Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from

Postgraduate Medical Journal (August 1973) 49, 573-583.

Antimalarial drugs and their actions W. PETERS M.D., B.S., D.T.M. & H. Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool L3 5QA

Summary malignant tertian parasite, Plasmodium New antimalarial drugs are required, partly because falciparum. The mortality from falciparum malaria of the emergence of drug resistant strains of malaria alone was 16%. This figure is appalling, especially parasites and partly because better compounds are so since (a) malaria is preventable and (b) treatable. needed to cure relapsing tertian malaria. In reviewing Most fatalities occur because the diagnosis is missed, the diverse modes of action of currently used anti- and the diagnosis is missed in most instances simply malarials, against a background of the patho- because the physician fails to ask the patient or his genesis of malaria, attention is drawn to deficiencies relatives the one question, 'Where have you been, in our knowledge. Even less do we understand how the and when?' This lesson is brought home by com- malaria parasite becomes resistant to certain drugs, paring falciparum mortality rates between civilian in particular . New approaches to the and military cases in the United States. Between problem include the application of combinations of 1966 and 1969, 10% of civilians with falciparum malaria died there (Neva et al., 1970). Among

existing antimalarials, and the search for new drugs on by copyright. an unprecedentedly vast scale. Out of over a quarter military personnel the fatality rate was only 0-3 % million compounds that have recently been screened, a (Canfield, 1972). handful are now in and are showing great A massive drive to eradicate malaria was spon- promise for the treatment of multiple resistant sored by the World Health Organization on the falciparum malaria. The paper concludes by sum- basis of guidelines laid down in 1957 (W.H.O., marizing current recommendations for the prophylaxis 1957). It was based primarily on the deployment of and therapy of malaria due to drug resistant parasites. DDT and other chlorinated hydrocarbon insecticides to break the cycle of malaria transmission by killing vector anophelines as they rested in houses. Anti- AT the turn of the century malaria was still endemic malarial drugs were given as a supplementary

in swampy areas of England such as the Thames measure, partly for the relief of acute malaria and http://pmj.bmj.com/ estuary. With increasing urbanization, land utiliza- partly to speed the elimination of the parasite pool tion and swamp clearance, breeding of the anophe- in the human population. Both prongs of this two- line mosquito vectors came under control and forked attack have been badly blunted by the autocthonous malaria rapidly faded away. Today, development of drug resistance. By the end of 1968 however, we are witnessing a resurgence of malaria, some fifteen vector anopheline species had become not acquired within these shores, but imported by resistant to DDT, thirty-six to dieldrin and thirteen travellers returning from the many parts of the of the fifteen to both. Already one species (Anopheles tropical world where the transmission of this disease albimanus in Central America) is resistant to the on October 2, 2021 by guest. Protected continues on a vast scale. In spite of some 20 years new generationof insecticides, the organophosphates. of international campaigns to control or eradicate On the parasite side the situation is no better. It has this threat, malaria still occurs in territory occupied taken very little time fromthelarge-scaleintroduction by some 1000 million people, nearly one third of the of a new drug to the appearance of parasites with the world's population. ability to survive it (Table 1). This has been a The scale of international travel to and from the particularly severe problem in the case of P. falci- world's more wealthy countries is increasing on an parum. unprecedented scale so that malaria, like other New antimalarial drugs are needed, not only 'exotic' diseases, preventable as it may be, neverthe- because of the resistance problem, but also because less is on the increase. In the U.K. an average of existing drugs do not include any that are able to 120 cases of malaria a year have been reported produce a radical cure of relapsing tertian malaria between 1960 and 1970, with a mortality of 4-7% due to unless given in subtoxic (Bruce-Chwatt, 1971). Most fatalities were due to the doses for at least a week. Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from

