Preparations: Fluidextract of Cinchona
"The dried bark of Cinchona Ledgeriana Moens, Cinchona Calisaya Weddell, and of hybrids of these with other species of Cinchona (Fam. Rubiaceae), yielding not less than 5 per cent. of the alkaloids of Cinchona." U. S.
Cinchonae Flavae Cortex; Yellow Cinchona Bark, Cinchona Flava, U. S. 1880, Yellow Cinchona, Calisaya Bark; Cortex Chinae Calisayae, Cortex Chinae Regiae; China Regia; Königschina, Calisayarinde, G.; Quinquina jaune royal, Quinquina Calisaya, Fr. Cod.; China gialla. It.; Quina calisaya, Quina amarilla, Sp.
Cinchona Rubra. U. S. (Br.)
Red Cinchona, Cinch. Rub.
"The dried bark of Cinchona succirubra Pavon (Fam. Rubiaceae), or of its hybrids, yielding not less than 5 per cent. of the alkaloids of Red Cinchona." U. S. "Red Cinchona Bark is the dried bark of the stem and branches of cultivated plants of Cinchona succirubra, Pav." Br.
Cinchonae Rubrae Cortex, Br.; Red Cinchona Bark; Cortex Chinae Ruber, China Rubra; Red Peruvian Bark; Red Bark; Quinquina rouge, Fr.; Cortex Chinee, P. G; Chinarinde, Rothe Chinarinde, G.; China rossa, It.; Quina roja, Sp.
"Though the Peruvian bark was introduced into Europe so early as 1640, it was not until the year 1737 that the plant producing it was known to naturalists. In that year La Condamine, on a journey from Quito to Lima, through the province of Loxa, had an opportunity of examining the tree, of which, upon his return, he published a very complete description, with plate, under the name Quinquina, stating that three species were recognized. (Mem. Ac., Paris, 1738, p. 226.) Four years later, Linne proposed a new name, Cinchona, in honor of the Countess of Chinchon, who first made the bark known in Europe. Linne recognized but one species, which he called C. officinalis, and this continued for a long time to be recognized by the Pharmacopoeias as the only source of the Peruvian bark of commerce. But a vast number of plants belonging to the Linnaean genus Cinchona were in the course of time discovered; and the list became at length so unwieldy and heterogeneous that botanists were compelled to distribute the species into several groups, each constituting a distinct genus, and all associated in the natural family of Rubiaceae.
For our knowledge of these plants as they existed naturally, we are chiefly indebted, to the following botanists, besides La Condamine, of whom we have before spoken: Joseph de Jussieu, who, in the year 1739, explored the country about Loxa, and gathered specimens which still exist in the cabinets of Europe; Mutis, who in 1772 discovered Cinchona trees in Colombia, and afterwards, aided by his pupil, Zea, made further investigations and discoveries in the same region; Ruiz and Pavon, who in 1777 began a course of botanical inquiries in the central portions of Lower Peru, and discovered several new species; Humboldt and Bonpland, who visited several of the Peruvian bark districts, and published the results of their observations after 1792; Poppig, who travelled in Peru so late as 1832, and published an account of his journey about the year 1835; Wed-dell, whose researches in Bolivia are so well known and have been productive of valuable information in relation to the Calisaya bark and allied species; while Karsten, Caldas, Martius, Ledger, Markham, and other intrepid explorers have in later times largely added to our information. At the present time (1917) thirty or forty more or less clearly defined species of Cinchona are recognized. Of all of these probably but four with their cultivated hybrids yield the Cinchona Bark of commerce. The principal sources of information bearing on this phase of the subject are the several reports of the plantations in Java, India, and Jamaica. Howard's Quinology of the East Indian Plantations, Markham's Peruvian Bark, Kuntze's Arten, Hybriden und Cultur der Chininbäume, Hooper in the Pharmacographia Indica, several contributions by Trimen to the Tropical Agriculturist, and Rusby in the Pharmaceutical Record, October, 1887. The literature of the cinchona hybrids is hopelessly confused by the same name being frequently used by different authorities for the different hybrids and the one hybrid having various names. Thus, C. robusta of Trimen is known in Ceylon as C. lanosa, and in the Neilgherry Hills as C. magnifolia, also as C. pubescens.
C. Calisaya Weddell, is tall, usually surpassing those about it, the trunk often more than two feet in diameter. Leaves petiolate, the blade ovate-oblong to slightly obovate, 7 to 17.5 cm. long by 2.5 to 7 cm. broad, obtuse, the base acute or slightly attenuated, very thin, smooth, and, especially below, with a satiny luster, above dark green, below emerald-green or deep purple-green, scrobiculate, the glands scarcely visible above. Stipules oblong, about equalling the petioles, very smooth, very obtuse. Panicles ovate to subcorymbose. Calyx pubescent, with a cup-shaped limb and short triangular teeth. Corolla rose-colored (in cultivation often white or nearly so), the tube cylindrical and about 8 mm. long, the laciniae more deeply colored, the edges white-hairy. Stamens included. Capsule ovate, scarcely as long as the flowers. Seeds elliptical lanceolate, the margin irregularly fimbriate-toothed. Bolivia and Southern Peru, 4000 to 6000 feet. Source of the Calisaya or Yellow Bark. The species presents many forms, and two varieties are recognized.
C. Ledgeriana Moens., formerly recognized as a variety of C. Calisaya, differs from the type chiefly in its thicker, narrower, oblong leaves, with attenuate base, often bluish-green below. It yields a thick and remarkably rich bark, and is probably the most valued of all the cinchonas. This species was named in honor of Ledger, who first brought seed of this species from Bolivia.
C. succirubra Pavon, Mas. (Howard in P. J., Oct., 1856, p. 209, with a figure). Extreme size even greater than that of the last. Branches silvery. Petiole pubescent, leaf ovate to oval, acute with a very short point, the base more or less narrowing, often 6 by 9 inches, dark green and smooth above, below paler and pubescent to a variable degree, especially on the veins, not scrobiculate, the margin slightly revolute. Stipules entire, oblong, obtuse, sub-amplexicaul. Flowers much as in the last, but rather smaller. Fruit lanceolate. Western slopes of Mt. Chimborazo. The source of the Red Bark.
