Nov., 1922.] THERAPEUTICS OF CINCHONA ALKALOIDS: CHOPRA. 401 and in the Himalayan range near Darjeeling. The cinchona trees are now so extensively culti- Original Articles. vated in Java, and to a lesser degree in India, that the world is entirely independent of South America The Dutch soon realised the great com- ~%HE THERAPEUTICS OF THE CIN- mercial possibilities of these plantations and devel- the cultivation of trees and CHONA ALKALOIDS. oped collection of the 1/ bark on a thoroughly scientific basis, thus making By R. N. CHOPRA, m.a., m.d. (Cantab.), Java the most important cinchona area in the world. Most of the bark at MAJOR, I.M.S., present is derived var. from C. calisaya ledgeriana, which grows Pharmacology, School island Professor of of Tropical luxuriously in that and has a very high Medicine, Calcutta. quinine yield. It contains 6 per cent, of this alkaloid and in exceptional cases 10 to 12 per PART 1. ? cent C. succirubra (red bark) yields 5 per cent of total alkaloids, of which 2 per cent, is I have written this as, a paper although great quinine ; C. calisaya (yellow bark) has 6 per cent, deal of work has been done the 3 recently-on of alkaloids, of which per cent, is quinine ; and .of cinchona bark, 1 have not been able alkaloids C officinalis contains 5 per cent, of total alka- to find a connected account of the modern views loids, of which 3^ per cent, is quinine. C. suc- of their action and from the therapeutics general ciruba has proved to be the hardiest and most of view. I have the practitioners' point Further, easily cultivated and is largely grown in India. of associated with H. W. privilege being Major It o-ives a high yield of total alkaloids 10 ? per Acton, whose classical researches on the i.m.sv cent. but the quinidine and cinchonine contents alkaloids are well in the :further cinchona known, predominate over that of quinine. The cultivation are now carried out in researches which being of C. ledgeriana is, therefore, now have had the of dis- being pushed this School and opportunity forward in India. The trees possess the with maxi- these alkaloids him, and this mum alkaloid cussing paper amount of yield when are embodies his views. they from 6 to 9 years old. The therapeutic effects of The genus Cinchona, from which this most vain- the bark are due to the alkaloids, of which is quinine able 'bark is obtained, indigenous to South is the best known : other alkaloids, quinidine, cin- embraces 36 America and species of evergreen chonine and cinchonidine have until recently been shrubs. They are all restricted to the eastern little used in medicine. of the in slopes Andes, extending from Western The bark is collected the rainy season, when Peru to Venezuela through Bolivia. At an alti- it separates easily from the stem. The old method tude between to 10,000 trees of the trees and 3,000 feet, these felling stripping the bark was a warm and flourish in moist climate, generally very wasteful, and Maclvor suggested removal of or even not forming forests groups, but attaining longitudinal strips 4 to 5 cm. wide at intervals, as in a considerable size, 'being much as 100 feet the trunk afterwards being protected with a cover- The trees at a lower altitude of when a fresh height. growing ing moss, growth takes its place ; contain little alkaloids. 1 he natives of these this is richer in alkaloid contents. This " process " had only an imperfect of the is known as mossing and Shav- parts knowledge " renewing."" of the a bark, as, they ing is modification of as febiifuge properties " although only mossing," here name of Kinakina," or a bark is gave it the bark of barks, only portion of the removed by shaving, it. In 1639 the its the left they seldom used bark found remainder being behind to protect the soon " way to Spain ; its fame spread to Italy and trunk. Another method of collecting is coppic- were in in which the tree is cut the Jesuits probably chiefly instrumental ing," down to form a it into France and Gradu- stool, and from this shoots introducing England. arise which yield a ally the properties of the bark became more and very good quality of quill bark. use became as the more known, its extended and Composition of Cinchona Bark.?The finely of the bark at that time bark is made only method collecting powdered into a stiff paste fears were a was by felling the tree, entertained that with slaked lime, sufficient quantity of hark from South America would water added. The the supply of being paste is dried and ex- to cease altogether. Attempts were then made tracted with hot petroleum which dissolves all into the transplant some of the species other countries alkaloids, and from this they are recovered named was and a German botanist Hasskarl by shaking with successive quantities of dilute sul- Dutch on an commissioned by the Government phuric acid. The alkaloids are