Division I.—Vegetable Alkaloids (part 2)

§ 415. Pharmaceutical Preparations.—Cocaine hydrochlorate is officinal. Gelatine discs, weighing 1·31 mgrms. (⁄50 grain), and each containing 0·33 mgrm. (⁄200 grain) of the salt are officinal, and used by ophthalmic surgeons. A solution of the hydrochlorate, containing 10 per cent. of cocaine hydrochlorate and (for the purposes of preserving the solution) 0·15 per cent. of salicylic acid is also officinal. Stronger solutions may also be met with; for instance, a 20 per cent. solution in oil of cloves for external application in cases of neuralgia.

§ 416. Separation of Cocaine and Tests.—Cocaine may be shaken out of solutions made slightly alkaline by ammonia by treatment with benzene; it also passes into petroleum ether under the same circumstances. The best method is to extract a solution, made feebly alkaline, thoroughly by ether, and then shake it out by benzene and evaporate the separated benzene at the ordinary air temperature. The property of the alkaloid to melt at or below the temperature of boiling water, and the ready decomposition into benzoic acid and other products, render cocaine easy of identification. If, for instance, a small particle of cocaine is put in a tube, a drop of strong sulphuric acid added and warmed by the water-bath, colourless crystals of benzoic acid sublime along the tube, and an aromatic odour is produced.

Flückiger has recommended the production of benzoate of iron as a useful test both for cocaine and for cocaine hydrochlorate.

One drop of a dilute solution of ferric chloride added to a solution of 20 mgrms. of cocaine hydrochlorate in 2 c.c. of water, gives a yellow fluid, which becomes red on boiling from the production of iron benzoate. This reaction is of little use unless a solution of the same strength of ferric chloride, but to which the substance to be tested has not been added, is boiled at the same time for comparison, because all solutions of ferric chloride deepen in colour on heating.

A solution of the alkaloid evaporated to dryness on the water-bath, after being acidulated with nitric acid, and then a few drops of alcoholic solution of potash or soda added, develops an odour of benzoic ethyl-ester. Cocaine hydrochlorate, when triturated with calomel, blackens by the slightest humidity or by moistening it with alcohol. Cocaine in solution is precipitated by most of the group reagents, but is not affected by mercuric chloride, picric acid, nor potassic bichromate.

Added to the tests above mentioned, there is the physiological action; cocaine dilates the pupil, tastes bitter, and, for the time, arrests sensation; hence the after-effect on the tongue is a sensation of numbness.

§ 417. Symptoms.—A large number of accidents occur each year from the external application of cocaine; few, however, end fatally. Cocaine has thus produced poisonous symptoms when applied to the eye, to the rectum, to the gums, to the urethra, and to various other parts. There have been a few fatal cases, both from its external and internal administration; Mannheim, for example, has collected eleven of such instances.

The action of cocaine is twofold; there is an action on the central and the peripheral nervous system. In small doses cocaine excites the spinal cord and the brain; in large it may produce convulsions and then paralysis. The peripheral action is seen in the numbing of sensation. There is always interference with the accommodation of vision, and dilatation of the pupil. The eyelids are wider apart than normal, and there may be some protrusion of the eyeball.

The usual course of an acute case of poisoning is a feeling of dryness in the nose and throat, difficulty of swallowing, faintness, and there is often vomiting; the pulse is quickened; there is first cerebral excitement, followed usually by great mental depression. Occasionally there is an eruption on the skin. Hyperæsthesia of the skin is followed by great diminution of sensation, the pupils, as before stated, are dilated, the eyes protruding, the eyelids wide open, the face is pale, and the perspiration profuse. Convulsions and paralysis may terminate the scene. Death takes place from paralysis of the breathing centre; therefore the heart beats after the cessation of respiration. As an antidote, nitrite of amyl has apparently been used with success.

There is a form of chronic poisoning produced from the taking of small doses of cocaine daily. The symptoms are very various, and are referable to disturbance of the digestive organs, and to the effect on the nervous system. The patients become extremely emaciated, and it seems to produce a special form of mania.

§ 418. Post-mortem Appearances.—The appearances found in acute cases of poisoning have been hyperæmia of the liver, spleen, and kidneys, as well as of the brain and spinal cord.

In the experimental poisoning of mice with cocaine Ehrlich found a considerable enlargement of the liver.

§ 419. Fatal Dose.—The fatal dose, according to Mannheim, must be considered as about 1 grm. (15·4 grains); the smallest dose known to have been fatal is 0·08 grm. (1·2 grain) for an adult, and 0·05 grm. (0·7 grain) for a child.

6. Corydaline.

§ 420. Corydaline (C22H28NO4) is an alkaloid discovered by Wackenroder (1826) in the tubers of Corydalis tuberosa; crystallised in the cold and away from light, out of a mixture of absolute alcohol and ether, corydaline forms colourless, flat, prismatic crystals, which quickly turn yellow on exposure to light or heat. Pure corydaline changes colour at about 125°, softens at about 133°, and melts finally at 134° to 135°. It dissolves in ether, chloroform, carbon disulphide, and benzene, but not so readily in alcohol. It is almost insoluble in cold water, and but slightly soluble in boiling water. Water precipitates it from a solution in alcohol. It is also soluble in dilute hydrochloric and sulphuric acids. It gives a precipitate with potassium iodide if a solution of the hydrochloride be used. The precipitate crystallises out of hot water in clusters of short lemon-yellow prismatic crystals, and has the formula of C22H28NO4HI. Corydaline platinochloride has the composition of (C22H28NO4)2H2PtCl6, containing Pt 16·94 per cent., and 2·44 per cent. of N.—Dobbie & Lauder, Journ. Chem. Soc., March 1892, 244.

Corydaline in large doses causes epileptiform convulsions. Death takes place from respiratory paralysis.

V.—The Aconite Group of Alkaloids.

§ 421. The officinal aconite is the Aconitum napellus—monkshood or wolfsbane—a very common garden plant in this country, and one cultivated for medicinal purposes. Many varieties of aconite exist in other regions, which either are, or could be, imported. Of these the most important is the Aconitum ferox, a native of the Himalayan mountains, imported from India.

All the aconites, so far as known, are extremely poisonous, and it appears probable that different species contain different alkaloids. The root of A. napellus is from 2 to 4 inches long, conical in shape, brown externally, and white internally. The leaves are completely divided at the base into five wedge-shaped lobes, each of the five lobes being again divided into three linear segments. The numerous seeds are three-sided, irregularly twisted, wrinkled, of a dark-brown colour, in length one-sixth of an inch, and weighing 25 to the grain (Guy). The whole plant is one of great beauty, from 2 to 6 feet high, and having a terminal spike of conspicuous blue flowers. The root has been fatally mistaken for horse-radish, an error not easily accounted for, since no similarity exists between them.

§ 422. Pharmaceutical Preparations of Aconite.—The preparations of aconite used in medicine are—

Aconitine, officinal in all the pharmacopœias.

Aconite liniment (linimentum aconiti), made from the root with spirit, and flavoured with camphor; officinal in the British Pharmacopœia. It may contain about 2·0 per cent. of aconitine.

Aconite tincture, officinal in all the pharmacopœias.

Aconite ointment, 8 grains of aconitine to the oz. (i.e., 1·66 per cent.); officinal in the British Pharmacopœia.

Aconite extract, the juice of the leaves evaporated; officinal in most of the pharmacopœias. The strength in alkaloid of the extract varies; in six samples examined by F. Casson, the least quantity was 0·16 per cent., the maximum 0·28 per cent.

Fleming’s tincture of aconite is not officinal, but is sold largely in commerce. It is from three to four times stronger than the B.P. tincture.

§ 423. The Alkaloids of Aconite.—The researches of Dr. Alder Wright and Luff, and especially those of Professor Dunstan, have established that in the root of the true aconite there exist four alkaloids, one only of which has been as yet crystallised.

Three of the alkaloids have been fairly well worked out; the fourth homo-napelline has not yet been satisfactorily investigated.

The three alkaloids are aconitine, aconine and benzoyl-aconine; besides which pyraconitine and pyraconine can be obtained by suitable treatment from aconitine and aconine.

The formulæ of the alkaloids and their derivatives are as follows:—

Aconitine (acetyl-benzoyl-aconine), m.p., 188·60°, C33H45NO12

Benzoyl-aconine, m.p., 268·0°, C31H43NO11

Pyraconitine (anhydro-benzoyl-aconine), m.p., 188-190°, C31H41NO10

Aconine, m.p., 132°, C24H39NO10

Pyraconine (anhydro-aconine), C24H37NO9

§ 424. Aconitine, C33H45NO12.—This base has been shown by Dunstan to be acetyl-benzoyl-aconine; one molecule of the base breaking up, on complete hydrolysis, into one molecule of aconine, one of acetic acid, and one of benzoic acid—

Acetic
Acid. Benzoic
Acid. Aconine.

C33H45NO12 + 2H2O = C2H4O2 + C7H6O2 + C24H39NO10.

That is to say that 100 parts of aconitine, according to theory, should yield:—

Acetic acid, 9·37 per cent.; benzoic acid, 18·85 per cent.; and aconine, 77·52 per cent.

Pure aconitine has a tube melting-point of 188·6°. The behaviour of a sample of Merck’s aconitine in the subliming cell, which had a melting-point of 184°, was as described at page 259.

