PART VI.—ALKALOIDS AND POISONOUS VEGETABLE PRINCIPLES SEPARATED FOR THE MOST PART BY ALCOHOLIC SOLVENTS. (continued 4)
Reading edition
Should there be sufficient aconitine recovered to convert it into the gold salt, the properties of the gold salt (that is, its melting-point, and the percentage of gold left after burning) assist materially in the identification.
A minute quantity of aconitine dissolved in water, acidified with acetic acid, and a particle of KI added and the solution allowed to evaporate, gives crystals of aconitine hydriodide, from which water will dissolve out the KI. Iodine water gives a precipitate of a reddish-brown colour in a solution of 1 : 2000.[468]
The chemical tests are supplementary to the physiological; if the alkaloidal extract does not give the tingling, numbing sensation, aconitine cannot be present.
§ 426. Benzoyl-aconine (“isaconitine”), C31H43NO11, is obtained from aconitine by heating an aqueous solution of the sulphate or hydrochloride in a closed tube at 120°-130° for two or three hours, a molecule of acetic acid (9·27 per cent.) being split off, and benzoyl-aconine left.
It may be separated from the mixed alkaloids of the Aconitum napellus by dissolving in a 5 per cent. solution of hydrobromic acid (excess of acid being avoided), precipitating with a slight excess of ammonia, and shaking out with ether. The residue left after the ether is evaporated chiefly consists of aconitine; it is dissolved in just sufficient hydrobromic acid and the exactly neutral hydrobromate solution allowed to evaporate spontaneously in a desiccator; crystals of aconitine hydrobromide separate out, the mother liquor containing some benzoyl-aconine and “homonapelline.” The aqueous solution which has been exhausted with ether is now shaken out with chloroform. This chloroform solution contains most of the benzoyl-aconine, and on separation the residue is dissolved in just sufficient hydrochloric acid to form a neutral solution; this solution is concentrated on the water-bath with constant stirring, crystals of the hydrochloride form, and are filtered off from time to time and washed with a little cold water, the washings being added to the original liquid; the different fractions are mixed together, and the process repeated until they have a melting-point of 268°. Benzoyl-aconine is obtained from the hydrochloride by precipitating the aqueous solution by the addition of dilute ammonia, and extracting the solution with ether; the solution in ether is washed with water, dried by means of calcium chloride, and then distilled off. Benzoyl-aconine is left as a transparent colourless non-crystalline varnish of a melting-point near 125°.
The solution in water is alkaline to litmus. The base is readily soluble in alcohol, in chloroform, and in ether. The alcoholic solution is dextrorotatory. The solutions are bitter, but do not give the tingling sensation characteristic of aconitine. The hydrochloride, the hydrobromide, the hydriodide, and the nitrate have been obtained in a crystalline state. The most characteristic salt is, however, the aurochlor derivative. When aqueous solutions of benzoyl-aconine chloride and auric chloride are mixed, a yellow precipitate is thrown down, which (dissolved in alcohol, after being dried over calcium chloride, and slowly evaporated in a desiccator) deposits colourless crystals entirely different from the yellow crystals of aconitine gold chloride. These crystals have the composition C31H42(AuCl2)NO11, and therefore, by theory, should yield 22·6 per cent. of gold, and 8·2 per cent. of chlorine.
By hydrolysis benzoyl-aconine yields benzoic acid, which can be shaken out of an acid solution by ether and identified; one molecule of benzoic acid is formed from one molecule of benzoyl-aconine. Twenty per cent. of benzoic acid should, according to the formula, be obtained; Professor Dunstan found only 18·85 per cent.[469]
Benzoic acid in the subliming cell begins to give a cloud at about 77°-80°, and at or near 100° sublimes most rapidly.
Benzoic acid, recovered from an acid solution by shaking out with ether, may be recognised as follows:—To the film left on evaporating off the ether add a drop of H2SO4, and a few crystals of sodic nitrate, and heat gently for a short time; pour the clear liquid into ammonia water, and add a drop of ammonium sulphide. A red-brown colour indicates benzoic acid. The rationale of the test is as follows:—Dinitro-benzoic acid is first formed, and next, by the action of ammonium sulphide, this is converted into the red-brown ammonium diamidobenzoate.—E. Mohler, Bull. Soc. Chem. (3), iii. 414-416.
§ 427. Pyraconitine, C31H41NO10, is anhydro-benzoyl-aconine; it differs from benzoyl-aconine by a molecule of water; picraconitine is obtained by keeping aconitine at its melting-point (188°-190°) for some time, when acetic acid distils over and pyraconitine is left. Pyraconitine is an amorphous varnish, sparingly soluble in water, but readily dissolving in alcohol, chloroform, and ether; it gives a pale yellow precipitate with gold chloride, and forms crystalline salts with hydriodic, hydrobromic, and hydrochloric acids. Pyraconitine readily undergoes hydrolysis by the action of dilute acids, or by potash or soda, or with water in a closed tube; the products are benzoic acid and an alkaloid, to which the name of pyraconine has been given.
§ 428. Pyraconine, C24H37NO9.—This base is anhydro-aconine, the formula differing from aconine by one atom of water. It is amorphous, closely resembling aconine; it is soluble in water and ether; the aqueous solution has a somewhat sweet taste, and is lævorotatory; it combines with acids to form crystalline salts, which are very soluble in water.
§ 429. Aconine, C24H39NO10, m.p. 132°.—Aconine does not crystallise. Its aqueous solution is decidedly alkaline, and, like aconitine, it is lævorotatory, although to a less degree. Its taste is bitter, but causes no tingling sensation. Aconine is very soluble in water or alcohol, and slightly in chloroform, but insoluble in ether or in petroleum ether. It does, however, dissolve, in the presence of aconitine, slightly in ether. The aqueous solutions reduce the salts of gold and silver, and also Fehling’s solution. A solution of aconine gives precipitates with the general alkaloidal reagents; with mercuric chloride it gives a copious yellow precipitate, which darkens on standing.
Aconine hydrochloride, the hydriodide, the hydrobromide, and the sulphate, have all been crystallised; solutions of these salts are lævorotatory.
§ 430. Commercial Aconitine and the Lethal Dose of Aconitine.—Commercial aconitine has in the past varied in appearance from that of a gummy amorphous mass up to a purer kind in white crystals.
Professor Dunstan[470] has recently examined fourteen samples, some of them of considerable age, and only found two samples (one of English, another of German make) which approached in melting-point and crystalline appearance pure aconitine; the one, the English, melted at 186°-187°, and contained about 3 per cent. of benzoyl-aconine; the other, a German specimen, was almost pure; the melting-point was 187·5°. At the present time it is, however, not difficult to obtain fairly pure crystalline aconitine, and to assay it accurately by determining the proportion of acetic and benzoic acids. The physiological action of commercial aconitine is, however, in all cases the same, the difference being in quantitative not qualitative action; in the small doses usually administered, the physiological action depends wholly upon the true aconitine present, the other bases being practically without toxic action. Professor Plugge[471] has made some researches on the fatal dose (for the lower animals) of Petit’s, Merck’s, and Friedländer’s aconitine nitrate, which in 1882 were the purest in commerce. He administered the following doses to the animals mentioned:—
TABLE SHOWING FATAL DOSES (FOR ANIMALS) OF ACONITINE.
PETIT’S CRYSTALLINE ACONITINE NITRATE.
Animals Experimented upon. Dose Given. Dose per Kilogrm. Result.
A Frog, ·4 mgrm. 16 ·0 Death in 160 Minutes.
A Rabbit, ·8 „ ·5- ·6 Dea„h in 130 Min„
A Dog, 1 ·6 „ ·21 Dea„h in 120 Min„
A D„ ·45 „ ·10 Dea„h in 140 Min„
A D„ ·50 „ ·054 Recovered.
A D„ ·60 „ ·075 Recovered.
A Pigeon ·07 „ ·22 Death in 21 Minutes.
MERCK’S ACONITINE NITRATE.
Animals Experimented upon. Dose Given. Dose per Kilogrm. Result.
A Frog, ·4 mgrm. 16 Recovered.
A F„ 1 ·0 „ 40 Died in 110-360 Min.
A F„ 2 ·0 „ 80 Died„in 175-130 M„
A F„ 4 ·0 „ 160 Died„in 150-130 M„
A Rabbit, 3 ·5 „ 2 Died„in 175-130 M„
A Ra„ 10 „ 6 ·50 Died„in 115-130 M„
A Dog, 10 „ 1 ·65 Died„in 115-130 M„
A Pigeon, ... 1 ·65 Recovered.
FRIEDLÄNDER’S ACONITINE NITRATE.
Animals Experimented upon. Dose Given. Dose per Kilogrm. Result.
A Frog, 4 mgrms. 160 Recovered.
A F„ 10 „ 400 - Death in more than 60 minutes.
A F„ 20 „ 800
A F„ 40 „ 1600
A Rabbit, 6 „ 4 ·11 Recovered.
A Ra„ 24 „ 18 ·00 Reco„
A Ra„ 50 „ 85 ·50 Reco„
A Dog, 28 „ 6 ·00 Reco„
A Pigeon, 10 „ 33 ·4 Reco„
The conclusions Plugge draws from his researches are that Petit’s aconitine was at least eight times stronger than that of Merck, and seventy times more toxic than that of Friedländer, while Merck’s “aconitine again was twenty to thirty times stronger than Friedländer’s.” He was inclined to put seven commercial samples which he has examined in the following diminishing order of toxicity:—(1) Petit’s crystalline aconitine nitrate; (2) Morson’s aconitine nitrate; (3) Hottot’s aconitine nitrate; (4) Hopkins & Williams’ pseudaconitine; (5) Merck’s aconitine nitrate; (6) Schuchart’s aconitine sulphate; and (7) Friedländer’s aconitine nitrate.
From a study of Dr. Harley’s experiments,[472] however, made a few years ago, there would appear to have been but little difference between the activity of Petit’s and Morson’s aconitine. Dr. Harley experimented on a young cat, 3 lbs. in weight, and nearly killed it with a 1⁄1000 of a grain of Morson’s aconitine; two other cats, also weighing 3 lbs. each, died in seven and a half hours and three-quarters of an hour respectively, killed from a subcutaneous dose of of a grain. Reducing these values to the ordinary equivalents, the dose, after which the cat recovered with difficulty, is equal to about ·048 mgrm. per kilo., while a certainly fatal dose is ·092 mgrm. per kilo.; therefore, it seems likely that the least fatal dose for Morson’s, as for Petit’s, is some number between ·075 and ·09 mgrm. per kilo.
