Continued from previous page.
- Allied species - Description - Description of the drug - Microscopical structure of cimicifuga racemosa - Constituents - The alleged "crystallizable neutral principle" of Cimicifuga racemosa - The fresh juice - The green rhizome
ALLIED SPECIES.—The two species of Actaea described in the preceding article have such a close resemblance to black snakeroot that there is no doubt that they are indiscriminately gathered by root diggers. Indeed, it takes very close observation to distinguish between the plants by the leaves alone. We have known root gatherers who would not be convinced that Actaea alba was not black snakeroot, and when shown the small flower spikes of the former plant maintained that they were "young plants."
There is no other species of Cimicifuga that is abundant enough to ever supply any amount of the drug that is gathered for black snakeroot. Cimicifuga americana, were it common, would be impossible to be distinguished by root gatherers from the plant under consideration, but it is a very rare plant even to botanists.
On account of the importance of Cimicifuga racemosa as a drug, we give a description of the three other native species of the genus. The two Eastern species are rare, and the Western species has never been investigated, and neither is likely to be ever of any importance.
Cimicifuga Americana.—In the entire list of native plants we do not know of any other two evidently distinct species that bear as close resemblance to each other as Cimicifuga americana and Cimicifuga racemosa. No one but a close observing botanist would ever suspect that they were different plants, and botanists can tell them apart only when in fruit. [In our experience, trying to obtain the rhizome of Cimicifuga americana for comparison, we corresponded with quite a number of botanists who at first thought they knew the plant, but afterwards found that they had mistaken for it the Cimicifuga racemosa, and in one instance a quantity of the rhizome of Cimicifuga racemosa was expressed us for it. Our rhizomes of the plant were obtained through the kindness of J. Donnell Smith, of Baltimore, than whom there is no more careful botanist nor acute observer. Although he is perfectly familiar with both species, he was compelled to wait until the gynoecium had formed in the bud before he could distinguish the Cimicifuga americana from the other.]
The first printed reference we can find to the plant is in Raevschel's Nomenclator Botanicus, published in 1797, where the name "Actaea pentagyna from Carolina," evidently refers to this species. No description of the plant is given, and no authority for the name, and we are unable to find the source of Raevschel's information. Michaux first described the plant in 1803 as Cimicifuga americana, which name it has since retained. De Candolle referred the plant to the genus Actaea and substituted another specific name for it, calling it Actaea podocarpa. [The meaning of podocarpa is having carpels with a foot or stipitate base.]
De Candolle's specific name was adopted by Eaton and also by Elliott, who named it, in accordance with their generic views, respectively Macrotys podocarpa and Cimicifuga podocarpa.
The stem is more slender and the flowers are smaller and not as closely placed on the raceme as they are in Cimicifuga racemosa. The raceme is also more slender and has usually more branches.
In the fruit, however, the two species differ widely. The fruit of Cimicifuga americana consists of (normally five) usually three or four flat, membranous pods. At the apex they are tipped with a slender, subulate style, and at the base they are supported on a stipitate stalk about half the length of the pod. They contain a few, eight to twelve, laterally compressed, roughened seeds. This extremely rare plant, Cimicifuga americana is found only in the Allegheny Mountains. It grows with its allied species, Cimicifuga racemosa, which is everywhere abundant. When in fruit the two plants can be easily distinguished, but otherwise it is very difficult.
Cimicifuga Cordifolia, Pursh.—This species is common in certain peaks of the southern Allegheny Mountain, but as it is confined to a restricted territory not much frequented by botanists, it is a rare plant in collections. It does not extend as far north as the Cimicifuga americana.
The plant was discovered by Pursh, in 1805, in his trip to the mountains of Virginia and North Carolina and by him named Cimicifuga cordifolia. [Viz., heart leaved Cimicifuga, from the shape of the leaflets.] It has escaped all synonyms except by De Candolle, who referred it to Actaea as Actaea cordifolia, and by Eaton who called it Macrotys cordifolia. The plant is about three feet high, and has the general aspect of Cimicifuga racemosa, but can be distinguished readily by the leaves which are mostly biternate, and the leaflets which are large, oblique and broadly cordate. In structure of the fruit the plant is closely related to Cimicifuga americana, but the pods are sessile (not stipitate) on the pedicel.
Cimicifuga Elata, Nuttall.—This species is a native of the extreme Northwest (Oregon and Washington). It was first collected by Lewis and Clark (about 1805), and described by Pursh in 1814. Pursh considered it the same as the Cimicifuga foetida, of Europe, which it closely resembles, and called it by that name. Hooker maintained the same erroneous views, but used Linnaeus' name, Actaea Cimicifuga. Nuttall first described it as a separate species, under the name Cimicifuga elata, in a manuscript description published in Torrey and Gray's Flora (1838).
