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§ 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.

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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.

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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]

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§ 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.

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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.

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The structural formula of muscarine, and its connection with choline, is as follows:—

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.

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§ 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.

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§ 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]

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DIVISION II.—GLUCOSIDES.

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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	„

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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.

§ 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.

§ 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]

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§ 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.

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

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

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

	Single Dose.						Per Day.
	Grains or Minims.			Grammes or c.c’s.			Grains or Minims.			Grammes or c.c’s.
Powdered Leaves,	4	1⁄2	grns.		·3	grm.	15	·4	grns.	1	·0	grm.
Infusion,	480		m.	28	·3	c.c.	1440		m.	84	·9	c.c.
Tincture,	45		m.	3		c.c.	135		m.	9		c.c.
Digitalin,		·03	grn.		·002	grm.		·09	grn.		·006	grm.
Extract,	3	·0	„		·2	„	12	·0	„		·8	„

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

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

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