April, 1934] EDITORIAL 215,

Indian Medical Gazette

APRIL

THE TOTAL CINCHONA ALKALOIDS

The employment of the total cinchona alkaloids in the treatment of malaria is so

largely an economic question that whenever it is raised at a medical conference, someone in- variably kills any discussion by pointing out that it has gone beyond the scope of such a

conference. We have never been privileged to attend the deliberations of those responsible for the finances of either India or any of its

provinces, but we have little doubt that when these are concerned with the policy of the

country or province with regard to the cultiva- tion of cinchona, and the provision of a cheap malaria treatment for the people, they are

frequently hampered because these experts find themselves led into discussions that are

primarily medical. The consequence is that no particular policy

is adopted, and that we muddle on year after year; India produces only a small fraction of the drugs she requires yearly for the treatment of her malaria-stricken population, and there seems no prospect in the near future of her

being able to reduce the discrepancy between her production and her requirements, yet there are in this country large tracts of land suitable for the cultivation of cinchona bark, which if

planted now would make India entirely in-

dependent of foreign quinine, or other anti-

malarials, within a very few years, and would provide a very considerable margin for export. There is a never-failing supply of excuses

for inaction in this matter, but one that has been used frequently during the last few years has been that the League of Nations' Health Organization is considering the matter. The report of the League of Nations' Malaria

Commission on this particular subject appeared last June in the Quarterly Bulletin of the Health Organization. In our last issue we discussed this report and

reprinted extracts from it. Further extracts will be found in our present issue; these include the opening paragraphs of the report in which the general aims of the commission are set forth. To those who have followed the cin- chona-alkaloids controversy and have awaited this report of the commission with high hopes that an authoritative statement would be pro- duced, these paragraphs provide almost tragic reading, in view of the nature of the rest of the report. One's hopes were raised to a high level because one felt that the problem, as it

exists in India to-day, seemed to be so fully understood; no words could express India's needs better than do the following, which are quoted from this section of the report :?' The

aim of large-scale antimalarial effort by means of drugs is not concerned with providing a

medicine which is the most effective anti- malarial remedy known to medical science. What is aimed at is to provide a remedy that is so abundant and can be obtained so cheaply that it can be made readily available to the whole population of malarious countries. The endeavour of the Malaria Commission is to

arrange a scheme of that kind. In such a

plan there is no question of providing the most effective remedy known, nor even, necessarily, of providing a remedy as effective as quinine. The object is simply to provide, preferably by local cultivation of C. succirubra, or by other action in the malarious countries themselves, an abundant supply of a medicine, which will mitigate the severity of malarial attacks and

prevent the disease from terminating fatally Having thus shown that they understood

what was the most urgent requirement of malaria-stricken nations, the commission then

proceeded to devote almost the whole of the rest of the report to secondary matters. There is certainly reference, to the composition and standardization of totaquina (but this, though it was the work of the commission, is now old

history), to certain experiments with the total alkaloids in bird malaria carried out by Pro- fessor Giemsa, to the results of treatment in five cases of induced malaria with each of the two varieties of totaquina, and to the difficul- ties of clinical investigation (in this connection they have drawn up certain rules to be observed for testing totaquina clinically); but otherwise they appear to have been lured away from their main purpose by the glitter of the new

synthetic antimalarials. We should be the last to deny the extreme value of the work that was reported upon, as far as the treatment of the individual malarial patient was concerned, but it has left the problem that they set forth in the first paragraphs of the report exactly where it was before.

Many of our readers will be familiar with the total-cinchona-alkaloids problem, but, for those who are not, we will give a brief resume of the main points. Cinchona bark contains a number of alkaloids; of these quinine is the one that has achieved most popularity in the treatment of malaria and is therefore most in demand. This has led to the cultivation of the particular species of cinchona tree that will

produce bark giving the highest yield of

quinine, but it is not a hardy species and it will only grow in certain areas; in India these areas are very limited. Nevertheless, while the main demand is for quinine only, it is not an

economically sound policy to grow, even in

India, any but Cinchona ledgeriana with its

high quinine yield. However, it has been shown that the other alkaloids of cinchona bark also have antimalarial properties; it has been claimed by some workers that with cer- tain species of Plasmodium the action is even