It is a tall plant, with large biternately leaves, thin, prominently three lobed, cordate leaflets, and slender but rather short racemes. The flowers are small and not crowded. The fruit on the lower part of the main raceme is two or three carpeled, but above and on the branches the flowers have only one pistil. The fruit pods are flattened and sessile on the pedicel like the fruit of Cimicifuga cordifolia. We know nothing of the rhizome or its properties.
DESCRIPTION OF THE DRUG.—The fresh rhizome of Cimicifuga racemosa, appears in irregular matted clumps, averaging from four to eight ounces in weight. In exceptional cases the rhizome grows much larger, and we have seen specimens weighing over four pounds. The rhizome is horizontal and has numerous short, upward curved branches, which thickly beset the main rhizome, and give it a rough, irregular appearance. These branches are sometimes the remains of former leaf stems, or radical leaves, but for the most part they are undeveloped buds which are produced and grow for a short time, and then become latent. The main rhizome and all its branches are thickly marked with approximate, annular scars, which almost completely encircle them. These scars are left by the decayed bud scales. From the under side of the rhizome proceed numerous fleshy roots, which are from six to ten inches long, and taper from about one-twelfth of an inch in diameter at their place of attachment. These roots are for the most part undivided, but send out several small rootlets.
Fresh cimicifuga rhizome is internally of a white color. It is brittle and breaks with nearly a smooth fracture. It consists of a large central firm pith, surrounded with a circle of concentric, flat, woody rays, and covered with a firm bark. The fresh rhizome is very dark brown, excepting at the base of the leaf stem, and the young buds which are white and have a pinkish cast.
The dried drug is a shrunken representation of the fresh rhizome. Internally it is dark, excepting the woody rays, which are of a lighter color, and thus prominent in a broken cross-section resembling the spokes in a wagon wheel. The dried roots are very brittle and easily broken; hence, in the commercial drug they are for the most part missing or represented by mere fragments. The larger roots, when broken, exhibit a peculiar structure, which is plainly discernable to the naked eye. It consists of a star or cross formed by the projecting rays of the central woody tissue These rays are from two to five in number, according to the size of the root. When the root dries, the rays, being somewhat firm, prevent the regular shrinking of the root, and it assumes an angular appearance, more marked near the rhizome, as illustrated by figure 94. This peculiar structure is also characteristic of many of the roots of Actaea alba.
Fresh cimicifuga is acrid and disagreeable to the taste; the odor of the fresh, broken root is penetrating and peculiar. The freshly broken or sliced root is white, but turns pink immediately when covered with alcohol, and imparts a pink color to the liquid, which ultimately changes to yellowish brown, while the final color of the sliced root is a dark buff or gray, occasionally streaked with a green ring beneath the bark. When the fresh rhizome is broken and exposed to the air, it turns dark gray on short exposure, and ultimately nearly black, but does not assume the pink hue.
MICROSCOPICAL STRUCTURE OF CIMICIFUGA RACEMOSA.—(Written for this publication by Louisa Reed Stowell.)—Rhizome.—Beginning with the outside of the rhizome, there are two or three rows of small, dark brown cells, resembling compressed cork cells.
The remaining structure, except the pith, is in color a light yellow or white. The parenchyma forming the bark is composed of small oval or compressed cells, loaded with starch grains. The walls are somewhat thickened, and occasionally reticulated marks are present.
The woody bundles are numerous, long and narrow, frequently composed of only one row of thick-walled prosenchymatous cells. Seive tissue, or a form of seive opening, is frequent between these cells at their extremities.
These woody bundles are separated by wider and quite regular medullary rays. These cells are tabular in shape and contain starch grains.
The starch grains of the rhizome are small, round, and free from any mark or wrinkle over the nucleus. They are more regular in size and appearance than the starch grains of any of the allied species.
Root.—The outer two or three rows of cells of the root, as well as the rhizome, are dark brown, while the inner part is a light yellow. The cortical portion is thick and darker, with much firmer walls than the corresponding part in the rhizome. These are filled with starch grains. The cells of the parenchyma show clearly defined reticulated marks. The walls are thick and firm and show a laminated structure their entire length. They frequently show a double set of lines crossing each other at an oblique angle.
A single row of cells, dark yellow in color, surrounds-the woody cord the same as a nucleus sheath.
The woody cord of the center of the root (or rootlet of many writers), is the most characteristic of any of the structures of Cimicifuga racemosa. It is composed generally of four distinct woody bundles arranged in the form of a cross. These are separated by four wide, prominent medullary rays; composed of thin walled, rectangular-shaped parenchyma.
