PART VI.—ALKALOIDS AND POISONOUS VEGETABLE PRINCIPLES SEPARATED FOR THE MOST PART BY ALCOHOLIC SOLVENTS. (continued 3)

To extract apomorphine, the bases are precipitated by sodic bicarbonate, and the precipitate extracted by ether or chloroform, either of which solvents leaves morphine undissolved. The apomorphine is again converted into hydrochloride, and once more precipitated by sodic bicarbonate, and is lastly obtained as a snow-white substance, rapidly becoming green on exposure to the air. The mass dissolves with a beautiful green colour in water, and also in alcohol, whilst it colours ether purple-red, and chloroform violet.

A test for apomorphine is the following:—The chloride is dissolved in a little acetic acid and shaken with a crystal of potassic iodate (KIO₃); this immediately turns red from liberated iodine on shaking it up with a little chloroform; on standing, the chloroform sinks to the bottom, and is coloured by the alkaloid a beautiful blue colour; on now carefully pouring a little CS₂ on the surface of the liquid at the point of junction it is coloured amethyst owing to dissolved iodine, and apocodeine gives a similar reaction.

Apomorphine is the purest and most active emetic known: whether injected beneath the skin or taken by the mouth, the effect is the same—there is considerable depression, faintness, and then vomiting. The dose for an adult is about 6 mgrms. (·092 grain) subcutaneously administered.

§ 381. The reactions of some of the rarer alkaloids of opium with sulphuric acid and ferric chloride are as follows: none of them have at present any toxicological importance:—

TABLE SHOWING SOME OF THE REACTIONS OF THE RARER ALKALOIDS OF OPIUM.

Alkaloid. Formula. Reaction with Warm Sulphuric Acid. Reaction with Ferric Chloride.

Codamine, C₂₀H₂₅NO₄ - Dirty red-violet colour, turning dark violet on the addition of HNO₃. - Dark green.

Landamine, C₂₀H₂₅NO₄

Landanosine, C₂₀H₂₇NO₄ - Dirty green to brownish-green. - No colour.

Protapine, C₂₀H₁₉NO₅

Lanthopine, C₂₃H₂₅NO₄ Dark brown or black. No colour.

Hydrocotarnine, C₁₂H₁₅NO₃ Dirty red-violet; not changed by trace of HNO₃. No colour.

§ 382. Tritopine (C₄₂H₅₄N₂O₇).—This is a rare alkaloid that has been found in small quantities in opium. It is crystalline, separating in transparent prisms. Melting-point 182°. It is soluble in alcohol and chloroform, and slightly soluble in ether.[417]

§ 383. Meconin (Opianyl) (C₁₀H₁₀O₄) is in the form of white glittering needles, which melt under water at 77° and in air at 90°, again coagulating at 75°. It may be sublimed in beautiful crystals. It is soluble in 22 parts of boiling, and 700 of cold water; dissolves easily in alcohol, ether, acetic acid, and ethereal oil, and is not precipitated by acetate of lead. Its solution in concentrated sulphuric acid becomes, on warming, purple, and gives, on the addition of water, a brown precipitate. Meconin may be prepared by treating narcotine with nitric acid. Meconin, in large doses, is a feeble narcotic; 1·25 grm. (20 grains) has been given to man without result.

§ 384. Meconic Acid (C₇H₄O₇) crystallises in white shining scales or small rhombic prisms, with three atoms of water (C₇H₄O₇ + 3H₂O), but at 100° this is lost, and it becomes an opaque white mass. It reddens litmus, and has a sourish taste. It is soluble in 115 parts of cold, but dissolves in 4 parts of boiling water; it dissolves easily in alcohol, less so in ether. It forms well-marked salts; the barium and calcium salt crystallise with one atom of water, the former having the composition BaH₄(C₇HO₇)₂; the latter, if ammonium meconate is precipitated by calcium chloride, CaH₄(C₇HO₇)₂; but if calcium chloride is added to the acid itself, the salt has the composition C₇H₂CaO₇ + H₂O. If meconic acid is gently heated, it decomposes into carbon dioxide and comenic acid (C₆H₄O₅). If the heat is stronger, pyromeconic acid (C₅H₄O₃)—carbon dioxide, water, acetic acid, and benzole are formed. Pyromeconic acid is readily sublimed in large transparent tables. Chloride of iron, and soluble iron salts generally, give with meconic acid (even in great dilution) a lively red colour, which is not altered by heat, nor by the addition of HCl nor by that of gold chloride. Sugar of lead and nitrate of silver each give a white precipitate; and mercurous and mercuric nitrates white and yellow precipitates. In any case where the analyst has found only meconic acid, the question may be raised in court as to whether it is a poison or not. The early experiments of Sertürner,[418] Langer, Vogel, Sömmering, and Grape[419] showed that, in comparatively speaking large doses, it had but little, if any, action on dogs or men. Albers[420] has, however, experimented on frogs, and found that in doses of ·1 to ·2 grm. there is, first, a narcotic action, and later, convulsions and death. According to Schroff,[421] there is a slight narcotic action on man.

The most generally accepted view at the present time is that the physiological action of meconic acid is similar to that of lactic acid—viz., large doses cause some depression and feeble narcosis.

In a special research amongst organic fluids for meconic acid, the substances are extracted by alcohol feebly acidulated with nitric acid; on filtration the alcohol, after the addition of a little water, is distilled off, and to the remaining fluid a solution of acetate of lead is added, and the whole filtered. The filtrate will contain any alkaloids, whilst meconic acid, if present, is bound up with the lead on the filter. The meconate of lead may be either washed or digested in strong acetic acid to purify it, suspended in water, and freed from lead by SH₂; the filtrate from the lead sulphide may be tested by ferric chloride, or preferably, at once evaporated to dryness, and weighed. After this operation it is identified. If the quantity is so small that it cannot be conveniently weighed, it may be estimated colorimetrically, by having a standard solution of meconic acid, containing 1 mgrm. in every c.c. A few drops of neutral ferric chloride are added in a Nessler cylinder to the liquid under examination; and the tint thus obtained is imitated in the usual way, in another cylinder, by means of ferric chloride, the standard solution, and water. It is also obvious that the weight of the meconic acid may be increased by converting it into the barium salt—100 parts of anhydrous baric meconate, (Ba₂C₇H₂O₇), being equivalent to 42·3 of meconic acid (C₇H₄O₇).

IV.—The Strychnine or Tetanus-Producing[422] Group of Alkaloids.

1. NUX VOMICA GROUP—STRYCHNINE—BRUCINE—IGASURINE.

§ 385. Nux vomica is found in commerce both in the entire state and as a powder. It is the seed of the Strychnos nux vomica, or Koochla tree. The seed is about the size of a shilling, round, flattened, concavo-convex, of a yellowish-grey or light-brown colour, covered with a velvety down of fine, radiating, silky hairs, which are coloured by a solution of iodine beautiful gold-yellow; the texture is tough, leathery, and not easily pulverised; the taste is intensely bitter. The powder is not unlike that of liquorice, and, if met with in the pure state, gives a dark orange-red colour with nitric acid, which is destroyed by chloride of tin; the aqueous infusion gives a precipitate with tincture of galls, is reddened by nitric acid, and gives an olive-green tint with persulphate of iron. The best method, however, of recognising quickly and with certainty that the substance under examination is nux vomica powder, is to extract strychnine from it by the following simple process:—The powder is completely exhausted by boiling alcohol (90 per cent.), the alcoholic extract evaporated to dryness, and then treated with water; the aqueous solution is passed through a wet filter, and concentrated by evaporation to a small bulk. To this liquid a drop or so of a concentrated solution of picric acid is added, and the yellow precipitate of picrates thus obtained is separated, treated with nitric acid, the picric acid removed by ether, and the pure alkaloid precipitated by soda, and shaken out by chloroform.

§ 386. Chemical Composition.—Nux vomica contains at least four distinct principles:—

(1.) Strychnine.

(2.) Brucine.

(3.) Igasurine.

(4.) Strychnic or igasuric acid.

§ 387. Strychnine (C₂₁H₂₂N₂O₂) is contained in the bean of S. ignatius, in the bark (false angustura bark) and seeds of the Strychnos nux vomica, in the Strychnos colubrina, L., in the Strychnos tieuté, Lesch, and probably in various other plants of the same genus.

Commercial strychnine is met with either in colourless crystals or as a white powder, the most usual form being that of the alkaloid itself; but the nitrate, sulphate, and acetate are also sold to a small extent.

The microscopical appearance of strychnine, as thrown down by the solution of vapour of ammonia, may be referred to three leading forms—the long rectangular prism, the short hexagonal prism, or the regular octahedron. If obtained from the slow evaporation of an alcoholic solution, it is usually in the form of four-sided pyramids or long prisms; but if obtained by speedy evaporation or rapid cooling, it appears as a white granular powder. If obtained from a benzene solution, the deposit is usually crystalline, but without a constant form, though at times the crystals are extremely distinct, the short six-sided prism prevailing; but triangular plates, dodecahedral, rhomboidal, and pentagonal, may also be met with. An ethereal solution on evaporation assumes dendritic forms, but may contain octahedra and four-sided prisms. A chloroform solution deposits rosettes, veined leaves, stellate dotted needles, circles with broken radii, and branched and reticulated forms of great delicacy and beauty.—Guy.

Strychnine is very insoluble in water, although readily dissolved by acidulated water. According to Wormley’s repeated experiments, one part of strychnine dissolves in 8333 parts of cold water; and, according to Pelletier and Cahours, it dissolves in 6667 parts of cold, and 2500 parts of boiling water. It may be convenient, then, to remember that a gallon of cold water would hardly dissolve more than 10 grains (·142 grm. per litre); the same amount, if boiling, about 30 grains (·426 grm. per litre) of strychnine. The solubility of one part of strychnine in other menstrua is as follows:—Cold alcohol, 0·833 specific gravity, 120, boiling, 10 parts (Wittstein); cold alcohol, 0·936 specific gravity, 240 parts (Merck); cold alcohol, 0·815 specific gravity, 107 parts (Dragendorff); amyl alcohol, 181 parts; benzene, 164; chloroform, 6·9 (Schlimpert), 5 (Pettenkofer); ether, 1250 parts; carbon disulphide, 485 parts; glycerin, 300 parts. Creosote and essential and fixed oils also dissolve strychnine.

