Podophyllum. U. S. (Br.) Podophyllum. Podoph. [Mandrake, May Apple Rhizome]

Related entry: Indian Podophyllum

"The dried rhizome and roots of Podophyllum peltatum Linné (Fam. Berberidaceae), yielding not less than 3 per cent. of resin." U. S. "Podophyllum Rhizome is the dried rhizome and roots of Podophyllum peltatum, Linn." Br.

Podophylli Rhizoma, Br.; Podophyllum Root, Wild Mandrake, Devil's Apple, Umbrella Plant, Vegetable Calomel, Mandrake, American Mandrake, Wild Lemon, Ground Lemon, Hog Apple, Indian Apple, Raccoon Berry, Duck's Foot, Rhizome de Podophyllum, Fr. Cod.; Fuss-blattwurzel, G.; Podofillo, It.; Podofilo (Rizoma de), Sp.

Podophyllum peltatum (May-apple) is an indigenous herbaceous plant. The rhizome is perennial, creeping, usually several feet in length, about one-quarter of an inch thick, brown externally, smooth, jointed, and furnished with roots at the joints. The stem is about a foot high, erect, round, smooth. The basal leaves are centrally peltate, with six or seven wedge-shaped lobes, irregularly incised at their summits, yellowish-green on their upper surface, paler and slightly pubescent beneath. The flower-bearing stems bear from one to three similar leaves. The flower is nodding, and appears between two leaves at the apex of the stem or at the base of the upper leaf when three leaves are present. The calyx is composed of three oval, obtuse, concave, deciduous sepals. The corolla has from six to nine white, fragrant petals, which are obovate, obtuse, concave, with delicate transparent veins. The stamens are from thirteen to twenty, shorter than the petals, with oblong, yellow anthers, of twice the length of the filaments. The stigma is sessile, and rendered irregular on its surface by numerous folds or convolutions. The fruit is a large oval berry, crowned with the persistent stigma, and containing a sweetish fleshy pulp, in which about twelve ovate seeds are embedded. It is, when ripe, of a lemon-yellow color, diversified by round brownish spots. Two species of the genus Podophyllum are known as growing in China while Podophyllum Emodi, which inhabits the interior ranges of the Himalayas and is very abundant in Cashmere, is recognized in the Br.

The plant has been found on Mount Togakushi, in Japan, and is extensively diffused through the Eastern United States, growing luxuriantly in moist shady woods and in low marshy grounds from Canada, to Minnesota and southward to Florida and Texas. It is propagated by its creeping rhizome, and is often found in large patches. The flowers appear about the end of May and the beginning of June, and the fruit ripens in the latter part of September. The leaves are said to be poisonous. The fruit has a subacid, sweetish, peculiar taste, agreeable to some palates, and may be eaten freely with impunity. From its color and shape, it is sometimes called wild lemon. The rhizome is the official portion, and is said to be most efficient when collected after the falling of the leaves. It shrinks considerably in drying.

Properties.—The dried rhizome is much wrinkled lengthwise, is yellowish or reddish-brown externally, and furnished with roots of a similar but somewhat paler color. It was determined, by an experiment of Wm. Saunders, that these roots contain as much active matter as the rhizome itself. It is officially described as follows: "Rhizome horizontal, nearly cylindrical, jointed, compressed on the upper and lower surfaces, sometimes branched; in pieces from 3 to 20 cm. in length, the intemodes from 2 to 9 mm. in diameter; externally dark brown, longitudinally wrinkled or nearly smooth with irregular, somewhat V-shaped scars of scale leaves, nodes annulate, upper portion marked with large, circular, depressed stem-scars and sometimes with buds or stem-bases; at or near the nodes on the lower portion occur numerous root-scars or roots from 2 to 7 cm. in length and about 2 mm. in thickness; fracture short; internally, bark light brown, wood with small yellowish, vascular bundles, pith large and white; odor slight; taste sweetish, disagreeably bitter and acrid. Under the microscope, a transverse section of the rhizome of Podophyllum show's an outer layer of one or two rows of reddish-brown cells; parenchyma of cortex and pith with numerous single, spherical, polygonal, or 2- to 6-compound starch grains, or rosette aggregates of calcium oxalate; vascular bundles from 24 to 34, arranged in a circle between cortex and pith. The powder is light brown, with a pronounced and characteristic odor; starch grains numerous, spherical, polygonal or 2- to 6-compound, the individual grains from 0.003 to 0.015 mm. in diameter; calcium oxalate crystals few, in rosette aggregates from 0.05 to 0.08 mm. in diameter and occasionally in raphides from 0.03 to 0.09 mm. in length; tracheae with simple pores or reticulate thickenings; fragments of starch-bearing parenchyma and reddish-brown cork cells. Podophyllum yields not more than 3 per cent. of ash.

