Some observations on the therapeutics of malaria in Ceylon

233 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE. July, 1936. Vol. xxx. No. 2.

SOME

OBSERVATIONS

ON THE THERAPEUTICS IN CEYLON.

OF

MALARIA

BY LIEUT.-COL. Late Special Malaria

C. L.

DUNN,

OfJicer and Director

C.I.E., of

D.P.H.,

Public Health,

I.M.S.

(RETD.).

United Provinces, India.

FOREWORD.

These observations are based on an enquiry into the malaria epidemic in Ceylon of 1934-35, carried out by me over a period of 9 weeks from 27th October, 1935, with the support of the Colonial Office and the London School of Hygiene and Tropical Medicine. I received every possible assistance from the Government of Ceylon in the Ministry of Health, and of the officers of the Medical and Sanitary Departments, and had complete access to all Government files and publications connected with the subject. I received great personal help and consideration from Dr. R. BRIERCLIFFE, C.&?.G., O.B.E., Director, Medical and Sanitary Services, from Mr. CARTER, Medical Entomologist and from Lt.-Col. W. W. CLEMESHA, C.I.E., I.M.S. (retd.), Malariologist to the Ceylon Estates Proprietary Association, and made extensive tours in the island in the company of these and other officers. Without their help and co-operation it would not have been possible for me to gain the extensive information I did in this short period.

234

TREATMENT OF MALARIA IN CEYLON. l.-THERAPEUTIC

MEASURES

USED BY GOVERNMENT

AGENCY.

The routine treatment for malaria in the Government Hospitals in Ceylon is the administration of a stock mixture containing 74 grains of quinine bisulphate per dose. This mixture is given three times daily until the febrile symptoms have disappeared and for as many more days as the patient can be persuaded to remain in hospital; and 2 days’ further supply is handed to each patient on leaving hospital. The great majority of patients, however, left hospital as soon as they felt well, and did not continue the treatment. The average stay in hospital under this treatment was between 6 and 7 days. Serious cases were given intravenous and intramuscular injections when considered necessary by the physicians. In addition to quinine, large quantities of plasmoquine were issued and used, generally in conjunction with varying amounts of quinine. Atebrin was also issued and used, chiefly in hospitals, but some attempts at mass treatment with this drug were tried. Atebrin musonate supplied by the makers, on payment, was also tried in hospitals under test conditions as far as possible ; and was also tried in the field. I also came across a few instances of other therapeutic agents being used, such as esanofele, tebetren, etc., but these instances were so few as to be negligible. Combinations of plasmoquine and quinine, atebrin and quinine and plasmoquine and atebrin were also tried in some hospitals and their effects observed. Z.-THERAPEUTIC

MEASURES

USED BY THE CEYLON ASSOCIATION.

ESTATES

PROPRIETARY

Out of about 1,300 tea, rubber and cocoanut estates which subscribe to the above Association, about 560 subscribe to the Malaria Control Scheme of the Association, a very high percentage of the estates situated in the malarial zone. These estates cover an area of 420,000 acres, and are populated by about The expert adviser of the Malaria 300,000 Tamil coolies and their dependants. Control Committee is Lt.-Col. W. W. CLEMESHA, who has been 6 years in the employ of the Association. CLEMESHA, as the result of many years’ experience in India and Ceylon, applies a standard treatment to all the adult population of these estates, which consists of quinine bisulphate or quinine bihydrochloride 30 grains until the febrile symptoms subside ; or, in some estates, the same quantity of cinchona febrifuge. Children under 10 years are getting a standard treatment of euquinine and milk, with a dosage according to age. The quinine treatment is followed up among adults and children over 10, by S$ grains of quinine and $ grain of

