Podophyllum (U. S. P.)—Podophyllum.

Fig. 201. Podophyllum peltatum; with rhizome and fruit. Photo: Podophyllum peltatum 2. Preparations: Extract of Podophyllum - Fluid Extract of Podophyllum - Pills of Podophyllum, Belladonna, and Capsicum - Compound Powder of Mandrake - Tincture of Podophyllum
Related entry: Resin of Podophyllum

"The rhizome and rootlets of Podophyllum peltatum, Linné"—(U. S. P.).
Nat. Ord.—Berberideae.
COMMON NAMES: May apple, Mandrake, Wild lemon, Raccoon-berry, Wild mandrake, etc.
ILLUSTRATIONS: Bentley and Trimen. Med. Plants, 17, Johnson, Med. Bot. of N. A., Plate 1.

Botanical Source.—May apple is an indigenous, perennial herb, with a long, jointed, dark-brown rhizome or root, about half the size of the finger, spreading extensively in rich grounds in which it is introduced, and giving off fibers at the joints; internally, it is yellowish. The stem is simple, round, smooth, erect, dividing at top into 2 round petioles, from 3 to 6 inches long, each petiole supporting a leaf; is about a foot high, and invested at its base by the sheaths which covered it when in bud. The leaves are large, peltate-palmate, oftener cordate, in from 5 to 9 wedge-shaped lobes, each lobe 6 inches long from the insertion of the petiole, 2-lobed and dentate at the apex; smooth, yellowish-green on the upper surface, paler and slightly pubescent beneath. In barren stems which support but one leaf, the peltate character is the most perfect. The flower is solitary in the fork of the stem, on a round, nodding peduncle, 1 to 2 inches long, white, large, about 2 inches in diameter, and somewhat fragrant. The calyx consists of 3 oval, obtuse, concave, caducous sepals, which cohere in the bud by their scarious margins. The corolla is composed of from 6 to 9 white, obovate, obtuse, smooth, concave petals, curiously netted with slight, transparent veins. Stamens from 9 to 20, shorter than the petals, curving upward, with yellow, oblong anthers twice as long as the filaments, not opening by perfect uplifted valves. Ovary oval, compressed, and obscurely angular. Stigma subsessile, convex, its surface rendered irregular by numerous folds and convolutions. The fruit is fleshy, ovoid-oblong, 1-celled, 1 or 2 inches in length, of a lemon color, with brownish spots when ripe, and crowned with the large, persistent stigma; the flavor of the mucilaginous pulp is somewhat similar to that of a strawberry, and incloses 12 seeds in pulpy arils (L.—W.—G.). (For paper on microscopical structure of the rhizome of podophyllum, by Prof. E. S. Bastin, see Amer. Jour. Pharm., 1894, p. 417.)

History.—Intimately associated with the progress of Eclecticism is the drug, podophyllum and its resin, podophyllin. The introduction of the latter to the medical profession by Prof. John King, who first prepared it and indicated its therapy at a time when improved and reliable pharmaceuticals were most urgently demanded, and when the introduction of indigenous remedies that could be administered in small doses, freed from extraneous and inert materials, with certain and definite results, was a necessity, marks an epoch in the history of Eclectic medicine. Podophyllum was one of the earliest favorites of our school of practice, and before the introduction of podophyllin, was much more extensively employed than at present. By many, in the treatment of certain disorders, its use is still preferred to that of its resin.

This plant, which grows abundantly from Canada to Florida, and throughout the middle and western states, is one of the most attractive of our medicinal plants. It is said to be scarce in the New England states. In the middle states, it is familarly known as Mandrake, and farther west as the May apple. It has also borne the names of Wild mandrake and Mayflower, and, on account of its fruit, Raccoon-berry, Indian apple, and Wild lemon. The name podophyllum is derived from two Greek terms—poys, foot; phyllon, leaf—either on account of its resemblance to the webbed foot of some aquatic bird, or in allusion to its long, firm stalk, which bears the leaves. Making their appearance in the early spring, the conical shoots may be seen piercing the ground in large patches, and, in a short time, expanding into wide-spread, umbrella-like leaves, which almost completely hide the ground beneath them. The plant is found growing in rich, moist soil, along the border of woodlands and on the banks of streams, as well as in low meadows and marshy situations. The rhizomes occur in great abundance, from 1 to 2 inches underneath the surface of the soil. May apple is hardy and will thrive in fence corners of cultivated fields, often resisting the advance of agricultural improvements, when other common fence-weeds have been exterminated. It is not, as is the case with many other valuable medicinal plants, likely to be very soon eradicated.