C. officinalis Hooker fil..Petioles smooth, cylindrical, and, like the veins, reddish; blade 10 to 12.5 cm. long, varying from broadly oval to lanceolate, acute at both ends, the margins usually recurved, smooth and deep green above, paler, but bright green below, scrobiculate, the principal veins pubescent. Stipules equalling the petioles, ovate, acute, entire, pubescent. Flowers and fruit much as in C. Calisaya. Widely distributed in the equatorial Andes, at an elevation of from 5000 to 7500 feet. The source of the barks known as Pale, Crown, Loxa, Cuenca, and Huanuco. This is the original species, upon which the genus Quinquina or Cinchona was founded. All things considered, it is, perhaps, to be regarded as the principal species of the genus and its variability is extreme.
The specific variations produced by hybridization in the above characters may not be here considered, though it may be stated that they are entirely characteristic. The parentage of a hybrid is ordinarily fully and strongly indicated in its appearance. As a rule, also, the alkaloidal yield takes a mean between that of the parents, but sometimes this is conspicuously not the case. Goris and Reimers (Trav. Lab. Nat. med. Ecol. supe. Pharm., in Bot. Centralbl., 1906, p. 462) pointed out the use of Cinchona robusta Trimen as a collective name for all hybrids of C. succirubra and C. officinalis. Rosenthaler gives an account of the structural characteristics and alkaloidal content of C. robusta and other cinchona hybrids produced by grafting. (B. P. G., 1908, p. 126.)
The genuine Cinchona trees are natives exclusively of South America. In that continent, however, they are widely diffused, extending from the 19th degree of south latitude, considerably south of La Paz, in Bolivia, to the mountains of Santa Marta, or, according to Weddell, to the vicinity of Caracas, on the northern coast, in about the 10th degree of north latitude. They follow, in this distance, the circuitous course of the great mountain ranges, and for the most part occupy the eastern slope of the second range of the Cordilleras. Except northward from Guayaquil, both the western slope and the plateau are entirely too dry or too cold for these plants, which require a moderate and equable temperature and an abundant and fairly constant supply of water. Irrigation cannot supply the place of a humid climate, for the atmosphere as well as the soil must be well charged with moisture. A certain amount of dry weather is, however, required for the ripening of the capsules. Free drainage is an important condition. Cross and others, who have personally inspected the region in the Andes where the best barks are obtained, have found the Cinchona trees only on the well drained slopes, and never on wet ground. With regard to temperature, Cross found that in the region of the C. officinalis the variation was from 1.1° to 21.1° C. (34°-70° F.), a fall below 40° or a rise above 65° being rare, and the mean range being from 45° to 60°.
The limits of altitude and climatic conditions are closely drawn. In the most southern districts, the trees descend to about 2500 feet, "while in the warmest regions they scarcely ascend to the 10,000-foot level. The individual species are for the most part rigidly restricted as to altitude and latitude, and, indeed, it has not always been found easy to detect the climatic conditions which would cause one species or variety to thrive while another very near it would languish. This is especially true of the more valuable forms.
It is to be noted that at present the stocks of wild barks have been enormously reduced, as detailed under Commercial History. Indeed, in certain sections, as the Calisaya district, the tree was practically exterminated in the wild state, so far as relates to a bark supply. From the far interior, however, occasional bales of wild Calisaya have been received. The low price of cultivated bark since 1885 has resulted in checking the destruction of the wild trees, which have begun again to multiply, so that they may possibly become once more common or even abundant. The Crown Bark region of Ecuador is still fairly productive, and in Colombia and Venezuela there are vast supplies of more or less inferior barks which await some favorable change in the market—never very likely to take place—that will render their collection profitable. Even at present a limited and irregular supply of one of these barks is furnished. With the exceptions here noticed, our present supplies of bark are entirely the product of cultivation, to which, therefore, we must give our chief attention.
Cultivation and Production.
The alarming prospect of the failure of the supply of Cinchona bark (see Commercial History) induced Europeans, about the middle of the nineteenth century, to turn their attention to the possibility of introducing the trees to cultivation. So early as 1737, La Condamine had collected a large number of young plants, with a view of conveying them to Europe; but, after having descended the Amazon in safety for more than a thousand leagues, they were washed overboard, near the mouth of that river, from the boat containing them, and were all lost. After this failure, though the idea of transplanting the Cinchonas was occasionally suggested, nothing was done until 1846, when Weddell, now celebrated for his successful exploration of the region of the Calisaya bark, sent some seeds to France, which were planted with success in the Jardin des Plantes, and thus supplied some of the conservatories of Europe with specimens of the plant. But the first successful effort with a view to great practical results was made in 1853 by the Dutch government, by which Hasskarl, formerly superintendent of the Botanical Garden in Java, was sent to South America on this important mission. Five hundred Calisaya seedlings were forwarded by him directly across the Pacific to Batavia, which they reached before the close of 1854. From these, and from seeds obtained from other sources, which were planted in the mountains of Java, in sites selected for their supposed conformity in climate with the native locality of the Cinchona, have sprung the most important plantations now in existence.
Stimulated by the suggestions of Royle, and by the partial success of the Dutch, the English government engaged, in 1859, the services of Clements R. Markham, who proceeded to Bolivia, in South America, and, after almost incredible hardships, arising partly from the nature of the country and partly from the jealousy of the native authorities, succeeded in collecting and transmitting to England upwards of 400 Calisaya plants. Most of these, however, were so much injured on their way from England to India, by the excessive heat of the Red Sea, that very few, on their arrival in Hindostan, had sufficient life remaining to grow when planted. Happily, the deficiency was supplied by seeds of C. Calisaya sent from Java, to Calcutta, at the request of the English Governor-General. While Markham was in Bolivia, other agents were collecting other species in Peru and Ecuador, whence seeds of the pale and red bark Cinchonas reached India, and, being planted in the selected sites, proved to be very productive.
