On quinine

During these years it must not be thought that nothing was being attempted to eradicate the disease. About 1902 I had arrived at the conclusion that once a man was infected with malaria, he should take quinine after his apparent recovery daily and not once a week, as was the custom. I made this observation first of all from one of my dressers (Lewis) in Klang Hospital, who, although he took quinine once a week with a tonic in the interval after the pyrexia had disappeared, had a return of the pyrexia about every ten days for many weeks, and only got rid of it finally by constantly taking quinine for some months.

In 1904, having determined that there was much malaria on certain estates, I advised the administration of quinine at first in weekly doses of 10 grains, and later of bi-weekly doses.18

Tables 12.1–12.3 show the result of giving quinine in the above-mentioned doses. An estate bears the same number in all the tables. The administration of quinine is doubtful in estate No. 4. From it the manager was dismissed.

These figures appeared to me to be most encouraging, and I said of quinine administration, in a Presidential Address before the Native States Division of the British Medical Association in Ipoh in 1906:

Although many, without thinking, consider it acts merely by curing the individual after he has been infected, and aborting threatened attacks, it is in reality much more than this. It is a real prophylaxis, for by cutting short attacks, it diminishes the chances of mosquitoes becoming infected, and thus prevents other coolies from ever becoming infected. It is by no means a case of locking the stable door after the horse has been stolen, and there need be no hesitation in advocating its use.

Nevertheless, it is not a method which commands my unqualified approval, for the simple reason that it requires too much of the manager. He has other work to do, work which must be shown as done in his monthly report, or his directors will want to know why? Instead of spending perhaps the best and coolest time of the morning giving out quinine, he wishes to go out into the field. Again, the manager himself may fall ill, and there may be no one to see the coolies take their quinine. A new manager may come, and he has probably to learn by bitter experience, that the hours spent in giving out quinine are not only well spent, but must be so spent, if the labour force is to be kept together. Again, it is not given to every manager to have the patience to see every coolie, and especially every child, gets its quinine ration, and with new coolies more or less undisciplined, there may be great difficulty in getting down the quinine, as the coolie has little faith in it. It is a great point when a ‘Kangany’ realises the value of quinine, but at the same time, no native can be trusted entirely with this, and it is a considerable call on the manager’s time. Then when the necessity appears to pass off, there will always be a tendency to slackness, as with all human efforts. Therefore, while I value the method, I consider the call it makes on the manager, a very serious drawback.

I hoped by giving quinine daily to those who had malaria, to prevent the formation of gametocytes which would infect mosquitoes; and that if any new coolies should chance to become infected, quinine twice a week would destroy the parasites before they had time to develop to numbers sufficient to give fever to the host. As will be seen later, neither of these hopes have been fulfilled, since it has been impossible to give the large doses which would be necessary to attain this object in people who are working. And secondly, as I shall show later, what may be a sufficient dose when malaria is not intense, is quite insufficient when it is. My advice in 1906 was as follows:

1. (1)That every coolie should get a cup of hot coffee before starting work in the morning.
2. (2)That twice a week every coolie should get ten grains of quinine, and every child five grains.
3. (3)That every coolie who has fever should have a mark put against his name on the check roll when he resumes work, should receive no ‘Name’ for his day’s work until he has taken a dose of quinine, in the manager’s presence.

This advice was followed on one estate which was just being opened up, and the result was a total failure of the quinine even to hold the disease in check; so that on 6^th November every coolie was put on 10 grains of quinine daily, and those who were not at work on 20 grains; it being assumed that, if he did not work he might be unwell; and that the extra dose of quinine would do him good by preventing an attack of fever, even if he had no pyrexia at the time. The effect of the daily dose was to reduce sickness to a marked extent, as Table 12.4 shows.

It is interesting to observe that what we saw when malaria was reduced in Klang Town, namely the reduction in diseases other than those recognised by the general population of malaria, was reduced on this estate likewise with the reduction of the amount of malaria.