Man is evidently more sensitive to aconitine than any of the dogs or cats experimented upon, since, in the German cases to be recorded, 1·6 mgrm. of Petit’s aconitine nitrate, taken by the mouth, gave rise to symptoms so violent that it was evidently a dangerous dose, while 4 mgrms. were rapidly fatal; but if man took the same amount per kilo. as dogs or cats, he would require a little over 6 mgrms. to be certainly fatal. It seems, then, from the evidence obtainable, that ·03 grain (2 mgrms.) is about the least fatal dose for an adult man of standard weight. This dose is equal to ·028 mgrm. per kilo., and, of course, refers either to Morson’s aconitine or French aconitine, the alkaloid being taken by the mouth. If given by subcutaneous injection, probably 1·5 mgrm. would kill, for the whole of the poison is then thrown on the circulation at one time, and there is no chance of its elimination by vomiting.
The lethal dose of the pure alkaloid being even approximately settled, it is possible to get a more exact idea as to the suitable medicinal dose of the tincture and extract, and also to study more profitably the “quantitative toxicity.” The English officinal tincture, although variable in strength, may for our purposes be regarded as averaging 1 per cent. of alkaloid—that is, in every 100 parts by volume there will be 1 part of the alkaloid by weight, and Fleming’s tincture may be considered as one-third stronger, containing in every 100 parts 1·3 part of alkaloid. The medicinal dose of the P.B. tincture is laid down as from 5 to 15 min.—equal to from ·005 to ·015 grain of aconitine. The German pharmacopœia gives the maximum single dose as 1 c.c. (say 15 mins.), and the maximum quantity to be taken in the twenty-four hours as four times that quantity. As before stated, 2 mgrms. (·030 grain) of aconitine being considered a fatal dose, this is equivalent to about 2 c.c. (30 mins.) of the P.B. tincture, or to 1·2 c.c. (20 mins.) of Fleming’s tincture in a single dose; and on these theoretical grounds I should consider this dose dangerous, and in the absence of prompt treatment likely to be fatal to an adult man. The usual least fatal dose laid down in medical toxicological works, however, is greater than this—viz., 3·75 c.c. (a drachm).
In 1863 a woman took 70 minims of Fleming’s tincture, and a grain of acetate of morphine, and died in about four hours; but as this was a complex case of poisoning, it is not of much value. Fifteen minims of the tincture caused very serious symptoms in the case of a woman under the care of Dr. Topham,[473] the effects lasting many hours. Probably the smallest quantity of the tincture recorded as having destroyed life is in the case of Dr. Male, of Birmingham.[474] He died from the effects of 80 drops taken in ten doses, extending over a period of four days—the largest dose at any one time being 10 drops, the total quantity would perhaps equal ·08 grain of aconitine.
The P.B. extract is not a very satisfactory preparation, varying much in strength. It may be taken to average about ·6 per cent., and if so, applying the same reasoning as before, from ·26 to ·32 grm. (4 to 5 grains) would be a fatal dose.[475] On the other hand, there is an alcoholic extract which is very powerful, and averages 5 per cent. of aconitine: 40 mgrms. (·6 grain) of this extract would be likely to be fatal. With regard to the root itself, 3·8 grms. (60 grains) have been known to produce death, and from the average alkaloidal contents it is probable that ·648 grm. (10 grains) would be a highly dangerous dose. Dunstan’s researches will now alter probably the whole of the pharmacy of aconite, and the tendency will be to make the preparations of greater activity, and, consequently, to make the dangerous doses smaller than formerly.
§ 431. Effects of Aconitine on Animal Life.—There are few substances which have been experimented upon in such a variety of ways and upon so many classes of animals as aconitine in different forms; but there does not seem to be any essential difference in the symptoms produced in different animals save that which is explained by the organisation of the life-form under experiment.
Insects.—The author has made experiments with the active principles of aconite upon blow-flies. An extract was made by allowing the ordinary tincture to evaporate spontaneously at the temperature of the atmosphere. If a minute dot of this is placed upon the head of a blow-fly, absorption of the active principle takes place in from fifteen to thirty minutes, and marked symptoms result. The symptoms consist essentially of muscular weakness, inability to fly, and to walk up perpendicular surfaces; there is also, in all cases, a curious entanglement of the legs, and very often extrusion of the proboscis; trembling of the legs and muscular twitchings are frequent. A progressive paralysis terminates in from four to five hours in death; the death is generally so gradual that it is difficult to know when the event occurs, but in one case there were violent movements of the body, and sudden death.[476]
Fish.—The action on fish has been studied by Schulz and Praag. There is rapid loss of power and diminished breathing; the respiration seems difficult, and the fish rapidly die.
Reptiles—Frogs.—The most recent experiments on frogs are those of Plugge, and although his interpretation of the phenomena in some points is different from that of previous observers, the symptoms themselves are, as might have been expected, not different from those described by Achscharumow, L. v. Praag, and others. Plugge found no qualitative difference in the action of any of the commercial samples of aconitine. This fact gives the necessary value to all the old experiments, for we now know that, although they were performed with impure or weak preparations, yet there is no reason to believe that the symptoms described were due to any other but the alkaloid aconitine in varying degrees of purity or dilution. Frogs show very quickly signs of weakness in the muscular power; the respiration invariably becomes laboured, and ceases after a few minutes; the heart’s action becomes slowed, irregular, and then stops in diastole. The poisoned heart, while still pulsating, cannot be arrested either by electrical stimulation of the vagus or by irritation of the sinus, nor when once arrested can any further contraction be excited in it. Opening of the mouth and apparent efforts to vomit, Plugge observed both with Rana esculenta and Rana temporaria. He considers them almost invariable signs of aconitine poisoning. A separation of mucus from the surface of the body of the frog is also very constantly observed. Dilatation of the pupils is frequent, but not constant; there may be convulsions, both of a clonic and tonic character, before death, but fibrillar twitchings are seldom. (With regard to the dose required to affect frogs, see ante, pp. 355 and 356.)
Birds.—There is a discrepancy in the descriptions of the action of aconitine on birds. L. v. Praag thought the respiration and circulation but little affected at first; while Achscharumow witnessed in pigeons dyspnœa, dilatation of the pupils, vomiting, shivering, and paresis. It may be taken that the usual symptoms observed are some difficulty in breathing, a diminution of temperature, a loss of muscular power generally (but not constantly), dilatation of the pupils, and convulsions before death.
Mammals.—The effects vary somewhat, according to the dose. Very large doses kill rabbits rapidly. They fall on their sides, are violently convulsed, and die in an asphyxiated condition; but with smaller doses the phenomena first observed are generally to be referred to the respiration. Thus, in an experiment on the horse, Dr. Harley found that the subcutaneous administration of ·6 mgrm. (·01 grain) caused in a weakly colt some acceleration of the pulse and a partial paralysis of the dilator narium. Double the quantity given to the same animal some time after, caused, in six hours and a half, some muscular weakness, and an evident respiratory trouble. The horse recovered in eighteen hours. 2·7 mgrms. (1⁄24 grain) given in the same way, after a long interval of time, caused, at the end of an hour, more pronounced symptoms; the pulse, at the commencement 50, rose in an hour and a half to 68, then the respiration became audible and difficult. In an hour and three-quarters there were great restlessness and diminution of muscular power. Two hours after the injection the muscular weakness increased so much that the horse fell down; he was also convulsed. After eight hours he began to improve. In another experiment, 32·4 mgrms. (1⁄2 grain) killed a sturdy entire horse in two hours and twenty minutes, the symptoms commencing within the hour, and consisting of difficulty of breathing, irregularity of the heart’s action, and convulsions.
The general picture of the effects of fatal, but not excessive, doses given to dogs, cats, rabbits, &c., resembles closely that already described. The heart’s action is at first slowed, then becomes quick and irregular, there is dyspnœa, progressive paralysis of the muscular power, convulsions, and death in asphyxia. Vomiting is frequently observed, sometimes salivation, and very often dilatation of the pupil. Sometimes the latter is abnormally active, dilating and contracting alternately. Diarrhœa also occurs in a few cases. Vomiting is more frequent when the poison is taken by the mouth than when administered subcutaneously.[477]
§ 432. Statistics.—During the ten years, 1883-92, there were recorded in England and Wales, 40 accidental deaths from the various forms of aconite (19 males, 21 females); and 19 suicidal deaths (9 males, 10 females) from the same cause, which makes a total of 59.
§ 433. Effects on Man.—I have collected from European medical literature, 87 cases of poisoning by aconite in some form or other. These comprise only 2 cases of murder, 7 of suicide, and 77 which were more or less accidental. Six of the cases were from the use of the alkaloid itself; 10 were from the root; in two cases children eat the flowers; in 1, the leaves of the plant were cooked and eaten by mistake; in 7, the tincture was mistaken for brandy, sherry, or liqueur; the remainder were caused by the tincture, the liniment, or the extract.
§ 434. Poisoning by the Root.—A case of murder which occurred some years ago in America, and also the Irish case which took place in 1841 (Reg. v. M’Conkey), were, until the recent trial of Lamson, the only instances among English-speaking people of the use of aconite for criminal purposes; but if we turn to the Indian records, we find that it has been largely used from the earliest times as a destroyer of human life. In 1842 a tank of water destined for the use of the British army in pursuit of the retreating Burmese, was poisoned by intentional contamination with the bruised root of Aconitum ferox; it was fortunately discovered before any harm resulted. A preparation of the root is used in all the hill districts of India to poison arrows for the destruction of wild beasts. A Lepcha described the root to a British officer as being “useful to sportsmen for destroying elephants and tigers, useful to the rich for putting troublesome relations out of the way, and useful to jealous husbands for the purpose of destroying faithless wives.” From the recorded cases, the powdered root, mixed with food, or the same substance steeped in spirituous liquor, is usually the part chosen for administration. In M’Conkey’s case, the man’s wife purchased powdered aconite root, mixed it with pepper, and strewed it over some greens, which she cooked and gave to him. The man complained of the sharp taste of the greens, and soon after the meal vomited, and suffered from purging, became delirious with lock-jaw, and clenching of the hands; he died in about three hours. The chief noticeable post-mortem appearance was a bright red colour of the mucous membrane of the stomach.
The symptoms in this case were, in some respects, different from those met with in other cases of poisoning by the root. A typical case is given by Dr. Chevers (op. cit.), in which a man had taken by mistake a small portion of aconite root. Immediately after chewing it he felt a sweetish taste, followed immediately by tingling of the lips and tongue, numbness of the face, and severe vomiting. On admission to hospital he was extremely restless, tossing his limbs about in all directions and constantly changing his position. He complained of a burning sensation in the stomach, and a tingling and numbness in every part of the body, excepting his legs. The tingling was specially marked in the face and tongue—so much so that he was constantly moving the latter to and fro in order to scratch it against the teeth. Retching and vomiting occurred almost incessantly, and he constantly placed his hand over the cardiac region. His face was anxious, the eyes suffused, the lips pale and exsanguine, the eyelids swollen, moderately dilated, and insensible to the stimulus of light; the respiration was laboured, 64 in a minute; the pulse 66, small and feeble. There was inability to walk from loss of muscular power, but the man was perfectly conscious. The stomach-pump was used, and albumen and milk administered. Three and three-quarter hours after taking the root the symptoms were increased in severity. The tongue was red and swollen, the pulse intermittent, feeble, and slower. The tingling and numbness had extended to the legs. On examining the condition of the external sensibility with a pair of scissors, it was found that, on fully separating the blades and bringing the points in contact with the skin over the arms and forearms, he felt them as one, although they were 4 inches apart. But the sensibility of the thighs and legs was less obtuse, for he could feel the two points distinctly when they were 4 inches apart, and continued to do so until the distance between the points fell short of 23⁄4 inches. He began to improve about the ninth hour, and gradually recovered, although he suffered for one or two days from a slight diarrhœa. As in the case detailed (p. 363), no water was passed for a long time, as if the bladder early lost its power.