Careful attention to the conditions of growth enumerated under Geographical Distribution was found essential in the selection of sites for the plantations. Those selected were near the Sanitary Station of Ootacamund in the Neilgherry Hills of Southern India, at heights varying from 5000 to 7450 feet. These positions unite the peculiar characters of the native regions of the Cinchonas in the Andes, not only as regards elevation and latitude, but also as to atmospheric moisture. Other sites were selected for experimental plantations, and since the first introduction of the Cinchona trees, their culture has been extended to various points from Hakgalla, in the island of Ceylon, to the Himalaya Mountains,—as in the Wynaad, the Coorg, the hills of Travancore, and especially at Peermede in the Presidency of Madras; in Sikkim and Darjeeling in the Presidency of Bengal; at Lingmulla in the Presidency of Bombay; and in the valley of Kangra in the Punjab,—from the southern to the northern extremity of British India. Outside of India and Ceylon, culture by the British has been undertaken in the West Indies, particularly Jamaica, in Guiana, and in the Fiji Islands. The first plants taken by Weddell from Peru to Paris all perished, but the French afterward established plantations in the Isle of Bourbon, at Guadeloupe, and in Algiers, none of which are known now to exist. The Portuguese have established plantations upon the west coast of Africa, and these now yield considerable quantities of bark. Very extensive plantations have been formed, chiefly by the Germans, in Bolivia, A rather large plantation in Colombia is now old enough to be productive. In Mexico and Central America various attempts to introduce the industry have been made. The question of introducing it into the United States has frequently been raised, but it may be stated that there is no spot in North America where the conditions warrant the slightest hope of success in this direction.
The history of Cinchona cultivation affords a striking illustration of the importance of government aid in the establishment of a new industry of this kind. The early and repeated disappointments and failures, owing to the natural obstacles in the way of securing stocks, and to an almost total ignorance of the conditions determining the successful propagation and growth of the plant, and the composition of its bark, were such as to have discouraged the most hopeful of private enterprises. Repeated and expensive expeditions were necessary before the first transplantings were accomplished, and these stocks were preserved and propagated only through the instrumentality of well appointed public gardens and plantations. In Java, after these early difficulties had been surmounted and success apparently attained, it was found that owing to cross fertilization much of the progeny was entirely worthless, and the work of propagation had to be begun anew. The same difficulty was encountered elsewhere, and the slow and expensive method of propagation by cuttings was largely resorted to. In Ceylon the public were slow to become interested, and the officials were obliged not only to give away the young plants, but to solicit experiments with them as a personal favor. In Jamaica a hurricane visited the young and flourishing plantations and almost completely destroyed them. But at length, in spite of all, not only were thriving and permanent government plantations established, but private capital and enterprise upon a vast scale were enlisted. The question of commercial success is dominated not simply by climatological surroundings, but also by the price of labor. It is stated that both in India and Java the natives who work in the cinchona forests are paid from one dollar to one dollar and seventy cents per month, without food, according to the age and sex. The ability to extract the bark upon the spot is capable of largely counterbalancing a lack of market facilities; but it so happens that this advantage also inures to the benefit of the Eastern countries. Originally undertaken in India for the purpose of affording a cheap antiperiodic (the crude alkaloids known as "febrifuge" or "quinetum") home extraction has become a most important industry, and has assumed various forms. In Java the powdered bark is thrown into a 5 per cent. solution of caustic soda at 50° C. (122° F.) treating this with Java petroleum, separating, treating the petrolic solution with water acidulated with sulphuric acid and evaporating; the result is said to be a quinine containing less than 1 per cent. of cinchonine. (J. P. C; 1901.) It is imported largely into the United States—50,000 kilogrammes a year—but on account of its yellow color is chiefly employed in the making of proprietary medicines rather than tablets. Through the influence of the above conditions the locations of the important industry of Cinchona cultivation have been gradually wrought out, and at present about four-fifths of the cinchona barks of the world, outside of India, are furnished by Java. The first shipment from Java was of 900 pounds, in 1869. In 1902 it was 14,700,000 pounds and in 1911 over 20,000,000 pounds. India produces annually over 2,000,000 pounds; Ceylon about 400,000 pounds; Portuguese West Africa about 180,000 pounds, and South America 775,000 pounds. Tunmann estimates that the yearly output of cinchona bark is about 10,000,000 kilogrammes, and the production of quinine as about 500,000 kilogrammes. (Apoth. Zeit., 1910, p. 565.)
It is to be remembered that a great part of the Indian product is not exported.
Methods of Cultivation.
The history of Cinchona cultivation teems with evidence as to the difficulty of obtaining pure seeds, owing to the tendency of the plants towards cross-pollination. In every locality where the industry has been established has the disgust of the gardener been excited by the discovery that the plants which he had reared. with great care, and upon which he bad based great expectations, were contaminated by the admixture of foreign pollen. This was especially true in case of the earlier attempts, before this tendency had become known. Experience at length established the fact that absolute isolation of the seed-trees was essential. One of the curious developments of these experiments was the fact, already referred to, that the value of the progeny was not always assured by the value of its parentage. Some of the hybrids, even when least expected, would develop a surprisingly rich yield; and this tendency has been utilized to develop the most valuable stocks in existence. So certain is it that some of the plants from the best seed will prove worthless, that the careful selection of the seedlings while young is deemed necessary, and in South America, at least, all planting contracts are based upon this expectation, the contractor not being paid for his work until the plants have become old enough to show with certainty the proportion of good plants contained. Both in the selection of the young seedlings and the acceptance of the plantation, the test of identity is found in the leaf. Propagation by cuttings, extensively practised in some localities, has been found too slow and expensive to become general. A thorough preparation of the soil is as beneficial in the case of Cinchona as in that of other crops. Thorough tillage after transplantation is also essential, a free growth of weeds meaning destruction to a large number of the young trees. The cultivation of a secondary crop between the rows of trees is, however, practicable. A large percentage of profit depends upon the selection of a suitable age for collecting the bark. There comes a time when the use of the ground for starting a new crop is more valuable than the gain by permitting the present crop to remain, and after some years an actual deterioration of the bark sets in. This age is not the same for all the trees in the plantation. Several years' difference may occur in the maturing of trees germinated at the same time. In the case of Calisaya it occurs at from six to nine years from seed, and its indication is the it "chicken-leg" scaliness of the bark, as described under Classification. The "officinalis" matures somewhat less early. In the Bolivian plantations the most experienced hand is selected as the marker, and the cutters follow him, peeling the trees which he has indicated. How far these careful methods of selection are followed elsewhere, the writer is not informed.