The economic effect of the malaria and the effect of the quinine can also be observed from Table 12.5. The decrease in the out-turn of the labour of 1907 was due to unsatisfactory work of the dresser in charge, who had to be dismissed. It was found he was seriously neglecting his duties, as the coolies who did not turn out to work were not sought for and given the extra quinine. The unreliableness of native dressers will always be one of the great drawbacks to quinine administration. In this instance, the dresser, who by his hard work had helped so materially to obtain such good results in 1906 and the early part of 1907, now became lazy and mischievous for no apparent reason, and ultimately was convicted and sent to prison for six months for attempting to cause riot by setting one class of coolie against another.

The best results I have obtained, on Seafield Estate, are shown in Table 12.6. Writing in 1906 I described the condition of this estate in 1905 as follows:

In November, out of 212 coolies I found 27 down with fever on one day (where) 5 children had died in one week: (where) coolies were bolting daily, and the work of the estate was almost paralysed. This was followed by an outbreak of dysentery, and it was in the month of February before malaria was got in hand.

In 1906 or the beginning of 1907 it was discovered that the pills which were supposed to contain 4 grains of quinine contained much less than that amount, namely about one grain. The dose was then increased with a steady improvement in the death rate each year. It is interesting that the fall held good for each division of the estate. In 1905 in the month of October 245 coolies worked 3393 days, or 58%, of the possible working days. In October 1906, 260 coolies worked 2131 days, 70.9%, of the possible.

The economic effect of this quinine administration has been that the present small labour force now maintains in perfect order some 2000 acres at a minimum cost. That it is not due to any improvement in the health of the estate from other causes, will be seen from the following paragraphs relating to the limitations of quinine.

In 1908 and 1909 considerable attention was being paid to the presence of the Ankylostoma worm in coolies, and at the request of the Institute for Medical Research, I arranged in April 1909 for the examination of a large number of coolies. I chose for this purpose a healthy estate where no quinine was given, and the above-mentioned estate, on which quinine was being administered with such satisfactory results.

The result was to show that while Ankylostoma was present in large numbers on both estates, on the healthy one (Estate “V”) 2 out of 160, or 1-3%, of the coolies had parasites in their peripheral blood, and on the other estate no fewer than 56 out of 215 or 26%, showed the parasite. The examinations were made by Dr. A. T. Stanton of the Institute to whom I am indebted for the figures.

These results, in view of the splendid physique and work done by the force, appeared to warrant further inquiry. I accordingly visited the estate and examined all the coolies on it, paying particular attention to those who had been shown to have had parasites in their blood. I separated the 56 as shown in Table 12.7.

In other words, 75%, of the coolies with parasites in their peripheral blood were apparently in the most perfect health, while 87.5%, were in good health and fit for work. Of the 48 seen 30 or 62%, had enlarged spleens, and of the whole labour force of 345 I found 174 or 50.4% with enlargement.

On one division the coolies were getting 6 and on the other 8 grains, with double doses when they were ill or off work, often quinine in solution. As at this time mosquitoes were breeding freely on the estate in the ravines, close to which the coolies were living, and adult A. maculatus could be obtained in the lines at any time, this observation is of the greatest value in determining the effect of quinine. It clearly demonstrates that, while keeping the malaria in check, so that the coolies could carry on their work, three years’ administration of the drug had entirely failed to eradicate the disease. That the estate is really as unhealthy as ever is shown by the visitors to it, who contract malaria in about ten days, and even the head kangany suffered severely from malaria on his return to the estate after a visit to India.

Finally, out of nineteen A. maculatus captured in the lines, four or 21% had malaria; two with zygotes, one with sporozoites, and one with both zygotes and sporozoites.

Desiring to have further information on this important point, I took the blood of every man, woman, and child on an estate on which quinine was being given in the most thorough and systematic manner. The doses being given were 10 grains daily to each adult who worked, and 20 to those who did not work, the latter being given in solution. To the children 5 grains were given daily, and double doses also to those who did not work. Mr. R. W. B. Lazaroo kindly examined the slides for me, and reported the data shown in Table 12.8.

