Labeling of WAMPOLE'S PREPARATION containing Strychnine Sulfate 1/80 Grain
PERFECTED and PALATABLE
TONIC AND STIMULANT
ORIGINATED IN I88O
ALCOHOL ......... .12%
STRYCHNINE SULPHATE . 1/8OGR. IN EACH TABLESPOONFUL, combined
with a Solution of an Extractive from fresh
Cod Livers, the oil and its properties being
eliminated, Extract of Malt, Fluidextract of
Wild Cherry, Hypophosphites of Calcium,
Sodium* Potassium and Manganese, Iron
DOSE—Adults, 1 tablespoonful; children, 10 to 15 years, 2 teaspoonfuls; 6 to 10 years, 1 teaspoonful; 3 to6 years, 1A teaspoonful. Four doses per day, preferably before meals and be-fore retiring. May be taken for 2 or 3 weeks, then discontinued for week or 10 days, then dosage resumed for same period if desired.
CAUTION—Do not take more than dosage recommended. Should not be administered to children under 3 years, nor to elderly per* sons, except as directed by physician.
NONE GENUINE WITHOUT ABOVE FACSIMILE SIGNATURE,
THE NAME WAMPOLE'S AND THE SIGNATURE ARE REGISTERED
SN U. S. PATENT OFFICE AND IN FOREIGN COUNTRIES
PREPARED SOLELY BY
HENRY K.WAMPOLE & CO.
Nux Vomica seeds containing strychnine
This information has been taken from the United States Dispensatory Wood-Osol 23rd Edition 1943. The information contained is for historical purposes only.
NUX VOMICA Nux Vom. [Strychni semen, P. L]
"Nux Vomica is the dried ripe seed of Strych-nos Nux-vomica Linne (Fam. LoganiacecB), Nux Vomica yields not less than 1.15 per cent of strychnine." U. S. The Br. requires not less than 1.2 per cent of strychnine.
Dog Button; Quaker Button; Poison Nut. Fr. Noix vomique. Ger. Brecknusz; Krahenaugen; Strychnossa-men. It. Noce vomica. Sp. Nuez vomica.
Nux Vomica first appeared in Europe either during the 15th or 16th century. The seeds were first described by Valerius Cordus during the 16th century and are mentioned in Lang-ham's Garden of Health (1578). Gerard in The Herbal also wrote about the drug and gives good sketches (1597); he says that "because of its poisonous character, it was not to be given inwardly, but mixed with other compositions and that very cautiously by the hands of a faithful Apothecarie." Originally its Euro-pean use was confined to that of a drug-shop poison for killing animals. It was introduced into the U. S. P. of 1820 and its extract and tincture were given place in the Dublin Pharma-copoeia of 1826.
Strychnos Nux-vomica is a tree of a moderate size, with numerous strong branches, covered with a smooth, dark gray bark. The young branches are long, flexous, smooth, and dark green, with opposite, ovate, petiolate, entire, smooth, and shining leaves. The flowers are small, white, funnel-shaped and in terminal corymbs. The fruit is a round berry, about as large as an orange, with a smooth, yellow or orange-colored, hard, fragile rind, and many seeds in a juicy pulp. It has frequently been asserted that the pulp is innocuous, but Fliickiger and Hanbury, and also Dunstan and Short (P. J., 3d series, 15, 1) have demonstrated that it contains strychnine. Dunstan and Short have also proved that of the commercial varieties of nux vomica, Bombay seed stands first in percentage of con-tained strychnine, then Cochin, and lastly Madras. (P. J.} 1883, 14, 1053.)
The tree is a native of India, growing in Bengal, Malabar, on the Coromandel Coast, in Ceylon, in many islands of the Indian Archipelago, in Cochin China, and in northern Australia. The fruits are collected when fully mature and the seeds removed from the pulp by washing, or the pulp may be rotted off the seeds. These are then dried in the sun on mats, graded and marketed. Most of the world's supply comes from India, two-thirds of the available supply being furnished by the Madras Presidency. The chief importers are the United States and Great Britain. The drug is largely shipped to the United States in small sacks from Madras, Cochin, Cocanada, Calcutta and Bombay, some coming indirectly through London. During 1940 there were imported into the United States 3,467,829 pounds of nux vomica, the supplies coming from British India and French Indo-China.
The wood and root are very bitter, and were employed in the East Indies for the cure of intermittents. The radices colubrincs and lignum colubrinum of the older writers, long known in Europe as narcotic poisons, have been erro-neously ascribed to this species of • Strychnos; they are derived from S. Colubrina L, They were ascertained by Pelletier and Caventou's researches to contain a large quantity of strychnine. The bark has been mistaken for cusparia, and hence is sometimes referred to as false angustura. For a description of commercial varieties of nux vomica seeds, see a paper by Youngken and Slotter in A. J. P., 1920, p. 538.
