Pilocarpus. U. S.

Pilocarpus. U. S.

Pilocarpus. Pilocarp. [Jaborandi]

"The dried leaflets of Pilocarpus Jaborandi Holmes, known in commerce as Pernambuco Jaborandi, or of Pilocarpus microphyllus Stapf, known in commerce as Maranham Jaborandi (Fam. Rutaceae), without the presence or admixture of more than 5 per cent. of the stalks bearing the leaflets and stems of the same plant, or other matter, and yielding not less than 0.6 per cent. of the alkaloids of Pilocarpus." U. S.

Jaborandi Folia, Br. 1898; Jaborandi leaves, Pilocarpi Foliola; Jaborandi, Fr. Cod.; Folia Jaborandi, P. G.; Jaborandiblätter, G.; Jaborandi, It.; Jaborandi (Hoja de), Sp.

It is unfortunate in our opinion that this drug was omitted from the Br. Pharm., 1914; it was official in the Br. Pharm., 1898, under the title "Jaborandi Folia."

Pilocarpus was first introduced to the notice of the European profession by Coutinho (J. P. C., 4e ser., xx, 51) under the name of Jaborandi, a name which has adhered to the drug, although the terms Jaborandi, Iaborandi and Jamborandi are used in South America to designate various pungent, sudorific plants, most of which belong to the genus Piper, but some of which have no botanical relation at all with the peppers. Although the leaves of the Piper Jaborandi have been sent into commerce as Jaborandi, none of the true jaborandis of South America have any physiological relations with the official drug, which, in South America is known as Arruda do Mato or as Arruda brava or, rarely, as Jamguarandi or Jaurandi.

The genus Pilocarpus consists of woody shrubs belonging to the Rutaceae and inhabits tropical and subtropical America, including Cuba, Guadeloupe, Martinique, and probably other islands. For elaborate botanical and histological studies of the commercial species of Pilocarpus, see the articles by A. Duvall, B. Sc. Pharm., iii, pp. 41 and 98; Geiger, Ber. d. D. Phar. Ges., 1897, p. 356; Hartwich, Apoth. Zeit., 1900; Holmes P. J., 1903, p. 713; and 1904, p. 54; Schneider, Jour. of Pharmacology (N. Y. C. P.), 1897, No. 6; Tunman, S. W. P., xlvii, p. 177. The following species of the genus have been used in medicine:

P. Jaborandi Holmes (P. officinalis Poehl). —This plant inhabits the northern and northeastern part of Brazil whence its leaves find their way through Sergipe, Allogoa, Sobral and Ceara, etc., to Liverpool and Hamburg, the chief centers of European commerce in the drug. Like those of P. selloanus its leaves are two or three jugate and are especially separated from those of the P. pennatifolius by the fact that all of the leaflets except the terminal one have their bases cordate, while the bases of all the leaflets of P. pennatifolius are attenuate. This species is practically no longer obtainable in commerce, only occasional lots being imported.

P. pennatifolius Lemaire (P. simplex Baillon) inhabits the southern portion of Brazil and Paraguay, whence its leaves were formerly largely exported through Buenos Ayres and Rio Janeiro; at present they seem to have almost disappeared from commerce. The leaves are grayish-green in color, oval, elliptical, obtuse, attenuate at the summit, which is feebly emarginate, and also attenuate at their base but not petiolated. The species is recognized in the Belgian Pharmacopoeia.

In the original specimens of Jaborandi seen by Coutinho, and also in other specimens received from the doctor's family by F. V. Greene, U. S. N., some of the leaves are hairy, although most of them are smooth, and it seems probable that the species does contribute somewhat to the Jaborandi of commerce.

P. selloanus Engler, formerly official in the U. S. P., appears to be a variety of P. pennatifolius Lemaire, from which it differs almost solely in the length of its flower stalk, which is six times as long as the flower bud, while that of P. pennatifolius, is but three to four times as long as the bud. P. selloanus seems to be the more southern plant of the two, and is especially abundant in Paraguay.

