Postgrad Med J: first published as 10.1136/pgmj.28.315.5 on 1 January 1952. Downloaded from MEDICINE

THE CHEMOTHERAPY OF 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, 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 . 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; 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 , 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. This often happens in patients after quently they diminish the tendency of these their return from the tropics when they discon- infections to relapse. They also are capable of tinue their anti-malarial drug. Such attacks of destroying sporozoites or pre-erythrocytic forms, vivax, quartan and ovale malaria may occur but the dose required for this action is so close months after leaving the tropics owing to the long to the toxic dose that they cannot be used as persistence of the exo-erythrocytic reservoir in practical causal prophylactic agents; they also these infections. destroy gametocytes. Finally, certain drugs bring about the dis- Quinine o.65 g. (io gr.), preferably in solution, Postgrad Med J: first published as 10.1136/pgmj.28.315.5 on 1 January 1952. Downloaded from January 1952 MURGATROYD: The Chemotherapy of Malaria 7 for which a soluble salt or the addition of sufficient changes in the asexual parasites in the earlier acid is required, given three times a day by stages of their cycle, possibly through interfering mouth for about a week, will control an acute with their carbohydrate metabolism by inhibiting attack of malaria provided the drug is absorbed. the oxidization of pyruvic acid, but the exact If the patient is vomiting, if the circulation is so mechanism of action is obscure, as it is for all the depressed that the absorption is slow, in the anti-malarial drugs. presence of cerebral malaria or some severe com- Mepacrine (atebrin, quinacrine, acriquine) is plication demanding very rapid control, it is used, commonly as the hydrochloride, in doses of necessary to administer the first one or two doses 0.2 g. three times daily by mouth for one or two parenterally. For this purpose quinine dihydro- days, followed by o.I g. three times daily. by chloride, 0.5 g., may be given slowly intravenously mouth for five to seven days, for the control of and, to prevent thrombosis, preferably in dilute acute malarial attacks. Where parenteral injection solution; the drug may also be given intra- is indicated the drug may be givenintramuscularly; muscularly but then sometimes produces pain it may cause irritation and mepacrine methane- and local necrosis. sulphonate may be substituted. The drug may be given intravenously but the margin of safety QUININE by this route appears small; if so used, the drug H should be given in very dilute solutions and C slowly. H,C CH-CH=CH2 MEPACRINE HO-CH-HC CH2 CH2i CH3 NH-CH(CH2)3N(C2H5)2 CH30/\/% N ii h/\Y/\(OCH3 N copyright. 6-methoxy-c-(5-vinyl-2-quinuclidyl)- Cl N 4-quinolinemethanol 6-chloro-2-methoxy-9(4-diethylamino- acridine For suppressive treatment a daily dose of i-methylbutylamino) 0.3-0.6 g. is often used, but it is not always For suppressive treatment o.i g. mepacrine effective and repeated low-grade falciparum infec- daily, taken by mouth, usually is very efficient but tions may become established and so condition certain rare strains of P. falciparum may require the individual for the development of blackwater 0.2 g. daily for their suppression. As it takes which is therefore common in areas where some time for the concentration to reach a fever, plasma http://pmj.bmj.com/ quinine is relied upon for malarial suppression. schizonticidal level with a dosage of-o.i g. daily, Therapeutic doses may give rise to tinnitus and suppressive treatment should commence with deafness; more rarely to vertigo, visual disturb- loading doses as advised for the treatment of acute ances, nausea, headache, and very occasionally to attacks, or alternatively the normal suppressive urticarial rashes. regime should be started two' weeks before the Quinine has a good therapeutic action against individual will be exposed to the risk of infection. asexual erythrocytic parasites, although with some In therapeutic doses mepacrine does not usually strains of malaria the disappearance of parasites cause serious side effects although it may stain on October 1, 2021 by guest. Protected and subsidence of fever do not always occur as the skin yellow, and occasionally produce a blue rapidly as with. a large dose of mepacrine or pigmentation seen especially over the nail beds, chloroquine. Quinine is without action on exo- nose, palate, epiglottis and tracheal rings. Some- erythrocytic parasites and therefore does not times the drug produces gastro-intestinal symp- prevent relapses of vivax or quartan infections, toms, including nausea, vomiting and diarrhoea; and vivax malaria in some cases may relapse as more rarely mental excitation or toxic psychoses, early as one or two weeks after treatment. The visual disturbances and anaemia; while in a few drug has some action on the gametocytes of vivax persons mepacrine has been associated with skin and quartan infections, but none on those of lesions which may be excematoid, lichenoid