Rabbits are killed by doses of ·1 grm. per kilo. The symptoms

commence in about ten minutes after the administration, and consist

of apathy and a low temperature; the breathing is much slowed.

Convulsions set in suddenly before death, and the pupils become

dilated. The _post-mortem_ appearances in animals are intense

redness and injection of the meninges of the cerebellum, of the

medulla oblongata, and the spinal cord. Dark red blood is found in

the heart, and the kidneys are hyperæmic. The intestinal mucous

membrane is normal.

§ 465. =Separation of Solanine from the Tissues of the

Body.=--Dragendorff has proved the possibility of separating

solanine from animal tissues by extracting it from a poisoned pig.

The best plan seems to be to extract with cold dilute sulphuric acid

water, which is then made alkaline by ammonia, and shaken up with

warm amyl alcohol. This readily dissolves any solanine. The peculiar

property possessed by the alkaloid of gelatinising, and the play of

colours with Fröhde’s reagent, may then be essayed on the solanine

thus separated.

5. CYTISINE.

§466. =The Cytisus Laburnum.=--The laburnum tree, _Cytisus laburnum_, so

common in shrubberies, is intensely poisonous. The flowers, bark, wood,

seeds, and the root have all caused serious symptoms. The active

principle is an alkaloid, to which the name of Cytisine has been given.

The best source is the seeds. The seeds are powdered and extracted with

alcohol containing hydrochloric acid, the alcohol distilled off, the

residue treated with water and filtered through a wet filter to remove

any fatty oil, the filtrate treated with lead acetate; and, after

separating the precipitated colouring matter, made alkaline with caustic

potash, and shaken with amyl alcohol. The amyl alcohol is shaken with

dilute hydrochloric acid, the solution evaporated, the crude crystals

of hydrochloride thus obtained treated with alcohol to remove colouring

matters, and recrystallised several times from water; it then forms

well-developed, colourless, transparent prisms. From the hydrochloride

the free base is readily obtained.

=Cytisine=, C₁₁H₁₄N₂O.--To cytisine used to be ascribed the formula

C₂₀H₂₇N₃O, but a study of the salt and new determinations appear to

prove that it is identical with ulexine.[518] Cytisine is in the form of

white radiating crystals, consisting, when deposited from absolute

alcohol, of anhydrous prisms, which melt at from 152° to 153°. Cytisine

has a strong alkaline reaction; it is soluble in water, alcohol, and

chloroform, less so in benzene and amyl alcohol, almost insoluble in

cold light petroleum, and insoluble in pure ether. The specific rotatory

power in solution is [α]_{D}17° = -119·57.

[518] A. W. Gerrard and W. H. Symons dispute this; they ascribe to

ulexine the formula of C₁₁H₁₄N₂O, to cytisine C₂₀H₂₇N₃O. Ulexine is very

hygroscopic, cannot be sublimed, even in a vacuum, without

decomposition, and dissolves readily in chloroform; on the contrary,

cytisine is not hygroscopic, sublimes completely, and is almost

insoluble in chloroform, _Pharm. J._ (3), xx. 1017.

A. Partheil, _Ber._, xxiii. 3201-3203; _Arch. Pharm._, ccxxx. 448-498.

It is capable of sublimation in a current of hydrogen at 154·5°; the

sublimate is in the form of very long needles and small leaflets; at

higher temperatures it melts to a yellow oily fluid, again becoming

crystalline on cooling. Cytisine is a strong base; it precipitates the

earths and oxides of the heavy metals from solutions of the chlorides,

and, even in the cold, expels ammonia from its combinations.

Cytisine forms numerous crystalline salts, among which may be mentioned

two platinochlorides, C₁₁H₁₄N₂OH₂PtCl₆ + 2½H₂O and (C₁₁H₁₄N₂O)₂H₂PtCl₆,

crystallising in golden yellow needles, which are tolerably soluble in

water; and the aurochloride, C₁₁H₁₄N₂OHAuCl₄, crystallising in short,

red-brown, hook-shaped needles; m.p. 212° to 213°, without evolution of

gas.

§ 467. =Reactions of Cytisine.=--Concentrated sulphuric acid dissolves

cytisine without colour; if to the solution is added a drop of nitric

acid, it becomes orange-yellow, and on addition of a crystal of potassic

bichromate, first yellow, then dirty brown, and lastly green.

Concentrated nitric acid dissolves the base in the cold without colour,

but, on warming, it becomes orange-yellow. Picric, tannic, and

phosphomolybdic acids, potassic, mercuric, and potass. cadmium iodides,

and iodine with potassic iodide, all give precipitates. Neither potassic

bichromate nor mercuric chloride precipitates cytisine, even though the

solution be concentrated. The best single test appears to be the

reaction discovered by Magelhaes; this consists in adding thymol to a

solution of cytisine in concentrated sulphuric acid, when a yellow

colour, finally passing into an intense red, is produced.

§ 468. =Effects on Animals.=--W. Marmé found subcutaneous doses of from

30 to 40 mgrms. fatal to cats; death was from paralysis of the

respiration, and could be avoided by artificial respiration. Cattle are

sometimes accidentally poisoned by laburnum. An instance of this is

recorded in the _Veterinarian_ (vol. lv. p. 92). In Lanark a storm had

blown a large laburnum tree down to the ground; it fell into a field in

which some young heifers were grazing, and they began to feed on the

leaves and pods. Two or three died, and three more were ill for some

time, but ultimately recovered.

The laburnum, however, does not always have this effect, for there is a

case related in the _Gardeners’ Chronicle_, in which five cows browsed

for some time on the branches and pods of an old laburnum tree that had

been thrown aside. Rabbits and hares are said to feed eagerly, and

without injury, on the pods and branches.

§ 469. =Effects on Man.=--The sweet taste of many portions of the

laburnum tree, as well as its attractive appearance, has been the cause

of many accidents. F. A. Falck has been able to collect from medical

literature no less than 155 cases--120 of which were those of the

accidental poisoning of children: only 4 (or 2·6 per cent.), however,

died, so that the poison is not of a very deadly character.

One of the earliest recorded cases is by Christison.[519] A servant-girl

of Inverness, in order to excite vomiting in her fellow-servant (the

cook), boiled some laburnum bark in soup; very soon after partaking of

this soup, the cook experienced violent vomiting, which lasted for

thirty-six hours; she had intense pain in the stomach, much diarrhœa,

and great muscular weakness; she appears to have suffered from

gastro-intestinal catarrh for some time, but ultimately recovered.

[519] _Ed. Med. Journ._, 1843.

Vallance[520] has described the symptoms observed in the poisoning of

fifty-eight boys, who ate the root of an old laburnum tree, being

allured by its sweet taste. All were taken ill with similar symptoms,

differing only in severity; two who had eaten half an ounce (nearly 8

grms.) suffered with especial severity. The symptoms were first

vomiting, then narcosis, with convulsive movements of the legs and

strange movements of the arms: the pupils were dilated. This dilatation

of the pupil Sedgwick also saw in the poisoning of two children who ate

the root. On the other hand, when the flower, seeds, or other portions

of the laburnum have been eaten, the symptoms are mainly referable to

the gastro-intestinal tract, consisting of acute pain in the stomach,

vomiting, and diarrhœa. On these grounds it is therefore more than

probable that there is another active principle in the root, differing

from that which is in those portions of the tree exposed to the

influence of sunlight.[521]

[520] _Brit. Med. Journ._, 1875.

[521] See also a case related by Dr. Popham, in which ten children ate

laburnum seeds; the pupils were dilated. They all recovered. _B. and F.

Med. Chir. Review_, Ap. 1863; also a case reported by H. Usher, _Med.

Times and Gazette_, Sept. 15, 1862.

The _post-mortem_ appearances are, so far as known, in no way

characteristic.

VII.--The Alkaloids of the Veratrums.

§ 470. The alkaloids of the veratrums have been investigated by Dr.

Alder Wright, Dr. A. P. Luff, and several other chemists.[522]

[522] “The Alkaloids of the Veratrums,” by C. R. Alder Wright, D.Sc.,

and A. P. Luff, _Journ. Chem. Soc._, July 1879; “The Alkaloids of

_Veratrum viride_,” by C. Alder Wright, D.Sc., _ib._, 1879.

The method which Wright and Luff adopted to extract and separate these

alkaloids from the root of _V. album_ and _V. viride_, essentially

consisted in exhausting with alcohol, to which a little tartaric acid

has been added, filtering, distilling off the alcohol, dissolving the

residue in water, alkalising with caustic soda, and shaking up with

ether. The ethereal solution was next separated, and then washed with

water containing tartaric acid, so as to obtain a solution of the bases

as tartrates: in this way the same ether could be used over and over

again. Ultimately a rough separation was made by means of the different

solubilities in ether, pseudo-jervine being scarcely soluble in this

medium, whilst jervine, veratralbine, veratrine, and cevadine are very

soluble in it.

The yield of Wright and Luff’s alkaloids was as follows:--

TABLE SHOWING THE ALKALOIDS IN THE VERATRUMS.

+---------------+------------+---------------------+

| | V. album. | V. viride. |

| | Per Kilo. | Per Kilo. |

| +------------+---------------------+

|Jervine, | 1·3 grm. | ·2 grm. |

|Pseudo-jervine,| ·4 „ | ·15 „ |

|Rubi-jervine, | ·25 „ | ·02 „ |

|Veratralbine, | 2·2 „ | Traces. |

|Veratrine, | ·05 „ | Less than ·004 grm. |

|Cevadine, | Absent. | „ ·43 „ |

+---------------+------------+---------------------+

From whence it appears that _V. album_ has only a very small quantity of

veratrine, that it is almost absent in _V. viride_; on the other hand,

_V. viride_ contains a fair quantity of cevadine, an alkaloid absent in

_V. album_.

Besides the six principles enumerated, G. Salzberger has recently

separated two other crystalline substances, to which he has given the

names of _protoveratrine_ and _protoveratridine_, and Pehkschen has also

separated a ninth substance, to which he has given the name of

_veratroidine_.

The formulæ of the nine bodies which have been separated from hellebore

root are as follows:--

Melting-point.

1. Veratrine, C₃₇H₅₃NO₁₁, ...

2. Cevadine, C₃₂H₄₉NO₉, 205°-206°

3. Protoveratrine, C₃₂H₅₁NO₁₁, 245°-250°

4. Pseudo-jervine, { C₂₉H₄₃NO₇ (_Wright_), 299°-300°

{ C₂₉H₄₉NO₁₂ (_Pehkschen_), ...

5. Veratralbine, C₂₈H₄₃NO₅, ...

6. Protoveratridine, C₂₆H₄₅NO₈, 265°

7. Rubi-jervine, { C₂₆H₄₃NO₂ (_Wright_ and _Luff_), 236°

{ (_Salzberger_), 240°-245°

8. Jervine, C₂₆H₃₇NO₃2H₂O, 237°-239°

9. Veratroidine, C₃₂H₅₃NO₉, 149°

Three of these alkaloids possess powerful sternutatory properties, the

least quantity applied to the nostrils exciting sneezing; the three are

veratrine, cevadine, and protoveratrine.

Protoveratrine, C₃₂H₅₁NO₁₁, has been obtained by G. Salzberger[523] from

powdered hellebore root, by the following process:--

[523] _Arch. Pharm._, ccxxviii. 462-483.

The powdered root is first freed from fatty and resinous matters by

treatment with ether, and then the fat-free powder is exhausted with

alcohol. The alcohol is evaporated off in a vacuum, the extract mixed

with much acetic acid water, filtered from the insoluble residue, and

treated with metaphosphoric acid; the voluminous precipitate contains

much amorphous matter, with insoluble compounds of jervine and

rubi-jervine. The precipitate is filtered off, and the filtrate treated

with excess of ammonia and shaken up with ether. On separating the ether

and distilling, protoveratrine crystallises out, and can be obtained

pure by recrystallisation from strong alcohol.

Protoveratrine crystallises in four-sided plates, which melt with

charring at 245° to 250°. The base is insoluble in water, benzene, and

light petroleum; chloroform and boiling 96 per cent. alcohol dissolve it

somewhat; cold ether scarcely touches it, boiling ether dissolves it a

little.

Concentrated sulphuric acid dissolves the alkaloid slowly with the

production of a greenish colour, which passes to cornflower blue, and,

after some hours, becomes violet. Sulphuric acid and sugar gives a

different colour to that produced by commercial veratrine. There is

first a green colour which darkens into olive green, then becomes dirty

green, and finally dark brown. When warmed with strong sulphuric,

hydrochloric, or phosphoric acids, there is a strong odour of

isobutyric acid developed. Dilute solutions of the salts are

precipitated by ammonia, Nessler’s reagent, gold chloride, potassium

mercury iodide, cadmium iodide, phosphotungstic acid, and picric acid;

no precipitate is produced by tannin, platinum chloride, or mercuric

chloride.