§ 435. Poisoning by the Alkaloid Aconitine.—Probably the earliest instance on record is the case related by Dr. Golding Bird in 1848.[478] What kind of aconitine was then in commerce I know not, and since apparently a person of considerable social rank was the subject of the poisoning, the case has been imperfectly reported. It seems, however, that, whether for purposes of suicide, or experiment, or as a medicine, two grains and a half of aconitine were swallowed. The symptoms were very violent, consisting of vomiting, collapse, and attacks of muscular spasm; the narrator describes the vomiting as peculiar. “It, perhaps, hardly deserved that title; the patient was seized with a kind of general spasm, during which he convulsively turned upon his abdomen, and with an intense contraction of the abdominal muscles, he jerked out, as it were, with a loud shout the contents of his stomach, dependent apparently on the sudden contraction of the diaphragm.” On attempting to make him swallow any fluid, a fearful spasm of the throat was produced; it reminded his medical attendants of hydrophobia. The patient recovered completely within twenty-four hours.
One of three cases reported by Dr. Albert Busscher,[479] of poisoning by aconitine nitrate, possesses all the exact details of an intentional experiment, and is of permanent value to toxicological literature.
A labourer of Beerta, sixty-one years of age, thin, and of somewhat weak constitution, suffered from neuralgia and a slight intermittent fever; Dr. Carl Meyer prescribed for his ailment:—
℞. Aconiti Nitrici, 2 grm.
Tr. Chenopodii Ambrosioid., 100 grms. M.D.S.
Twenty drops to be taken four times daily. The patient was instructed verbally by Dr. Meyer to increase the dose until he attained a maximum of sixty drops per day.
The doses which the man actually took, and the time of taking them, are conveniently thrown into a tabular form as follows:—
No. 1. March 14, 7 p.m., 5 drops equal to aconitine nitrate, ·4 mgrm.
„ 2. „ 9 p.m., 20 „ „ „ 1 ·6 „
„ 3. March 15, 8 a.m., 20 „ „ „ 1 ·6 „
„ 4. „ 11 a.m., 20 „ „ „ 1 ·6 „
„ 5. „ 4 p.m., 20 „ „ „ 1 ·6 „
„ 6. „ 9 p.m., 20 „ „ „ 1 ·6 „
„ 7. March 16, 10 p.m., 10 „ „ „ ·8 „
In the whole seven doses, which were distributed over forty-eight hours, he took 9·2 mgrms. (·14 grain) of aconitine nitrate.
On taking dose No. 1, he experienced a feeling of constriction (Zusammenziehung), and burning spreading from the mouth to the stomach, but this after a little while subsided. Two hours afterwards he took No. 2, four times the quantity of No. 1. This produced the same immediate symptoms, but soon he became cold, and felt very ill. He had an anxious oppressive feeling about the chest, with a burning feeling about the throat; the whole body was covered with a cold sweat, his sight failed, he became giddy, there was excessive muscular weakness, he felt as if he had lost power over his limbs, he had great difficulty in breathing. During the night he passed no water, nor felt a desire to do so. About half an hour after he had taken the medicine, he began to vomit violently, which relieved him much; he then fell asleep.
Dose No. 3, equal as before to 1·6 mgrm., he took in the morning. He experienced almost exactly the same symptoms as before, but convulsions were added, especially of the face; the eyes were also prominent; twenty minutes after he had taken the dose, vomiting came on, after which he again felt better.
He took dose No. 4, and had the same repetition of symptoms, but in the interval between the doses he felt weaker and weaker; he had no energy, and felt as if paralysed. No. 5 was taken, and produced, like the others, vomiting, after which he felt relieved. Neither he nor his wife seemed all this time to have had any suspicion that the medicine was really doing harm, but thought that the effects were due to its constant rejection by vomiting, so, in order to prevent vomiting with No. 6, he drank much cold water. After thus taking the medicine, the patient seemed to fall into a kind of slumber, with great restlessness; about an hour and a half afterwards he cried, “I am chilled; my heart, my heart is terribly cold. I am dying; I am poisoned.” His whole body was covered with perspiration; he was now convulsed, and lost sight and hearing; his eyes were shut, his lips cracked and dry, he could scarcely open his mouth, and he was extremely cold, and thought he was dying. The breathing was difficult and rattling; from time to time the muscular spasms came on. His wife now made a large quantity of hot strong black tea, which she got him to drink with great difficulty; although it was hot, he did not know whether it was hot or cold. About five minutes afterwards he vomited, and did so several times; this apparently relieved him, and he sank into a quiet sleep; during the night he did not urinate. In the morning the wife went to Dr. Carl Meyer, described the symptoms, and accused the medicine. So convinced was Dr. Meyer that the medicine did not cause the symptoms, that he poured out a quantity of the same, equal to 4 mgrms. of aconitine nitrate, and took it himself in some wine, to show that it was harmless, and ordered them to go on with it. The unhappy physician died of aconitine poisoning five hours after taking the medicine.[480] In the meantime, the woman went home, and her husband actually took a seventh, but smaller dose, which produced similar symptoms to the former, but of little severity; no more was taken.
The absence of diarrhœa, and of the pricking sensations so often described, is in this case noteworthy. Both diarrhœa and formication were also absent in a third case reported by Dr. Busscher in the same paper.
§ 436. The most important criminal case is undoubtedly that of Lamson:—At the Central Criminal Court, in March, 1882, George Henry Lamson, surgeon, was convicted of the murder of his brother-in-law, Percy Malcolm John. The victim was a weakly youth of eighteen years of age, paralysed in his lower limbs from old standing spinal disease. The motive for perpetrating the crime was that Lamson, through his wife (Malcolm John’s sister), would receive, on the death of his brother-in-law, a sum of £1500, and, according to the evidence, it is probable that there had been one or more previous attempts by Lamson on the life of the youth with aconitine given in pills and in powders. However this may be, on November 24, 1880, Lamson purchased 2 grains of aconitine, came down on Dec. 3 to the school where the lad was placed, had an interview with his brother-in-law, and, in the presence of the head-master, gave Malcolm John a capsule, which he filled then and there with some white powder, presumed at the time to be sugar. Lamson only stayed altogether twenty minutes in the house, and directly after he saw his brother-in-law swallow the capsule, he left. Within fifteen minutes Malcolm John became unwell, saying that he felt as if he had an attack of heart-burn, and then that he felt the same as when his brother-in-law had on a former occasion given him a quinine pill. Violent vomiting soon set in, and he complained of pains in his stomach, a sense of constriction in his throat, and of being unable to swallow. He was very restless—so much so that he had to be restrained by force from injuring himself. There was delirium a few minutes before death, which took place about three hours and three-quarters after swallowing the fatal dose. The post-mortem appearances essentially consisted of redness of the greater curvature of the stomach, and the posterior portion of the same organ. In one part there was a little pit, as if a blister had broken; the rest of the viscera were congested, and the brain also slightly congested.[481]
§ 437. The symptoms of poisoning by the tincture, extract, or other preparation, do not differ from those detailed. As unusual effects, occasionally seen, may be noted profound unconsciousness lasting for two hours (Topham’s case), violent twitching of the muscles of the face, opisthotonos, and violent convulsions. It is important to distinguish the symptoms which are not constant from those which are constant, or nearly so. The tingling and creeping sensations about the tongue, throat, lips, &c., are not constant; they certainly were not present in the remarkable German case cited at p. 363. Speaking generally, they seem more likely to occur after taking the root or the ordinary medicinal preparations. A dilated state of the pupil is by no means constant, and not to be relied upon. Diarrhœa is seen after taking the root or tincture by the stomach, but is often absent. In short, the only constant symptoms are difficulty of breathing, progressive muscular weakness, generally vomiting, and a weak intermittent pulse.
§ 438. Physiological Action.—Aconitine, according to Dr. S. Ringer, is a protoplasmic poison, destroying the functions of all nitrogenous tissue—first of the central nervous system, next of the nerves, and last of the muscles. Aconitine without doubt acts powerfully on the heart, ultimately paralysing it; there is first a slowing of the pulse, ascribed to a central excitation of the vagus; then a quickening, due to paralysis of the peripheral termination of the vagus in the heart; lastly, the heart’s action becomes slow, irregular, and weak, and the blood-pressure sinks. The dyspnœa and convulsions are the usual result, seen among all warm-blooded animals, of the heart affection. Plugge found that the motor nerves, and more especially their intra-muscular terminations, were always paralysed; but if the dose was small the paralysis might be incomplete. Bœhm and Wartmann, on the other hand, considered that the motor paralysis had a central origin, a view not supported by recent research. The action of aconitine in this way resembles curare. The muscles themselves preserve their irritability, even after doses of aconitine which are five to ten times larger than those by which the nerve terminations are paralysed.
§ 439. Post-mortem Appearances.—Among animals (mammals) the appearances most constantly observed have been hyperæmia of the cerebral membranes and brain, a fulness of the large veins, the blood generally fluid—sometimes hyperæmia of the liver, sometimes not. When aconitine has been administered subcutaneously, there have been no inflammatory appearances in the stomach and bowels.
In the case of Dr. Carl Meyer, who died in five hours from swallowing 4 mgrms. of aconitine nitrate, the corpse was of a marble paleness, the pupils moderately dilated. The colour of the large intestine was pale; the duodenum was much congested, the congestion being most intense the nearer to the stomach; the mucous membrane of the stomach itself was strongly hyperæmic, being of an intense red colour; the spleen was enlarged, filled with much dark blood. The liver and kidneys were deeply congested, the lungs also congested; the right ventricle of the heart was distended with blood; in the pericardium there was a quantity of bloody serum. The brain was generally blood-red; in the cerebral hemispheres there were several large circumscribed subarachnoid extravasations. The substance of the brain on section showed many red bloody points.
In a case recorded by Taylor, in which a man died in three hours from eating a small quantity of aconitine root, the only morbid appearance found was a slight reddish-brown patch on the cardiac end of the stomach, of the size of half a crown; all the other organs being healthy.
§ 440. Separation of Aconitine from the Contents of the Stomach or the Organs.—It would appear certain that in all operations for the separation of aconite alkaloids (whether from the organic matters which make up the plant, or from those constituting animal tissues), mineral acids and a high heat should be avoided. A 1 per cent. sulphuric acid does not, however, hydrolyse, if acting in the cold, so that the process already given, p. 352, may be followed.