P. trachylophus Holmes.—The leaves of this species are smaller than those of the P. Jaborandi, and are oblong, elliptical, obtuse, and emarginate at the summit with cordate bases, symmetrically and shortly petiolate. The plant grows in Northeastern Brazil, especially in the provinces of Ceara and Maranhoa, and the leaves, although they contain so little of the alkaloid (about 0.2 per cent.) as to be of small value, have been sent into commerce in considerable quantities. Their color upon the surface is vivid green, below yellowish-green. The under surface is covered with short hairs.

P. microphyllus Stapf grows in the northeastern part of Brazil, whence the leaves, much mixed with the debris of the petioles, of the twigs and of the fruit, are sent to Liverpool and Hamburg. These leaves are alternate, imparipinnate having from one to five pairs of leaflets, or are often apparently simple owing to the failure of the lateral leaflets to develop. The leaflets are opposite, slightly pubescent, their petioles being marked by a deep longitudinal furrow. They vary very much in form, the base usually being attenuate and feebly cordate or unequal.

P. spicatus A. Saint-Hilaire (P. parviflorus Martins et Nees), inhabits the southern and northern portions of Brazil and can be recognized at once by its having simple leaves which are from 3 to 11 cm. long and from 1 to 4 cm. broad, and are tender or coriaceous and more or less pubescent and dotted. They are brownish-green above, paler beneath, and attached by a short twisted petiole. They appeared in commerce in 1895 under the name of Arocati jaborandi. P. subcoriaceus Engler is probably a variety of this species. P. racemosus Vahl, a native of Martinique, Cuba, Guadeloupe and probably other of the West Indian Islands, appeared first in commerce in 1903 as a new variety of jaborandi under the name of Guadeloupe jaborandi. The leaves are proportionately broader than those of Pernambuco jaborandi, more obovate in outline, of a purer green color, and are trifoliate or apparently simple. Considerable diversity of result has been obtained by chemists in the examination of the Guadeloupe jaborandi. Rocher (A. J. P., 1900) obtained 1 per cent. of total alkaloids of which 0.6 per cent. was believed to be pilocarpine, the remainder jaborine. In the laboratory of Wright, Layman and Umney, only 0.34 per cent. of total alkaloids were reported as existing, while in an assay by A. J. Cownley (P. J., 1903, lxxii) 0.6 per cent. of total alkaloids was obtained, about 50 per cent. of which was believed to be isopilocarpine. The commercial cultivation of jaborandi (may some day be successful, as the P. pennatifolius has been found to grow freely in Sicily and produce a leaf containing a fair proportion of alkaloid. Pilocarpus is usually bought by assay. The variation in the percentage of alkaloid, according to the observations of A. Duval, depends not merely on the original contents of the drug but upon the fact that the alkaloid disappears when the pilocarpus is kept for some length of time in a moist atmosphere. Pilocarpus was at one time adulterated with spurious jaborandis, other foreign leaves, stems, dirt and mouldy leaves. At the present time the commercial article is of good quality. There are, however, reports of the leaves of other plants being substituted. Weigel states that under the name of "Feuilles de Bois d'inde," the leaves of the logwood plant were substituted for Paraguay jaborandi. The most common adulterant appears to be in lots of P. microphyllus, which often contain leaves of the leguminous plant, Tunatea decipiens (Holmes), O. Kze. (Swartzia decipiens Holmes.. In general appearance the two leaves resemble one another, both being imparipinnate and having the leaflets about the same size and shape, but in P. microphyllus the leaflets are opposite and the petioles are only slightly pubescent, while in the Tunatea the leaflets are alternate, and the petioles very pubescent. Then again, the absence of secreting hairs, the deep green of the upper and lighter green of the lower surface of the leguminous leaf serve easily to distinguish it from the true drug.