Collection of Bark.
Four principal methods of collecting the bark are in vogue, these being variously modified in different sections. The first is uprooting, the most primitive, by which the trees are simply uprooted at the proper age, and the ground replanted. The barks of root, stem, and branches are preserved and marketed separately. The second method is coppicing, by which, after peeling a quill from the lower portion of the trunk, the latter is cut a few inches from the ground and the remainder of the stem bark and the branch bark are removed. The "coppice" is formed by a second growth of two shoots from each of the stumps. A second coppice is commonly grown, and this is harvested by uprooting. By the third method, scraping, the outer bark is scraped off, leaving the liber untouched. This has been found especially applicable to young trees, in which the second growth of bark is rapidly formed and contains 20 to 30 per cent. more alkaloid than that which has been taken off. It seems to be a general opinion among the planters that scraping checks the growth of the tree after it is five years old, so that from three to five years is the age at which it is best practised. The fourth method is known as mossing. It having been noticed that the Cinchona alkaloids, especially in any other form than that of sulphate, were apt, on exposure to the direct light of the sun, to become reddened by the generation of coloring matter, at the expense of the alkaloid, it was a very natural inference that a similar change might take place in the living plant, as a consequence of which the proportion of alkaloids they were capable of producing might be greatly diminished. It was also observed that the bark upon that side of the tree where the sun struck it was less rich than that upon the shady side. To obviate this presumed effect, Maelvor was induced to make the experiment of covering the stems of the growing trees with a layer of moss, so as to completely protect the bark against the influence of sunlight. The result was favorable beyond all expectation, and the yield of alkaloids in the bark thus protected is said to be doubled, tripled, or increased even in larger proportion. A tree can thus be made continuously productive; for if a slip is removed longitudinally from the trunk, from top to bottom, by covering the decorticated portion with moss, the bark is renewed at least as rich as previously in the alkaloids, while from time to time other strips may be taken, until the whole of the old bark is removed, and the new ready for removal by a repetition of the same process; and the tree is thus preserved indefinitely, probably for the whole normal length of its life. Hooper says that renewed bark is always of greater value than the mossed, and mossed than the natural, so long as the trees are under twenty years old, for it has been found that after that time the bark ceases to thicken, and the alkaloids remain stationary or even decrease. Perhaps twenty years is even too old. The practical difficulty with the process is that it requires skilled workmen, not always attainable, and hence the " coppicing system" still largely prevails in India.
The methods of packing the bark have also undergone important modifications since the early days of cultivation. The extensive adulteration practised when the wild bark brought very high prices led to a demand for it in large pieces which could be readily and quickly examined; hence the appearance of the large tabla and quill forms, the latter afterwards becoming the standard for the cultivated bark. The bark of the trunk, and sometimes of the branches when very large, is cut into two-foot lengths, and each length removed in a single piece, which in drying rolls up to form a quill. Such peeling can of course be successfully practised only at the appropriate season of the year. The bark or the roots, branches, and dead or dry trunks must be removed by chipping, scraping, or shaving, commonly the latter. The quills, after thoroughly drying, are carefully packed in bales, or preferably in boxes, to avoid breakage, and are marketed in packages of from 100 to 250 pounds. Large quantities of cultivated bark are still marketed in this way, but, increasing competition having lowered prices so that economy in freight has become a very important item, most of the bark is now broken up, and its bulk even reduced by high pressure, and in fact only a trifling amount of wild South American bark comes into commerce. Cultivation has very greatly increased, not only the quantity, but also the quality of bark. For some years, in India the attempt was made largely to increase the general average in total alkaloids rather than in quinine, so as to increase the production of the impure alkaloids which are so largely used as febrifuges in the British East Indies. Of recent years, however, even in India, efforts have been directed to the obtaining of quinine rather than of inferior alkaloids. The barks of Ceylon have always been of poor quality, while those of Java to-day are probably the best that have ever been put upon the market. The effect of the efforts of arborculturists is well shown by the facts that in 1889 the average percentage of quinine in Java bark was 4; in 1893 it had risen to 4.6; while in the five years, from 1900 to 1904 inclusive, the average quinine percentage of all the Java barks sold in the Amsterdam market was 5.37. The result does great credit to Java, for during the early history of her bark. enterprise her plantations were stocked with discouraging quantities of poor or even worthless barks, which have been eliminated by the most steady enterprise and patient industry. David Howard presented a comprehensive survey of cinchona barks and their cultivation. (J. Soc. Ch. Indus; 1906, p. 97.) Winkler describes the methods employed in the cultivation of Cinchona in Java, also the manner of collecting the bark and preparing it for market. (Der Tropenpflanzer, 1906, p. 222.) Bohringer gives a review of the progress in the cultivation of Cinchona in Ceylon. (Tropenpflanzer, 1909, p. 269.) Schneider discusses the possibility of cultivating Cinchona in California. (W. D., 1906, p. 136.)
The above general history of Cinchona leaves little necessary to be said of its commercial history, except to deduce from the facts already presented certain practical conclusions showing the present conditions of supply and demand, these bearing especially upon our concluding remarks concerning pharmacognosy and classification.
For more than a century after Peruvian bark came into use, it was procured almost exclusively from the neighborhood of Loxa. In a memoir published in 1738, La Condamine speaks of the bark of Riobamba, Cuenca, Ayavaca, and Jaen de Bracomoros. Of these places, the first two, together with Loxa, lie within the ancient kingdom of Quito, at the southern extremity; the others are in the same vicinity, within the borders of Peru.