§ 471. =Veratrine= (C₃₇H₅₃NO₁₁) is a crystallisable alkaloid, which is a

powerful irritant of the sensory nerves of the mucous membrane, and

excites violent sneezing. Treated with concentrated sulphuric acid, it

dissolves with a yellow colour, deepening into orange, then into

blood-red, and finally passing into carmine-red. If the freshly-prepared

sulphuric acid solution is now treated with bromine water, a beautiful

purple colour is produced. Concentrated hydrochloric acid dissolves

veratrine without the production of colour, but, with careful warming,

it becomes beautifully red. This reaction is very delicate, occurring

with ·17 mgrm. On saponification veratrine yields veratric acid.

Veratric acid is procatechu-dimethylether acid, and has the

constitutional formula,

COOH

/

C₆H₃

\

(OCH₃)₂

Veratric acid forms colourless needles and four-sided prisms which have

a marked acid reaction; it melts on heating to a colourless fluid, and

sublimes without decomposition; it is easily soluble in hot alcohol, but

insoluble in ether. If dissolved in nitric acid, water separates

nitro-veratric acid, C₉H₉(NO₂)O₄ which crystallises out of alcohol in

small yellow scales. Veratric acid unites with bases forming crystalline

salts; the silver salt has the composition of C₉H₉AgO₄ = 37·37 per cent.

silver, and may assist in identification. It is crystalline with a

melting point of 205° to 206°.

=Cevadine=, C₃₂H₄₉NO₉ (Merck’s veratrine).--It has powerful sternutatory

properties, and, under the influence of alcoholic potash, yields

tiglic[524] acid and cevine, C₂₇H₄₃NO₈.

[524] Tiglic acid, C₅H₈O₂, is a volatile acid, m.p. 64°, boiling point,

198·5°; it forms a soluble barium salt, and an insoluble silver salt.

According to Ahrens, angelic acid is first formed, and then converted

into tiglic acid. When the alkaloid is boiled with hydrochloric acid,

tiglic acid is formed, and a ruby red mass. Nitric acid oxidises

cevadine completely; with potassic permanganate it yields acetic and

oxalic acids; with chromic acid it forms acetaldehyde and carbon

dioxide.[525]

[525] _Ber._, xxiii. 2700-2707.

The Continental authorities always give to cevadine the name of

veratrine. Cevadine forms a crystalline aurochloride, a crystalline

mercurochloride, C₃₂H₄₉NO₉HHgCl₃, and a crystalline picrate,

C₃₂H₄₉NO₉C₆H₃N₈O₇. The mercury salt crystallises in small silvery

plates, and melts with decomposition at 172°. The picrate forms stable

crystals blackening at 225°; both of the latter salts are but little

soluble in water, but are soluble in alcohol. Cevadine also unites with

bromine, forming a tetrabromide, an amorphous yellow powder insoluble in

water, but readily soluble in alcohol, ether, and chloroform.

§ 472. =Jervine=, (C₂₆H₃₇NO₃2H₂O) (_Wright_ and _Luff_), C₁₄H₂₂NO₂

(_Pehkschen_),[526] crystallises in white needles, and, when anhydrous,

melts at 237·7°. It is slightly lævorotatory. At 25° one part of the

base dissolves in 1658 benzene, 268 ether, 60 chloroform, and 16·8

absolute alcohol. It is insoluble in light petroleum, and but slightly

soluble in ethyl acetate, water, or carbon bisulphide. It forms a very

insoluble sulphate, and a sparingly soluble nitrate and hydrochloride.

Jervine gives, with sulphuric acid and sugar, a violet colour, passing

to blue. Treated with strong sulphuric acid it dissolves to a yellow

fluid, which becomes successively dark yellow, brownish yellow, and then

greenish. The green shade is immediately developed by diluting with

water. Jervine does not produce sneezing.

[526] _Jour. Pharm._ (5), xxii. 265-269.

§ 473. =Pseudo-jervine=, C₂₉H₄₃NO₇ (_Wright_), m.p. 299°; C₂₉H₄₉NO₁₂,

m.p. 259° (_Pehkschen_), may be obtained in a crystalline state. One

part is soluble in 10·9 parts of light petroleum, 372 parts of benzene,

1021 parts of ether, 4 of chloroform, and 185 of absolute alcohol. The

pure base gives no colour with sulphuric, nitric, or hydrochloric acids.

It does not produce sneezing.

§ 474. =Protoveratridine=, C₂₆H₄₅NO₈, is probably derived from

protoveratrine. Salzberger[527] isolated it from powdered hellebore

roots by treating the powder with barium hydroxide and water, and

extracting with ether. The ether extract was separated and freed from

ether in a current of hydrogen at a low temperature.

[527] _Arch. Pharm._, ccxxviii. 462-483.

From the dark green syrup obtained jervine crystallised out, and from

the mother liquor ultimately protoveratridine was separated.

Protoveratridine crystallises in colourless four-sided plates, which

melt at 265°. It is almost insoluble in alcohol, chloroform, methyl

alcohol, and acetone, and insoluble in benzene, light petroleum, and

ether. Concentrated sulphuric acid gives a violet, then a cherry-red

colour. Its solution in concentrated hydrochloric acid becomes light red

on warming, and there is an odour of isobutyric acid. It is readily

soluble in dilute mineral acids, and the solution, on the addition of

ammonia, yields the alkaloid in a crystalline condition. The sulphuric

acid solution gives precipitates with phosphotungstic, picric, and

tannic acids, and with potassium mercury iodide; but gives no

precipitate with platinum chloride, potassium-cadmium iodide, or with

Millon’s reagent.

It forms a platinum salt, (C₂₆H₄₅NO₈)₂H₂PtCl₆ + 6H₂O, which is

precipitated in large six-sided plates on adding alcohol to a mixed

solution of platinum chloride and a salt of the base.

Protoveratridine is not poisonous, and does not cause sneezing. Its

solutions are very bitter.

§ 475. =Rubi-jervine=, C₂₆H₄₃NO₂, is a crystallisable base wholly

different from jervine, yet probably closely allied to it. It forms a

light yellow, indistinctly crystalline gold salt (C₂₆H₄₃NO₂,HCl,AuCl₃):

it gives a different play of colours from jervine with sulphuric acid.

The concentrated acid dissolves rubi-jervine to a clear yellow fluid,

becoming successively dark yellow, brownish yellow, and brownish

blood-red, changing after several hours to a brownish purple. On

diluting slightly with water the brownish-red liquid, it becomes

successively crimson, purple, dark lavender, dark violet, and ultimately

light indigo. Its hydrochloride and sulphate are both more soluble than

either of the corresponding salts of jervine or pseudo-jervine.

§ 476. =Veratralbine=, C₂₈H₄₃NO₅, an amorphous non-sternutatory base,

gives, when a speck of the substance is dissolved in sulphuric acid, a

play of colours, becoming successively yellow, dark yellow, brownish

orange, and brownish blood-red, with a strong green fluorescence. It

yields no acid on saponification.

§ 477. =Veratroidine=, C₃₂H₅₃NO₉, is another base which has been

separated by C. Pehkschen.[528] Its melting point is 149°. One part

dissolves in 13 of benzene, 59 of chloroform, and 9 of ether. It yields

amorphous salts with the mineral acids, and with oxalic and acetic

acids. It is precipitated by most of the group reagents. With 11 per

cent. solution of hydrochloric acid it gives a beautiful rose colour.

[528] _Op. cit._

§ 478. =Commercial Veratrine.=--Commercial veratrine is a mixture of

alkaloids, and has usually fairly constant properties, one of which is

its intense irritant action on the nostrils. Placed on moist blue-red

litmus paper it gives a blue spot. It is but little soluble in water,

1 : 1500; but readily dissolves in alcohol and chloroform; it is but

little soluble in amyl alcohol, benzene, and carbon disulphide.

When a very small quantity is treated with a drop of sulphuric acid, the

acid in the cold strikes a yellow colour; on warming, the colour becomes

violet, slowly changing to orange and cherry red. Sensible to 100th of

mgrm. If this test is performed in a test-tube, a green-yellow

fluorescence is also seen on the sides of the test-tube.

Commercial veratrine strikes a pink-red colour with hydrochloric acid in

the cold if a long time is allowed to elapse, but it at once appears if

the acid is warmed, and is permanent. The solution becomes fluorescent

if two drops of acetic acid are added.

If a small quantity of commercial veratrine is added to melted oxalic

acid and the warming continued, a blood-red colour is obtained.

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

butyric acid.

A dark green colour, followed by reddish purple and blue colours, is

obtained by adding a sprinkling of finely-powdered sugar to a solution

of veratrine in sulphuric acid. This is best seen with a solution of 1

to 10,000; if in dilution of 1 to 100,000 a grass-green colour is

produced, followed by purple and blue colours, quickly changing to brown

or black.[529]

[529] _Flückiger’s Reactions_, 1893.

When two or three drops of sulphuric acid and furfur aldehyde (5 drops

to 10 c.c. of acid) are added to minute particles of alkaloids, a more

or less characteristic colour makes its appearance; this is particularly

the case with veratrine. A few particles rubbed with a glass rod, and

moistened with the reagent, gives first a yellowish-green, then an

olive-green mixture, the edges afterwards becoming a beautiful blue. On

warming, the mixture gradually acquires a purple-violet colour. The blue

substance obtained in the cold is insoluble in alcohol, ether, or

chloroform. The least amount of water decolorises the solution, and, on

adding much water, a fairly permanent yellow solution is obtained.[530]

[530] A. Wender, _Chem. Zeitung_, xvii. 950, 951.

§ 479. =Pharmaceutical Preparations.=--The alkaloid is officinal in the

English, American, and Continental pharmacopœias. There is also an

_unguentum veratrinæ_--strength about 1·8 per cent. In the London

pharmacopœia of 1851 there used to be a wine of white hellebore, the

active principle of 20 parts of the root by weight being contained in

100 parts by measure of the wine. Such a wine would contain about 0·084

per cent. of total alkaloids. Of the green hellebore there is a tincture

(_tinctura veratri viridis_), to make which four parts by weight of the

root are exhausted by 20 parts by measure of spirits; the strength

varies, but the average is 0·02 per cent. of total alkaloids.

§ 480. =Fatal Dose.=--The maximum dose of the commercial alkaloid is

laid down as 10 mgrms. (·15 grain), which can be taken safely in a

single dose, but nothing sufficiently definite is known as to what is a

lethal dose. 1·3 grm. of the powdered rhizome has caused death, and, on

the other hand, ten times that quantity has been taken with impunity, so

that at present it is quite an open question.

§ 481. =Effects on Animals--Physiological Action.=--Experiments on

animals have proved that the veratrums act on the sensory nerves of the

skin, and those of the mucous membranes of the nose and intestinal

canal; they are first excited, afterwards paralysed. When administered

to frogs, sugar and lactic acid appear in the urinary excretion.[531]

It exercises a peculiar influence on voluntary muscle; the

contractility is changed, so that, when excited, there is a

long-continuing contraction, and from a single stimulus more heat is

disengaged than with healthy muscle; the motor nerves are also affected.

The respiration, at first quickened, is then slowed, and finally

paralysed. The heart’s action is also first quickened, the

blood-pressure at the same time is raised, and the small arteries

narrowed in calibre; later follow sinking of the pressure, slowing of

the heart, and dilatation of the vessels, and the heart becomes finally

paralysed.

[531] _Zeit. Phys. Chem._, xvi. 453-459.

§ 482. =Effects on Man.=--Poisoning by veratrum, sabadilla, or

pharmaceutical preparations containing veratrine, is not common. Plenk

witnessed a case in which the external application of sabadilla powder

to the head caused delirium, and Lentin also relates a case in which an

infant at the breast seems to have died from an external application

made for the purpose of destroying lice. In both instances, however,

there is a possibility that some of the medicament was swallowed.

Blas recorded, in 1861, the case of two children who drank a decoction

of white hellebore, the liquid being intended as an external application

to an animal. They showed serious symptoms, but ultimately recovered.

A scientific chemist took 3·8 grms. (58 grains) of the tincture of green

hellebore for the purpose of experiment. There followed violent symptoms

of gastric irritation, vomiting, and diarrhœa, but he also

recovered.[532]

[532] _Med. Times and Gazette_, Jan. 3, 1863.

Casper relates the poisoning of a whole family by veratrum; from the

stomach of the mother (who died) and the remains of the repast (a

porridge of lentils) veratrine was separated.

Faber[533] recorded the poisoning of thirty cows by veratrum; eight

died, and it is noteworthy that violent poisonous symptoms were produced

in animals partaking of their flesh and milk.

[533] _Zeitschr. f. Staatsarzneik._, 1862.

§ 483. The symptoms appear soon after the ingestion, and consist of a

feeling of burning in the mouth, spreading downwards to the stomach,

increased secretion of saliva, and difficulty of swallowing; then follow

violent vomiting and diarrhœa, with great pain in the bowels, often

tenesmus; there is also headache, giddiness, a feeling of anxiety, and

the pupils are dilated. The consciousness is ordinarily intact; the

pulse is weak and slow, and the breathing embarrassed; the skin is

benumbed. There may be also formicating feelings, and twitchings in the

muscles with occasionally the tetanic cramps, which are constantly seen

in frogs. In cases which end fatally, the disturbance of the breathing

and circulation increases, and death takes place in collapse.

