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 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.
[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.
A third case may be quoted, which differs very markedly from the preceding, and shows what a protean aspect digitalin poisoning may assume. A woman, twenty-three years old, took on June 26th, at 7 A.M., for the purpose of suicide, 16 granules of digitalin. Two hours later there was shivering and giddiness, so that she was obliged to go to bed. In the course of the day she had hallucinations. In the evening at 8 P.M., after eating a little food, she had a shivering fit so violent that her teeth chattered; there was cold sweat, and difficulty in breathing; she became gradually again warm, but could not sleep. At 1 A.M. the difficulty of breathing was so great that she dragged herself to the window, and there remained until 3 A.M., when she again went back to bed, slept until 7 A.M., and woke tolerably well. Since this attempt of self-destruction had failed, she took 40 granules. After one hour she became giddy, had hallucinations, chilliness, cold sweats, copious vomiting, and colicky pains; there was great muscular weakness, but no diarrhœa. Towards evening the vomiting became worse. There was no action of the bowels, nor was any urine passed; she felt as if her eyes were prominent and large. The sufferings described lasted during the whole night until five o’clock the following day, when the vomiting ceased, whilst the hallucinations, chilliness, and cold sweat continued; and the thirst, sick feeling, and weakness increased. The next morning, a physician found her motionless in bed, with pale face, notable double exophthalmus, dilated pupils, and cold skin, covered with sweat; the pulse was small and intermittent, sometimes scarcely to be felt (46 to 48 per minute); the epigastrium was painful on pressure. She passed this second night without sleep, and in the morning the pulse had risen from 56 to 58 beats, but was not quite so intermittent. There was some action of the bowels, but no urine was passed, nor had any been voided from the commencement; the bladder was not distended. The following (third) day some red-coloured, offensive urine was passed; the skin was warmer, and the pulse from 60 to 64, still somewhat intermittent—from this time she began to improve, and made a good recovery.[568]
[568] Related by Ducroix: De l’Empoisonnement par la Digitale et la Digitaline. Paris, 1864.
§ 540. Physiological Action of the Digitalins.—Whatever other physiological action this group may have, its effect on the heart’s action is so prominent and decided, that the digitalins stand as a type of heart poisons. The group of heart poisons has been much extended of late years, and has been found to include the following:—Antiarin, an arrow poison; helleborin, a glucoside contained in the hellebore family; a glucoside found in the Apocynaceæ, Thevatii neriifolia, and Thevatia iccotli; the poisonous principle of the Nerium oleander and N. odorum; the glucoside of Tanghinia venenifera; convallamarin, derived from the species of Convallaria; scillotoxin, from the squill; superbin, from the Indian lily; and the alkaloid erythrophlœin from the Erythrophlœum judiciale (see [p. 432] et seq.). This list is yearly increasing.
§ 541. Local Action.—The digitalins have an exciting or stimulating action if applied to mucous membranes—e.g., if laid upon the nasal mucous surface, sneezing is excited; if applied to the eye, there is redness of the conjunctivæ with smarting; if to the tongue, there is much irritation and a bitter taste. The leaves, the extract, and the tincture all have this directly irritating action, for they all redden and inflame mucous membranes.
§ 542. Action on the Heart.—The earlier experimenters on the influence of digitalis on the heart were Stannius and Traube. Stannius[569] experimented on cats, and found strong irregularity, and, lastly, cessation in diastole, in which state it responded no longer to stimuli. Rabbits and birds—especially those birds which lived on plants—were not so susceptible, nor were frogs.
[569] Arch. f. Physiol.
Traube[570] made his researches on dogs, using an extract, and administering doses which corresponded to from ·5 to 4·0 grms. He divided the symptoms witnessed into four stages:—
[570] Ann. d. Charité-Krankenhauses, vol. ii. p. 785.
1st Stage.—The pulse frequently diminishes, while the pressure of the blood rises.
2nd Stage.—Not seen when large doses are employed; pulse frequency, as well as blood pressure, abnormally low.
3rd Stage.—Pressure low, pulse beats above the normal frequency.
The slowing of the heart[571] is attributed to the stimulus of the inhibitory nerves, but the later condition of frequency to their paralysis. After the section of the vagi the slow pulse frequently remains, and this is explained by the inhibitory action of the cardiac centre. The vagus, in point of time, is paralysed earlier than the muscular substance of the heart.