Of all the above solvents, it is evident that chloroform is the best for purposes of separation, and next to chloroform, benzene.

If a speck of strychnine be placed in the subliming cell, it will be found to sublime usually in a crystalline form at 169°. A common form at this temperature, according to the writer’s own observations, is minute needles, disposed in lines; but, as Dr. Guy has remarked, the sublimate may consist of drops, of waving patterns, and various other forms; and, further, while the sublimates of morphia are made up of curved lines, those of strychnine consist of lines either straight or slightly curved, with parallel feathery lines at right angles. On continuing the heat, strychnine melts at about 221°, and the lower disc, if removed and examined, is found to have a resinous residue; but it still continues to yield sublimates until reduced to a spot of carbon. The melting-point taken in a tube is 268°.

Strychnine is so powerfully bitter, that one part dissolved in 70,000 of water is distinctly perceptible; it is a strong base, with a marked alkaline reaction, neutralising the strongest acids fully, and precipitating many metallic oxides from their combinations, often with the formation of double salts. Most of the salts of strychnine are crystalline, and all extremely bitter. Strychnine, in the presence of oxygen, combines with SH₂ to form a beautiful crystalline compound:—

2C₂₁H₂₂N₂O₂ + 6H₂S + O₃ = 2C₂₁H₂₂N₂O₂3H₂S₂ + 3H₂O.

On treatment with an acid this compound yields H₂S₂.—Schmidt, Ber. Deutsch. Chem. Ges., 8, 1267.

An alcoholic solution of strychnine turns the plane of polarisation to the left, [α]r = -132·08° to 136·78° (Bouchardat); but acid solutions show a much smaller rotatory power.

The salts used in medicine are—the sulphate, officinal only in the French pharmacopœia; the nitrate, officinal in the German, Austrian, Swiss, Norse, and Dutch pharmacopœias; and the acetate, well known in commerce, but not officinal.

The commercial Sulphate (C₂₁H₂₂N₂O₂H₂SO₄ + 2H₂O) is an acid salt crystallising in needles which lose water at 150°, the neutral sulphate (2C₂₁H₂₂N₂O₂,H₂SO₄ + 7H₂O) crystallises in four-sided, orthorhombic prisms, and is soluble in about 50 parts of cold water.

The Nitrate (C₂₁H₂₂N₂O₂,HNO₃) crystallises on evaporation from a warm solution of the alkaloid in dilute nitric acid, in silky needles, mostly collected in groups. The solubility of this salt is considerable, one part dissolving in 50 of cold, in 2 of boiling water; its solubility in boiling and cold alcohol is almost the same, taking 60 of the former and 2 of the latter.

The Acetate crystallises in tufts of needles; as stated, it is not officinal in any of the European pharmacopœias.

The chief precipitates or sparingly soluble crystalline compounds of strychnine are—

(1.) The Chromate of Strychnine (C₂₁H₂₂N₂O₂CrHO₂), formed by adding a neutral solution of chromate of potash to a solution of a strychnine salt, crystallises out of hot water in beautiful, very insoluble, orange-yellow needles, mixed with plates of various size and thickness. The salt is of great practical use to the analyst; for by its aid strychnine may be separated from a variety of substances, and in part from brucine—the colour tests being either applied direct to the strychnine chromate, or the chromate decomposed by ammonia, and the strychnine recovered from the alkaline liquid by chloroform.

(2.) Sulphocyanide of Strychnine (C₂₁H₂₂N₂O₂CNHS) is a thick, white precipitate, produced by the addition of a solution of potassic sulphocyanide to that of a strychnine salt; on warming it dissolves, but on cooling reappears in the form of long silky needles.

(3.) Double Salts.—The platinum compound obtained by adding a solution of platinic chloride to one of strychnine chloride has the composition C₂₁H₂₂N₂O₂HClPtCl₂, and crystallises out of weak boiling alcohol (in which it is somewhat soluble) in gold-like scales. The similar palladium compound (C₂₁H₂₂N₂O₂HCl,PdCl) is in dark brown needles, and the gold compound (C₂₁H₂₂N₂O₂HClAuCl₃) in orange-coloured needles.

(4.) Strychnine Trichloride.—The action of chlorine on strychnine—by which chlorine is substituted for a portion of the hydrogen—has been proposed as a test. The alkaloid is dissolved in very dilute HCl, so as to be only just acid; on now passing through chlorine gas, a white insoluble precipitate is formed, which may be recrystallised from ether; it has probably the composition C₂₁H₁₉Cl₃N₂O₂, and is extremely insoluble in water.

(5.) The Iodide of Strychnine (C₂₁H₂₂N₂O₂HI₃) is obtained by the action of iodine solution on strychnine sulphate; on solution of the precipitate in alcohol, and evaporation, it forms violet-coloured crystals, very similar to those of potassic permanganate.

§ 388. Pharmaceutical and other Preparations of Nux Vomica and Strychnine, with Suggestions for their Valuation.

An aqueous extract of nux vomica, officinal in the German pharmacopœia, appears to contain principally brucine, with a small percentage of strychnine; the proportion of brucine to strychnine being about four-fifths to one-fifth. Blossfield found in a sample 4·3 per cent. of total alkaloid, and two samples examined by Grundmann consisted (No. 1) of strychnine, 0·6 per cent.; brucine, 2·58 per cent.—total, 3·18 per cent.; (No. 2) strychnine, 0·68 per cent.; brucine, 2·62 per cent.—total, 3·3 per cent. A sample examined by Dragendorff yielded—strychnine, 0·8 per cent.; brucine, 3·2 per cent.—total, 4 per cent. The maximum medicinal dose is put at ·6 grm. (9¹⁄₁₄ grains).

The spirituous extract of nux vomica, officinal in the British and all the Continental pharmacopœias, differs from the aqueous in containing a much larger proportion of alkaloids, viz., about 15 per cent., and about half the total quantity being strychnine. The medicinal dose is 21·6-64·8 mgrms. (¹⁄₃ grain to a grain).

There is also an extract of St. Ignatius bean which is used in the United States; nearly the whole of its alkaloid may be referred to strychnine.

The tincture of nux vomica, made according to the British Pharmacopœia, contains in 1 fl. oz. 1 grain of alkaloids, or 0·21 part by weight in 100 by volume, but the strength of commercial samples often varies. Lieth found in one sample 0·122 per cent. of strychnine and 0·09 per cent. brucine; and two samples examined by Wissel consisted respectively of 0·353 per cent. and 0·346 per cent. of total alkaloids. Dragendorff found in two samples ·2624 per cent. and ·244 per cent. of total alkaloids, about half of which was strychnine.

Analysis.—Either of the extracts may be treated for a few hours on the water-bath, with water acidulated by sulphuric acid, filtered, the residue well washed, the acid liquid shaken up with benzene to separate impurities, and, on removal of the benzene, alkalised with ammonia, and shaken up two or three times with chloroform; the chloroform is then evaporated in a tared vessel, and the total alkaloids weighed. The alkaloids can then be either (a) treated with 11 per cent. of nitric acid on the water-bath until all the brucine is destroyed, and then (the liquid being neutralised) precipitated by potassic chromate; or (b) the alkaloids may be converted into picrates. Picrate of strychnine is very insoluble in water, 1 part requiring no less than 10,000 of water.[423] The tincture is analysed on precisely similar principles, the spirit being got rid of by distillation, and the residue treated by acidified water, &c.

The nux vomica powder itself may be valued as follows:—15 to 20 grms., pulverised as finely as possible, are treated three times with 150 to 300 c.c. of water, acidified with sulphuric acid, well boiled, and, after each boiling, filtered and thoroughly pressed. The last exhaustion must be destitute of all bitter taste. The united filtrates are then evaporated to the consistence of a thick syrup, which is treated with sufficient burnt magnesia to neutralise the acid. The extract is now thoroughly exhausted with boiling alcohol of 90 per cent.; the alcoholic extract, in its turn, is evaporated nearly to dryness, and treated with acidulated water; this acid solution is freed from impurities by shaking up with benzene, and lastly alkalised with ammonia, and the alkaloids extracted by shaking up with successive portions of chloroform. The chloroformic extract equals the total alkaloids, which may be separated in the usual way.

In four samples of nux vomica examined by Dragendorff, the total alkaloids ranged from 2·33 to 2·42 per cent. Grate found in two samples 2·88 per cent. and 2·86 per cent. respectively; while Karing from one sample separated only 1·65 per cent. The strychnine and brucine are in about equal proportions, Dragendorff[424] finding 1·187 per cent. strychnine and 1·145 per cent. brucine.[425]

The vermin-killers in use in this country are those of Miller, Battle, Butler, Clift, Craven, Floyd, Gibson, Hunter, Stenier, and Thurston. Ten samples from these various makers were examined recently by Mr. Allen (Pharm. Journal, vol. xii., 1889), and the results of the analyses are embodied in the following table:—

Name or Mark. Weight of Powder in Grains. Price. Strychnine. Nature of Starch. Colouring Matter.

Weight in Grains. Per- centage.

1 5·6 3d. 0·61 10·9 Wheat ?

2 11·8 3d. 0·80 6·7 Wheat Ultramarine.

3 13·1 3d. 1·12 8·7 Rice Ultramarine.

4 11·6 3d. 1·28 11·1 Rice Ultramarine.

5 13·1 3d. 1·70 13·0 Rice Ultramarine.

6 21·5 6d. 2·42 11·2 Wheat Prussian blue.

