[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.
§ 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,
hence it is a pyridine derivative, and its graphic formula probably
The nitrate and hydrochloride are at present much used in pharmacy. Pilocarpine gives a precipitate with phosphomolybdic acid, potassio-mercuric iodide, and most general alkaloidal reagents, but none that are very distinctive. When a solution of gold chloride is added to one of pilocarpine, a salt falls, having the composition C11H16N2O2,HCl + AuCl3. It is not very soluble in water (about 1 in 4600), and has been utilised for the estimation of pilocarpine. Pilocarpine fused with potash yields trimethylamine, carbon dioxide, butyric, and traces of acetic acid. Pilocarpine dissolves without the production of colour in sulphuric acid; but, with bichromate of potash and sulphuric acid, a green colour is produced. It may be extracted from an aqueous solution made alkaline by ammonia, by shaking up with chloroform or benzene.
§ 497. Tests.—When a little of the alkaloid is mixed with ten times its weight of calomel, and rubbed, and moistened by the breath, the calomel is blackened; cocaine also acts similarly; but the two could not be mistaken for each other. If a solution of mercur-potassium iodide is added to a solution of the hydrochloride, the amorphous precipitate becomes, in the course of a day or two, oily drops. “A solution of iodine in potassium iodide gives in pilocarpine solutions a brown precipitate that often crystallises to feathery brown crystals (microscopically), and of serrated form, something like the blade of a scroll-saw, when the crystallisation is incomplete.”—Flückiger’s Reactions.
§ 498. Effects.—Pilocarpine, given subcutaneously in doses of about 32 mgrms. (1⁄2 grain), causes within five minutes a profuse perspiration and salivation, the face becomes flushed, and the whole body sweats; at the same time, the buccal secretion is so much increased that in a few hours over a pint may be secreted. The tears, the bronchial secretion, and the intestinal secretions are also augmented; there are generally headache and a frequent desire to pass water; the pulse is much quickened, and the temperature falls from 1°·4 to 4°: the symptoms last from two to five hours. Langley has shown that the over-action of the submaxillary gland is not affected by section either of the chorda tympani or of the sympathetic supplying the gland. Although pilocarpine quickens the pulse of man, it slows, according to Langley,[542] the heart of the warm-blooded animals, and that of the frog. With regard to the frog, Dr. S. Ringer’s researches are confirmatory. With large doses the heart stops in diastole. If to the heart thus slowed, or even when recently stopped, a minute quantity of atropine be applied, it begins to beat again. There is also a most complete antagonism between atropine and pilocarpine in other respects, atropine stopping the excessive perspiration, and relieving the headache and pain about the pubes, &c. Pilocarpine, given internally, does not alter the size of the pupil, but the sight may, with large doses, be affected. If a solution is applied direct to the eye, then the pupil contracts. No fatal case of its administration has occurred in man. The probable dangerous dose would be about 130 mgrms. (2 grains) administered subcutaneously. Pilocarpine must be classed among the heart poisons.
[542] “The Action of Jaborandi on the Heart,” by J. N. Langley, B.A., Journ. Anat. and Physiol., vol. x. p. 187.
§ 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.
§ 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.
§ 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 31⁄2 drachms of colchicum wine, taken in divided doses, caused death on the fourth day. The quantity of the active principle in the colchicum wine, as found by Johannson (Dragendorff), being 0·18 per cent., it follows that 24·4 mgrms. (·378 grain) were fatal, though not given as one dose, so that this quantity may be considered as the least fatal one. Casper puts the lethal dose of colchicine at from 25 to 30 mgrms. (·385 to ·463 grain). It is, however, incontestable that there are cases of recovery from as much as 70 mgrms. (1·08 grain). The lethal dose of the pharmaceutical preparations of colchicum may, on these grounds, be predicted from their alkaloidal contents, and, since the latter is not constant, in any medico-legal inquiry, it may be necessary, where facility is given, to ascertain the strength of the preparation administered.
§ 512. Effects of Colchicine on Animals.—The researches of Rossbach show that the carnivoræ are more sensitive to colchicine than any other order of mammals. Frogs show a transitory excitement of the nervous system, then there is loss of sensation, paralysis of motion, and of the respiratory apparatus; the heart beats after the respiration has ceased. Death follows from paralysis of the respiration. The mucous membrane of the intestine is much congested and swollen.
I have seen cattle die from the effects of eating the meadow-saffron; the animals rapidly lose condition, suffer great abdominal pain, and are generally purged. The farmers, in certain parts of the country, have had extensive losses from want of care and knowledge with regard to colchicum poisoning.
§ 513. Effects of Colchicum on Man.—Colchicum poisoning in man[550] is not very common: 2 deaths (accidental) are recorded in England and Wales during the ten years ending 1892. F. A. Falck was able to collect from medical literature, prior to 1880, 55 cases, and he gives the following analysis of the cases:—In 2, colchicum was taken for suicidal purposes; of the unintentional poisonings, 5 were from too large a medicinal dose of colchicum wine, syrup, or extract, given in cases of rheumatism; in 13 cases, colchicum was used as a purgative; 42 cases were owing to mistaking different preparations for drinks, or cordials—the tincture in 5, and the wine in 14, being taken instead of orange tincture, quinine wine, schnapps or Madeira; in 1 case the corms were added to mulled wine, in another, the leaves consumed with salad; in 16 cases (all children), the seeds of colchicum were eaten. Forty-six of the 55 died—that is, 83·7 per cent.
[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. (3⁄5 grain). Dr. Budd considered that the whole of the pills, which were of a stony hardness, remained in the bowels for some time undigested, so that the ultimate result was the same as if the whole had been taken in one dose.