[571] Slowing of the pulse was mentioned first by Withering (An Account of the Foxglove, Lond., 1785). Beddoes afterwards observed that digitalis increased the force of the circulation, the slowing of the pulse not being always observed; according to Ackermann, if the inhibitory apparatus is affected by atropine, or if the patient is under deep narcosis, the slowing is absent.
The increased blood pressure Traube attributed to increased energy of the heart’s contraction, through the motor centre being stimulated later; the commencing paralysis explains the abnormally low pressure.
There is, however, also an influence on vaso-motor nerves. What Dr. Johnson has described as the “stop-cock” action of the small arteries comes into play, the small arteries contract and attempt, as it were, to limit the supply of poisoned blood. Ackermann,[572] indeed, witnessed this phenomenon in a rabbit’s mesentery, distinctly seeing the arteries contract, and the blood pressure rise after section of the spinal cord. This observation, therefore, of Ackermann’s (together with experiments of Böhm[573] and L. Brunton[574]) somewhat modifies Traube’s explanation, and the views generally accepted respecting the cause of the increased blood pressure may be stated thus:—The pressure is due to prolongation of the systolic stroke of the cardiac pump, and to the “stop-cock” action of the arteries; in other words, there is an increase of force from behind (vis a tergo), and an increased resistance in front (vis a fronte).
[572] Deutsch. Arch. f. klin. Med., vol. xix. p. 125.
[573] Archiv f. d. Ges. Phys., vol. v. p. 153.
[574] On Digitalis, with Some Observations on the Urine, Lond., 1868.
§ 543. Action of the Digitalins on the Muco-Intestinal Tract and other Organs.—In addition to that on the heart, there are other actions of the digitalins; for example, by whatever channel the poison is introduced, vomiting has been observed. Even in frogs this, in a rudimentary manner, occurs. The diuretic action which has been noticed in man is wanting in animals, nor has a lessened diminution of urea been confirmed.
Ackermann found the temperature during the period of increased blood pressure raised superficially, but lowered internally. According to Boeck[575] there is no increase in the decomposition of the albuminoids.
[575] Intoxication, p. 404.
§ 544. The Action of Digitalin on the Common Blow-fly.—The author has studied the effects of digitalin, made up into a thin paste with water, and applied to the head of the common blow-fly. There are at once great signs of irritation, the sucker is extruded to its full length, and the fly works its fore feet, attempting to brush or remove the irritating agent. The next symptom is a difficulty in walking up a perpendicular glass surface. This difficulty increases, but it is distinctly observed that weakness and paralysis occur in the legs before they are seen in the wings. Within an hour the wings become paralysed also, and the fly, if jerked from its support, falls like a stone. The insect becomes dull and motionless, and ultimately dies in from ten to twenty-four hours. A dose, in itself insufficient to destroy life, does so on repetition at intervals of a couple of hours. The observation is not without interest, inasmuch as it shows that the digitalins are toxic substances to the muscular substance of even those life-forms which do not possess a heart.
§ 545. Action of the Digitalins on the Frog’s Heart.—The general action of the digitalins is best studied on the heart of the frog. Drs. Fagge and Stevenson have shown[576] that, under the influence of digitalin, there is a peculiar form of irregularity in the beats of the heart of the frog; the ventricle ultimately stops in the white contracted state, the voluntary power being retained for fifteen to twenty minutes afterwards; in very large doses there is, however, at once paralysis. Lauder Brunton[577] considers the action on the heart to essentially consist in the prolongation of the systole.
[576] Guy’s Hospl. Reports, 3rd ver., vol. xii. p. 37.
[577] On Digitalis, with Some Observations on the Urine, Lond., 1868.
Atropine or curare have no influence on the heart thus poisoned. If the animal under the influence of digitalin be treated with muscarine, it stops in diastole instead of systole. On the other hand, the heart poisoned by muscarine is relieved by digitalin, and a similar influence appears to be exercised by atropine. The systolic stillness of the heart is also removed by substances which paralyse the heart, as delphinin, saponin, and apomorphin.