Aconitine dissolves in water at 22° in the proportion of 1 in 4431 (Dunstan); it is soluble in 37 of absolute alcohol, 64 of anhydrous ether, 5·5 parts of chloroform and benzene (A. Jurgens); it has basic properties, and a cold watery solution has an alkaline reaction to cochineal, but not to litmus nor to phenol-phthalein. Aconitine is not precipitated by mercuric potassium iodide, but gives a voluminous precipitate with an aqueous solution of iodine in potassium iodide.

It gives a crystalline yellow gold compound with gold chloride, which has a melting-point of 135·5°, and according to its composition, C33H45NO12HAuCl4, should give 19·9 per cent. of gold.

Aconitine is best extracted from the plant, or from organic matters generally, by a 1 per cent. sulphuric acid; this strength is stated not to hydrolyse aconitine if acting in the cold; after purifying the acid liquid by shaking it with amyl alcohol, and then with chloroform, always operating in the cold, the liquid is precipitated by ammonia in very slight excess, and the liquid shaken with ether; the ether is removed, dehydrated by standing over calcium chloride, and then evaporated spontaneously; should the aconitine be mixed with the other alkaloids, advantage can be taken of the method of separating aconitine by converting it into hydrobromide, as described under “Benzoyl-aconine.”

§ 425. Tests for Aconitine.—The most satisfactory and the most delicate is the physiological test; the minutest trace of an aconite-holding liquid, applied to the tongue or lips, causes a peculiar numbing, tingling sensation which, once felt, can readily be remembered.

An alkaloidal substance which, heated in a tube, melts approximately near the melting-point of aconitine, and gives off an acid vapour, would render one suspicious of aconitine, for most alkaloids give off alkaline vapours. Aconitine also may, by heating with dilute acids, be made to readily yield benzoic acid, an acid easy of identification. Aconitine dissolved in nitric acid, evaporated to dryness, and then treated with alcoholic potash, gives off an unmistakable odour of benzoic ester.

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.

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.

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 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 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, 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 ⁄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, 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. 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. 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.

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 .)

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. (⁄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. (⁄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.

§ 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 2⁄4 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. 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, 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. 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.

§ 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.

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, 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.

From a research by W. Schütte, 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.

§ 443. Pharmaceutical Preparations.—(a.) Of the leaves. Extract of Belladonna.—This contains, according to Squire, 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, 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 ⁄50 grain, and containing for ophthalmic use ⁄5000 grain of atropine sulphate. Similar discs are made for hypodermic use, but stronger; each containing ⁄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. 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. This action on the iris has been studied by Ruyter, 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.

§ 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; 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. 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. 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, 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. (⁄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. (⁄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, 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 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. 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. 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, in another, 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.” 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.

§ 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, 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, 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, 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.), and in Scopola carmolica, a solanaceous plant indigenous to Austria and Hungary; 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.

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, 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 (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. (⁄10 grain), carefully increased. I have seen it extensively used in asylums to calm violent or troublesome maniacs. Thirty-two mgrms. (⁄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. (⁄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 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, 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.

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 separated 30 to 50 mgrms.

R. Firbas, 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—C52H93NO184⁄2H2O; 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 1⁄2H2O. 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, 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. 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 + 2⁄2H2O 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. 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 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.

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.

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 from powdered hellebore root, by the following process:—

The powdered root is first freed from fatty and resinous matters by treatment with ether, and then the fat-free powder is exhausted with alcohol. The alcohol is evaporated off in a vacuum, the extract mixed with much acetic acid water, filtered from the insoluble residue, and treated with metaphosphoric acid; the voluminous precipitate contains much amorphous matter, with insoluble compounds of jervine and rubi-jervine. The precipitate is filtered off, and the filtrate treated with excess of ammonia and shaken up with ether. On separating the ether and distilling, protoveratrine crystallises out, and can be obtained pure by recrystallisation from strong alcohol.

Protoveratrine crystallises in four-sided plates, which melt with charring at 245° to 250°. The base is insoluble in water, benzene, and light petroleum; chloroform and boiling 96 per cent. alcohol dissolve it somewhat; cold ether scarcely touches it, boiling ether dissolves it a little.

Concentrated sulphuric acid dissolves the alkaloid slowly with the production of a greenish colour, which passes to cornflower blue, and, after some hours, becomes violet. Sulphuric acid and sugar gives a different colour to that produced by commercial veratrine. There is first a green colour which darkens into olive green, then becomes dirty green, and finally dark brown. When warmed with strong sulphuric, hydrochloric, or phosphoric acids, there is a strong odour of isobutyric acid developed. Dilute solutions of the salts are precipitated by ammonia, Nessler’s reagent, gold chloride, potassium mercury iodide, cadmium iodide, phosphotungstic acid, and picric acid; no precipitate is produced by tannin, platinum chloride, or mercuric chloride.

§ 471. Veratrine (C37H53NO11) is a crystallisable alkaloid, which is a powerful irritant of the sensory nerves of the mucous membrane, and excites violent sneezing. Treated with concentrated sulphuric acid, it dissolves with a yellow colour, deepening into orange, then into blood-red, and finally passing into carmine-red. If the freshly-prepared sulphuric acid solution is now treated with bromine water, a beautiful purple colour is produced. Concentrated hydrochloric acid dissolves veratrine without the production of colour, but, with careful warming, it becomes beautifully red. This reaction is very delicate, occurring with ·17 mgrm. On saponification veratrine yields veratric acid.

Veratric acid is procatechu-dimethylether acid, and has the constitutional formula,

Veratric acid forms colourless needles and four-sided prisms which have a marked acid reaction; it melts on heating to a colourless fluid, and sublimes without decomposition; it is easily soluble in hot alcohol, but insoluble in ether. If dissolved in nitric acid, water separates nitro-veratric acid, C9H9(NO2)O4 which crystallises out of alcohol in small yellow scales. Veratric acid unites with bases forming crystalline salts; the silver salt has the composition of C9H9AgO4 = 37·37 per cent. silver, and may assist in identification. It is crystalline with a melting point of 205° to 206°.

Cevadine, C32H49NO9 (Merck’s veratrine).—It has powerful sternutatory properties, and, under the influence of alcoholic potash, yields tiglic acid and cevine, C27H43NO8.

According to Ahrens, angelic acid is first formed, and then converted into tiglic acid. When the alkaloid is boiled with hydrochloric acid, tiglic acid is formed, and a ruby red mass. Nitric acid oxidises cevadine completely; with potassic permanganate it yields acetic and oxalic acids; with chromic acid it forms acetaldehyde and carbon dioxide.

The Continental authorities always give to cevadine the name of veratrine. Cevadine forms a crystalline aurochloride, a crystalline mercurochloride, C32H49NO9HHgCl3, and a crystalline picrate, C32H49NO9C6H3N8O7. The mercury salt crystallises in small silvery plates, and melts with decomposition at 172°. The picrate forms stable crystals blackening at 225°; both of the latter salts are but little soluble in water, but are soluble in alcohol. Cevadine also unites with bromine, forming a tetrabromide, an amorphous yellow powder insoluble in water, but readily soluble in alcohol, ether, and chloroform.

§ 472. Jervine, (C26H37NO32H2O) (Wright and Luff), C14H22NO2 (Pehkschen), crystallises in white needles, and, when anhydrous, melts at 237·7°. It is slightly lævorotatory. At 25° one part of the base dissolves in 1658 benzene, 268 ether, 60 chloroform, and 16·8 absolute alcohol. It is insoluble in light petroleum, and but slightly soluble in ethyl acetate, water, or carbon bisulphide. It forms a very insoluble sulphate, and a sparingly soluble nitrate and hydrochloride. Jervine gives, with sulphuric acid and sugar, a violet colour, passing to blue. Treated with strong sulphuric acid it dissolves to a yellow fluid, which becomes successively dark yellow, brownish yellow, and then greenish. The green shade is immediately developed by diluting with water. Jervine does not produce sneezing.

§ 473. Pseudo-jervine, C29H43NO7 (Wright), m.p. 299°; C29H49NO12, m.p. 259° (Pehkschen), may be obtained in a crystalline state. One part is soluble in 10·9 parts of light petroleum, 372 parts of benzene, 1021 parts of ether, 4 of chloroform, and 185 of absolute alcohol. The pure base gives no colour with sulphuric, nitric, or hydrochloric acids. It does not produce sneezing.

§ 474. Protoveratridine, C26H45NO8, is probably derived from protoveratrine. Salzberger isolated it from powdered hellebore roots by treating the powder with barium hydroxide and water, and extracting with ether. The ether extract was separated and freed from ether in a current of hydrogen at a low temperature.

From the dark green syrup obtained jervine crystallised out, and from the mother liquor ultimately protoveratridine was separated.

Protoveratridine crystallises in colourless four-sided plates, which melt at 265°. It is almost insoluble in alcohol, chloroform, methyl alcohol, and acetone, and insoluble in benzene, light petroleum, and ether. Concentrated sulphuric acid gives a violet, then a cherry-red colour. Its solution in concentrated hydrochloric acid becomes light red on warming, and there is an odour of isobutyric acid. It is readily soluble in dilute mineral acids, and the solution, on the addition of ammonia, yields the alkaloid in a crystalline condition. The sulphuric acid solution gives precipitates with phosphotungstic, picric, and tannic acids, and with potassium mercury iodide; but gives no precipitate with platinum chloride, potassium-cadmium iodide, or with Millon’s reagent.

