PART VI.—ALKALOIDS AND POISONOUS VEGETABLE PRINCIPLES SEPARATED FOR THE MOST PART BY ALCOHOLIC SOLVENTS. (continued 5)

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[524] 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.[525]

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),[526] 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[527] 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.[528] 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.[529]

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.[530]

§ 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.[531] 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.[532]

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[533] 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,[534] 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,[535] was described by him as both chemically and physiologically analogous to veratrine. A. M. Deleziniere[536] 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.[537] 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[538] 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[539] 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 ¹⁄₅₀th grain, and containing ¹⁄₁₀₀₀ 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[540] 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,[541] 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. (¹⁄₂ 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,[542] 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.[543]

§ 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,[544] 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[545] 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,[546] 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.[547]

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.[548] 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[549] 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 3¹⁄₂ 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[550] 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,[551] 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. (³⁄₅ 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[552] 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.”[553]

§ 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[554] 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.[555] It is a trimethylammonium base, and has lately been formed synthetically by Schmiedeberg and Harnack,[556] 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:—

Choline.

Muscarine.

Choline.

Muscarine.

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,[557] 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,[558] 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[559] 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.[560]

DIVISION II.—GLUCOSIDES.

I.—Digitalis Group.

§ 526. The Digitalis purpurea, or foxglove, is a plant extremely common in most parts of England, and poisoning may occur from the accidental use of the root, leaves, or seeds. The seeds are very small and pitted; they weigh 1126 to a grain (Guy), are of a light brown colour, and in form somewhat egg-shaped. The leaves are large, ovate, crenate, narrowed at the base, rugous, veined, and downy, especially on the under surface. Their colour is a dull green, and they have a faint odour and a bitter, nauseous taste. The leaf is best examined in section. Its epidermis, when fresh, is seen to consist of transparent, hexagonal, colourless cells, beneath which, either singly or in groups, there are round cells of a magenta tint, and beneath these again a layer of columnar cells, and near the lower surface a loose parenchyma. The hairs are simple, appearing scantily on the upper, but profusely on the lower, surface; each is composed of from four to five joints or cells, and has at its base a magenta-coloured cell. The small leaves just below the seed-case, and the latter itself, are studded with glandular hairs. The root consists of numerous long slender fibres.

§ 527. Chemical Composition.—It is now generally accepted that there exist in the foxglove, at least, four distinct principles—digitalin, digitonin, digitoxin, and digitalein. Besides these there are several others of more or less definite composition, which are all closely related, and may be derived from a complex glucoside by successive removals of hydrogen in the form of water.

The following is the theoretical percentage composition of the digitalins, the identity of which has been fairly established. They are arranged according to their percentage in carbon:—

TABLE SHOWING THE COMPOSITION OF THE DIGITALINS.

Name. Formula. Percentage Composition.

Digitalein, C₂₁H₄₆O₁₁ C. 53·16 per cent. H. 8·08 per cent.

Digitonin,[561] C₃₁H₅₂O₁₇ C. 53·44 „ H. 7·46 „

Digitalin, C₅₄H₈₄O₂₇ C. 58·16 „ H. 3·65 „

Digitaletin, C₄₄H₃₀O₁₈ C. 62·41 „ H. 3·54 „

Digitoxin, C₂₁H₃₂O₇ C. 63·63 „ H. 8·08 „

Digitaleretin, C₄₄H₃₈O₁₈ C. 66·05 „ H. 4·58 „

Paradigitaletin, C₄₄H₃₄O₁₄ C. 67·17 „ H. 4·3 „

§ 528. Digitalein is a colourless, amorphous body, easily soluble in water and in cold absolute alcohol. It may be precipitated from an alcoholic solution by the addition of much ether. It is with difficulty soluble in chloroform, and insoluble in ether. It is precipitated from a watery solution by tannin, or by basic lead acetate; saponification by dilute acids splits it up into glucose and digitaleretin. It has a sharp, acrid taste, and the watery solution froths on shaking.

§ 529, Digitonin, a white amorphous body, has many of the characters of saponin. Like saponin, it is easily soluble in water, and the solution froths, and, like saponin again, it is precipitated by absolute alcohol, by baryta water, and by basic lead acetate. It may be readily distinguished from saponin by treating a watery solution with sulphuric or hydrochloric acid. On saponifying, it is split up into digitogenin, galactose, and dextrose. On heating, a beautiful red colour develops. It does not give the bromine reaction.