574 W. Peters

TABLE 1. Appearance of drug resistance secondary exoerythrocytic liver schizonts that are Year resistance first responsible for relapses in benign tertian malaria Year recognized in man, due to P. vivax and ovale. (The existence of this Drug introduced and where phase in Plasmodium malariae is still in dispute.) The pathogenic effects of malaria are all related to 'Antifols' the asexual 1948 1949 (experimental) erythrocytic stages of the parasites (i.e. 1950 Java (in field use) the direct damage they do to their host cells), the 1952 1952 Gambia more distant effects due to the products of their metabolism, and the immunological response of the embonate 1963 1964 S. Rhodesia host. The direct damage consists of acute haemo- Sulphadoxine 1964 1968 Cambodia 1935 1946 New Guinea lysis, both of infected and uninfected red cells, with Chloroquine 1945 1961 Colombia (but probably its attendant anaemia. The indirect damage is caused seen and not by various factors, such as the release of toxic mat- recognized in erials of unknown nature (see review by Maegraith Panama, 1956) & Fletcher, 1972), which trigger a chain of events that include changes in capillary permeability, the Pathogenesis of malaria and the place of antimalarial production of pharmacologically active peptides, drugs in prevention and treatment anoxic anoxia, and possibly some degree of dissemi- The malaria parasite undergoes two phases of nated intravascular coagulation. These events may asexual reproduction in man, the first in paren- occur to a lesser or greater degree in malaria caused chymal cells of the liver and the second in red blood by any of the species of Plasmodium that infect man cells. From parasites of the latter phase are derived but are usually more severe in falciparum infection. gametocytes which undergo further development This type of disease, justifiably known as 'malignant culminating in sexual reproduction only after they tertian malaria', is aggravated in addition by the are ingested by a suitable mosquito. The mosquito tendency of the infected erythrocytes to adhere by copyright. to phase terminates in the production of infective capillaries of the deep circulation, and particularly to forms, the sporozoites that enter the circulation of a those of the brain. In this situation interference new mammalian host together with secretions of the with cerebral microcirculation can lead to the con- mosquito's salivary glands. The cycle is represented dition known as cerebral malaria. in Fig. 1. Disturbances of renal vascular function may give rise to decreasing glomerular filtration and anuria with all its consequences. Sudden haemolytic crises * cc: PrOPb I cs aC i associated with falciparum malaria can produce the -in condition known as 'blackwater fever'. The patho-

genesis of this syndrome is still incompletelyhttp://pmj.bmj.com/ understood. It is known that it used to be associated with the administration of and that incidence of this complication has diminished greatly in 1 :$+ (mu C*}'.C').: recent years, but it is also possible that host genetic cy*6.SA _ factors such as G-6-PD deficiency may play a role. Treatment of malaria consists of the administra- tion of specific drugs to destroy the intraerythrocytic (Noc-b parasites and of non-specific supportive measures on October 2, 2021 by guest. Protected aimed at correcting the general disturbances of host function. Certainhighlyeffectiveblood schizontocides in fact possess general pharmacological properties FIG.I. Diagram oflife-cycle ofmalaria parasites showing that are of value also in a general manner. The anti- sites of action of antimalarials. inflammatory action of chloroquine, for example, undoubtedly plays a role in the remarkably rapid Antimalarial drugs may affect one or more phases response of a child with cerebral malaria to systemic of this cycle. The compounds are given names that administration of this compound. describe the type of action for which they are A few drugs are of value, not only for their action normally employed, e.g. chloroquine is known as a on the asexual blood stages, but also as a means of 'blood schizontocide', whereas is usually blocking the transmission of the parasites through described either as an 'anti-relapse drug', a 'tissue the anopheline vectors. Such drugs are pyri- schizontocide' or a 'gametocytocide'; the first two of methamine which has a potent sporontocidal action, these both describe the action of primaquine on the and primaquine which appears to act upon the Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from Antimalarial drugs 575 gametocytes, rendering them non-infective. Prima- properties of a modest nature was , quine, while having some action too upon the and further work on this type of chemical structure asexual blood stages, is too toxic to be employed led in the 1920's to the evolution of a number of generally for treatment, but is at present the drug 8-aminoquinolines. In the early 1930's pamaquine of choice for the elimination of the secondary tissue was developed by Schulemann and his collaborators stages of relapsing (i.e. 'radical cure'). of the I.G. Farbenindustrie. It proved to be a very Malaria may be prevented by drugs such as pro- poor blood schizontocide, although it was found to guanil that inhibit the development of the pre- have considerable activity against exoerythrocytic erythrocytic liver phase (i.e. 'causal prophylactics') stages. Later the 9-aminoacridine mepacrine was or by any blood schizontocide that is able to sup- developed by other German workers and mepacrine press the erythrocytic asexual parasites. In time, proved, unlike its predecessor, to be a highly effective with continuing exposure to malaria infection, and compound for the treatment of acute malaria. The especially with the repeated stimulus of the erythro- mepacrine type of structure was later simplified and cytic parasitaemia, even at sub-threshold levels, a a series of 4-aminoquinolines resulted. The most degree of immunity may be built up that permits the active of these eventually proved to be chloroquine, individual to tolerate further infections without the which received its first clinical challenge during aid of continuous chemoprophylaxis and without the Second World War. Other derivatives of the same clinical symptoms. However, undue stress, such as series were introduced within a few years and these secondary infection, trauma or pregnancy, may included such compounds as , which reduce the protection afforded by the immune has come into very wide use, and the related deriva- mechanisms, and acute malaria may ensue. In the tives amopyroquine and cycloquine. Further case of infection due to P. malariae, pathogenic development of the 8-aminoquinolines led to a much changes occasionally occur in the kidneys or other less toxic analogue of pamaquine, namely prima- organs due to the deposition of antigen-antibody quine. The structures of these compounds are complexes. Current concepts on immunity in malaria illustrated below (Figs. 2 and 3). were reviewed recently by McGregor (1972). The 8-aminoquinolines have an entirely different by copyright. mode of action from quinine, mepacrine or the The evolution of antimalarials 4-aminoquinolines. It is now known that the Ever since Pelletier & Caventou isolated the active 8-aminoquinolines suppress the mitochondrial func- principle of quinine in 1820, research workers have tions of malaria parasites, at least in the exoerythro- been endeavouring to produce a synthetic product cytic stages, and possibly also the activity of struc- with the properties of the original antimalarial but tures equivalent to mitochondria in the erythrocytic without its toxicity. One of the first compounds to forms. Moreoever, it seems very likely that it is not be developed which proved to have antimalarial the 8-aminoquinolines themselves that are active http://pmj.bmj.com/

