631 Postgrad Med J: first published as 10.1136/pgmj.36.420.631 on 1 October 1960. Downloaded from THERAPEUTIC SYMPOSIA-3: TROPICAL DISEASES

THE TREATMENT OF MALARIA SIR NEIL HAMILTON FAIRLEY, K.B.E., D.Sc., M.D., F.R.C.P., F.R.S. Consulting Physician, The Hospital for Tropical Diseases, London, N. W. I

Hyperinfection in Malignant Tertian When the rectal temperature reaches Io02F. Infection hydrotherapy should be stopped. Where there is hyperinfection associated with Finally, if haemolytic anaemia be severe the cerebral features, where algid malaria is found, patient should be transfused; in severe cases where the patient cannot swallow or when vomiting several pints of blood may be given. Oral and diarrhoea are severe, anti-malaria drugs medication with iron should follow. should be given intravenously. For this purpose, quinine hydrochloride gr. I0 in I0 to 20 ml. of Ordinary M.T. Malarial Attack isotonic saline may be slowly injected at the rate of i gr. per minute and repeated in six hours if Bed rest during the febrile period and for at Protected by copyright. necessary. The injection must be given slowly least three days after the temperature is normal is owing to the severe drop of blood pressure essential, especially in the first attack of malignant resulting from rapid injection. Never more than tertian malaria. Should there be anaemia, a pill three injections should be given in the first 24 containing ferrous sulphate (gr. 3) should be given hours. If the blood pressure is unduly low or thrice daily and if the anaemia proves severe, algid symptoms are present, quinine hydro- blood transfusion will help convalescence. chloride may be given slowly in one pint of saline For M.T. malaria one of the more active rather than in concentrated form. schizonticidal drugs should be given orally. Chloroquine hydrochloride in a dosage of 200 Proguanil (paludrine) and pyrimethamine (dara- to 300 mg. may be injected intramuscularly and prim) though effective schizonticides, act too repeated in eight hours, or 400 mg. of base in slowly in reducing the temperature and for this 500 ml. normal saline may be given slowly by reason drugs like chloroquine sulphate or diphos- intravenous drip, taking one hour for the in- phate and mepacrine hydrochloride are preferable. jection. The sulphate in a dosage of 200 mg. base Chloroquine sulphate or diphosphate is given http://pmj.bmj.com/ may be given intravenously and repeated in eight orally to non-immunes in the following dosage: hours. Parenteral medication is stopped when six tablets (or goo mg.) on the first day; two the patient regains consciousness and when shock tablets (or 300 mg.) on the second and third days. and symptoms of collapse improve. In partial immunes, four tablets (or 6oo mg.) are It is often necessary in this condition to combat given on one day only. Chloroquine is probably dehydration and to maintain blood volume by the best drug to use for the routine treatment of intravenous injections of isotonic saline (o.85 per malaria. on September 25, 2021 by guest. cent.) or glucose (5 per cent.) given by continuous Mepacrine hydrochloride is a very effective drip or intermittently. schizonticidal drug. It is given to non-immunes Mepacrine hydrochloride (0.3 g.) may also be in a dosage of 300 mg. thrice daily for the first day, administered intramuscularly if other drugs given twice daily on the second day and then ioo mg. by the intravenous route are not available. A thrice daily for five days. Some 300 to 500 mg. total of i.o g. mepacrine parenterally should not be of mepacrine are given to partial immunes in a exceeded in the first 24 hours of treatment. single dose. Lumbar puncture with the withdrawal of 20 ml. Quinine dihydrochloride or sulphate in a dosage of cerebrospinal fluid may be helpful. In addition, of io gr. thrice daily is given for five to seven days should hyperpyrexia be present, the naked patient to non-immunes. This drug is not used so much is placed under a fan on a wire mattress and now in chronic M.T. malaria owing to the danger covered with a sheet sprayed with ice-cold water. of its precipitating blackwater fever. 