It forms a platinum salt, (C26H45NO8)2H2PtCl6 + 6H2O, which is precipitated in large six-sided plates on adding alcohol to a mixed solution of platinum chloride and a salt of the base.

Protoveratridine is not poisonous, and does not cause sneezing. Its solutions are very bitter.

§ 475. Rubi-jervine, C26H43NO2, is a crystallisable base wholly different from jervine, yet probably closely allied to it. It forms a light yellow, indistinctly crystalline gold salt (C26H43NO2,HCl,AuCl3): it gives a different play of colours from jervine with sulphuric acid. The concentrated acid dissolves rubi-jervine to a clear yellow fluid, becoming successively dark yellow, brownish yellow, and brownish blood-red, changing after several hours to a brownish purple. On diluting slightly with water the brownish-red liquid, it becomes successively crimson, purple, dark lavender, dark violet, and ultimately light indigo. Its hydrochloride and sulphate are both more soluble than either of the corresponding salts of jervine or pseudo-jervine.

§ 476. Veratralbine, C28H43NO5, an amorphous non-sternutatory base, gives, when a speck of the substance is dissolved in sulphuric acid, a play of colours, becoming successively yellow, dark yellow, brownish orange, and brownish blood-red, with a strong green fluorescence. It yields no acid on saponification.

§ 477. Veratroidine, C32H53NO9, is another base which has been separated by C. Pehkschen. Its melting point is 149°. One part dissolves in 13 of benzene, 59 of chloroform, and 9 of ether. It yields amorphous salts with the mineral acids, and with oxalic and acetic acids. It is precipitated by most of the group reagents. With 11 per cent. solution of hydrochloric acid it gives a beautiful rose colour.

§ 478. Commercial Veratrine.—Commercial veratrine is a mixture of alkaloids, and has usually fairly constant properties, one of which is its intense irritant action on the nostrils. Placed on moist blue-red litmus paper it gives a blue spot. It is but little soluble in water, 1 : 1500; but readily dissolves in alcohol and chloroform; it is but little soluble in amyl alcohol, benzene, and carbon disulphide.

When a very small quantity is treated with a drop of sulphuric acid, the acid in the cold strikes a yellow colour; on warming, the colour becomes violet, slowly changing to orange and cherry red. Sensible to 100th of mgrm. If this test is performed in a test-tube, a green-yellow fluorescence is also seen on the sides of the test-tube.

Commercial veratrine strikes a pink-red colour with hydrochloric acid in the cold if a long time is allowed to elapse, but it at once appears if the acid is warmed, and is permanent. The solution becomes fluorescent if two drops of acetic acid are added.

If a small quantity of commercial veratrine is added to melted oxalic acid and the warming continued, a blood-red colour is obtained.

Veratrine, warmed with syrupy phosphoric acid, develops an odour of butyric acid.

A dark green colour, followed by reddish purple and blue colours, is obtained by adding a sprinkling of finely-powdered sugar to a solution of veratrine in sulphuric acid. This is best seen with a solution of 1 to 10,000; if in dilution of 1 to 100,000 a grass-green colour is produced, followed by purple and blue colours, quickly changing to brown or black.

When two or three drops of sulphuric acid and furfur aldehyde (5 drops to 10 c.c. of acid) are added to minute particles of alkaloids, a more or less characteristic colour makes its appearance; this is particularly the case with veratrine. A few particles rubbed with a glass rod, and moistened with the reagent, gives first a yellowish-green, then an olive-green mixture, the edges afterwards becoming a beautiful blue. On warming, the mixture gradually acquires a purple-violet colour. The blue substance obtained in the cold is insoluble in alcohol, ether, or chloroform. The least amount of water decolorises the solution, and, on adding much water, a fairly permanent yellow solution is obtained.

§ 479. Pharmaceutical Preparations.—The alkaloid is officinal in the English, American, and Continental pharmacopœias. There is also an unguentum veratrinæ—strength about 1·8 per cent. In the London pharmacopœia of 1851 there used to be a wine of white hellebore, the active principle of 20 parts of the root by weight being contained in 100 parts by measure of the wine. Such a wine would contain about 0·084 per cent. of total alkaloids. Of the green hellebore there is a tincture (tinctura veratri viridis), to make which four parts by weight of the root are exhausted by 20 parts by measure of spirits; the strength varies, but the average is 0·02 per cent. of total alkaloids.

§ 480. Fatal Dose.—The maximum dose of the commercial alkaloid is laid down as 10 mgrms. (·15 grain), which can be taken safely in a single dose, but nothing sufficiently definite is known as to what is a lethal dose. 1·3 grm. of the powdered rhizome has caused death, and, on the other hand, ten times that quantity has been taken with impunity, so that at present it is quite an open question.

§ 481. Effects on Animals—Physiological Action.—Experiments on animals have proved that the veratrums act on the sensory nerves of the skin, and those of the mucous membranes of the nose and intestinal canal; they are first excited, afterwards paralysed. When administered to frogs, sugar and lactic acid appear in the urinary excretion. It exercises a peculiar influence on voluntary muscle; the contractility is changed, so that, when excited, there is a long-continuing contraction, and from a single stimulus more heat is disengaged than with healthy muscle; the motor nerves are also affected. The respiration, at first quickened, is then slowed, and finally paralysed. The heart’s action is also first quickened, the blood-pressure at the same time is raised, and the small arteries narrowed in calibre; later follow sinking of the pressure, slowing of the heart, and dilatation of the vessels, and the heart becomes finally paralysed.

§ 482. Effects on Man.—Poisoning by veratrum, sabadilla, or pharmaceutical preparations containing veratrine, is not common. Plenk witnessed a case in which the external application of sabadilla powder to the head caused delirium, and Lentin also relates a case in which an infant at the breast seems to have died from an external application made for the purpose of destroying lice. In both instances, however, there is a possibility that some of the medicament was swallowed.

Blas recorded, in 1861, the case of two children who drank a decoction of white hellebore, the liquid being intended as an external application to an animal. They showed serious symptoms, but ultimately recovered.

A scientific chemist took 3·8 grms. (58 grains) of the tincture of green hellebore for the purpose of experiment. There followed violent symptoms of gastric irritation, vomiting, and diarrhœa, but he also recovered.

Casper relates the poisoning of a whole family by veratrum; from the stomach of the mother (who died) and the remains of the repast (a porridge of lentils) veratrine was separated.

Faber recorded the poisoning of thirty cows by veratrum; eight died, and it is noteworthy that violent poisonous symptoms were produced in animals partaking of their flesh and milk.

§ 483. The symptoms appear soon after the ingestion, and consist of a feeling of burning in the mouth, spreading downwards to the stomach, increased secretion of saliva, and difficulty of swallowing; then follow violent vomiting and diarrhœa, with great pain in the bowels, often tenesmus; there is also headache, giddiness, a feeling of anxiety, and the pupils are dilated. The consciousness is ordinarily intact; the pulse is weak and slow, and the breathing embarrassed; the skin is benumbed. There may be also formicating feelings, and twitchings in the muscles with occasionally the tetanic cramps, which are constantly seen in frogs. In cases which end fatally, the disturbance of the breathing and circulation increases, and death takes place in collapse.

An important case of slow poisoning is on record, in which two brothers, aged twenty-one and twenty-two years, died after nine and eleven weeks of illness, evidently from repeated small doses of the powder of Veratrum album. They became very weak and thin, suffered from diarrhœa and bloody stools, sleeplessness, disturbance of the intellect, and delirium.

§ 484. The post-mortem signs do not appear distinctive; even in the case just mentioned—in which one would expect to find, at all events, an extensive catarrh of the intestinal canal—the results seem to have been negative.

§ 485. Separation from Organic Matters.—The method of Stas (by which the organic matters, whether the contents of the stomach or the tissues, are treated with alcohol, weakly acidified by tartaric acid) is to be recommended. After filtering, the alcoholic extract may be freed from alcohol by careful distillation, and the extract taken up with water. By now acidifying gently the watery extract, and shaking it up with ether and chloroform, fatty matters, resinous substances, and other impurities, are removed, and it may then be alkalised by soda or potash, and the veratrine extracted by ether. The residue should be identified by the hydrochloric acid and by the sulphuric acid and bromine reactions; care should also be taken to ascertain whether it excites sneezing.

A ptomaine, discovered by Brouardel, was described by him as both chemically and physiologically analogous to veratrine. A. M. Deleziniere has since investigated this substance. Only when in contact with air does the analogy to veratrine obtain, and Deleziniere, to ascertain its reactions, studied it when in an atmosphere of nitrogen. It appears to be a secondary monamine, C32H31N, and is in the form of a colourless, oily liquid, with an odour like that of the hawthorn. It is insoluble in water, but alcohol, ether, toluene, and benzene dissolve it readily. It oxidises in the presence of air. The salts are deliquescent.

VIII.—Physostigmine.