An important case of slow poisoning is on record,[534] in which two

brothers, aged twenty-one and twenty-two years, died after nine and

eleven weeks of illness, evidently from repeated small doses of the

powder of _Veratrum album_. They became very weak and thin, suffered

from diarrhœa and bloody stools, sleeplessness, disturbance of the

intellect, and delirium.

[534] Nivet and Géraud, _Gaz. Hebdom._, 1861.

§ 484. The _post-mortem_ signs do not appear distinctive; even in the

case just mentioned--in which one would expect to find, at all events,

an extensive catarrh of the intestinal canal--the results seem to have

been negative.

§ 485. =Separation from Organic Matters.=--The method of Stas (by which

the organic matters, whether the contents of the stomach or the tissues,

are treated with alcohol, weakly acidified by tartaric acid) is to be

recommended. After filtering, the alcoholic extract may be freed from

alcohol by careful distillation, and the extract taken up with water. By

now acidifying gently the watery extract, and shaking it up with ether

and chloroform, fatty matters, resinous substances, and other

impurities, are removed, and it may then be alkalised by soda or potash,

and the veratrine extracted by ether. The residue should be identified

by the hydrochloric acid and by the sulphuric acid and bromine

reactions; care should also be taken to ascertain whether it excites

sneezing.

A ptomaine, discovered by Brouardel,[535] was described by him as both

chemically and physiologically analogous to veratrine. A. M.

Deleziniere[536] has since investigated this substance. Only when in

contact with air does the analogy to veratrine obtain, and Deleziniere,

to ascertain its reactions, studied it when in an atmosphere of

nitrogen. It appears to be a secondary monamine, C₃₂H₃₁N, and is in the

form of a colourless, oily liquid, with an odour like that of the

hawthorn. It is insoluble in water, but alcohol, ether, toluene, and

benzene dissolve it readily. It oxidises in the presence of air. The

salts are deliquescent.

[535] _Moniteur Scient._ (3), 10, 1140.

[536] _Bull. Soc. Chim._ (3), 1, 178-180.

VIII.--Physostigmine.

§ 486. The ordeal bean of Calabar (_Physostigma faba_) is a large, all

but tasteless, kidney-shaped bean, about an inch in length, and half an

inch thick; its convex edge has a furrow with elevated ridges, and is

pierced by a small hole at one extremity. The integuments are

coffee-brown in colour, thin, hard, and brittle; they enclose two white

cotyledons, easily pulverisable, and weighing on an average 3·98 grms.

(61 grains). The seed contains at least one alkaloid, termed

_Physostigmine_ (first separated in 1864 by Jobst and Hesse), and

possibly a second, according to Harnack and Witkowsky, who have

discovered in association with physostigmine a new alkaloid, which they

call _Calabarine_, and which differs from physostigmine in being

insoluble in ether and soluble in water. It is also soluble in alcohol;

and further, the precipitate produced by potassium iodo-hydrargyrate in

calabarine solutions is insoluble in alcohol.

§ 487. =Physostigmine=, or =eserine=, is not easily obtained in a

crystalline state, being most frequently extracted as a colourless

varnish, drying into brittle masses. It is, however, quite possible to

obtain it in the form of partially-crystalline crusts, or even rhombic

plates, by care being taken to perform the evaporation, and all the

operations, at as low a temperature as possible, and preferably in a

dimly-lit room; for, if the temperature rises to 40°, much of the

alkaloid will be decomposed. Hesse recommends that the beans be

extracted, alcohol by the alcoholic solution alkalised by sodic

carbonate, and the liquid shaken up with ether, which will retain the

alkaloid. The ether solution is now separated, and acidified slightly

with very dilute sulphuric acid; the fluid, of course, separates into

two layers, the lower of which contains the alkaloid as a sulphate, the

upper is the ether, which is withdrawn, and the acid fluid passed

through a moist filter. The whole process is then repeated as a

purification.

Again, Vee, who has repeatedly obtained the alkaloid in a crystalline

condition, directs the extraction of the beans by alcohol, the alcoholic

solution to be treated as before with sodic carbonate, and then with

ether; the ethereal solution to be evaporated to dryness, dissolved in

dilute acid, precipitated by sugar of lead, and the filtrate from this

precipitate alkalised by potassic bicarbonate, and then shaken up with

ether. The ethereal solution is permitted to evaporate spontaneously,

the crystalline crusts are dissolved in a little dilute acid, and the

solution is lastly alkalised by potassic bicarbonate, when, after a few

minutes, crystalline plates are formed.

The formula ascribed to physostigmine is C₁₅H₂₁N₃O₂. It is strongly

alkaline, fully neutralising acids and forming tasteless salts. It is

easily melted, and perhaps partly decomposed, at a temperature of 45°;

at 100° it is certainly changed, becoming of a red colour, and forming

with acids a red solution. It dissolves easily in alcohol, ether,

chloroform, and bisulphide of carbon, but is not easily soluble in

water.

The salts formed by the alkaloid with the acids are generally

hygroscopic and uncrystallisable, but an exception is met with in the

hydrobromide, which crystallises in stellate groups.[537] If CO₂ is

passed into water containing the alkaloid in suspension, a clear

solution is obtained; but the slightest warmth decomposes the soluble

salt and reprecipitates the alkaloid. The hydrarg-hydroiodide

(C₁₅H₂₁N₃O₂,HI,2HgI) is a white precipitate, insoluble in water,

becoming yellow on drying, soluble in ether and alcohol, and from such

solutions obtained in crystalline prismatic groups. A heat of 70° melts

the crystals, and they solidify again in the amorphous condition.

[537] M. Duquesnel, _Pharm. J. Trans._ (3), v. 847.

It gives a precipitate with gold chloride, reducing the gold; also one

with mercuric chloride easily soluble in hydrochloric acid. It gives no

precipitate with platinum chloride.

§ 488. =Tests.=--Da Silva’s[538] test for eserine is as follows:--A

minute fragment of eserine or one of its salts is dissolved in a few

drops of fuming nitric acid; this makes a yellow solution, but

evaporated to complete dryness it is pure green. The green substance,

called by others chloreserine, dissolves to a non-fluorescent green

solution; in water and also in strong alcohol it shows a band in the red

between λ670 and λ688, a broader but more nebulous band in the blue and

violet between λ400 and λ418, and a very feeble band in the orange.

[538] S. J. Ferreira da Silva, _Compt. Rend._, cxvii. 330, 331.

J. B. Nagelvoort[539] has recommended the following tests:--(_a_) An

amorphous residue of a permanent blue colour is obtained if a trace of

the alkaloid, or one of its salts, is evaporated in the presence of an

excess of ammonia; this blue alkaloid dissolves in dilute acids with a

red colour; sensitiveness 0·00001 gm. (1 : 100000). The solution has

beautiful red fluorescence in reflected light; when evaporated, it

leaves a residue that is green at first, changing to blue afterwards,

the blue residue being soluble in water, alcohol, and chloroform, but

not in ether. Chloroform extracts the blue colour from the watery

ammoniacal solution only partially. The blue solutions are reddened at

first by H₂S, and discoloured afterwards. The blue colour is restored by

expelling the H₂S on the water-bath. (_b_) A red fluid is obtained when

0·010 gm. eserine or its salicylate, 0·050 gm. of slacked lime, and 1

c.c. of water are added together. Warmed in a water-bath, it turns

green, and a piece of red litmus-paper suspended in the test-tube turns

blue; a glass rod moistened with HCl gives off the well-known white

clouds characteristic of an ammonia reaction. The green solution does

not lose its colour by evaporation. Baryta water, added to an eserine

solution, gives a white precipitate that turns red when strongly

agitated, sensitive to 0·01 mgrm. (1 : 100000).

[539] _Flückiger’s Reactions_, 1893.

§ 489. =Pharmaceutical Preparations.=--The only preparations officinal

in this country are a spirituous extract (_Extractum physostigmatis_),

used principally for external application, the dose of which is not more

than 18·1 mgrms. (·18 grain), and gelatine discs for the purpose of the

ophthalmic surgeon, each disc weighing about 1/50th grain, and

containing 1/1000 gr. of the alkaloid.

§ 490. =Effects on Animals.=--A large number of experiments have been

made upon animals with physostigmine, most of them with the impure

alkaloid, which is a mixture of calabarine and physostigmine. Now, the

action of calabarine seems to be the opposite to that of

physostigmine--that is, it causes tetanus. Hence, these experiments are

not of much value, unless the different proportions of the alkaloids

were known. Harnack and Witkowsky[540] made, however, some researches

with pure physostigmine, of which the following are the main

results:--The smallest fatal dose for rabbits is 3 mgrms. per kilo.;

cats about the same; while dogs take from 4 to 5 mgrms. per kilo. Frogs,

under the influence of the alkaloid, lie paralysed without the power of

spontaneous movement, and the sensibility is diminished; later, the

breathing ceases, and the reflex irritability becomes extinguished. The

activity of the heart is through ·5 mgrm. slowed, but at the same time

strengthened.

[540] _Arch. f. Pathol. u. Pharm._, 1876, Bd. v.

The warm-blooded animals experimented upon show rapid paralysis of the

respiratory centre, but the animal by artificial respiration can be

saved. Fibrillar muscular twitching of all the muscles of the body are

observed. Death follows in all cases from paralysis of the respiration.

Experiments (first by Bexold, then by Fraser and Bartholow, and lastly

by Schroff) have amply shown that atropine is, to a certain extent, an

antidote for physostigmine poisoning. Fraser also maintains an

antagonism between strychnine and physostigmine, and Bennet that chloral

hydrate is antagonistic to physostigmine.

=Effects on Man.=--The bean has long been used by the superstitious

tribes of the West Coast of Africa as an ordeal, and is so implicitly

believed in that the innocent, when accused of theft, will swallow it,

in the full conviction that their innocency will protect them, and that

they will vomit up the bean and live. In this way, no doubt, life has

often been sacrificed. Christison experimented upon himself with the

bean, and nearly lost his life. He took 12 grains, and was then seized

with giddiness and a general feeling of torpor. Being alarmed at the

symptoms, he took an emetic, which acted. He was giddy, faint, and

seemed to have lost all muscular power; the heart and pulse were

extremely feeble, and beat irregularly. He afterwards fell into a sleep,

and the next day he was quite well.

In August 1864 forty-six children were poisoned at Liverpool by eating

some of the beans, which had been thrown on a rubbish heap, being part

of the cargo of a ship from the West Coast of Africa. A boy, aged six,

ate six beans, and died. In April of the same year, two children, aged

six and three years, chewed and ate the broken fragments of one bean;

the usual symptoms of gastric irritation and muscular weakness followed,

but both recovered. Physostigmine contracts the iris to a point; the

action is quite local, and is confined to the eye to which it is

applied. When administered internally, according to some, it has no

effect on the eyes, but according to others, it has a weak effect in

contracting the pupil. In any case, the difference of opinion shows that

the effect, when internally administered, is not one of a marked

character.

§ 491. =Physiological Action.=--The physiological action of

physostigmine is strikingly like that of nicotine, which it resembles in

being a respiratory poison, first exciting, afterwards paralysing the

vagus. Like nicotine, also, it produces a great loss of muscular power;

it first excites, and then paralyses the intra-muscular terminations of

the nerves; and, again, like nicotine, it induces a tetanus of the

intestine. A difference between physostigmine and nicotine exists in the

constant convulsive effects of the former, and in the greater influence

on the heart of the latter.

§ 492. =Post-mortem Appearances.=--But little is known relative to the

_post-mortem_ appearances likely to be found in human poisoning; redness

of the stomach and intestines is probably the chief sign.

§ 493. =Separation of Physostigmine.=--For the extraction of

physostigmine from the fluids of the body, Dragendorff recommends

benzene: the alcoholic filtered extract (first acidified) may be

agitated with such solvents as petroleum and benzene, in order to remove

colouring matter; then alkalised and shaken up with benzene, and the

latter allowed to evaporate spontaneously--all the operations being, as

before stated, carried on under 40°. If much coloured, it may be

purified according to the principles before mentioned. In cases where

enough of the extract (or other medicinal preparation) has been taken to

destroy life, the analyst, with proper care, would probably not have

much difficulty in separating a small quantity of the active principle.