632 POSTGRADUATE MEDICAL JOURNAL October I960 Postgrad Med J: first published as 10.1136/pgmj.36.420.631 on 1 October 1960. Downloaded from Lapudrine was discovered by Curd, Davey Prevention of Transmission et al. in 1950.2 It has one more chlorine atom The 8-amino-quinolines in non-toxic dosage than proguanil in the benzene ring and is more also destroy the sexual forms of P. falciparum in active than proguanil. It is more effective the peripheral blood and the administration of therapeutically and prevents the development of pamaquine IO mg. t.d.s. or of primaquine 7 mg. oocysts in the mosquito stomach. t.d.s. for two or three days are effective from this viewpoint. Proguanil, lapudrine and pyrimetha- Radical Cure of Vivax and Quartan Malaria mine do not destroy the gametocytes in the blood stream, but they do prevent their development in There is no evidence that in falciparum malaria the mosquitoes' stomach so that infection of the late exo-erythrocytic forms persist. Once parasites salivary glands does not occur. In consequence, have all been destroyed in the peripheral blood by mosquitoes feeding on patients taking these drugs schizonticidal drugs radical cure has been achieved; in appropriate dosage do not transmit the disease the so-called relapses are due either to the per- sistence of erythrocytic forms in sub-microscopic to others. numbers in the peripheral blood or to reinfection. Causal Prophylaxis and Suppression In vivax and quartan malaria, and possibly in In experimentally infected volunteers in Cairns P. ovale infections also, this is not the case. With it was found with the South West Pacific strains by benign tertian and quartan parasites late exo- Fairley et al.5 that quinine (gr. io) daily failed to erythocytic forms often persist and produce re- suppress malignant tertian malaria and a propor- lapses despite the previous total eradication of tion of benign tertian infections also. Sulphadia- parasites in the circulating blood by schizonticidal zine proved reasonably satisfactory in a dosage of drugs. We are dependent on the 8-amino- I.O g. daily in M.T. infections, but overt attacks of quinoline drugs for the radical cure of both these malaria species of parasite. Pamaquine has been success- B.T. very frequently occurred. When mepacrine (o.i g.) was given every dayProtected by copyright. fully used for this purpose for many years and more invariably, it was found that malignant tertian in- recently American workers have successfully fections were both suppressed and radically cured produced several new 8-amino-quinoline drugs in- and that benign tertian infections were suppressed cluding pentaquine, iso-pentaquine and prima- throughout the period of mepacrine administra- quine which are even more effective. tion. Benign tertian relapses, however, generally It was found that primaquine in a dosage of occurred from two to seven weeks after the drug I5 to 30 mg. daily for I4 days completely eradi- was stopped, but malignant tertian malaria never cated P. vivax parasites by destroying the per- reappeared. sistent exo-erythrocytic forms in the liver. Toxic Factors generally regarded as precipitating side-effects include gastro-intestinal disturbances, relapses in latent malaria were also investigated. and haemoly-tic anaemia to which negroes are These included exposure to wet and cold, physical prone; the latter may be associated with haemo- exhaustion, anoxia and chill as in high altitude globinuria. Concurrent administration of sul- flying, blood loss, anaesthetics, surgical operations phadiazine and mepacrine may increase the and alcoholic excesses and strong emotions ofhttp://pmj.bmj.com/ toxicity of the 8-amino-quinolines, and for this anger and fear associated with outpouring of reason must be avoided. adrenalin. No volunteers, however, developed Reports were published on primaquine by malaria fever while mepacrine was being taken. authority of the Council on Pharmacy and Immediately following these experimental re- Chemistry, U.S.A."1 If fever be present prima- sults a military conference was held in Queensland quine is given in combination with one of the and all the measures suggested were adopted. schizonticidal drugs such as chloroquine or In consequence, malignant tertian malaria and quinine but not mepacrine. Four groups of blackwater fever practically disappeared in the on September 25, 2021 by guest. patients were treated. The first comprised 232 South West Pacific and though benign tertian and men who received chloroquine 1.5 g. in divided quartan malaria frequently followed cessation of doses over three days; 64 patients (27 per cent.) mepacrine administration, fatalities were