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576 W. Peters

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Chloroquine Amodiaquine Mepacrine FIG. 3. but 5,6-quinolinequinone derivatives formed by Chloroquine, together with amodiaquine, prima- metabolization of the 8-aminoquinolines in the quine, proguanil and pyrimethamine provided an mammalian organism. This, however, remains to armamentarium of synthetic antimalarials that for a be proven. number of years following the Seond World War During the search for new antimalarials in the appeared to provide all that could be desired in the Second World War it was discovered that many field of malarial chemoprophylaxis and chemo- sulphonamides and sulphones have good anti- therapy. It was, however, only a matter of a very few malarial activity against avian malaria, but the years before resistance began to appear in the field promise of these compounds was not borne out by to proguanil and pyrimethamine. Nevertheless, this clinical studies against human malaria parasites. proved no cause for alarm, since parasites which It is now known that this was partly because many appeared to be resistant to those compounds still of the compounds tested were rapidly excreted in responded to treatment with chloroquine or mepa- man, and some modern, more long-acting sulphon- crine, and in certain cases (when it was still used), amides have been shown now to have a far more quinine. It was indeed only in about 1959 when theby copyright. satisfactory blood schizontostatic activity (Fig. 4). first cases of P. falciparum infection resistant to Also during the Second World War research pro- chloroquine were found, that serious concern began gramme a new type ofchemical structure was evolved to be shown about a possible breakdown in our by chemists of I.C.I. from which the compound we drug weapons against malaria. Since this happened know as proguanil emerged. Proguanil proved to to coincide with a period in history when consider- be by far the most active compound known, and in able numbers of non-immune troops were being addition it was the only truly causal prophylactic deployed in a highly malarious part of Southeast antimalarial ever discovered up until that time. Asia, namely the Republic of South Vietnam, the Shortly afterwards pyrimethamine was produced by coincidence of the emergence of chloroquine resis- other British workers in the Wellcome research tance and of a major war set in train a series of organization. It was only when the mode of action research programmes which, up to the present time, http://pmj.bmj.com/ of proguanil was revealed that it was realized in have culminated in the study of well over 200,000 retrospect how similar pyrimethamine was to the new compounds in the search for better antimalarials active metabolite of the earlier drug, which we now (Peters, 1970; Kinnamon, 1972). Furthermore, call cycloguanil (Fig. 5). considerable effort was devoted to studying the mode

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COOH Cycloguanil embonate FIG. 5. of action of even the older compounds, since this of the mode of action of chloroquine. It has long http://pmj.bmj.com/ topic had been largely ignored up to this time. been known that this drug is highly concentrated in Fortunately a new and very useful laboratory model parasitized erythrocytes, and it is now clear that the had been developed during the interim period. This concentration takes place very rapidly in the para- was a malaria parasite of rodents which was readily sites themselves. The immediate effect of exposure to adaptable to ordinary laboratory mice, namely chloroquine is clumping of the malarial pigment, Plasmodium berghei. This has proved extremely which is maximal after a period of about 60 min.