Description.—"Unground Nux Vomica.—Seed orbicular, nearly flat, occasionally somewhat bent, from 10 to 30 mm. in diameter, and from 3 to 6 mm. in thickness; externally grayish or from pale brown to pale olive, covered with appressed hairs, giving it a silky luster; hilum indicated by a circular scar at the center of one of the flat-tened sides, and connected with the micropyle by a radial raphe; very hard when dry; beneath the thin and hairy seed-coat is a large yellow to weak yellowish green endosperm at one end of which is embedded a small embryo with two cordate 5- to 7-nerved cotyledons; inodorous; taste intensely and persistently bitter.
"Histology.—Transverse sections of the seed exhibit a thin spermoderm of collapsed cells from which project numerous appressed, twisted, thick-walled, lignified hairs with enlarged bases possess-ing slit-like pits and branched lumina, their long, bent bodies possessing walls with long, curved, narrow slits. Beneath the spermoderm occurs a broad endosperm of polygonal cells showing well-marked plasmodesmata, very thick walls of reserve cellulose, and lumina containing oily plasma and occasional aleurone grains.
"Powdered Nux Vomica.—Pale brown to yel-lowish gray; consisting chiefly of thick-walled endosperm cells containing globules of a fixed oil and a few small aleurone grains up to 30 microns in diameter, fragments of strongly lignified, non-glandular hairs, the walls of the latter possessing large, circular, or long, slit-like pores. In the tissues of the adhering pulp occur a few small, nearly spherical starch grains." U. S.
The seeds are destitute of odor, but have an acrid, very bitter taste, which is much stronger in the kernel than in the investing membrane. They impart their virtues to water, but more readily to diluted alcohol. For a method of distinguishing powdered nux vomica from pow-dered ignatia and other powders, see Proc. A. Ph. A., 1897, 503.
Tunmann (A. Pharm., 1910, 644) has studied the distribution of the alkaloids in the germinat-ing seeds of Strychnos Nux-vomica, and con-cludes that the embryo of the seed contained only brucine and that strychnine, which was con-tained in the endosperm only in the cell plasma of the cell content, appears to act as a protection for the growing plant. Rusby has reported the shipment of nux vomica which consisted of small inferior seeds which had been rolled in some mix-ture of clay. (Proc. A. Ph. A., 1908, 56, 794.) Powdered nux vomica has been adulterated with ground olive stones and the raspings of vegetable ivory. (See Rep. d. Pharm., 1909, p. 241.)
Assay.—"Place 15 Gm. of Nux Vomica, in coarse powder, in a flask or bottle, add 150 cc., measured at 25° C., of a mixture of 3 volumes of ether and 1 volume of chloroform, tightly stopper the flask, shake the mixture, and allow it to stand for about 2 minutes. Then add 10 cc. of stronger ammonia T.S., stopper the flask tightly, shake frequently, but gently, during 1 hour, and allow the mixture to stand over night at a temperature not over 25° C. Again shake the flask gently for 15 minutes, and allow the liquids to separate at 25° C. Then quickly trans-fer to a separator exactly 100 cc. of the liquid, representing 10 Gm. of Nux Vomica, rinse the measuring vessel with a little chloroform, and add the rinsings to the separator. Add about 40 ,cc. of approximately normal sulfuric acid to the separator, and shake the mixture gently for 5 minutes, then allow the liquids to separate, and draw off the acid layer into another separa-tor. Repeat the extraction with successive por-tions of the acid, until the ether solution is com-pletely extracted (see Purification of the Alka-loids} .
"To the combined acid solutions in the sepa-rator, add a small piece of red litmus paper and 50 cc. of chloroform, and follow with sufficient ammonia T.S. to render the aqueous layer alka-line, and after gently shaking, add 2 or 3 cc. more of the ammonia T.S. Now shake the mixture thoroughly, but gently, for about 10 minutes, and allow the liquids to separate. Draw off the chlo-roform into a container, and repeat the extraction with additional portions of chloroform until all of the alkaloid is extracted. Extract the combined chloroform solutions with successive portions of approximately normal sulfuric acid until completely extracted. Then render the combined acid solutions alkaline with ammonia T.S., add 2 or 3 cc. more of the ammonia T.S., and com-pletely extract the alkaloids with successive portions of chloroform.