Towards the end of the eighteenth century, however, the trees were discovered to exist in Colombia, in central Peru, near Lima (whence the name Lima bark, at one time applied to the drug) and in Bolivia.
The consequence of these discoveries was a vast increase in the supply of bark, which was now shipped from the ports of Guayaquil, Payta, Luna, Africa, Buenos Ayres, Cartagena, and Santa Marta. At the same time the average quality was probably deteriorated; for, though many of the new varieties were possessed of excellent properties, yet equal care in superintending the collection and assorting of the bark could scarcely be exercised in a field so. much more extended. The varieties poured into the market soon became so numerous as to burden the memory if not to defy the discrimination of the druggist, and the best pharmacologists found themselves at a loss to discover any permanent peculiarities which might serve as the basis of a proper and useful classification. More or less perplexity attending the recognition of the barks continued until after the firm establishment of the bark culture and the cheapening of the price, to the exclusion of the worthless varieties, as already described.
One of the most important developments of the modern bark trade is the fixing of the price in accordance with the quality as determined by assay. The most accurate method of selecting a characteristic sample for assay is a subject which has received much study, without the discovery of any method which does not depend for its value upon the discrimination and care exercised in its employment. The plan which is regarded as the safest, is to take a given weight, say eight ounces, from the inner portion of each package constituting the lot, mix and powder the whole of it, and furnish to applicants the required amount of the resulting powder. If any portion of any bale or bales is damaged, care is taken to add a proportionately large fragment of such portion. The bark is then recorded as containing so many units, a " unit" being each per cent. of quinine contained in a pound of bark. In rich bark the units are of course worth more than in poor, owing to the increased yield of alkaloid for the same cost of manufacture.
In the United States, at least, some difficulty has been experienced by druggists in securing the better grades of bark at regular rates, owing to the activity of the manufacturers in draining the market of the most desirable stock. The finer appearing packages of unbroken bark, having been marketed at greater cost, are necessarily held at higher prices. Possessing no special value for manufacturing purposes, these fall to the share of the druggist, but at higher prices than broken bark of the same richness. This fact has led to the recognition of two distinct classes, known as manufacturers' bark and druggists' bark. Druggists' bark, though in quills or unbroken pieces, and of a much finer appearance than manufacturers' bark, is on the average, inferior in quinine percentage. The druggists' bark finds its entrance into commerce through various channels but the bulk of the cinchona trade, including practically all that is known as manufacturers' bark, centres in Amsterdam and London; of these marts that at Amsterdam is much the more important. In 19.1-6 there were imported into the United States 3,947,320 pounds of cinchona barks, and 1,791,738 pounds of quinine sulphate and other salts of the cinchona alkaloids. The bark which is sold in Amsterdam comes almost exclusively from Java; that in London from India, Ceylon, and South America. Manufacturers' bark is sold, without respect to its physical characters or place of origin, entirely by its chemical analysis, the buyer in London being furnished with samples of the different lots of the bark sufficient time before the sale to enable him to make his own analysis, while in Amsterdam the percentage of quinine sulphate in any lot is given in the catalogue and often tagged upon the bale.
Formation of the Alkaloids.—In a very careful series of experiments made at the Java governmental cinchona plantations, Lotsy (Bull. Inst. Botanique Buitenzorg, 3, 1900) found that the seeds of C. succirubra and C. Ledgeriana contain no alkaloids, but that these alkaloids appear in the cotyledons shortly after they become green. They exist chiefly in the bark in combination with a tannic acid. Lotsy found that the percentage of alkaloids is ten times greater in young than in old leaves; also that the petioles are richer in alkaloids than is the blade, and that the branch bark contains more than the trunk bark, and that the root bark is practically free from alkaloids. During the active life of the parenchymatous cells of the leaves, wood, and cortex, the alkaloids can always be found in the active protoplasmic contents, but when these cells pass into the inactive condition, are deposited in the cell-walls. The alkaloids found in the leaves are, however, never crystalline, hence it would appear that these organs produce by direct synthesis, probably as the result of the action of cinchonic acid with ammonia, a fundamental alkaloidal base, which probably in the cambium layer of the tree, and during its deposition in the growing bark, is elaborated into the true cinchona alkaloids.
Extreme difficulty attended the earlier attempts to classify the Cinchona barks of commerce,—difficulties not probably encountered elsewhere in the Materia Medica. The varieties have, however, been reduced to a very few, and the whole subject decreased greatly in importance by the chemical method of the sale now in vogue. Most of the discarded barks will be found described in previous editions of this work. We find it necessary to enumerate and describe here only the Pale bark, from C. officinalis, the Red bark, from C. succirubra, the Yellow bark, from C. Calisaya and its var. Ledgeriana, and the Hard Yellow or Maracaibo bark, and to refer briefly to the hybrid forms. First, a few words concerning the forms in which Cinchona bark occurs. We have (1) the large flat pieces or chips of irregular shape and size,—this referring at present almost wholly to the Maracaibo variety; (2) the small chips or broken bark, referring in large part to the root bark, and to other bark broken for close packing; (3) the shaved bark, referring to some root bark and to stem bark taken from dry stems, but chiefly to branch bark; (4) the quill bark, referring to natural bark taken from the stem and root in quill form, this including the uncultivated pale bark and all the varieties of cultivated bark; and (5) the renewed and mossed bark, which may be of any cultivated variety. The classification of all varieties and forms into druggists' and manufacturers' barks enables us to dispense in great part with a description of some of these forms. The manufacturer cares nothing for form, appearance, or structure, and but little for the variety of his supplies. He is interested wholly in its composition, and this he determines by assay. For this reason most of the broken bark goes to him. The druggist requires the quill or large chip bark; so that the great bulk of the branch bark is also thrown, at low prices, upon the hands of the manufacturer.