Digitogenin is insoluble in water and aqueous alkalies; it is somewhat soluble in alcohol, chloroform, and glacial acetic acid; it forms a crystalline compound with alcoholic potash, which is strongly alkaline, and not very soluble in alcohol.

§ 530. Digitalin, when perfectly pure, forms fine, white, glittering, hygroscopic needles, or groups of crystalline tufts; it is without smell, but possesses a bitter taste, which is at once of slow development and of long endurance. On warming, it becomes soft under 100°, and, above that temperature, is readily decomposed with evolution of white vapours. It is insoluble in water, in dilute soda solution, in ether, and in benzene. It is soluble in chloroform, especially in chloroform and alcohol, and dissolves easily in warm acetic acid; twelve parts of cold and six of boiling alcohol of 90 per cent. dissolve one of digitalin. Dilute hydrochloric or sulphuric acid decompose it into glucose and digitaletin (C₄₄H₃₀O₁₈); if the action is prolonged, digitaleretin (C₄₄H₃₈O₁₈), and finally dehydrated digitaleretin, are formed. Concentrated sulphuric acid dissolves it with the production of a green colour, which by bromine passes into violet-red, but on the addition of water becomes green again. Hydrochloric acid dissolves it with the production of a greyish-yellow colour, passing gradually into emerald green; water precipitates from this solution a resinous mass.

§ 531. Digitaletin.—A substance obtained by Walz on treating his digitalin by dilute acids. It is crystalline, and its watery solution tastes bitter. It melts at 175°, and decomposes, evolving an acid vapour at about 206°. It dissolves in 848 parts of cold, and 222 of boiling, water; in 3·5 parts of cold, and in from 2 to 4 of boiling, alcohol. It is with difficulty soluble in ether. It dissolves in concentrated sulphuric acid, developing a red-brown colour, which, on the addition of water, changes to olive-green. On boiling with dilute acids, it splits up into sugar and digitaleretin.

§ 532. Digitoxin always accompanies digitalin in the plant, and may by suitable treatment be obtained in glittering needles and tabular crystals. It is insoluble in water and in benzene. It dissolves with some difficulty in ether, and is readily dissolved by alcohol or by chloroform. On boiling with dilute acids, it is decomposed into an amorphous, readily soluble body,—Toxiresin. Digitoxin, according to Schmiedeberg, only exists in the leaves of the digitalis plant, and that in the proportion of 1 part in 10,000. Digitalin and digitoxin are par excellence the poisonous principles of the plant. Toxiresin is also intensely poisonous. It may be obtained in crystals by extracting the dry exhausted leaves with alcohol of 50 per cent., precipitating with lead acetate, and washing the precipitate first with a dilute solution of sodium carbonate (to remove colouring-matter), and then with ether, benzene, and carbon disulphide, in all of which it is insoluble; on decomposing the lead compound, digitoxin may be obtained in colourless scales or needle-shaped crystals.

§ 533. Digitaleretin, the origin of which has been already alluded to, is a yellowish-white, amorphous powder, possessing no bitter taste, melting at 60°, soluble in ether or in alcohol, but insoluble in water.

Paradigitaletin is very similar to the above, but it melts at 100°, and is insoluble in ether.

§ 534. Several other derivatives have been obtained and described, such as the inert digitin, digitalacrin, digitalein, and others, but their properties are, as yet, insufficiently studied. Digitalin, as well as digitoxin, may now be obtained pure from certain firms, but the ordinary digitalin of commerce is, for the most part, of two kinds, which may be distinguished as French and German digitalin. The French digitalin, or the digitalin of Homolle, is prepared by treating an aqueous extract of the digitalis plant with lead acetate, and freeing the filtrate from lead, lime, and magnesia, by successive additions of alkaline carbonate, oxalate, and phosphate, and then precipitating with tannin. The tannin precipitate is treated with litharge, and the digitalins boiled and extracted from the mass by means of alcohol, and lastly, purifying with animal charcoal. Crystals are in this way obtained, and by removing all substances soluble in ether by that solvent, digitalin may be separated. The German digitalin is prepared according to the process of Walz, and is extracted from the plant by treatment with alcohol of ·852. The alcohol is removed by evaporation, and the alcoholic extract taken up with water; the watery extract is treated with lead acetate and litharge, filtered, the filtrate freed from lead by hydric sulphate, and the excess of acid neutralised by ammonia, and then tannin added to complete precipitation. The precipitate is collected and rubbed with hydrated oxide of lead, and the raw digitalin extracted by hot alcohol. The alcohol, on evaporation, leaves a mixture of digitalin mixed with other principles and fatty matter. If sold in this state, it may contain from 2 to 3 per cent. of digitalein and digitonin. On treating the mixture with ether, digitalin with some digitaletin is left behind, being almost insoluble in ether. Since, however, digitaletin is very insoluble in cold water, by treating the mixture with eight parts of its weight of cold water, digitalin is dissolved out in nearly a pure state. It may be further purified by treating the solution with animal charcoal, recrystallisation from spirit, &c.