Cimicifuga Americana.—Rhizome and Root.—The rhizome is composed almost entirely of parenchyma filled with starch grains. The woody bundles are short, only about one-eighth the length of the radius of the rhizome. They are fewer in number and more irregular in shape and position than those of Cimicifuga racemosa. In the bark parenchyma between the medullary rays are occasionally found bundles of bright yellow prosenchyma.
The starch grains are larger and more regular than the starch grains of Cimicifuga racemosa. They have very much the peculiar appearance of corn starch, angular, depressed on some of the faces, and with frequent crosses or stellate marks in the center of the faces.
The outer row of cells of the root are regular, with walls thickened and colored a dark red, the rest of the structure to the central cord is composed of regular parenchyma loaded with starch grains. These starch grains are smaller than the starch grains of the rhizome and are free from any markings. They are generally round.
The central woody cord is not conspicuous and sometimes has several rays.
CONSTITUENTS.—The first analysis of this plant was by Dr. G. W. Mears, in 1827. [Philadelphia Monthly Journal of Medicine and Surgery, Sept. 1827, pp. 168, 169.] He obtained tannin, extractive matter, gallic acid, resin, gum, starch, and a bitter (acrid) substance. He endeavored to find an alkaloid, being convinced that such a substance ("alkali") was present, but failed.
In 1834 [American Journal of Pharmacy, 1834, p. 14.] Mr. John H. Tilghman made an analysis of the rhizome, and endeavored to produce a crystalline substance similar to that which he states was then sold by a pharmacist of Philadelphia as being obtained from cimicifuga. [We can find no other reference to this material in any work at our command.] He failed to make it, however, and then he investigated the crystalline substance of the pharmacist and found it to be a calcium compound. He identified in cimicifuga, gum, starch, resin, tannin, wax, gallic acid, sugar, an oily body, chlorophyll, extractive, and salts of iron, calcium, magnesium and potassium. He sums up, "These experiments have not led me to any decided conclusion as to the nature of the active principles of cimicifuga."
Mr. J. S. Jones [American Journal of Pharmacy, 1844, p.1.] next investigated the plant, and again obtained the bodies that Messrs. Mears and Tilghman had previously found.
In 1861 [American Journal of Pharmacy, 1861, p. 391.] Mr. Geo. H. Davis made a careful examination, and obtained albumen in addition to those already named, and he split the resinous body into two substances, one soluble in both ether and alcohol, and another soluble in alcohol, but insoluble in ether. He found salts of silica in addition to the inorganic bodies the others had named.
In 1871 [American Journal of Pharmacy, 1871, p. 151.] a paper from Mr. T. E. Conard appeared on "A Neutral Crystallizable Principle in Black Snake Root." This was obtained by extracting the fresh rhizomes with alcohol; adding solution of subacetate of lead to precipitate the resin, tannin, etc.; passing sulphuretted hydrogen into the liquid to free it from lead; filtering; evaporating the filtrate to dryness; washing the residue with ether to remove fat; and dissolving it in sixteen times its weight of alcohol to form a "saturated solution." [This will not make a saturated solution.—L.] This solution was mixed with aluminium hydroxide and agitated for twenty-four hours, and then evaporated to dryness. The residue was extracted with hot alcohol and filtered, from which filtrate, by evaporation of the alcohol, "there remained a crystalline substance of a light yellow color, not of a very regular or decided shape, but of a massy appearance, resembling almost exactly the crystals of sulphate of aluminium on a small scale." This substance was nearly tasteless, but its alcoholic solution was acrid and sharp. It dissolved in chloroform, dilute alcohol, slightly in ether, insoluble in benzine, turpentine and bisulphide of carbon. It fused by application of heat, then took fire, and finally was entirely dissipated. It refused to affect litmus or to unite with acids, and did not evolve vapor of ammonia with caustic alkalies, (all of which applies to resin of cimicifuga.—L.)