As regards the root barks, no classified description is available. In their structure they correspond very closely to the stem barks of the same variety. They can be readily distinguished from the latter by being thinner, having lighter external and darker inner color, greater softness, and twisted or contorted structure. They occur in short, irregular quills or chips, or sometimes as shavings, and contain very much more dust than any other form. Except partly as regards structure, the description of stem barks will not apply to branch barks of the same variety, for the characteristic markings do not appear in the young condition. The branch bark appears in shavings, to the inner surfaces of many of which more or less wood adheres. If the branches were shaved while yet fresh, these shavings will be more or less rolled up and curled; but if dry before being removed, this rolling and curling will not occur. Shaved bark taken from living trees is thin, soft, and brittle, consisting of the outer bark only. The large quills are of uniform length from the same plantation, but not necessarily so from different plantations or different sections. They are commonly from two to three feet in length, but some have been marketed having a length of five feet. Usually they represent the entire circumference of the stem, but occasionally only half of it. In drying they roll up very tightly from one or both edges, and rarely one will be wholly or partly involved in another. The periderm, with all its markings, remains intact, and no other form so well displays the natural appearance as this. Mossed bark differs from natural stem bark in its great thickness and weight, less breadth of the quills, freedom from lichens, very dark color, and rough, corrugated or warty surface. The outer bark or cellular portion bears a greater ratio to the inner or fibrous portion than in natural bark. Renewed bark is lighter, both in color and weight, thinner, soft and brittle, and marked by a very peculiar external smoothness, sometimes very marked indeed. In its general appearance it is strikingly like a root bark, except for the relative straightness of its fibres. Like the mossed bark, it is in narrow, only partly rolled quills or bands, and is entirely free from lichens.
As they differ so greatly among themselves in coloration, lichen-growth, degree and form of exfoliation, structure and consequent fracture, there are but few characters which can be combined in a general description of the Cinchona barks which we consider. The external color varies from light ashy gray to nearly black, the inner varies less in its shades of yellow-brown and red-brown. All are more or less bitter, and most are astringent, but only Loxa bark has a distinctive odor. The fracture is never very long-splintery and never tough. As to structure, the bast fibers are loosely arranged, the radial rows being neither continuous nor very long. The fibers themselves are always unbranched, which distinguishes the true from the false barks, are rather short and obtuse, brittle, and usually easily detached from the bark. Laticiferous ducts and stone-cells may or may not be present. The former become less conspicuous as the bark grows older, so that their relative absence becomes indicative of a stage in which the due proportion of alkaloid should have been acquired.
It may be noted here that by far the greater portion of the alkaloid, particularly quinine, is stored in the outer bark, though that in the inner bark is in a purer state. The latter is not stored in the fibers, but in the cellular tissue between them.
As regards the former classification of barks by color, it referred only in small part to the external color, chiefly to the powder. These colors were never regarded as absolutely characteristic, as the three barks, yellow, red and pale, exhibited gradations by which they mingled at their extremes. Under present conditions, the lines of demarcation have become even more indistinct, and, as a matter of fact, in the market the terms " yellow " and " red " are used with great looseness. It is true that we receive much pure-blooded Yellow Bark, Ledgeriana from the East, and Calisaya both from there and from South America; but it is also undeniable that much of the bark sold under the several names is of mixed hybrid, and the typical characters are often greatly obscured. The presence in our market of these mixed forms has made the terms even less valuable than they once were, and dealers cannot be found to agree as to the character of many samples. Nevertheless, the occurrence of the typical forms, and appearance in a hybrid of the blended characters, render it desirable to preserve this classification, and to group the new forms around the types.
Yellow or Calisaya bark. Cinchona flava.
The official description is as follows: "In quills or curved pieces of variable length, bark from 3 to 5 mm. in thickness, or in small broken fragments or in transversely curved pieces from 3 to 7 mm. in thickness, externally gray, rarely brownish-gray, with numerous intersecting-transverse and longitudinal fissures having nearly vertical sides, and usually with patches of foliaceous lichens with their small, brownish-black apothecia; when the outer bark is absent, the color externally is cinnamon-brown; inner surface light cinnamon-brown, finely striate; fracture of the outer bark short and granular, of the inner bark finely splintery; odor faintly aromatic; taste very bitter and somewhat astringent. The powder is reddish-brown; bast-fibers spindle-shaped, yellowish, from 0.3 to 1.35 mm. in length, with thick, strongly lignified, lamellated walls having slit-like, oblique pores; starch grains single or 2- to 5-compound, the individual grains spherical or plano-convex and from 0.003 to 0.015 mm. in diameter; sphenoidal micro-crystals of calcium oxalate numerous. Heat 1 Gm. of powdered Cinchona in a dry test tube; a tarry distillate forms, having a purplish color and a somewhat granular appearance." U. S.
Its lichens are thin and closely adherent, not rendering it shaggy. External markings very characteristic, consisting of a very light longitudinal ridging or none at all, but of numerous transverse and longitudinal fissures or cracks, the presence and arrangement of which constitute the chief characteristic of Calisaya. Upon the young stems and branches they do not appear. The first to appear are the usually large primary fissures, which encircle the stem at the nodes, or points where pairs of leaves once stood. Subsequently, numerous smaller secondary transverse fissures appear upon the internodes, and these quickly become connected and crossed by longitudinal cracks, thus dividing the periderm up into more or less quadrangular checks, which may remain attached or fall away. This gives to mature Calisaya bark an appearance of scaliness like that upon the tarsus of a fowl, and this is known to the South American collectors by a term which signifies the "chicken-leg appearance." It has also been spoken of as a "carving-like" marking. Like the roughness upon a musk-melon, its great development is regarded as an indication of high quality, and especially is this true of a close proximity of the primary fissures. This roughness is also regarded as a sure indication of maturity. There are excellent distinctions between these and the somewhat similar fissures upon the bark of C. officinalis. In the latter they are coarser and more gaping. Even more important is the absence from Pale Bark of most of the longitudinal cracks, so that it does not become " chicken-legged," or at most only very slightly so. The external color of Yellow Bark is lighter than that of the Pale Bark. Longitudinal ridges are few if any, short, irregular, and inconspicuous. In fine South American bark some very small bright-red spots can be detected upon the periderm. East Indian Calisaya can commonly be recognized by its somewhat dingy or brownish shade of gray, the gray of the South American bark being bright and somewhat bluish-steel-colored.