§ 535. Reactions of the Digitalins.—Digitonin is dissolved by dilute sulphuric acid (1 : 3) without colour, and the same remark applies to hydrochloric acid; on warming with either of these acids, a violet-red colour appears; this reaction thus serves to distinguish digitonin from the three other constituents, as well as from saponin.

Sulphuric and gallic acids colour the glucosides of digitalin, digitalein, and digitonin, red, but not digitoxin, which can be identified in this way.

Sulphuric acid and bromine give with digitalin a red, and with digitalein a violet coloration, which, on the addition of water, change respectively into emerald and light green. This, the most important chemical test we possess, is sometimes called Grandeau’s test; it is not of great delicacy, the limit being about ·1 mgrm.

§ 536. Pharmaceutical Preparations of Digitalin.—Digitalin itself is officinal in the French, Belgium, Portuguese, Russian, Spanish, and Austrian pharmacopœias. It is prepared in our own by making a strong tincture of the leaves at 120° F.; the spirit is then evaporated off, and the extract heated with acetic acid, decolorised by animal charcoal, and filtered. After neutralisation with ammonia, the digitalin is precipitated with tannin, and the tannate of digitalin resolved into tannate of lead and free digitalin, by rubbing it with oxide of lead and spirit.

Digitalis leaf is officinal in most of the pharmacopœias.

Tincture of digitalis is officinal in our own and all the Continental pharmacopœias, and an ethereal tincture is used in France and Germany.

An Acetum digitalis is officinal in the Netherlands and Germany; an extract and infusion are also used to some extent.

With regard to the nature of the active principle in these different preparations, according to Dragendorff, digitonin and digitalein are most plentiful in the acetic and aqueous preparations; whilst in the alcoholic, digitalin, digitoxin, and digitalein are present.

According to Schmiedeberg, commercial digitalin contains, in addition to digitoxin, digitonin, digitalin, and digitalein; of these, digitonin is greatest in amount.[562]

§ 537. Fatal Dose.—The circumstance of commercial digitalin consisting of varying mixtures of digitoxin, digitalin, and digitalein, renders it difficult to be dogmatic about the dose likely to destroy life. Besides, with all heart-poisons, surprises take place; and very minute quantities have a fatal result when administered to persons with disease of the heart, or to such as, owing to some constitutional peculiarity, have a heart easily affected by toxic agents. Digitoxin, according to Kopp’s[563] experiments, is from six to ten times stronger than digitalin or digitalein. Two mgrms. caused intense poisonous symptoms. Digitoxin is contained in larger proportions in Nativelle’s digitalin than in Homolle’s, or in the German digitalin. The digitalin of Homolle is prescribed in 1 mgrm. (·015 grain) doses, and it is thought dangerous to exceed 6 mgrms.

Lemaistre has, indeed, seen dangerous symptoms arise from 2 mgrms. (·03 grain), when administered to a boy fifteen years old. It may be predicated from recorded cases and from experiment, that digitoxin would probably be fatal to an adult man in doses of 4 mgrms. (¹⁄₁₆ grain), and digitalin, or digitalein, in doses of 20 mgrms. (·3 grain). With regard to commercial digitalin, as much as from 10 to 12 mgrms. (·15 to ·18 grain) have been taken without a fatal result; on the other hand, 2 mgrms. gave rise to poisonous symptoms in a woman (Battaille). Such discrepancies are to be explained on the grounds already mentioned. It is, however, probable that 4 mgrms. (or ¹⁄₁₆ grain) of ordinary commercial digitalin would be very dangerous to an adult.