The creeping rhizome, which often attains a length of 1 to 6 feet, and is about one-fifth of an inch in thickness, sends up a stem to the height of about 1 foot. This stem then forks at the top and each petiole so created bears a single peltate leaf of palmate variety, having 6 or 7 lobes. Flowerless plants have only 1 leaf, generally centrally peltate, with from 7 to 9 lobes. In the fork of the stem the flower appears-a single, fragrant, beautiful, waxy-white blossom, about 2 inches wide. The flowers are eagerly sought for by the children of cities, and on account of their beauty and delightful fragrance, find ready purchasers among the lovers of "wild beauties." The bloom, which appears in May, hence the names May flower and May apple, is followed in August and September by a small, yellowish-green, lemon-like, succulent berry, about the size of a plum. Its flavor is agreeable to many persons, and its taste is sub-acid and sweetish. It may be eaten with impunity, though all other parts of the plant produce pronounced physiological effects. It is, however, slightly laxative, and possesses diuretic properties. The young shoots, it is said, were used by the aborigines for suicidal purposes. Like most drugs of the order Berberideae, podophyllum has a bitter, acrid taste. Its therapeutic activity is due to a resinous principle of a compound nature, known as podophyllin (see Resina Podophylli). The root was well known to the Indians as an active cathartic; the proper time for collecting it is in the latter part of October, or early part of November, soon after the ripening of the fruit. The medicinal properties of the leaves are not satisfactorily determined, though by some deemed poisonous (see Chemical Composition).

Podophyllum has been extensively used in domestic practice, oftentimes to the detriment of the patient. The Cherokee Indians, according to Rafinesque, employed the "fresh juice of the root for deafness, putting a few drops of the juice in the ear." Settlers learned from the Wyandottes, that roasting the root deprived it somewhat of its drastic qualities. The famous "Indian Doctor" Hough recommended the "powdered root as an escharotic to cleanse foul and ill-conditioned ulcers, and to dispose them to heal and to promote the exfoliation or removal of carious or rotten bones." The powder was sprinkled on the parts once, and again, if necessary, in from 2 to 5 days. In domestic veterinary (?) practice, which often amounts to barbarity, the drug was employed to cure poll-evil in horses, the root being plunged into the sore and allowed to remain several days. Both Bigelow and Eberle praised the purgative qualities of this drug.

Description.—The U. S. P. thus describes the root: "Of horizontal growth, consisting of joints about 5 Cm. (2 inches) long, flattish, cylindrical, about 5 Mm. (1/5 inch) thick, but somewhat enlarged at the end, which has a circular scar on the upper side, a tuft of about ten, nearly simple, fragile roots, on the lower side, and is sometimes branched latterly; smooth or somewhat wrinkled, orange-brown, internally white and mealy, with a circle of small wood-bundles; pith large; nearly inodorous; taste sweetish, somewhat bitter and acrid "—(U. S. P.). It is readily reduced to a grayish powder, having somewhat the odor of ipecacuanha, and breaks with a short fracture. Its active principles are readily taken up by alcohol, or ether; water takes up only a portion of its activity.