§ 486. The ordeal bean of Calabar (Physostigma faba) is a large, all but tasteless, kidney-shaped bean, about an inch in length, and half an inch thick; its convex edge has a furrow with elevated ridges, and is pierced by a small hole at one extremity. The integuments are coffee-brown in colour, thin, hard, and brittle; they enclose two white cotyledons, easily pulverisable, and weighing on an average 3·98 grms. (61 grains). The seed contains at least one alkaloid, termed Physostigmine (first separated in 1864 by Jobst and Hesse), and possibly a second, according to Harnack and Witkowsky, who have discovered in association with physostigmine a new alkaloid, which they call Calabarine, and which differs from physostigmine in being insoluble in ether and soluble in water. It is also soluble in alcohol; and further, the precipitate produced by potassium iodo-hydrargyrate in calabarine solutions is insoluble in alcohol.

§ 487. Physostigmine, or eserine, is not easily obtained in a crystalline state, being most frequently extracted as a colourless varnish, drying into brittle masses. It is, however, quite possible to obtain it in the form of partially-crystalline crusts, or even rhombic plates, by care being taken to perform the evaporation, and all the operations, at as low a temperature as possible, and preferably in a dimly-lit room; for, if the temperature rises to 40°, much of the alkaloid will be decomposed. Hesse recommends that the beans be extracted, alcohol by the alcoholic solution alkalised by sodic carbonate, and the liquid shaken up with ether, which will retain the alkaloid. The ether solution is now separated, and acidified slightly with very dilute sulphuric acid; the fluid, of course, separates into two layers, the lower of which contains the alkaloid as a sulphate, the upper is the ether, which is withdrawn, and the acid fluid passed through a moist filter. The whole process is then repeated as a purification.

Again, Vee, who has repeatedly obtained the alkaloid in a crystalline condition, directs the extraction of the beans by alcohol, the alcoholic solution to be treated as before with sodic carbonate, and then with ether; the ethereal solution to be evaporated to dryness, dissolved in dilute acid, precipitated by sugar of lead, and the filtrate from this precipitate alkalised by potassic bicarbonate, and then shaken up with ether. The ethereal solution is permitted to evaporate spontaneously, the crystalline crusts are dissolved in a little dilute acid, and the solution is lastly alkalised by potassic bicarbonate, when, after a few minutes, crystalline plates are formed.

The formula ascribed to physostigmine is C15H21N3O2. It is strongly alkaline, fully neutralising acids and forming tasteless salts. It is easily melted, and perhaps partly decomposed, at a temperature of 45°; at 100° it is certainly changed, becoming of a red colour, and forming with acids a red solution. It dissolves easily in alcohol, ether, chloroform, and bisulphide of carbon, but is not easily soluble in water.

The salts formed by the alkaloid with the acids are generally hygroscopic and uncrystallisable, but an exception is met with in the hydrobromide, which crystallises in stellate groups. If CO2 is passed into water containing the alkaloid in suspension, a clear solution is obtained; but the slightest warmth decomposes the soluble salt and reprecipitates the alkaloid. The hydrarg-hydroiodide (C15H21N3O2,HI,2HgI) is a white precipitate, insoluble in water, becoming yellow on drying, soluble in ether and alcohol, and from such solutions obtained in crystalline prismatic groups. A heat of 70° melts the crystals, and they solidify again in the amorphous condition.

It gives a precipitate with gold chloride, reducing the gold; also one with mercuric chloride easily soluble in hydrochloric acid. It gives no precipitate with platinum chloride.

§ 488. Tests.—Da Silva’s test for eserine is as follows:—A minute fragment of eserine or one of its salts is dissolved in a few drops of fuming nitric acid; this makes a yellow solution, but evaporated to complete dryness it is pure green. The green substance, called by others chloreserine, dissolves to a non-fluorescent green solution; in water and also in strong alcohol it shows a band in the red between λ670 and λ688, a broader but more nebulous band in the blue and violet between λ400 and λ418, and a very feeble band in the orange.

J. B. Nagelvoort has recommended the following tests:—(a) An amorphous residue of a permanent blue colour is obtained if a trace of the alkaloid, or one of its salts, is evaporated in the presence of an excess of ammonia; this blue alkaloid dissolves in dilute acids with a red colour; sensitiveness 0·00001 gm. (1 : 100000). The solution has beautiful red fluorescence in reflected light; when evaporated, it leaves a residue that is green at first, changing to blue afterwards, the blue residue being soluble in water, alcohol, and chloroform, but not in ether. Chloroform extracts the blue colour from the watery ammoniacal solution only partially. The blue solutions are reddened at first by H2S, and discoloured afterwards. The blue colour is restored by expelling the H2S on the water-bath. (b) A red fluid is obtained when 0·010 gm. eserine or its salicylate, 0·050 gm. of slacked lime, and 1 c.c. of water are added together. Warmed in a water-bath, it turns green, and a piece of red litmus-paper suspended in the test-tube turns blue; a glass rod moistened with HCl gives off the well-known white clouds characteristic of an ammonia reaction. The green solution does not lose its colour by evaporation. Baryta water, added to an eserine solution, gives a white precipitate that turns red when strongly agitated, sensitive to 0·01 mgrm. (1 : 100000).

§ 489. Pharmaceutical Preparations.—The only preparations officinal in this country are a spirituous extract (Extractum physostigmatis), used principally for external application, the dose of which is not more than 18·1 mgrms. (·18 grain), and gelatine discs for the purpose of the ophthalmic surgeon, each disc weighing about ⁄50th grain, and containing ⁄1000 gr. of the alkaloid.

§ 490. Effects on Animals.—A large number of experiments have been made upon animals with physostigmine, most of them with the impure alkaloid, which is a mixture of calabarine and physostigmine. Now, the action of calabarine seems to be the opposite to that of physostigmine—that is, it causes tetanus. Hence, these experiments are not of much value, unless the different proportions of the alkaloids were known. Harnack and Witkowsky made, however, some researches with pure physostigmine, of which the following are the main results:—The smallest fatal dose for rabbits is 3 mgrms. per kilo.; cats about the same; while dogs take from 4 to 5 mgrms. per kilo. Frogs, under the influence of the alkaloid, lie paralysed without the power of spontaneous movement, and the sensibility is diminished; later, the breathing ceases, and the reflex irritability becomes extinguished. The activity of the heart is through ·5 mgrm. slowed, but at the same time strengthened.

The warm-blooded animals experimented upon show rapid paralysis of the respiratory centre, but the animal by artificial respiration can be saved. Fibrillar muscular twitching of all the muscles of the body are observed. Death follows in all cases from paralysis of the respiration. Experiments (first by Bexold, then by Fraser and Bartholow, and lastly by Schroff) have amply shown that atropine is, to a certain extent, an antidote for physostigmine poisoning. Fraser also maintains an antagonism between strychnine and physostigmine, and Bennet that chloral hydrate is antagonistic to physostigmine.

Effects on Man.—The bean has long been used by the superstitious tribes of the West Coast of Africa as an ordeal, and is so implicitly believed in that the innocent, when accused of theft, will swallow it, in the full conviction that their innocency will protect them, and that they will vomit up the bean and live. In this way, no doubt, life has often been sacrificed. Christison experimented upon himself with the bean, and nearly lost his life. He took 12 grains, and was then seized with giddiness and a general feeling of torpor. Being alarmed at the symptoms, he took an emetic, which acted. He was giddy, faint, and seemed to have lost all muscular power; the heart and pulse were extremely feeble, and beat irregularly. He afterwards fell into a sleep, and the next day he was quite well.

In August 1864 forty-six children were poisoned at Liverpool by eating some of the beans, which had been thrown on a rubbish heap, being part of the cargo of a ship from the West Coast of Africa. A boy, aged six, ate six beans, and died. In April of the same year, two children, aged six and three years, chewed and ate the broken fragments of one bean; the usual symptoms of gastric irritation and muscular weakness followed, but both recovered. Physostigmine contracts the iris to a point; the action is quite local, and is confined to the eye to which it is applied. When administered internally, according to some, it has no effect on the eyes, but according to others, it has a weak effect in contracting the pupil. In any case, the difference of opinion shows that the effect, when internally administered, is not one of a marked character.

§ 491. Physiological Action.—The physiological action of physostigmine is strikingly like that of nicotine, which it resembles in being a respiratory poison, first exciting, afterwards paralysing the vagus. Like nicotine, also, it produces a great loss of muscular power; it first excites, and then paralyses the intra-muscular terminations of the nerves; and, again, like nicotine, it induces a tetanus of the intestine. A difference between physostigmine and nicotine exists in the constant convulsive effects of the former, and in the greater influence on the heart of the latter.

§ 492. Post-mortem Appearances.—But little is known relative to the post-mortem appearances likely to be found in human poisoning; redness of the stomach and intestines is probably the chief sign.

§ 493. Separation of Physostigmine.—For the extraction of physostigmine from the fluids of the body, Dragendorff recommends benzene: the alcoholic filtered extract (first acidified) may be agitated with such solvents as petroleum and benzene, in order to remove colouring matter; then alkalised and shaken up with benzene, and the latter allowed to evaporate spontaneously—all the operations being, as before stated, carried on under 40°. If much coloured, it may be purified according to the principles before mentioned. In cases where enough of the extract (or other medicinal preparation) has been taken to destroy life, the analyst, with proper care, would probably not have much difficulty in separating a small quantity of the active principle. It is rapidly eliminated by the saliva and other secretions. In most cases it will be necessary to identify physostigmine by its physiological activity, as well as by its chemical characters. For this purpose a small quantity of the substance should be inserted in the eye of a rabbit; if it contains the alkaloid in question, in twenty minutes, at the very latest, there will be a strong contraction of the pupil, and a congested state of the conjunctival vessels. Further researches may be made with a small quantity on a bird or frog. The chief symptoms observed will be those of paralysis of the respiratory and voluntary muscles, followed by death. If a solution is applied to the web of a frog’s foot, the blood-vessels become dilated. Physostigmine appears, according to Dragendorff and Pander, to act as an irritant, for they always observed gastro-enteritis as a result of the poison, even when injected subcutaneously. The enhanced secretion from all mucous surfaces, and the enlargement of the blood-vessels, are also very constant symptoms. But of all these characteristics, the contraction of the pupil is, for the purposes of identification, the principal. A substance extracted from the tissue or other organic matters, in the manner mentioned, strongly contracting the pupil and giving the bromine reaction, would, in the present state of our knowledge, be indicative of physostigmine, and of that alone.