It is rapidly eliminated by the saliva and other secretions. In most

cases it will be necessary to identify physostigmine by its

physiological activity, as well as by its chemical characters. For this

purpose a small quantity of the substance should be inserted in the eye

of a rabbit; if it contains the alkaloid in question, in twenty minutes,

at the very latest, there will be a strong contraction of the pupil, and

a congested state of the conjunctival vessels. Further researches may be

made with a small quantity on a bird or frog. The chief symptoms

observed will be those of paralysis of the respiratory and voluntary

muscles, followed by death. If a solution is applied to the web of a

frog’s foot, the blood-vessels become dilated. Physostigmine appears,

according to Dragendorff and Pander, to act as an irritant, for they

always observed gastro-enteritis as a result of the poison, even when

injected subcutaneously. The enhanced secretion from all mucous

surfaces, and the enlargement of the blood-vessels, are also very

constant symptoms. But of all these characteristics, the contraction of

the pupil is, for the purposes of identification, the principal. A

substance extracted from the tissue or other organic matters, in the

manner mentioned, strongly contracting the pupil and giving the bromine

reaction, would, in the present state of our knowledge, be indicative of

physostigmine, and of that alone.

§ 494. =Fatal Dose of Physostigmine.=--One mgrm. (·015 grain) as

sulphate, given by Vee to a woman subcutaneously, caused vomiting, &c.,

after half an hour. A disciple of Gubler’s took 2 mgrms. without

apparent effect; but another mgrm., a little time after, caused great

contraction of the pupil and very serious symptoms, which entirely

passed off in four hours. It would thus seem that three times this

(_i.e._, 6 mgrms.) would be likely to be dangerous. If so, man is far

more sensitive to physostigmine than dogs or cats; and 3 mgrms. per

kilo.--that is, about 205 mgrms. (3 grains)--would be much beyond the

least fatal dose.

IX.--Pilocarpine.

§ 495. From the leaves of the jaborandi, _Pilocarpus pennatafolius_

(Nat. Ord. _Rutaceæ_), two alkaloids have been separated--_jaborandi_

and _pilocarpine_.

=Jaborandi= (C₁₀H₁₂N₂O₃) is a strong base, differing from pilocarpine in

its sparing solubility in water, and more ready solubility in ether; its

salts are soluble in water and alcohol, but do not crystallise. P.

Ghastaing,[541] by treating pilocarpine with a large quantity of nitric

acid, obtained nitrate of jaborandi, and operating in the same way with

hydrochloric acid, obtained the hydrochlorate of jaborandi; hence, it

seems that jaborandi is derived from pilocarpine.

[541] _Compt. Rend._, vol. xciv. p. 223.

§ 496. =Pilocarpine= (C₁₁H₁₆N₂O₂) is a soft gelatinous mass, but it

forms with the mineral acids crystallisable salts. The solutions are

dextra-rotatory. On boiling with water, it decomposes into

trimethylamine and m-pyridine lactic acid,

CH₃

/

C₁₁H₁₆N₂O₂ + H₂O = N(CH₃)₃ + C₅H₄NCHO :

\

COOH

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

CO--O

|

C₅H₄N--C--N(CH₃)₃

|

CH₃

The nitrate and hydrochloride are at present much used in pharmacy.

Pilocarpine gives a precipitate with phosphomolybdic acid,

potassio-mercuric iodide, and most general alkaloidal reagents, but none

that are very distinctive. When a solution of gold chloride is added to

one of pilocarpine, a salt falls, having the composition C₁₁H₁₆N₂O₂,HCl

+ AuCl₃. It is not very soluble in water (about 1 in 4600), and has been

utilised for the estimation of pilocarpine. Pilocarpine fused with

potash yields trimethylamine, carbon dioxide, butyric, and traces of

acetic acid. Pilocarpine dissolves without the production of colour in

sulphuric acid; but, with bichromate of potash and sulphuric acid, a

green colour is produced. It may be extracted from an aqueous solution

made alkaline by ammonia, by shaking up with chloroform or benzene.

§ 497. =Tests.=--When a little of the alkaloid is mixed with ten times

its weight of calomel, and rubbed, and moistened by the breath, the

calomel is blackened; cocaine also acts similarly; but the two could not

be mistaken for each other. If a solution of mercur-potassium iodide is

added to a solution of the hydrochloride, the amorphous precipitate

becomes, in the course of a day or two, oily drops. “A solution of

iodine in potassium iodide gives in pilocarpine solutions a brown

precipitate that often crystallises to feathery brown crystals

(microscopically), and of serrated form, something like the blade of a

scroll-saw, when the crystallisation is incomplete.”--_Flückiger’s

Reactions._

§ 498. =Effects.=--Pilocarpine, given subcutaneously in doses of about

32 mgrms. (½ grain), causes within five minutes a profuse perspiration

and salivation, the face becomes flushed, and the whole body sweats; at

the same time, the buccal secretion is so much increased that in a few

hours over a pint may be secreted. The tears, the bronchial secretion,

and the intestinal secretions are also augmented; there are generally

headache and a frequent desire to pass water; the pulse is much

quickened, and the temperature falls from 1°·4 to 4°: the symptoms last

from two to five hours. Langley has shown that the over-action of the

submaxillary gland is not affected by section either of the _chorda

tympani_ or of the sympathetic supplying the gland. Although pilocarpine

quickens the pulse of man, it slows, according to Langley,[542] the

heart of the warm-blooded animals, and that of the frog. With regard to

the frog, Dr. S. Ringer’s researches are confirmatory. With large doses

the heart stops in diastole. If to the heart thus slowed, or even when

recently stopped, a minute quantity of atropine be applied, it begins to

beat again. There is also a most complete antagonism between atropine

and pilocarpine in other respects, atropine stopping the excessive

perspiration, and relieving the headache and pain about the pubes, &c.

Pilocarpine, given internally, does not alter the size of the pupil,

but the sight may, with large doses, be affected. If a solution is

applied direct to the eye, then the pupil contracts. No fatal case of

its administration has occurred in man. The probable dangerous dose

would be about 130 mgrms. (2 grains) administered subcutaneously.

Pilocarpine must be classed among the heart poisons.

[542] “The Action of Jaborandi on the Heart,” by J. N. Langley, B.A.,

_Journ. Anat. and Physiol._, vol. x. p. 187.

X.--Taxine.

§ 499. =Properties of Taxine.=--The leaves and berries, and probably

other portions of the yew tree (_Taxus baccata_), are poisonous. The

poison is alkaloidal, and was first separated by Marmé.

=Taxine= (C₃₇H₅₂O₁₀N).--Taxine cannot be obtained in crystals, but as a

snow-white amorphous powder, scarcely soluble in water, but dissolving

in alcohol, in ether, and in chloroform; insoluble in benzene. It melts

at 82°, gives an intense purple-red, with sulphuric acid, and colours

Fröhde’s reagent reddish-violet.

A slightly acid aqueous solution of the alkaloid gives precipitates with

all the group reagents and with picric acid.

The salts are soluble in water; the hydrochloride may be obtained by

passing gaseous HCl into anhydrous ether. The platinichloride forms a

yellow micro-crystalline powder (C₃₇H₅₂O₁₀N)₂H₂PtCl₆. The salts are

generally difficult to crystallise.[543]

[543] A. Hilger and F. Brande, _Ber._, xxiii. 464-468.

§ 500. =Poisoning by Yew.=--Falck has been able to collect no less than

32 cases of poisoning by different parts of the yew--9 were from the

berries, and the rest from the leaves. They were all accidental; 20

persons died, or 62·5 per cent.

§ 501. =Effects on Animals--Physiological Action.=--From the researches

of Marmé-Borchers, it appears that taxine acts upon the nervous

centres--the nervous trunks themselves and the muscles remaining with

their excitability unimpaired, even some time after death. Taxine kills

through paralysis of the respiration, the heart beating after the

breathing has stopped. The leaves contain much formic acid, and their

irritant action on the intestine is referred to this cause.

§ 502. =Effects on Man.=--Several deaths from yew have resulted in

lunatic asylums from the patients chewing the leaves. For example, a few

years ago, at the Cheshire County Asylum, a female, aged 41, was

suddenly taken ill, apparently fainting, her face pale, her eyes shut,

and pulse almost imperceptible. Upon the administration of stimulants,

she somewhat revived, but in a little while became quite unconscious.

The pupils were contracted, and there were epileptiform convulsions,

succeeded by stertorous breathing. These convulsions returned from time

to time, the action of the heart became weaker, and there was a

remarkable slowing of the respirations, with long intervals between the

breathing. The woman died within an hour from the time when her illness

was first observed, and within two hours of eating the leaves. Yew

leaves were found in her stomach. In another case that occurred at the

Parkside Asylum,[544] the patient died suddenly in a sort of epileptic

fit. Yew leaves were again found in the stomach. In a case quoted by

Taylor, in which a decoction of the leaves was drunk by a girl, aged 15,

for the purpose of exciting menstruation, she took the decoction on four

successive mornings. Severe vomiting followed, and she died eight hours

after taking the last dose. In another case there were also no symptoms

except vomiting, followed by rapid death. Mr. Hurt, of Mansfield, has

recorded a case of poisoning by the berries. The child died in

convulsions before it was seen by any medical man.

[544] _Pharm. Journ._ (3), No. 294.

From these and other recorded cases, the symptoms seem generally to be a

quick pulse, fainting or collapse, nausea, vomiting, convulsions, slow

respiration, and death, as a rule sudden and unexpected. We may suppose

that the sudden death is really due to a rapid paralysis of the

respiration, and suffocation.

§ 503. =Post-Mortem Appearances.=--In the case of the girl who drank the

decoction, nothing unusual was observed in the stomach or organs of the

body; but when the leaves have been eaten, usually more or less

congestion of the mucous membrane of the stomach, as well as of the

bowels, is apparent. In the case of the child who ate the berries

(Hurt’s case), the stomach was filled with mucous and half-digested pulp

of the berries and seeds. The mucous membrane was red in patches and

softened, and the small intestines were also inflamed.

XI.--Curarine.

§ 504. Commercial curare is a black, shining, resinoid mass, about 83

per cent. of which is soluble in water, and 79 in weak spirit. It is a

complicated mixture of vegetable extracts, from which, however, a

definite principle possessing basic characters (_curarine_) has been

separated.

The extract is an arrow poison[545] prepared by different tribes of

Indians in South America, between the Amazon and the Orinoco;

therefore, samples are found to vary much in their poisoning properties,

although it is noticeable that qualitatively they are the same, and

produce closely analogous symptoms. It is supposed that some of the

curare is derived from different species of strychnos. This is the more

probable, because, as before stated, the South American strychnines

paralyse, and do not tetanise. It is not unlikely that the active

principles of curare (or woorari) may be methyl compounds similar to

those which have been artificially prepared, such as methyl strychnine

and methyl brucine, both of which have a curare-like action.

[545] A constituent of the Borneo arrow poison is “derrid,” a toxic

principle obtained from a leguminous plant, the _Derris elliptica_; it

is a resinous substance, which has not yet been obtained in the pure

state. It is said not to be a glucoside, nor to contain any nitrogen

(Greshoff, _Ber._, xxiii. 3537-3550).

The Comalis on the east coast of Africa prepare an arrow poison from the

aqueous extract of the root of Oubaion, a tree closely related to

_Carissa Schimperii_.

Oubain is prepared by treating the aqueous extract with lead acetate,

getting rid of excess of lead by SH₂, and concentrating in a vacuum. The

syrup is boiled with six times its volume of alcohol of 85°, and allowed

to cool in shallow vessels; crystals are obtained which are

recrystallised, first from alcohol, and afterwards from water.

Oubain, C₃₀H₄₆O₁₂, forms thin white nacreous lamellæ. It is tasteless,

odourless, and neutral, almost insoluble in cold water, and soluble in

boiling water; it dissolves readily in moderately concentrated alcohol,

is almost insoluble in absolute alcohol, and insoluble in ether and

chloroform. Its melting-point is 200°. The solution of oubain in water

is lævorotatory [α]_{D} = -340. It is a glucoside, yielding on boiling

with dilute acids a sugar. It is very poisonous; 2 mgrms. will kill a

dog of 12 kilos. weight in a few minutes, if subcutaneously injected;

but, taken by the stomach, it produces no effect.--Arnaud, _Compt.

Rend._, cvi. 1011-1014.

=Curarine= was first separated by Preyer in a crystalline form in 1865.

He extracted curare with boiling alcohol, to which a few drops of soda

solution had been added, evaporated off the alcohol, took up the extract

with water, and, after filtration, precipitated by phosphomolybdic acid,

which had been acidified with nitric acid. The precipitate was dried up

with baryta water, exhausted with boiling alcohol, and curarine

precipitated from the alcoholic solution by anhydrous ether. It may also

be obtained by precipitating with mercuric chloride solution, and

throwing out the mercury afterwards by means of hydric sulphide, &c.