These figures agree very closely with the ones obtained by Dr. Stanton, and they at once supply the reason why no improvement has taken place in the hill land estates despite the use of quinine in what appear very large doses for constant administration. Now this failure to eradicate malaria falls into line with our knowledge generally of quinine. I would indicate the following as the limitations of quinine:

1. (1)However thorough the dosing has been, malaria is very liable to return to a patient although the possibility of reinfection is excluded. In other words quinine does not poison the parasite outright.
2. (2)When a person is attacked by malignant malaria (subtertian) for the first time, even with the most thorough administration of quinine in solution, some four or five days elapse before the temperature falls, and Rogers has published figures which show that 60 grains daily have no advantage over 20 grains or less.19
3. (3)In bad epidemics I have watched cases of malaria admitted to hospital, who have had no pyrexia, but rather who have been in the algid state; who despite the administration of quinine by the mouth, by the rectum, and intramuscularly to the extent of 40 grains daily, have continued for four days in this algid condition and then died. During this time the skin was in a condition of a cold clammy sweat. No diminution appeared in the number of parasites in the blood. The patient apparently failed to react any way.
4. (4)It is common experience that a patient, particularly if he is suffering from benign tertian malaria, must be put to bed before pyrexia will leave him, even when on full doses of quinine.

Finally, when we remember that thousands and thousands of people, who do not take nor have the opportunity of taking quinine, recover from the disease yearly, it is evident that the human subject of the disease must depend on some power within himself to save him from death. Daniels, in his Presidential Address to the British Medical Association in 1909 in Belfast [22], appears to me to strike the right note when he insists that the protozoal diseases, of which malaria is a member, may persist for years without sexual regeneration, and despite any drugs which may be given; and that freedom from the disease can be acquired only by the development of resistant powers within the human host. It is when we consider malaria as an infection of the human host by a parasite, which in the majority of infections lasts for at least three or four months, and in exceptional cases for years; in which the relationship of the parasite to its host is that of enemies at constant war; where for a time first one and then the other may be in the ascendant; and where victory in the end may be to either, that we can understand the apparently contradictory results of quinine.

When from any cause the health of the host is depressed, the parasite increases in numbers and may be found in the peripheral blood. As the struggle continues and the life of the parasite is threatened, in harmony with the rule of nature generally, the parasite produces the sexual forms destined to continue its existence as a species. Thus, from time to time, the human host becomes dangerous to others, if anophelines which form a congenial breeding place for the sexual forms (i.e., capable of carrying malaria) are present.

When, on the other hand, the health of the host is improved from any cause, the parasites are reduced in numbers and may disappear from the peripheral blood. The parasites may, in the end, die or be killed out by the host. It is not unlikely that two separate immunities are required by the host before the parasite is destroyed. It appears to me to be not uncommon for the host to become immune to the poison causing pyrexia long before it acquires powers to reduce the number of parasites; for cases with numerous parasites and without pyrexia over considerable periods are not uncommon, indeed are recorded by every writer on malaria.20

The true action of quinine appears to be to assist the human host in working out for himself the resistant power which will ultimately free him from the disease. It acts either by attenuating the virus within the host, or by increasing the resisting power of the host in some unknown way, or possibly by both. Without quinine in many cases, especially in very unhealthy spots, the human host would die before he had acquired his resistant powers. We thus see that, if quinine in sufficient doses be given, the man will gradually overcome the parasites, and apparently suffer little from them; but at the same time we see that during this period he is capable of infecting others. The man is for a time a “malaria carrier” not unlike the typhoid carrier.

There must be an optimum dose of quinine, possibly it varies with the individual, and, from time to time, in the same individual; but whatever that dose be, it must bear a close resemblance to the ordinary therapeutic dose.

Finally if, as has been shown, the immunity from malaria produced by quinine leaves the patient infective while he is acquiring the immunity, then it will be impossible in the presence of many anophelines, and in the presence of many new arrivals (such as newly born children) ever to eradicate malaria by quinine. It follows, too, that if drainage be an alternative, even although more expensive, drainage must be the method which should be adopted. Even if a community possessed no money for drainage, money might be borrowed with which to carry out the works, and at the end there would be an asset to show for the expenditure. Borrowing, however, would be impossible if the object were to buy quinine, since in the end nothing could be shown for the money, except a people still liable to malaria, and possibly some agriculture which could not be maintained without the constant use of the drug.