useful for large-scale screening of drugs for anti- The malaria pigment that forms within vesicles in on October 2, 2021 by guest. Protected malarial activity and has proven to be a far better which the parasites digest host cell haemoglobin is model for human malaria than the avian parasite probably the end product of the breakdown of the Plasmodium gallinaceum that was the basis of most haemoglobin protein chains. Interference with this drug screening during the Second World War process by chloroquine must quite clearly also programme. Still more recently an even better model interfere with the production of the basic amino acid has been discovered in a combination of human building blocks required by the parasites. At a later P. falciparum in the little South American monkey stage of its action chloroquine induces a breakdown known as Aotus trivirgatus. This is the only simian of the larger RNA particles of the malaria parasites. species in which human malaria parasites will Electron micrographs show that chloroquine leads fairly readily develop. to the development of large cytolysosomes which contain all the haemozoin together with a consider- Mode of action of chloroquine and quinine-type able number of malarial ribosomes. A number of compounds compounds have been shown by Warhurst et al. P. berghei has been used extensively for the study (1971) to interfere with this process of cytolysosome Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from 578 W. Peters

H formation (Type B). On the other hand, several com- H to same of action pounds can be seen have the type 0 as chloroquine, namely the induction of haemozoin \N clumping and cytolysosome formation (Type A) (Table 2). Drugs that produce such an effect are TABLE 2. Mode of action of chloroquine and quinine- Br F3C related compounds WR 33063 WR 122455 Type A Type B H CF,

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Antimalarial drugs 579

TABLE 4. Half-life of repository drugs control of malaria if drug resistance had not appeared within a very short time. Approximate 'half-life' (weeks) Resistance to the antifols appears to be due to the Mouse Man development by the parasites of a mutant enzyme Cycloguanil embonate 6-8 24 with a decreased affinity for the drug (Ferone, 1970). Acedapsone* 6-13 7 Moreover, the mutant enzyme is produced in a larger quantity than the normal enzyme, thus com- * Dadds. pensating for the presence of the inhibitory drug. For example, sulphonamides with a prolonged Nevertheless, if such a resistant strain, or indeed a half-life in man are proving to be remarkably strain which is resistant both to an antifol such as effective antimalarial agents, as indeed are such pyrimethamine and to a sulphonamide, is exposed to newer sulphone derivatives as the diformyl analogue a combination of these two compounds, the com- of dapsone. bination proves to be effective. This has been shown Proguanil and its active metabolite cycloguanil, not only by ourselves and others in experimental pyrimethamine and trimethoprim inhibit the con- situations (Peters, 1971), but also by our American version of dihydrofolate to tetrahydrofolate in the colleagues in human volunteers infected with malaria parasite. Their selectively toxic action against multiple-resistant strains of P. falciparum. malaria parasites is due to the fact that they are more strongly bound to the enzyme ofthe parasites than to Experimental investigation ofresistance to chloroquine the enzyme ofthe host (Ferone, Burchall & Hitchings, The main laboratory model used up to 1948 for 1969). If sulphonamides or sulphones are given at the the investigation of antimalarial drugs was the same time as one ofthese antifols, a marked potentia- avian parasite P. gallinaceum in the chick. In this tion is observed. This is found not only in systems model it proved very easy to produce resistance to employing the blood forms of malarial parasites but the sulphonamides and to the antifols. It was, how- in ever, by no means the same case with the newly also in the mosquito stages, and indeed even by copyright. the liver stages in the few cases where this has developed compounds of the chloroquine type. been examined. The same situation applies not only Numerous attempts to develop strains of P. gallin- in experimental laboratory models (Peters, 1968) but aceum resistant to mepacrine or to chloroquine also in the treatment of human malaria and parti- failed. This induced a false sense of security in the cularly in P. falciparum. potential value of these modern synthetic anti- One of the problems, apart from any question of malarials. This sense of security was abruptly drug resistance, has been the desirability of having shattered, however, when chloroquine-resistant antimalarial compounds which can be given at strains of P. falciparum were demonstrated first in irregular intervals under field conditions where South America, and then, within a year to two, in regular chemoprophylaxis is an impracticable pro- parts of Southeast Asia. Investigations were started position. In their search for such long-acting com- rapidly to try to discover how malaria parasites could http://pmj.bmj.com/ pounds, the late Paul Thompson and his colleagues become resistant to chloroquine. One of the first of the Parke-Davis organization developed poorly experiments revealed that chloroquine-resistant soluble salts of cycloguanil and of dapsone. These P. berghei concentrated chloroquine to a much were found to have extremely long activity, both in lower degree than did normally chloroquine- mice and in man, when given in an injectable sensitive parasites (Macomber, O'Brien & Hahn, repository formulation (for formulae of cycloguanil 1966). Peters, Fletcher & Staubli (1965) showed embonate and acedapsone, see Figs. 5 and 4 respec- that chloroquine-resistant P. berghei failed to pro- tively). Moreover, it was hoped that by giving a duce normal malarial pigment and that the parasites on October 2, 2021 by guest. Protected combination of cycloguanil pamoate and acedap- lived in immature rather than in mature red cells. sone one could avoid stimulating the development While investigating the respiration of normal and of parasite strains resistant to one or other of the resistant parasites, Howells et al. (1970) found that individual components. Unfortunately this did not there is a cyclical change in the mode of respiration prove to be the case when the mixture of these two of P. berghei between the mammalian and mosquito- compounds was applied in extensive field trials. stages. Nevertheless, even cycloguanil pamoate alone While the forms in the red blood cells utilized proved in human volunteers to protect against anaerobic respiration of the Embden-Meyerhof type, sporozoite challenge with both P. falciparum and the mosquito stages more fully utilized glucose by P. vivax, in some cases for more than 1 year. Under opening up pathways of the aerobic Krebs cycle. It field conditions the duration of protection was far was shown that blood stages of the highly chloro- less, usually only about 3 months, but even this quine-resistant parasites also utilized Krebs cycle could have offered a considerable advantage for the pathways. The hypothesis was put forward that the Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from