In 1876 [American Journal of Pharmacy, 1876, p. 385.] Mr. L. F. Beach reports an examination of commercial resin of cimicifuga (cimicifugin), in which, by following Conard's process, he obtained a crystallized principle that formed in the hexagonal system. In 1878 [American Journal of Pharmacy, 1878, p. 468.] Mr. F. H. Trimble endeavored to obtain this crystalline body, but failed, although his work seems to have been very carefully performed. In 1884 [American Journal of Pharmacy, 1884, p. 459.] Mr. Milton S. Falck published a paper, stating that from the juice of the fresh plant, he obtained by Conard's process a substance that in some respects resembled the mass Conard obtained, and which also appeared to be crystalline. In alcoholic solution it was neutral to litmus paper, and yielded alkaline fumes when fused in a test tube with caustic potash, and it gave a precipitate with some alkaloidal reagents whereby Mr. Falck suggested that it be of alkaloidal nature. However, in many respects it is different from the substance described by Mr. Conard. It will be seen from the literature on the subject, that the only important point of difference is the crystalline body reported by Mr. Conard, and, taking the medical history of the plant into consideration, supported by its chemistry, it is evident that the resins are the important constituents. From the first analysis (1827) to the present day, every examination gave the resin. Until Mr. Conard announced a crystalline body, such a substance was unknown, excluding inorganic salts, and it is desirable that Mr. Conard's claims should be substantiated or disproved. On this subject we have the written records of Mr. Beach and Mr. Falck, in which the substance is claimed to have been found, and that of Mr. Trimble, who failed to produce it; and we will further add that we have never seen it obtained from the commercial drug.
In this connection we would call attention to certain features of the report of Mr. Conard, with our experience with dried cimicifuga:
1st. The amount of solution of subacetate of lead he used (three fluid ounces), will not precipitate the resin from two pints of tincture of cimicifuga. Indeed, subacetate of lead will not precipitate this resin at all. [Mr. T. H. Trimble decided (1879) that the portion precipitated by subacetate of lead yields a crystallizable acid.—Nat. Disp.] The astringents are thrown from solution by the lead and a certain amount of resin is precipitated by the water of the lead solution.
2d. The residue from Conard's evaporated tincture (after passing sulphureted hydrogen through it) is mostly resin and sugar.
3d. The washing with benzine is unnecessary, as nothing of importance is removed.
4th. The extracting by water of this residue (after washing with benzine), separates only sugar and such bodies as are found in most plants and are classed as extractive matters.
5th. The resin left from these experiments will not saturate sixteen times its weight of alcohol. It is very soluble in alcohol.
6th. This resin is not rendered insoluble by digestion with alumina. The only effect that we have observed from this manipulation, is the separation of minute amounts of coloring matter.
7th. This resin has never in our hands assumed a crystalline form.
To sum up, in our opinion Mr. Conard's plan of procedure does not separate the well known resin of cimicifuga, but purifies it from many extraneous substances. If it assumed a crystalline form (and he is not very positive, saying, "not of a very regular or decided shape, but of a massy appearance"), it was an unusual occurrence. We have worked some thousands of pounds of cimicifuga for the resin since Mr. Conard's paper appeared, and have often endeavored to obtain a proximate crystalline substance by his process, and have in every instance failed; and we feel satisfied that the product of Mr. Conard's examination with the officinal drug, is simply a purified resin. [It is not always easy to decide as to the crystalline nature of an evaporated liquid. Sometimes it leaves a substance that appears to be semi-crystalline, but which is really devoid of any crystals. Again, an amorphous, glossy like layer of residue will contain well defined crystals, nearly invisible while surrounded by the amorphous substance in which they are imbedded, but which become distinct when this envelope is removed by an appropriate solvent. in this connection we will say, that often we place too much stress upon a crystalline body. While it is true that many of our most valuable principles are crystalline, it is also true that many uncrystalline substances are equally valuable. The characteristic principle of cimicifuga is a resinous amorphous principle.]
However, in order to produce other evidence, we interested Prof. Robt. R. Warder in the subject, and he spent a couple of weeks in our laboratory and carefully investigated the matter. He reports as follows: [Prof. Warder repeats part of the historical portions already introduced, but which, however, renders his paper more complete.]
THE ALLEGED "CRYSTALLIZABLE NEUTRAL PRINCIPLE" OF CIMICIFUGA RACEMOSA.—(An investigation instituted for this publication by Robt. R. Warder, Professor of Chemistry in Purdue University, Lafayette, Ind.) —This well known plant was examined more than fifty years ago by Tilghman, [Journal of the Philadelphia College of Pharmacy, 1834, pp. 14, 20.] and later by Jones [American Journal of Pharmacy, 1843, pp. 1, 5.] and by Davis. [American Journal of Pharmacy, 1861, pp. 391, 396.] These authorities show it to contain starch, sugars, tannic acid, gallic acid, oils, coloring matters, resins, etc. The most prominent feature of the alcoholic extract is a resinous mixture of bodies, easily precipitated by the addition of water, known in unofficinal pharmacy under the name of cimicifugin, macrotin or macrotyn.
