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Picrotoxinum (U. S. P.)—Picrotoxin.

[image:12519 align=left hspace=1]Preparation: Ointment of Cocculus Indicus

"A neutral principle obtained from the seed of Anamirta paniculata, Colebrooke"—(U. S. P.). (Anamirta Cocculus, Wight and Arnott; Menispermum Cocculus, Linné; Coccus suberosus, De Candolle.)
Nat. Ord.—Menispermaceae.

[image:12520 align=right hspace=1]Botanical Source and History.—The seeds furnishing this body are known as Cocculus indicus (Fructus cocculi), Fishberries or Indian berries. The plant furnishing them is a strong, climbing shrub, with a corky, ash-colored bark, with deep cracks or fissures. The leaves are dense, smooth, shining, coriaceous, roundish, acute, very slightly cordate, if at all, sometimes truncate at the base, with 5 digitate ribs, about 6 inches long, and as many broad. The stalks are a little shorter than the leaves, tumid at both ends, especially the lower. Flowers dioecious; the female flowers being in lateral compound racemes. The calyx is composed of 6 sepals in a double series, with 2 closely-pressed bractioles. The stamens are united into a central column dilated at the apex. Anthers numerous, covering the whole globose apex of the column. The drupes, from 1 to 3 in number, are globose, 1-celled and 1-seeded. The seed is globose and deeply excavated at the hilum. Albumen fleshy. Cotyledons very thin, linear-oblong, distant, diverging, and very membranous (L.—W.—A.).

Cocculus indicus inhabits Malabar, the Eastern Islands, etc., of India. Other plants, especially the Coccus lacunosus of Celebes and the Molucca Isles, and a Malabar species, Cocculus plunkenetii, are stated by some authors to furnish a portion of commercial fishberries.

THE FRUIT (Fructus cocculi).—The fruit, as met with in commerce, consists of a dry, light, roundish nut, nearly 1/2 inch in diameter, of a grayish-black color, wrinkled, inodorous, subreniform, and composed of an external, slightly bitter shell or layer, beneath which is a white, thin, ligneous endocarp, containing an oleaginous, whitish-yellow, odorless, but intensely bitter nucleus or seed of a semilunar form, within which arises a central placenta contracted at the base, but enlarged and divided into two cells superiorly.

Preparation of Picrotoxin.—According to Prof. E. Schmidt (1883), the grains, coarsely powdered, are deprived of most of their fatty oil by warm pressure, boiled out with water, the solution precipitated with lead acetate, filtered, the lead removed from the filtrate by means of hydrogen sulphide, the liquid again filtered and evaporated to crystallization. The crude picrotoxin is recrystallized from water and strong alcohol. Picrotoxin may also be extracted by means of alcohol or petroleum ether. (For Wittstein's process, see details in this Dispensatory, preceding editions. The yield according to this process is 1 ounce or 1 1/2 ounces from 8 pounds of berries, or about 1.2 per cent.)

Chemical Composition.—The husk of cocculus grains contains two isomeric, non-poisonous, non-bitter, crystallizable alkaloidsmenispermine and para-menispermine (C18H24N2O2, Pelletier and Couerbe, 1834). The former is soluble in ether, the latter insoluble. Both are insoluble in water, but soluble in warm alcohol. Menispermine is also soluble in diluted acids, forming well-crystallizable salts; it melts at 120° C. (248° F.). The husk also contains a yellow resin, fat, wax, chlorophyll, and the problematical hypo-picrotoxic acid of Pelletier and Couerbe, insoluble in boiling water and ether, readily soluble in alkalies with brown color.

The seeds, or nuclei, of cocculus grains contain resin, gum, starch, and large amounts of fat (23.6 per cent, Römer, 1882), of which more than one-third consists of free fatty acid, principally stearic acid. The seeds also contain the very poisonous, bitter principle, picrotoxin (C30H34O13, Schmidt and Loewenhardt; Paterno and Oglialoro, 1881; picrotoxic acid of Pelletier and Couerbe), which was first isolated by P. Boullay (1812). It is accompanied by the crystallizable, tasteless cocculin or anamirtin (C19H26O10, E. Schmidt and E. Loewenhardt, 1884), crystallizable from hot water, insoluble in alcohol and ether.

