Cinchonism is the name applied to the congeries of toxic symptoms
which follow the prolonged administration of quinine, but may
appear after one small dose in certain persons. The symptoms
closely resemble those of salicylism, and also, though in less degree,
those of carbolism. The patient is deaf, but complains of ringing
in the ears, which may assume various forms, especially in musical
people. There is headache, which, with the continuance of the
drug, becomes exceedingly severe, the vision and equilibrium are
affected, and there is often some gastro-intestinal irritation. In
cases where the drug has been deliberately given for its poisonous
action the results are still more severe. There may be bleeding from
the nose, cutaneous congestion, deafness, blindness, coma or delirium,
and even death from cardiac failure. After death there is
found one noteworthy lesion, a commencing acute inflammation
of the internal ear. In persons who have a marked idiosyncrasy
towards cinchonism, the symptoms may often be successfully averted
if small doses of hydrobromic acid—10 minims of the dilute solution—are
given with the quinine.
A non-official preparation of quinine—Warburg’s Tincture—occasionally succeeds where the ordinary preparations fail. The dose is 1 to 4 drachms. It contains 1 part of quinine in 50. Of the thirteen or more other ingredients, there may specially be noticed the salicylic and benzoic acids.
The, other alkaloids of cinchona bark—quinidine, cinchonidine, and cinchonine—also possess similar properties, but all are much less effective than quinine. This is also the case with the cinchona febrifuge prepared from C. succirubra.
The great disadvantage of the official preparations is the bitter taste and insolubility. It is found, however, that all the soluble salts are bitter, whilst the tasteless ones are insoluble. Substitutes may therefore be divided into those administered orally and those administered hypodermically. Of the insoluble salts we may notice the tannate, the propionic acid ester (euquinine) and carbonic acid ester (aristoquin), the salicylic acid ester (saloquinine); and of the soluble substitutes, quinopyrine (a compound of quinine hydrochloride and antipyrine) and quinine hydrochlorocarbamide (a compound of quinine, urea and hydrochloric acid).
Until 1867 English manufacturers of quinine were entirely dependent upon South America for their supplies of cinchona bark, which were obtained exclusively from uncultivated trees, growing chiefly in Bolivia, Peru, and Ecuador, the principal species which were used for the purpose being Cinchona Calisaya; C. officinalis; C. macrocalyx, var. Palton; C. Pitayensis, C. micrantha and C. lancifolia. Since the cultivation of cinchona trees was commenced in Java, India, Ceylon and Jamaica, several other species, as well as varieties and hybrids cultivated in those countries, have been used.[1] Later, C. lancifolia, var. Calisaya, known as the calisaya of Santa Fé, was strongly recommended for cultivation, because the shoots of felled trees afford bark containing a considerable amount of quinine; C. Pitayensia has been introduced into the Indian plantations on account of yielding the valuable alkaloid quinidine, as well as quinine.
The first importation from India took place in 1867, since which time the cultivated bark has arrived in Europe in constantly increasing quantities, London being the chief market for the Indian barks and Amsterdam for those of Java. Cinchona Calisaya has also been cultivated extensively in Bolivia and in Tolima, United States of Columbia.
In order to obtain the cultivated bark as economically as possible, experiments were made which resulted in the discovery that, if the bark were removed from the trunks in alternate strips so as not to injure the cambium, or actively growing zone, a new layer of bark was formed in one year which was richer in quinine than the original bark and equal in thickness to that of two or three years ordinary growth. This is known in commerce as “renewed bark.” The process has been found to be most conveniently practised when the trees are eight years old, at which age the bark separates most easily. The yield of quinine has been ascertained to increase annually until the eleventh year, at which it seems to reach its maximum. The portion of the trunk from which the bark has been removed is sometimes protected by moss, and the new bark which forms is then distinguished by the name of “mossed bark.” The species which yield the largest amount of quinine are by no means the easiest to cultivate, and experiments have consequently been made in cross-fertilization and grafting with the view of giving vigour of growth to delicate trees yielding a large amount of alkaloid or of increasing the yield in strong-growing trees affording but little quinine. Grafting, however, has not been found to answer the purpose, since the stock and the graft have been found to retain their respective alkaloids in the natural proportion just as if growing separately. Hybridization also is very uncertain, and is very difficult to carry out effectually; hence the method of propagating the best varieties by cuttings has been adopted, except in the case, of those which do not strike readily, as in C. Ledgeriana, in which the plants are grown from the shoots of felled trees.