Large doses of digitalin, thrown suddenly on the circulation by intravenous injection, cause convulsions and sudden death, from quick palsy of the heart. With frogs under these circumstances there are no convulsions, but a reflex depression, which, according to Weil[578] and Meihuizen,[579] disappears on decapitation. The central cerebral symptoms are without doubt partly due to the disturbance of the circulation, and there is good ground for attributing them also to a toxic action on the nervous substance. The arteries are affected as well as the heart, and are reduced in calibre; the blood pressure is also increased.[580] This is essentially due to the firm, strong contraction of the heart, and also to the “stop-cock” action of the small arteries.[581]
[578] Archiv f. Anat. u. Physiol., 1871, p. 282.
[579] Archiv f. d. Ges. Physiol., vol. vii. p. 201.
[580] The following is a brief summary of observations on the blood pressure; four stages may be noticed—(1) Rise of normal blood pressure, not necessarily accompanied with a diminution of pulse frequency; (2) continuation of heightened blood pressure, the pulse being raised beyond the normal rate; (3) continued high pressure, with great irregularity of the heart and intermittent pulse; (4) quick depression of pressure, sudden stopping of the heart, and death.
[581] According to Boehm (Arch. f. d. Ges. Physiol., Bd. v. S. 189) and to Williams (Arch. f. exper. Pathol., Bd. xiii. S. 2), the rise of pressure is due entirely to the heart, and not to the contractions of the small arteries; but I fail to see how the small arteries can contract, and yet not heighten the pressure.
§ 546. Post-mortem Appearances.—In the case of the recruit poisoned by digitalis leaf ([p. 425]), the blood was found dark and fluid; the right ventricle and auricle of the heart were filled with blood, the left empty; the brain and its membranes were anæmic; the stomach and mucous membrane of the intestines were in parts ecchymosed, and there were patches of injection. In the case of the widow De Pauw, poisoned with digitalin by the homœopath (Conty de la Pommerais), the only abnormality discovered was a few hyperæmic points in the mucous membrane of the stomach and small intestines. It is then certain that although more or less redness of the lining membrane of the intestine track may be present, yet, on the other hand, the active principle of the digitalis may destroy life, and leave no appreciable sign.
§ 547. Separation of the Digitalins from Animal Tissues, &c.—It is best to make an alcoholic extract after the method of Stas, the alcohol being feebly acidulated by acetic acid, and all operations being carried on at a temperature below 60°. The alcoholic extract is dissolved in water feebly acidulated by acetic acid, and shaken up, first with petroleum ether to remove impurities (the ether will not dissolve any of the digitalins), then with benzene, and, lastly, with chloroform. The benzene dissolves digitalein, and the chloroform, digitalin and digitoxin. On allowing these solvents to evaporate spontaneously, residues are obtained which will give the reactions already detailed. Neither the bromine nor any other chemical test is sufficient to identify the digitalins; it is absolutely necessary to have resource to physiological experiment. The method used by Tardieu in the classical Pommerais case may serve as a model, more especially the experiments on frogs. Three frogs were properly secured, the hearts exposed, and the beats counted. The number of beats was found to be fairly equal. Frog No. 1 was placed under such conditions that the heart was constantly moist. Frog No. 2 was poisoned by injecting into the pleura 6 drops of a solution in which 10 mgrms. of digitalin were dissolved in 5 c.c. of water. The third frog was poisoned by a solution of the suspected extract. The number of beats per minute were now counted at definite intervals of time as follows:—
TABLE SHOWING THE ACTION OF DIGITALIN ON THE FROG’S HEART.
| Frog No. 1. Unpoisoned. | Frog No. 2. Poisoned by a known quantity of digitalin. | Frog No. 3. Poisoned by the suspected extract. | |||||
|---|---|---|---|---|---|---|---|
| No. of beats per minute. | No. of beats per minute. | No. of beats per minute. | |||||
| After | 6 | minutes, | 42 | 20 | 26 | ||
| „ | 10 | „ | 40 | 16 | irregular. | 24 | irregular. |
| „ | 20 | „ | 40 | 15 | 20 | irre„ | |
| „ | 28 | „ | 38 | 0 | 12 | very irregular. | |
| „ | 31 | „ | 36 | 0 | 0 | ||
In operating in this way—which is strictly comparative, and, with care, has few sources of error—if the heart of the frog poisoned with the unknown extract behaves in the number and irregularity of its contractions similarly to that of the digitalin-poisoned heart, it is a fair inference that, at all events, a “heart-poison” has been separated; but it is, of course, open to question whether this is a digitalin or one of the numerous groups of glucosides acting in the same way. If sufficient quantity has been separated, chemical reactions, especially the bromine test (Grandeau’s test), may decide, but with the larger number (yearly increasing) of substances acting similarly on the heart, great caution in giving an opinion will be necessary.