§ 494. Fatal Dose of Physostigmine.—One mgrm. (·015 grain) as sulphate, given by Vee to a woman subcutaneously, caused vomiting, &c., after half an hour. A disciple of Gubler’s took 2 mgrms. without apparent effect; but another mgrm., a little time after, caused great contraction of the pupil and very serious symptoms, which entirely passed off in four hours. It would thus seem that three times this (i.e., 6 mgrms.) would be likely to be dangerous. If so, man is far more sensitive to physostigmine than dogs or cats; and 3 mgrms. per kilo.—that is, about 205 mgrms. (3 grains)—would be much beyond the least fatal dose.

IX.—Pilocarpine.

§ 495. From the leaves of the jaborandi, Pilocarpus pennatafolius (Nat. Ord. Rutaceæ), two alkaloids have been separated—jaborandi and pilocarpine.

Jaborandi (C10H12N2O3) is a strong base, differing from pilocarpine in its sparing solubility in water, and more ready solubility in ether; its salts are soluble in water and alcohol, but do not crystallise. P. Ghastaing, by treating pilocarpine with a large quantity of nitric acid, obtained nitrate of jaborandi, and operating in the same way with hydrochloric acid, obtained the hydrochlorate of jaborandi; hence, it seems that jaborandi is derived from pilocarpine.

§ 496. Pilocarpine (C11H16N2O2) is a soft gelatinous mass, but it forms with the mineral acids crystallisable salts. The solutions are dextra-rotatory. On boiling with water, it decomposes into trimethylamine and m-pyridine lactic acid,

hence it is a pyridine derivative, and its graphic formula probably

The nitrate and hydrochloride are at present much used in pharmacy. Pilocarpine gives a precipitate with phosphomolybdic acid, potassio-mercuric iodide, and most general alkaloidal reagents, but none that are very distinctive. When a solution of gold chloride is added to one of pilocarpine, a salt falls, having the composition C11H16N2O2,HCl + AuCl3. It is not very soluble in water (about 1 in 4600), and has been utilised for the estimation of pilocarpine. Pilocarpine fused with potash yields trimethylamine, carbon dioxide, butyric, and traces of acetic acid. Pilocarpine dissolves without the production of colour in sulphuric acid; but, with bichromate of potash and sulphuric acid, a green colour is produced. It may be extracted from an aqueous solution made alkaline by ammonia, by shaking up with chloroform or benzene.

§ 497. Tests.—When a little of the alkaloid is mixed with ten times its weight of calomel, and rubbed, and moistened by the breath, the calomel is blackened; cocaine also acts similarly; but the two could not be mistaken for each other. If a solution of mercur-potassium iodide is added to a solution of the hydrochloride, the amorphous precipitate becomes, in the course of a day or two, oily drops. “A solution of iodine in potassium iodide gives in pilocarpine solutions a brown precipitate that often crystallises to feathery brown crystals (microscopically), and of serrated form, something like the blade of a scroll-saw, when the crystallisation is incomplete.”—Flückiger’s Reactions.

§ 498. Effects.—Pilocarpine, given subcutaneously in doses of about 32 mgrms. (⁄2 grain), causes within five minutes a profuse perspiration and salivation, the face becomes flushed, and the whole body sweats; at the same time, the buccal secretion is so much increased that in a few hours over a pint may be secreted. The tears, the bronchial secretion, and the intestinal secretions are also augmented; there are generally headache and a frequent desire to pass water; the pulse is much quickened, and the temperature falls from 1°·4 to 4°: the symptoms last from two to five hours. Langley has shown that the over-action of the submaxillary gland is not affected by section either of the chorda tympani or of the sympathetic supplying the gland. Although pilocarpine quickens the pulse of man, it slows, according to Langley, the heart of the warm-blooded animals, and that of the frog. With regard to the frog, Dr. S. Ringer’s researches are confirmatory. With large doses the heart stops in diastole. If to the heart thus slowed, or even when recently stopped, a minute quantity of atropine be applied, it begins to beat again. There is also a most complete antagonism between atropine and pilocarpine in other respects, atropine stopping the excessive perspiration, and relieving the headache and pain about the pubes, &c. Pilocarpine, given internally, does not alter the size of the pupil, but the sight may, with large doses, be affected. If a solution is applied direct to the eye, then the pupil contracts. No fatal case of its administration has occurred in man. The probable dangerous dose would be about 130 mgrms. (2 grains) administered subcutaneously. Pilocarpine must be classed among the heart poisons.

X.—Taxine.

§ 499. Properties of Taxine.—The leaves and berries, and probably other portions of the yew tree (Taxus baccata), are poisonous. The poison is alkaloidal, and was first separated by Marmé.

Taxine (C37H52O10N).—Taxine cannot be obtained in crystals, but as a snow-white amorphous powder, scarcely soluble in water, but dissolving in alcohol, in ether, and in chloroform; insoluble in benzene. It melts at 82°, gives an intense purple-red, with sulphuric acid, and colours Fröhde’s reagent reddish-violet.

A slightly acid aqueous solution of the alkaloid gives precipitates with all the group reagents and with picric acid.

The salts are soluble in water; the hydrochloride may be obtained by passing gaseous HCl into anhydrous ether. The platinichloride forms a yellow micro-crystalline powder (C37H52O10N)2H2PtCl6. The salts are generally difficult to crystallise.

§ 500. Poisoning by Yew.—Falck has been able to collect no less than 32 cases of poisoning by different parts of the yew—9 were from the berries, and the rest from the leaves. They were all accidental; 20 persons died, or 62·5 per cent.

§ 501. Effects on Animals—Physiological Action.—From the researches of Marmé-Borchers, it appears that taxine acts upon the nervous centres—the nervous trunks themselves and the muscles remaining with their excitability unimpaired, even some time after death. Taxine kills through paralysis of the respiration, the heart beating after the breathing has stopped. The leaves contain much formic acid, and their irritant action on the intestine is referred to this cause.

§ 502. Effects on Man.—Several deaths from yew have resulted in lunatic asylums from the patients chewing the leaves. For example, a few years ago, at the Cheshire County Asylum, a female, aged 41, was suddenly taken ill, apparently fainting, her face pale, her eyes shut, and pulse almost imperceptible. Upon the administration of stimulants, she somewhat revived, but in a little while became quite unconscious. The pupils were contracted, and there were epileptiform convulsions, succeeded by stertorous breathing. These convulsions returned from time to time, the action of the heart became weaker, and there was a remarkable slowing of the respirations, with long intervals between the breathing. The woman died within an hour from the time when her illness was first observed, and within two hours of eating the leaves. Yew leaves were found in her stomach. In another case that occurred at the Parkside Asylum, the patient died suddenly in a sort of epileptic fit. Yew leaves were again found in the stomach. In a case quoted by Taylor, in which a decoction of the leaves was drunk by a girl, aged 15, for the purpose of exciting menstruation, she took the decoction on four successive mornings. Severe vomiting followed, and she died eight hours after taking the last dose. In another case there were also no symptoms except vomiting, followed by rapid death. Mr. Hurt, of Mansfield, has recorded a case of poisoning by the berries. The child died in convulsions before it was seen by any medical man.

From these and other recorded cases, the symptoms seem generally to be a quick pulse, fainting or collapse, nausea, vomiting, convulsions, slow respiration, and death, as a rule sudden and unexpected. We may suppose that the sudden death is really due to a rapid paralysis of the respiration, and suffocation.

§ 503. Post-Mortem Appearances.—In the case of the girl who drank the decoction, nothing unusual was observed in the stomach or organs of the body; but when the leaves have been eaten, usually more or less congestion of the mucous membrane of the stomach, as well as of the bowels, is apparent. In the case of the child who ate the berries (Hurt’s case), the stomach was filled with mucous and half-digested pulp of the berries and seeds. The mucous membrane was red in patches and softened, and the small intestines were also inflamed.

XI.—Curarine.

§ 504. Commercial curare is a black, shining, resinoid mass, about 83 per cent. of which is soluble in water, and 79 in weak spirit. It is a complicated mixture of vegetable extracts, from which, however, a definite principle possessing basic characters (curarine) has been separated.

The extract is an arrow poison prepared by different tribes of Indians in South America, between the Amazon and the Orinoco; therefore, samples are found to vary much in their poisoning properties, although it is noticeable that qualitatively they are the same, and produce closely analogous symptoms. It is supposed that some of the curare is derived from different species of strychnos. This is the more probable, because, as before stated, the South American strychnines paralyse, and do not tetanise. It is not unlikely that the active principles of curare (or woorari) may be methyl compounds similar to those which have been artificially prepared, such as methyl strychnine and methyl brucine, both of which have a curare-like action.