"Carefully evaporate the combined chloroform extracts to dryness on a water bath, dissolve the residue by warming with 15 cc. of approximately 3 per cent sulfuric acid, cool to 25° C., and add 3 cc. of a mixture of equal parts of nitric acid and a 5 per cent solution of sodium nitrite in distilled water. Thoroughly stir this mixture, and allow it to stand for exactly 10 minutes at room temperature. At the expiration of this pe-riod, pour at once the red solution into a separator containing 50 cc. of chloroform and 15 cc. of 10 per cent sodium hydroxide solution, and rinse the flask with distilled water, adding the rinsings to the separator. Add sufficient 10 per cent sodium hydroxide solution to the contents of the separator to render it distinctly alkaline to litmus paper, and then add a few cc. more of the sodium hydroxide solution. Shake the mix-ture gently for 10 minutes and allow the liquids to separate. Draw off the chloroform layer into another separator and repeat the extraction with additional portions of chloroform until the alkaloid is completely removed. Add 10 cc. of distilled water to the combined chloroform extract, shake the mixture gently, and add a small piece of red litmus paper. The litmus paper should indicate not more than a slight alkalinity. If the water, after shaking with the chloroform, is strongly alkaline, draw off the chloroform into another separator, and shake it with another 10 cc, of distilled water. Draw off the chloroform, passing it through a filter paper moistened with chloroform, into a container. Wash the filter paper with warm chloroform, and add these rins-ings also to the container. Now shake the com-bined aqueous extract with 5 cc. of chloroform and draw off this chloroform, passing it through the chloroform-moistened filter paper into the main chloroform solution.
"Evaporate the combined chloroform extracts very carefully on a water bath nearly, but not quite, to dryness. Add to the moist residue 7 cc. of tenth-normal sulfuric acid, accurately measured, follow with 30 cc. of distilled water, and heat the mixture on a water bath until the alka-loid is dissolved and the odor of chloroform is dissipated. Cool to room temperature, and titrate the excess of acid with fiftieth-normal sodium hydroxide, using 1 drop of methyl red T.S. as the indicator. Each cc. of tenth-normal sulfuric acid is equivalent to 0.03344 Gm. of strychnine." U.S.
The Br. assay of Nux Vomica, while differing from that of the U. S. in details, is based upon the same general principles as the U. S. determination of strychnine. An unusual feature of the Br. assay is the direction to multiply the result of the strychnine determination by 1.02 in order to correct for the loss of strychnine.
For the process of total alkaloids in nux vom-ica see U. S. D., 21st ed., p. 718.
Constituents.—The therapeutic value of nux vomica is due entirely to the two alkaloids, brucine and strychnine, although there are other substances present of some interest. The total alkaloidal content ranges from 2 to 2.7 per cent.
Strychnine (C2iH2202N2) was discovered by Pelletier and Caventou in 1818, in both the nux vomica and the bean of St. Ignatius. It gen-erally constitutes a little less than one-half of the total alkaloids. For account of a method of preparation and its chemical properties see Strychnina.
Brucine (C2sH2604N2) is a dimethoxy-strych-nine. Morrison and Bliss (/. A. Ph. A., 1932, 21, 753) found a larger proportion of brucine than strychnine in seven out of eight samples of nux vomica; of the total alkaloids strychnine represented from 41 to 54 per cent. Brucine may be separated from strychnine by virtue of the lesser solubility of its oxalate in dehydrated alcohol or of its hydriodide in water, or by the insolubility of strychnine chromate in water. Potassium ferrocyanide precipitates the strych-nine from a hydrochloric acid solution of the alkaloids, the brucine remaining in solution. Brucine is crystallizable from aqueous alcohol, the crystals then containing 4H20. It is without odor, but of a permanent, harsh, very bitter taste; is sparingly soluble in water; very soluble in alcohol, whether hot or cold; it dissolves in 4 parts of chloroform, 440 parts of ether, 60 parts of benzene, and 120 parts of petroleum benzin. It is permanent in the air. The hydrated crys-tals melt at 105° C., while the anhydrous base melts at 178° C., changing color, and depositing carbon. It forms crystallizable salts with acids.
Concentrated nitric acid produces with brucine or its salts an intense crimson color, which changes to yellow by heat, and upon the addition of stannous chloride becomes violet. Dissolved in diluted sulfuric acid, brucine gives with potassium dichromate a red color changing to orange. Brucine oxidized with bromine yields a red color when heated with hydrochloric acid; or a brown color changing to green, then yellow, when heated with ammonia; this yellow solution develops a green fluorescence when hydrochloric acid is added. These and other color reactions of brucine are described by Frangois (Bull. trav. soc. pharm, Bordeaux, 1930, 68, 156). Micro-chemical tests for brucine have been described by Whitmore and Wood (Mikrochemie, 1939, 27, 249; 28, i). A study of the quantitative separation of strychnine and brucine in mixtures is presented by Horn and co-workers (/. A. Ph. A., 1940, 29, 183).