Curarine, when pure, forms colourless, four-sided, very hygroscopic

prisms of bitter taste, and weakly alkaline reaction; soluble in water

and alcohol in all proportions, but with difficulty soluble in amyl

alcohol and chloroform, and not at all in anhydrous ether, bisulphide of

carbon, or benzene. The base forms crystallisable salts with

hydrochloric, nitric, and acetic acids. Curarine strikes a purple colour

with strong nitric acid. Concentrated solutions of curarine mixed with

dilute glycerin, give an amorphous precipitate with potassic bichromate,

and the precipitate treated with sulphuric acid strikes a beautiful blue

colour. Curarine chromate is distinguished from strychnine chromate by

its amorphous character, and by its comparatively easy solubility. If

the chromates of strychnine and curarine be mixed, and the mixed

chromates be treated with ammonia, strychnine will be precipitated, and

curarine pass into solution, thus forming a ready method of separating

them.

§ 505. =Physiological Effects.=--According to Voisin and Liouville’s

experiments, subcutaneous injections of curare on man cause, in small

doses, strong irritation at the place of application, swelling, and

pain. The temperature of the body is raised from 1° to 2°, and the

number of respirations increased from 4 to 8 per minute. The pulse

becomes somewhat stronger and more powerful. The urine is increased, and

contains sugar. Large doses administered to warm-blooded animals cause,

after a short time, complete paralysis of voluntary motion and of reflex

excitability, and the animal dies in asphyxia, the heart continuing to

beat.

This state is best produced for the purpose of experiment on frogs, and,

indeed, is the best test for the poison. A very minute dose injected

beneath the skin of a frog soon paralyses both the voluntary and

respiratory muscles; the animal continues to breathe by the skin; the

heart beats normally, or, perhaps, a little weakly, and the frog may

remain in this motionless condition for days and yet recover. Only

curare and its congeners have this effect. By tying the femoral artery

of one of the frog’s legs before administering the poison, an insight

into the true action of the drug is obtained. It is then found that the

reflex excitability and power of motion in the leg are retained,

although all the rest of the body is paralysed. The only explanation of

this is that curare does not act centrally, but paralyses the

intramuscular ends of the motor nerves. Curare is eliminated partly

through the liver and partly through the kidneys. Dragendorff found it

in the fæces, while a striking proof that it is excreted by the kidneys

is given by the experiment of Bidder,[546] in which the urine of a frog

poisoned by curare was made to poison a second, and the urine of the

second, a third. The easy excretion of curare through the kidneys

furnishes an explanation of the relatively large dose of curare which

can be taken by the stomach without injury. A dose which, given by

subcutaneous injection, would produce violent symptoms, perhaps death,

may yet be swallowed, and no ill effects follow. It is hence presumed

that, in the first case, the poison is, comparatively speaking, slowly

absorbed, and almost as fast separated, and put, as it were, outside the

body by going into the urine; while, in the other case, the whole dose

is thrown suddenly into the circulation.

[546] _Arch. f. Anat. u. Physiol._, 1879, p. 598.

§ 506. =Separation of Curarine.=--It is hardly probable that the

toxicologist will have to look for curarine, unless it has entered the

body by means of a wound or by subcutaneous injection; so that in all

cases the absorbed poison alone must be sought for. The seat of entry,

the liver, the kidneys, and the urine are the only parts likely to be of

any use. Dragendorff recommends the extraction of the tissues with water

feebly acidulated with a mineral acid, to precipitate albuminous

matters, &c., by strong alcohol, and separate, by means of benzene,

fatty matters. The liquid is then made alkaline, and shaken up with

petroleum ether, which removes certain alkaloidal matters. It is now

evaporated to dryness, mixed with finely-powdered glass, and extracted

with absolute alcohol. The alcohol is evaporated to dryness, and any

curarine extracted from this residue with water. By very careful drying

up of this last extract, and taking it up in alcohol, the alkaloid is

said to be obtained so pure as to respond to chemical tests. The

identification may be by the colour reaction of sulphuric acid described

_ante_, in all cases supplemented by its physiological action on

frogs.[547]

[547] It is known that curare may cause slight symptoms of excitation

before the paralysis comes on. M. Couty has succeeded in isolating these

symptoms by employing feeble extracts of _Strychnos triplinervia_, or

small doses of certain native preparations. By these means, in dogs, a

new phase of intoxication may be present for ten or even twenty minutes.

In the first instance the animal is agitated, jumping, scratching,

barking, as if in a state of general hyperæsthesia. Then it presents

half choreic shocks or tremors; the pupils dilate, and are alternately

dilated and contracted. The heart’s action is increased or diminished in

frequency; sometimes there is vomiting, micturition, or defecation; and

there is always salivation. Finally, the central and peripheral

temperature are raised, and the excitability of the muscles and nerves

becomes highly increased. With the native preparation of curare, it is

impossible to prolong this stage, and symptoms of paralysis soon become

associated with those of excitement. The choreic shocks were found to be

arrested by section of the sciatic nerve. Other experiments proved that

the spasms originated from the spinal cord, and were influenced by its

preceding functional condition. If the cord was tied in the mid-dorsal

region, and the curare injected, the spasms were still produced in the

hind legs; but if, after the operation, the excitability of the

posterior segment became lowered, the spasm was no longer produced in

the hind legs. This dependence on a perfect functional activity is a

point of difference of these spasms from those produced by strychnine,

and by asphyxia. The action of small doses of curare is not, however,

limited to the spinal cord. The diminished frequency of the heart

continues after section of the pneumogastrics, and will even occur if

the pneumogastrics have been previously divided. From these facts M.

Couty considers that curare must not be regarded as entirely destitute

of a “convulsant” action, nor of an action on the central nervous

system.

XII.--Colchicine.

§ 507. The whole of the _Colchicum autumnale_, or common meadow-saffron,

is poisonous, owing to the presence of an alkaloid (discovered by

Pelletier and Caventou) called _Colchicine_.

According to Johannson’s experiments, the dried colchicum seeds contain

1·15 per cent. of colchicine; the leaves, 1·459 per cent.; the bulbs,

from 1·4 to 1·58 per cent.; and the roots, 0·634 per cent. The frequent

poisoning of cattle in the autumn by colchicum, its use in quack pills

for rheumatism, and its supposed occasional presence in beer, give it

an analytical importance.

§ 508. =Colchicine= (C₂₂H₂₅NO₆) may be extracted from the seeds, &c., in

the manner recommended by Hübler:--The seeds are treated, without

crushing, by hot 90 per cent. alcohol, and the alcoholic solution

evaporated to a syrup, which is diluted with twenty times its bulk of

water and filtered; the liquid is next treated with acetate of lead,

again filtered, and the lead thrown out by phosphate of soda. Colchicine

is now precipitated as a tannate.[548] The precipitation is best

fractional, the first and last portions being rejected as containing

impurities. The tannate is decomposed in the usual way with litharge and

extracted by alcohol.

[548] The purest tannic acid must be used. The commercial tannin may be

purified by evaporating to dryness with litharge, exhausting the tannate

of lead repeatedly with boiling alcohol and water, and, lastly,

suspending in water, and separating the lead by SH₂.

A simpler method is, however, extraction by chloroform from an aqueous

solution, feebly acidified, as recommended by Dragendorff. The parts of

the plant are digested in very dilute acid water, and the resulting

solution concentrated and shaken up with chloroform, which is best done

in a separating tube.

Colchicine contains four methoxyl groups, and its constitutional formula

is considered to be C₁₅H₉[NH(CH₃CO)](COOCH₃)(OCH₃)₃.

Its melting-point is 143°-147°. It is usually a white, gummy mass. It is

easily soluble in cold water, in alcohol, and in chloroform. The

solutions are lævorotatory. It is hardly soluble in ether. Boiling with

dilute acids or alkalies in closed tubes yields colchiceine.

Colchiceine contains three methoxyl groups. It melts at 150°, dissolves

but little in cold, copiously in boiling water. Colchiceine appears to

be an acid, forming salts with the alkalies.

Zeisel[549] has formed acetotrimethylcolchicinamide

(NHAcC₁₅H₉(OMe)₃CONH₃) by heating colchicine with alcoholic ammonia in

closed tubes for four hours at 100°. The amide is crystallised from hot

alcohol; it is readily soluble in dilute HCl, almost insoluble in water;

when a strong hydrochloric acid solution of the amide is treated with a

small amount of potassium nitrite a splendid violet colour is produced.

[549] _Monatsh._, ix. 1-30.

§ 509. =Tests.=--Ferric chloride, if added to an alcoholic solution of

the alkaloid, strikes a garnet red; if to an aqueous solution a green or

brownish-green; nitric acid added to the solid substance gives a violet

colour. Erdmann’s reagent (nitrosulphuric acid) gives in succession

green, dark blue, and violet colours, ultimately turning yellow,

changed, on addition of an alkali, to raspberry-red. Mandelin’s reagent

(1 grm. of ammonium vanadate in 200 grms. of sulphuric acid) gives a

green colour.

§ 510. =Pharmaceutical Preparations.=--Colchicine itself is officinal in

Austria--the wine in the British, French, and Dutch, and the seeds

themselves in all the pharmacopœias. The wine of colchicum, officinal in

nearly all the pharmacopœias, is made with very different proportions of

seeds or bulbs.

The tincture of colchicum is officinal in our own and in all the

Continental pharmacopœias; in the British, one part of seeds is

exhausted by eight parts of proof spirit.

A tincture of colchicum seeds, examined by Johannson, contained ·18 per

cent. of colchicine, and a tincture prepared from the bulbs ·14 per

cent.

Colchicum vinegar is not officinal in Britain, but one containing 5·4

per cent. of acetic acid is so in the Netherlands, Germany, and France;

the strength appears to be about ·095 per cent. of colchicine.

An extract of colchicum is officinal in Britain and France; and an

acetic extract in Britain. The latter is the most active of all the

pharmaceutical preparations of colchicum.

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

Netherlands.

=Quack and Patent Medicines.=--In all specifics for gout the analyst

will naturally search for colchicum. Most gout pills contain the

extracts; and liquids, such as “Reynolds’ gout specific,” the wine or

the tincture, variously flavoured and disguised.

The strength of the different pharmaceutical preparations may be

ascertained by dissolving in chloroform, evaporating off the chloroform,

dissolving in water (which is finally acidified by from 7 to 10 per

cent. of sulphuric acid), and titrating with Mayer’s reagent (see p.

263). If the solution is diluted so that there is about one part of

colchicine in 600 of the solution, then each c.c. of Mayer’s reagent

equals 31·7 mgrms. colchicine.

§ 511. =Fatal Dose.=--In Taylor’s _Principles of Medical Jurisprudence_

is mentioned an instance in which 3½ drachms of colchicum wine, taken in

divided doses, caused death on the fourth day. The quantity of the

active principle in the colchicum wine, as found by Johannson

(_Dragendorff_), being 0·18 per cent., it follows that 24·4 mgrms. (·378

grain) were fatal, though not given as one dose, so that this quantity

may be considered as the least fatal one. Casper puts the lethal dose of

colchicine at from 25 to 30 mgrms. (·385 to ·463 grain). It is, however,

incontestable that there are cases of recovery from as much as 70 mgrms.

(1·08 grain). The lethal dose of the pharmaceutical preparations of

colchicum may, on these grounds, be predicted from their alkaloidal

contents, and, since the latter is not constant, in any medico-legal

inquiry, it may be necessary, where facility is given, to ascertain the

strength of the preparation administered.

§ 512. =Effects of Colchicine on Animals.=--The researches of Rossbach

show that the carnivoræ are more sensitive to colchicine than any other

order of mammals. Frogs show a transitory excitement of the nervous

system, then there is loss of sensation, paralysis of motion, and of the

respiratory apparatus; the heart beats after the respiration has ceased.

Death follows from paralysis of the respiration. The mucous membrane of

the intestine is much congested and swollen.

I have seen cattle die from the effects of eating the meadow-saffron;

the animals rapidly lose condition, suffer great abdominal pain, and are

generally purged. The farmers, in certain parts of the country, have had

extensive losses from want of care and knowledge with regard to

colchicum poisoning.

§ 513. =Effects of Colchicum on Man.=--Colchicum poisoning in man[550]

is not very common: 2 deaths (accidental) are recorded in England and

Wales during the ten years ending 1892. F. A. Falck was able to collect

from medical literature, prior to 1880, 55 cases, and he gives the

following analysis of the cases:--In 2, colchicum was taken for suicidal

purposes; of the unintentional poisonings, 5 were from too large a

medicinal dose of colchicum wine, syrup, or extract, given in cases of

rheumatism; in 13 cases, colchicum was used as a purgative; 42 cases

were owing to mistaking different preparations for drinks, or

cordials--the tincture in 5, and the wine in 14, being taken instead of

orange tincture, quinine wine, schnapps or Madeira; in 1 case the corms

were added to mulled wine, in another, the leaves consumed with salad;

in 16 cases (all children), the seeds of colchicum were eaten. Forty-six

of the 55 died--that is, 83·7 per cent.

[550] For the curious epidemic of diarrhœa which broke out in the Rhone

Gorge in 1785, and was referred to colchicine, see “Foods,” p. 287.

