THE CHEMOTHERAPY of MALARIA by PROFESSOR F
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Postgrad Med J: first published as 10.1136/pgmj.28.315.5 on 1 January 1952. Downloaded from MEDICINE THE CHEMOTHERAPY OF MALARIA By PROFESSOR F. MURGATROYD, M.D., F.R.C.P., D.T.M.* Wellcome Professor of Clinical Tropical Medicine, University of London, and Director, Department of Clinical Tropical Medicine, London School of Hygiene and Tropical Medicine; Physician, Hospitalfor Tropical Diseases, London The chemotherapy of malaria is complicated Segmentation and rupture of these mature pre-erythro- the fact that no anti-malarial so far dis- cytic schizonts on the seventh to the ninth day liberate by drug numerous small parasites known as merozoites, the covered is therapeutically effective against all majority of which are destroyed by phagocytes while the stages of human malaria. Not only do malarial survivors invade the red blood corpuscles of the cir- parasites differ in their reactions to drugs at culation to initiate the normal erythrocytic cycle of different stages in their complicated life cycles, malaria with which is associated the characteristic signs but different species of parasites at comparable and symptoms of the disease. of show different Having entered the red blood corpuscle, the mero- stages development responses, zoite develops a vacuole and forms the typical malarial and finally, strains within a given species may 'ring'; the parasite is now known as a trophosoite and show significant differences in susceptibility to steadily grows. The trophozoite becomes amoeboid, treatment. Furthermore, the treatment of patients develops granules of pigment from metabolism of in whom be is not haemoglobin, and its nucleus divides repeatedly, giving immunity may disregarded rise to an erythrocytic schizont. Segmentation of the necessarily that most suitable for the partially parasite and rupture of the erythrocyte liberates a immune and indigenous patients of a malarious number of merozoites which immediately invade further region. red blood corpuscles. This asexual erythrocytic cycle is These matters must be in mind if treat- then repeated serially, and with it is associated the copyright. kept characteristic periodic fever of malaria. With P. falci- ment is to be intelligently applied, and as a basis parum, P. vivax and P. ovale the cycle takes about 48 some understanding of modern views regarding hours and with P. malariae about 72 hours, so that the the of malaria in man is necessary. first three parasites produce a tertian type of fever and development the last a quartan fever. Malarial Cycle in Man After a time certain erythrocyticparasitesenlarge with- out nuclear division and form gametocytes, which are dif- There are four human species of malarial para- ferentiated into male and female parasites; they appear site, namely, Plasmodium fakiparum, which pro- in irregular waves in the blood and survive for about duces the severe and dangerous malignant tertian a week. Gametocytes as such cause no symptoms in malaria, P. vivax, the of tertian man, and are solely concerned with carrying on the http://pmj.bmj.com/ parasite benign development of the parasite after ingestion by suitable malaria, P. malariae, producing quartan malaria, anopheline mosquitoes, the other forms of the parasite and P. ovale, with which is associated tertian merely dying after being taken up by the mosquito. fever resembling that of vivax malaria. These parasites follow the same general pattern of It seems that with P. vivax and probably also development, but P. falciparum shows certain with P. malariae and P. ovale, some of the pre- differences which have an important bearing on erythrocytic parasites persist in an exo-erythrocytic a reservoir of treatment. phase forming parasites from which on October 1, 2021 by guest. Protected Infective forms of the malaria parasite, known as circulating erythrocytes may from time to time sporozoites, are injected into man with the saliva of the become re-infected when immunity is waning, biting infective female anopheline mosquito, and these and after the initial circulate for a short time, less than an hour, in the blood. perhaps long attack, thus They then disappear from the circulation, and the blood giving rise to the relapses which are so charac- then remains non-infective for some seven to nine days, teristic of these infections. With P. falciparum it during which time, the incubation period of the disease, seems that the exo-erythrocytic phase does not the patient remains free from significant symptoms. In continue this period the parasites undergo development and long beyond the pre-erythrocytic period. multiplication in the parenchyma cells of the liver and, Consequently, a recrudescence of fever with as this multiplication precedes the invasion of the red P. falciparum is probably due to persisting infec- blood corpuscles, this stage of development is known as tion of the red blood corpuscles and follows the the pre-erythrocytic phase. This pre-erythrocytic attack at schizogony finally