216 THE INDIAN MEDICAL GAZETTE [April, 1934

greater, and it is generally acknowledged that the action on any species is only slightly less, than that of, quinine. If therefore all the alka- loids of cinchona were utilized in the treatment of malaria, the amount of antimalarial drug that could be extracted from each pound of cinchona bark would be much greater and, further, it would become unnecessary to use

only .the special tree giving a high quinine yield, and hardier species, such as Cinchona succi-

rubra, which give a high yield of the total

alkaloids, could be planted extensively. Not

only is this mixture of the alkaloids of cinchona bark cheaper than the pure alkaloid quinine, but, if it were in demand, it could, after the few years which would be necessary for the extension of the plantations, be produced in almost limitless quantities in this country. Exactly why it is not in demand, it is difficult to say, but there is no doubt that' cinchona feb- rifuge ', a generic name applied to all mixtures of the cinchona alkaloids, has never achieved any real popularity though in certain provinces in India it has been, and is still, used exten- sively. One reason undoubtedly is that from time to time various mixtures of the residue from quinine manufacture have been placed on the market and labelled ' cinchona febrifuge'; these mixtures contain very little quinine, and an abundance of the amorphous alkaloids which are not only practically inactive but tend to make the tablets of cinchona febrifuge hard and insoluble.

The introduction of this new standard mix- ture of the cinchona alkaloids, totaquina, is a

very definite step in the right direction. It will not be an exact mixture of the alkaloids but one whose composition varies within cer-

tain limits: these limits are sufficiently rigid to allow the clinician to advocate a standard dosage from which he may expect a response that will vary only within the usual range of clinical experience with quinine, and at the same time will not be so rigid as to complicate manufacture or to prevent the mixture from being made directly from the hardy C. succi- rubra or C. robusta, without the addition of alkaloids from another source.

These observations refer to totaquina (type I). We cannot, however, see why the commis- sion found it necessary to complicate matters by introducing a second type; the only useful function totaquina (type II) appears to per- form is to provide the quinine manufacturer with a means of disposing of his residue. The

few tests that have been made suggest that this

type II displays a very low degree of efficacy, and we think it is a pity that the name

' tota-

quina ' should have to bear the stigmata that

it will acquire if the quinine manufacturers are allowed to place this poor-quality antimalarial on the market under this name.

In view of the fact that the areas where Cv ledqeriana grows well are limited and that these areas are mostly in Java, the Dutch

planters exercise a complete control over the

quinine market of the world. At present there is a glut on the quinine market, but, by virtue of this control, the high price has been maintained. When we say

'

glut' we do not mean that

there is more quinine made than is required, but more than malaria-stricken nations can

afford to pay for; India cannot afford to buy more than about one-tenth her real require- ments. We may therefore assume "that foreign cinchona planters and quinine manufacturers will be definitely ranged against the suggestion for the widespread use of totaquina, but those in control of the plantations and factories in this country, which are all government-owne(i> are both willing and anxious to co-operate if

they can get a clear lead from the medical profession; this would be indicated by an in-

creasing demand for totaquina. The uncertainty regarding the composition

of the cinchona-alkaloid mixtures, which -has been the excuse used by medical men in this

country for adhering doggedly to quinine, now no longer holds good if totaquina (type I) is

prescribed, and one hopes that when- this

product is generally available we shall see an

increase in the demand for the total alkaloids of cinchona.

Outside medical circles there is a distinct feeling that the substitution of '

cinchona febri- fuge

' for quinine in provincial dispensaries is an attempt to foist an inferior article on to

the poor. For this entirely wrong interpreta- tion, the medical profession must bear some of the responsibility, as public opinion in such a

matter is naturally influenced by medical

opinion. Trials that have been conducted with total-

alkaloid mixtures at Kasauli and elsewhere in this country have shown that for practical pur- poses they are equal to mixtures containing .the single alkaloid quinine. The League of Nations' Malaria Commission have confirmed this in the following words It appears from, these results that totaquina type I (total alkaloids of C. succirubra or C. robusta), when used in ordinary clinical therapeutic doses for curative purposes?e.g., 1.2 grm. (20 grains) daily.;for five to seven days?should give about the same good result as is given by quinine in the same doses. If this is so, and if this type of tota- quina can be obtained more cheaply than

quinine, it would be advantageous to use it for

general purposes instead of the single alka- loid.

However, in view of the extreme paucity of the trials that were conducted under their aus-

pices and of the lack of prominence given to this conclusion, it cannot carry much weight, and we feel that a wonderful opportunity of

placing this question of the efficacy of the

total-alkaloid mixtures beyond any possible doubt, and of making a really authoritative pronouncement on the subject has been missed.

.April, 1934] ~

, , .V .;/?> MEDICAL NEWS; ; 217

If a .commission of the League- of Nations, whose-expressed'purpose was to investigate this problem and who fully understood the posi- tion in "India, to-day, failed to produce an

authoritative answer,- one-almost despairs' of this ever being' given; yet until it : is given we can expect no progress in the matter of. the cinchona policy in this country _