In the remarkable trial at the Central Criminal Court, in 1862, of

Margaret Wilson (_Reg._ v. _Marg. Wilson_), who was convicted of the

murder of a Mrs. Somers, the evidence given rendered it fairly probable

that the prisoner had destroyed four people at different dates by

colchicum. The symptoms in all four cases were--burning pain in the

throat and stomach, intense thirst, violent vomiting and purging,

coldness and clamminess of the skin, excessive depression, and great

weakness. One victim died on the second day, another on the fifth, a

third on the eighth, and the fourth on the fourteenth day. Schroff

witnessed a case in which a man took 2 grms. (nearly 31 grains) of the

corms; in one and a half hours he experienced general _malaise_; on the

next day there were flying muscular pains, which at length were

concentrated in the diaphragm, and the breathing became oppressed;

there was also pain in the neighbourhood of the duodenum, the abdomen

was inflated with gas; there was a sickly feeling and faintness. Then

came on a sleepy condition, lasting several hours, followed by fever,

with excessive pain in the head, noises in the ears, and delirium; there

was complete recovery, but the abdomen continued painful until the fifth

day.

In another instance, a gentleman, aged 50,[551] had taken twenty-eight

of Blair’s gout-pills in four and a half days for the relief of a

rheumatic affection. He suffered from nausea, griping pains in the

belly, considerable diarrhœa, vomiting, and hiccough; towards the end

there was stupor, convulsive twitchings of the muscles, paralysis, and

death. The fatal illness lasted fourteen days; he was seen by three

medical men at different dates--the first seems to have considered the

case one of diarrhœa, the second one of suppressed gout; but Dr. C. Budd

was struck with the similarity of the symptoms to those from an acrid

poison, and discovered the fact that the pills had been taken. These

pills I examined; they were excessively hard, and practically consisted

of nothing else than the finely-ground colchicum corms; six pills

yielded 8 mgrms. of colchicine, so that the whole twenty-eight would

contain 39 mgrms. (⅗ grain). Dr. Budd considered that the whole of the

pills, which were of a stony hardness, remained in the bowels for some

time undigested, so that the ultimate result was the same as if the

whole had been taken in one dose.

[551] See _Lancet_, vol. i., 1881, p. 368.

§ 514. The general symptoms produced by colchicum are--more or less

burning pain in the whole intestinal tract, vomiting, diarrhœa, with not

unfrequently bloody stools; but sometimes diarrhœa is absent. In single

cases tenesmus, dysuria, and, in one case, hæmaturia have been noted.

The respiration is usually troubled, the heart’s action slowed, the

pulse small and weak, and the temperature sinks. In a few cases there

have been pains in the limbs; cerebral disturbance is rare; but in two

cases (one described _ante_) there was stupor. Muscular weakness has

been observed generally. In a few cases there have been cramps in the

calves and in the foot, with early collapse and death.

=Post-mortem Appearances.=--Schroff found in rabbits poisoned with from

·1 to 1·0 grm. of colchicine, tolerably constantly enteritis and

gastritis, and always a thick, pitch-like blood in the heart and veins.

Casper has carefully recorded the _post-mortem_ appearances in four

labourers, ages ranging from fifteen to forty years, who, finding a

bottle of colchicum-wine, and supposing it to be some kind of brandy,

each drank a wine-glassful. They all died from its effects. In all four

there was great hyperæmia of the brain membranes and of the kidneys. The

large veins were filled with thick, dark, cherry-red blood, very similar

to that seen in sulphuric acid poisoning. There was an acid reaction of

the contents of the stomach. The lungs were moderately congested. The

mucous membrane of the stomach of the one who died first was swollen and

scarlet with congestion; with the second there was some filling of the

vessels at the small curvature; while the stomachs of the third and

fourth were quite normal. In 5 cases described by Roux there was also

hyperæmia of the brain and kidneys, but no gastritis or enteritis. It

is, therefore, evident that there are in man no constant pathological

changes from colchicine poisoning.

§ 515. =Separation of Colchicine from Organic Matters.=--W.

Obolonski[552] has recommended the following process:--The finely

divided viscera are triturated with powdered glass and digested for

twelve hours with alcohol. The liquid is squeezed out and the dry

residue washed with alcohol. The extract is concentrated at a

temperature not exceeding 80°, and the cooled residue made up to the

original volume with alcohol. The filtered liquid is evaporated as

before, and this operation repeated until no more clots separate on

addition of water. The residue is then dissolved in water, the solution

purified by shaking with light petroleum, and the colchicine finally

extracted with chloroform.

[552] _Zeit. anal. Chem._, xxix. 493.

In cases of poisoning by colchicum at Berlin, Wittstock used the

following process:--The contents of the stomach were mixed with a large

amount of alcohol, a few drops of HCl added, and the whole well shaken;

the fluid was then filtered, and the filtrate evaporated to a syrupy

consistence at 37°. The resulting residue was dissolved in distilled

water, the fat, &c., filtered off, and the liquid carefully evaporated.

From the extract foreign matter was again separated by treatment with

alcohol and filtration, and the last filtrate was evaporated to a syrupy

consistence. The syrupy fluid was taken up by distilled water, filtered,

evaporated to 30 grms., and 2 grms. of calcined magnesia with 90 grms.

of ether were added. After a time, the ether was removed, and allowed to

evaporate spontaneously. The residue was once more taken up with water,

filtered from fat, &c., and evaporated. This final residue gave all the

reactions of colchicine. In medico-legal researches, it must be

remembered that colchicine is absorbed but slowly, a not insignificant

portion remaining in the bowels, with the fæces.

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

§ 516. =The Amanita Muscaria=, or fly-blown agaric, is a very

conspicuous fungus, common in fir-plantations, about the size and shape

of the common mushroom; but the external surface of the pileus is of a

bright red, or sometimes of a yellowish cast, and studded over with

warts. The common name of the fungus denotes that it was used in former

times as a popular insecticide; the fungus was bruised, steeped in milk,

and the milk exposed, in the same way as we now expose arsenical

fly-papers.

Some peculiar properties of the agaric have long been known to the

natives of Kamschatka, and of the north-eastern part of Asia generally.

They collect the fungi in the hottest months, and hang them up to dry.

The fungus is then rolled up in a kind of bolus, and swallowed without

chewing. One large, or two small, fungi will produce a kind of

intoxication, which lasts a whole day. It comes on in about two hours’

time, and is very similar to that of alcohol. There is a giddy feeling,

the spirits are exalted, the countenance becomes flushed, involuntary

actions and words follow, and sometimes loss of consciousness. It

renders some persons remarkably active, and proves highly stimulant to

muscular exertion; by too large a dose violent spasmodic effects are

produced. “So very exciting to the nervous system in many individuals is

this fungus, that the effects are often very ludicrous. If a person

under its influence wishes to step over a straw or small stick, he takes

a stride or a jump sufficient to clear the trunk of a tree. A talkative

person cannot keep silence or secrets, and one fond of music is

perpetually singing. The most singular effect of the amanita is the

influence which it has over the urine. It is said that from time

immemorial the inhabitants have known that the fungus imparts an

intoxicating quality to that secretion, which continues for a

considerable time after taking it. For instance, a man moderately

intoxicated to-day will, by the next morning, have slept himself sober,

but (as is the custom) by taking a teacup of his urine he will be more

powerfully intoxicated than he was the preceding day. It is, therefore,

not uncommon for confirmed drunkards to preserve their urine as a

precious liquor against a scarcity of the fungus. The intoxicating

property of the urine is capable of being propagated; for every one who

partakes of it has his urine similarly affected. Thus, with a very few

amanitas, a party of drunkards may keep up their debauch for a week. Dr.

Langsdorf mentions that by means of the second person taking the urine

of the first, the third of the second, and so on, the intoxication may

be propagated through five individuals.”[553]

[553] Lindley’s _Vegetable Kingdom_.

§ 517. A few cases of poisoning by the fly-blown agaric from time to

time have occurred in Europe, where it has been eaten in mistake for the

edible fungi, or taken by children allured by the bright attractive

colours. In these cases the poisonous symptoms noticed have been those

of gastro-intestinal irritation, as shown by vomiting and diarrhœa,

_dilated_[554] pupils, delirium, tetanic convulsions, slow pulse,

stertorous breathing, collapse, and death. In a few cases epileptic

attacks and trismus have been observed. The course is usually a rapid

one, the death occurring within twelve hours. In cases of recovery,

convalescence has been prolonged.

[554] This is the more curious, for muscarine strongly contracts the

pupil. It, however, tends to prove what is stated in the text--viz.,

that there is more than one poisonous substance in _Amanita_.

=The post-mortem characteristics are not distinctive=, a fluid condition

of the blood, hyperæmia of the brain, liver, and kidneys has been

noticed.

§ 518. =Muscarine.=--These effects are partly due to an undiscovered,

toxic substance--which seems to be destroyed at the temperature of

boiling water, and is probably of rather easy destructibility--and of a

very definite poisonous alkaloid (_muscarine_) first separated by a

complex process by Schmiedeberg and Koppe in 1869.[555] It is a

trimethylammonium base, and has lately been formed synthetically by

Schmiedeberg and Harnack,[556] by treating cholin with nitric acid.

Muscarine is isomeric with betain and oxycholin, from which it is

separated by its fluorescence and poisonous properties.

[555] _Das Muscarin, das giftige Alkaloid des Fliegenpilzes._ Leipzig,

1869.

[556] _Arch. f. exper. Path._, Bd. 4 u. 5.

The structural formula of muscarine, and its connection with choline, is

as follows:--

CH₂OH

|

CH₂

|

N(CH₃)₃OH

_Choline._

CH₂OH

|

CHOH

|

N(CH₃)₃OH

_Muscarine._

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

hydroxyl.

Muscarine is a colourless, strongly alkaline, syrupy fluid, which, if

allowed to stand over sulphuric acid, becomes gradually crystalline, but

liquefies again on exposure to the atmosphere. It dissolves in water in

every proportion, and also in alcohol, but is very little soluble in

chloroform, and insoluble in ether. It is not precipitated by tannin: it

forms salts with acids, and gives precipitates with auric chloride,

phosphotungstic, and phosphomolybdic acids, and also with

potassio-mercuric iodide. The last precipitate is at first amorphous,

but it gradually becomes crystalline. This was the compound used by the

discoverers to separate the base. With many other general alkaloidal

reagents muscarine forms no compound that is insoluble, and therefore

gives no precipitate, such, _e.g._, as iodine with potassic iodide,

picric acid, and platinic chloride. Muscarine is a stronger base than

ammonia, and precipitates copper and iron oxides from solutions of

their salts. Muscarine is very poisonous; 2 to 4 mgrms. are sufficient

in subcutaneous injection to kill cats in from two to twelve

hours--larger doses in a few minutes; but with rabbits the action is

less intense. Cats become salivated, their pupils contract, they vomit,

and are purged, the breathing becomes frequent, and there is marked

dyspnœa. At a later stage the respirations are slower, and there are

convulsions, and death.

The alkaloid has also been tried on man. Doses of from 3 to 5 mgrms.,

injected subcutaneously, cause, after a few minutes’ profuse salivation,

increased frequency of the pulse, nausea, giddiness, confusion of

thought and myosis, but no vomiting, and no diarrhœa. Small quantities

applied to the eye cause, after a few minutes, a derangement of the

accommodation, but no change in the size, of the pupil; larger

quantities cause also myosis, which depends upon an excitement of the

sphincter iridis, or of the oculomotorius.

§ 519. The actions of muscarine and atropine are to a great extent

antagonistic. This is especially and beautifully demonstrated by the

effects of the two substances on the frog’s heart. The action of

muscarine upon the heart is to excite the inhibitory nerve apparatus,

while the action of atropine is to paralyse the same system. One mgrm.

of muscarine, injected subcutaneously into a frog, arrests the heart _in

diastole_, but if a suitable dose of atropine is applied to the heart

thus arrested, it begins to beat again; or, if atropine is first given,

and then muscarine, the heart does not stop. The muscarine heart, when

it has ceased to beat, may be successfully stimulated by galvanism.

Muscarine at first excites the respiratory centre, and then paralyses

it.

§ 520. =Detection of Muscarine in the Body.=--Muscarine itself is not

likely to be taken as a poison or administered; but if it is sought for

in the fly-blown agaric, or in the tissues or organs of persons who have

been poisoned by the fungus, the process of Brieger appears the best.

The process depends upon the fact that muscarine gives a soluble

mercuric chloride compound, and is not precipitated by chloride of

platinum, whilst most other substances accompanying it give more or less

insoluble precipitates. The substances are treated with water acidulated

with hydrochloric acid, and the acidulated extract concentrated (best in

a vacuum) to a syrup. The syrupy residue is now treated with water, and

the solution precipitated by means of mercuric chloride solution and any

precipitate filtered off; the filtrate is freed from mercury by SH₂, and

evaporated to a syrup; the syrup is repeatedly extracted with alcohol,

and the alcoholic solution precipitated with platinum chloride and any

precipitate filtered off. The filtrate is freed from alcohol, and all

the platinum thrown out of solution by SH₂; the aqueous filtrate is now

concentrated to a small volume, and again platinum chloride added, any

precipitate which forms is filtered off, and the final filtrate allowed

to crystallise. If muscarine be present, a crystalline compound of

muscarine platinum chloride will form.