7 49·2 3d. 2·85 5·8 Wheat Soot.

8 30·5 3d. 3·45 11·3 Wheat Prussian blue.

9 16·6 3d. 3·81 19·4 Rice Carmine.

10 10·0 3d. 4·18 41·8 Rice Ultramarine.

§ 389. Statistics.—In England, during the ten years 1883-92, out of 6666 total deaths from poison, strychnine, nux vomica, and vermin-killer account for 325. Out of these deaths, 118 were ascribed to “vermin-killer.” “Vermin-killer” may be presumed to include not only strychnine mixtures, but also phosphorus and arsenic pastes and powders, so that there are no means of ascertaining the number of strychnine cases comprised under this heading. Taking the deaths actually registered as due to strychnine or nux vomica, they are about 4·7 per cent. of the deaths from all sorts of poison. Of these deaths, 268, or 82·4 per cent., were suicidal, 8 were homicidal, and 49 only were accidental.

Schauenstein has collected from literature 130 cases of poisoning by strychnine, but most of these occurred during the last twenty-five years; 62 of the 130, or about one-half, were fatal, and 15 were homicidal. It has been stated that strychnine is so very unsuitable for the purpose of criminal poisoning as to render it unlikely to be often used. Facts, however, do not bear out this view; for, allowing its intensely bitter taste, yet it must be remembered that bitter liquids, such as bitter ale, are in daily use, and a person accustomed to drink any liquid rapidly might readily imbibe sufficient of a toxic liquid to produce death before he was warned by its bitterness. It is, indeed, capable of demonstration, that taste is more vivid after a substance has been taken than just in the act of swallowing, for the function of taste is not a rapid process, and requires a very appreciable interval of time.

The series of murders by Thomas Neill, or, more correctly, Thomas Neill Cream, is an example of the use of strychnine for the purposes of murder. Thomas Neill Cream was convicted, October 21, 1892, for the murder of Matilda Clover on October 20, 1891; there was also good evidence that the same criminal had murdered Ellen Dunworth, October 13, 1891; Alice Marsh, April 12, 1892; Emma Shrivell, April 12, 1892, and had attempted the life of Louie Harvey. The agent in all these cases was strychnine. There was no evidence as to what form of the poison was administered in the case of Clover, but Ellen Dunworth, who was found dying in the streets at 7.45 P.M., and died less than two hours afterwards, stated that a gentleman gave her “two drops” of white stuff to drink.

In the cases of Marsh and Shrivell, Neill Cream had tea with them on the night of April 11, and gave them both “three long pills;” half an hour after Neill Cream left them they were found to be dying, and died within six hours. From Marsh 7 grains, from Shrivell nearly 2 grains of strychnine were separated; the probability is that each pill contained at least 3 grains of strychnine. The criminal met Louie Harvey on the Embankment, and gave her “some pills” to take; she pretended to do so, but threw them away. Hence it seems probable that Neill Cream took advantage of the weakness that a large number of the population have for taking pills, and mostly poisoned his victims in this manner. Clover’s case was not diagnosed during life, but strychnine was found six or seven months after burial in the body. It may be mentioned incidentally that the accused himself furnished the clue which led to his arrest, by writing letters charging certain members of the medical profession with poisoning these poor young prostitutes with strychnine.

§ 390. Fatal Dose.—In a research, which may, from its painstaking accuracy, be called classical, F. A. Falck has thrown much light upon the minimum lethal dose of strychnine for various animals. It would seem that, in relation to its size, the frog is by no means so sensible to strychnine as was believed, and that animals such as cats and rabbits take a smaller dose in proportion to their body-weight. The method used by Falck was to inject subcutaneously a solution of known strength of strychnine nitrate, and, beginning at first with a known lethal dose, a second experiment was then made with a smaller dose, and if that proved fatal, with a still smaller, and so on, until such a quantity was arrived at, that the chances as determined by direct observation were as great of recovery as of death. Operating in this way, and making no less than 20 experiments on the rabbit, he found that the least fatal dose for that animal was ·6 mgrm. of strychnine nitrate per kilogramme. Cats were a little less susceptible, taking ·75 mgrm. Operating on fowls, he found that strychnine taken into the crop in the usual way was very uncertain; 50 mgrms. per kilo, taken with the food had no effect, but results always followed if the poison was introduced into the circulation by the subcutaneous needle—the lethal dose for fowls being, under those circumstances, 1 to 2 mgrms. per kilo. He made 35 experiments on frogs, and found that to kill a frog by strychnine nitrate, at least 2 mgrms. per kilo, must be injected. Mice take a little more, from 2·3 to 2·4 mgrms. per kilo. In 2 experiments on the ring adder, in one 62·5 mgrms. per kilo. of strychnine nitrate, injected subcutaneously, caused death in seven hours; in the second, 23·1 mgrms. per kilo. caused death in five days; hence the last quantity is probably about the least fatal dose for this particular snake.

These observations may be conveniently thrown into the following table (see next page), placing the animals in order according to their relative sensitiveness.[426]

Now, the important question arises, as to the place in this series occupied by man—a question difficult to solve, because so few cases are recorded in which strychnine has been administered by subcutaneous injection with fatal result. Eulenberg has observed poisonous symptoms, but not death, produced by 6 mgrms. (¹⁄₁₁ grain) and by 10 mgrms. (about ¹⁄₆ grain). Bois observed poisonous symptoms from the similar subcutaneous administrations of 8 mgrms. to a child six years old, and 4 mgrms. to another child four years old—the latter dose, in a case recorded by Christison, actually killing a child of three years of age. On the other hand, the smallest lethal dose taken by an adult was swallowed in solution. Dr. Warner took 32 mgrms. (¹⁄₂ grain) of strychnine sulphate, mistaking it for morphine sulphate, and died in twenty minutes. In other cases 48 mgrms. (⁷⁄₁₀ grain) have been fatal. It will be safe to conclude that these doses by the stomach would have acted still more surely and energetically if injected subcutaneously. The case of Warner is exceptional, for he was in weak health; and, if calculated out according to body-weight, presuming that Dr. Warner weighed 68 kilos., the relative dose as strychnine nitrate would be ·24 per kilo.—a smaller dose than for any animal hitherto experimented upon. There is, however, far more reason for believing that the degree of sensitiveness in man is about the same as that of cats or dogs, and that the least fatal dose for man is ·70 per kilo., the facts on record fairly bearing out this view. It is, therefore, probable that death would follow if 38 mgrms. (⁷⁄₁₀ grain) were injected subcutaneously into a man of the average weight of 68 kilos. (150 lbs.). Taylor estimates the fatal dose of strychnine for adults as from 32·4 to 129·6 mgrms. (·5 to 2 grains); Guy puts the minimum at 16·2 mgrms. (·25 grain).

TABLE SHOWING THE ACTION OF STRYCHNINE ON ANIMALS.

Animal. Manner of Application. Reckoned on 1 Kilo. of Body-weight.

Lowest Experimental Lethal Dose. Highest Experimental Lethal Dose.

Dose of Strychnine Nitrate in Mgrms.

Rabbit, Subcutaneous. 0 ·50 0 ·60

Cat, Subcut„ ... 0 ·75

Dog, Subcut„ ... 0 ·75

Do„ Taken by the Stomach. 2 ·0 3 ·90

Do„ Taken „by theRectum. ... 2 ·00

Do„ Taken „by theBladder. 5 ·50 ...

Fox, Subcutaneous. ... 1 ·00

Hedgehog, Subcut„ 1 ·00 2 ·00

Fowl, Subcut„ ... 2 ·00

Frog, Subcut„ 2 ·00 2 ·10

Mouse, Subcut„ 2 ·36 2 ·36

Ring Adder, Subcut„ ... 23 ·10

Large doses of strychnine may be recovered from if correct medical treatment is sufficiently prompt. Witness the remarkable instances on record of duplex poisonings, in which the would-be-suicide has unwittingly defeated his object by taking strychnine simultaneously with some narcotic, such as opium or chloral. In a case related by Schauenstein,[427] a suicidal pharmacist took ·48 grm. or ·6 grm. (7·4 to 9·25 grains) of strychnine nitrate dissolved in about 30 c.c. of bitter-almond water, and then, after half an hour, since no symptoms were experienced, ·6 grm. (9·25 grains) of morphine acetate, which he likewise dissolved in bitter-almond water and swallowed. After about ten minutes, he still could walk with uncertain steps, and poured some chloroform on the pillow-case of his bed, and lay on his face in order to breathe it. In a short time he lost consciousness, but again awoke, and lay in a half-dreamy state, incapable of motion, until some one entered the room, and hearing him murmur, came to his bedside. At that moment—two and a quarter hours after first taking the strychnine—the pharmacist had a fearful convulsion, the breathing was suspended, and he lost consciousness. Again coming to himself, he had several convulsions, and a physician who was summoned found him in general tetanus. There were first clonic, then tonic convulsions, and finally opisthotonus was fully developed. The treatment consisted of emetics, and afterwards tannin and codeine were given separately. The patient slept at short intervals; in ten hours after the taking of the poison the seizures were fewer in number and weaker in character, and by the third day recovery was complete. Dr. Macredy[428] has also placed on record an interesting case, in which the symptoms, from a not very large dose of strychnine, were delayed by laudanum for eight hours. A young woman, twenty-three years of age, pregnant, took at 10 A.M. a quantity of strychnine estimated at 1·5 grain, in the form of Battle’s vermin-killer, and immediately afterwards 2 ounces of laudanum. She was seen by Dr. Macredy in four hours, and was then suffering from pronounced narcotic symptoms. A sulphate of zinc emetic was administered. In eight hours after taking the strychnine, there were first observed some clonic convulsive movements of the hands, and, in a less degree, the legs. These convulsions continued, at times severe, for several hours, and were treated with chloral. Recovery was speedy and complete.