The following description of the drug is adapted from that of F. V. Greene, U. S. N., who had unquestionable specimens of the original jaborandi of Coutinho. The package contained several stems branched at an angle of about 20°, these branches being furnished with alternate leaves, which are imparipinnate, with from two to five opposite leaflets (Planchon has met with leaves having as many as seven or nine, and, more rarely, eleven leaflets) articulated to the rachis by short petiolules, thickened at the base. The leaflets, which are coriaceous in texture, vary considerably in size and outline. As a rule, they may be considered as oblong-lanceolate, and are entire, emarginate, with an unequal base. The midrib rises very little above the upper surface of the leaflet, but is very prominent and sharp on the lower. The veins, which are rather more prominent on the lower surface, leave the midrib at an angle of about 60°, pursue a parallel course across the leaflet, and finally turn up and anastomose within about a quarter of an inch of the margin. The leaflets are pellucidly punctate; the dots are the receptacles of secretion, are numerously and irregularly distributed over the whole surface, and are plainly visible when the leaflet is held up to the light. According to Conroy, the leaflets yield 0.76 per cent., the leafstalks only 0.37 per cent. of alkaloid. The fruit consists of five carpels, of which not more than two or three are usually developed to maturity; when ripe, the carpels dehisce into two valves, and then remind one strongly of miniature cockle shells with the valves open exposing the animals. The black, shining, reniform seeds (one for each carpel) have a lancet-shaped hilum, a sharp ridge on the back near the apex, and a smooth, pale yellow endocarp surrounding it.

Paraguay jaborandi from P. pennatifolius and P. selloamis is an inferior variety of the drug, which reaches European commerce from Buenos Ayres and from Rio Janeiro, and is believed to be collected in Paraguay. The leaves are thinner than those of the Pernambuco jaborandi, and have only two or three, never four, pairs of leaflets. It is also noticeable in the Paraguay variety that the lateral veins are not prominent, that the base is so tapered that the widest portion is above the middle, and that the upper surface is grayish-green.

Properties.—The Pernambuco and Maranham jaborandis are official, being described as follows:

"Pernambuco Jaborandi.—Leaflets when entire, oval, oblong, or elliptical, from 4 to 10.5 cm. in length and from 2 to 4 cm. in breadth and with short, stout petiolules; summits more or less rounded or acute and emarginate; bases rounded or acute and mostly unequal; margins entire and narrowly revolute; very smooth, shiny, coriaceous and glandular-punctate; upper surfaces grayish to brownish-green, midribs mostly depressed, under surfaces yellowish- or greenish-brown and slightly pubescent on the prominent midvein; peculiarly aromatic when crushed; taste bitterish, becoming somewhat pungent and having a sialogogue effect.

"Maranham Jaborandi.—Leaflets rhomboid-ally oval to obovate or elliptical from 1.5 to 5 crn-in length and from 1 to 3 cm. in breadth, the lateral ones nearly sessile, the terminal ones on margined petiolules, from 0.5 to 1.5 cm. in length; of a nearly uniform grayish or yellowish-green color, rather thin but otherwise resembling Pernambuco Jaborandi.

"Under the microscope, transverse sections of Pilocarpus show the upper epidermal cells with a yellowish layer of cutin from 0.005 to 0.01 mm. in thickness; palisade cells, 1 to 3 rows deep, being filled with chloroplastids; among the palisade cells occur large, nearly circular, oil-secretion reservoirs from 0.08 to 0.15 mm. in diameter; the dorsal pneumatic layer, from 10 to 20 rows in depth, the cells occasionally containing rosette aggregates of calcium oxalate from 0.01 to 0.025 mm. in diameter; distributed in the center of the leaf are the collateral fibro-vascular bundles each surrounded by a more or less interrupted circle of several rows of thick-walled, slightly lignified bast-fibers, tracheae associated with strongly lignified wood-fibers; among the cells of the lower epidermis occur numerous stomata. On surface view the stomata are broadly elliptical, from 0.025 to 0.04 mm. in length, being uniformly smaller in Maranham Jaborandi. Upon both surfaces of Pernambuco Jaborandi occur a number of non-glandular, one-celled hairs, more or less bent or curved, from 0.08 to 0.5 mm. in length, thick-walled and with numerous, slight, centrifugal projections.