235

C. L. DUNN.

plasmoquine daily for 6 days. For 14 days tonic iron pills are given, and the quinine-plasmoquine treatment again given for a further 6 days. CLEMESHA'S treatment is an attempt to cure each clinical attack of malaria as it arises, and to eliminate human carriers of the gametocytes of Plasmodium falciparum. CLEMESHA also carried out one interesting experiment with atebrin on the Halvatura Estate. From 1st December, 1934, until 11th June, 1935, all cases of malaria were treated with 3 grains of atebrin daily. During this period, 328 cases occurred, but a large number only had partial treatment. 106 cases, however, received 5 consecutive days’ treatment (15 grains of atebrin) between 1st December, 1934, and 1st March, 1935 ; and were still employed by the Estate on 1st June, 1935. Of these, fifty-six relapsed. The relapse rate was thus 52.8 per cent. The dosage however, was two-thirds the amount recommended by the makers and this large relapse rate would appear to be due to insufficient dosage. S.--RESULTS

OBTAINED

WITH

THE VARIOUS

TREATMENTS

USED.

It is obvious that during the course of an epidemic of such devastating proportions as that which occurred in Ceylon, there were almost insuperable difficulties in any attempts to carry out controlled comparative experiments CLEMESHA only made the one referred with the therapeutic agents employed. to in the previous paragraph, but BRIERCLIFFE (1933) and his staff carried out several experiments in order to ascertain whether the wholesale use of the synthetic remedies would not be more efficacious than quinine in cutting short the epidemic, especially in view of the success reported with the extensive use of atebrin in Malaya by HOOPS (1933), BARROWMAN (1933) and DUNCAN (1933). BRIERCLIFFE tried no experiments with combinations of quinine and plasmoquine, the success of which has been reported by several observers. Atebrin

Tablets per OS.

179,000 tablets of atebrin were issued to the hospitals and dispensaries, and medical officers were asked to use this drug and observe its effects. The dosage recommended by the makers, l+ grains three times a day after food for 5 days, was employed. After extensive enquiries in the hospitals and dispensaries and an examination of the hospital returns, I found that it was only possible to arrive at general impressions as to the value of this treatment. It was impossible to differentiate between relapses and reinfections when the hospital books showed that patients had returned for second and third courses of treatment, and in many cases, the courses of treatment were incomplete owing to patients leaving hospital and ceasing to attend dispensaries as out-patients when the febrile symptoms subsided, From a study of the

236

TREATMENT

hospital registers, fairly accurate. Control

qf Febrile

however,

OF MALARIA

the following

IN

CEYLON.

conclusions

may be regarded

as

Attacks.

In the epidemic area in Ceylon, atebrin took longer to control the febrile attack than quinine, the average time being between 2 and 3 days as against 18 days. Relapses. Patients treated with atebrin appeared to have fewer relapses or re-infections than with quinine. Toxicity. Medical officers recorded their opinions, that there was a frequency of abdominal discomfort and even great pain. Atebrin was considered unsuitable for children owing to the high percentage of cases in which vomiting and convulsions were induced. Discoloration of the skin was rare and has not raised any barrier to the use of this drug in Ceylon. Symptoms of mental derangement These symptoms usually lasted for 2 or 3 days. The were fairly frequent. number of such cases observed among 792 patients at three dispensaries, was eight, or 1 per cent. Atebrin

and Quinine.

If these two drugs were given together, there appeared to be a greater incidence of toxic symptoms, but if given consecutively, these symptoms were less in evidence. No clinical advantage in this combination was observed. Atebrin and Plasmoquine. A combination of these drugs seemed to produce a high degree of toxicity even when the plasmoquine component was as little as -&-grain per diem for 5 days. The toxicity of the combination was higher than that of either drug used alone. Quinine and Plasmoquine. As given consecutively by CLEMESHA (page 234) produced no toxic sympCLEMESHA (1935) gives many results of his standard toms worth recording. treatment, and certainly these results afford a strong testimony of the efficacy of his treatment as compared with the results obtained in the same areas with the routine quinine treatment. Plasmoquine Simplex. I found no record of this treatment dispensaries in Ceylon.

being used at any of the hospitals or

C. L.

DUNN.