Chemical Composition.—The active principle of the root is a resinous body, soluble in alcohol and practically insoluble in cold water. It was discovered by Dr. John King, in 1844 (see historical notes, by J. U. Lloyd, Amer. Jour. Pharm., 1890, p. 242), and named by him "Resin of Podophyllum." It was afterward known as podophyllin (also see Resina Podophylli). Mr. John R. Lewis (ibid., 1847 165) found, in addition, gum, starch, albumen, gallic acid, fixed oil, etc. Prof. F. B. Power (Proc. Amer. Pharm. Assoc., 1877, p. 420) disproved the statement of Prof. F. F. Mayer (1863) that berberine and saponine occur in the root. The resin of podophyllum was thoroughly investigated by Podwissotzky (see Prof. F. B. Power's abstract in Amer. Jour. Pharm., 1882, pp. 102-115). According to this authority, the resin may be differentiated by ether into the insoluble, inert brown resin podophyllic acid, which is also insoluble in petroleum ether and water, soluble in alcohol and chloroform; and the soluble active principle, podophyllotoxin. This substance is a white, resinous, amorphous powder, very bitter, of slightly acid reaction, soluble in diluted alcohol and hot water, completely soluble in chloroform, also soluble in ether when free from the aforenamed podophyllic acid. It is insoluble in petroleum ether; hence pure podophyllotoxin may be obtained by treating a chloroformic extract of the rhizome with ether, and precipitating the ethereal solution with petroleum benzin, which keeps fatty matters dissolved. Both chloroform and ether must be alcohol-free, as far as possible, otherwise the podophyllotoxin will be contaminated with the yellow crystallizable coloring matter, podophyllo-quercetin, which is soluble in alcohol, ether and alkaline solutions, sparingly soluble in chloroform, insoluble in water. It produces a dark, greenish-brown coloration, with ferric chloride. R. Kürsten (Archiv der Pharm., 1891, p. 220) obtained 0.2 per cent of podophyllotoxin in well-defined crystals melting at 93° to 95° C. (199.4° to 203° F.) and having the composition, C23H24O9+2H2O. Podophyllotoxin, according to Podwissotzky, is not a uniform body, but is a mixture of inert, resinous picropodophyllic acid and the cathartic, crystallizable, bitter principle picropodophyllin, the latter being held in solution by the former and falling out when the solvent is neutralized by an alkali. From the filtrate the acid is precipitated upon the addition of mineral acid. Picropodophyllin, the active principle, crystallizes in silky needles, and is a neutral body. It shares in general the solubilities of podophyllotoxin except that it is insoluble in water. For this reason Podwissotzky prefers the more soluble podophyllotoxin as a therapeutic agent. Picropodophyllin is soluble in 90 to 95 per cent alcohol, but hardly soluble in alcohol of 50 to 80 per cent. It also dissolves readily in glacial acetic acid. By warming its alcoholic solution or evaporating this solution with excess of ammonia, it is converted into an inert, amorphous, acid substance.

Podophyllotoxin was found by Dunstan and Henry (see Amer. Jour. Pharm., 1898, p. 246) to be the active principle of both the Indian and American podophyllum, but these authors consider it to be a well-defined body of the composition C15H14O6, which differs from the formula arrived at by Kürsten (1891). It is strongly laevo-rotatory, and acts as a powerful purgative and intestinal irritant. When heated with alkalies it takes water and is converted into the salt of an unstable gelatinous acid (podophyllic acid, C15H26O7). This readily loses water again, being converted into the crystalline picropodophyllin of Podwissotzky, which, as Kürsten (loc. cit.) has ascertained, is an isomer of podophyllotoxin. Warming with aqueous alkalies again converts it into podophyllic acid. Picropodophyllin is claimed by Dunstan and Henry to be therapeutically inert. An uncrystallizable resin, podophylloresin was also isolated and found to be purgative.

The leaves of Podophyllum peltatum were analyzed by T. J. Husband (Amer. Jour. Pharm., 1860, p. 200), who states that they are devoid of cathartic properties, and, when dried, are probably non-poisonous. B. F. Carter (ibid., 1886, p. 449) collected leaves soon after flowering and found them to contain 6 per cent of a greenish-black bitter resin, all of which was soluble in alkali and alcohol, 90 per cent being soluble in ether, a hard resin remaining; 86 per cent in chloroform, 40 per cent in petroleum benzin, etc., and a considerable quantity being soluble in boiling water. This resin seems to exert a milder action than that from the rhizome.

Action, Medical Uses, and Dosage.—Physiologically podophyllum acts as a certain, but slow cathartic. Small and repeated doses short of catharsis may induce ptyalism; on this account both podophyllum and podophyllin have been called "vegetable mercury" and "vegetable calomel." Under the influence of a cathartic dose, the intestinal and hepatic secretions are augmented and after a considerable time copious alvine evacuations result. Considerable pain and griping may attend its action, which, however, may be modified by such agents as leptandra, hyoscyamus and belladonna. Common salt increases its purgative power. Unlike other cathartics, its effects are permanent and leave the bowels in an improved condition. If the dose be too large, violent emeto-catharsis may result . Although the cholagogue value of this drug was asserted by our practitioners for years, it took extensive physiological investigations, conducted by Rutherford and Vignal, to convince our regular friends that it really possessed such a property. The green root internally administered, acts as an irritant poison, causing hypercatharsis, hyperemesis, gripings, and other unpleasant symptoms; even the recently dried root, in doses of from 30 to 60 grains, is a drastic cathartic and emetic; but the violence of its action is materially modified by age, or roasting. Either the green or the dried root continuously applied to the cutaneous structure, occasions irritation, followed by suppuration. Irritation of the mucous membrane is the result of contact with the powder, and workers in this drug and its resin are liable to conjunctival inflammation. Overdoses of podophyllum have produced death, and the drug, when contraindicated, may give rise to prolonged gastro-intestinal irritation and even inflammation. As a cathartic, very little tormina is produced by it when compared with the completeness of its purgative action. It acts somewhat like jalap, though more slowly. To render its hydragogue, it should be administered with potassium bitartrate on which account it has been found serviceable in dropsical affections.