In a similar case related by Dr. Harrison,[429] a man, aged 54, took a packet of Battle’s vermin-killer, mixed with about a drachm and a half of laudanum and some rum. At the time he had eaten no food for days, and had been drinking freely; yet fifty minutes elapsed before the usual symptoms set in, and no medical treatment was obtained until four hours after taking the dose. He was then given chloral and other remedies, and made a rapid recovery.

§ 391. Action on Animals.—The action of strychnine has been experimentally studied on all classes of animals, from the infusoria upwards. The effects produced on animal forms which possess a nervous system are strikingly alike, and even in the cephalopoda, tetanic muscular spasm may be readily observed. Of all animals the frog shows the action of strychnine in its purest form, especially if a dose be given of just sufficient magnitude to produce toxic effects. The frog sits perfectly still and quiet, unless acted upon by some external stimuli, such as a breath of air, a loud noise, or the shaking of the vessel which contains it, then an immediate tetanic convulsion of all the muscles is witnessed, lasting a few seconds only, when the animal again resumes its former posture. This heightened state of reflex action has its analogue in hydrophobia as well as in idiopathic tetanus. If the frog thus poisoned by a weak dose is put under a glass shade, kept moist, and sheltered from sound, or from other sources of irritation, no convulsions occur, and after some days it is in its usual health. If, on the other hand, by frequent stimuli, convulsions are excited, the animal dies. M. Richet[430] has contributed a valuable memoir to the Academy of Sciences on the toxic action of strychnine. He has confirmed the statement of previous observers that, with artificial respiration, much larger doses of strychnine may be taken without fatal result than under normal conditions, and has also recorded some peculiar phenomena. Operating on dogs and rabbits, after first securing a canula in the trachea, and then injecting beneath the skin or into the saphena vein 10 mgrms. of strychnine hydrochlorate, the animal is immediately, or within a few seconds, seized with tetanic convulsions, and this attack would be mortal, were it not for artificial respiration. Directly this is practised the attack ceases, and the heart, after a period of hurried and spasmodic beats, takes again its regular rhythm. Stronger and stronger doses may then be injected without causing death. As the dose is thus augmented, the symptoms differ. M. Richet distinguishes the following periods:—(1.) A period of tetanus. (2.) A period of convulsion, characterised by spasmodic and incessant contraction of all the muscles. (3.) A little later, when the quantity exceeds 10 mgrms. per kilo., a choreic period, which is characterised by violent rhythmic shocks, very sudden and short, repeated at intervals of about three to four seconds; during these intervals there is almost complete relaxation. (4.) A period of relaxation; this period is attained when the dose exceeds 40 mgrms. per kilo. Reflex action is annihilated, the spontaneous respiratory movements cease, the heart beats tumultuously and regularly in the severe tetanic convulsions at first, and then contracts with frequency but with regularity. The pupils, widely dilated at first, become much contracted. The arterial pressure, enormously raised at the commencement, diminishes gradually, in one case from 0·34 mm. to 0·05 mm. The temperature undergoes analogous changes, and during the convulsions is extraordinarily elevated; it may even attain 41° or 42°, to sink in the period of relaxation to 36°. Dogs and rabbits which have thus received enormous quantities of strychnine (e.g., 50 mgrms. per kilo.), may, in this way, live for several hours, but the slightest interruption to the artificial respiration, in the relaxed state, is followed by syncope and death.

§ 392. Effects on Man: Symptoms.—The commencement of symptoms may be extremely rapid, the rapidity being mainly dependent on the form of the poison and the manner of application. A soluble salt of strychnine injected subcutaneously will act within a few seconds;[431] in a case of amaurosis, related by Schuler,[432] 5·4 mgrms. of a soluble strychnine salt were introduced into the punctum lachrymale;—in less than four minutes there were violent tetanic convulsions. In a case related by Barker, the symptoms commenced in three minutes from a dose of ·37 grm. (5·71 grains).[433] Here the poison was not administered subcutaneously. Such short periods, to a witness whose mind was occupied during the time, might seem immediate. On the other hand, when nux vomica powder has been taken, and when strychnine has been given in the form of pill, no such rapid course has been observed, or is likely to occur, the usual course being for the symptoms to commence within half an hour. It is, however, also possible for them to be delayed from one to two hours, and under certain circumstances (as in the case related by Macredy) for eight hours. In a few cases, there is first a feeling of uneasiness and heightened sensibility to external stimuli, a strange feeling in the muscles of the jaw, and a catching of the respiration; but generally the onset of the symptoms is as sudden as epilepsy, and previous to their appearance the person may be pursuing his ordinary vocation, when, without preliminary warning, there is a shuddering of the whole frame, and a convulsive seizure. The convulsions take the form of violent general tetanus; the limbs are stretched out involuntarily, the hands are clenched, the soles of the feet incurved, and, in the height of the paroxysm, the back may be arched and rigid as a board, the sufferer resting on head and heels, and the abdomen tense. In the grasp of the thoracic muscles the walls of the chest are set immovable, and from the impending suffocation the face becomes congested, the eyes prominent and staring. The muscles of the lower jaw—in “disease tetanus” the first to be affected—are in “strychnos tetanus,” as a rule, the last; a distinction, if it were more constant, of great clinical value. The convulsions and remissions recur until death or recovery, and, as a rule, within two hours from the commencement of the symptoms the case in some way or other terminates. The number of the tetanic seizures noted has varied—in a few cases the third spasm has passed into death, in others there have been a great number. The duration of the spasm is also very different, and varies from thirty seconds to five or even eight minutes, the interval between lasting from forty-five seconds[434] to one or even one and a half hours.[435]

§ 393. Diagnosis of Strychnine Poisoning.—However striking and well defined the picture of strychnine tetanus may be, mistakes in diagnosis are rather frequent, especially when a medical man is hastily summoned, has never seen a case of similar poisoning, and has no suspicion of the possible nature of the seizure. If a young woman, for instance, is the subject, he may put it down to hysteria, and certainly hysteria not unfrequently affects somewhat similar convulsions. In a painful case in which the author was engaged, a young woman either took or was given (for the mystery was never cleared up fully) a fatal dose of strychnine, and though the symptoms were well marked, the medical attendant was so possessed with the view that the case was due to hysteria, that, even after making the post-mortem examination, and finding no adequate lesion, he theorised as to the possibility of some fatal hysteric spasm of the glottis, while there was ample chemical evidence of strychnine, and a weighable quantity of the alkaloid was actually separated from the contents of the stomach. The medical attendant of Matilda Clover, one of Neill’s victims, certified that the girl died from delirium tremens and syncope, although the symptoms were typically those produced by strychnine. Such cases are particularly sad, for we now know that, with judicious treatment, a rather large dose may be recovered from.

If the case is a male, a confusion with epilepsy is possible, though hardly to be explained or excused; while in both sexes idiopathic tetanus is so extremely similar as to give rise to the idea that all cases of idiopathic tetanus are produced by poison, perhaps secreted by the body itself. As for the distinction between idiopathic and strychnic tetanus, it is usually laid down (1) that the intervals in the former are characterised by no relaxation of the muscles, but that they continue contracted and hard; and (2) that there is a notable rise of temperature in disease tetanus proper, and not in strychnine tetanus. Both statements are misleading, and the latter is not true, for in strychnic poisoning the relaxation is not constant, and very high temperatures in animals have been observed.

§ 394. Physiological Action.—The tetanic convulsions are essentially reflex, and to be ascribed to a central origin; the normal reflex sensibility is exaggerated and unnaturally extended. If the ischiatic plexus supplying the one leg of an animal is cut through, that leg takes no part in the general convulsions, but if the artery of the leg alone is tied, then the leg suffers from the muscular spasm, as well as the limbs in which the circulation is unrestrained. In an experiment by Sir B. W. Richardson, a healthy dog was killed, and, as soon as practicable, a solution of strychnine was injected through the systemic vessels by the aorta—the whole body became at once stiff and rigid as a board. These facts point unmistakably to the spinal marrow as the seat of the toxic influence. Strychnine is, par excellence, a spinal poison. On physiological grounds the grey substance of the cord is considered to have an inhibitory action upon reflex sensibility, and this inhibitory power is paralysed by strychnine. The spinal cord, it would appear, has the power of collecting strychnine from the circulation and storing it up in its structure.[436]

Much light has been thrown upon the cause of death by Richet’s experiments.[437] It would seem that, in some cases, death takes place by a suffocation as complete as in drowning, the chest and diaphragm being immovable, and the nervous respiratory centres exhausted. In such a case, immediate death would be averted by a tracheal tube, by the aid of which artificial respiration might be carried on; but there is another asphyxia due to the enormous interstitial combustion carried on by muscles violently tetanised. “If,” says Richet, “after having injected into a dog a mortal dose of strychnine, and employed artificial respiration according to the classic method twenty or thirty times a minute, the animal dies (sometimes at the end of ten minutes, and in every case at the end of an hour or two), and during life the arterial blood is examined, it will be ascertained that it is black, absolutely like venous blood.”

This view is also supported by the considerable rise of temperature noticed: the blood is excessively poor in oxygen, and loaded with carbon dioxide. That this state of the blood is produced by tetanus, is proved by the fact that an animal poisoned by strychnine, and then injected subcutaneously with curare in quantity just sufficient to paralyse the muscular system, does not exhibit these phenomena. By the aid of artificial respiration, together with the administration of curare, an animal may live after a prodigious dose of strychnine.

Meyer[438] has investigated carefully the action of strychnine on the blood-pressure—through a strong excitement of the vaso-motor centre, the arteries are narrowed in calibre, and the blood-pressure much increased; the action of the heart in frogs is slowed, but in the warm-blooded animals quickened.