The chemical examination in the Lamson case was entrusted to Dr. Stevenson, assisted by Dr. Dupré, and was conducted on the principles detailed. The contents of the stomach were treated with alcohol, and digested at the ordinary temperature of the atmosphere; the contents were already acid, so no acid in this first operation was added. The mixture stood for two days and was then filtered. The insoluble portion was now exhausted by alcohol, faintly acidulated by tartaric acid, and warmed to 60°; cooled and filtered, the insoluble part being washed again with alcohol. The two portions—that is, the spirituous extract acid from acids pre-existing in the contents of the stomach, and the alcohol acidified by tartaric acid—were evaporated down separately, exhausted by absolute alcohol, the solutions filtered, evaporated, and the residue dissolved in water. The two aqueous solutions were now mixed, and shaken up with ether, which, as the solution was acid, would not remove any alkaloid, but might remove various impurities; the residue, after being thus partially purified by ether, was alkalised by sodic carbonate, and the alkaloid extracted by a mixture of chloroform and ether. On evaporation of the chloroform and ether, the resulting extract was tested physiologically by tasting, and also by injections into mice. By means analogous to those detailed, the experts isolated aconitine from the vomit, the stomach, liver, spleen, and urine, and also a minute quantity of morphine, which had been administered to the patient to subdue the pain during his fatal attack. When tasted, the peculiar numbing, tingling sensation lasted many hours. These extracts were relied upon as evidence, for their physiological effect was identical with that produced by aconitine. For example, the extract obtained from the urine caused symptoms to commence in a mouse in two minutes, and death in thirty minutes, and the symptoms observed by injecting a mouse with known aconitine coincided in every particular with the symptoms produced by the extraction from the urine.
With regard to the manner of using “life tests,” since in most cases extremely small quantities of the active principle will have to be identified, the choice is limited to small animals, and it is better to use mice or birds, rather than reptiles. In the Lamson case, subcutaneous injections were employed, but it is a question whether there is not less error in administering it by the mouth. If two healthy mice are taken, and the one fed with a little meal, to which a weighed quantity of the extract under experiment has been added, while to the other some meal mixed with a supposed equal dose of aconitine is given, then the symptoms may be compared; and several objections to any operative proceeding on such small animals are obviated. It is certain that any extract which causes distinct numbness of the lips will contain enough of the poison to kill a small bird or a mouse, if administered in the ordinary way.[482]
VI.—The Mydriatic Group of Alkaloids—Atropine—Hyoscyamine—Solanine—Cytisine.
1. ATROPINE.
§ 441. Atropine (Daturine), C17H23NO3.—This important alkaloid has been found in all parts of the Atropa belladonna, or deadly nightshade, and in all the species of Datura.
The Atropa belladonna is indigenous, and may be found in some parts of England, although it cannot be said to be very common. It belongs to the Solanaceæ, and is a herbaceous plant with broadly ovate entire leaves, and lurid-purple axillary flowers on short stalks; the berries are violet-black, and the whole of the plant is highly poisonous. The juice of the leaves stains paper a purple colour. The seeds are very small, kidney-shaped, weighing about 90 to the grain; they are covered closely with small, round projections, and are easily identified by an expert, who may be supposed to have at hand (as is most essential) samples of different poisonous seeds for comparison. The nightshade owes its poisonous properties to atropine.
The yield of the different parts of belladonna, according to Gunther,[483] is as follows:—
TABLE SHOWING THE ALKALOIDAL CONTENT OF VARIOUS PARTS OF THE BELLADONNA PLANT.
Quantity of Alkaloids in the Fresh Substance, per cent. Quantity of Alkaloids in the Dry Substance, per cent.
(a.) By Weighing. (b.) By Titration. (a.) By Weighing. (b.) By Titration.
Leaves, 0 ·2022 0 ·20072 0 ·838 0 ·828
Stalk, 0 ·0422 ... 0 ·146 ...
Ripe fruit, 0 ·2128 0 ·20258 0 ·821 0 ·805
Seed, 0 ·26676 ... 0 ·407 ...
Unripe fruit, 0 ·1870 0 ·1930 0 ·955 0 ·955
Root, 0 ·0792 ... 0 ·210 ...
Atropine appears to exist in the plant in combination with malic acid. According to a research by Ladenburg, hyoscyamine is associated with atropine, both in the Belladonna and Datura plants.[484]
From a research by W. Schütte,[485] it appears that the younger roots of wild belladonna contain hyoscyamine only, whilst the older roots contain atropine as well as hyoscyamine, but only in small proportion; the same was observed to be the case in the older cultivated roots.
The ripe berries of cultivated Atropa belladonna nigra contain atropine and hyoscyamine; those of the wild plant contain atropine only; the ripe fruit of Atropa belladonna lutea contains only atropine and another base, perhaps identical with atropamine; the unripe fruit of wild Atropa belladonna nigra contains hyoscyamine, with only a small quantity of atropine.
The leaves of the yellow and black-fruited wild Atropa belladonna contain hyoscyamine and atropine, the latter being in small quantity only.
Fresh and old seeds of Datura Stramonium contain chiefly hyoscyamine; small quantities of atropine and scopolamine are also present.
§ 442. The Datura Stramonium or Thorn-apple is also indigenous in the British Islands, but, like belladonna, it cannot be considered a common plant. Datura belongs to the Solanaceæ; it grows from 1 to 2 feet in height, and is found in waste places. The leaves are smooth, the flowers white; the fruit is densely spinous (hence the name thorn-apple), and is divided into four dissepiments below, two at the top, and containing many seeds.
The Datura, or the Dhatura-plants, of India have in that country a great toxicological significance, the white-flowered datura, or Datura alba, growing plentifully in waste places, especially about Madras. The purple-coloured variety, or Datura fastuosa, is also common in certain parts. There is a third variety, the Datura atrox, found about the coast of Malabar. The seeds of the white datura have been mistaken in India for those of capsicum. The following are some of the most marked differences:—
Seeds of the Common or White Datura. Seeds of Capsicum.
(1.) Outline angular. Outline rounded.
(2.) Attached to the placenta by a large, white, fleshy mass separating easily, leaving a deep furrow along half the length of the seed’s concave border. Attached to the placenta by a cord from a prominence on the concave border of the seed.
(3.) Surface scabrous, almost reticulate, except on the two compressed sides, where it has become almost glaucous from pressure of the neighbouring seeds. Uniformly scabrous, the sides being equally rough with the borders.
(4.) Convex border thick and bulged with a longitudinal depression between the bulgings, caused by the compression of the two sides. Convex border thickened, but uniformly rounded.
(5.) A suitable section shows the embryo curved and twisted in the fleshy albumen. The embryo, exposed by a suitable section, is seen to resemble in outline very closely the figure 6.
(6.) The taste of the datura seeds is very feebly bitter. The watery decoction causes dilatation of the pupil. The taste of capsicum is pungent; a decoction irritates the eye much, but does not cause dilatation of the pupil.
The identity of the active principle in both the datura and belladonna tribes is now completely established.[486]
§ 443. Pharmaceutical Preparations.—(a.) Of the leaves. Extract of Belladonna.—This contains, according to Squire,[487a] from 0·73 to 1·7 per cent. of total alkaloids. Belladonna Juice (succus belladonnæ).—Strength in alkaloid about 0·05 per cent. Tincture of Belladonna.—Half the strength of the juice, and therefore yielding about 0·025 per cent. of alkaloid.
(b.) Belladonna Root.—Belladonna plaster contains 20 per cent. of alcoholic extract of belladonna. Alcoholic Extract of Belladonna.—This extract, according to Squire,[487b] contains from 1·6 to 4·45 per cent. of alkaloid. Belladonna liniment is an alcoholic extract with the addition of camphor; its strength is about equal to 0·2 per cent. of alkaloid. Belladonna ointment contains about 10 per cent. of the alcoholic extract.
(c.) The Alkaloid.—Atropine Discs (lamellæ atropinæ).—These are discs of gelatin, each weighing about 1⁄50 grain, and containing for ophthalmic use 1⁄5000 grain of atropine sulphate. Similar discs are made for hypodermic use, but stronger; each containing 1⁄120 grain. Solution of Atropine Sulphate.—Strength about 1 per cent. Atropine Ointment.—Strength about 1 in 60, or 1·60 per cent. of atropine.
(d.) Stramonium.—An extract of the seeds is officinal in Britain; the alkaloidal content is from 1·6 to 1·8 per cent. There is also a tincture which contains about 0·06 per cent. of alkaloid.
§ 444. Properties of Atropine, C17H23NO3.—Atropine, hyoscyamine, and hyoscine have all the same formula, but differ in their molecular constitution. Atropine by hydrolysis, either by heating it with hydrochloric acid or baryta water, is decomposed into tropine and tropic acid:—
C17H23NO3 + H2O = C8H15NO + C9H10O3.
Atropine. Tropine. Tropic acid.
On the other hand, by heating tropic acid and tropine together, atropine is regenerated. Hence it is proved by analysis and synthesis, that atropine is tropic acid-tropine, just as aconitine is benzoyl-aconine. Tropic acid has been produced synthetically by boiling β-chlorphenyl-propionic acid with potash, which at once shows its constitutional formula, viz.:—
Tropic acid has a melting-point of 117° to 118°. Tropine is a four-fold hydrated oxethyl-methyl-pyridine, and has the constitutional formula of C5H3(H4)(C2H4OH)N(CH3); hence the constitutional formula of atropine is—
Tropine is a white, crystalline, strongly alkaline mass, melting at 60°, and volatilising at 230° undecomposed. It is soluble in water, alcohol, and ether, and gives precipitates with tannic acid, iodised hydriodic acid, Mayer’s reagent, gold chloride, and mercuric chloride. Tropine gold chloride melts at 210° to 212°. Atropic acid (C9H8O2), melting-point 198° to 200°, and isatropic acid (C9H8O2), may also be obtained by the action of hydrochloric acid—the first, in radiating crystals, melting at 106°, and capable of distillation; the second, in thin rhombic plates, melting about 200°, and not volatile. Picric acid also gives a precipitate of beautiful plates. To obtain this the carbazotic acid must be in excess, and time must be given for the precipitate to form.
Atropine forms colourless crystals (mostly in groups or tufts of needles and prisms), which are heavier than water, and possess no smell, but an unpleasant, long-enduring, bitter taste. The experiments of E. Schmidt place the melting-point between 115° and 115·5°. It is said to sublime scantily in a crystalline form, but the writer has been unable to obtain any crystals by sublimation; faint mists collect on the upper disc, at about 123°, but they are perfectly amorphous.
Its reaction is alkaline; one part requires, of cold water, 300; of boiling, 58; of ether, 30; of benzene, 40; and of chloroform, 3 parts for solution. In alcohol and amyl alcohol it dissolves in almost every proportion. It turns the plane of polarisation weakly to the left.