almost relapsed. The second group of 246 men received unknown. Comparable results were obtained the same dose of chloroquine plus 27 mg. prima- amongst British troops in Burma but the incidence quine daily as three divided doses for I4 days; of malaria in Japanese troops persisted at a very one patient relapsed. The third group of 23I high level throughout the whole war. men received the-same dosage of chloroquine and Chloroquine diphosphate was discovered and primaquine in a single daily dose of I5 mg. for patented in Germany in 1938 and was synthesized 14 days; none relapsed and there were no signifi- in U.S.A. during the war. Fairley et al.6 found it cant toxic effects. prevented symnptoms of malaria developing in October I960 FAIRLEY: The Treatment of Malaria 633 Postgrad Med J: first published as 10.1136/pgmj.36.420.631 on 1 October 1960. Downloaded from volunteers experimentally infected with M.T. Lapudrine. Robertson9 reported that I5 mg. malaria while taking o.i g. daily. Subinoculations once a week is an effective prophylactic. on the eighth day were always positive, but after Pyrimethamine (daraprim). Rollo10 described ceasing the daily dose on the 23rd day, parasites tests of antimalaria activity against the blood forms had been destroyed and they never reappeared in and exo-erythrocytic forms of P. gallinaceum and blood smears. On the 8ist day the volunteers also against the blood forms of P. berghei. were again successfully reinfected, no evidence of Goodwin8 stated that good reports on the sup- premunity being found. Similar results were pressive action of pyrimethamine had been -re- recorded in a few volunteers taking 50 mg. of ceived from the Belgian Congo, the Gambia, Indo- chloroquine daily. As with mepacrine, benign China and Tunisia but less so from Malaya. tertian infections were completely suppressed with Foy and Kondi7 investigated the action of pyri- chloroquine, but relapses generally occurred within methamine on the gametocytes of P. fakiparum. two months of cessation of drug prophylaxis. They showed it rendered gametocytes uninfective. Davey and Robertson4 in Nairobi working on to A. gambiae. It is now recognized that the best Army volunteers confirmed Fairley's findings that value of paludrine and daraprim is for prophylactic. chloroquine in a dosage of 50 mg. daily was an and suppressive purposes since both these drugs. effective prophylactic against M.T. malaria, elimi- act slowly in the febrile attack. Daraprim in a nating the infection entirely. dosage of 25 mg. per week is given to adults;, Proguanil was discovered by Curd, Davey and children under the age of 6 years receive 6.25 mg. Roses to be effective in bird malaria. It was per week and those from 6 to Iz years receive- investigated in man by Adams et al.l and by I2.5 mg. per week. Fairley et al.6 In M.T. malaria it was found to be an excellent- prophylactic drug destroying the pre- REFERENCES erythrocytic forms in the liver before they reached I.ADAMS, A. R. D., MAEGRAITH, B. G., KING, J. D.,.Protected by copyright. the blood stream. Subinoculation on the eighth TOWNSHEND, R. H., DAVEY, R. H., and HARVARD,. R. E. (I945), Ann. trop. Med. Parasit., 39, 22S. day was always negative in these patients, whereas 2. CURD, F. H. S., DAVEY, D. G., HENDRY, J. A., and with mepacrine and chloroquine it was invariably ROSE, F. L. (I950), Brit. J. Pharmacol., 5, 438. 3. CURD, F. H. S., DAVEY, D. G., and ROSE, F. L. (194S),. positive, the parasites being destroyed by these Ann. trop. Med. Parasit., 39, 208. drugs in the blood stream later. With B.T. and 4. DAVEY, D. G., and ROBERTSON, G. I. (I957), Trans. roy.. quartan infected volunteers, fever failed to develop Soc. trop. Med. & Hyg., 5!, 463, 502. 5. FAIRLEY, N. H., et al. (I945), Ibid., 38, 311. while they were taking proguanil, but generally 6. FAIRLEY, N. H., et al. (1946), Ibid., 40,229. appeared within two months when drug administra- 7. FOY, H., and KONDI, A. (I952), Ibid., 46, 370. tion ceased. The dosage of proguanil for non- 8. GOODWIN, R. G. (1952), Ibid., 46, 485. immune adults is ioo mg. daily; for children under 9. ROBERTSON, G. I. (I957), Ibid., 5!, 457. 6 years it is 25 mg. daily and from 6 to I2 years it Io. ROLLO, I. M. (I952), Y. Amer. med. Ass., 46, 474. iI. REPORTS published by authority of Council of Phannacy- is 50 mg. daily. (1952), Ibid., I49, I558. http://pmj.bmj.com/ on September 25, 2021 by guest.