§ 395. Post-mortem Appearances.—There is but little characteristic in the post-mortem appearances from strychnine poisoning. The body becomes very stiff a short time after death, and this rigidity remains generally a long time. In the notorious Palmer case, the body was rigid two months after death, but, on the other hand, the rigor mortis has been known to disappear within twenty-four hours. If the convulsions have been violent, there may be minute hæmorrhages in the brain and other parts. I have seen considerable hæmorrhage in the trachea from this cause. When death occurs from asphyxia, the ordinary signs of asphyxia will be found in the lungs, &c. The heart mostly has its right side gorged with blood, but in a few cases it is empty and contracted.

In a case which Schauenstein has recorded[439] he found strychnine still undissolved, coating the stomach as a white powder; but this is very unusual, and I believe unique. The bladder often contains urine, which, it need scarcely be said, should be preserved for chemical investigation.

§ 396. Treatment.—From the cases detailed, and from the experiments on animals, the direction which treatment should take is very clear. As a matter of course, if there is the slightest probability of any of the poison remaining in the stomach, it should be removed. It is doubtful whether the stomach pump can be ever applied with benefit in strychnine poisoning, the introduction of the tube is likely to aggravate the tetanus, but apomorphine can be injected subcutaneously. Large and frequent doses of chloral should be administered in order to lessen the frequency of convulsions, or prevent their occurrence, and it may be necessary in a few cases, where death threatens by suffocation, to perform tracheotomy, and to use artificial respiration. Where chloral or chloroform is not at hand, and in cases of emergency, where this may easily happen, the medical man must administer in full doses the nearest narcotic at hand.[440]

§ 397. Separation of Strychnine from Organic Matters.—The separation of strychnine from organic matters, &c., is undertaken strictly on the general principles already detailed. It may happen, however, that in cases of poisoning there is the strongest evidence from symptoms in the person or animal that strychnine alone is to be sought for. In an instance of the kind, if a complex organic liquid (such as the contents of the stomach) is under examination, it is best to remove the solid substances by filtration through glass, wool, or linen, and evaporate nearly to dryness over the water-bath, acidifying with acetic acid, and then exhausting the residue repeatedly with boiling alcohol of 80 per cent. The alcoholic extract is in its turn evaporated to dryness, and taken up with water; the aqueous solution is passed through a wet filter, and then shaken up with the usual succession of fluids, viz., petroleum ether, benzene, chloroform, and amyl alcohol, which will remove a great number of impurities, but will not dissolve the strychnine from the acid solution. The amyl alcohol may lastly be removed by petroleum ether; and on removal of the final extractive (which should be done as thoroughly as possible) chloroform is added, and the fluid is alkalised by ammonia, which precipitates the alkaloid in the presence of the solvent. Should the reverse process be employed—that is, ammonia added first, and then chloroform—the strychnine is not so perfectly dissolved, since it has time to assume a crystalline condition. On separation and evaporation of the chloroform, the residue (if much discoloured, or evidently impure) may be dissolved in alcohol or benzene, and recrystallised several times. Cushman has published an improved method of separating strychnine, which, according to test experiments, appears to give good results. He describes the method as follows:[441]—

“The stomach contents or viscera properly comminuted are weighed, and an aliquot part taken for analysis. The mass is digested in a beaker over night, at a warm temperature, with water acidulated with acetic acid. The contents of the beaker are filtered by pressing through muslin, and then passing through paper. The clear filtrate is evaporated on the water-bath to soft dryness, an excess of ordinary 80 per cent. alcohol added, and boiled ten minutes with stirring, and allowed to stand one half hour at a warm temperature. This extraction is repeated, the alcohol extracts united, filtered, evaporated to soft dryness, and the residue taken up with a little water acidulated with acetic acid, and shaken out with pure acetic ether in a separating funnel. Successive fresh portions of acetic ether are used until the solvent shows by its colour, and by the evaporation of a few drops, that it does not contain extractive matter. As many as twelve extractions are sometimes necessary to accomplish this. Care should be taken in each case to allow time for as complete separation as possible between the two layers. The purified acid aqueous liquid, which need not exceed in bulk 50 c.c., is now returned to the separator, an equal quantity of fresh acetic ether added, and enough sodic carbonate in solution to render the mixture slightly alkaline, and the separator is then thoroughly shaken for several minutes. All the alkaloid should now be in solution in the acetic ether, but a second shaking of the alkaline liquid, with acetic ether, is always made, the two extracts united, and evaporated in a glass dish over hot water to dryness. It will now be found that the residue shows the alkaloid fairly pure, but not pure enough for quantitative results. The residue is dissolved in a few drops of dilute acetic acid, warmed to complete solution, filtered if necessary, diluted to about 30 c.c., and the solution transferred to a small separating funnel; 30 c.c. of ether-chloroform (1-1) are now added, and the separator shaken. After separation the heavier ether-chloroform is allowed to run off, another lot of 30 c.c. of ether-chloroform is added, the separator shaken, and immediately enough ammonia-water added to render the mixture alkaline, and the whole vigorously agitated for several minutes. After separation is complete, the ether-chloroform layer is run out into a clean 50 c.c. glass-stoppered burette. The alkaline water solution is agitated with 20 c.c. more of the ether-chloroform, separated, and this extract added to that in the burette. The burette is now supported over a small weighed glass dish, which is kept warm on a water-bath, and the liquid allowed to evaporate gently, drop by drop, until a sufficient quantity of the pure alkaloid has collected in the centre of the dish to render an accurate weighing possible, or else all of the alkaloid may be collected and weighed at once. After all possible tests have been made upon the weighed alkaloid, the remainder is re-dissolved in a drop or two of acetic acid, a little water added, and the dish exposed under a bell-glass to the fumes of ammonia. After standing some time all the strychnine is found crystallised out in the beautiful characteristic needle-formed crystals. The mother-liquor is drawn off with a small fine-pointed tube and rubber bulb, the crystals carefully washed with a little water and dried over sulphuric acid. The glass dish containing these crystals is kept as the final exhibit, and is shown in evidence. Another convenient exhibit may be prepared by moistening a small filter-paper with a solution of the alkaloid in dilute acetic acid, then moistening with a solution of potassium dichromate: this paper, on being dried, may be kept indefinitely. On moistening it, and touching it at any time with a drop of strong sulphuric acid, a violet film, changing to cherry-red, is formed at the place of contact.”

Should search be made for minute portions of strychnine in the tissues, considering the small amount of the poison which may produce death, it is absolutely necessary to operate on a very large quantity of material. It would be advisable to take the whole of the liver, the brain, spinal cord, spleen, stomach, duodenum, kidneys, all the blood that can be obtained, and a considerable quantity of muscular tissue, so as to make in all about one-eighth to one-tenth of the whole body; this may be cut up into small pieces, and boiled in capacious flasks with alcohol, acidified with acetic acid. Evaporation must be controlled by adapting to the cork an upright condenser.

Should the analyst not have apparatus of a size to undertake this at one operation, it may be done in separate portions—the filtrate from any single operation being collected in a flask, and the spirit distilled off in order to be used for the next. In this way, a large quantity of the organs and tissues can be exhausted by half a gallon of alcohol. Finally, most of the alcohol is distilled off, and the remainder evaporated at a gentle heat in a capacious dish, the final extract being treated, evaporating to a syrup, and using Cushman’s process (ante, p. 334) as just described. It is only by working on this large scale that there is any probability of detecting absorbed strychnine in those cases where only one or two grains have destroyed life, and even then it is possible to miss the poison.

Strychnine is separated by the kidneys rapidly. In a suicidal case recorded by Schauenstein,[442] death took place in an hour and a half after taking strychnine, yet from 200 c.c. of the urine, Schauenstein was able to separate nitrate of strychnine in well-formed crystals. Dr. Kratter[443] has made some special researches on the times within which strychnine is excreted by the kidneys. In two patients, who were being treated by subcutaneous injection, half an hour after the injection of 7·5 mgrms. of strychnine nitrate the alkaloid was recognised in the urine. The strychnine treatment was continued for eight to ten days, and then stopped; two days after the cessation, strychnine was found in the urine, but none on the third day, and the inference drawn is that the elimination was complete within forty-eight hours.

Strychnine has been detected in the blood of dogs and cats in researches specially undertaken for that purpose, but sometimes a negative result has been obtained, without apparent cause. Dragendorff[444] gave dogs the largest possible dose of strychnine daily. On the first few days no strychnine was found in the urine, but later it was detected, especially if food was withheld. M’Adam was the first who detected the absorbed poison, recognising it in the muscles and urine of a poisoned horse, and also in the urine of a hound. Dragendorff has found it in traces in the kidneys, spleen, and pancreas; Gay, in different parts of the central nervous system, and in the saliva. So far as the evidence goes, the liver is the best organ to examine for strychnine; but all parts supplied with blood, and most secretions, may contain small quantities of the alkaloid. At one time it was believed that strychnine might be destroyed by putrefaction, but the question of the decomposition of the poison in putrid bodies may be said to be settled. So far as all evidence goes, strychnine is an extremely stable substance, and no amount of putrescence will destroy it. M’Adam found it in a horse a month after death, and in a duck eight weeks after; Nunneley in 15 animals forty-three days after death, when the bodies were much decomposed; Roger in a body after five weeks’ interment; Richter in putrid tissues exposed for eleven years to decomposition in open vessels; and, lastly, W. A. Noyes[445] in an exhumed body after it had been buried 308 days.

It would appear from Ibsen’s[446] experiments that strychnine gets dissolved in the fluids of the dead body—so that whether strychnine remains or not, greatly depends as to whether the fluids are retained or are allowed to soak away; it is, therefore, most important in exhumations to save as much of the fluid as possible.

§ 398. Identification of the Alkaloid.—A residue containing strychnine, or strychnine mixed with brucine, is identified—

(1.) By its alkaline reaction and its bitter taste. No substance can possibly be strychnine unless it tastes remarkably bitter.

(2.) By the extremely insoluble chromate of strychnine, already described.[447] A fluid containing 1 : 1000 of strychnine gives with chromate of potash (if allowed to stand over-night) a marked precipitate, dissimilar to all others, except those of lead and baryta chromates, neither of which can possibly occur if any of the processes described are followed.

