alkaline base (morphium), a remarkable substance which shows much analogy with ammonia.”

Sertürner’s discovery excited much interest and emulation, and its importance was fully endorsed when, in 1831, the French Institute awarded to him a prize of 2,000 francs “for having opened the way to important medical discoveries by his isolation of morphine and his exposition of its character.”

Before Sertürner had definitely established the nature of alkaloids, Vauquelin had separated from tobacco a substance which he regarded as its active principle, and which was undoubtedly an impure nicotine. This was in 1809. The alkaloidal character of this extract was not, however, recognised until 1828, when Posselt and Reimann produced it in a pure form.

Vauquelin had in 1812 extracted daphnine from mezereon root, and in describing his experiments had alluded to its alkaline character. For this reason the credit of having been the first to have discovered an organic alkali has been attributed to him; and when in 1818 Pelletier and Caventou discovered an alkaloid in St. Ignatius’s beans, to which they gave the name of strychnine, they stated that it had been their original intention to designate the substance Vauqueline in honour of the celebrated chemist who had first established the existence of an organic alkali. It had, however, been pointed out to them by distinguished members of the Academy that it would have been a doubtful compliment to associate such an honoured name as that of Vauquelin with such an evil (malfaisant) substance as this new product.

A number of chemists narrowly missed the discovery of quinine. As early as 1746 Count Claude de la Garaye obtained from cinchona bark a crystalline salt which he termed sel essentiel de quinquina. Two other French chemists, Buquet and Cornette, subsequently introduced another sel essentiel de quinquina. Both these products were simply kinate of lime. A Swedish physician named Westerling announced in 1782 that he had discovered the active principle of cinchona, and he gave it the designation of vis coriaria. His product was in fact cinchotannic acid. Seguin perhaps made the worst mistake of all the investigators in coming to the conclusion that what was precipitated by tannin was the essence of cinchona from a medicinal point of view, and he actually recommended that gelatin should be substituted for cinchona in cases when price was an object. Fourcroy made several attempts to ascertain the true chemical constitution of the bark. In 1790 he separated a resinous principle, mixed with some colouring matter, since called cinchonic red. This he at first supposed was the essential medical constituent of the bark. Vauquelin later adopted this erroneous theory, and so missed his way. In 1792 Fourcroy got nearer to the truth when he observed incidentally that the water in which the bark had been macerated turned litmus paper green; and he also remarked that lime water caused a greenish precipitate in the infusion. He did not pursue the investigation, but his comment on what he had stated is noteworthy. “These researches,” he said, “will no doubt lead to the discovery one day of an anti-periodic febrifuge, which once known may be extracted from various vegetables.” Berthollet followed on Fourcroy’s lines, but came to the conclusion that the precipitate which lime water gave with decoctions of cinchona was magnesia, which he believed was a constituent of the bark in combination with hydrochloric acid.

In 1811 Gomez, of Lisbon, described a crystalline substance which Dr. Duncan, of Edinburgh, had obtained from certain species of cinchona, and gave to this product the name of cinchonine. Lambert later prepared it in a state of considerable purity. But neither of these chemists suspected its alkaline nature. In 1820 Pelletier and Caventou studied the whole chemistry of cinchona and succeeded in showing that the cinchonine of Gomez was a mixture of two alkaloids, to the second of which they gave the name of quinine. Quinidine was isolated by Henry and Delondre in 1833, and cinchonidine by Winckler in 1844, but the name of the latter was given by Pasteur in 1853. Pasteur also produced the alkaloidal derivatives cinchonicine and quinicine.

Robiquet had the idea that as the coffee plant belongs to the same family of plants as the cinchonas it might be possible to find quinine in coffee. In searching for it he isolated caffeine. This was in 1821. In 1827 Oudry found an alkaloid in tea and called it theine. Jobst and Mulder in 1838 proved that these alkaloids are identical. It is now recognised that the alkaloids of cocoa, of guarana, and of Paraguay tea are all the same substance, or closely related.