580 W. Peters

parasites were chloroquine-resistant by virtue of their hope. What is not clear at the moment is whether ability to 'switch on' the Krebs cycle enzymes pre- these failures are due to resistance of the parasites maturely, that is, in the red cells rather than waiting or to some inherent difference in the host, such as a to go into the mosquito. It was suggested that this more rapid excretion or a failure of absorption or would enable the parasites to make up for any loss of utilization of the compounds themselves. This amino acids, which may be caused by the interference clearly requires further investigation. It may reveal, in their digestive processes by chloroquine, by pro- for example, a genetic difference, such as a rapid ducing Krebs cycle intermediates which they could acetylation and excretion of sulphonamides or a then transaminate to produce their own amino acids. failure to metabolize certain compounds to their Unfortunately, however, we were unable to demon- active derivatives. strate the presence of Krebs cycle enzymes in the malaria parasites themselves in electron microscope Summary of recommendations for prophylaxis and cytochemical studies. therapy Howells et al. (1972) have been able to show that Where there is no question of drug resistance there is indeed an increase in Krebs cycle enzymes being present, prevention is simple. The regular con- in red cells inhabited by malaria parasites, but that sumption of chloroquine or of proguanil or pyri- the increase is an increase in the host cell enzymes methamine will provide adequate protection against and not in the parasite enzymes. It is relevant, how- all the human malarias. In the case of an acute ever, that this increase is much more marked in red attack of malaria developing because of the failure cells inhabited by chloroquine-resistant P. berghei to take adequate prophylaxis, malaria is simple than in red cells inhabited by drug-sensitive enough to treat, provided that it is diagnosed rapidly organisms. We believe now that, while this may be and accurately. Details of the dosage of the various the way in which parasites are able to survive once drugs will be found in any medical textbook as well they are resistant to chloroquine, the chloroquine as in the specialized monographs listed below (e.g. resistance itself is due to a decrease in high affinity Ross Institute, 1972; Covell et al., 1955; Peters,by copyright. binding sites for chloroquine, as suggested originally 1970). by Fitch (1969, 1970). This is probably associated The problem arises where there is suspicion that with a simple mutation which is inherited in the drug resistance may be present. It is essential that normal manner and which is stable through mos- the physician who is concerned with giving advice on quito passage. It is interesting to note that we found this matter should make himself familiar with the in our experimental model that exposure of parasites situation regarding antimalarial drug resistance in of chloroquine-resistant strains of P. berghei in the the areas to which his patients are going. mouse to chloroquine led to the production of higher If it is known that resistance to proguanil and/or infection rates in mosquitoes subsequently feeding on pyrimethamine is present, then the drug of choice those mice than would appear if the mice had not for is one of the 4-amino- received chloroquine prior to the mosquito feed quinolines, such as chloroquine or amodiaquine. Inhttp://pmj.bmj.com/ (Ramkaran & Peters, 1969). This situation, if it parts of South America and Southeast Asia where applies also to chloroquine-resistant P. falciparum chloroquine resistance is known to occur, the regular in the field, may facilitate the spread of such resistant consumption of 200 mg of proguanil per day, or mutants. This perhaps is one way in which chloro- even 25-50 mg of pyrimethamine once per week may quine resistance has become so rapidly extended provide adequate protection in spite of the fact that from what were probably relatively limited foci in some measure of resistance may also be present to South America and Southeast Asia. these antifols. It is, however, not easy to prescribe on October 2, 2021 by guest. Protected What is perhaps a little more difficult to under- malarial prophylaxis with confidence in areas such stand is why chloroquine resistance in P. falciparum as these where multiple drug resistance is known to has never yet been proven to exist anywhere on the occur. Some take a sulphonamide-antifol combina- African continent. We believe that the different host tion, but it is probably wiser not to do this, since response to P. falciparum by African people may such potentiating combinations are still extremely play a significant role in this phenomenon. Fortu- useful drugs on which to fall back if one needs to for nately, the potentiating combinations of sulphon- the treatment of an acute attack. It is perhaps wiser amides or sulphones with antifols are effective even to recommend simply a double dose of one of the against the vast majority of strains of P. falciparum antifols and to reserve the combination for treatment which are resistant to chloroquine, to antifols alone, in the event of a breakthrough. or indeed to sulphonamides and sulphones alone. Most multiple-resistant strains of P. falciparum There is, however, already some indication that will still respond, at least in the first instance, to certain strains are showing up which do not respond intensive treatment with quinine. Fortunately, to these potentiating combinations as one would several new antimalarial drugs of the phenanthrene- Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from