When I first began quinine administration systematically to large bodies of coolies, I advised quinine sulphate in solution and in the morning. I advised the solution because in solution its action is more certain, and it would thus be possible to use a smaller quantity of the drug; I advised the morning because the parasites usually sporulate in the forenoon, and consequently would then meet with the quinine in full strength.

In practice it was found that there were serious objections both to the time and the form of administration. In solution the action was so certain, that in 10-grain doses cinchonism was so marked that the coolies could not work in the sun. In addition, they were frequently sick after the dose; ultimately it was suspected that they deliberately vomited the dose to avoid the unpleasant after-effects. Since then, it has been given when work is finished for the day, that is, about 2.30 P.M.

When I decided to abandon the solution, I considered that the compressed forms as usually supplied were too much compressed, and coolies were taught to make quinine pills with bread. They became astonishingly expert at this. The pills were supposed to contain 4 grains of quinine, but after a time it was found they were putting in too large a proportion of bread as the pills were thereby more easily made.

In order to standardise the dose, in 1907 I obtained machines from England, and hoped to make tablets, compressing the drug just enough to keep it in a mass. The machines were not a success, as the rate at which the tablets could be turned out was far below that of the coolie making pills by hand, and quite insufficient to meet the demand. I therefore returned to the pills, but now (1909) have them made by mixing dry quinine sulphate with so much gum solution, that when made the pills can be crushed easily between the finger and thumb. There are at the present moment just over 4000 coolies taking 10 grains daily, with double doses when off work.21

The efficiency with which the drug is administered depends on the manager of the estate. Each year the drug is being given over larger areas and with greater efficiency, as its value is being better recognised. A change of manager is usually followed by less care being taken to give the drug, and this is a serious drawback.

Europeans tell me that it is impossible to continue the use of quinine solution for any length of time. If taken in the morning, they cannot take food and cannot work in the sun. If taken at night, even dry quinine prevents sleep. I hoped at one time that, if taken at night, larger doses could be taken, the effects of which would pass off during sleep. But men are unanimous that taken at this time it prevents proper sleep, and the drug is now rarely taken at night.

Quinine sulphate in powder often fails to have any effect on an attack of malaria if there is gastric disturbance; this even when 20 or 30 grains are given in the course of twenty-four hours, and for a period of a week. In such cases I give quinine hydrochloride with a little morphia in solution. This effectively controls the sickness, and the temperature is usually down in thirty-six hours. I have often wished to try the old native remedy of opium with the quinine, but have never felt quite justified in doing so, on a large enough scale to be of value.

Warburg’s tincture I have used both for pyrexial attacks and as a preventive. It appears to have no special advantage over a simple mixture of hydrochloride and morphia. I have also given it over considerable periods, combined with additional quinine, to bring the dose of the latter up to 15 or 10 grains as the case might be. I cannot see that it has any special advantage.

Small children learn to swallow pills very quickly. For infants I find the easiest way to administer quinine, is to give euchinine (quinine ethyl carbonate) broken up in a little sweetened condensed milk.

On estates, where quinine has been much used, it is not uncommon to find coolies ask for solution in preference to pills, when they have fever or suspect an attack is coming on. Kanganies are often found to carry pills in their pockets, and give them out to any coolie who complains or asks for them during the day. On the other hand, I recently found the conductor on an estate, where quinine has been given daily to the coolies for four years with the best results, who had suffered from malaria himself and taken quinine for it, would not give his wife quinine when she was almost dead with malaria, until literally forced to do so. If such happens with a native who reads and writes English, who lives on an estate, where if on any place in the world quinine has shown its power to control malaria, it is impossible to believe that native populations will ever be induced voluntarily to take quinine in such doses as will effect any marked difference on the death rate of the disease.