In structure, the zone of large, rather numerous laticiferous ducts just outside the bast is conspicuous in young, and therefore inferior, samples. The rather small bast fibers are loosely scattered, almost uniformly single or a radial arrangement being apparent. The fracture is rough-splintery, though not coarse. Stone cells few or none. Odorless, more bitter, and less astringent than the Pale Bark. Ledger bark is the same as Calisaya in all its essential characters, but does not reach so great a size. In hybrids of Calisaya with succirubra the characters and quality of the latter appear to predominate.
This bark is scarcely collected in a wild state, but cultivated in all plantations. It is the largest quinine yielder, its amount being 70 to 80 per cent. of the total alkaloids contained in the bark. The var. Ledgeriana yields a very valuable hybrid bark with C. succirubra. C. Calisaya also hybridizes with the latter species. Hartwich describes the microscopical characteristics of Cinchona and related barks in S. W. P., 1909, p. 249. Grutterink discusses the micro-chemistry of Cinchona alkaloids, with illustrations in Zeit. anal. Chem., 1912, p. 215. Rosenthaler reviews the pyro-analytical results that have been obtained with Cinchona bark and describes the crystals found in the tar. (B. P. G., 1911, p. 203.)
Red bark. Cinchona rubra.
This bark is recognised by the U. S. and Br. Pharmacopoeias (for definition, see page 333). It is described in the U. S. P. IX as "in quills or curved pieces of variable length, bark from 2 to 4 mm. in thickness, or in small broken fragments or in transversely curved pieces from 3 to 7 mm. in thickness; externally gray, grayish-brown, or reddish-brown, more or less rough from corky protuberances, occasionally with transverse fissures which are rarely numerous or much intersected, and having their sides sloping, and with occasional patches of foliaceous lichens; inner surface reddish or orange-brown, distinctly striate; fracture short and granular in the outer bark, shortly and rather coarsely splintery in the inner bark; odor slight; taste very bitter and astringent. The powder is light brown; bast-fibers and sphenoidal micro-crystals of calcium oxalate, resembling those in cinchona; starch grains resembling those of cinchona relatively few, from 0.003 to 0.01 mm. in diameter. Heat 1 Gm. of powdered Red Cinchona in a dry test tube; a tarry distillate forms having a bright red color." U. S.
In the British Pharmacopoeia it is described as "In quilled or curved pieces, length varying from 5 to 30 cm. or more; usually from about 2.5 to 6 mm. thick; cork brownish or reddish-brown, with longitudinal ridges which are most apparent in the branch bark, and sometimes with reddish warts; inner surface brick-red or deep reddish-brown, irregularly and coarsely striated; fracture shortly fibrous in the smaller, and finely fibrous in the larger, pieces. In transverse section in the cortex, cells filled with minute crystals of calcium oxalate, and also large secretion tubes; in the bast numerous, large, strongly-thickened fibers usually 0.050 to 0.070 mm. wide and about 1 mm. long, isolated or in small groups. The powdered Bark is brownish or reddish-brown, exhibits abundant parenchymatous tissue with brownish cell-walls, and often with brownish contents, small starch grains, and large isolated bast fibers about 0.060 mm. in diameter, with distinctly striated walls. No marked odor; taste bitter and somewhat astringent."
The quills are similar to those of Calisaya, though running somewhat broader and thicker. Externally of a dingy brown gray, less lichen-bearing than either of the others. Inner surface of a more reddish cinnamon-brown than in Calisaya. Powder reddish-brown.
The important characteristic of red bark is the prominent longitudinal ridges, many of them short and confluent, with intervening furrows or elongated meshes. The ridges are suberous, bear numerous small warty protuberances, and may be traversed by faint fissures. Transverse fissures may or may not be present in red bark. If so, they are few, short, and irregularly disposed, and not connected by longitudinal cracks to give the checkered appearance of Calisaya. Hybrids with "officinalis" display numerous transverse fissures, and the external color is lighter and more dingy. Fracture short-splintery, not coarse. Odor none. Taste bitter and astringent.
It is scarcely collected in a wild state, but cultivated in all plantations except those of South America. Demand and production rapidly decreasing. A large alkaloid yielder, but of this only about 20 per cent. is quinine. Largely hybridized with C. officinalis. Also hybridized with C. Calisaya and its var. Ledgeriana.
Varieties and Synonyms.—Crown Bark, Loxa or Loja Bark, Cuenca Bark, Huanuco Bark. Derived from C. officinalis. Collected in a wild state above Loxa and other parts of Ecuador, and cultivated in all plantations except the South American, especially in India. Demand and production decreasing. Quinine constitutes 60 to 70 per cent. of the total alkaloids. Largely hybridized with C. succirubra.
Description.—Quills single or double, irregularly broken or entire, attaining a length of nearly 2 dm., a width of nearly 2.5 cm., and having a very wide range in thickness, the natural mostly 2 to 4 mm. thick. Shaggy, with more abundant lichens than in any other species, the abundance of these having been considered, not entirely without reason, as an indication of the relative quality. Color of periderm darker than in the other species, but varying much from a brown gray to nearly black. Inner surface of a paler brown than in the other species, finely striate. Color of powder pale brown. The external markings consist of transverse fissures and longitudinal ridges, some of them wart-bearing. It is only in the thinner samples, in which the warts and fissures scarcely appear, that the ridges are continuous and conspicuous. In the prominence and breadth of its fissures and the inconspicuousness of its ridges, this bark is most distinct from the Red Bark. These characters are yet sufficiently distinct from the somewhat similar ones of Calisaya, as noted in describing that bark.
Fracture short, the inner fibrous zone sharp and narrow. Taste not so bitter as in the others. Odor of the genuine Loxa variety peculiar and characteristic. Its structure shows the rather short and not numerous bast fibers in short interrupted single or double radial rows, and much disposed to occur in bundles of three to six or more. Stone cells rarely seen, and lactiferous ducts conspicuous only when young.