"Rhizome nearly cylindrical, of very variable length, usually about five millimetres thick; dark reddish-brown, smooth or only slightly wrinkled; enlarged at intervals of about five centimetres, the upper surface of each enlargement being marked by a depressed circular scar, below which, on the under surface, are rather stout, brittle, brown roots, or the scars corresponding to them. In transverse section, either nearly white and starchy, or pale yellowish-brown and horny. Characteristic odor; taste slightly bitter and acrid." Br.

The root in its aggregate state is nearly inodorous, but in powder has a sweetish not unpleasant odor. The taste is at first sweetish, afterwards bitter, nauseous, and slightly acrid. Both the decoction and the tincture are bitter, but alcohol is said to be the best solvent of the active matter. V. Podwyssotzki (Ph. Z. R., Bd. xx, 777) announced the active principle to be solely a neutral crystalline principle, picropodophyllin. This principle is associated with an inactive resin-acid, picropodophyllic acid, and the combination of the two he named podophyllotoxin. Picropodophyllin is in colorless, silky, extremely delicate needles, very soluble in chloroform, readily soluble in 95 per cent. alcohol, but very slightly in 75 per cent. alcohol. It is soluble in ether, and crystallizes from a warm saturated solution on cooling. It is insoluble in water, turpentine, or benzin. Podophyllotoxin is a bitter, white, resinous powder, soluble in weak alcohol and hot water. It may be precipitated from its alcoholic solution by water in large quantity. (P. J., 1882, 1011.) Podwyssotzki also obtained podophylloquercetin, the coloring principle, which is closely allied to quercetin and is the cause of the varying color of resin of Podophyllum. His results have since been corrected and supplemented by R. Kürsten (A. J. P., 1891, 485), who has obtained the several principles in a purer state. The results of Kürsten's investigation are as follows: The podophyllotoxin prepared by Podwyssotzki's method was not constant in composition, and its melting point varied from 100° to 125° C. (212°-257° F.); further, the podophyllic acid of that author is composed mainly of a crystallizable, active, but very impure substance.

Podophyllotoxin, C23H24O9, is obtained by extracting the coarsely powdered rhizome with cold, light petroleum, until freed from fat; after drying in the air, the extraction is continued with chloroform, until the liquid comes away almost free from yellow color. As it is not possible to work with alcohol-free chloroform, too prolonged extraction with chloroform would yield a more impure extract. The chloroform extract is distilled and the residue is dried over a not too warm water bath, partially dissolved in benzene, filtered, and the filtrate allowed to remain from three to eight days, when a brownish-yellow mass of well-formed, thick, strongly refractive prisms is produced. This is purified by washing with a 50 per cent. alcohol, then with ether, recrystallizing first from boiling benzene, and finally from solution in hot 45 per cent. alcohol; the compound is thus obtained in long, well-formed prisms which melt at 94° C. (201.2° F.).

Podophyllotoxin, when oxidized in an alkaline solution in the cold by means of potassium permanganate, yielded, besides a little carbonic anhydride and a brown amorphous substance, principally two compounds, the more considerable of which was podophyllic acid, obtained as well-formed, colorless crystals from solution in a mixture of benzene and alcohol. The compound is without action on animals. It melts at from 158° to 160° C.(316.4°-320° F.). Its aqueous solution, neutralized with aqueous potassium hydroxide, gives no precipitate with gold, calcium, or barium chlorides; silver nitrate gives a white precipitate, soluble in much water; copper acetate gives a blue precipitate. The copper salt was prepared as beautiful light green prisms and analyzed.

Picropodophyllin results from the action of alkalies on podophyllotoxin; thus, on heating the latter with aqueous ammonia, a well-crystallized product is obtained, which at first was recrystallized from strong alcohol; but this was found to be unnecessary, as the melting point, 227° C. (440.6° F.), was not affected by it. Picropodophyllin has the same composition as podophyllotoxin, but they differ in melting point and in their action on polarized light,—the former inactive, the latter laevo-rotatory; the former is less soluble in all liquids than the latter; the latter gives Millon's reaction, the former does not. By oxidation and reduction the two compounds yield the same products.