w-i

Atebrin Musonate. BRIERCLIFFE (1935) supervised some tests of the efficacy of injections of this drug, in April and May, 1935, as compared with two injections of quinine bihydrochloride followed by quinine by the mouth. The dosage of atebrin musonate given was that recommended by the makers, i.e. 0.375 grammes on 2 consecutive days. Quinine bihydrochloride 15 grains, was given to the control cases on 2 consecutive days, followed by 22& grains of quinine bisulphate mixture for 6 days. The tests were carried out on 1,105 hospital patients in twelve hospitals : 681 patients were treated with atebrin musonate, and 424 with quinine. The two series of cases were strictly comparable as to type of case. The result observed was the length of time taken to stabilize the temperatwe, among males and females. in cases of benign tertian and malignant tertian fever, and BRIERCLIFFE gives complete tables of the results recorded. These briefly were that both drugs stablized the temperature in about 81 per cent. of the cases within 6 days, and that the atebrin musonate stabilized the temperature on the average about 9 hours sooner than the quinine treatment. The average for atebrin was 61& hours, and for quinine, 709 hours. Cases of benign tertian fever were stablized on the average about 16 hours sooner than malignant tertian cases. The toxicity of both treatments was also observed. Among the 623 atebrin musonate cases, there were twenty-three cases or 3.4 per cent. of cases of vomiting or abdominal pain, as compared with one case, O-2 per cent. with quinine ; thirteen cases or 1.9 per cent. of mental derangement as compared with one or O-2 per cent. ; two cases or 0.3 per cent. of collapse as compared with nil ; and four deaths or 0.6 per cent. as compared with nil. BRIERCLIFFE gives full details of the postmortem examination of the deaths, which establish beyond doubt that the deaths were due to atebrin poisoning. Atebrin could not be recovered from the kidneys or urine in these cases. It is therefore concluded that atebrin poisoning supervenes if the kidneys fail to eliminate the drug from the blood. The Yelapse rate could not be observed as the stay in hospital was so short, but Dr. P. B. FERNANDO of the Colombo General Hospital observed seventy patients who, for a minimum of 3 weeks, were kept in hospital where the risk of re-infection was negligible. Of these, twenty cases relapsed. Dr. FERNANDO only included among his cases of relapse patients who had both a return of fever and of parasites in the blood. Risk of infection was negligible. Dr. C. G. HOOLE treated twenty policemen with atebrin musonate ; two had severe toxic symptoms, and ten relapsed within a month. Risk of infection negligible. Dr. S. DE SILVA treated eighteen policemen in the Mahara jail, and eight Risk of infection slight. relapsed in a month. In Kurunegala, sixty-five of the hospital staff were treated by Dr. SIMEONS with atebrin musonate and only seven relapsed in 6 weeks, but none of these were suffering from fever when injected.

238

TREATMENT OF MALARIA IN CEYLON.

Field Treatment with Atebrin

Musonate.

In May, 1935, 1,387 persons in three groups of malarious villages received atebrin musonate treatment as an experiment. The cases were carefully selected, all suffering from nephritis, severe hookworm infection, oedema, advanced debility and anaemia being excluded. Of the cases followed up, 7 per cent. had febrile relapses in 14 days, but in 117 of these cases, where blood films were taken, forty-nine had parasitic relapses or 41.8 per cent. Among these there were few toxic cases, but fifty-three cases had nausea, vomiting, collapse, etc., and there were eight cases of mental derangement ; one had to be kept in a strait jacket, five were detained for more than a week, and one died of exhaustion from mania. Many had painful swellings and seven developed abscesses. The expense of this experiment worked out at Rs.4.24 per head treated. The treatment was most unpopular with the villagers owing chiefly to the mental symptoms caused in a small number of cases. Other Experiments

with Atebrin Musonate.