II.—Other Poisonous Glucosides Acting on the Heart.
§ 548. Several members of these glucosides have been studied by Schmiedeberg,[582] and his convenient divisions will be followed here:—
[582] Beiträge zur Kentniss der pharmakol. Gruppe des Digitalins.
1. CRYSTALLISABLE GLUCOSIDES.
Antiarin (C14H20O5).—Antiarin is an arrow poison obtained from the milky juice of the Antiaris toxicaria growing in Java. Antiarin is obtained in crystals, by first treating the inspissated milky juice with petroleum ether to remove fatty and other matters, and then dissolving the active principle out with absolute alcohol. The alcoholic extract is taken up with water, precipitated with lead acetate, filtered, and from the filtrate antiarin obtained by freeing the solution from lead, and then evaporating. De Vry and Ludwig obtained about 4 per cent. from the juice. Antiarin is crystalline, the crystals containing 2 atoms of water. Its melting-point is given as 220·6°; the crystals are soluble in water (254 parts cold, 27·4 parts boiling), they are not soluble in benzene, and with difficulty in ether; 1 part of antiarin requiring 2792 parts of ether.
The watery solution is not precipitated by metallic salts. On warming with dilute mineral acids, antiarin splits up into a resin and sugar. Concentrated sulphuric acid gives with antiarin a yellow-brown solution, hydrochloric and nitric acids strike no distinctive colours.
§ 549. Effects.—Antiarin is essentially a muscular and a heart poison. When given in a sufficient dose, it kills a frog in from half an hour to an hour. Its most marked effect is on the cardiac muscle, the heart beats more and more slowly, and at last stops, the ventricle being firmly contracted. As with digitalin, there is a very marked prolongation of the systole, and as with digitalin, after the beats have ceased, a forcible dilatation of the ventricle will restore them (Schmiedeberg). It is doubtful whether by physiological experiment antiarin could be differentiated from digitalin.
§ 550. Separation of Antiarin.—In any case of poisoning by antiarin, it would be best to extract with alcohol, evaporate, dissolve the alcoholic extract in water, precipitate with lead acetate, filter, free the filtrate from lead, and then, after alkalising with ammonia, shake the filtrate successively with petroleum ether, benzene, and a small quantity of ether in the manner recommended at [page 247], et seq. The liquid, now freed from all fatty, resinous, and alkaloidal bodies, is neutralised and evaporated to dryness in a vacuum, and the dry residue taken up with absolute alcohol, filtered, the alcohol evaporated at a very low temperature, and finally the extract dissolved in a small quantity of water, and submitted to physiological tests.
§ 551. The Active Principles of the Hellebores.—The Christmas rose (Helleborus niger), as well as H. viridis, H. fœtidus, and, in short, all the species of hellebore, are poisonous, and if the root is treated with alcohol, from the alcoholic extract may be separated two glucosides, helleborin and helleborein.
Helleborin is in the form of white, glittering needles, which, if placed on the tongue, are almost tasteless, but if dissolved in alcohol, and then tasted, give a burning, numbing sensation. By boiling with zinc chloride, helleborin splits up into sugar and a resin—helleboresin. Concentrated sulphuric acid dissolves the crystals with the production of a beautiful red colour; on standing, the solution after a while becomes colourless, and a white powder separates.
Helleborein forms colourless crystals, mostly consisting of fine needles; they have a bitter taste, excite sneezing, and are very hygroscopic. The crystals easily dissolve in water and dilute alcohol, but are with difficulty soluble in absolute alcohol, and not soluble in ether. They dissolve in fatty oils. Helleborein splits by the action of mineral acids into sugar and amorphous helleboretin.
Helleboretin is in the moist condition of a beautiful violet-blue colour, becoming, when dried at 100°, dirty green. Concentrated sulphuric acid dissolves it with the production of a brown-yellow colour, which on standing passes into violet and then into brown.
Marmé separated from H. fœtidus, in addition, a white, intensely odorous substance, but too small in quantity to thoroughly investigate its properties.