Some years ago it was discovered that a bark imported from Colombia under the name of cuprea bark, or “hard” bark, and derived from Remijia pedunculata, Triana, and other species, contained quinine to the extent of 12 to 212%, and in 1881 this bark was exported in enormous quantities from Santander, exceeding in amount the united importations of all the other cinchona barks; and by reason of its cheapness this has since that date been largely used for the manufacture of quinine.
Cinchona bark as imported is never uniform in quality. The South American kinds contain a variable admixture of inferior barks, and the cultivated Indian barks comprise, under the respective names of yellow, pale, and red barks, a number of varieties of unequal value.
The alkaloids are contained, according to Howard, chiefly in the cellular tissue next to the liber. No definite knowledge has as yet been attained of the exact steps by which quinine is formed in nature in the tissues of the bark. From analyses of the leaves, bark and root, it appears that quinine is present only in small quantities in the leaves, in larger quantity in the stem bark, and increasing in proportion as it approaches the root, where quinine appears to decrease and cinchonine to increase in amount, although the root bark is generally richer in alkaloids than that of the stem. The altitude at which the trees are grown seems to affect the production of quinine, since it has been proved that the yield of quinine in C. officinalis is less when the trees are grown below 6000 ft. than above that elevation, and that cinchonidine, quinidine, and resin are at the same time increased in amount. It has also been shown by Broughton that C. Peruviana, which yields cinchonine but no quinine at a height of 6000 ft., when grown at 7800 ft. gives nearly as much quinine, and almost as readily, as C. officinalis. Karsten also ascertained by experiments made at Bogota on C. lancifolia that the barks of one district were sometimes devoid of quinine, while those of the same species from a neighbouring locality yielded 312 to 412% of the sulphate; moreover, Dr De Vrij found that the bark of C. officinalis cultivated at Utakamand varied in the yield of quinine from 1 to 9%. In these cases the variation may have been due to altitude. Free access of air to the tissues also seems to increase the yield of quinine, for the renewed bark is found to contain more quinine than the original bark.
QUINOLINE (Benzopyridine), C9H7N, an organic base first obtained from coal-tar in 1834 by F. Runge (Pogg. Ann., 1834, 31, p. 68), and later by C. Gerhardt by the distillation of cinchonine, quinine and other alkaloids with caustic potash (Ann., 1842, 42, p. 310; 44, p. 279). It also occurs with pyridine and its homologues in bone-oil. It may be prepared by distilling cinchoninic acid with lime; by the reduction of ortho-aminocinnamic aldehyde (A. Baeyer and V. Drewson, Ber., 1883, 16, p. 2207); by passing the vapour of allyl aniline over heated lead oxide; by the condensation of ortho-aminobenzaldehyde with acetaldehyde in the presence of aqueous caustic soda (P. Friedländer and C. F. Gohring, Ber., 1882, 15, p. 2572; 1883, 16, p. 1833); by the action of orthotoluidine on glyoxal at 150° C. (V. Kulisch, Monats., 1894, 15, p. 276); by the action of phosphorus pentachloride on hydrocarbostyril (the inner anhydride of ortho-aminohydrocinnamic acid), the chlorinated compound first formed being then reduced by hydriodic acid (A. Baeyer):
C6H4 |
CH2 – CH2 | → C6H4 |
CH=C·Cl | → C6H4 |
CH=CH |
| | | | | | ; | |||
| NH – CO | N=C·Cl | N= CH |
and by the so-called “Skraup” reaction, which consists in oxidizing a mixture of aniline, glycerin and concentrated sulphuric acid, with nitrobenzene (Z. Skraup, Monats., 1880, 1, p. 316; 1881, 2, p. 141). This reaction is a very violent
- ↑ In Java, C. Calisaya, vars. anglica, javanica, Hasskarliana and Ledgeriana; C. officinalis, var. angustifolia; C. lancifolia, C. caloptera C. micrantha and C. succirubra. In India, C. succirubra, C. officinalis, vars. angustifolia, crispa, Uritusinga and Bonplandiana, and to a lesser extent C. Calisaya, vars. Boliviano and microcarpa; C. micrantha, C. Peruviana and C. nitida form only a small proportion of the plantations. Since J. E. Howard pointed out that C. Pahudiana, and C. Calisaya, vars. javanica, Hasskarliana and anglica, were likely to lead to disappointment as quinine yielding species, these have been replaced in the plantations as rapidly as possible by the more valuable species, of which C. Ledgeriana, yielding from 5 to 10% or even more of quinine, C. officinalis, and a hybrid between C. officinalis and C. succirubra, which has been named C. robusta, are the most important.