§ 445. Tests.—Atropine mixed with nitric acid exhibits no change of colour. The same is the case with concentrated sulphuric acid in the cold; but on heating, there ensues the common browning, with development of a peculiar odour, likened by Gulielmo to orange flowers, by Dragendorff to the flowers of the Prunus padus, and by Otto to the Spiræa ulmaria—a sufficient evidence of the untrustworthiness of this as a distinctive test. The odour, indeed, with small quantities, is certainly not powerful, nor is it strongly suggestive of any of the plants mentioned. A far more intense odour is given off if a speck of atropine is evaporated to dryness with a few drops of strong solution of baryta, and heated strongly; the scent is decidedly analogous to that of hawthorn-blossom, and unmistakably agreeable.
By boiling a small quantity of atropine, say 1 mgrm., with 2 mgrms. of calomel and a very little water, the calomel blackens, and crystals may be obtained of a double salt; this reaction is, however, given also by hyoscyamine and homatropine. Mercuric potassium iodide solution, and mercuric bromide solution give amorphous precipitates, which, after a time, become crystalline, and have characteristic forms.
A solution of iodine in potassium iodide gives a precipitate with acidulated solutions of atropine in even a dilution of 1 : 10,000. Tannin precipitates, and the precipitate is soluble in excess of the reagent. If atropine be dissolved in dilute hydrochloric acid, and a 5 per cent. of gold chloride solution be added, a precipitate of a gold compound (C17H23NO3HClAuCl3) separates. The precipitate is in the form of rosettes or needles; melting-point 137°. On boiling it with water, however, it melts into oily drops, and this peculiar behaviour distinguishes it from the analogous salt of hyoscyamine, which does not melt in boiling water. The percentage of gold left on a combustion of atropine gold chloride is 31·35 per cent. 100 parts of the gold salt are equal to 46·2 of atropine. A platinum salt may also be obtained, (C17H23NO3HCl)2,PtCl4, containing 29·5 per cent. of platinum.
Vitali’s test is important; it consists in the production of a violet colour with alcoholic potash after oxidation.
The test may be applied as follows:—Equal parts, say 1 mgrm., of nitrate of sodium and of the substance to be tested, are rubbed together with a glass rod on a porcelain slab, and to this mixture 1 drop of sulphuric acid is added; the mixture is spread out in a thin film; upon this is strewn a little powdered potassium hydrate, and finally 1 drop of alcohol added; a violet colour is produced which passes into a fine red; according to the author of the test, 0·001 mgrm. of atropine sulphate can by this test be detected. Strychnine obscures this reaction.
Atropine, homatropine, and hyoscyamine show an alkaline reaction with phenolphthalein: atropine and homatropine give a precipitate with HgCl2. Hyoscyamine, not cocaine, precipitates HgCl2, and is alkaline to litmus, but not to phenolphthalein. Atropine behaves as follows:—(1) Sodium nitrate, sulphuric acid, and afterwards sodium hydroxide, gives a violet colour; (2) the test as before, but with nitrite instead of nitrate, gives orange colour, which, on dilution with sodium hydroxide solution, changes to red, violet, or lilac; (3) when heated with glacial acetic acid and sulphuric acid for a sufficient time, a greenish-yellow fluorescence is produced.—Flückiger, Pharm. Journ. Trans. (3), vol. xvi. p. 601-602.
The two alkaloids, strychnine and atropine, are not likely to be often together in the human body, but that it may sometimes occur is shown by a case recorded by L. Fabris.[488] A patient in the hospital at Padua had for some time been treated with daily injections of 3 mgrms. of strychnine nitrate; unfortunately, one day, instead of the 3 mgrms. of strychnine, the same quantity of atropine sulphate was injected, and the patient died after a few hours, with symptoms of atropine poisoning.
On chemical treatment of the viscera, a mixture of alkaloids was obtained which did not give either the reactions of strychnine or of atropine. To test the possibility of these alkaloids obscuring each other’s reactions, mixtures of 3 per cent. solutions (the strength of the injections) of atropine sulphate and strychnine nitrate were mixed together, and strychnine tested for by the dichromate and sulphuric acid test.
A mixture of equal parts gave the strychnine reaction very clearly, but the atropine reaction not at all; 1 strychnine with 3 of atropine gave strychnine reaction, but not that of atropine; 1 strychnine with 4 atropine gave indistinct reaction for both alkaloids; 1 of strychnine with 5 of atropine gave a momentary atropine reaction, the violet was, however, almost immediately replaced by a red colour. Vitali’s reaction was not clearly shown until the mixture was in the proportion of 9 of atropine to 1 of strychnine, but mixtures in the proportion of 3 strychnine and 1 atropine will give distinct mydriasis.
In such a case, of course, the strychnine should be separated from the atropine; this can be effected by precipitating the strychnine as chromate, filtering and recovering from the filter the atropine by alkalising and shaking it out with ether.
The atropine may be farther purified by converting it into oxalate, dissolving the oxalate in as small a quantity of alcohol as possible, and precipitating the oxalate out with ether; the precipitate is collected, dissolved in as small a quantity of water as possible, the water made alkaline, and the base shaken out with ether.
The most reliable test for atropine, or one of the mydriatic alkaloids, is its action on the iris; a solution of atropine, even so weak as 1 : 130,000, causing dilatation.[489] This action on the iris has been studied by Ruyter,[490] Donders, and von Graefe.
The action is local, taking effect when in dilute solution only on the eye to which it has been applied; and it has been produced on the eyes of frogs, not only in the living subject, but after the head has been severed from the body and deprived of brain. The thinner the cornea, the quicker the dilatation; therefore, the younger the person or animal, the more suitable for experiment. In frogs, with a solution of 1 : 250, dilatation commences in about five minutes; in pigeons, seven minutes; and in rabbits, ten minutes. In man, a solution of 1 : 120 commences to act in about six to seven minutes, reaches its highest point in from ten to fifteen minutes, and persists more or less for six to eight days. A solution of 1 : 480 acts first in fifteen to twenty minutes, and reaches its greatest point in twenty minutes; a solution of 1 : 48,000 requires from three-quarters of an hour to an hour to show its effect. Dogs and cats are far more sensible to its influence than man, and therefore more suitable for experiment. If the expert chooses, he may essay the proof upon himself, controlling the dilatation by Calabar bean; but it is seldom necessary or advisable to make personal trials of this nature.[491]
§ 446. Statistics of Atropine Poisoning.—Since atropine is the active principle of belladonna and datura plants, and every portion of these—root, seeds, leaves, and fruit—has caused toxic symptoms, poisoning by any part of these plants, or by their pharmaceutical or other preparations, may be considered with strict propriety as atropine poisoning. Our English death statistics for the ten years ending 1892, record 79 deaths (50 males and 29 females) from atropine (for the most part registered under the head of belladonna); 29 (or 36·7 per cent.) were suicidal, the rest accidental.
The greatest number of the accidental cases arise from mistakes in pharmacy; thus, belladonna leaves have been supplied for ash leaves; the extract of belladonna has been given instead of extract of juniper; the alkaloid itself has been dispensed in mistake for theine;[492] a more curious and marvellously stupid mistake is one in which it was dispensed instead of assafœtida (Schauenstein, op. cit., p. 652). Further, valerianate of atropine has been accidentally substituted for quinine valerianate, and Schauenstein relates a case in which atropine sulphate was administered subcutaneously instead of morphine sulphate; but the result was not lethal. Many other instances might be cited. The extended use of atropine as an external application to the eye naturally gives rise to a few direct and indirect accidents. Serious symptoms have arisen from the solution reaching the pharynx through the lachrymal duct and nose. A curious indirect poisoning, caused by the use of atropine as a collyrium, is related by Schauenstein.[493] A person suffered from all the symptoms of atropine poisoning; but the channel by which it had obtained access to the system was a great mystery, until it was traced to some coffee, and it was then found that the cook had strained this coffee through a certain piece of linen, which had been used months before, soaked in atropine solution, as a collyrium, and had been cast aside as of no value.
§ 447. Accidental and Criminal Poisoning by Atropine.—External applications of atropine are rapidly absorbed, e.g., if the foot of a rat be steeped for a little while in a solution of the alkaloid, and the eyes watched, dilatation of the pupils will soon be observed. If the skin is broken, enough may be absorbed to cause death. A case is on record in which ·21 grm. of atropine sulphate, applied as an ointment to the abraded skin, was fatal.[494] Atropine has also been absorbed from the bowel; in one case, a clyster containing the active principles of 5·2 grms. (80 grains) of belladonna root was administered to a woman twenty-seven years of age, and caused death. Allowing the root to have been carefully dried, and to contain ·21 per cent. of alkaloid, it would seem that so little as 10·9 mgrms. (·16 grain) may even prove fatal, if left in contact with the intestinal mucous membrane. Belladonna berries and stramonium leaves and seeds are eaten occasionally by children. A remarkable series of poisonings by belladonna berries occurred in London during the autumn of 1846.
Criminal poisoning by atropine in any form is of excessive rarity in Europe and America, but in India it has been frightfully prevalent. In all the Asiatic cases the substance used has been one of the various species of datura, and mostly the bruised or ground seeds, or a decoction of the seeds. In 120 cases recorded in papers and works on Indian toxicology, I find no less than 63 per cent. of the cases criminal, 19 per cent. suicidal, and 18 per cent. accidental. In noting these figures, however, it must be borne in mind that known criminal cases are more certain to be recorded than any other cases. The drug has been known under the Sanscrit name of dhatoora by the Hindoos from most remote times. It was largely used by the Thugs, either for the purpose of stupefying their victim or for killing him; by loose wives to ensure for a time the fatuity of their husbands; and, lastly, it seems in Indian history to have played the peculiar rôle of a state agent, and to have been used to induce the idiocy or insanity of persons of high rank, whose mental integrity was considered dangerous by the despot in power. The Hindoos, by centuries of practice, have attained such dexterity in the use of the “datura” as to raise that kind of poisoning to an art, so that Dr. Chevers, in his Medical Jurisprudence for India,[495] declares that “there appears to be no drug known in the present day which represents in its effects so close an approach to the system of slow poisoning, believed by many to have been practised in the Middle Ages, as does the datura.”
§ 448. Fatal Dose.—It is impossible to state with precision the exact quantity which may cause death, atropine being one of those substances whose effect, varying in different cases, seems to depend on special constitutional tendencies or idiosyncracies of the individual. Some persons take a comparatively large amount with impunity, while others scarcely bear a very moderate dose without exhibiting unpleasant symptoms. Eight mgrms. (1⁄8 grain) have been known to produce poisonous symptoms, and ·129 grm. (2 grains) death. We may, therefore, infer that about ·0648 grm. (1 grain) would, unchecked by remedies, probably act fatally; but very large doses have been recovered from, especially when treatment has been prompt.
Atropine is used in veterinary practice, from 32·4 to 64·8 mgrms. (1⁄2 to 1 grain) and more being administered subcutaneously to horses; but the extent to which this may be done with safety is not yet established.