Curarine was first separated by Preyer in a crystalline form in 1865. He extracted curare with boiling alcohol, to which a few drops of soda solution had been added, evaporated off the alcohol, took up the extract with water, and, after filtration, precipitated by phosphomolybdic acid, which had been acidified with nitric acid. The precipitate was dried up with baryta water, exhausted with boiling alcohol, and curarine precipitated from the alcoholic solution by anhydrous ether. It may also be obtained by precipitating with mercuric chloride solution, and throwing out the mercury afterwards by means of hydric sulphide, &c.

Curarine, when pure, forms colourless, four-sided, very hygroscopic prisms of bitter taste, and weakly alkaline reaction; soluble in water and alcohol in all proportions, but with difficulty soluble in amyl alcohol and chloroform, and not at all in anhydrous ether, bisulphide of carbon, or benzene. The base forms crystallisable salts with hydrochloric, nitric, and acetic acids. Curarine strikes a purple colour with strong nitric acid. Concentrated solutions of curarine mixed with dilute glycerin, give an amorphous precipitate with potassic bichromate, and the precipitate treated with sulphuric acid strikes a beautiful blue colour. Curarine chromate is distinguished from strychnine chromate by its amorphous character, and by its comparatively easy solubility. If the chromates of strychnine and curarine be mixed, and the mixed chromates be treated with ammonia, strychnine will be precipitated, and curarine pass into solution, thus forming a ready method of separating them.

§ 505. Physiological Effects.—According to Voisin and Liouville’s experiments, subcutaneous injections of curare on man cause, in small doses, strong irritation at the place of application, swelling, and pain. The temperature of the body is raised from 1° to 2°, and the number of respirations increased from 4 to 8 per minute. The pulse becomes somewhat stronger and more powerful. The urine is increased, and contains sugar. Large doses administered to warm-blooded animals cause, after a short time, complete paralysis of voluntary motion and of reflex excitability, and the animal dies in asphyxia, the heart continuing to beat.

This state is best produced for the purpose of experiment on frogs, and, indeed, is the best test for the poison. A very minute dose injected beneath the skin of a frog soon paralyses both the voluntary and respiratory muscles; the animal continues to breathe by the skin; the heart beats normally, or, perhaps, a little weakly, and the frog may remain in this motionless condition for days and yet recover. Only curare and its congeners have this effect. By tying the femoral artery of one of the frog’s legs before administering the poison, an insight into the true action of the drug is obtained. It is then found that the reflex excitability and power of motion in the leg are retained, although all the rest of the body is paralysed. The only explanation of this is that curare does not act centrally, but paralyses the intramuscular ends of the motor nerves. Curare is eliminated partly through the liver and partly through the kidneys. Dragendorff found it in the fæces, while a striking proof that it is excreted by the kidneys is given by the experiment of Bidder, in which the urine of a frog poisoned by curare was made to poison a second, and the urine of the second, a third. The easy excretion of curare through the kidneys furnishes an explanation of the relatively large dose of curare which can be taken by the stomach without injury. A dose which, given by subcutaneous injection, would produce violent symptoms, perhaps death, may yet be swallowed, and no ill effects follow. It is hence presumed that, in the first case, the poison is, comparatively speaking, slowly absorbed, and almost as fast separated, and put, as it were, outside the body by going into the urine; while, in the other case, the whole dose is thrown suddenly into the circulation.

§ 506. Separation of Curarine.—It is hardly probable that the toxicologist will have to look for curarine, unless it has entered the body by means of a wound or by subcutaneous injection; so that in all cases the absorbed poison alone must be sought for. The seat of entry, the liver, the kidneys, and the urine are the only parts likely to be of any use. Dragendorff recommends the extraction of the tissues with water feebly acidulated with a mineral acid, to precipitate albuminous matters, &c., by strong alcohol, and separate, by means of benzene, fatty matters. The liquid is then made alkaline, and shaken up with petroleum ether, which removes certain alkaloidal matters. It is now evaporated to dryness, mixed with finely-powdered glass, and extracted with absolute alcohol. The alcohol is evaporated to dryness, and any curarine extracted from this residue with water. By very careful drying up of this last extract, and taking it up in alcohol, the alkaloid is said to be obtained so pure as to respond to chemical tests. The identification may be by the colour reaction of sulphuric acid described ante, in all cases supplemented by its physiological action on frogs.

XII.—Colchicine.

§ 507. The whole of the Colchicum autumnale, or common meadow-saffron, is poisonous, owing to the presence of an alkaloid (discovered by Pelletier and Caventou) called Colchicine.

According to Johannson’s experiments, the dried colchicum seeds contain 1·15 per cent. of colchicine; the leaves, 1·459 per cent.; the bulbs, from 1·4 to 1·58 per cent.; and the roots, 0·634 per cent. The frequent poisoning of cattle in the autumn by colchicum, its use in quack pills for rheumatism, and its supposed occasional presence in beer, give it an analytical importance.

§ 508. Colchicine (C22H25NO6) may be extracted from the seeds, &c., in the manner recommended by Hübler:—The seeds are treated, without crushing, by hot 90 per cent. alcohol, and the alcoholic solution evaporated to a syrup, which is diluted with twenty times its bulk of water and filtered; the liquid is next treated with acetate of lead, again filtered, and the lead thrown out by phosphate of soda. Colchicine is now precipitated as a tannate. The precipitation is best fractional, the first and last portions being rejected as containing impurities. The tannate is decomposed in the usual way with litharge and extracted by alcohol.

A simpler method is, however, extraction by chloroform from an aqueous solution, feebly acidified, as recommended by Dragendorff. The parts of the plant are digested in very dilute acid water, and the resulting solution concentrated and shaken up with chloroform, which is best done in a separating tube.

Colchicine contains four methoxyl groups, and its constitutional formula is considered to be C15H9[NH(CH3CO)](COOCH3)(OCH3)3.

Its melting-point is 143°-147°. It is usually a white, gummy mass. It is easily soluble in cold water, in alcohol, and in chloroform. The solutions are lævorotatory. It is hardly soluble in ether. Boiling with dilute acids or alkalies in closed tubes yields colchiceine.

Colchiceine contains three methoxyl groups. It melts at 150°, dissolves but little in cold, copiously in boiling water. Colchiceine appears to be an acid, forming salts with the alkalies.

Zeisel has formed acetotrimethylcolchicinamide (NHAcC15H9(OMe)3CONH3) by heating colchicine with alcoholic ammonia in closed tubes for four hours at 100°. The amide is crystallised from hot alcohol; it is readily soluble in dilute HCl, almost insoluble in water; when a strong hydrochloric acid solution of the amide is treated with a small amount of potassium nitrite a splendid violet colour is produced.

§ 509. Tests.—Ferric chloride, if added to an alcoholic solution of the alkaloid, strikes a garnet red; if to an aqueous solution a green or brownish-green; nitric acid added to the solid substance gives a violet colour. Erdmann’s reagent (nitrosulphuric acid) gives in succession green, dark blue, and violet colours, ultimately turning yellow, changed, on addition of an alkali, to raspberry-red. Mandelin’s reagent (1 grm. of ammonium vanadate in 200 grms. of sulphuric acid) gives a green colour.

§ 510. Pharmaceutical Preparations.—Colchicine itself is officinal in Austria—the wine in the British, French, and Dutch, and the seeds themselves in all the pharmacopœias. The wine of colchicum, officinal in nearly all the pharmacopœias, is made with very different proportions of seeds or bulbs.

The tincture of colchicum is officinal in our own and in all the Continental pharmacopœias; in the British, one part of seeds is exhausted by eight parts of proof spirit.

A tincture of colchicum seeds, examined by Johannson, contained ·18 per cent. of colchicine, and a tincture prepared from the bulbs ·14 per cent.

Colchicum vinegar is not officinal in Britain, but one containing 5·4 per cent. of acetic acid is so in the Netherlands, Germany, and France; the strength appears to be about ·095 per cent. of colchicine.

An extract of colchicum is officinal in Britain and France; and an acetic extract in Britain. The latter is the most active of all the pharmaceutical preparations of colchicum.

Lastly, an oxymel of colchicum is in use in Germany, France, and the Netherlands.

Quack and Patent Medicines.—In all specifics for gout the analyst will naturally search for colchicum. Most gout pills contain the extracts; and liquids, such as “Reynolds’ gout specific,” the wine or the tincture, variously flavoured and disguised.

The strength of the different pharmaceutical preparations may be ascertained by dissolving in chloroform, evaporating off the chloroform, dissolving in water (which is finally acidified by from 7 to 10 per cent. of sulphuric acid), and titrating with Mayer’s reagent (see p. 263). If the solution is diluted so that there is about one part of colchicine in 600 of the solution, then each c.c. of Mayer’s reagent equals 31·7 mgrms. colchicine.

§ 511. Fatal Dose.—In Taylor’s Principles of Medical Jurisprudence is mentioned an instance in which 3⁄2 drachms of colchicum wine, taken in divided doses, caused death on the fourth day. The quantity of the active principle in the colchicum wine, as found by Johannson (Dragendorff), being 0·18 per cent., it follows that 24·4 mgrms. (·378 grain) were fatal, though not given as one dose, so that this quantity may be considered as the least fatal one. Casper puts the lethal dose of colchicine at from 25 to 30 mgrms. (·385 to ·463 grain). It is, however, incontestable that there are cases of recovery from as much as 70 mgrms. (1·08 grain). The lethal dose of the pharmaceutical preparations of colchicum may, on these grounds, be predicted from their alkaloidal contents, and, since the latter is not constant, in any medico-legal inquiry, it may be necessary, where facility is given, to ascertain the strength of the preparation administered.