The crystals are usually octahedral in form, and have the composition

(C₅H₁₄NO₂Cl)₂PtCl₄; the percentage of platinum is 30·41.

It would probably be necessary to identify farther, by the action of the

poison on a frog.

§ 521. =The Agaricus phalloides=, a common autumn fungus, has been

several times mistaken for mushrooms, and has proved fatal; of some 53

cases collected by Falck, no less than 40, or 75 per cent., were fatal;

the real mortality is much lower than this, for it is only such cases

that are pronounced and severe which are likely to be recorded. The

fungus contains a toxalbumin which has been named “phallin.” The action

of this toxalbumin is to dissolve the blood corpuscles; according to

Kobert, even one 250,000th dilution produces “polycholie,” with all its

consequences, such as the escape of hæmoglobin and its decomposition

products in the blood and urine, multiple blood coagulation through the

fibrin ferment becoming free, and serious cerebral disturbance. If into

a dog, cat, or rabbit, only 0·5 mgrm. of phallin be injected

intravenously, within from twenty to thirty minutes blood from a vein

shows that the serum has a red colour.

The symptoms in man first appear in from three to forty-eight hours;

there is mostly diarrhœa, violent vomiting, with cramp in the legs,

cyanosis, and collapse. There are also nervous phenomena, convulsions,

trismus, and, in a few cases, tetanic spasms. The pulse, in seven cases

described by Maschka, was very small, thready, and quick, but in others,

again, small and slow. The pupils have in some cases been dilated, in

others unchanged. Death is generally rapid. In two of Maschka’s cases

from sixty to sixty-eight hours after the investigation, but in the rest

from twelve to eighteen hours. Life may, however, be prolonged for

several days. In a case recorded by Plowright,[557] in which a boy had

eaten a piece of the pileus, death occurred on the fourth day.

[557] _Lancet_, 1879.

§ 522. =The post-mortem appearances= observed in Maschka’s seven cases

were--absence of cadaveric rigidity, dilatation of the pupil, a dark red

fluid condition of the blood, numerous ecchymoses in the pleura, in the

substance of the lungs, the pericardium, the substance of the heart, the

liver, kidneys, and spleen. The mucous membrane of the digestive canal

presented nothing characteristic. In two cases there were a few

ecchymoses, and in one the mucous membrane of the stomach was softened,

red, and easily detached. In one case only were any remnants of the

fungus found, by which the nature of the substance eaten could be

determined. The bladder in each case was full. In three cases a fatty

degeneration of the liver had commenced. The same appearance was met

with in some of the older cases related by Orfila.

§ 523. =The Agaricus pantherinus= is said to be poisonous, although

Hertwig found it to have no action when given to dogs.

=The Agaricus ruber=, a bright-hued fungus, growing profusely on the

Hampshire coast, of a purple-red colour--the colouring-matter not only

covering the pileus, but also extending down the stipe--is poisonous,

and has recently been chemically investigated by Phipson,[558] who has

identified a colouring-matter _ruberine_, and an alkaloid _agarythrine_.

Agarythrine is separated by macerating the fungus (from which the skin

containing the colouring-matter has been removed) as completely as

possible in water acidulated with 8 per cent. of hydrochloric acid. The

filtered solution is neutralised by sodic carbonate, and the alkaloid

shaken up with ether. On evaporation the ether leaves a white, somewhat

greasy-looking substance, having a bitter burning taste, and easily

fusible into yellow globules, giving forth an odour like quinoleine; it

is soluble in alcohol and ether. From Phipson’s observations it would

appear probable that the red colouring-matter is derived from a

decomposition of this alkaloidal substance. A rose-red colour is

produced by the action of nitric acid, and chlorinated lime first

reddens and then bleaches it. Buchwald[559] has recorded three cases of

poisoning by this fungus; the patients were labourers, who, after eating

the fungus, suffered from vomiting, thirst, a “drunken” condition,

cramp, albuminuria, and disturbance of the sensory functions. The fungus

causes in cats myosis, but is said not to affect rabbits.

[558] _Chem. News_, p. 199, 1882.

[559] _Industr. Bl._, 1876.

§ 524. =The Soletus satanas, or luridus= (=Lenz=), is poisonous; very

small quantities of the uncooked fungus caused in Lenz, who experimented

upon its properties, violent vomiting. In cases in which this fungus has

been eaten accidentally, the symptoms have been very similar to cholera.

§ 525. =The Common Morelle= seems under certain conditions to be

poisonous. From six to ten hours after ingestion there have appeared

depression, nausea, jaundice, dilated pupils, and in the worst cases at

the end of the first day, delirium, somnolence, and muscular cramps,

followed by collapse and death. In a case observed by Kromholz, the

_post-mortem_ appearances were jaundice, a dark fluid state of the

blood, and hyperæmia of the brain and liver. Boström fed a dog with 100

grms. of the fresh young morelle; the animal died on the third day, and

the canaliculi of the kidney were found filled with hæmoglobin, partly

amorphous, and partly crystalline.[560]

[560] See Casper’s _Viertelj._, 1844; Keber, _Preuss. Vereinszeitg._

1846; Boström, _Ber. d. Phys. Med. Soc._, Erlangen, 1880; Schauenstein,

“Giftige Schwämme” in Maschka’s _Handbuch_, &c.

DIVISION II.--GLUCOSIDES.

I.--Digitalis Group.

§ 526. =The Digitalis purpurea=, or foxglove, is a plant extremely

common in most parts of England, and poisoning may occur from the

accidental use of the root, leaves, or seeds. The seeds are very small

and pitted; they weigh 1126 to a grain (_Guy_), are of a light brown

colour, and in form somewhat egg-shaped. The leaves are large, ovate,

crenate, narrowed at the base, rugous, veined, and downy, especially on

the under surface. Their colour is a dull green, and they have a faint

odour and a bitter, nauseous taste. The leaf is best examined in

section. Its epidermis, when fresh, is seen to consist of transparent,

hexagonal, colourless cells, beneath which, either singly or in groups,

there are round cells of a magenta tint, and beneath these again a layer

of columnar cells, and near the lower surface a loose parenchyma. The

hairs are simple, appearing scantily on the upper, but profusely on the

lower, surface; each is composed of from four to five joints or cells,

and has at its base a magenta-coloured cell. The small leaves just below

the seed-case, and the latter itself, are studded with glandular hairs.

The root consists of numerous long slender fibres.

§ 527. =Chemical Composition.=--It is now generally accepted that there

exist in the foxglove, at least, four distinct principles--_digitalin_,

_digitonin_, _digitoxin_, and _digitalein_. Besides these there are

several others of more or less definite composition, which are all

closely related, and may be derived from a complex glucoside by

successive removals of hydrogen in the form of water.

The following is the theoretical percentage composition of the

digitalins, the identity of which has been fairly established. They are

arranged according to their percentage in carbon:--

TABLE SHOWING THE COMPOSITION OF THE DIGITALINS.

+------------------+--------+-------------------------------------+

| Name. |Formula.| Percentage Composition. |

+------------------+--------+-------------------------------------+

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

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

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

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

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

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

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

+------------------+--------+-------------------------------------+

[561] According to Kiliani, digitonin has the composition of C₂₇H₄₄O₁₃,

and it breaks up, when heated with hydrochloric acid, as follows:--

C₂₇H₄₄O₁₃ + 2H₂O = C₁₆H₂₄O₃ + 2C₆H₁₂O₆.

Digitonin. Digitogenin. Dextrose.

--_Ber._, xxiii. 1555-1568.

§ 528. =Digitalein= is a colourless, amorphous body, easily soluble

in water and in cold absolute alcohol. It may be precipitated from

an alcoholic solution by the addition of much ether. It is with

difficulty soluble in chloroform, and insoluble in ether. It is

precipitated from a watery solution by tannin, or by basic lead

acetate; saponification by dilute acids splits it up into glucose

and digitaleretin. It has a sharp, acrid taste, and the watery

solution froths on shaking.

§ 529, =Digitonin=, a white amorphous body, has many of the

characters of saponin. Like saponin, it is easily soluble in water,

and the solution froths, and, like saponin again, it is precipitated

by absolute alcohol, by baryta water, and by basic lead acetate. It

may be readily distinguished from saponin by treating a watery

solution with sulphuric or hydrochloric acid. On saponifying, it is

split up into digitogenin, galactose, and dextrose. On heating, a

beautiful red colour develops. It does not give the bromine

reaction.

=Digitogenin= is insoluble in water and aqueous alkalies; it is somewhat

soluble in alcohol, chloroform, and glacial acetic acid; it forms a

crystalline compound with alcoholic potash, which is strongly alkaline,

and not very soluble in alcohol.

§ 530. =Digitalin=, when perfectly pure, forms fine, white, glittering,

hygroscopic needles, or groups of crystalline tufts; it is without

smell, but possesses a bitter taste, which is at once of slow

development and of long endurance. On warming, it becomes soft under

100°, and, above that temperature, is readily decomposed with evolution

of white vapours. It is insoluble in water, in dilute soda solution, in

ether, and in benzene. It is soluble in chloroform, especially in

chloroform and alcohol, and dissolves easily in warm acetic acid; twelve

parts of cold and six of boiling alcohol of 90 per cent. dissolve one of

digitalin. Dilute hydrochloric or sulphuric acid decompose it into

glucose and digitaletin (C₄₄H₃₀O₁₈); if the action is prolonged,

digitaleretin (C₄₄H₃₈O₁₈), and finally dehydrated digitaleretin, are

formed. Concentrated sulphuric acid dissolves it with the production of

a green colour, which by bromine passes into violet-red, but on the

addition of water becomes green again. Hydrochloric acid dissolves it

with the production of a greyish-yellow colour, passing gradually into

emerald green; water precipitates from this solution a resinous mass.

§ 531. =Digitaletin.=--A substance obtained by Walz on treating his

digitalin by dilute acids. It is crystalline, and its watery

solution tastes bitter. It melts at 175°, and decomposes, evolving

an acid vapour at about 206°. It dissolves in 848 parts of cold, and

222 of boiling, water; in 3·5 parts of cold, and in from 2 to 4 of

boiling, alcohol. It is with difficulty soluble in ether. It

dissolves in concentrated sulphuric acid, developing a red-brown

colour, which, on the addition of water, changes to olive-green. On

boiling with dilute acids, it splits up into sugar and

digitaleretin.

§ 532. =Digitoxin= always accompanies digitalin in the plant, and may by

suitable treatment be obtained in glittering needles and tabular

crystals. It is insoluble in water and in benzene. It dissolves with

some difficulty in ether, and is readily dissolved by alcohol or by

chloroform. On boiling with dilute acids, it is decomposed into an

amorphous, readily soluble body,--_Toxiresin_. Digitoxin, according to

Schmiedeberg, only exists in the leaves of the digitalis plant, and that

in the proportion of 1 part in 10,000. Digitalin and digitoxin are _par

excellence_ the poisonous principles of the plant. Toxiresin is also

intensely poisonous. It may be obtained in crystals by extracting the

dry exhausted leaves with alcohol of 50 per cent., precipitating with

lead acetate, and washing the precipitate first with a dilute solution

of sodium carbonate (to remove colouring-matter), and then with ether,

benzene, and carbon disulphide, in all of which it is insoluble; on

decomposing the lead compound, digitoxin may be obtained in colourless

scales or needle-shaped crystals.

§ 533. =Digitaleretin=, the origin of which has been already alluded

to, is a yellowish-white, amorphous powder, possessing no bitter

taste, melting at 60°, soluble in ether or in alcohol, but insoluble

in water.

=Paradigitaletin= is very similar to the above, but it melts at

100°, and is insoluble in ether.

§ 534. Several other derivatives have been obtained and described, such

as the inert _digitin_, _digitalacrin_, _digitalein_, and others, but

their properties are, as yet, insufficiently studied. Digitalin, as well

as digitoxin, may now be obtained pure from certain firms, but the

ordinary digitalin of commerce is, for the most part, of two kinds,

which may be distinguished as French and German digitalin. The French

digitalin, or the digitalin of Homolle, is prepared by treating an

aqueous extract of the digitalis plant with lead acetate, and freeing

the filtrate from lead, lime, and magnesia, by successive additions of

alkaline carbonate, oxalate, and phosphate, and then precipitating with

tannin. The tannin precipitate is treated with litharge, and the

digitalins boiled and extracted from the mass by means of alcohol, and

lastly, purifying with animal charcoal. Crystals are in this way

obtained, and by removing all substances soluble in ether by that

solvent, digitalin may be separated. The German digitalin is prepared

according to the process of Walz, and is extracted from the plant by

treatment with alcohol of ·852. The alcohol is removed by evaporation,

and the alcoholic extract taken up with water; the watery extract is

treated with lead acetate and litharge, filtered, the filtrate freed

from lead by hydric sulphate, and the excess of acid neutralised by

ammonia, and then tannin added to complete precipitation. The

precipitate is collected and rubbed with hydrated oxide of lead, and the

raw digitalin extracted by hot alcohol. The alcohol, on evaporation,

leaves a mixture of digitalin mixed with other principles and fatty

matter. If sold in this state, it may contain from 2 to 3 per cent. of

digitalein and digitonin. On treating the mixture with ether, digitalin

with some digitaletin is left behind, being almost insoluble in ether.