Podophyllum may be used in nearly all cases in which podophyllin is useful, though there are some conditions where the former gives better results than the latter. These conditions we will briefly notice. It is conceded that as an alterative it is infinitely more decided in its action than the resin. It exerts a powerful influence upon the whole glandular system. Associated with proper hygienic measures and the indicated tonics and other alterative drugs, it will give good results in constitutional syphilis, rheumatism. and scrofula. The dose should be small, not sufficient to produce any marked intestinal activity. In stomach troubles, podophyllum is superior to podophyllin. It acts as a gentle stimulant tonic, improves the appetite, and is particularly valuable in atonic dyspepsia, gastric and intestinal catarrh, and all atonic forms of indigestion, when the patient complains of dizziness, loss of appetite and heavy headache. There is indisposition to exertion, the movements being heavy and sluggish, the tongue is dirty and flabby, and the superficial veins, abdomen, and tissues in general, are characterized by fullness. Its action on the hepatic viscus renders it particularly serviceable where gastric disturbances are due to hepatic torpor. In stomach troubles, hydrastis, iris, lobelia, agrimonia and ipecac may also be indicated and associated with this drug. Podophyllum, iris, chionanthus and chelidonium are excellent agents for chronic hepatitis. By its slow and thorough action, yet permanent in its effects in restoring and maintaining the normal hepatic and intestinal secretions, podophyllum is one of the very best agents to overcome habitual constipation, and more especially if it be due to portal engorgement. The small dose should be given and continued until the evacuations become regular and normal. Formerly this drug was much employed in bilious, remittent and intermittent fevers. Cathartic and sometimes emeto-cathartic doses were employed with the result of producing so profound an impression on the hepatic function and on the portal circle and general glandular system that, it is asserted, the disease was often aborted, or at least rendered milder and of short duration. It is never so employed at the present day. As an emeto-cathartic it should be given in warm ginger tea. When a cathartic is needed, which, however, is not often, the specific podophyllum may be combined with compound syrup of rhubarb and potassa (neutralizing cordial), or to render it milder, lobelia, ipecac, leptandra, hyoscyamus or belladonna may be administered with it. As a cathartic in dropsy it has done good service, and should, in this disease, be given with cream of tartar. It has likewise been found very beneficial in dysmenorrhoea, amenorrhoea, incontinence of urine, worms, and some affections of the bladder. Further uses of this drug will be given when considering podophyllin. The usual medicinal dose of specific podophyllum ranges from 1 to 10 drops. Dose of the powdered root, as a cathartic, from 10 to 30 grains; of the tincture, from 10 to 60 drops; as a sialagogue and alterative, from 1 to 5 grains of the powder, or from 1 to 10 drops of the tincture.

Specific Indications and Uses.—Podophyllum is specifically indicated by fullness of tissues, and particularly by fullness of superficial veins; oppressed full pulse; dirty yellowish coating of tongue and dizziness. It is contraindicated by pinched features and tissues, contracted skin and tongue.

Related Species.Podophyllum Emodi, Wallich. Dymock and Hooper report (Pharm. Jour. Trans., 1889, Vol. XIX, p. 585) that this plant of the Kashmere valleys and other Himalayan points contains in its rhizome 12 per cent of a cathartic resin. It is altogether probable that the constituents of the latter are identical with those of our podophyllin. One-half grain of it purges. It was thought that the Indian drug might supplant P. peltatum, owing to its supposed superiority in active principle. John C. Umney, however, points out (Amer. Jour. Pharm., 1893, p. 24) that while P. Emodi yields 11.4 per cent and P. peltatum only 5.9 per cent of resin, the latter contains nearly twice as much of the active podophyllotoxin as the resin obtained from the Indian drug. The inferior medicinal action of the latter agrees with this result.

Podophyllum montanum of Rafinesque, having a slender, deeply furrowed stem; the leaves with sharp, bifid segments, palmate, not peltate, with narrow sinuses, and many unequal teeth; the petals 6 to 7, oblong, obtuse; stamens 7 to 9, and berry yellowish, oblong, is possessed of similar medicinal properties.

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