§ 552. There is little doubt that hellebore owes its properties to the glucosides just described. There are several instances of poisoning by hellebore root,[583] and by the pharmaceutical preparations, but none of poisoning by the pure active principles. Morgagni mentions a case in which 2 grms. (nearly 31 grains) of the watery extract of H. Niger caused death within eight hours; and Ferrari saw, after the use of the wine in which the root had been boiled, two persons poisoned with a like result. A more recent case was recorded by Felletar, in 1875, in which a person died from an infusion of hellebore; there was, however, old standing heart-disease, so that there may be a doubt as to the real cause of death in this instance. Schauenstein mentions a case in which the roots of hellebore were accidentally used in soup, but the bitter taste prevented any quantity being eaten. The physiological action, especially of helleborein, is that of an intense heart poison, and the symptoms produced by the hellebores are so strikingly like those of the digitalins that it might be difficult to distinguish clinically between them. In any case of poisoning, the active principle must be separated in the form of an alcoholic extract, and identified as a heart poison by physiological experiment.
[583] There used to be a tincture officinal in our pharmacopœia; the root of H. viridis is officinal in the German pharmacopœia, maximum single dose, ·3 grm.; maximum total quantity in twenty-four hours, 1·2 grm. The tincture is also officinal on the Continent.
§ 553. Euonymin is found in a resin obtained from the Euonymus atropurpureus; it is crystalline, crystallising in colourless, cauliflower-like masses consisting of groups of stellate needles, which are soluble in water, but with difficulty in alcohol. It is a glucoside, and a powerful heart poison, 1 mgrm. causing the heart of a frog to cease in diastole.[584]
[584] Schmiedeberg, op. cit., from unpublished researches of Professor H. Meyer, Dorpat.
§ 554. Thevetin (C54H48O2).—A glucoside which has been separated from the Thevetia nereifolia, and perhaps also from the Cerbera Odallam. It is soluble in 124 parts of water at 14°, and is easily soluble in spirit, but not in ether. It is coloured by sulphuric acid red-brown, passing into cherry-red, and then, in a few hours, into violet. On boiling with diluted acids, it splits up into sugar and theveresin. Both thevetin and theveresin are powerful heart poisons.[585]
[585] Husemann, Archiv f. exper. Path. u. Pharmakol., Bd. v., S. 228, 1876.
2. SUBSTANCES PARTLY CRYSTALLISABLE BUT WHICH ARE NOT GLUCOSIDES.
§ 555. Strophantin is a very poisonous substance which belongs physiologically to this group, but does not seem to be a glucoside. It is soluble in water and in alcohol, less so in ether and chloroform. It is found in the kombé, manganja, inée, or onaje, a West African poison derived from the Strophanthus hispidus of the family of Apocynaceæ. The poison has been investigated by several observers.[586]
[586] Digitoxin (see ante, [p. 420]) belongs to this group.
Dr. Fraser considers, from his experiments, (1) That strophantin acts primarily on the heart, producing, as an end result, heart paralysis, with permanence of the ventricular systole. (2) He found the pulmonary respiration to continue in cold-blooded animals many minutes after the heart was paralysed. (3) The striped muscles of the body are affected, and twitches occur in them; their tonicity is exaggerated, and finally their functional activity is destroyed. This change is referred to an action on the muscular structure itself, independent of that upon the heart, and also independent of the cerebro-spinal nervous system. (4) The reflex action of the spinal cord is suspended after the heart is paralysed, but the motor conductivity of the spinal cord and of the nerve trunks continue after the striped muscles of the body are paralysed. (5) The lymph-hearts of the frog continue to contract for many minutes after the blood-heart has been paralysed.
§ 556. Apocynin.—In the root of Apocynum cannabinum a non-crystallisable substance, soluble in alcohol and ether, but not soluble easily in water, has been separated and found to have a physiological activity similar to that of the digitalins.[587]
[587] Hardy et Callois, “Sur la matière active du Strophanthus Hispidus ou Inée,” Gaz. Med. de Paris; Pelikan, Compt. Rend., t. 60, p. 1209, 1815; Sharpey, Proc. Roy. Soc., May, 1865; Fagge and Stevenson, Pharm. Journ., p. 11, 1865-66; Fraser, Journ. of Anatom. and Phys., also Proc. of Roy. Soc. of Edin.; Poillo and Carville, Arch. de Physiol. Norm. et Pathol., 1872; G. Valentin, Zeitschr. et. Biologie., x. 133, 1874.