Although quinine sulphate may not be absorbed when there is gastric disturbance, there can be no question about its being absorbed in the majority of cases. For a week after a coolie or a European begins the daily consumption of quinine powder or pills, quite definite symptoms are felt in the head. After that period no unpleasantness is experienced, unless the dose be increased. Instinctively men have learned to take their total quantity broken up into two or three doses. And my object now on the most intensely malarious places is to have from 10 to 15 grains taken daily without producing symptoms. After an attack of malaria I advise 20 grains in solution daily for a week, and then reduce the dose to 10 grains in pill form, resuming 20 grains should the person feel unwell, and find his temperature 100°F or more taken in the mouth.

I prefer the sulphate for continuous use because the more soluble forms are more apt to produce cinchonism. There is reason to believe the sulphate is absorbed not only from the stomach, but from the intestines. Its slower rate of absorption, therefore, leads to less violent fluctuation in the amount circulating in the blood, than where more soluble preparations are used. It has the advantage, too, that a dose will, therefore, have a more continuous action, and be present in the tissues and fluid for a longer period, than where the preparation is more rapidly absorbed and presumably more rapidly eliminated or destroyed.

Nor is it an unimportant advantage where thousands of coolies are receiving comparatively large doses daily, that the price of the sulphate is some 30 to 50% less than the other common preparations.

It has been with a due sense of responsibility, and no little anxiety, that I have found myself the instrument in causing large numbers of people to take quinine for prolonged periods in doses which appear excessive to many, and doses which year to year tend to increase in amount. I have watched the effect of its administration with care, and if it is producing any ill-effects, they are of such a nature as not easily to be detected—at any rate I have not detected them—and they are of infinitely less consequence than malaria.

I have rarely given more than 20 grains daily unless on microscopic examination the patient’s blood was so full of parasites as to show there was immediate danger to life. In such cases I have given up to 40 grains mostly per rectum, retaining the mouth for the administration of nourishment.

I have never seen a case of quinine blindness,23 nor have I had in my practice any patient who complained of deafness or ear symptoms for more than a few days. Occasionally a patient, the subject of malaria who does not take quinine in sufficient doses, complains of “indigestion.” If on sulphate, I may order hydrochloride in increased doses, which usually puts him right. Time and again, when a man has complained that he has “not been up to the mark” and thought he has been taking too much of the drug, I have advised increasing instead of reducing the dose with the most satisfactory results; so, too, when a man who has had malaria says he is feeling “particularly well.”

Miscarriage is often attributed to a dose of quinine. Yet I could quote instances of patients who have taken quinine throughout pregnancy and been delivered at full time. On the other hand an attack of malaria is notorious as producing abortion; and if the attack comes on within the last two months of pregnancy, labour will almost certainly follow. It is true quinine is often given in these cases; but the futility of quinine in ordinary doses when given to induce, or accelerate labour, in a healthy woman excludes the theory that quinine is the active agent in producing the abortion of the malarious patient.

Occasionally, but very rarely, a cutaneous eruption appears, when doses of quinine are first given, but the rash disappears with the continued use of the drug. One man when first put on 15 grains daily developed a severe nettle-rash which was intensely irritating. It disappeared within a week.

It must not be forgotten, too, that the administration of quinine in effective doses in a malarious locality is by no means an inexpensive method of combating malaria. To give 10 grains daily to 1000 people without any extra to those who actually have pyrexia for ten years, would cost about £1900 sterling.24 Such a sum, if lent by a Government to a community at a reasonable rate of interest, would free a very large area from malaria, if drainage methods suitable to the local anophelines were employed. And in ten years the community would have some years of prosperity and health in which to repay the loan. In the case of many small villages it would probably be possible to eradicate the breeding places of anophelines, where they were in the midst of the community, at a mere fraction of the money which would be required to dose the population effectively with quinine even for a year. While for larger communities the cost of drainage would be relatively much cheaper than in the case of the smaller ones, since the same expenditure would protect a relatively larger number of people.