In April, 1871, Mr. T. Elwood Conard, [American Journal of Pharmacy, 1871, pp. 151, 153.] after a tedious investigation, announced the discovery of a crystallizable neutral principle, obtained from the perfectly fresh root, by a circuitous process. Beach [American Journal of Pharmacy, 1876, p. 151.] obtained this principle from macrotin by the same process; and he states that the crystals belong to the hexagonal system. Trimble [American Journal of Pharmacy, 1878, p. 468.] precipitated the resin by water, purified it by benzine, and separated it by chloroform into a soluble and an insoluble portion. Each of them was separately treated with subacetate of lead (the latter also with alumina), yielding only a resinous mass, similar in properties to Conard's principle, but amorphous. Quite recently, Falck [American Journal of Pharmacy, 1884, p. 459.] has again announced Conard's crystalline substance, as found in extract of the fresh drug.
The following experiment was made to isolate the "crystallized principle," if possible, and to make a fuller examination of it; for there is no record of analyses, nor even of the melting point, and therefore no evidence that a pure substance was obtained:
Ten pounds of the dry and powdered drug were moistened with alcohol and carefully exhausted by percolation. One-half of the percolate was treated with six fluid ounces of solution of subacetate of lead, and a bulky precipitate of dirty yellow color was filtered off. The filtrate was again treated with the same quantity of subacetate, yielding about one-fourth as much precipitate as before, and of a lighter color. Conard expressly states that his subacetate of lead - completely precipitated the resin, tannin, etc., and most of the coloring matter," and it was my intention to follow strictly the process indicated. The filtrate would now remain clear for a few moments on the addition of a small quantity of lead acetate, but a larger proportion of water produced an immediate precipitate of resin, and an addition of lead solution caused a gradual separation of white, curdy precipitate, which was believed to result from the simple decomposition of the subacetate or from diluting the alcoholic solution of resin. Sulphuretted hydrogen removed a large quantity of lead from the solution; the alcohol was distilled off, the residue evaporated at about 80° C. with constant stirring, and solidified on cooling to a sticky, resinous, flexible cake. This was removed from the evaporating dish and pulverized in a mortar with the aid of benzine; repeated washing with this menstruum removed a small quantity of pale yellow oil. The residue, when freed from benzine by drying, weighed four ounces. This was repeatedly washed with water, first by trituration in a mortar, then on a filter, with the removal of a half ounce of crude glucose and extractive matter of very dark color. The residue obtained by these series of operations had all the usual appearance, taste, and physical aspects of the resinous substance precipitated by water from the alcoholic extract, except that it was a little paler. This was completely dissolved in twelve fluid ounces of cold alcohol and shaken at intervals with freshly prepared moist alumina, which showed little tendency to combine with the remaining coloring matter. The fluid was evaporated to dryness in contact with the alumina, as in Conard's process; the mass was again dissolved in alcohol, filtered from the alumina, and again exposed to spontaneous evaporation; but only an amorphous product was obtained, as in Trimble's experiment; and this resembled ordinary cimicifugin in color, taste, and tenacity, and in solubility. In fact, the lead had served to precipitate tannin with part of the coloring matter, and benzine removed only traces of im. purity, while simple dilution of the original extract would seem to accomplish nearly the same pur. pose with far less delay.
It is difficult to understand how Conard obtained any crystals free from fixed matter, by the course he describes, or how Beach determined the system of crystallization. The testimony of Trimble, that crystals are not obtained by similar processes, was fully confirmed, so far at least as the dried material is concerned. Some crystalline substance may yet be obtained among the constituents of the resin, or derived by a partial decomposition of those constituents; but the study of this subject had previously been undertaken by Prof. Coblentz. [See page 269.]
THE FRESH JUICE [We return our thanks to Mr. C. S. Ashbrook for valuable assistance in a line of these examinations.].—Expressed from the green rhizome, this has a sweet taste and the odor of the rhizome. It contains glucose in abundance, but no resin, or at least but traces of it. It is reported by Mr. Falck that by following Conard's process, from this juice he obtained a crystalline body. [See page 265.] We expressed a quantity of the juice, and could not do so. After the final washing of the extractive matter by benzol and water, all of it had disappeared. Glucose is the main constituent of the juice.
To sum up, by referring to our statement regarding the resin of cimicifuga and to the paper of Prof. Coblentz on this substance, [See pp. 268, 269.] it will be seen that all our endeavors to obtain crystals from that body were ineffectual. We are convinced that cimicifuga does not contain a crystalline proximate principle, and that the gentlemen who thought to have obtained it, either mistook a salt of lead or aluminium for a product of cimicifuga, or were mistaken as regards the crystalline structure of the substance they observed.
Continued on next page
Drugs and Medicines of North America, 1884-1887, was written by John Uri Lloyd and Curtis G. Lloyd.