3. NON-CRYSTALLISABLE GLUCOSIDES ALMOST INSOLUBLE IN WATER.
§ 557. Scillain, or Scillitin, a glucoside which has been separated from the bulbs of the common squill. It is insoluble or nearly so in water, but easily dissolves in alcohol. It is little soluble in ether. It acts upon the heart, and is poisonous.
Adonidin, a very similar substance, has been separated from the root of the Adonis vernalis (Nat. Ord. Ranunculaceæ), to which the name of adonidin has been given.[588] It is an amorphous, colourless substance, without odour; soluble in alcohol, but with difficulty soluble in ether and water. It is precipitated by tannin, and on saponification by mineral acids, splits up into sugar and a substance soluble in ether. The effects on animals are identical with those of digitalin. The root has been used recently in medicine, and found to slow the heart and increase the urinary secretion; in this also it is like digitalis.
[588] Cervello, Archiv für exp. Path. Pharm., 1882, p. 338.
§ 558. Oleandrin.—Oleander leaves contain two chemically-different, nitrogen-free substances. The one is probably identical with digitalein; but as this is not certain, Schmiedeberg proposes to call it provisionally neriin. The other active substance is essentially the same as the oleandrin of Lukomske[589] and Betelli.[590] Oleandrin has basic properties, and is separated in the form of an amorphous mass, soluble in alcohol, ether, and chloroform, and slightly soluble in water. Schmiedeberg obtained a third product from African leaves, which he calls nerianthin. This, on treatment with sulphuric acid and bromine, gives a beautiful colour peculiar to oleander leaves. It is very similar in physiological and chemical properties to digitalin, and is probably derived by decomposition from one of the principles already described. There is also a product similar to digitaliresin.
[589] Repert. de Chimie de Wurtz et Bareswill, t. iii. p. 77, 1861.
[590] Bull. Med. di Bologna, t. xix. p. 321, 1865.
The active principles of the oleander are separated by digestion of the leaves with alcohol of 50 per cent., and precipitating the alcoholic extract with lead acetate and ammonia. The first precipitate is yellow, and is probably composed of a tannin-like substance; the next precipitate is white, consisting of the lead compound of neriin. The precipitates are filtered off, and the filtrate concentrated; nerianthin, after a while, separates in light flocks, and the filtrate from this contains some of the other products.
§ 559. Neriin or Oleander Digitalin.—Neriin is, in the presence of much free mineral acid, precipitated by potass-bismuth iodide, a reaction first pointed out by Marmé,[591] as useful in the isolation of the helleborins; or it may be precipitated by tannin, and then the precipitate decomposed by dissolving in alcohol, and evaporating it to dryness with zinc oxide on the water-bath. It is next extracted by absolute alcohol, and precipitated by the addition of much ether. The further purification consists of resolution in alcohol, and fractional precipitation by ether. If, however, the potass-bismuth iodide process is used, the liquid must be acidified strongly with sulphuric acid, and the precipitate washed with diluted sulphuric acid. The precipitate may be decomposed by baryta, filtered, and the filtrate freed from baryta by carbon dioxide; the filtrate from this contains neriin with baric iodide; it is therefore treated with silver sulphate, then again with baryta, next with carbon dioxide, and also with SH2 to get rid of the last trace of silver.
The filtrate will also contain some oleandrin which, by evaporating slowly in a vacuum, separates gradually in the form of a clear, resinous mass. It can be filtered off, and the neriin then may be precipitated pure by fractional precipitation. Its physiological action is the same as that of digitalein.
[591] Zeitschr. f. rat. Med. (3 R.), Bd. xxvi., S. 1, 1866.
§ 560. The nerium oleander has several times caused grave symptoms of poisoning, and they have usually fairly agreed with those produced by foxglove. For example, Maschka[592] relates the case of a boy, two years old, who ate two handfuls of the nerium oleander. The effects commenced in ten minutes, the child was uneasy, and vomited. In six hours a sleepy condition came on; the face was pale, the skin cold, the pupils contracted, and the pulse slow and irregular. After the sickness the boy woke up, but again fell asleep, and this occurred frequently; coffee was given, which appeared to do good. The pulse was intermittent. On the following day the child was still ill, with an intermittent pulse, frequent vomiting, feebleness, sleeplessness, and dilatation of the pupil; there was no diarrhœa, on the contrary, the bowels were confined. On the third day recovery followed.