Pelletier and Caventou isolated strychnine from the St. Ignatius beans in 1818, and brucine from false angostura bark (Brucæa anti-dysenterica) in 1819; in the same years they obtained veratrine from cevadilla seeds and white hellebore root; but it would appear that in their investigation of cevadilla seeds, which was the first to yield the alkaloid, they were preceded by a very short time by Meissner. Pelletier and Magendie produced emetine from ipecacuanha in 1817, and Pelletier alone is credited with narceine in 1832. Codeine was discovered by Robiquet in 1821 when he was examining a new process for obtaining morphine which had been suggested by Dr. William Gregory, of Edinburgh. Belladonna had been studied by Vauquelin and many chemists after him, but it was not until 1833 that atropine in a state of purity was isolated from it. This was accomplished simultaneously by Geiger and Hess, two German chemists, and by Mein, a German pharmacist.

ANÆSTHETICS.

The greatest triumph achieved in any department of medicine, and worthy, perhaps, to be described as almost, if not quite, the most beneficent discovery in the world’s history, is that of the successful employment of anæsthetics. This great glory belongs to the nineteenth century. Indian hemp had been employed for centuries in the East, mandragora had a classical reputation, and from time to time the possibilities of hypnotism had been expounded by one or another of its professors. But it is only within the past sixty years that the terrible anxiety and suffering associated with surgical operations have been so far mitigated as largely to increase the prospects of success, and to annihilate the pain. To Sir Humphry Davy is due the credit of first suggesting the line of advance towards this precious goal by describing his experiences of the inhalation of nitrous oxide gas which he found had the effect of relieving toothache and other pains; “uneasiness swallowed up for a few minutes by pleasure,” were his own words; and he foresaw the possibility of this agent being employed as an inhalation “in such surgical operations as involved no great effusion of blood.” That was in the year 1800. About 1830 Faraday observed and noted the effect of ether on the nervous system, which he stated was similar to that of nitrous oxide gas.

The possibility of painless operations began to be imagined about this time, but not much serious experimental work seems to have been attempted. In 1842, Dr. Long, of Athens, Georgia, U.S.A., claimed to have removed a tumour from a patient under the influence of ether, and about the same time Dr. Jackson, of Boston, U.S.A., also professed to have carried out successfully a similar operation. These experiments have not been rigorously established, but there is no question about the authenticity of the next. Horace Wells, a dentist of Hartford, Connecticut, U.S.A., suffering from toothache, resolved to experiment on himself. He induced a colleague named Rigg to draw a molar while he was under the influence of nitrous oxide gas, and did not feel the pain of the extraction. This was in 1844. Wells then, in association with another dentist, named William Thomas Green Morton, started to demonstrate the discovery publicly. The first exhibition was an ignominious failure, and the two pioneers were derided as impostors. Wells suffered so severely from his disappointment on this occasion that he died insane a few years later. Morton, however, continued his investigations, and he and the Dr. Jackson already mentioned worked together on ether, and assured themselves of its anæsthetic powers by experiments on animals. Morton then inhaled it himself on September 30, 1846, and awoke from deep unconsciousness a few minutes later, convinced of the reality of his discovery. Just then a patient rang the bell. It was towards evening, but the visitor was shown into the surgery. He was in agony with the toothache, and begged the doctor to mesmerise him in the hope of getting some relief. The nerve was so sore, he said, that he could not summon up courage to have the tooth drawn. Morton, greatly excited, told his patient that he could do better for him than mesmerising him. He could take the tooth out without pain if he would consent. The sufferer agreed eagerly, and Morton, with two assistants, proceeded to operate. A handkerchief, saturated with ether, was applied to the mouth and nostrils, and unconsciousness was produced almost immediately. A tooth, a firmly-rooted bicuspid, was extracted without arousing the patient. Then followed a minute of intense fear. The man remained motionless, and Morton felt convinced he was dead. Seizing a glass of water he dashed it into the face of this first subject, who at once revived. “Are you ready to have your tooth drawn?” asked Morton. Rather hesitating assent was given, and then the extracted tooth was shown to the patient in the chair. His name, which ought to be recorded in the annals of surgery, was Eben Frost.

On October 16, 1846, a tumour was removed from a patient at the Massachusetts General Hospital, Boston. Morton administered the ether, and Dr. Collins Warren, the senior surgeon, operated. The patient made no sound, and after he recovered consciousness declared that he had experienced no pain. “Gentlemen, this is no humbug,” said Dr. Warren to the other surgeons who had witnessed the operation. Morton died in 1868.