The powder is dark green or greenish-brown; epidermal cells on surface view 5-or 6-sided; stomata broadly elliptical, from 0.02 to 0.04 mm. in length, usually with four neighboring cells; fragments of fibro-vascular bundles showing tracheae with simple or bordered pores or spiral thickenings, associated with thick-walled and strongly lignified wood-fibers; bast-fibers few, walls thick and only slightly lignified; calcium oxalate in rosette aggregates, from 0.01 to 0.025 mm. in diameter; fragments of laminae showing large, oil-secretion reservoirs and usually containing one or more globules of oil; non-glandular hairs having thick walls, usually more or less broken, are occasionally found. Pilocarpus yields not more than 7 per cent. of ash." U. S.

An alkaloid was isolated in 1875 from Jaborandi almost simultaneously by A. W. Gerrard and M. Hardy. To this the name of pilocarpine was given. Gerrard at the same time stated that there were at least two alkaloids in the leaves, and this view seemed to be confirmed when jaborine was discovered. He also obtained a volatile oil, tannic acid, a peculiar volatile acid, and potassium chloride. Pilocarpine may be prepared as follows. The leaves are exhausted with 80 per cent. alcohol containing 8 grammes of hydrochloric acid in a liter, the tincture is distilled and evaporated to the consistence of a liquid extract, and this is mixed with a small quantity of water, and filtered. The filtrate is treated with a slight excess of ammonia, and then with a large quantity of chloroform. The chloroform solution is agitated with water, to which hydrochloric acid is added, drop by drop, in sufficient quantity to neutralize the alkaloid, the hydrochloride of which is obtained in long needles on evaporating the aqueous solution, while foreign principles remain dissolved in the chloroform. By dissolving the crystals in water, treating the solution with ammonia and chloroform, and evaporating the latter solution, pilocarpine is obtained as a soft viscous mass, which is only slightly soluble in water, but is freely soluble in alcohol, ether, and chloroform.

Kingzett originally assigned pilocarpine the formula C23H24O4N4 + 4H2O. Hamack and Meyer, on the other hand, give it as C11H16O2N2. The latter has been accepted, and is recognized by the U. S. Pharmacopoeia. It was later definitely established as correct by the synthesis of pilocarpine afterwards effected by Hardy and Calmels. (C. R. A. S., cv, pp. 68 to 71; also A. J. P., 1887, p. 632.) By the action of hydrochloric acid or of barium hydroxide, pilocarpine, C11H16O2N2, is changed into pilocarpidine, C10H14O2N2, by the loss of a methyl group. Now Hardy and Calmels have converted ß-pyridine-a-lactic acid, into pilocarpidine, the methyliodide of which by oxidation is converted into pilocarpine. The synthetical pilocarpidine and pilocarpine yield gummy derivatives similar to those obtained by Harnack and Meyer from the natural products. The physiological action of synthetical pilocarpine is identical with that of the natural alkaloid. Knudsen, E. Merck, and Petit and Polonovski all dispute the conclusions of Hardy and Calmels, and state that they failed to get pilocarpine by the synthetic method of these investigators. (Proc. A. Ph. A., 1897, 716.) Petit and Polonovski (J. P. C. (6), v, 481) obtained pilocarpic and pilocarpidic acids from pilocarpine and pilocarpidine. Harnack and Meyer first stated that jaborine is easily formed from pilocarpine, and may be produced by simply heating the latter alkaloid. They also showed that pilocarpine has physiological effects analogous to those of nicotine, while jaborine resembles atropine in its effects.

Uses.—The therapeutic virtues of jaborandi appear to be due entirely to the alkaloid pilocarpine and the crude drug is very rarely employed.

When an overdose of jaborandi, or its principle alkaloid, has been taken, the symptoms begin with flushing of the face and neck, soon followed by free sweating and salivation, both of which may be extremely profuse. Frequently there is nausea and sometimes vomiting, the pulse is usually somewhat more rapid than normal, the pupils contracted, and often there is diarrhea. In patients with circulatory disturbances, pulmonary edema may occur, and prove rapidly fatal. The antagonism between pilocarpine and atropine is about as complete as between any two drugs, and the most certain treatment for cases of poisoning by jaborandi, after evacuating the stomach, is the prompt administration of a full dose of atropine, or some substance containing it.

Dose, of jaborandi, from twenty to forty grains (1.3-2.6 Gm.).

Off. Prep.—Fluidextractum Pilocarpi, U. S.

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