[592] Vierteljahrsschrift f. gericht. Med., Bd. ii., No. 17, 1860. Brit. and For. Med. Chir. Review, vol. xxvi. p. 523, 1860.
In an Indian case,[593] the symptoms were altogether peculiar, and belonged rather to the convulsive order. A wood-cutter, aged thirty-five, near Kholapore, took, for the purpose of suicide, a little over an ounce of the expressed juice of the oleander. The symptoms began so rapidly that he had not time to walk five yards before he fell insensible; he was brought to the hospital in this state; the face on his arrival was noticed to be flushed, the breathing stertorous, there were violent spasmodic contractions of the whole body, more marked on the left than on the right side. The effect of this was remarkable. During the intervals of the spasm, the patient lay evenly on his back, and when the convulsions commenced the superior contraction of the left side threw him on to the right, in which position he remained during the paroxysm, after the subsidence of which he fell back into his old position. The evacuations were involuntary and watery; the man was insensible, with frequent convulsions of the kind described, for two days, but on the third day became conscious, and made a good recovery.
[593] Transac. of Med. and Phys. Soc. of Bombay, 1859.
In any case of poisoning, the methods by which neriin and oleandrin are separated from the plant can be applied to separate them from the tissues with more or less success. Here, as in all the other digitalin-like glucosides, physiological tests are alone of value in the final identification.
§ 561. The Madagascar Ordeal Poison.—To this group may also belong the poison of the Tanghinia venenifera, a tree in the Island of Madagascar, the fruit of which is used as an ordeal poison. It may be obtained in crystals; it is insoluble in water, and very poisonous. The upas of Singapore is also said to contain with strychnine a glucoside similar to antiarin.
4. SUBSTANCES WHICH, WITH OTHER TOXIC EFFECTS, BEHAVE LIKE THE DIGITALIS.
§ 562. Erythrophlein is an alkaloid, not a glucoside, and is obtained from the bark of the Erythrophlœum guineense (West Africa). It acts on the heart like digitalis, and has also effects similar to picrotoxin.
III.—Saponin—Saponin Substances.
§ 563. The term “saponin” of late years has been applied to a class of glucosides which possess the common property of being poisonous, and, when dissolved in water, forming solutions which froth on shaking like soap-suds.
The substances which have these properties are not all of the same series chemically, but those of the general formula, CnH2n-8O10, are most numerous, and the following is a list:—
Possibly also dulcamarin C22H34O10 and syringen C17H26O10 may belong to this series.
There are some 150 distinct plants which thus yield saponins; a few of these plants are as follows:—Saponaria officinalis, Gypsophila struthium, Agrostemma githago (corn cockle), Polygala senega, Monimia polystachia, the bark of Quillaja saponaria, and Chrysophyllum glycyphleum.
The saponin separated from Saponaria, and from the corn cockle will be here described.
§ 564. Properties.—Saponin is a white amorphous powder, very soluble in water, to which it gives the curious property of frothing just like soap solution. To obtain this effect there must be at least 1 mgrm. in 1 c.c. of liquid. Saponin is neutral in reaction, it has no odour, but causes sneezing if applied to the mucous membrane of the nose; the taste is at first sweet, and then sharp and acrid. It is almost entirely insoluble in absolute alcohol, but dissolves in hot alcohol of 83° to separate again nearly completely on cooling. It is precipitated by basic lead acetate, and also by baryta water, but in each case it is advisable to operate on concentrated solutions. Picric acid, mercuric chloride, and alkaloidal “group reagents” give no precipitate. When a little of the solid substance is treated with “Nessler” reagent, there is a greenish or yellow colour produced. A drop of strong sulphuric acid, mixed with a minute quantity of saponin, strikes slowly a bright red colour, which, on heating, deepens to maroon-brown. Nordhausen sulphuric acid shows this better and more rapidly. If saponin is boiled with dilute acid it breaks up into sapogenin and sugar, and therefore the liquid after neutralisation reduces “Fehling.” This reaction is probably after the following equation:—
2C17H26O10 + 2H2O = 2C8H11O2 + 3C6H12O6.
Sapogenin may be separated by evaporating the neutralised liquid to dryness, treating the dry residue with ether, which dissolves out the sapogenin, and finally recovering the substance from the ethereal solution, and crystallising it from hot alcohol. Crystals are readily obtained if the alcoholic solution is allowed to evaporate spontaneously. A solution of saponin exposed to the air gets turbid, and develops carbon dioxide; not unfrequently the solution becomes mouldy.