§ 512. Effects of Colchicine on Animals.—The researches of Rossbach show that the carnivoræ are more sensitive to colchicine than any other order of mammals. Frogs show a transitory excitement of the nervous system, then there is loss of sensation, paralysis of motion, and of the respiratory apparatus; the heart beats after the respiration has ceased. Death follows from paralysis of the respiration. The mucous membrane of the intestine is much congested and swollen.

I have seen cattle die from the effects of eating the meadow-saffron; the animals rapidly lose condition, suffer great abdominal pain, and are generally purged. The farmers, in certain parts of the country, have had extensive losses from want of care and knowledge with regard to colchicum poisoning.

§ 513. Effects of Colchicum on Man.—Colchicum poisoning in man is not very common: 2 deaths (accidental) are recorded in England and Wales during the ten years ending 1892. F. A. Falck was able to collect from medical literature, prior to 1880, 55 cases, and he gives the following analysis of the cases:—In 2, colchicum was taken for suicidal purposes; of the unintentional poisonings, 5 were from too large a medicinal dose of colchicum wine, syrup, or extract, given in cases of rheumatism; in 13 cases, colchicum was used as a purgative; 42 cases were owing to mistaking different preparations for drinks, or cordials—the tincture in 5, and the wine in 14, being taken instead of orange tincture, quinine wine, schnapps or Madeira; in 1 case the corms were added to mulled wine, in another, the leaves consumed with salad; in 16 cases (all children), the seeds of colchicum were eaten. Forty-six of the 55 died—that is, 83·7 per cent.

In the remarkable trial at the Central Criminal Court, in 1862, of Margaret Wilson (Reg. v. Marg. Wilson), who was convicted of the murder of a Mrs. Somers, the evidence given rendered it fairly probable that the prisoner had destroyed four people at different dates by colchicum. The symptoms in all four cases were—burning pain in the throat and stomach, intense thirst, violent vomiting and purging, coldness and clamminess of the skin, excessive depression, and great weakness. One victim died on the second day, another on the fifth, a third on the eighth, and the fourth on the fourteenth day. Schroff witnessed a case in which a man took 2 grms. (nearly 31 grains) of the corms; in one and a half hours he experienced general malaise; on the next day there were flying muscular pains, which at length were concentrated in the diaphragm, and the breathing became oppressed; there was also pain in the neighbourhood of the duodenum, the abdomen was inflated with gas; there was a sickly feeling and faintness. Then came on a sleepy condition, lasting several hours, followed by fever, with excessive pain in the head, noises in the ears, and delirium; there was complete recovery, but the abdomen continued painful until the fifth day.

In another instance, a gentleman, aged 50, had taken twenty-eight of Blair’s gout-pills in four and a half days for the relief of a rheumatic affection. He suffered from nausea, griping pains in the belly, considerable diarrhœa, vomiting, and hiccough; towards the end there was stupor, convulsive twitchings of the muscles, paralysis, and death. The fatal illness lasted fourteen days; he was seen by three medical men at different dates—the first seems to have considered the case one of diarrhœa, the second one of suppressed gout; but Dr. C. Budd was struck with the similarity of the symptoms to those from an acrid poison, and discovered the fact that the pills had been taken. These pills I examined; they were excessively hard, and practically consisted of nothing else than the finely-ground colchicum corms; six pills yielded 8 mgrms. of colchicine, so that the whole twenty-eight would contain 39 mgrms. (⁄5 grain). Dr. Budd considered that the whole of the pills, which were of a stony hardness, remained in the bowels for some time undigested, so that the ultimate result was the same as if the whole had been taken in one dose.

§ 514. The general symptoms produced by colchicum are—more or less burning pain in the whole intestinal tract, vomiting, diarrhœa, with not unfrequently bloody stools; but sometimes diarrhœa is absent. In single cases tenesmus, dysuria, and, in one case, hæmaturia have been noted. The respiration is usually troubled, the heart’s action slowed, the pulse small and weak, and the temperature sinks. In a few cases there have been pains in the limbs; cerebral disturbance is rare; but in two cases (one described ante) there was stupor. Muscular weakness has been observed generally. In a few cases there have been cramps in the calves and in the foot, with early collapse and death.

Post-mortem Appearances.—Schroff found in rabbits poisoned with from ·1 to 1·0 grm. of colchicine, tolerably constantly enteritis and gastritis, and always a thick, pitch-like blood in the heart and veins. Casper has carefully recorded the post-mortem appearances in four labourers, ages ranging from fifteen to forty years, who, finding a bottle of colchicum-wine, and supposing it to be some kind of brandy, each drank a wine-glassful. They all died from its effects. In all four there was great hyperæmia of the brain membranes and of the kidneys. The large veins were filled with thick, dark, cherry-red blood, very similar to that seen in sulphuric acid poisoning. There was an acid reaction of the contents of the stomach. The lungs were moderately congested. The mucous membrane of the stomach of the one who died first was swollen and scarlet with congestion; with the second there was some filling of the vessels at the small curvature; while the stomachs of the third and fourth were quite normal. In 5 cases described by Roux there was also hyperæmia of the brain and kidneys, but no gastritis or enteritis. It is, therefore, evident that there are in man no constant pathological changes from colchicine poisoning.

§ 515. Separation of Colchicine from Organic Matters.—W. Obolonski has recommended the following process:—The finely divided viscera are triturated with powdered glass and digested for twelve hours with alcohol. The liquid is squeezed out and the dry residue washed with alcohol. The extract is concentrated at a temperature not exceeding 80°, and the cooled residue made up to the original volume with alcohol. The filtered liquid is evaporated as before, and this operation repeated until no more clots separate on addition of water. The residue is then dissolved in water, the solution purified by shaking with light petroleum, and the colchicine finally extracted with chloroform.

In cases of poisoning by colchicum at Berlin, Wittstock used the following process:—The contents of the stomach were mixed with a large amount of alcohol, a few drops of HCl added, and the whole well shaken; the fluid was then filtered, and the filtrate evaporated to a syrupy consistence at 37°. The resulting residue was dissolved in distilled water, the fat, &c., filtered off, and the liquid carefully evaporated. From the extract foreign matter was again separated by treatment with alcohol and filtration, and the last filtrate was evaporated to a syrupy consistence. The syrupy fluid was taken up by distilled water, filtered, evaporated to 30 grms., and 2 grms. of calcined magnesia with 90 grms. of ether were added. After a time, the ether was removed, and allowed to evaporate spontaneously. The residue was once more taken up with water, filtered from fat, &c., and evaporated. This final residue gave all the reactions of colchicine. In medico-legal researches, it must be remembered that colchicine is absorbed but slowly, a not insignificant portion remaining in the bowels, with the fæces.

XIII.—Muscarine and the Active Principles of Certain Fungi.

§ 516. The Amanita Muscaria, or fly-blown agaric, is a very conspicuous fungus, common in fir-plantations, about the size and shape of the common mushroom; but the external surface of the pileus is of a bright red, or sometimes of a yellowish cast, and studded over with warts. The common name of the fungus denotes that it was used in former times as a popular insecticide; the fungus was bruised, steeped in milk, and the milk exposed, in the same way as we now expose arsenical fly-papers.

Some peculiar properties of the agaric have long been known to the natives of Kamschatka, and of the north-eastern part of Asia generally. They collect the fungi in the hottest months, and hang them up to dry. The fungus is then rolled up in a kind of bolus, and swallowed without chewing. One large, or two small, fungi will produce a kind of intoxication, which lasts a whole day. It comes on in about two hours’ time, and is very similar to that of alcohol. There is a giddy feeling, the spirits are exalted, the countenance becomes flushed, involuntary actions and words follow, and sometimes loss of consciousness. It renders some persons remarkably active, and proves highly stimulant to muscular exertion; by too large a dose violent spasmodic effects are produced. “So very exciting to the nervous system in many individuals is this fungus, that the effects are often very ludicrous. If a person under its influence wishes to step over a straw or small stick, he takes a stride or a jump sufficient to clear the trunk of a tree. A talkative person cannot keep silence or secrets, and one fond of music is perpetually singing. The most singular effect of the amanita is the influence which it has over the urine. It is said that from time immemorial the inhabitants have known that the fungus imparts an intoxicating quality to that secretion, which continues for a considerable time after taking it. For instance, a man moderately intoxicated to-day will, by the next morning, have slept himself sober, but (as is the custom) by taking a teacup of his urine he will be more powerfully intoxicated than he was the preceding day. It is, therefore, not uncommon for confirmed drunkards to preserve their urine as a precious liquor against a scarcity of the fungus. The intoxicating property of the urine is capable of being propagated; for every one who partakes of it has his urine similarly affected. Thus, with a very few amanitas, a party of drunkards may keep up their debauch for a week. Dr. Langsdorf mentions that by means of the second person taking the urine of the first, the third of the second, and so on, the intoxication may be propagated through five individuals.”