(3.) If the chromate just described is treated on a porcelain plate with a drop of pure strong sulphuric acid, a deep rich blue colour, passing through purple into red, rapidly makes its appearance. This colour possesses an absorption spectrum (figured at p. 55). Dr. Guy, neglecting intermediate colours, aptly compares the succession—(1) to the rich blue of the Orleans plum; (2) to the darker purple of the mulberry; and (3) to the bright clear red of the sweet orange. These characters—viz., alkalinity, bitterness, and the property of precipitation by potassic chromate in a definite crystalline form, the crystals giving the colours detailed—belong to no other substance known save strychnine, and for all purposes sufficiently identify the alkaloid. The same colour is obtained by mixing a drop of sulphuric acid with strychnine and a crystal, or speck, of any one of the following substances:—Ferridcyanide of potash, permanganate of potash, peroxide of lead, peroxide of manganese, and cerous hydroxide.

Potassic permanganate and sulphuric acid is the most delicate, and will detect 0·001 mgrm. of strychnine; cerous hydroxide is, on the other hand, most convenient, for cerous hydroxide is white; all the others have colours of their own. Cerous hydroxide is prepared strychnine; 3 gave 3·811 of the chromate, = 78·77 per cent. of strychnine.—Mohr. by dissolving cerium oxalate in dilute sulphuric acid and precipitating with ammonia, filtering and well washing the precipitate; and the latter may be used while moist, and responds well to ¹⁄₁₀₀ mgrm. of strychnine.

The influence of mixtures on the colour reactions of strychnine have been studied by Flückiger, who states:—

“No strychnine reaction appears with sulphuric acid containing chromic acid (made by dissolving 0·02 grm. of pot. bichromate in 10 c.c. of water, and then adding 30 grms. strong sulphuric acid) when brucine and strychnine mixed in equal parts are submitted to the test; it succeeds, however, in this proportion with sulphuric acid containing potassium permanganate (·02 grm. pot. permanganate in 10 c.c. of water, and 30 grms. of strong sulphuric acid).

“If the brucine is only one-tenth of the mixture, the blue-violet colour is obtained. A large excess of atropine does not prevent or obscure the strychnine reaction. A solution of 1 milligrm. atropine sulphate evaporated to dryness, together with 5 c.c. of a solution of strychnine (1 : 100,000) has no influence on the reaction, neither in the proportion of 1 mgrm. to 1 c.c. of the same solution; neither has cinchonine nor quinine any effect.

“Morphine obscures the reaction in the following proportions:—

“A solution of 0·01 mgrm. strychnine evaporated with a solution of 1 mgrm. of morphine sulphate on a water-bath, yields a blurred strychnine reaction when the residue is dissolved in sulphuric acid, and a crystal of potassic permanganate added. But still there is evidence whereby to suspect the presence of strychnine.

“A solution of 2 mgrms. of morphine sulphate treated in like manner with 0·01 mgrm. of strychnine yields like results.

“A solution of 3 mgrms. of morphine sulphate evaporated to dryness, with a solution of 0·01 mgrm. strychnine yielded results with the potassic permanganate test the same as if no strychnine was present.

“A solution of 1 mgrm. of morphine sulphate, treated as above, with a solution of 0·1 mgrm. strychnine, offered positive proof of the presence of the latter.”[448]

Dragendorff was able to render evident ·025 mgrm. mixed with twenty times its weight of quin. sulphate; the same observer likewise recognised ·04 mgrm. of strychnine in thirty-three times its weight of caffeine. Veratrine is likewise not injurious.

The physiological test consists in administering the substance to some small animal (preferably to a frog), and inducing the ordinary tetanic symptoms. It may be at once observed that if definite chemical evidence of strychnine has been obtained, the physiological test is quite unnecessary; and, on the other hand, should the application of a liquid or substance to a frog induce tetanus, while chemical evidence of the presence of strychnine was wanting, it would be hazardous to assert that strychnine was present, seeing that caffeine, carbolic acid, picrotoxin, certain of the opium alkaloids, hypaphorine, some of the ptomaines, and many other substances induce similar symptoms. The best method (if the test is used at all) is to take two frogs,[449] and insert under the skin of the one the needle of a subcutaneous syringe, previously charged with a solution of the substance, injecting a moderate quantity. The other frog is treated similarly with a very dilute solution of strychnine, and the two are then placed under small glass shades, and the symptoms observed and compared. It is not absolutely necessary to inject the solution under the skin, for if applied to the surface the same effects are produced; but, if accustomed to manipulation, the operator will find the subcutaneous application more certain, especially in dealing with minute quantities of the alkaloid.[450]

§ 399. Hypaphorine.—One substance is known which neither physiological test nor the colour reactions suffice to distinguish from strychnine, viz., hypaphorine,[451] the active matter of a papilionaceous tree growing in Java—the Hypaphorus subumbrans; a small quantity of the alkaloid is in the bark, a larger quantity is in the seed.

Hypaphorine forms colourless crystals which brown, without melting, above 220°, and exhale a vapour smelling like napththylamine. The free alkaloid is soluble in water, but has no action on litmus. The salts are less soluble than the free alkaloid, so that acids, such as nitric or hydrochloric, produce in a short time precipitates on standing. Solutions of the salts are not precipitated by alkalies; chloroform, ether, benzene, all fail to extract it from either alkaline or acid solutions. It gives no precipitate with potassic chromate, but most general alkaloidal reagents precipitate.

It gives a precipitate with iodine trichloride, and has therefore probably a pyridine nucleus, it may be an acid anilide.[452] It gives the same colours as strychnine with sulphuric acid and potassic permanganate or potassic chromate; it causes in frogs tetanus, but the dose has to be much larger than that of strychnine. The duration of life in doses of 15 mgrms. may extend to five days, and frogs may even recover after 50 mgrms.

The distinction between strychnine and hypaphorine is therefore easy; besides it will not occur in a chloroform extract, and it will not give a precipitate with potassic chromate.

§ 400. Quantitative Estimation of Strychnine.—The best process of estimating the proportion of each alkaloid in a mixture of strychnine and brucine, is to precipitate them as picrates, and to destroy the brucine picrate by nitric acid after obtaining the combined weight of the mixed picrates; then to weigh the undestroyed strychnine picrate.

To carry out the process, the solution of the mixed alkaloids must be as neutral as possible. A saturated solution of picric acid is added drop by drop to complete precipitation. A filter paper is dried and weighed, and the precipitate collected on to this filter paper; the precipitate is washed with cold water, dried at 105°, and weighed. This weight gives the combined weight of both strychnine and brucine picrates.

The precipitate is now detached from the filter, washed into a small flask, and heated on the water-bath for some time with nitric acid diluted to 1·056 gravity (about 11 per cent. HNO₃). This process destroys the brucine picrate, but leaves the strychnine picrate untouched. The acid liquid is now neutralised with ammonia or soda, and a trace of acetic acid added; the precipitate of strychnine picrate is now collected and weighed. The weight of this subtracted from the first weight, of course, gives that of the brucine picrate.

One part of strychnine picrate is equal to 0·5932 strychnine; and one part of brucine picrate is equal to 0·6324 brucine.

From the strychnine picrate the picric acid may be recovered and weighed by dissolving the picrate in a mineral acid and shaking out with ether; from the acid liquid thus deprived of picric acid the alkaloid may be separated by alkalising with ammonia and shaking out with chloroform.

§ 401. Brucine (C₂₃H₂₆N₂O₄ + 4H₂O)[453] occurs associated with strychnine in the plants already mentioned; its best source is the so-called false angustura bark, which contains but little strychnine. Its action is similar to that of strychnine. If crystallised out of dilute alcohol it contains 4 atoms of water, easily expelled either in a vacuum over sulphuric acid or by heat. Crystallised thus, it forms transparent four-sided prisms, or arborescent forms, like boric acid. If thrown down by ammonia from a solution of the acetate, it presents itself in needles or in tufts.

The recently-crystallised alkaloid has a solubility different from that which has effloresced, the former dissolving in 320 parts of cold, and 150 parts of boiling water; whilst the latter (according to Pelletier and Caventou) requires 500 of boiling, and 850 parts of cold water for solution. Brucine is easily soluble in absolute, as well as in ordinary alcohol; 1 part dissolves in 1·7 of chloroform, in 60·2 of benzene. Petroleum ether, the volatile and fatty oils and glycerine, dissolve the alkaloid slightly, amyl alcohol freely; it is insoluble in anhydrous ether. The behaviour of brucine in the subliming cell is described at p. 260. Anhydrous brucine melts in a tube at 178°. The alcoholic solution of brucine turns the plane of polarisation to the left [α]r = -11·27°. The taste is bitter and acrid. Soubeiran maintains that it can be recognised if 1 part is dissolved in 500,000 parts of water. If nitric trioxide be passed into an alcoholic solution of brucine, first brucine nitrate is formed; but this passes again into solution, from which, after a time, a heavy, granular, blood-red precipitate separates: it consists of dinitro-brucine (C₂₃H₂₄(NO₂)₂N₂O₄). Brucine fully neutralises acids, and forms salts, which are for the most part crystalline. The neutral sulphate (C₂₃H₂₅N₂O₄SH₂O₄ + 3¹⁄₂H₂O) is in long needles, easily soluble in water. The acetate is not crystalline, that of strychnine is so (p. 321).

Brucine is precipitated by ammonia, by the caustic and carbonated alkalies, and by most of the group reagents. Ammonia does not precipitate brucine, if in excess; on the other hand, strychnine comes down if excess of ammonia is added immediately. This has been proposed as a method of separation; if the two alkaloids are present in acid solution, ammonia in excess is added, and the solution is immediately filtered; the quantitative results are, however, not good, the strychnine precipitate being invariably contaminated by brucine.