It must also, in considering the dose of digitalin, be ever remembered that it is a cumulative poison, and that the same dose—harmless if taken once—yet, frequently repeated, becomes deadly: this peculiarity is shared by all poisons affecting the heart. When it is desired to settle the maximum safe dose for the various tinctures, extracts, and infusions of digitalis used in pharmacy, there is still greater difficulty, a difficulty not arising merely from the varying strength of the preparations, but also from the fact of the vomiting almost invariably excited by large doses. Individuals swallow quantities without death resulting, simply because the poison is rapidly expelled; whereas, if the œsophagus was ligatured (as in the experiments on the lower animals formerly favoured by the French school of toxicologists), death must rapidly ensue. The following table is a guide to the maximum single dose, and also the amount safe to administer in the twenty-four hours in divided doses. As a general rule, it may be laid down that double the maximum dose is likely to be dangerous:—

TABLE SHOWING THE MAXIMUM SINGLE DOSE, AND MAXIMUM QUANTITY OF THE DIFFERENT PREPARATIONS OF DIGITALIS, WHICH CAN BE ADMINISTERED IN A DAY.

Single Dose. Per Day.

Grains or Minims. Grammes or c.c’s. Grains or Minims. Grammes or c.c’s.

Powdered Leaves, 4 ¹⁄₂ grns. ·3 grm. 15 ·4 grns. 1 ·0 grm.

Infusion, 480 m. 28 ·3 c.c. 1440 m. 84 ·9 c.c.

Tincture, 45 m. 3 c.c. 135 m. 9 c.c.

Digitalin, ·03 grn. ·002 grm. ·09 grn. ·006 grm.

Extract, 3 ·0 „ ·2 „ 12 ·0 „ ·8 „

§ 538. Statistics.—The main knowledge which we possess of the action of digitalis is derived from experiments on animals, and from occasional accidents in the taking of medicines; but in comparison with certain toxic agents more commonly known, the number of cases of death from digitalis is very insignificant. Of 42 cases of digitalis-poisoning collected by Husemann, 1 was criminal (murder); 1 the result of mistaking the leaves for those of borage; 42 were caused in medicinal use—in 33 of these last too large a dose had been given, in 3 the drug was used as a domestic remedy, in 2 of the cases the prescription was wrongly read, and in 1 digitalis was used as a secret remedy. Twenty-two per cent. of the 45 were fatal.

§ 539. Effects on Man.—It was first distinctly pointed out by Tardieu that toxic doses of digitalis, or its active principles, produced not only symptoms referable to an action on the heart, but also, in no small degree, gastric and intestinal irritation, similar to that produced by arsenic. Tardieu also attempted to distinguish the symptoms produced by the pharmaceutical preparations of digitalis (the tincture, extract, &c.), and the glucoside digitalin; but there does not appear a sufficient basis for this distinction. The symptoms vary in a considerable degree in different persons, and are more or less tardy or rapid in their development, according to the dose. Moderate doses continued for some time (as, for example, in the persistent use of a digitalis medicine) may produce their first toxic effects even at the end of many days; but when a single large dose is taken, the symptoms are rarely delayed more than three hours. They may commence, indeed, in half an hour, but have been known to be retarded for more than twenty-four hours, and the longer periods may be expected if digitalis is given in hard, not easily soluble pills. There is commonly a feeling of general malaise, and then violent retching and vomiting. The pulse at first may be accelerated, but it soon is remarkably slowed—it sinks commonly down to 50, to 40, and has even been known as low as 25. To these symptoms, referable to the heart and to the digestive tract, are added nervous troubles; there are noises in the ears, and disturbances of vision. In a case related by Taylor, a red-coal fire seemed to the patient to be of a blue colour; in another, related by Lersch,[564] there was blindness for eighteen hours, and for some time a confusion in the discrimination in colours; quiet delirium has also been noticed. As the case proceeds, the gastric symptoms also increase in severity; the tongue Christison, in one case, noticed to be enormously swollen, and the breath fœtid. Diarrhœa is commonly present, although also sometimes absent. The action of the kidneys is suppressed. Hiccough and convulsions close the scene.

In the cumulative form, the symptoms may suddenly burst out, and the person pass into death in a fainting-fit without any warning. As a rare effect, hemiplegia may be mentioned.