Antimalarial drugs 581

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-URGvAv on October 2, 2021 by guest. Protected FIG. 7. Distribution of chloroquine-resistant strains of P. falciparum in South and Central America. Stipple, chloroquine resistance proven; vertical hatching, chloroquine resistance suspected. and quinoline-methanol series are currently being provide a 14-day course of a tissue schizontocide, tested which also are very effective against multiple- such as primaquine, in order to exclude the possibility resistant strains of P. falciparum. So far it is only in of relapses due to secondary exoerythrocytic schi- this species of parasite that resistance to chloro- zonts. Primaquine is also extremely valuable in the quine has been clearly shown to occur. Chloroquine treatment of multiple drug-resistant malaria, not so is still a very effective drug for the prevention or much from the point of view of the patient as of the treatment of malaria due to the other three parasites community. Primaquine has been shown clearly to of man. retain a marked gametocytocidal action even against An exception, however, is in the radical cure of strains of this parasite which are highly resistant to infection due to relapsing P. vivax or ovale malaria. chloroquine, and to most other drugs as far as the Here it is essential, in addition to chloroquine, to asexual erythrocytic infection is concerned. An Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from

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FIG. 8. Distribution of chloroquine-resistant strains of P. falciparum in Southeast Asia. Stipple, chloroquine resistance proven; vertical hatching, chloroquine resistance suspected. excellent statement of current recommendations for References malaria chemoprophylaxis and chemotherapy will BRUCE-CHWATT, L.J. (1971) Malaria. Epidemiology. British be found in the publication of the Ross Institute Medical Journal, 2, 91. listed below. CANFIELD, C.J. (1972) Malaria in U.S. military personnel 1965-1971. Proceedings of the Helminthological Society Acknowledgments of Washington, 39 (Suppl.), 15. I should like to thank Mr S. N. McDermott for preparing COVELL, G., COATNEY, G.R., FIELD, J.W. & SINGH, J. (1955) the figure and Mrs D. Steedman for the careful preparation Chemotherapy of malaria. W.H.O. Monograph Series of the manuscript. No. 27. W.H.O., Geneva. Postgrad Med J: first published as 10.1136/pgmj.49.574.573 on 1 August 1973. Downloaded from

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