§ 449. Action on Animals.—The action of atropine has been studied on certain beetles, on reptiles (such as the salamander, triton, frogs, and others), on guinea-pigs, hedgehogs, rats, rabbits, fowls, pigeons, dogs, and cats. Among the mammalia there is no essential difference in the symptoms, but great variation in the relative sensibility; man seems the most sensitive of all, next to man come the carnivora, while the herbivora, and especially the rodents, offer a considerable resistance. According to Falck the lethal dose for a rabbit is at least ·79 mgrm. per kilo. It is the general opinion that rabbits may eat sufficient of the belladonna plant to render their flesh poisonous, and yet the animals themselves may show no disturbance in health; but this must not be considered adequately established. Speaking very generally, the higher the animal organisation the greater the sensibility to atropine. Frogs are affected in a peculiar manner. According to the researches of Fraser,[496] the animal is first paralysed, and some hours after the administration of the poison lies motionless, the only signs of life being the existence of a slight movement of the heart and muscular irritability. After a period of from forty-eight to seventy-two hours, the fore limbs are seized with tetanic spasms, which develop into a strychnine-like tetanus.
§ 450. Action on Man.—When atropine is injected subcutaneously, the symptoms, as is usually the case with drugs administered in this manner, may come on immediately, the pupil not unfrequently dilating almost before the injection is finished. This is in no way surprising; but there are instances in which decoctions of datura seeds have been administered by the stomach, and the commencement of symptoms has been as rapid as in poisoning by oxalic or even prussic acid. In a case tried in India in July 1852, the prosecutor declared that, while a person was handing him a lota of water, the prisoner snatched it away on pretence of freeing the water from dirt or straws, and then gave it to him. He then drank only two mouthfuls, and, complaining of the bitter taste, fell down insensible within forty yards of the spot where he had drunk, and did not recover his senses until the third day after. In another case, a man was struck down so suddenly that his feet were scalded by some hot water which he was carrying.—Chevers.
When the seeds, leaves, or fruit of atropine-holding plants are eaten, there is, however, a very appreciable period before the symptoms commence, and, as in the case of opium poisoning, no very definite rule can be laid down, but usually the effects are experienced within half an hour. The first sensation is dryness of the mouth and throat; this continues increasing, and may rise to such a degree that the swallowing of liquids is an impossibility. The difficulty in swallowing does not seem to be entirely dependent on the dry state of the throat, but is also due to a spasmodic contraction of the pharyngeal muscles. Tissore[497] found in one case such constriction that he could only introduce emetics by passing a catheter of small diameter. The mucous membrane is reddened, and the voice hoarse.[498] The inability to swallow, and the changed voice, bear some little resemblance to hydrophobia—a resemblance heightened to the popular mind by an inclination to bite, which seems to have been occasionally observed; the pupils are early dilated, and the dilatation may be marked and extreme; the vision is deranged, letters and figures often appear duplicated; the eyeballs are occasionally remarkably prominent, and generally congested; the skin is dry, even very small quantities of atropine arresting the cutaneous secretion; in this respect atropine and pilocarpine are perfect examples of antagonism. With the dryness of skin, in a large percentage of cases, occurs a scarlet rash over most of the body. This is generally the case after large doses, but Stadler saw the rash produced on a child three months old by ·3 mgrm. of atropine sulphate. It appeared three minutes after the dose, lasted five hours, and was reproduced by a renewed dose.[499] The temperature of the body with large doses is raised; with small, somewhat lowered. The pulse is increased in frequency, and is always above 100—mostly from 115 to 120, or even 150, in the minute. The breathing is at first a little slowed, and then very rapid. Vomiting is not common; the sphincters may be paralysed so that the evacuations are involuntary, and there may be also spasmodic contractions of the urinary bladder. The nervous system is profoundly affected; in one case there were clonic spasms,[500] in another,[501] such muscular rigidity, that the patient could with difficulty be placed on a chair. The lower extremities are often partly paralysed, there is a want of co-ordination, the person reels like a drunken man, or there may be general jactitation. The disturbance of the brain functions is very marked; in about 4 per cent. only of the recorded cases has there been no delirium, or very little—in the majority delirium is present. In adults this generally takes a garrulous, pleasing form, but every variety has been witnessed. Dr. H. Giraud describes the delirium from datura (which it may be necessary to again repeat is atropine delirium) as follows:—“He either vociferates loudly or is garrulous, and talks incoherently; sometimes he is mirthful, and laughs wildly, or is sad and moans, as if in great distress; generally he is observed to be very timid, and, when most troublesome and unruly, can always be cowed by an angry word, frequently putting up his hands in a supplicating posture. When approached he suddenly shrinks back as if apprehensive of being struck, and frequently he moves about as if to avoid spectra. But the most invariable accompaniment of the final stage of delirium, and frequently also that of sopor, is in the incessant picking at real or imaginary objects. At one time the patient seizes hold of parts of his clothes or bedding, pulls at his fingers and toes, takes up dirt and stones from the ground, or as often snatches at imaginary objects in the air, on his body, or anything near him. Very frequently he appears as if amusing himself by drawing out imaginary threads from the ends of his fingers, and occasionally his antics are so varied and ridiculous, that I have seen his near relatives, although apprehensive of danger, unable to restrain their laughter.”[502] This active delirium passes into a somnolent state with muttering, catching at the bedclothes, or at floating spectra, and in fatal cases the patient dies in this stage. As a rule, the sleep is not like opium coma; there is complete insensibility in both, but in the one the sleep is deep, without muttering, in the other, from atropine, it is more like the stupor of a fever. The course in fatal cases is rapid, death generally taking place within six hours. If a person live over seven or eight hours, he usually recovers, however serious the symptoms may appear. On waking, the patient remembers nothing of his illness; mydriasis remains some time, and there may be abnormality of speech and weakness of the limbs, but within four days health is re-established. In cases where the seeds have been swallowed, the symptoms may be much prolonged, and they seem to continue until all the seeds have been voided—perhaps this is due to the imperfect but continuous extraction of atropine by the intestinal juices.
Chronic poisoning by atropine may, from what has been stated, be of great importance in India. It is probable that its continuous effect would tend to weaken the intellect, and there is no reason for any incredulity with regard to its power as a factor of insanity. Rossbach has ascertained that if dogs are, day after day, dosed with atropine, they become emaciated; but a certain tolerance is established, and the dose has to be raised considerably after a time to produce any marked physiological effect.
§ 451. Physiological Action of Atropine.—From the numerous experiments on animals which have been performed for the purpose of elucidating the action of atropine, it is clear that the terminations of the vagus in the heart muscle are first excited, and then paralysed. The excitor-motor ganglion is also paralysed, and finally the heart itself; death resulting from heart paralysis. The respiratory disturbance is also to be ascribed to the vagus; the terminations in the lung are paralysed, and, at the same time, the poison circulating through the respiratory nervous centre stimulates it first, and then it also becomes finally paralysed. The small vessels are generally widened after a previous transitory narrowing. Organs containing unstriped muscular fibre are generally paralysed, as well as the ends of the nerves regulating secretion—hence the dryness of the skin. The action on the iris is not thoroughly elucidated.
§ 452. The diagnosis of atropine poisoning may be very difficult unless the attention of the medical man be excited by some suspicious circumstance. A child suffering from belladonna rash, with hot dry skin, quick pulse, and reddened fauces, looks not unlike one under an attack of scarlet fever. Further, as before mentioned, some cases are similar to rabies; and again, the garrulous delirium and the hallucinations of an adult are often very similar to those of delirium tremens, as well as tomania.
§ 453. Post-mortem Appearances.—The post-mortem appearances do not seem to be characteristic, save in the fact that the pupils remain dilated. The brain is usually hyperæmic, and in one case the absence of moisture seems to have been remarkable. The stomach and intestines may be somewhat irritated if the seeds, leaves, or other parts of the plant have been eaten; but the irritation is not constant if the poisoning has been by pure atropine, and still less is it likely to be present if atropine has been administered subcutaneously.
§ 454. Treatment.—The great majority of cases recover under treatment. In 112 cases collected by F. A. Falck, 13 only were fatal (11·6 per cent.). The greater portion of the deaths in India are those of children and old people—persons of feeble vitality. The Asiatic treatment, which has been handed down by tradition, is the application of cold water to the feet; but the method which has found most favour in England is treatment by pilocarpine, a fifth of a grain or more being injected from time to time. Pilocarpine shows as perfect antagonism as possible; atropine dries, pilocarpine moistens the skin; atropine accelerates, pilocarpine slows the respiration. Dr. Sydney Ringer and others have published a remarkable series of cases showing the efficacy of this treatment, which, of course, is to be combined where necessary with emetics, the use of the stomach-pump, &c.[503]
§ 455. Separation of Atropine from Organic Tissues, &c.—From the contents of the stomach, atropine may be separated by acidulating strongly with sulphuric acid (15 to 20 c.c. of dilute H2SO4 to 100 c.c.), digesting for some time at a temperature not exceeding 70°, and then reducing any solid matter to a pulp by friction, and filtering, which can generally be effected by the aid of a filter-pump. The liver, muscles,[504] and coagulated blood, &c., may also be treated in a precisely similar way. The acid liquid thus obtained, is first, to remove impurities, shaken up with amyl alcohol, and after the separation of the latter in the usual manner, it is agitated with chloroform, which will take up any of the remaining amyl alcohol,[505] and also serve to purify further. The chloroform is then removed by a pipette (or the separating flask before described), and the fluid made alkaline, and shaken up with ether, which, on removal, is allowed to evaporate spontaneously. The residue will contain atropine, and this may be farther purified by converting it into oxalate, as suggested, page 374.
From the urine,[506] atropine may be extracted by acidifying with sulphuric acid, and agitation with the same series of solvents. Atropine has been separated from putrid matters long after death, nor does it appear to suffer any decomposition by the ordinary analytical operations of evaporating solutions to dryness at 100°. In other words, there seems to be no necessity for operations in vacuo, in attempts at separating atropine.
TABLE SHOWING THE ALKALOIDAL CONTENT OF VARIOUS PARTS OF THE HENBANE PLANT.
Plant Destitute of Flowers. Plant in Flower. Plant in Fruit.
Hyosc.- Albus. Hyosc.- Niger. Hyosc.- Albus. Hyosc.- Niger. Hyosc.- Albus. Hyosc.- Niger.
1868. 1869. 1868. 1869. 1868. 1869. 1868. 1869. 1868. 1869. 1868. 1869.