produces ovoid plasmodial bodies primary a short interval. These facts which reach 40 to 6o0L in diameter and come to contain, have important bearings on the nature and dura- by nuclear division, some 1o,ooo to 30,000 small nuclei. tion of treatment that are required, and on the * As this goes to press, we learn with the greatest regret of the sudden death of Professor Murgatroyd on December i6th. Postgrad Med J: first published as 10.1136/pgmj.28.315.5 on 1 January 1952. Downloaded from 6 POSTGRADUATE MEDICAL JOURNAL January 1952 long-term prognosis in the various types of appearance of gametocytes or prevent their further infection. development in the mosquito. Because gameto- cytes as such give rise to no symptoms in man, General Chemotherapeutic Considerations drugs acting on them are of no direct therapeutic From what has been said, it is clear that there interest, although they may be of some indirect are several different stages at which a drug may value in limiting the spread of malarial infection. act upon the malarial parasite. For example, a drug which could Fe taken continuously without Specific Drugs toxic effects and which would maintain in the Besides the standard anti-malarial drugs, many blood a concentration lethal to sporozoites, would other compounds exert some anti-malarial activity kill these parasites on their introduction by the but their potency is usually limited. On the mosquito, and such a drug would therefore act as other hand, a number of new and promising com- a true cau3al prophylactic agent. Unfortunately, pounds are under trial, but these have not yet there is no such compound which is sufficiently come into practical use. The drugs at present non-'oxic to man that it can be so used in practice. used in practice fall into five groups:- Furthelmore, there is no drug in practical use I. Cinchona alkaloids. Of these quinine in which alone can with certainty be relied upon to various salts is most used, although other cinchona destroy all pre-erythrocytic parasites; proguanil in alkaloids have been employed; on the grounds of therapeutic doses destroys pre-erythrocytic para- cheapness considerable use has been made of sites of certain strains of P. falciparum but does totaquina, a standardized mixture of total cin- not appear to destroy all strains, and it is relatively chona alkaloids containing not less than 70 per inactive against pre-erythrocytic forms of the cent. of crystallizable alkaloids of which not less other species. than 15 per cent. is quinine. The e are, however, several drugs which in 2. 9-amino-acridine- compounds. The out- therapeutic doses have a very powerful action standing representative is mepacrine. against the erythrocytic trophozoites and schizonts 3. 4-amino-quinoline compounds. These in- of malaria, and as these stages of the parasites are clude chloroquine, camoquin, and a number ofcopyright. responsible for the clinical manifestations of related compounds. malaria, s-ch drugs, commonly known as 4. Biguanide derivatives. Of these the practical schizonticiles, furnish most powerful weapons example is proguanil. for the control of the acute stages of the disease. 5. 8-amino-quinoline compounds. These in- They do not, however, destroy exo-erythrocytic clude pamaquin, pentaquine and isopentaquine. forms of vivax, quartan or ovale parasites, and The first four act as schizonticidal agents, consequently with any of these infections suc- destroying the asexual parasites in the erythro- cessful ti etment of the acute attack does not cytes. Through this action they can be used necessarily mean that relapse may not occur. either to control acute malarial attacks or, if taken http://pmj.bmj.com/ Many of the schizonticidal drugs are suffi- continuously, to suppress the development of ciently non-toxic to be taken continuously in parasites in the blood, thereby preventing the doses which maintain a schizonticidal concen- development of clinical symptoms. In addition, tration in the blood and thereby suppress the proguanil destroys pre-erythrocytic forms of cer- initial development of the erythrocytic parasites tain strains of P. falciparum and also prevents from the pre-erythrocytic stages. This sup- gametocytes from developing fully in the mosquito. pressive action is greatly used in practice to keep Compounds of the fifth group, the 8-amino- on October 1, 2021 by guest. Protected individuals who are exposed to the risk of malaria quinoline derivatives, are mainly used for their free from symptoms of the disease. It is obvious, action against the exo-erythrocytic parasites. however, that such drugs, acting only on the They are used in conjunction with one of the erythrocytic forms, will not prevent delayed schizonticidal drugs in the treatment of attacks of primary attacks, arising from a persisting exo- vivax, quartan and ovale malaria. They appear erythrocytic reservoir of infection, from becoming to devitalize the exo-erythrocytic parasites, par- manifest after the suppressive treatment is dis- ticularly if given along with quinine, and conse- continued.