Prior to BRIERCLIFFE’S tests, great success in effecting a rapid clinical cure with atebrin musonate had been recorded in a series of twenty-one cases by BLAZE and SIMEONS (1935) and about 300 people were treated by medical officers in collaboration with Dr. SIMEONS with success in controlling the symptoms, but no record was kept in any of these cases of any untoward happenings, and the relapse rate also could not be observed. In addition, several other medical officers tried the treatment in their hospitals, and although the therapeutic effects were usually good, untoward effects of many kinds are referred to by BRIERCLIFFE as having occurred, such as sudden deaths among children, a few minutes to a few hours after injections, convulsions are stated to have been collapse, convulsions, etc. Epileptiform extremely rare, only occurring about “ once in every 900 to 1,000 treatments ” (BRIERCLIFFE, 1935) ; but deaths preceded by collapse probably occurred more than once in every 200 cases. BRIERCLIFFE'S conclusions on the merits and demerits of the drugs used in the circumstances and under the conditions, i.e. during the progress of a severe epidemic, are briefly as follows :(1) Atebrin musonate is as effective as quinine Atebrin by the mouth is almost equally effective.

in controlling

symptoms.

(2) It was not possible to arrive at definite conclusions as to the relapse rate, but the impression is gained that 5 days’ treatment with atebrin by the mouth is more effective in preventing relapses than a week’s treatment with quinine in the Ceylon standard dosage. (3) Pain and swelling at the site of injection so frequently as after quinine.

occurs after atebrin,

but not

C. L.

DUNN.

239

(4) Minor toxic manifestations occurred in a small percentage of patients after atebrin injections, but did not occur so frequently as after atebrin by the mouth. (5) The temporary mental derangement which may occur after atebrin, a very serious objection to the use of this drug.

is

(6) The greatest care is necessary for the selection of patients for treatment with atebrin musonate. Probably rather more than 4 per cent. of hospital patients treated with this drug, have died from its effects. (7) The manufacturers state that there are no contra-indications, but experience in Ceylon indicates that atebrin treatment per OSor by injection is definitely contra-indicated where there is any disturbance of the kidneys. Chronic poisoning appears’ to be associated with imperfect excretion of the drug. Small children appear to be specially liable to collapse and convulsions. (8) Medical officers may ask “ when should atebrin injections be used ? ” The majority of patients do not require injections of any drug, but if injections are indicated, quinine is to be preferred because of its greater safety. $.---~~scuss~o~

OF

THE

RESJLTS

OF

ATEERIN

TREATMENTS.

As the result of my own investigations and the perusal of the literature on the subject, I am in full agreement with BRIERCLIFFE’S general conclusions. Atebrin appears to be unsuitable for mass treatment, but is certainly a useful addition to our list of therapeutic agents for use in hospital practice when quinine is found less suitable, or ineffective. As GREEN (1934) says, “ Is it justifiable in dealing with a condition, which almost always responds readily to quinine, to employ instead, in the expectation of lessening the tendency to relapse, a drug of similar potency but somewhat uncertain toxicity ? ” This remark of GREEN’S is in my opinion the most logical conclusion that can be arrived at by a study of the results obtained with atebrin treatment. GREEN arrived at this conclusion in spite of the highly encouraging results reported by the Malayan workers, results which, as regards toxicity and relapse rates when compared with those obtained in Ceylon, are much more favourable to atebrin therapy. GREEN’S opinion is supported by KINGSBURY (1934) who describes cases of mental disturbance and minor untoward effects in Malaya. The low relapse rate obtained in Malaya has not been approached in any other country with atebrin alone, but lower rates have been obtained there by combinations of atebrin and plasmoquine, and in the tests carried out by the Army in India which will be published shortly. MORISHITA, MIYAHARA and ISIOKA (1934) on the contrary, report a relapse rate of 50 per cent. using the standard atebrin per OS treatment and KOMP and CLARK (1934) working in Panama in controlled villages for a period of 8 months, found the parasite rate only reduced

240

TREATMENT OF MALARIA, IN CEYLON.