The first operation under ether in Great Britain was performed by Liston at University College Hospital in December, 1846. In January, 1847, James Young Simpson commenced to employ it in midwifery cases in Edinburgh. Simpson had already acquired a high reputation as a gynecologist, and was an enthusiast in his profession. Delighted though he was with the results of his trials of ether, he felt sure that an anæsthetic with more lasting effect could be found or made, and with characteristic courage and pertinacity he and his two assistants, Drs. Keith and Duncan, carried on personal experiments at Simpson’s private house on such evenings as they could spare. At the same time the scientific world was appealed to for suggestions. About this time David Waldie, a Scotch pharmacist then settled in Liverpool, where he was manager of the Liverpool Apothecaries Company, was visiting Edinburgh and had a conversation with Simpson on his absorbing topic. Waldie had had some special experience with chloric ether at Liverpool, and had made experiments on its chemical character, which had led him to the conclusion that the chloric ether then used was chemically only a mixture of chloroform with some undecomposed spirit. Chloroform, it must be remembered, was then but little known. Dr. Samuel Guthrie, formerly an army surgeon, but later practising at Jewelsville, Jefferson County, N.Y., published an account of a chloric ether he had made from alcohol and chloride of lime in May, 1831. In October of the same year Soubeiran in France, and a month later Liebig in Germany, announced the discovery of a similar compound. None of these products was an absolute chloroform, but all were heavy substances. Dr. Guthrie called his chloric ether, and familiarly sweet whisky, Soubeiran’s was a bichloric ether, and Liebig described his as a trichloride of carbon, but Dumas showed in 1834 that the essential substance was a trichloride of formyl, HCCl_{3} and a substitution product of marsh gas. He invented the name chloroform. It appears too that another French chemist, Flourens, in March, 1847, reported to the Academy of Sciences of Paris some experiments he had made with chloroform on animals, which indicated its anæsthetic properties; but probably neither Simpson nor Waldie was aware of this paper. This was the chemical which Waldie recommended to Simpson in the summer of 1847, and the chemist promised to send some to Simpson on his return to Liverpool. A fire in the laboratory of his establishment prevented the fulfilment of this promise, and also, Waldie said, prevented him from experimenting on himself with chloroform, as he had intended to do. Simpson got chloroform from Duncan and Flockhart in Edinburgh, but did not expect it would answer on account of its density. The sample was set aside for some time, but on November 4, 1847, he and Duncan and Keith resolved to test it. They all inhaled some from a tumbler, and almost immediately became loquacious and hilarious. Then unconsciousness came on, and Simpson, who was the first to recover, found Duncan under the table, eyes staring, and snoring vigorously, while Keith was kicking at the supper table. The experiment was repeated a few evenings later, and this time a niece of Simpson was induced to take a turn. After inhaling the vapour she fell asleep, murmuring “I’m an angel; I’m an angel.” Simpson at once began the use of chloroform in his practice, and his great reputation and powerful advocacy soon caused its general adoption.

(From a drawing by T. M. Pape, lent by the publishers of the Century Magazine.)]

A MYSTERIOUS ANÆSTHETIC.

A strange and little known story is told by Professor Franck. Van Swieten was a Dutch physician, a pupil of Boerhaave. He did not succeed in his native land so well as he ought to have done, for he was a devout Catholic. He went to Vienna, where he attained the highest medical position and the utmost esteem from his patroness, the Empress Maria Theresa. On May 1, 1771, three young gentlemen called on Van Swieten and were shown into his study. The professor was then an old man, 71 years of age.

“What do you desire, my children?” he asked, as he fingered his beads.

“We come to teach Van Swieten what he knows not,” answered one of the young men.

“That is not difficult,” replied the veteran. Then they told him they wished to show him a medicine new to the world, and as the doctor smiled incredulously, one of his visitors added:

“Like the philosopher of old, we will say to Pain:--Thou art but an idle word.”

Van Swieten was doubtful, but after further explanation he invited them to come to his hospital the next morning and demonstrate their secret. When they were gone he went to Maria Theresa and told her of the interview. The Empress declared her intention of being present at the experiment.

The next day when the three young men appeared at the hospital they found Van Swieten and a veiled lady awaiting them. Certain chemicals had previously been placed in retorts by them, and a mastiff was made to inhale the product. The animal exhibited symptoms of inebriation, and soon fell on the floor unconscious. One of the strangers made a deep incision into the dog’s chest and covered the wound with a surgical dressing. The animal showed no sign of pain, and shortly afterwards recovered consciousness, got on his feet, and walked about as if nothing had happened.

“This is indeed a miracle,” said the Empress.