§ 565. Effects.—Pelikan[594] has studied the effects of various saponins on frogs. One to two drops of a saturated watery solution of saponin applied subcutaneously to the leg, caused, in from five to six minutes, great weakness, accompanied by a loss of sensibility; but strong mechanical, chemical, or electrical stimuli applied to the foot excited reflex action, for the ischiatic nerve still retained its functions. Nevertheless, from the commencement, the excitability of the poisoned muscles was much weakened, and just before death quite disappeared. Section of the ischiatic nerve delayed the phenomena. Curarine did not seem to have any effect on the poisonous action. A concentrated solution applied to the heart of a frog soon arrests its beats, but weaker doses first excite, and then retard.[595]
[594] Berl. klin. Wochschr., 36, 186.
[595] J. Hoppe, Nervenwirkung der Heilmittel, H. 4, 37.
The author has studied the general action of saponin on kittens, insects, and infusoria. Small doses, such as from 13 to 32 mgrms. (1⁄5 to 1⁄2 grain), were injected beneath the loose skin of the back of the neck of a kitten, when there were immediate symptoms of local pain. In from five to ten minutes the respiration notably quickened, and the animal fell into a lethargic state, with signs of general muscular weakness; just before death the breathing became very rapid, and there were all the signs of asphyxia. The pathological appearances after death were fulness in the right side of the heart, and intense congestion of the intestinal canal, the stomach generally being perfectly normal in appearance, and the kidneys and other organs healthy. The least fatal dose for a kitten seems to be 13 mgrms., or ·04 grm. to a kilogram.[596]
[596] The action of saponin when applied in concentrated solution to flies is that of an intense irritant. There is protrusion of the sucker, and progressive paralysis. The common infusoria live for some time in dilute solutions of saponin—this is also true of some of the higher forms; for example, a Cyclops quadricornis seemed in no way affected by a 2 per cent. solution.
§ 566. Action on Man.—The effects of saponin on man have been but little studied; it has been administered by the mouth in doses of from ·1 to ·2 grm., and in those doses seems to have distinct physiological effects. There is increased mucous secretion, and a feeling of nausea; but neither diaphoresis nor diuresis has been observed. From the foregoing study it may be predicated that 2·6 grms. (40 grains), if administered subcutaneously to an adult, would endanger life. The symptoms would be great muscular prostration, weakness of the heart’s action, and probably diarrhœa. In fatal cases, some signs of an irritant or inflammatory action on the mucous membranes of the stomach and intestines would be probable.
§ 567. Separation of Saponin.—Saponin is separated from bread, flour, and similar substances by the process given at p. 153, “Foods.” The process essentially consists in extracting with hot spirit, allowing the saponin to separate as the spirit cools, collecting the precipitate on a filter, drying, dissolving in cold water, and precipitating with absolute alcohol. In operating on animal tissues, a more elaborate process is necessary. The author has successfully proceeded as follows:—The finely divided organ is digested in alcohol of 80 to 90 per cent. strength, and boiled for a quarter of an hour; the alcohol is filtered hot and allowed to cool, when a deposit forms, consisting of fatty matters, and containing any saponin present. The deposit is filtered off, dried, and treated with ether to remove fat. The insoluble saponin remaining is dissolved in the least possible quantity of water, and precipitated with absolute alcohol. It is also open to the analyst to purify it by precipitating with baryta water, the baryta compound being subsequently decomposed by carbon dioxide. Basic lead acetate may also be used as a precipitant, the lead compound being, as usual, decomposed by hydric sulphide; lastly, a watery solution may be shaken up with chloroform, which will extract saponin. By some one of these methods, selected according to the exigencies of the case, there will be no difficulty in separating the glucoside in a fairly pure state. The organ best to examine for saponin is the kidney. In one of my own experiments, in a cat poisoned with a subcutaneous dose of saponin (·2 grm.), evidence of the glucoside was obtained from the kidney alone. The time after death at which it is probable that saponin could be detected is unknown; it is a substance easily decomposed, and, therefore, success in separating it from highly putrid matters is not probable.
§ 568. Identification of Saponin.—An amorphous white powder, very soluble in water, insoluble in cold alcohol or ether, having glucosidal reactions, striking a red colour with sulphuric acid, imparting a soap-like condition to water, and poisonous to animals, is most probably a saponin.