Since, however, digitaletin is very insoluble in cold water, by

treating the mixture with eight parts of its weight of cold water,

digitalin is dissolved out in nearly a pure state. It may be further

purified by treating the solution with animal charcoal,

recrystallisation from spirit, &c.

§ 535. =Reactions of the Digitalins.=--Digitonin is dissolved by dilute

sulphuric acid (1 : 3) without colour, and the same remark applies to

hydrochloric acid; on warming with either of these acids, a violet-red

colour appears; this reaction thus serves to distinguish digitonin from

the three other constituents, as well as from saponin.

Sulphuric and gallic acids colour the glucosides of digitalin,

digitalein, and digitonin, red, but not digitoxin, which can be

identified in this way.

Sulphuric acid and bromine give with digitalin a red, and with

digitalein a violet coloration, which, on the addition of water, change

respectively into emerald and light green. This, the most important

chemical test we possess, is sometimes called _Grandeau’s test_; it is

not of great delicacy, the limit being about ·1 mgrm.

§ 536. =Pharmaceutical Preparations of Digitalin.=--Digitalin itself is

officinal in the French, Belgium, Portuguese, Russian, Spanish, and

Austrian pharmacopœias. It is prepared in our own by making a strong

tincture of the leaves at 120° F.; the spirit is then evaporated off,

and the extract heated with acetic acid, decolorised by animal charcoal,

and filtered. After neutralisation with ammonia, the digitalin is

precipitated with tannin, and the tannate of digitalin resolved into

tannate of lead and free digitalin, by rubbing it with oxide of lead and

spirit.

Digitalis leaf is officinal in most of the pharmacopœias.

Tincture of digitalis is officinal in our own and all the Continental

pharmacopœias, and an ethereal tincture is used in France and Germany.

An _Acetum digitalis_ is officinal in the Netherlands and Germany; an

extract and infusion are also used to some extent.

With regard to the nature of the active principle in these different

preparations, according to Dragendorff, digitonin and digitalein are

most plentiful in the acetic and aqueous preparations; whilst in the

alcoholic, digitalin, digitoxin, and digitalein are present.

According to Schmiedeberg, commercial digitalin contains, in addition to

digitoxin, digitonin, digitalin, and digitalein; of these, digitonin is

greatest in amount.[562]

[562] H. Kiliani, _Ber._, xxiii.

§ 537. =Fatal Dose.=--The circumstance of commercial digitalin

consisting of varying mixtures of digitoxin, digitalin, and digitalein,

renders it difficult to be dogmatic about the dose likely to destroy

life. Besides, with all heart-poisons, surprises take place; and very

minute quantities have a fatal result when administered to persons with

disease of the heart, or to such as, owing to some constitutional

peculiarity, have a heart easily affected by toxic agents. Digitoxin,

according to Kopp’s[563] experiments, is from six to ten times stronger

than digitalin or digitalein. Two mgrms. caused intense poisonous

symptoms. Digitoxin is contained in larger proportions in Nativelle’s

digitalin than in Homolle’s, or in the German digitalin. The digitalin

of Homolle is prescribed in 1 mgrm. (·015 grain) doses, and it is

thought dangerous to exceed 6 mgrms.

[563] _Archiv f. exp. Pathol. u. Pharm._, vol. iii. p. 284, 1875.

Lemaistre has, indeed, seen dangerous symptoms arise from 2 mgrms. (·03

grain), when administered to a boy fifteen years old. It may be

predicated from recorded cases and from experiment, that digitoxin would

probably be fatal to an adult man in doses of 4 mgrms. (1/16 grain), and

digitalin, or digitalein, in doses of 20 mgrms. (·3 grain). With regard

to commercial digitalin, as much as from 10 to 12 mgrms. (·15 to ·18

grain) have been taken without a fatal result; on the other hand, 2

mgrms. gave rise to poisonous symptoms in a woman (Battaille). Such

discrepancies are to be explained on the grounds already mentioned. It

is, however, probable that 4 mgrms. (or 1/16 grain) of ordinary

commercial digitalin would be very dangerous to an adult.

It must also, in considering the dose of digitalin, be ever remembered

that it is a cumulative poison, and that the same dose--harmless if

taken once--yet, frequently repeated, becomes deadly: this peculiarity

is shared by all poisons affecting the heart. When it is desired to

settle the maximum safe dose for the various tinctures, extracts, and

infusions of digitalis used in pharmacy, there is still greater

difficulty, a difficulty not arising merely from the varying strength of

the preparations, but also from the fact of the vomiting almost

invariably excited by large doses. Individuals swallow quantities

without death resulting, simply because the poison is rapidly expelled;

whereas, if the œsophagus was ligatured (as in the experiments on the

lower animals formerly favoured by the French school of toxicologists),

death must rapidly ensue. The following table is a guide to the maximum

single dose, and also the amount safe to administer in the twenty-four

hours in divided doses. As a general rule, it may be laid down that

double the maximum dose is likely to be dangerous:--

TABLE SHOWING THE MAXIMUM SINGLE DOSE, AND MAXIMUM QUANTITY OF THE

DIFFERENT PREPARATIONS OF DIGITALIS, WHICH CAN BE ADMINISTERED IN A DAY.

+----------------+----------------------+--------------------------+

| | Single Dose. | Per Day. |

| +----------+-----------+-------------+------------+

| | Grains or| Grammes | Grains or |Grammes |

| | Minims. | or c.c’s. | Minims. |or c.c’s. |

+----------------+----------+-----------+-------------+------------+

|Powdered Leaves,| 4½ grns. | ·3 grm. | 15·4 grns. | 1·0 grm. |

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

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

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

|Extract, |3·0 „ | ·2 „ | 12·0 „ | ·8 „ |

+----------------+----------+-----------+-------------+------------+

§ 538. =Statistics.=--The main knowledge which we possess of the action

of digitalis is derived from experiments on animals, and from occasional

accidents in the taking of medicines; but in comparison with certain

toxic agents more commonly known, the number of cases of death from

digitalis is very insignificant. Of 42 cases of digitalis-poisoning

collected by Husemann, 1 was criminal (murder); 1 the result of

mistaking the leaves for those of borage; 42 were caused in medicinal

use--in 33 of these last too large a dose had been given, in 3 the drug

was used as a domestic remedy, in 2 of the cases the prescription was

wrongly read, and in 1 digitalis was used as a secret remedy. Twenty-two

per cent. of the 45 were fatal.

§ 539. =Effects on Man.=--It was first distinctly pointed out by Tardieu

that toxic doses of digitalis, or its active principles, produced not

only symptoms referable to an action on the heart, but also, in no small

degree, gastric and intestinal irritation, similar to that produced by

arsenic. Tardieu also attempted to distinguish the symptoms produced by

the pharmaceutical preparations of digitalis (the tincture, extract,

&c.), and the glucoside digitalin; but there does not appear a

sufficient basis for this distinction. The symptoms vary in a

considerable degree in different persons, and are more or less tardy or

rapid in their development, according to the dose. Moderate doses

continued for some time (as, for example, in the persistent use of a

digitalis medicine) may produce their first toxic effects even at the

end of many days; but when a single large dose is taken, the symptoms

are rarely delayed more than three hours. They may commence, indeed, in

half an hour, but have been known to be retarded for more than

twenty-four hours, and the longer periods may be expected if digitalis

is given in hard, not easily soluble pills. There is commonly a feeling

of general _malaise_, and then violent retching and vomiting. The pulse

at first may be accelerated, but it soon is remarkably slowed--it sinks

commonly down to 50, to 40, and has even been known as low as 25. To

these symptoms, referable to the heart and to the digestive tract, are

added nervous troubles; there are noises in the ears, and disturbances

of vision. In a case related by Taylor, a red-coal fire seemed to the

patient to be of a blue colour; in another, related by Lersch,[564]

there was blindness for eighteen hours, and for some time a confusion in

the discrimination in colours; quiet delirium has also been noticed. As

the case proceeds, the gastric symptoms also increase in severity; the

tongue Christison, in one case, noticed to be enormously swollen, and

the breath fœtid. Diarrhœa is commonly present, although also sometimes

absent. The action of the kidneys is suppressed. Hiccough and

convulsions close the scene.

[564] _Rhen. West. Corr. Bl._, 15, 1848; Husemann in Maschka’s

_Handbuch_.

In the cumulative form, the symptoms may suddenly burst out, and the

person pass into death in a fainting-fit without any warning. As a rare

effect, hemiplegia may be mentioned.

This brief _résumé_ of the symptoms may be further illustrated by the

following typical cases:--A recruit, aged 22, desiring to escape from

military service, went to a so-called “_Freimacher_” who gave him 100

pills, of which he was to take eight in two doses daily. Eleven days

after the use of the pills, he became ill, and was received into

hospital, where he suddenly died after three weeks’ treatment. His

malady was at first ascribed to gastric catarrh; for he suffered from

loss of appetite, nausea, and constipation. He complained of pain in the

head, and giddiness. His breath smelled badly, and the region of the

stomach was painful on pressure. The pulse was slow (56), the

temperature of the body normal. Towards the end, the pulse sank to 52;

he suffered from vomiting, noise in the ears, troubles of vision, great

weakness, and later, hiccough and swelling in the neck. The mere act of

standing up in order to show his throat caused him to faint; on the same

day on which this occurrence took place, he suddenly died on the way to

the nightstool. Thirteen of the pills were found in the patient’s

clothes, and from a chemical and microscopical examination it was found

that they contained digitalis leaf in fine powder. The quantity which

the unfortunate man took in the four weeks was estimated at 13·7 grms.

(= about 211 grains).

Two of his comrades had also been to the “_Freimacher_,” and had

suffered from the same symptoms, but they had left off the use of the

medicine before any very serious effect was produced.[565][566]

[565] Köhnhorn, _Vierteljahrsschr. f. ger. Med._, 1876, n. F. xxiv. p.

402.

[566] There is an interesting case on record, in which a woman died from

the expressed juice of digitalis. She was twenty-seven years of age, and

took a large unknown quantity of the freshly expressed juice for the

purpose of relieving a swelling of the limbs. The symptoms came on

almost immediately, she was very sick, and was attacked by a

menorrhagia. These symptoms continued for several days with increasing

severity, but it was not until the fifth day that she obtained medical

assistance. She was then found semi-comatose, the face pale, pulse slow,

epigastrium painful on pressure, diarrhœa, and hiccough were frequent.

She died on the twelfth day. The _post-mortem_ appearances showed

nothing referable to digitalis save a few spots of inflammation on the

stomach.--Caussé, _Bull. de Thérapeutique_, vol. lvi. p. 100; _Brit. and

For. Med. Chir. Review_, vol. xxvi., 1860, p. 523.

An instructive case of poisoning by digitoxin occurred in the person of

Dr. Koppe, in the course of some experiments on the drug. He had taken

1·5 mgrm. in alcohol without result; on the following day (May 14) he

took 1 mgrm. at 9 A.M., but again without appreciable symptoms. Four

days later he took 2 mgrms. in alcoholic solution, and an hour

afterwards felt faint and ill, with a feeling of giddiness; the pulse

was irregular, of normal frequency, 80 to 84. About three hours after

taking the digitoxin, Dr. Koppe attempted to take a walk, but the

nausea, accompanied with a feeling of weakness, became so intense that

he was obliged to return to the house. Five hours after the dose, his

pulse was 58, intermittent after about every 30 to 50 beats. Vomiting

set in, the matters he threw up were of a dark green colour; after

vomiting he felt better for a quarter of an hour, then he again vomited

much bilious matter; the pulse sank to 40, and was very intermittent,

stopping after every 2 or 3 beats. Every time there was an intermission,

he felt a feeling of constriction and uneasiness in the chest. Six and a

quarter hours after the dose there was again violent vomiting and

retching, with paleness of the face. The muscular weakness was so great

that he could not go to bed without assistance. He had a disorder of

vision, so that the traits of persons well-known to him were changed,

and objects had a yellow tint. He had a sleepless night, the nausea and

vomiting continuing. During the following day the symptoms were very

similar, and the pulse intermittent, 54 per minute. He passed another

restless night, his short sleep being disturbed by terrible dreams. On

the third day he was somewhat better, the pulse was 60, but irregular

and still intermittent; the nausea was also a little abated. The night

was similar in its disturbed sleep to the preceding. He did not regain

his full health for several days.[567]

[567] _Arch. f. exp. Path. u. Pharm._, vol. iii. p. 289, 1875.