dissolved in acid and solvent and are expedition, and he successfully brought plants precipitated by adding excess of seeds which were started in caustic soda to neutralize by plantations Java. the acid, and this con- Robert was sent A few years later Sir Markham stitutes the cinchona febrifuge, which is manufac- on a the tured similar errand 'by Indian Government and issued by the Government of India in suc- the and he succeeded in introducing Cinchona form of tablets, each supposed to contain 3-1 some into cirubra, C. officinalis and other species grains of the alkaloids. According to MacGil- and were started in christ India, plantations the Nilgiris (1915), the average composition of 402 THE INDIAN MEDICAL GAZETTE. [Nov., 1922. cinchona febrifuge prepared from C. succirubra The quinine derivatives are formed by alterations bark at Mungpoo, is as follows :? in the three groups, methoxy, hydroxyl and vinyl For ... 16*58% groups. example, cinchonidine differs from ld'n6 quinine in the absence of the methoxy group, Quinine 7*40% O. and if the is Quinidine ... 23 83% CH3 methoxy group replaced Amorphous alkaloids ...{Cinchonine Grouped under by an (OH) radicle, we get cupreidine. Quinoidin ... 29*12% A number of insoluble esters of Refuse, Moisture, Ash, etc.... ... 16*12% large quinine are prepared the II of the The bark also contains, in addition, certain by substituting (OH) group by another group. Such compounds are acids, neutral a volatile gums, principles, oil, insoluble and therefore tasteless and can be and matter.. easily starches, colouring less side Since Pelletiere and Dumas first isolated administered, produce actions, though quinine are not devoid of cinchonism. In and cinchonine, fourteen alkaloids have been dis- they altogether the stomach they remain unchanged, and 011 reach- covered to be present in the bark, but most of ing the duodenum, split up into quinine base, these occur in very small quantities and from a producing in this way a gradual and somewhat therapeutic point of view one need only consider weaker action. To this group aristochin alkaloids which can be in two belong eight grouped carbonic series :? (diquinine ester), eu-quinine (quinine carbonic sali- A. The cinchonine series which include cincho- ethyl ester), soloquinine (quinine cylic ester), and chenophenin (phenetidin quinine nine and its isomeri'de cinchonidine and the hydro- carbonic ester). The last two compounds exhibit alkaloids of the same, hydro-cinchonine and the action of both the constituents, i.e., of quinine hydro-cinchonidine. and acid and and These alkaloids occur in cinchona and salicylic quinine phenecetin. cuprea Hydro-quinine, from which most of the valuable barks, though the amount present shows great hydro-derivatives are obtained, is formed by con- variations. They can easily be separated from version of the vinyl CH : CH2 group into : the associated alkaloids, are diacid bases and form CH2 In the they are prepared pass- two series of salts, i.e., neutral and acid. CH;i. laboratory by gas solutions of natural alka- B. cinchonine or series ing hydrogen through Methoxy quinine loids in the of This which includes and its isomeride presence platinum. change quinine quinidine makes the alkaloids much more stable to the action and the and hydro-alkaloids, hydro-quinine hydro- of and to MacGilchrist Like the cinchonine series also oxidising agents according quinidine. they act more in the as are form a mono- and bi-series of salts. they efficiently body, they not so readily acted on by the tissues. Two closely related alkaloids cuprein and its The interesting point in connection with the isomeride and hydro-cuprein and cupreidine pharmacological action of the cinchona alkaloids have also to be considered, which hydro-cupreidine and their derivatives is that from the piperidine are found in cuprea bark?Remijia pedunculata? ring they come close to nicotine, and their antisep- along with other cinchona alkaloids. Both these tic are attributable to the pre- alkaloids are derivatives of cinchonine. properties mainly hydroxy sence of a in the molecule. Chemical constitution the cinchona alkaloids. quinoline ring of to have so far met ?To understand the between Attempts synthesize quinine relationship with but success. first N. the different alkaloids found in cinchona partial By preparing bromotoxins, then with alkali to produce a brief reference to the constitutional heating bark, ketones and reducing them, substances resembling formula will be necessary. This has been now cinchona alkaloids in constitution and having a established by the laborious researches of Konig, toxic action on infusoria were synthetically pre- Skraup and Rabe and is as follows:? pared. Their toxicity on man is, however, very C2> slight, and much more research is needed in this N CI- direction before success can be expected.