Dunstan and Henry (Proc. Chem. Soc., March, 1898) find that the constituents of the Indian Podophyllum (Podophyllum Emodi) and of the American Podophyllum (Podophyllum peltatum) are identical. The chief constituent is the podophyllotoxin of Podwyssotzki and Kiirsten. It is strongly laevorotatory, and acts as a powerful purgative and intestinal irritant. They found that when heated with alkalies, it is converted by hydration into the salt of an unstable gelatinous acid, podophyllic acid, C15H16O7, of which several salts were obtained and analyzed. This acid very readily loses water, and furnishes the crystalline picropodophyllin of Podwyssotzki and Kürsten, which is isomeric with podophyllotoxin. It passes again into podophyllic acid when warmed with aqueous alkalies. Podophyllotoxin and picropodophyllin furnish identical decomposition products; when oxidized with nitric acid, oxalic acid is the principal product; when fused with alkalies, orcinol and acetic acid are produced. Both substances contain three methyl groups and no hydroxyl. It is likely that picropodophyllin is the lactone of podophyllic acid. Picropodophyllin is therapeutically inactive. The yellow coloring matter of Podophyllum, called by Podwyssotzki podophylloquercetin, was proved by the authors to be identical with quercetin, the yellow coloring matter of quercitron bark. An uncrystallizable resin, podophylloresin, was also isolated and found to exert a purgative action. A fatty oil has been separated from the rhizome of Podophyllum by Dohme and Engelhardt. (See Proc. A. Ph. A., 1904, 340.) Gordin and Merrell (Proc. A. Ph. A., 1902, 343) proposes to judge of the quality of resin of Podophyllum by an assay based on the percentage of crude picropodophyllin and the following requirements: Pure podophyllin must be completely soluble in about twice its weight of cold alcohol. 2. It should contain about 64 per cent. ether-soluble and about 74 per cent. chloroform-soluble matter. 3. It should yield about 22 per cent. crude picropodophyllin when assayed by the method described by them.

Manlius Smith recommended that the resin should be prepared by forming an alcoholic tincture of the root, evaporating the tincture until most of the alcohol is driven off, and throwing the residue into water, by which the resin is precipitated. The concentration should not be carried too far, as otherwise the resin separates in clots, which cannot be easily washed. According to Smith, the resin, when pure, is white, and purges actively. It has been called Podophyllin for many years. (A. J. P., xxiv. 306. See Resina Podophylli.) The proportion of resin contained in the root of the P. peltatum appears to vary very much, the variation possibly depending upon the season of the year at which the drug has been gathered. John Barclay (P. J., 1903, Feb., 164) obtained a percentage of 1.6 to 3.86 per cent., stating that these figures were confirmed by the results of the manufacturers of Podophyllin on a large scale, but J. C. Umney states that in five years' experience working with batches of 1000 pounds, the rhizome averaged a yield of 6.6 per cent. Both observers noticed that the Indian rhizome (P. Emodi) contains a much larger proportion of resin, the average according to Umney being 11.4 per cent. How far the proportion of podophyllotoxin varies in the different rhizomes does not seem to have been determined. (See B. B. Dott, P. J., 1903, Mar. 460.) (P. J., 1911, lxxxvii, p. 156.)

From the leaves of P. peltatum Thos. J. Husband, Jr., obtained berberine and a resin which was free from purgative properties, 8 grains producing no other effect than slight headache. (A. J. P., 1869.)

B. F. Carter (A. J. P., 1886, p. 449) also examined the leaves. He found tannin, uncrystallized sugar, coloring matter, and 6 per cent, of resin. This latter seems to be of twofold character, ether dissolving the soft resin, while the hard resin remains behind. The resin has a bitter taste and a much milder action than that of the rhizome. Fused with potassium hydroxide a small amount of protocatechuic acid seems to be formed.

A method of assay for Podophyllum has been proposed by W. M. Jenkins (J. I. and, E. C., 1914, p. 671) which is based upon a shaking out method using a mixture of chloroform and alcohol.

Uses.—Podophyllum is a slow but active and certain cathartic producing copious liquid discharges often with much griping. It has been attributed with cholagogic properties and is used in various forms of hepatic torpor but its virtues in this direction are probably no greater than that of other active purgatives. In small doses it is frequently used in chronic constipation, especially in conjunction with aloes or cascara.

In overdoses Podophyllum acts as an irritant poison; an amount estimated at five grains of the resin caused death in a woman sixty years old (N. Y. M. E., April, 1890); the symptoms were vomiting and purging, followed some hours after their cessation by coma, full soft pulse, slight elevation of temperature, and haemoglobinuria.

Dose, five to ten grains (0.32-0.65 Gm.), but it is rarely exhibited in the crude form.

Off. Prep.—Fluidextractum Podophylli, U. S.; Resina Podophylli, U. S. (Br.); Tinctura Podophylli (from Resin), Br.; .Extractum Podophylli, N. F.; Pilulae Aloes et Podophylli Compositae (from Resin), N. F.; Pilulae Aloes, Hydrargyri et Podophylli (from Resin), N. F.; Pilulae Aloini Compositae (from Resin), N. F.; Pilulae Catharticae Vegetabiles (from Resin), N. F.; Pilulae Colocynthidis et Podophylli (from Resin), N. F.; Pilulae Laxativae Post Partum (from Resin), N. F.

The Dispensatory of the United States of America, 1918, was edited by Joseph P. Remington, Horatio C. Wood and others.