Chapter XXXI: Part VI: Alkaloids and Poisonous Vegetable Principles Separated for the (5)

§ 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.

[418] _Ann. Phys._, xxv. 56; xxvii. 183.

[419] _De opio et de illis quibus constat partibus_, Berol., 1822.

[420] _Arch. Path. Anat._, xxvi. 248.

[421] _Med. Jahresb._, 1869.

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.

[422] To this group also belong some of the opium alkaloids. See “Thebaine,” “Landamine,” “Codeine,” “Hydrocotarnine.”

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. (9⁹⁄₁₄ 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. (⅓ 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.

[423] Dolzler, _Arch. Pharm._ [3], xxiv. 105-109.

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]

[424] Dragendorff, _Die chemische Werthbestimmung einiger starkwirkenden Droguen_, St. Petersburg, 1874.

[425] These details are very necessary, as bearing on the question of the fatal dose of nux vomica, which Taylor tells us (_Med. Jurisprud._, i. 409) was of some importance in _Reg._ v. _Wren_, in which 47 grains were attempted to be given in milk. The fatal dose of nux vomica must be ruled by its alkaloidal content, which may be so low as 1 per cent., and as high as nearly 3 per cent. 30 grains have proved fatal (_Taylor_); if the powder in this instance was of the ordinary strength, the person died from less than a grain (·0648 grm.) of the united alkaloids.

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 |Weight of | | Strychnine. |Nature | |
| or | Powder |Price.+---------+---------+ of | Colouring |
|Mark.|in Grains.| |Weight in| Per- |Starch.| Matter. |
| | | |Grains. |centage. | | |
+-----+----------+------+---------+---------+-------+--------------+
| | | | | | | |
| 1 | 5·6 | 3_d._| 0·61 | 10·9 | Wheat | ? |
| 2 | 11·8 | 3_d._| 0·80 | 6·7 | Wheat | Ultramarine. |
| 3 | 13·1 | 3_d._| 1·12 | 8·7 | Rice | Ultramarine. |
| 4 | 11·6 | 3_d._| 1·28 | 11·1 | Rice | Ultramarine. |
| 5 | 13·1 | 3_d._| 1·70 | 13·0 | Rice | Ultramarine. |
| 6 | 21·5 | 6_d._| 2·42 | 11·2 | Wheat |Prussian blue.|
| 7 | 49·2 | 3_d._| 2·85 | 5·8 | Wheat | Soot. |
| 8 | 30·5 | 3_d._| 3·45 | 11·3 | Wheat |Prussian blue.|
| 9 | 16·6 | 3_d._| 3·81 | 19·4 | Rice | Carmine. |
| 10 | 10·0 | 3_d._| 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]

[426] According to Christison’s researches, 0·2 grm. (about ⅓ grain) is fatal to swine; ·03 grm. (½ grain) to bears, if injected into the pleura. 1 to 3 grains (·0648 to ·1944 grm.) is given to horses in cases of paralysis, although 3 grains cannot but be considered a dangerous dose, unless smaller doses have been previously administered without effect; 10 grains would probably kill a horse, and 15 grains (·972 grm.) have certainly done so.

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 ⅙ 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. (½ 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.

+------------+----------------------+--------------------------------+
| | | Reckoned on 1 Kilo. of |
| | | Body-weight. |
| | +-----------------|--------------+
| | Manner of | Lowest | Highest |
| Animal. | Application. | Experimental | Experimental |
| | | Lethal Dose | Lethal Dose. |
| | +-----------------+--------------+
| | | Dose of Strychnine Nitrate in |
| | | Mgrms. |
+------------+----------------------+-----------------+--------------+
| Rabbit, | Subcutaneous. | 0·50 | 0·60 |
| Cat, | „ | ... | 0·75 |
| Dog, | „ | ... | 0·75 |
| „ | Taken by the Stomach.| 2·0 | 3·90 |
| „ | „ Rectum. | ... | 2·00 |
| „ | „ Bladder.| 5·50 | ... |
| Fox, | Subcutaneous. | ... | 1·00 |
| Hedgehog, | „ | 1·00 | 2·00 |
| Fowl, | „ | ... | 2·00 |
| Frog, | „ | 2·00 | 2·10 |
| Mouse, | „ | 2·36 | 2·36 |
| Ring Adder,| „ | ... | 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.

[427] Maschka’s _Handbuch_, from Tschepke, _Deutsche Klinik_, 1861.

[428] _Lancet_, November 28, 1882.

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.

[429] _Lancet_, May 13, 1882.

§ 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.

[430] _De l’Action de la Strychnine à très forte dose sur les Mammifères. Comptes Rend._, t. xcl. p. 131.

§ 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]

[431] In one of M. Richet’s experiments, a soluble strychnine salt injected into a dog subcutaneously acted in fourteen seconds.

[432] Quoted by Taylor from _Med. Times and Gazette_, July, 1861.

[433] A non-fatal dose may show its effects rapidly, _e.g._, there is a curious case of symptoms of poisoning caused by the _last_ dose of a mixture which is recorded in _Pharm. Journ._, 1893, 799. A medical practitioner prescribed the following mixture:--

℞. Tr. strophanthi, ʒi.
Liq. strychni hydrochlorici, ʒiiss.
Sol. bismuthi et pepsin. (Richardson’s), ℥iss.
Sp. ammon. aromat., ...
Sp. chloroformi, aa. ℥iss.
Aquam ad, ℥vi.
ft. mist.
Shake the bottle.
Two teaspoonfuls when the attack threatens, and repeat in an hour if
necessary.

Richardson’s liquor bismuth contains 1/20 grain of strychnine in each drachm. The mixture was alkaline; it contained 1·7 grain of strychnine and 38·25 minims of chloroform.

The patient, a woman, 54 years of age, had taken the previous doses with considerable relief; but ten minutes after the last dose, which she described as far more bitter than those she had taken previously, she was seized with the usual symptoms of strychnine poisoning, but recovered after five hours.

The explanation is pretty obvious; the mixture was alkaline, so that the strychnine was not in the form of a salt, but in the free state, and was therefore dissolved by the chloroform; the amount of strychnine taken in each dose wholly depended on whether or not the mixture was shaken violently and poured out into the teaspoon immediately after shaking; if allowed to repose the globules of chloroform saturated with strychnine would settle at the bottom, and there form a stratum rich in strychnine; so that the last dose would certainly contain an excess.

[434] White, _Brit. Med. Journ._, 1867.

[435] Folkes, _Med. Times_, 1869.

§ 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]

[436] R. W. Lovett, _Journ. Physiol._, ix. 99-111.

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.”

[437] _Op. cit._

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.

[438] _Wiener Akad. Sitzungsber._, 1871.

§ 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.

[439] _Op. cit._

§ 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]

[440] It is certain that lutidine would be a valuable antidote for strychnine. C. G. Williams found that lutidine injected into frogs already under the influence of strychnine, arrested the convulsions, or if given first, and then followed by a fatal dose of strychnine, it prevented the appearance of the tetanus. (See _ante_, p. 276, footnote.)

§ 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]--

[441] “The _post-mortem_ Detection and Estimation of Strychnine,” by Allerton S. Cushman--_Chem. News_, vol. lxx. 28.

“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.