from 21.6 to 18.6 per cent. The results obtained with atebrin musonate in controlling the febrile attack slightly more quickly than with quinine bihydrochloride injections have recently been more or less confirmed by FIELD and NIVEN (1936) working in Malaya. They treated 286 cases of acute malaria due to P. falciparum, P. vivax and P. malariae alternately with two atebrin musonate injections and quinine bihydrochloride administered orally for 7 days, the dosage being in accordance with the body weight. The fever in malignant tertian cases was stabilised in about 5 days with both treatments, but in benign tertian cases, the atebrin stabilised the temperature in an appreciably shorter period. Two toxic cases (epileptic fits), one of which was severe, occurred among the atebrin cases. The relapse rate could not be observed but an analysis of the cases returning to hospital within 10 weeks, suggested that relapses after atebrin musonate are fairly common. CARMAN and CORMACK (1936) working in Kenya, treated sixty-eight cases of which sixty-six were malignant tertian fever in a controlled experiment in which every alternate case received one to three intravenous or intramuscular injections of atebrin musonate plus 0.01 gramme of plasmoquine three times daily for 5 days ; and the others with 30 grains of quinine bihydrochloride daily plus 0.01 gramme plasmoquine for 5 days ; but no hard and fast rule was observed, and injections were also given In all the cases the temperature returned to as the severity of the case indicated. normal within 5 days, but the atebrin cases were controlled slightly more quickly, the percentage of cases showing asexual parasites was much less with the quininetreated cases, and very much less in the case of sexual parasites. It is surprising in view of the results obtained by other workers, that no toxicity was observed in either series with these comparatively large doses of plasmoquine. The toxicity of combinations of atebrin and plasmoquine has been reported These workers, as well as FIELD and NIVEN, by many workers in India. emphasize the high cost of atebrin musonate and remark on its consequent unsuitability for routine use among natives. 5.-~1scuss1o~

OF THE RESULTS OF QUININE TREATMENT.

AND PLASMOQUINE

As noted above, this treatment was used extensively by CLEMESHA among the populations of the tea, rubber and cocoanut estates under the Malaria Control Scheme, and in his report he records the success he has obtained over a series of years, in reducing the incidence of malaria by very large percentages among the people treated, and has compared this reduction with the high incidence of malaria in adjacent comparable populations. The success of this combination has been reported at various times, by SINTON and a large number of other workers in the Army in India, and in Bengal, and the United Provinces, in the Annual Report of the Directors of Public Health. A combination of

C.

L.

DUNN.

241

these drugs has also been adopted by the United Fruit Company of America. CLEMESHA’S treatment is directed at curing the primary febrile attack clinically with quinine, reducing the relapse rate by a follow-up treatment of quinine and plasmoquine, and eliminating the sexual forms, which-in his experience and that of others-are prone to appear in the peripheral blood after the 7th day, and a further course of quinine and plasmoquine at a time when he has been led to expect a later appearance of parasites, sexual and asexual. Although CLEMESHA was unable to show me direct proof of his theories in this respect, his opinions must be treated with respect in view of his wide experience in treating thousands of tea garden coolies in India and Ceylon for many years. At my request he is this year going to carry out some controlled comparative experiments with quinine, and with quinine and plasmoquine, in comparable estates ; while BRIERCLIFFE is carrying out similar experiments in all parts of Ceylon, alternate admissions to the jail hospitals being used for the experiment. The treatment will be 3 days quinine 30 grains and plasmoquine 0.02 gramme daily, as compared with quinine bisulphate 22+ grains daily for 7 days. This very short course of quinine and plasmoquine is being tried in order to ascertain whether such a short course will be reasonably effective, as it is necessary to endeavour to apply the shortest effective course to mass therapy in the tropics, owing to the difficulties met with in endeavouring to persuade patients to continue treatment after the febrile symptoms have subsided. The treatment was that used extensively under my direction in the United Provinces in 1931 and 1932 as the result of controlled experiments. In one experiment carried out in twenty villages, 856 cases were treated in 4 months with a febrile relapse rate of 8 per cent. In another, carried out in the Central and District Jails, Lucknow, at the same time, 734 cases were treated with a febrile relapse rate of 15.2 per cent. The control in reporting relapses in the latter experiment, was unimpeachable, which it naturally could not be in the villages. This treatment is, as far as I am aware, the shortest treatment yet recommended and extensively used for malarial therapy. The United Fruit Company of America use a standard treatment of 24 grains of quinine and 0.02 gramme of plasmoquine daily for 6 days as a routine treatment. SINTON and his colleagues (1930) used a dosage of 20 grains of quinine and 0.06 and 0.04 grammes of plasmoquine for 21 days, but this course was specially directed against chronic relapsing cases of benign tertian fever, when other treatments had failed. With the latter treatment the relapse rate was 8.4 per cent. Other Army workers with similar dosage for a similar period among patients admitted to the military hospitals, have recorded relapse rates between 4.1 and 8 per cent. MORISHITA, MIYAHARA and ISIOKA (1934) record a relapse rate of 12.9 per cent. with this combination, but these were parasitic relapses observed over 8 weeks, while the Army in India results are expressed as febrile relapses only. PETER (1935) states that this combination gives a lower relapse rate than any other therapeutic measure. I do not think that this short S-day course will