Chromate and dichromate of potassium give no precipitate with neutral salts of brucine; on the other hand, strychnine chromate is at once formed if present. It might, therefore, be used to separate strychnine from brucine. The author has attempted this method, but the results were not satisfactory.

§ 402. Physiological Action.—The difference between the action of strychnine and that of brucine on man or animals is not great. Mays states that strychnine affects more the anterior, brucine the posterior extremities. In strychnine poisoning, convulsions occur early, and invariably take place before death; but death may occur from brucine without any convulsions, and in any case they develop late. Brucine diminishes local sensibility when applied to the skin; strychnine does not.[454] In a physiological sense, brucine may be considered a diluted strychnine. The lethality of brucine, especially as compared with strychnine, has been investigated by F. A. Falck.[455] He experimented on 11 rabbits, injecting subcutaneously brucine nitrate, in doses of varying magnitude, from 100 mgrms. down to 20 mgrms. per kilogram of body-weight. He found that brucine presented three stages of symptoms. In the first, the respiration is quickened; in 3 of the 11 cases a strange injection of the ear was noticed; during this period the pupils may be dilated. In the second stage, there are tetanic convulsions, trismus, opisthotonus, oppressed respiration, and dilated pupils. In the third stage, the animal is moribund. Falck puts the minimum lethal dose for rabbits at 23 mgrms. per kilo. Strychnine kills 3·06 times more quickly than brucine, the intensity of the action of strychnine relative to that of brucine being as 1 : 117·4. Falck has also compared the minimum lethal dose of strychnine and brucine with the tetanising opium alkaloids, as shown in the following table:—

TABLE SHOWING THE LETHAL DOSES OF VARIOUS TETANISING POISONS.

Minimum Lethal Dose for every Kilogram Weight of Rabbit. Proportional Strength.

Mgrms.

Strychnine nitrate, 0·6 ...

Thebaine nitrate, 14·4 24 ·0

Brucine nitrate, 23·0 38 ·33

Landanine nitrate, 29·6 49 ·33

Codeine nitrate, 51·2 85 ·33

Hydrocotarnine nitrate, 203·8 339 ·66

If these views are correct, it follows that the least fatal dose for an adult man would be 1·64 grm. (about 24·6 grains) of brucine nitrate.

Brucine Crystals. (From a Photograph.)

§ 403. Tests.—If to a solution of brucine in strong alcohol a little methyl iodide is added, at the end of a few minutes circular rosettes of crystal groups appear (see fig.): they are composed of methyl brucine iodide (C₂₃H₂₅(CH₃)N₂O₄HI). Crystals identical in shape are also obtained if an alcoholic solution of iodine, or hydriodic acid with iodine, is added to an alcoholic solution of brucine. A solution of strychnine gives with methyl iodide no similar reaction. Strychnine in alcoholic solution, mixed with, brucine in no way interferes with the test. The methyl iodide test may be confirmed by the action of nitric acid. With that reagent it produces a scarlet colour, passing into blood-red, into yellow-red, and finally ending in yellow. This can be made something more than a mere colour test, for it is possible to obtain a crystalline body from the action of nitric acid on brucine. If a little of the latter be put in a test-tube, and treated with nitric acid of 1·4 specific gravity (immersing the test-tube in cold water to moderate the action), the red colour is produced. On spectroscopic examination of the blood-red liquid a broad, well-marked absorption band is seen, the centre of which (see page 55) is between E. & F. [W. L. about 500]. There is also a development of nitric oxide and carbon dioxide, and the formation of methyl nitrite, oxalic acid, and kakotelin (C₂₃H₂₆N₂O₄ + 5NHO₃ = C₂₀H₂₂N₄O₉ + N(CH₃)O₂ + C₂H₂O₄ + 2NO + 2H₂O). On diluting abundantly with water, the kakotelin separates in yellow flocks, and may be crystallised out of dilute hydrochloric or dilute nitric acid in the form of yellow or orange-red crystals, very insoluble in water, but dissolving readily in dilute acid. On removal by dilution of the product just named, neutralisation with ammonia, and addition of a solution of chloride of calcium, the oxalate of lime is thrown down. The nitric acid test is, therefore, a combined test, consisting of—the production by the action of nitric acid (1) of a red colour; (2) of yellow scales or crystals insoluble in water; (3) of oxalic acid. No alkaloid save brucine is known to give this reaction.

There are other methods of producing the colour test. If a few drops of nitric acid are mixed with the substance in a test-tube, and then sulphuric acid cautiously added, so as to form a layer at the bottom, at the junction of the liquids a red zone, passing into yellow, is seen.

A solution of brucine is also coloured red by chlorine gas, ammonia changing the colour into yellow.

Flückiger[456] has proposed as a test mercurous nitrate, in aqueous solution with a little free nitric acid. On adding this reagent to a solution of brucine salt, and gently warming, a fine carmine colour is developed.

In regard to the separation of brucine from organic fluids or tissues, the process already detailed for strychnine suffices. It is of very great importance to ascertain whether both strychnine and brucine are present or not—the presence of both pointing to nux vomica or one of its preparations. The presence of brucine may, of course, be owing to impure strychnine; but if found in the tissues, that solution of the question is improbable, the commercial strychnine of the present day being usually pure, or at the most containing so small a quantity of brucine as would hardly be separated from the tissues.

§ 404. Igasurine is an alkaloid as yet but little studied; it appears that it can be obtained from the boiling-hot watery extract of nux vomica seeds, through precipitating the strychnine and brucine by lime, and evaporation of the filtrate. According to Desnoix,[457] it forms white crystals containing 10 per cent. of water of crystallisation.

It is said to be poisonous, its action being similar to that of strychnine and brucine, and in activity standing midway between the two.

§ 405. Strychnic Acid.—Pelletier and Caventou obtained by boiling with spirit small, hard, warty crystals of an organic acid, from S. ignatius, as well as from nux vomica seeds. The seeds were first exhausted by ether, the alcohol solution was filtered and evaporated, and the extract treated with water and magnesia, filtered, and the residue first washed with cold water, then with hot spirit, and boiled lastly with a considerable quantity of water. The solution thus obtained was precipitated with acetate of lead, the lead thrown out by SH₂, and the solution evaporated, the acid crystallising out. It is a substance as yet imperfectly studied, and probably identical with malic acid.

2. THE QUEBRACHO GROUP OF ALKALOIDS.

§ 406. The bark of the Quebracho Blanco[458] (Aspidosperma quebracho) contains, according to Hesse’s researches, no fewer than six alkaloids—Quebrachine, Aspidospermine, Aspidospermatine, Aspidosamine, and Hypoquebrachine. The more important of these are Aspidospermine and Quebrachine.

Aspidospermine (C₂₂H₃₀N₂O₂) forms colourless needles which melt at 206°. They dissolve in about 6000 parts of water at 14°—48 parts of 90 per cent. alcohol, and 106 parts of pure ether. The alkaloid gives a fine magenta colour with perchloric acid.

Quebrachine (C₂₁H₂₆N₂O₃) crystallises in colourless needles, melting-point (with partial decomposition) 215°. The crystals are soluble in chloroform, with difficulty soluble in cold alcohol, but easily in hot. The alkaloid, treated with sulphuric acid, and peroxide of lead, strikes a beautiful blue colour. It also gives with sulphuric acid and potassic chromate the strychnine colours. Quebrachine, dissolved in sulphuric acid containing iron, becomes violet-blue, passing into brown. The alkaloid, treated with strong sulphuric acid, becomes brown; on adding a crystal of potassic nitrate, a blue colour is developed; on now neutralising with caustic soda no red coloration is perceived. Dragendorff has recently studied the best method of extracting these alkaloids for toxicological purposes. He recommends extraction of the substances with sulphuric acid holding water, and shaking up with solvents. Aspidospermine is not extracted by petroleum ether or benzene from an acid watery extract, but readily by chloroform or by amyl alcohol. It is also separated from the same solution, alkalised by ammonia, by either amyl alcohol or chloroform; with difficulty by petroleum ether; some is dissolved by benzene. Quebrachine may be extracted from an acid solution by chloroform, but not by petroleum ether. Alkalised by ammonia, it dissolves freely in chloroform and in amyl alcohol. Traces are taken up by petroleum, somewhat more by benzene. Aspidospermine is gradually decomposed in the body, but Quebrachine is more resistant, and has been found in the stomach, intestines, blood, and urine. The toxicological action of the bark ranks it with the tetanic class of poisons. In this country it does not seem likely to attain any importance as a poison.

3. PEREIRINE.

§ 407. Pereirine—an alkaloid from pereira bark—gives a play of colours with sulphuric acid and potassic bichromate similar to but not identical with that of strychnine. Fröhde’s reagent strikes with it a blue colour. On dissolving pereirine in dilute sulphuric acid, and precipitating by gold chloride, the precipitate is a beautiful red, which, on standing and warming, is deepened. Pereirine may be extracted from an acid solution, after alkalising with ammonia, by ether or benzene.

4. GELSEMINE.

§ 408. Gelsemine (C₂₂H₂₈N₂O₄) is an alkaloid[459] which has been separated from Gelsemium sempervirens, the Carolina jessamine, a plant having affinities with several natural orders, and placed by De Candolle among the Loganiaceæ, by Chapman among the Rubiaceæ and by Decaisne among the Apocynaceæ. It grows wild in Virginia and Florida.[460] Gelsemine is a strong base; it is yellowish when impure, but a white amorphous powder when pure. It fuses below 100° into a transparent vitreous mass, at higher temperatures it condenses on glass in minute drops; its taste is extremely bitter; it is soluble in 25 parts of ether, in chloroform, bisulphide of carbon, benzene, and in turpentine; it is not very soluble in alcohol, and still less soluble in water, but it freely dissolves in acidulated water. The caustic alkalies precipitate it, the precipitate being insoluble in excess; it is first white, but afterwards brick-red. Tannin, picric acid, iodised potassic iodide, platinic chloride, potassio-mercuric iodide, and mercuric chloride all give precipitates. Fröhde’s reagent gives with gelsemine a brown changing to green.