Seeds, ... ... ... ... ... ... ... ... 0·162 0·172 0·075 0·118
Leaves, 0·588 0·469 0·154 0·192 0·359 0·329 0·147 0·206 0·211 0·153 0·065 0·110
Stalk, 0·012 ... 0·070 0·017 0·036 0·048 0·032 0·030 0·027 0·029 0·009 0·010
Root, 0·128 0·176 0·027 0·080 0·146 0·262 0·127 0·138 0·106 0·086 0·028 0·056
2. HYOSCYAMINE.
§ 456. This powerful alkaloid is contained in small quantities in datura and belladonna, and also is found in the common lettuce (·001 per cent.),[507] and in Scopola carmolica, a solanaceous plant indigenous to Austria and Hungary[508]; but its chief source is the Hyoscyamus niger and Hyoscyamus alba (black and white henbane): it is also found in the Duboisia myoporoides. The latter plant was considered to contain a new alkaloid, “Duboisine,” but duboisine is a mixture of hyoscyamine and hyoscine. Ladenburg’s hyoscine accompanies hyoscyamine, and is an isomeride of both atropine and hyoscyamine; its chemical reactions are similar to those of hyoscyamine, as well as its physiological effects.[509]
Hyoscyamine (C17H23NO3), as separated in the course of analysis, is a resinoid, sticky, amorphous mass, difficult to dry, and possessing a tobacco-like odour. It can, however, be obtained in well-marked odourless crystals, which melt at 108°-109°, a portion subliming unchanged. It liquefies under boiling water without crystallisation. According to Thorey,[510] hyoscyamine crystallises out of chloroform in rhombic tables, and out of benzene in fine needles; but out of ether or amyl alcohol it remains amorphous. When perfectly pure, it dissolves with difficulty in cold, but more readily in hot, water; if impure, it is hygroscopic, and its solubility is much increased. In any case, it dissolves easily in alcohol, ether, chloroform, amyl alcohol, benzene, and dilute acids. Hyoscyamine neutralises acids fully, and forms crystallisable salts, which assume for the most part the form of needles. It is isomeric with atropine, and is converted into atropine by heating to 110°, or warming with alcoholic potash. The gold salt melts at 159°, and does not melt in boiling water like the atropine gold salt.
§ 457. Pharmaceutical and other Preparations of Henbane.—The leaves are alone officinal in the European pharmacopœias; but the seeds and the root, or the flowers, may be met with occasionally, especially among herbalists. The table[511] (p. 382) will give an idea of the alkaloidal content of the different parts of the plant.
In order to ascertain the percentage of the alkaloid in any part of the plant, the process followed by Thorey has the merit of simplicity. The substance is first exhausted by petroleum ether, which frees it from fat; after drying, it is extracted with 85 per cent. alcohol at a temperature not exceeding 40°. The alcoholic extracts are then united, the alcohol distilled off, and the residue filtered. The filtrate is now first purified by agitation with petroleum ether, then saturated by ammonia, and shaken up with chloroform. The latter, on evaporation, leaves the alkaloid only slightly impure, and, after washing with distilled water, if dissolved in dilute sulphuric acid, a crystalline sulphate may be readily obtained.
A tincture and an extract of henbane leaves and flowering tops are officinal in most pharmacopœias; an extract of the seeds in that of France.
An oil of hyoscyamus is officinal in all the Continental pharmacopœias, but not in the British.
Henbane juice is recognised by the British pharmacopœia; it is about the same strength as the tincture.
An ointment, made of one part of the extract to nine of simple ointment, is officinal in the German pharmacopœia.
The tincture (after distilling off the spirit) and the extracts (on proper solution) may be conveniently titrated by Mayer’s reagent (p. 263), which, for this purpose, should be diluted one-half; each c.c. then, according to Dragendorff, equalling 6·98 mgrms. of hyoscyamine. Kruse found 0·042 per cent. of hyoscyamine in a Russian tincture, and ·28 per cent. in a Russian extract. Any preparation made with extract of henbane will be found to contain nitrate of potash, for Attfield has shown the extract to be rich in this substance. The ointment will require extraction of the fat by petroleum ether; this accomplished, the determination of its strength is easy.
The oil of hyoscyamus is poisonous, and contains the alkaloid. An exact quantitative research is difficult; but if 20 grms. of the oil are shaken up for some time with water acidified by sulphuric acid, the fluid separated from the oil, made alkaline, shaken up with chloroform, and the latter removed and evaporated, sufficient will be obtained to test successfully for the presence of the alkaloid, by its action on the pupil of the eye.
§ 458. Dose and Effects.—The dose of the uncrystalline hyoscyamine is 6 mgrms. (1⁄10 grain), carefully increased. I have seen it extensively used in asylums to calm violent or troublesome maniacs. Thirty-two mgrms. (1⁄2 grain) begin to act within a quarter of an hour; the face flushes, the pupils dilate, there is no excitement, all muscular motion is enfeebled, and the patient remains quiet for many hours, the effects from a single dose not uncommonly lasting two days. 64·8 mgrms. (1 grain) would be a very large, and possibly fatal, dose. The absence of delirium or excitement, with full doses of hyoscyamine, is a striking contrast to the action of atropine, in every other respect so closely allied; yet there are cases on record showing that the henbane root itself has an action similar to that of belladonna, unless indeed one root has been mistaken for another; e.g., Sonnenschein relates the following ancient case of poisoning:—In a certain cloister the monks ate by error the root of henbane. In the night they were all taken with hallucinations, so that the pious convent was like a madhouse. One monk sounded at midnight the matins, some who thereupon came into chapel could not read, others read what was not in the book, others sang drinking songs—in short, there was the greatest disturbance.
§ 459. Separation of Hyoscyamine from Organic Matters.—The isolation of the alkaloid from organic tissues or fluids, in cases where a medicinal preparation of henbane, or of the leaves, root, &c., has been taken, is possible, and should be carried out on the principles already detailed. Hyoscyamine is mainly identified by its power of dilating the pupil of the eye. It is said that so small a quantity as ·0083 mgrm. (1⁄4000 grain) will in fifteen minutes dilate the eye of a rabbit. It is true that atropine also dilates the pupil; but if sufficient of the substance should have been isolated to apply other tests, it can be distinguished from atropine by the fact that the latter gives no immediate precipitate with platinic chloride, whilst hyoscyamine is precipitated by a small quantity of platinic chloride, and dissolved by a larger amount, and also by the characters of the gold salt.
3. HYOSCINE.
§ 460. Hyoscine, C17H23NO3.—According to E. Schmidt[512] the formula is C17H21NO4 + H2O, and the alkaloid is identical with scopolamine. Scopolamine has a m.p. of 59°, gives an aurochloride, crystallising in needles, the m.p. of which is 212° to 214°; when boiled with baryta water, it splits up into atropic acid and scopoline, a base (C8H13NO), m.p. 110°, boiling-point, 241° to 243°; scopoline forms an aurochloride, m.p. 223°-225°; and a platinochloride, m.p. 228°-230°; but Ladenburg,[513] in answer to Schmidt, asserts that hyoscine exists, and is not identical with scopolamine. A sample of commercial hyoscine hydrobromide Nagelvoort found to melt, water-free, at 198°; other commercial samples of hydrobromide melted at 179° and 186°; the latter sample giving an aurochloride which melted at 192°. Pure hyoscine gold chloride is stated to melt at 198°. Its reactions are much the same as those of atropine, but it does not blacken calomel. It is very poisonous.
According to experiments on animals, the heart is first slowed, then quickened; the first effect being due to a stimulation of the inhibitory nervous apparatus, the second to a paralysing action on the same. The temperature is not altered. The pupils are dilated, the saliva diminished. The irritability of the brain is lessened.[514]
4. SOLANINE.
§ 461. Distribution of Solanine.—Solanine is a poisonous nitrogenised glucoside found in all parts of the plants belonging to the nightshade order. The English common plants in which solanine occurs are the edible potato plant (Solanum tuberosum), the nightshade (Solanum nigrum), and the Solanum dulcamara, or bitter-sweet. The berries of the Solanum nigrum and those of S. dulcamara contain about 0·3 per cent. Mature healthy potatoes appear to contain no solanine, but from 150 grms. of diseased potatoes G. Kassner[515] separated 30 to 50 mgrms.
R. Firbas,[516] in a research on the active substances or young shoots of the S. tuberosum found two products—one crystalline, Solanine; the other amorphous, Solaneine. He gives the following formula to solanine—C52H93NO1841⁄2H2O; when dried at 100° it becomes anhydrous. From a solution in 85 per cent. alcohol it crystallises in colourless needles, m.p. 244°; these are almost insoluble in ether and alcohol, but are readily dissolved in dilute hydrochloric acid. On hydrolysis solanine breaks up into solanidine and a sugar, according to the equation—
C52H93NO18 = C40H61NO2 + 2C6H12O6 + 4H2O.
§ 462. Properties of Solanine.—The reaction of the crystals is weakly alkaline; the taste is somewhat bitter and pungent. Solanine is soluble in 8000 parts of boiling water, 4000 parts of ether, 500 parts of cold, and 125 of boiling alcohol. It dissolves well in hot amyl alcohol, but is scarcely soluble in benzene. An aqueous solution froths on shaking, but not to the degree possessed by saponine solutions.
The amyl alcohol solution has the property of gelatinising when cold. It does this if even so little as 1 part of solanine is dissolved in 2000 of hot amyl alcohol. The jelly is so firm that the vessel may be inverted without any loss. This peculiar property is one of the most important tests for the presence of solanine. The hot ethylic alcohol solution will, on cooling, also gelatinise, but a stronger solution is required. From very dilute alcoholic solutions (and especially with slow cooling) solanine may be obtained in crystals. In dilute mineral acids solanine dissolves freely, and forms salts, which for the most part have an acid reaction and are soluble in alcohol and in water, but with difficulty in ether. The compounds with the acids are not very stable, and several of them are broken up on warming the solution, solanine separating out from the aqueous solutions of the solanine salts. The alkaloid may be precipitated by the fixed and volatile alkalies, and by the alkaline earths. Solanine will stand boiling with strongly alkaline solutions without decomposition; but dilute acids, on warming, hydrolyse. By heating solanine in alcoholic solution with ethyl iodide in closed tubes, and then treating the liquid with ammonia, ethyl solanine in well-formed crystals can be obtained. Solanine is precipitated by phosphomolybdic acid, but by very few other substances. It gives, for example, no precipitate with the following reagents:—Platinic chloride, gold chloride, mercuric chloride, potassic bichromate, and picric acid. Tannin precipitates it only after a time. Sodic phosphate gives a crystalline precipitate of solanine phosphate, if added to a solution of solanine sulphate. Both solanine and solanidine give with nitric acid at first a colourless solution, which, on gentle warming, passes into blue, then into light red, and lastly becomes weakly yellow. Solanine, dissolved in strong sulphuric acid, to which a little Fröhde’s reagent is added, at first colours the fluid light brown; after standing some time the edges of the drop becomes reddish-yellow, and finally the whole a beautiful cherry-red, which gradually passes into dark violet when violet-coloured flocks separate.