242

TREATMENT OF MALARIA IN CEYLON.

be found highly effective in “ preventing relapses,” which is, after all, another way of expressing “ effecting a radical cure,” nor in preventing the spread of the disease by destroying the viability of the gametocytes as they are not necessarily to be found in the peripheral blood during the febrile attack. It will, however, in nearly all cases effect a clinical cure and allow the patient to return to work. It will also conform to the policy advocated by the Malaria Commission of the League of Nations (1933) in dealing with mass therapy, and assist the patient to acquire “ tolerance ” and “ immunity.” I do not think that this treatment will be sufficient to employ in a “ highly susceptible ” population with no acquired “ tolerance ” ; but for mass treatment among the “ tolerant ” populations of the malarious tracts of India and Ceylon, it will be adequate. Some doubts have been expressed with regard to the danger of using plasmoquine in mass treatment. In my experience, in the dosage recommended, it is perfectly safe. CLEMESHA has had the same experience, and so has SUR (1932) m * B en g a1, and the workers under the United Fruit Company of America. It is only when doses of over 0.02 gramme per day are used, that serious toxic symptoms are recorded. I am aware that there is a great diversity of opinion on the efficacy of combinations of quinine and plasmoquine. The Malaria Commission pronounced definitely against this combination, but expressed themselves prepared to review their attitude if the efficacy of this combination in non-toxic doses could be proved by clinical trials on induced malaria in man. I think the I recorded evidence of workers from most countries is favourable to its use, especially in malarious countries for mass treatment. In primary outbreaks in a “ susceptible ” population, a more prolonged treatment will be repuired to effect a clinical cure, but even in such cases a B-day treatment should be sufficient. It is not contended that this treatment will suffice in severe cases with a heavy infestation of parasites, or in algid and cerebral cases. Such cases, which are usually the result of incorrect treatment or no treatment at all, must, of course, be dealt with on their merits with more drastic remedies. It is also not contended that this treatment will be equally effective in all malarious countries. It is well known that the virulence of the strains of parasites varies greatly in different countries, which accounts for the failure of this treatment in the hands of SWELLENGREBEL and DE BUCK (1932) on patients infested with multiple bites, and the Madagascar strain of parasite. But in India and in Ceylon, this treatment has been found effective as well as in America, and it is thus\ on account of the ease with which it can be distributed, its safety and cheapness, to be preferred to quinine alone or to atebrin alone, or in combination with other therapeutic agents. A combination of quinine and plasmoquine is more effective than quinine alone, and adds little to the expense of a treatment. It is safer than atebrin per OS,half the cost and more effective.

C.

6.-SUMMARY

L.

DUNN.

243

OF CONCLUSIONS.