Sulphuric acid dissolves gelsemine with a reddish or brownish colour; after a time it assumes a pinkish hue, and if warmed on the water-bath, a more or less purple colour; if a small crystal of potassic bichromate be slowly stirred in the sulphuric acid solution, reddish purple streaks are produced along the path of the crystal; ceric oxide exhibits this better and more promptly, so small a quantity as ·001 grain showing the reaction. This reaction is something like that of strychnine, but nitric acid causes gelsemine to assume a brownish-green, quickly changing to a deep green—a reaction which readily distinguishes gelsemine from strychnine and other alkaloids.

§ 409. Fatal Dose.—10 mgrms. killed a frog within four hours, and 8 mgrms. a cat within fifteen minutes. A healthy woman took an amount of concentrated tincture, which was equivalent to 11 mgrms. (¹⁄₆ grain), and died in seven and a half hours.

§ 410. Effects on Animals—Physiological Action.—Gelsemine acts powerfully on the respiration; for example, Drs. Sydney Ringer and Murrell[461] found, on operating on the frog, that in two minutes the breathing had become distinctly slower; in three and a half minutes, it had been reduced by one-third; and in six minutes, by one-half; at the expiration of a quarter of an hour, it was only one-third of its original frequency; and in twenty minutes, it was so shallow and irregular that it could no longer be counted with accuracy. In all their experiments they found that the respiratory function was abolished before reflex and voluntary motion had become extinct. In several instances the animals could withdraw their legs when their toes were pinched, days after the most careful observations had failed to detect the existence of any respiratory movement. The heart was seen beating through the chest wall long after the complete abolition of respiration.

In their experiments on warm-blooded animals (cats), they noticed that in a few minutes the respirations were slowed down to 12 and even to 8, and there was loss of power of the posterior extremities, while at short intervals the upper half of the body was convulsed. In about half an hour paralysis of the hind limbs was almost complete, and the respiratory movements so shallow that they could not be counted. In the case of a dog, after all respiration had ceased tracheotomy was performed, and air pumped in: the animal recovered.

Ringer and Murrell consider that gelsemine produces no primary quickening of the respiration, that it has no direct action on either the diaphragm or intercostal muscles, that it paralyses neither the phrenic nor the intercostal nerves, and that it diminishes the rate of respiration after both vagi have been divided. They do not consider that gelsemine acts on the cord through Setschenow’s inhibitory centre, but that it destroys reflex power by its direct action on the cord, and that probably it has no influence on the motor nerves. Dr. Burdon Sanderson has also investigated the action of gelsemine on the respiration, more especially in relation to the movements of the diaphragm. He operated upon rabbits; the animal being narcotised by chloral, a small spatula, shaped like a teaspoon, was introduced into the peritoneal cavity through an opening in the linea alba, and passed upwards in front of the liver until its convex surface rested against the under side of the centrum tendineum. The stem of the spatula was brought into connection with a lever, by means of which its to-and-fro movements (and consequently that of the diaphragm) were inscribed. The first effect is to augment the depth but not the frequency of the respiratory movements; the next is to diminish the action of the diaphragm both in extent and frequency. This happens in accordance with the general principle applicable to most cases of toxic action—viz., that paresis of a central organ is preceded by over-action. The diminution of movement upon the whole is progressive, but this progression is interrupted, because the blood is becoming more and more venous, and, therefore, the phenomena of asphyxia are mixed up with the toxical effects. Dr. Sanderson concludes that the drug acts by paralysing the automatic respiratory centre; the process of extinction, which might be otherwise expected to be gradual and progressive, is prevented from being so by the intervention of disturbances of which the explanation is to be found in the imperfect arterialisation of the circulating blood. Ringer and Murrell have also experimented upon the action of gelsemine on the frog’s heart. In all cases it decreased the number of beats; a small fatal dose produced a white contracted heart, a large fatal dose, a dark dilated heart; in either case arrest of the circulation of course followed.

§ 411. Effects on Man.—The preparations used in medicine are the fluid extract and the tincture of gelsemine; the latter appears to contain the resin of the root as well as the active principle. There are several cases on record of gelsemine, or the plant itself, having been taken with fatal effect.[462] Besides a marked effect on the respiration, there is an effect upon the eye, better seen in man than in the lower animals; the motor nerves of the eye are attacked first, objects cannot be fixed, apparently dodging their position, the eyelids become paralysed, droop, and cannot be raised by an effort of the will; the pupils are largely dilated, and at the same time a feeling of lightness has been complained of in the tongue; it ascends gradually to the roof of the mouth, and the pronunciation is slurred. There is some paresis of the extremities, and they refuse to support the body; the respiration becomes laboured, and the pulse rises in frequency to 120 or 130 beats per minute, but the mind remains clear. The symptoms occur in about an hour and a half after taking an overdose of the drug, and, if not excessive, soon disappear, leaving no unpleasantness behind. If, on the other hand, the case proceeds to a fatal end, the respiratory trouble increases, and there may be convulsions, and a course very similar to that seen in experimenting on animals. Large doses are especially likely to produce tetanus, which presents some clinical differences distinguishing it from strychnine tetanus. Gelsemine tetanus is always preceded by a loss of voluntary reflex power, respiration ceases before the onset of convulsions, the posterior extremities are most affected, and irritation fails to excite another paroxysm till the lapse of some seconds, as if the exhausted cord required time to renew its energy; finally, the convulsions only last a short time.

§ 412. Extraction from Organic Matters, or the Tissues of the Body.—Dragendorff states that, from as little as half a grain of the root, both gelsemine and gelsemic acid may be extracted with acid water, and identified. On extracting with water acidified with sulphuric acid, and shaking up the acid liquid with chloroform, the gelsemic acid (æsculin?) is dissolved, and the gelsemine left in the liquid. The chloroform on evaporation leaves gelsemic acid in little micro-crystals; it may be identified by (1) its crystallising in little tufts of crystals; (2) its strong fluorescent properties, one part dissolved in 15,000,000 parts of water showing a marked fluorescence, which is increased by the addition of an alkali; and (3) by splitting up into sugar and another body on boiling with a mineral acid. After separation of gelsemic acid, the gelsemine is obtained by alkalising the liquid, and shaking up with fresh chloroform; on separation of the chloroform, gelsemine may be identified by means of the reaction with nitric acid, and also the reaction with potassic bichromate and sulphuric acid.

5. COCAINE.

§ 413. Cocaine (C₁₇H₂₁NO₄).—There are two cocaines—the one rotating a ray of polarised light to the left, the other to the right. The left cocaine is contained in the leaves of Erythroxylon coca with other alkaloids, and is in commerce.

Cocaine has been used most extensively in medicine since the year 1884—its chief use being as a local anæsthetic. Chemically cocaine is a derivative of ecgonin, being ecgonin-methyl-ester. It has a pyridine nucleus, and may be written C₅H₄N(CH₃)—H₃CHO—(COC₆H₅)—CH₂COOCH₃, or expressed graphically as follows:—

Properties.—Cocaine is in the form of four- to six-sided prisms of the monoclinic system. It is one of the few alkaloids which melt under the temperature of boiling water, the melting-point being as low as 85° in water. It readily furnishes a sublimate at 100°, partially decomposing. On boiling with hydrochloric acid cocaine is decomposed into methyl alcohol, ecgonin, and benzoic acid, according to the following reaction:—

Cocaine. Benzoic acid. Ecgonin. Alcohol.

C₁₇H₂₁NO₄ + 2H₂O = C₆H₅COOH + C₉H₁₅NO₃ + CH₃OH.

Cocaine is but little soluble in water, but easily dissolves in ether, alcohol, benzene, chloroform, and carbon disulphide; an aqueous solution is alkaline to methyl-orange, but not to phenol-phthalein. It can be made synthetically by the reaction of ecgonin-methyl-ester with benzoyl chloride.

§ 414. Cocaine Hydrochlorate (C₁₇H₂₁NO₄HCl).—Crystallised from alcohol, cocaine hydrochlorate appears in prismatic crystals; these crystals, according to Hesse,[463] when perfectly pure, should melt at 186°, although the melting-point is generally given as 200° or even 202°. Cocaine hydrochlorate is soluble in half its weight of water, insoluble in dry ether, but readily soluble in alcohol, amyl alcohol, or chloroform.

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

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

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

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

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

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

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

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

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

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

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

In the experimental poisoning of mice with cocaine Ehrlich[464] found a considerable enlargement of the liver.

§ 419. Fatal Dose.—The fatal dose, according to Mannheim,[465] must be considered as about 1 grm. (15·4 grains); the smallest dose known to have been fatal is 0·08 grm. (1·2 grain) for an adult, and 0·05 grm. (0·7 grain) for a child.

6. CORYDALINE.

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

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

V.—The Aconite Group of Alkaloids.

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

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

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

Aconitine, officinal in all the pharmacopœias.

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

Aconite tincture, officinal in all the pharmacopœias.

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

Aconite extract, the juice of the leaves evaporated; officinal in most of the pharmacopœias. The strength in alkaloid of the extract varies; in six samples examined by F. Casson, the least quantity was 0·16 per cent., the maximum 0·28 per cent.[466]

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

§ 423. The Alkaloids of Aconite.—The researches of Dr. Alder Wright and Luff, and especially those of Professor Dunstan,[467] have established that in the root of the true aconite there exist four alkaloids, one only of which has been as yet crystallised.

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

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

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

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

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

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

Aconine, m.p., 132°, C₂₄H₃₉NO₁₀

Pyraconine (anhydro-aconine), C₂₄H₃₇NO₉

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

Acetic Acid. Benzoic Acid. Aconine.

C₃₃H₄₅NO₁₂ + 2H₂O = C₂H₄O₂ + C₇H₆O₂ + C₂₄H₃₉NO₁₀.

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

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

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

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

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

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

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

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