In addition to the two chief alkaloids several other bases have been described. Boorsma has reported (P. J., 1902) a base which he calls strychnicine; this is of very low toxicity. Ruickoldt (A. E. P. P., 1930, 149, 370) has de-scribed an alkaloid vomicine which, while pos-sessed of some physiological powers, differs ma-terially from strychnine. Schaefer (/. A. Ph. A., 1914, 3, 1677) found an alkaloid, which he has named struxine, C2iHso04N2, in the drug coming from Cochin China, in an amount of 0.1 per cent. It is probably a decomposition product of either brucine or strychnine. Warnat (Hell). C. A.} 1931, 14, 997) obtained the three new alkaloids pseudo-strychnine, alpha-colubrine,' and beta-colubrine from the mother liquors of strychnine crystallization. Pseudo-strychnine is believed to be a hydroxy-strychnine, while the two colubrines appear to be isomeric mono-methoxy-strychnines, thus standing midway between strychnine and brucine, which is a di-methoxy derivative. Pseudo-strychnine is not bitter and is only mildly toxic; the isomeric colubrines stand between strychnine and brucine in toxicity.
Dunstan and Short (P. J., 1883, 14, 1025) found in the nux vomica seeds, but more abun-dantly in the pulp surrounding them, a glycoside loganin, C25H340i4. It is present in the pulp to the amount of 4 or 5 per cent and is contained in small quantity also in the seeds. It was obtained by exhausting the pulp with a mixture of chloro-form and alcohol (100:25). Loganin is easily soluble in water and alcohol, less soluble in ether, chloroform, and benzene. Its most char-acteristic reaction is found in its behavior with concentrated sulfuric acid. A very small quan-tity of loganin, when gently warmed with a few drops of concentrated sulfuric acid, yields a fine red color, which, on standing, develops into a deep purple.
In addition to these constituents, there are present a yellow coloring matter, a fixed oil, gum, sfarcd, & SKiztf quantify of WSLK, ancf several earthy phosphates. The unsaponifiable portion of the oil was identified as a mixture of phyto-sterins. (A. Pharm., 1912, p. 398.) There is present also an organic acid which has been called igasuric add but Sander (A. Pharm., 1897, 133) believes it to be caffeo-tannic acid. Meyer investigated the fatty oil, and found it to consist of the glycerides of capric, caprylic, caproic, butyric and palmitic acids. (A. J. P., 1874, 405.) Allied Plants.—The following species of Strychnos have been shown to contain either strychnine or brucine, or both: S. ignatia (see Ignatia, Part II); S. cinnamomifolia Thw. (Short, Yearbook Pharm., 1924); S. colubrina L. (Greenish, P. J., 1878); S. ligustrina Blume (Greenish, Yearbook Pharm., 1879); S. Rheedii (Clark and Dunstan, Imp. Inst. Rep., 1901-1902) ; S. Tieute Lesch (A. J. P., 1866). The Congo poison known as Cupua Apus, according to Vinci (A. I. P. T., 1911), is produced from the Strychnos Kipapa Gilg. The bark of the root contains 6 per cent of strychnine and the wood 0.1 per cent. Strychnos Nux-blanda Hill, of Burma produces seeds which contain neither strychnine nor brucine and are devoid of bitterness. According to A. W. Hill this species differs from S. Nux-•uomica in the long calyx segments, the larger, abruptly acute leaves, larger fruits with more numerous seeds, the latter having a felty-white surface, without the satiny luster of genuine nux vomica seeds (Kew Bull., 1917, p. 121). The seeds of S. potatorum, L. fil., of India and Ceylon contain no alkaloids and are used in India for clearing muddy water. They have been substituted for nux vomica from which they may readily be distinguished by means of the ammonium vanadate reagent.
Uses.—The medicinal and toxic properties of nux vomica are those of its alkaloid. (See Strychnina.} The belief held by some physicians that it acts more favorably as a bitter upon the stomach has only this much of justification namely, that it is more slowly absorbed, and therefore acts locally somewhat more persistently.
BRUCINE.—On account of the difficulty of separating strychnine from brucine, it has been found by physiologists difficult to determine the exact action upon the human organism of the pure alkaloid. It was formerly taught that bru-cine closely resembled strychnine in its physio-logical action, except that it was less poisonous and that it was depressant to the peripheral sensory nerves. Dickson and Harvey (P. J., 1908, 81, 367), experimenting with a chemi-cally pure brucine, reach the conclusion that its dominant action is a paralysis of the peripheral motor nerves, and that the convulsive action which is the characteristic effect of strychnine is almost entirely absent in the case of brucine. Morrison and Bliss (/. A. Ph. A., 1932, 21, 753) report that brucine causes violent convulsions in doses about 40 times as large as strychnine. Ac-cording to the observation of Mays, brucine is an active paralyzant to the sensory nerves and a 5 or JO per cent solution applied to the month tzaszy &
Dose, of nux vomica, one to four grains (0.06-0.25 Gm.).
Off. Prep.—Tinctura Nucis Vomics, U. S., Br.; Extractum Nucis Vomicae; Fluidextractum Nucis Vomicae, N. F., (Br.).