Hard yellow, or maracaibo bark. Puerto Cabello bark.
Derivation not at all certain. Collected only in a wild state in the mountains of Southern Colombia, and yielding almost the whole of the inferior wild bark now collected for market. Importation and sale in the United States quite irregular and unimportant. One of the best of the lower-grade barks, but not to be compared with any of those already described. Said to yield about 2 per cent. of crystallizable sulphates, three-fourths of which is quinine sulphate, but a characteristic specimen assayed for this investigation by Virgil Coblentz yielded 2.65 per cent. of total alkaloids, only a trace of which was quinine. Contains a large amount of resin. The common or commercial names by which have been designated the several barks of the northern countries related to this one are of very irregular application. At the time when the trade in them was large and important, the term "Maracaibo Bark" was restricted to the less resinous variety, derived from C. cordifolia. It was also formerly sold simply as "Yellow Bark," and it's not impossible that it was sometimes accepted, under this synonym, for Calisaya. The investigations of Morgenthau into the value of certain derivatives of cuprein may give these barks a real value. For a description of Cuprea Bark, see 19th ed., U. S. D., p. 349.
Description.—Rusby described it as occurring in irregular broken pieces, mostly from 5 to 15 cm. long, 2.5 to 7 cm. broad, and 3 to 10 mm. thick. Formerly it included many much smaller fragments as well as much dust, but these portions are now mostly sifted and winnowed out before marketing. The pieces are more or less flat, the thinner and narrower ones somewhat incurved, the broader and thicker recurved. The bark is compact, heavy, and fibrous. Most of the pieces display upon the outer surface more or less of the periderm, forming silvery-white or yellowish-white patches, very thin and rather soft. Occasionally the periderm is instead dark, hard, very rough, and much fissured. From many pieces the entire periderm is absent, disclosing the outer face of the bast, very similar to the inner face. This is compactly and rather finely fibrous, of a deep yellow, with a slight rust-brown tinge. Throughout, the bast is of this structure and color. Between it and the periderm there may be seen with varying distinctness, in most pieces, a characteristic resinous band of irregular width, dark reddish-brown and waxy-lustrous on the cut surface. The radial rows of bast fibres are irregular. The fracture is long-fibrous. The odor is distinct, and the taste quite bitter.
I have deleted 14 pages of agonizingly precise discussion of the alkaloids of Cinchona ... trust me—you don't need to know ... (--Michael Moore)
Uses.—This valuable remedy was unknown to the civilized world until about the middle of the seventeenth century, though the natives of Peru are generally supposed to have been long previously acquainted with its febrifuge powers. Humboldt, however, is of a different opinion. In his memoir on the Cinchona forests, he states that it is unknown as a remedy to the Indians inhabiting the country where it grows, and, as these people adhere pertinaciously to the habits of their ancestors, he concludes that it never was employed by them. They have generally the most violent prejudices against it, considering it poisonous, and in the treatment of fever prefer the milder indigenous remedies. Ruiz and Pavon, however, ascribe the discovery to the Indians; and Tschudi states, in his "Travels in Peru" (Am. cd., ii, 280), that the inhabitants of the Peruvian forests drink an infusion of the green bark as a remedy in intermittent fever. On the other hand, the statements of Humboldt have been confirmed by the travellers Markham and Spence, the former remarking that the native Indian doctors did not use the bark, and the latter that the Cascarilleros of Ecuador believed that their red bark is used solely for dyeing. It is uncertain whether, as Jussieu stated in 1739, the Jesuit fathers received their knowledge from the Indians, or, as Humboldt believes, discovered the virtues of the drug for themselves, having been led to make trial of it by its extreme bitterness. The Countess Chinchon, wife of the Viceroy of Peru, having in her own person experienced the beneficial effects of the bark is said, on her return to Spain in the year 1640, to have first introduced the remedy into Europe. Hence the name of pulvis Comitissae, by which it was first known. After its introduction it was distributed and sold by the Jesuits, who are said to have obtained for it the price of its weight in silver. From this circumstance it was called Jesuits' powder, a title which it long retained. In 1653, Chifflet, physician to the Archduke Leopold, directed the attention of all Europe to the bark by his work entitled Pulvis Febrifugus Orbis Americani. This gave rise to a very active controversy, the high price of the drug aiding very greatly those who opposed its introduction. According to Stunn, twenty doses in 1658 cost sixty florins. It seems first to have been advertised in England for sale in 1658 by a James Thomson, and by 1660 it was much employed. It still, however, encountered much prejudice and ignorance, and was not made official in the London Pharmacopoeia until 1677. Sir Robert Talbot (or Talbor) used it as a secret remedy with so much address and success that in 1679 he cured Charles II of a tertian, and subsequently sold his secret to Louis XIV of France, who published it in 1681.
When taken into the stomach, the bark usually excites in a short time a sense of warmth in the epigastrium, which often diffuses itself over the abdomen and even the breast, and is sometimes attended with considerable gastric and intestinal irritation. Nausea and vomiting are sometimes produced, especially if the stomach was previously in an inflamed or irritated state; and its action is not unfrequently accompanied by purging. If the dose of the cinchona bark has been large enough, the symptoms of cinchonism may result. At one time cinchona bark and its preparations were used as antiperiodics, but at present for such purpose one of its alkaloids is always selected. The best preparation for use as a tonic is the compound tincture.
Dose, ten grains to one drachm (0.65-3.9 Gm.).
Red cinchona.—Extractum Cinchonae Liquidum, Br.; Infusum Cinchonae Acidum, Br.; Tinctura Cinchonae, Br.; Tinctura Cinchonae Composita, U. S. (Br., from Tincture); Fluidextractum Cinchonae Aquosum, N. F.: Gargarisma Guaiaci Compositum (from Compound Tincture of Cinchona), N. F.
The Dispensatory of the United States of America, 1918, was edited by Joseph P. Remington, Horatio C. Wood and others.