The chemical composition of picrotoxin agrees best with the formula C30H34O13. Barth and Kretschy (1884) asserted that picrotoxin is not a uniform body, being a mixture of the poisonous picrotoxinin (C15H16O6) and the bitter, non-poisonous picrotin, separation being effected by boiling with benzol, in which picrotoxinin is soluble, picrotin very little soluble. Schmidt and Loewenhardt (Jahresb. der Pharm., 1883-84, p. 774), on the other hand, maintained that picrotoxin is a definite body, being decomposed by boiling benzol into the constituents named, as follows: C30H34O13 (picrotoxin) = C15H16O6 (picrotoxinin) + C15H18O7 (picrotin). Quite recently, Richard Joseph Meyer succeeded in obtaining picrotoxin, with all its characteristics synthetically, by the mere crystallization of a mixture of 2 molecules of picrotoxinin and 1 molecule of picrotin, and concludes that picrotoxin is a mixture of picrotoxinin (C15H16O6+H2O) and picrotin (C15H18O7) in the approximate proportion of 2 molecules of the former and 1 molecule of the latter (Berichte der Deutsch. Pharm. Ges., 1897, p. 16). He has also shown that the molecular weight of picrotoxin, as determined by the kryoscopic method, is only one-third of that represented by the formula C30H34O13; that the above decomposition is not equimolecular, but picrotin invariably forms only one-third of the picrotoxin employed.

Description and Tests.—Picrotoxin is officially described as forming "colorless, flexible, shining, prismatic crystals, or a micro-crystalline powder; odorless, and having a very bitter taste; permanent in the air. Soluble, at 15° C. (59° F.), in 240 parts of water, and in 9 parts of alcohol; in 25 parts of boiling water, and in 3 parts of boiling alcohol; also soluble in solutions of the alkalies, and in acids. Very slightly soluble in ether or chloroform"—(U. S. P.). It is also soluble in amyl alcohol and glacial acetic acid. "Picrotoxin is neutral to litmus paper. When heated to 200° C. (392° F.), picrotoxin melts, forming a yellow liquid, and upon ignition it is consumed, leaving no residue. Concentrated sulphuric acid dissolves picrotoxin with a golden-yellow color, very gradually changing to reddish-brown, and showing a brown fluorescence. On mixing about 0.2 Gm. of powdered sodium nitrate with 3 or 4 drops of sulphuric acid, in a small, flat-bottomed capsule, sprinkling a minute quantity of picrotoxin over it, and then adding, from a pipette, concentrated solution (1 in 4) of sodium hydrate, drop by drop, until it is in excess, the particles of picrotoxin will acquire a brick-red to deep-red color, which fades after some hours. On diluting 2 Cc. of alkaline cupric tartrate V.S. with 10 Cc. of water, and adding a small portion of picrotoxin, red cuprous oxide will be separated within half an hour at ordinary temperatures, and much more rapidly upon the application of heat. The aqueous solution of picrotoxin should remain unaffected by mercuric or platinic chloride T.S., tannic acid T.S., mercuric potassium iodide T.S., or other reagents for alkaloids (absence of alkaloids)"—(U S. P.).

The fact that picrotoxin may be shaken out from acidulated aqueous liquids by means of ether or amyl alcohol, facilitates its detection in certain articles of food, e. g., beer, to which it has been fraudulently added in order to impart bitterness to it. Flückiger (Pharmacognosie, 3d ed., 1891, p. 790) recommends evaporating the sample to dryness with calcined magnesia, extracting with alcohol, dissolving the evaporated alcoholic extract with hot distilled water, acidulating with sulphuric acid, and shaking out with ether; recrystallize from water, and apply the tests for picrotoxin as given above.

Action, Medical Uses, and Dosage.—Cocculus indicus is occasionally given internally, though very poisonous. Given to animals it acts on the cerebro-spinal system, causing giddiness, staggering, tetanic convulsions, and coma. It also produces gastric irritation. The powder, or an ointment, has been applied in barber's itch, scald-head, itch, and other unyielding diseases of the skin, as well as to kill lice. Given to fish, it poisons them, depriving them of sensibility, and has been used for the purpose of catching them. Extraordinary claims have been made by Planat for cocculus, as an agent in spasmodic disorders, including epilepsy, infantile convulsions, chorea, etc. Others, however, claim that it aggravates, at least in epilepsy. It has likewise been employed in paralysis of the sphincters and limbs. By some physicians, cocculus and picrotoxin, in minute doses, are recommended in disorders for which strychnine and nux vomica are employed. It is also an antagonist to these drugs, and may be used in cases of poisoning by them. Nervous debility, paresis, mild forms of paralysis, facial paralysis, paralysis agitans, and alcoholic tremor are conditions in which minute doses have rendered good service. Spasms of the muscles of locomotion, with cold skin and deficient capillary circulation, are said to be benefited by cocculus. It has also been advised in gastric atony and intestinal dyspepsia, with torpor of the parts involved. Dr. John Fearn recommends 2-grain doses of the 3 x trituration as a certain remedy for profuse sweating. It has been endorsed by others as exceedingly efficient in night-sweats, the above doses being given every 2 hours, in the evening, for 3 or 4 days. An attenuation of cocculus, as employed by Homoeopaths, is an efficient remedy to prevent the nausea and sickness incident to travel by rail and upon water (sea-sickness). The dose of picrotoxin ranges from 1/150 to 1/64 grain.

King's American Dispensatory, 1898, was written by Harvey Wickes Felter, M.D., and John Uri Lloyd, Phr. M., Ph. D.

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