1. Quinine in solution was found to be the safest and most effective remedy for the mass therapeutics of malaria in Ceylon by the Medical Department, the course of treatment aimed at being 224 grains daily for 7 days. 2. In the Ceylon Estates Proprietary Association’s Malaria Control Scheme, a follow-up course of quinine and plasmoquine for two periods of 6 days each, after the febrile symptoms had been controlled by quinine, was found an effective standard treatment. 3. Atebrin per OSfor 5 days in l&grain tablets given three times a day, was found effective in controlling the febrile symptoms, and in reducing the relapse rate, but a small percentage of untoward symptoms such as abnormal disturbances and varying degrees of mental derangement among adults, and collapse and convulsions among children, led the officers of the Medical Department to form the opinion that it was unsuitable for mass distribution, but was useful in selected cases for hospital treatment under medical supervision. It was also found that a treatment with atebrin is 24 times more expensive than a routine treatment with quinine. 4. Atebrin musonate was found to be most effective in controlling the febrile symptoms, but was found unsuitable for administration except to carefully selected cases, owing to its toxicity in a small percentage of cases. It is quite unsuitable for mass therapy owing to the expense of its administration and cost, and its comparatively high accident rate. 5. Combinations of atebrin and quinine, and atebrin and plasmoquine, were found to be more toxic in their effects than when given alone. If given consecutively, the toxicity was reduced. 6. Atebrin in any form cannot, therefore, take the place of quinine, which in the vast majority of cases, is effective in producing a clinical cure, and often a radical cure, especially in mass therapy. 7. From the results obtained by the use of a combination of quinine and plasmoquine in short courses, and in non-toxic dosage, this would appear to be the best agent to use in mass therapy for all types of parasites, and in all their stages. Its usefulness has been proved in India and America, and it has given good results except when used on patients infested with virulent strains of parasites. In Ceylon, where none of the parasites found have shown any abnormal virulence, it should give good results in short courses among “ tolerant ” populations, and in longer courses among “ susceptible ” populations.

244

TREATMENT

OF MALARIA

IN

CEYLON.

REFERENCES. B. (1933). Chemotherapy in ante-malarial sanitation. Malaya. med. J., viii (3), 163. BLAZE, J. R. & SIMEON, A. T. W. (1935). Preliminary observations on a new soluble atebrin compound. Indian med. Gaz., lxx (4), 185. BRIERCLIFFE, R. (1935). The Ceylon Malaria Epidemic 1934-S. Sessional paper, xxii. Ceylon : Govt. Press. CARMAN, J. A. & CORMACK, R. P. (1936). A controlled experiment in the treatment of malaria with atebrin-musonate by injection. Trans. R. Sot. trop. Med. Hyg., xxix (4), 381. CLEMESHA, W. W. (1935). Report on the 1934 outbreak of malaria among the estates subscribing to the Malaria Control Scheme. (Published privately.) DUNCAN, D. (1933). Atebrin in the treatment of malaria in Malaya. Malay. med. J., viii (2) 79. FIELD, J. W. & NIVEN, J. C. (1936). A clinical comparison of atebrin-musonate with quinine bihydrochloride. Trans. R. Sot. trap. Med. Hyg., xxix (6) 647. GREEN, R. (1934). Lectures on the development and use of the synthetic anti-malarial drugs. Bull. Inst. med. Res. F.M.S., No. 2. HOOPS, A. L. (1933). A review of published results obtained with atebrin in the treatment of malaria. Malay. med. J., viii (4). KINGSBURY, A. N. (1934). Psychoses in cases of malaria following exhibition of atebrin. Lancet, ii, 979. A third year’s observations in Panama with KOMP, W. H. W. & CLARK, H. C. (1934). special reference to control with atabrine. Amer.3. trop. Med., xiv (5) 381. LEAGUE OF NATIONS. (1933). Third Report of the Malaria Commission. The therapeutics of malaria. Quart. Bull, Health Organ, ii, 181. MORISHITA, K., MIYAHARA, H. & ISIOKA, H. (1934). On the specific effect of various drugs on the parasitic types of malaria based on the occurrence of parasitic relapses. Kitasato Arch., xi, 10. PETER, F. M. (1935). The clinical testing of malaria remedies. Trans. R. Sot. trop. Med. Hyg., xxix (l), 41. SINTON, J. A., SMITH, S. & POTTINGER, D. (1930). Studies in malaria with special references to treatment, Part xii. IndianJ. med. lies., xvii, 793. SUR, S. N. (1934). A New Anti-Malaria Scheme for Bengal. Bengal : Govt. Press. SWELLENGREBEL, N. H, & DE BUCK, A. (1932). Progs. Komin. Akad. v. Wetensch., No. 6. BARROWMAN,