We have seen that quinine at its best, and when administered with a thoroughness, the result of a discipline impossible of attainment in an ordinary population, still leaves a large percentage of the population capable of infecting others. It can, therefore, never eradicate malaria in the presence of newcomers, and where there are many anophelines. We have seen, too, that to attain this best result in a malarious place costs a fairly considerable sum. Quinine, therefore, in my opinion, cannot for a moment be ranked with drainage.

It cannot be too strongly urged that efficient land drainage not only is a radical anti-malaria measure, but is of first-class importance in almost all forms of agriculture; and that malaria is essentially a rural disease. In dry forms of culture, it often makes the difference between good land and bad land, between good crops and poor crops. And in wet culture it is no less important. Cromer insists that in Egypt, the success of irrigation depends no less on the channels for taking off the water than on the irrigation channels for its supply. It is notorious, too, that badly drained irrigated land is not only of less value agriculturally, but is also more malarious than irrigated land, where by means of an efferent system, the water on the land is more fully under control.

Finally I would urge that when the time comes for unanimity as to what should be done, the malaria problem will still be, as it is, essentially a financial one. In the end the affected community must find the means of combating the disease. To me it appears that any means, which will enrich the population, will enable it to make greater effort to overcome the disease. If, by drainage, we can enrich not only the people and the land, but by the same measure help to reduce the disease, drainage must be the measure of first importance.

Whether quinine be supplied free by a Government or sold at cost price or at a loss to the Government, a price is being paid; and the people are in reality being assessed an amount, however small, which would still have paid the interest on a loan for a radical drainage work. Perhaps the work would only be a small one, but no matter; for it would definitely and for all time, if upkept, place the inhabitants beyond the reach of the disease.

It is here that I think a Government can help to break the vicious circle which makes the malarious poor and the poor malarious, and can assist a people to initiate drainage works, which from poverty they themselves cannot begin; even if Government cannot pay for drainage works out of revenue, then by pledging its credit, a Government can obtain money on loan. Both capital and interest can be paid by assessment of the land benefited.25

Of course care must be taken that the works will improve the area; to me it appears that in this direction lies the chief hope of eradicating malaria. Malaria over large areas cannot be eradicated in a day. But from what I have seen of the results of radical measures I feel strongly that by radical measures will the end be attained soonest; that every success will help others; that people will be saved who will never consent to take quinine in sufficient doses, if at all; and that only by radical measures will be stopped the infection from, and the death of, the vast mass of those who suffer from “malaria sine pyrexia,” those who fail to recognise they suffer from malaria,26 who as we saw from the Klang figures account for a very large percentage of the death rate of a malarious community.

1920 —The experience of the war bears out these conclusions. In Salonica, where infection and re-infection by mosquitoes constantly occurred, quinine failed entirely to protect the troops, just as it had failed in the Malay States.

In France, where re-infection did not take place, two divisions of malaria-stricken troops from Salonica were put in the firing line after two months’ thorough administration of quinine, carried out under Lieutenant-Colonel J. Dalrymple, C.M.G. Fifteen grains in solution were given for fourteen days; and for eight weeks 10 grains in solution. The strictest discipline was maintained in the administration.

In England, where re-infection does not occur, the routine treatment of the War Office and Ministry of Pensions is 10 grains of quinine daily in solution for nine to twelve weeks. Sir Ronald Ross, who is consultant to both departments, writes [23]:

But can we not cure the cases outright by some therapia magna sterilisans? I wish we could.

Unfortunately, though the War Office made innumerable experiments from early in 1917 onwards, no really satisfactory result was obtained. For details the reader should study the forthcoming War Office publication, Observations on Malaria, by medical officers of the Army and others (Stationery Office), The Annals of Tropical Medicine and Parasitology (Liverpool) for the last two years, and many papers in the Lancet and other journals. We tried intravenous and intramuscular injections, heroic doses, kharsivan,27 and almost everything we could think of. Not one treatment provided a certain cure; and the treatments which gave the most promising results required at least a month’s stay in hospital, and were, I think, almost more severe than the disease. We still live in hopes; but up to the present the daily dosage described above remains the best, as it is the oldest used. If I had malaria today, I should not dream of allowing any other ‘cure’ to be practised on me.