This brief résumé of the symptoms may be further illustrated by the following typical cases:—A recruit, aged 22, desiring to escape from military service, went to a so-called “Freimacher” who gave him 100 pills, of which he was to take eight in two doses daily. Eleven days after the use of the pills, he became ill, and was received into hospital, where he suddenly died after three weeks’ treatment. His malady was at first ascribed to gastric catarrh; for he suffered from loss of appetite, nausea, and constipation. He complained of pain in the head, and giddiness. His breath smelled badly, and the region of the stomach was painful on pressure. The pulse was slow (56), the temperature of the body normal. Towards the end, the pulse sank to 52; he suffered from vomiting, noise in the ears, troubles of vision, great weakness, and later, hiccough and swelling in the neck. The mere act of standing up in order to show his throat caused him to faint; on the same day on which this occurrence took place, he suddenly died on the way to the nightstool. Thirteen of the pills were found in the patient’s clothes, and from a chemical and microscopical examination it was found that they contained digitalis leaf in fine powder. The quantity which the unfortunate man took in the four weeks was estimated at 13·7 grms. (= about 211 grains).

Two of his comrades had also been to the “Freimacher,” and had suffered from the same symptoms, but they had left off the use of the medicine before any very serious effect was produced.[565][566]

An instructive case of poisoning by digitoxin occurred in the person of Dr. Koppe, in the course of some experiments on the drug. He had taken 1·5 mgrm. in alcohol without result; on the following day (May 14) he took 1 mgrm. at 9 A.M., but again without appreciable symptoms. Four days later he took 2 mgrms. in alcoholic solution, and an hour afterwards felt faint and ill, with a feeling of giddiness; the pulse was irregular, of normal frequency, 80 to 84. About three hours after taking the digitoxin, Dr. Koppe attempted to take a walk, but the nausea, accompanied with a feeling of weakness, became so intense that he was obliged to return to the house. Five hours after the dose, his pulse was 58, intermittent after about every 30 to 50 beats. Vomiting set in, the matters he threw up were of a dark green colour; after vomiting he felt better for a quarter of an hour, then he again vomited much bilious matter; the pulse sank to 40, and was very intermittent, stopping after every 2 or 3 beats. Every time there was an intermission, he felt a feeling of constriction and uneasiness in the chest. Six and a quarter hours after the dose there was again violent vomiting and retching, with paleness of the face. The muscular weakness was so great that he could not go to bed without assistance. He had a disorder of vision, so that the traits of persons well-known to him were changed, and objects had a yellow tint. He had a sleepless night, the nausea and vomiting continuing. During the following day the symptoms were very similar, and the pulse intermittent, 54 per minute. He passed another restless night, his short sleep being disturbed by terrible dreams. On the third day he was somewhat better, the pulse was 60, but irregular and still intermittent; the nausea was also a little abated. The night was similar in its disturbed sleep to the preceding. He did not regain his full health for several days.[567]

A third case may be quoted, which differs very markedly from the preceding, and shows what a protean aspect digitalin poisoning may assume. A woman, twenty-three years old, took on June 26th, at 7 A.M., for the purpose of suicide, 16 granules of digitalin. Two hours later there was shivering and giddiness, so that she was obliged to go to bed. In the course of the day she had hallucinations. In the evening at 8 P.M., after eating a little food, she had a shivering fit so violent that her teeth chattered; there was cold sweat, and difficulty in breathing; she became gradually again warm, but could not sleep. At 1 A.M. the difficulty of breathing was so great that she dragged herself to the window, and there remained until 3 A.M., when she again went back to bed, slept until 7 A.M., and woke tolerably well. Since this attempt of self-destruction had failed, she took 40 granules. After one hour she became giddy, had hallucinations, chilliness, cold sweats, copious vomiting, and colicky pains; there was great muscular weakness, but no diarrhœa. Towards evening the vomiting became worse. There was no action of the bowels, nor was any urine passed; she felt as if her eyes were prominent and large. The sufferings described lasted during the whole night until five o’clock the following day, when the vomiting ceased, whilst the hallucinations, chilliness, and cold sweat continued; and the thirst, sick feeling, and weakness increased. The next morning, a physician found her motionless in bed, with pale face, notable double exophthalmus, dilated pupils, and cold skin, covered with sweat; the pulse was small and intermittent, sometimes scarcely to be felt (46 to 48 per minute); the epigastrium was painful on pressure. She passed this second night without sleep, and in the morning the pulse had risen from 56 to 58 beats, but was not quite so intermittent. There was some action of the bowels, but no urine was passed, nor had any been voided from the commencement; the bladder was not distended. The following (third) day some red-coloured, offensive urine was passed; the skin was warmer, and the pulse from 60 to 64, still somewhat intermittent—from this time she began to improve, and made a good recovery.[568]

§ 540. Physiological Action of the Digitalins.—Whatever other physiological action this group may have, its effect on the heart’s action is so prominent and decided, that the digitalins stand as a type of heart poisons. The group of heart poisons has been much extended of late years, and has been found to include the following:—Antiarin, an arrow poison; helleborin, a glucoside contained in the hellebore family; a glucoside found in the Apocynaceæ, Thevatii neriifolia, and Thevatia iccotli; the poisonous principle of the Nerium oleander and N. odorum; the glucoside of Tanghinia venenifera; convallamarin, derived from the species of Convallaria; scillotoxin, from the squill; superbin, from the Indian lily; and the alkaloid erythrophlœin from the Erythrophlœum judiciale (see p. 432 et seq.). This list is yearly increasing.