§ 517. A few cases of poisoning by the fly-blown agaric from time to time have occurred in Europe, where it has been eaten in mistake for the edible fungi, or taken by children allured by the bright attractive colours. In these cases the poisonous symptoms noticed have been those of gastro-intestinal irritation, as shown by vomiting and diarrhœa, dilated pupils, delirium, tetanic convulsions, slow pulse, stertorous breathing, collapse, and death. In a few cases epileptic attacks and trismus have been observed. The course is usually a rapid one, the death occurring within twelve hours. In cases of recovery, convalescence has been prolonged.

The post-mortem characteristics are not distinctive, a fluid condition of the blood, hyperæmia of the brain, liver, and kidneys has been noticed.

§ 518. Muscarine.—These effects are partly due to an undiscovered, toxic substance—which seems to be destroyed at the temperature of boiling water, and is probably of rather easy destructibility—and of a very definite poisonous alkaloid (muscarine) first separated by a complex process by Schmiedeberg and Koppe in 1869. It is a trimethylammonium base, and has lately been formed synthetically by Schmiedeberg and Harnack, by treating cholin with nitric acid. Muscarine is isomeric with betain and oxycholin, from which it is separated by its fluorescence and poisonous properties.

The structural formula of muscarine, and its connection with choline, is as follows:—

An atom of hydrogen from the choline, CH2, group, being replaced by hydroxyl.

Muscarine is a colourless, strongly alkaline, syrupy fluid, which, if allowed to stand over sulphuric acid, becomes gradually crystalline, but liquefies again on exposure to the atmosphere. It dissolves in water in every proportion, and also in alcohol, but is very little soluble in chloroform, and insoluble in ether. It is not precipitated by tannin: it forms salts with acids, and gives precipitates with auric chloride, phosphotungstic, and phosphomolybdic acids, and also with potassio-mercuric iodide. The last precipitate is at first amorphous, but it gradually becomes crystalline. This was the compound used by the discoverers to separate the base. With many other general alkaloidal reagents muscarine forms no compound that is insoluble, and therefore gives no precipitate, such, e.g., as iodine with potassic iodide, picric acid, and platinic chloride. Muscarine is a stronger base than ammonia, and precipitates copper and iron oxides from solutions of their salts. Muscarine is very poisonous; 2 to 4 mgrms. are sufficient in subcutaneous injection to kill cats in from two to twelve hours—larger doses in a few minutes; but with rabbits the action is less intense. Cats become salivated, their pupils contract, they vomit, and are purged, the breathing becomes frequent, and there is marked dyspnœa. At a later stage the respirations are slower, and there are convulsions, and death.

The alkaloid has also been tried on man. Doses of from 3 to 5 mgrms., injected subcutaneously, cause, after a few minutes’ profuse salivation, increased frequency of the pulse, nausea, giddiness, confusion of thought and myosis, but no vomiting, and no diarrhœa. Small quantities applied to the eye cause, after a few minutes, a derangement of the accommodation, but no change in the size, of the pupil; larger quantities cause also myosis, which depends upon an excitement of the sphincter iridis, or of the oculomotorius.

§ 519. The actions of muscarine and atropine are to a great extent antagonistic. This is especially and beautifully demonstrated by the effects of the two substances on the frog’s heart. The action of muscarine upon the heart is to excite the inhibitory nerve apparatus, while the action of atropine is to paralyse the same system. One mgrm. of muscarine, injected subcutaneously into a frog, arrests the heart in diastole, but if a suitable dose of atropine is applied to the heart thus arrested, it begins to beat again; or, if atropine is first given, and then muscarine, the heart does not stop. The muscarine heart, when it has ceased to beat, may be successfully stimulated by galvanism. Muscarine at first excites the respiratory centre, and then paralyses it.

§ 520. Detection of Muscarine in the Body.—Muscarine itself is not likely to be taken as a poison or administered; but if it is sought for in the fly-blown agaric, or in the tissues or organs of persons who have been poisoned by the fungus, the process of Brieger appears the best. The process depends upon the fact that muscarine gives a soluble mercuric chloride compound, and is not precipitated by chloride of platinum, whilst most other substances accompanying it give more or less insoluble precipitates. The substances are treated with water acidulated with hydrochloric acid, and the acidulated extract concentrated (best in a vacuum) to a syrup. The syrupy residue is now treated with water, and the solution precipitated by means of mercuric chloride solution and any precipitate filtered off; the filtrate is freed from mercury by SH2, and evaporated to a syrup; the syrup is repeatedly extracted with alcohol, and the alcoholic solution precipitated with platinum chloride and any precipitate filtered off. The filtrate is freed from alcohol, and all the platinum thrown out of solution by SH2; the aqueous filtrate is now concentrated to a small volume, and again platinum chloride added, any precipitate which forms is filtered off, and the final filtrate allowed to crystallise. If muscarine be present, a crystalline compound of muscarine platinum chloride will form.

The crystals are usually octahedral in form, and have the composition (C5H14NO2Cl)2PtCl4; the percentage of platinum is 30·41.

It would probably be necessary to identify farther, by the action of the poison on a frog.

§ 521. The Agaricus phalloides, a common autumn fungus, has been several times mistaken for mushrooms, and has proved fatal; of some 53 cases collected by Falck, no less than 40, or 75 per cent., were fatal; the real mortality is much lower than this, for it is only such cases that are pronounced and severe which are likely to be recorded. The fungus contains a toxalbumin which has been named “phallin.” The action of this toxalbumin is to dissolve the blood corpuscles; according to Kobert, even one 250,000th dilution produces “polycholie,” with all its consequences, such as the escape of hæmoglobin and its decomposition products in the blood and urine, multiple blood coagulation through the fibrin ferment becoming free, and serious cerebral disturbance. If into a dog, cat, or rabbit, only 0·5 mgrm. of phallin be injected intravenously, within from twenty to thirty minutes blood from a vein shows that the serum has a red colour.

The symptoms in man first appear in from three to forty-eight hours; there is mostly diarrhœa, violent vomiting, with cramp in the legs, cyanosis, and collapse. There are also nervous phenomena, convulsions, trismus, and, in a few cases, tetanic spasms. The pulse, in seven cases described by Maschka, was very small, thready, and quick, but in others, again, small and slow. The pupils have in some cases been dilated, in others unchanged. Death is generally rapid. In two of Maschka’s cases from sixty to sixty-eight hours after the investigation, but in the rest from twelve to eighteen hours. Life may, however, be prolonged for several days. In a case recorded by Plowright, in which a boy had eaten a piece of the pileus, death occurred on the fourth day.

§ 522. The post-mortem appearances observed in Maschka’s seven cases were—absence of cadaveric rigidity, dilatation of the pupil, a dark red fluid condition of the blood, numerous ecchymoses in the pleura, in the substance of the lungs, the pericardium, the substance of the heart, the liver, kidneys, and spleen. The mucous membrane of the digestive canal presented nothing characteristic. In two cases there were a few ecchymoses, and in one the mucous membrane of the stomach was softened, red, and easily detached. In one case only were any remnants of the fungus found, by which the nature of the substance eaten could be determined. The bladder in each case was full. In three cases a fatty degeneration of the liver had commenced. The same appearance was met with in some of the older cases related by Orfila.

§ 523. The Agaricus pantherinus is said to be poisonous, although Hertwig found it to have no action when given to dogs.

The Agaricus ruber, a bright-hued fungus, growing profusely on the Hampshire coast, of a purple-red colour—the colouring-matter not only covering the pileus, but also extending down the stipe—is poisonous, and has recently been chemically investigated by Phipson, who has identified a colouring-matter ruberine, and an alkaloid agarythrine. Agarythrine is separated by macerating the fungus (from which the skin containing the colouring-matter has been removed) as completely as possible in water acidulated with 8 per cent. of hydrochloric acid. The filtered solution is neutralised by sodic carbonate, and the alkaloid shaken up with ether. On evaporation the ether leaves a white, somewhat greasy-looking substance, having a bitter burning taste, and easily fusible into yellow globules, giving forth an odour like quinoleine; it is soluble in alcohol and ether. From Phipson’s observations it would appear probable that the red colouring-matter is derived from a decomposition of this alkaloidal substance. A rose-red colour is produced by the action of nitric acid, and chlorinated lime first reddens and then bleaches it. Buchwald has recorded three cases of poisoning by this fungus; the patients were labourers, who, after eating the fungus, suffered from vomiting, thirst, a “drunken” condition, cramp, albuminuria, and disturbance of the sensory functions. The fungus causes in cats myosis, but is said not to affect rabbits.

§ 524. The Soletus satanas, or luridus (Lenz), is poisonous; very small quantities of the uncooked fungus caused in Lenz, who experimented upon its properties, violent vomiting. In cases in which this fungus has been eaten accidentally, the symptoms have been very similar to cholera.

§ 525. The Common Morelle seems under certain conditions to be poisonous. From six to ten hours after ingestion there have appeared depression, nausea, jaundice, dilated pupils, and in the worst cases at the end of the first day, delirium, somnolence, and muscular cramps, followed by collapse and death. In a case observed by Kromholz, the post-mortem appearances were jaundice, a dark fluid state of the blood, and hyperæmia of the brain and liver. Boström fed a dog with 100 grms. of the fresh young morelle; the animal died on the third day, and the canaliculi of the kidney were found filled with hæmoglobin, partly amorphous, and partly crystalline.