§ 463. Solanidine.—Solanidine has stronger basic properties than solanine. Its formula is C40H61NO2. It is obtained from an alcoholic solution in amorphous masses interspersed with needles; m.p. 191°. It dissolves readily in hot alcohol, with difficulty in ether. With hydrochloric acid it forms a hydrochloride—3(C40H61NO2HCl)HCl + H2O or 11⁄2H2O. This hydrochloride is a slightly yellow powder, only sparingly soluble in water, and carbonising without melting when heated to 287°. Solanidine also forms a sulphate, 3(C40H61NO2H2SO4)H2SO4 + 8H2O; this salt is in the form of scaly plates, melting at 247°; it dissolves readily in water.
The sugar obtained from the hydrolysis of solanidine is a yellow amorphous mass dissolving readily in water and wood spirit, and has a specific rotatory power of [α]D = + 28·623. With Phenylhydrazine hydrochloride and sodium acetate in aqueous solution it forms a glucosazone, melting at 199°. It is probably a mixture of sugars.
Solaneine is the name that has been given to the amorphous substance accompanying solanine; on hydrolysis it yields solanidine and the same sugar as solanine. Its formula is C52H82NO13 with 4H2O.
§ 464. Poisoning from Solanine.—Poisoning from solanine has been, in all recorded cases, induced, not by the pure alkaloid (which is scarcely met with out of the laboratory of the scientific chemist), but by the berries of the different species of Solanum, and has for the most part been confined to children. The symptoms in about twenty cases,[517] which may be found detailed in the medical literature of this century, have varied so greatly that the most opposite phenomena have been witnessed as effects of poisoning by the same substance. The most constant phenomena are a quick pulse, laboured respiration, great restlessness, and hyperæsthesia of the skin. Albumen in the urine is common. Nervous symptoms, such as convulsions, aphasia, delirium, and even catalepsy, have been witnessed. In some cases there have been the symptoms of an irritant poison—diarrhœa, vomiting, and pain in the bowels: in many cases dilatation of the pupil has been observed.
Rabbits are killed by doses of ·1 grm. per kilo. The symptoms commence in about ten minutes after the administration, and consist of apathy and a low temperature; the breathing is much slowed. Convulsions set in suddenly before death, and the pupils become dilated. The post-mortem appearances in animals are intense redness and injection of the meninges of the cerebellum, of the medulla oblongata, and the spinal cord. Dark red blood is found in the heart, and the kidneys are hyperæmic. The intestinal mucous membrane is normal.
§ 465. Separation of Solanine from the Tissues of the Body.—Dragendorff has proved the possibility of separating solanine from animal tissues by extracting it from a poisoned pig. The best plan seems to be to extract with cold dilute sulphuric acid water, which is then made alkaline by ammonia, and shaken up with warm amyl alcohol. This readily dissolves any solanine. The peculiar property possessed by the alkaloid of gelatinising, and the play of colours with Fröhde’s reagent, may then be essayed on the solanine thus separated.
5. CYTISINE.
§ 466. The Cytisus Laburnum.—The laburnum tree, Cytisus laburnum, so common in shrubberies, is intensely poisonous. The flowers, bark, wood, seeds, and the root have all caused serious symptoms. The active principle is an alkaloid, to which the name of Cytisine has been given. The best source is the seeds. The seeds are powdered and extracted with alcohol containing hydrochloric acid, the alcohol distilled off, the residue treated with water and filtered through a wet filter to remove any fatty oil, the filtrate treated with lead acetate; and, after separating the precipitated colouring matter, made alkaline with caustic potash, and shaken with amyl alcohol. The amyl alcohol is shaken with dilute hydrochloric acid, the solution evaporated, the crude crystals of hydrochloride thus obtained treated with alcohol to remove colouring matters, and recrystallised several times from water; it then forms well-developed, colourless, transparent prisms. From the hydrochloride the free base is readily obtained.
Cytisine, C11H14N2O.—To cytisine used to be ascribed the formula C20H27N3O, but a study of the salt and new determinations appear to prove that it is identical with ulexine.[518] Cytisine is in the form of white radiating crystals, consisting, when deposited from absolute alcohol, of anhydrous prisms, which melt at from 152° to 153°. Cytisine has a strong alkaline reaction; it is soluble in water, alcohol, and chloroform, less so in benzene and amyl alcohol, almost insoluble in cold light petroleum, and insoluble in pure ether. The specific rotatory power in solution is [α]D17° = -119·57.
It is capable of sublimation in a current of hydrogen at 154·5°; the sublimate is in the form of very long needles and small leaflets; at higher temperatures it melts to a yellow oily fluid, again becoming crystalline on cooling. Cytisine is a strong base; it precipitates the earths and oxides of the heavy metals from solutions of the chlorides, and, even in the cold, expels ammonia from its combinations.
Cytisine forms numerous crystalline salts, among which may be mentioned two platinochlorides, C11H14N2OH2PtCl6 + 21⁄2H2O and (C11H14N2O)2H2PtCl6, crystallising in golden yellow needles, which are tolerably soluble in water; and the aurochloride, C11H14N2OHAuCl4, crystallising in short, red-brown, hook-shaped needles; m.p. 212° to 213°, without evolution of gas.
§ 467. Reactions of Cytisine.—Concentrated sulphuric acid dissolves cytisine without colour; if to the solution is added a drop of nitric acid, it becomes orange-yellow, and on addition of a crystal of potassic bichromate, first yellow, then dirty brown, and lastly green. Concentrated nitric acid dissolves the base in the cold without colour, but, on warming, it becomes orange-yellow. Picric, tannic, and phosphomolybdic acids, potassic, mercuric, and potass. cadmium iodides, and iodine with potassic iodide, all give precipitates. Neither potassic bichromate nor mercuric chloride precipitates cytisine, even though the solution be concentrated. The best single test appears to be the reaction discovered by Magelhaes; this consists in adding thymol to a solution of cytisine in concentrated sulphuric acid, when a yellow colour, finally passing into an intense red, is produced.
§ 468. Effects on Animals.—W. Marmé found subcutaneous doses of from 30 to 40 mgrms. fatal to cats; death was from paralysis of the respiration, and could be avoided by artificial respiration. Cattle are sometimes accidentally poisoned by laburnum. An instance of this is recorded in the Veterinarian (vol. lv. p. 92). In Lanark a storm had blown a large laburnum tree down to the ground; it fell into a field in which some young heifers were grazing, and they began to feed on the leaves and pods. Two or three died, and three more were ill for some time, but ultimately recovered.
The laburnum, however, does not always have this effect, for there is a case related in the Gardeners’ Chronicle, in which five cows browsed for some time on the branches and pods of an old laburnum tree that had been thrown aside. Rabbits and hares are said to feed eagerly, and without injury, on the pods and branches.
§ 469. Effects on Man.—The sweet taste of many portions of the laburnum tree, as well as its attractive appearance, has been the cause of many accidents. F. A. Falck has been able to collect from medical literature no less than 155 cases—120 of which were those of the accidental poisoning of children: only 4 (or 2·6 per cent.), however, died, so that the poison is not of a very deadly character.
One of the earliest recorded cases is by Christison.[519] A servant-girl of Inverness, in order to excite vomiting in her fellow-servant (the cook), boiled some laburnum bark in soup; very soon after partaking of this soup, the cook experienced violent vomiting, which lasted for thirty-six hours; she had intense pain in the stomach, much diarrhœa, and great muscular weakness; she appears to have suffered from gastro-intestinal catarrh for some time, but ultimately recovered.
Vallance[520] has described the symptoms observed in the poisoning of fifty-eight boys, who ate the root of an old laburnum tree, being allured by its sweet taste. All were taken ill with similar symptoms, differing only in severity; two who had eaten half an ounce (nearly 8 grms.) suffered with especial severity. The symptoms were first vomiting, then narcosis, with convulsive movements of the legs and strange movements of the arms: the pupils were dilated. This dilatation of the pupil Sedgwick also saw in the poisoning of two children who ate the root. On the other hand, when the flower, seeds, or other portions of the laburnum have been eaten, the symptoms are mainly referable to the gastro-intestinal tract, consisting of acute pain in the stomach, vomiting, and diarrhœa. On these grounds it is therefore more than probable that there is another active principle in the root, differing from that which is in those portions of the tree exposed to the influence of sunlight.[521]
The post-mortem appearances are, so far as known, in no way characteristic.
VII.—The Alkaloids of the Veratrums.
§ 470. The alkaloids of the veratrums have been investigated by Dr. Alder Wright, Dr. A. P. Luff, and several other chemists.[522]
The method which Wright and Luff adopted to extract and separate these alkaloids from the root of V. album and V. viride, essentially consisted in exhausting with alcohol, to which a little tartaric acid has been added, filtering, distilling off the alcohol, dissolving the residue in water, alkalising with caustic soda, and shaking up with ether. The ethereal solution was next separated, and then washed with water containing tartaric acid, so as to obtain a solution of the bases as tartrates: in this way the same ether could be used over and over again. Ultimately a rough separation was made by means of the different solubilities in ether, pseudo-jervine being scarcely soluble in this medium, whilst jervine, veratralbine, veratrine, and cevadine are very soluble in it.
The yield of Wright and Luff’s alkaloids was as follows:—
TABLE SHOWING THE ALKALOIDS IN THE VERATRUMS.
V. album. Per Kilo. V. viride. Per Kilo.
Jervine, 1 ·3 grm. ·2 grm.
Pseudo-jervine, ·4 „ ·15 „
Rubi-jervine, ·25 „ ·02 „
Veratralbine, 2 ·2 „ Traces.
Veratrine, ·05 „ Less than ·004 grm.
Cevadine, Absent. Less„han ·43 4 „
From whence it appears that V. album has only a very small quantity of veratrine, that it is almost absent in V. viride; on the other hand, V. viride contains a fair quantity of cevadine, an alkaloid absent in V. album.
Besides the six principles enumerated, G. Salzberger has recently separated two other crystalline substances, to which he has given the names of protoveratrine and protoveratridine, and Pehkschen has also separated a ninth substance, to which he has given the name of veratroidine.
The formulæ of the nine bodies which have been separated from hellebore root are as follows:—
Melting-point.
1. Veratrine, C37H53NO11, ...
2. Cevadine, C32H49NO9, 205°-206°
3. Protoveratrine, C32H51NO11, 245°-250°
4. Pseudo-jervine, - C29H43NO7 (Wright), 299°-300°
C29H49NO12 (Pehkschen), ...
5. Veratralbine, C28H43NO5, ...
6. Protoveratridine, C26H45NO8, 265°
7. Rubi-jervine, - C26H43NO2 (Wright and Luff), 236°
C26H43NO2 (Salzberger), 240°-245°
8. Jervine, C26H37NO32H2O, 237°-239°
9. Veratroidine, C32H53NO9, 149°
Three of these alkaloids possess powerful sternutatory properties, the least quantity applied to the nostrils exciting sneezing; the three are veratrine, cevadine, and protoveratrine.
Protoveratrine, C32H51NO11, has been obtained by G. Salzberger[523] from powdered hellebore root, by the following process:—