§ 541. Local Action.—The digitalins have an exciting or stimulating action if applied to mucous membranes—e.g., if laid upon the nasal mucous surface, sneezing is excited; if applied to the eye, there is redness of the conjunctivæ with smarting; if to the tongue, there is much irritation and a bitter taste. The leaves, the extract, and the tincture all have this directly irritating action, for they all redden and inflame mucous membranes.

§ 542. Action on the Heart.—The earlier experimenters on the influence of digitalis on the heart were Stannius and Traube. Stannius[569] experimented on cats, and found strong irregularity, and, lastly, cessation in diastole, in which state it responded no longer to stimuli. Rabbits and birds—especially those birds which lived on plants—were not so susceptible, nor were frogs.

Traube[570] made his researches on dogs, using an extract, and administering doses which corresponded to from ·5 to 4·0 grms. He divided the symptoms witnessed into four stages:—

1st Stage.—The pulse frequently diminishes, while the pressure of the blood rises.

2nd Stage.—Not seen when large doses are employed; pulse frequency, as well as blood pressure, abnormally low.

3rd Stage.—Pressure low, pulse beats above the normal frequency.

The slowing of the heart[571] is attributed to the stimulus of the inhibitory nerves, but the later condition of frequency to their paralysis. After the section of the vagi the slow pulse frequently remains, and this is explained by the inhibitory action of the cardiac centre. The vagus, in point of time, is paralysed earlier than the muscular substance of the heart.

The increased blood pressure Traube attributed to increased energy of the heart’s contraction, through the motor centre being stimulated later; the commencing paralysis explains the abnormally low pressure.

There is, however, also an influence on vaso-motor nerves. What Dr. Johnson has described as the “stop-cock” action of the small arteries comes into play, the small arteries contract and attempt, as it were, to limit the supply of poisoned blood. Ackermann,[572] indeed, witnessed this phenomenon in a rabbit’s mesentery, distinctly seeing the arteries contract, and the blood pressure rise after section of the spinal cord. This observation, therefore, of Ackermann’s (together with experiments of Böhm[573] and L. Brunton[574]) somewhat modifies Traube’s explanation, and the views generally accepted respecting the cause of the increased blood pressure may be stated thus:—The pressure is due to prolongation of the systolic stroke of the cardiac pump, and to the “stop-cock” action of the arteries; in other words, there is an increase of force from behind (vis a tergo), and an increased resistance in front (vis a fronte).

§ 543. Action of the Digitalins on the Muco-Intestinal Tract and other Organs.—In addition to that on the heart, there are other actions of the digitalins; for example, by whatever channel the poison is introduced, vomiting has been observed. Even in frogs this, in a rudimentary manner, occurs. The diuretic action which has been noticed in man is wanting in animals, nor has a lessened diminution of urea been confirmed.

Ackermann found the temperature during the period of increased blood pressure raised superficially, but lowered internally. According to Boeck[575] there is no increase in the decomposition of the albuminoids.

§ 544. The Action of Digitalin on the Common Blow-fly.—The author has studied the effects of digitalin, made up into a thin paste with water, and applied to the head of the common blow-fly. There are at once great signs of irritation, the sucker is extruded to its full length, and the fly works its fore feet, attempting to brush or remove the irritating agent. The next symptom is a difficulty in walking up a perpendicular glass surface. This difficulty increases, but it is distinctly observed that weakness and paralysis occur in the legs before they are seen in the wings. Within an hour the wings become paralysed also, and the fly, if jerked from its support, falls like a stone. The insect becomes dull and motionless, and ultimately dies in from ten to twenty-four hours. A dose, in itself insufficient to destroy life, does so on repetition at intervals of a couple of hours. The observation is not without interest, inasmuch as it shows that the digitalins are toxic substances to the muscular substance of even those life-forms which do not possess a heart.