and falciparum infections. exfoliative. Quinine is rapidly metabolized and excreted, In its action the drug resembles quinine, and plasma concentrations falling by 90 per cent. if loading doses are given it controls'acute attacks within 24 hours after ceasing administration of as rapidly as does quinine. Exo-erythrocytic the drug. The drug appears to retard the growth, parasites are not affected and consequently arrest development and produce degenerative relapses of vivax or quartan malaria may occur, Postgrad Med J: first published as 10.1136/pgmj.28.315.5 on 1 January 1952. Downloaded from 8 POSTGRADUATE MEDICAL JOURNAL January 1952 but possibly owing to the slow elimination of the trations drop only about 60 per cent. per week drug the parasites do not usually reappear until after the last dose. Because of the drug's slow at least four to six weeks after treatment. The excretion and powerful effect, relatively few doses drug also resembles quinine in being inactive are required for the control of an acute malarial against gametocytes of P. falciparum. attack and, in the case of falciparum infections, Mepacrine accumulates, especially in the leuco- for radical cure; for the same reasons suppressive cytes, liver, spleen, heart and lungs, and is only doses can be widely spaced, for example at weekly slowly eliminated so that the plasma concen- intervals. trations fall only about 50 per cent. per week Proguanil (paludrine, chlorguanide, M.4888) is after the drug is discontinued. The drug used for the treatment of acute malaria, as the diminishes the amoeboid movement of the early hydrochloride, in doses of 0.3-0.6 g. divided into asexual erythrocytic parasites, and produces two or three doses daily, by mouth, for ten days. abnormal forms with clumping and extrusion of For parenteral use acetate and lactate are more the pigment; it possibly acts by interfering with soluble and are recommended, but in severe some phosphorylation reaction necessary for the falciparum infections where there is great urgency utilization of glucose by the parasite, or by many prefer or reactions riboflavin. physicians quinine mepacrine. inhibiting involving PROGUANIL Chloroquine (aralen, resochin, nivaquine, NH-C-NH-C-NH.CH(CH-)2 SN 7618, 3377 RP) in the treatment of acute II malaria is normally given as the diphosphate, by /\ NH NH mouth, in an initial dose of i g. followed after II six to eight hours by three doses each of o.5 g. at 24-hour intervals. Where rapid action is required Cl chloroquine hydrochloride, 0.5 g., may be given N1 intramuscularly or very slowly intravenously. -(p-chlorophenyl) N5 -isopropyl biguanide For malarial suppression, o.I g. proguanil percopyright. CHLOROQUINE day may be used. CH3 Proguanil is relatively non-toxic, very high dosage only sometimes producing gastro-intestinal NH-CH-(CH,)3N(C2H5)2 symptoms, evidence of renal irritation, and /\/\ increase in myelocytes or lymphocytes in the blood. Cl N In its action on asexual erythrocytic parasites proguanil resembles the drugs previously men- 7 - chloro - 4 - (4 - diethylamino - i - methylbutylamino) tioned but it does not eradicate the quinoline exo-erythro- http://pmj.bmj.com/ cytic phases, and relapses of vivax infection occur For malarial suppression, o.5 g. diphosphate with about the same frequency and at the same by mouth once a week suffices, because degrada- time as after mepacrine. Proguanil has, however, tion and excretion of the drug are very slow. an action on the pre-erythrocytic parasites of many In therapeutic doses the drug is relatively free strains. of P. falciparum; it also renders gameto- from side effects. Occasionally gastro-intestinal cytes of these parasites incapable of completing disturbances, pruritus, headache, and visual dis- their development in the mosquito. There turbances, such as blurring of vision or difficulty appear to be certain African strains of P.falciparum on October 1, 2021 by guest. Protected in accommodation, may occur; administration of which show some resistance to the action of the drug has also been associated with the occur- proguanil, and overt infections have been reported rence of a toxic psychosis, but this appears where the drug has been relied upon as a sup- extremely rare. pressant. Similarly, when used for the treatment Chloroquine acts mainly against asexual ery- of acute attacks with such strains, the drug has throcytic parasites and it rapidly brings about the failed to eradicate the infections, particularly termination of a malarial attack. It does not primary infections; certain of these infections eradicate exo-erythrocytic parasites; consequently were radically cured when either quinine or vivax and quartan relapses may occur, although not mepacrine was given on the first day of the usually until at least two to three months after course of proguanil. Parasites also appear to treatment. ,Gametocytes of P. falciparum appear become resistant to proguanil rather easily and in resistant to the drug. areas where proglanil is used, proguanil-resistant The drug accumulates in the liver, spleen, strains of parasites may arise. kidney, lungs and leucocytes. Excretion of the Proguanil is fairly rapidly absorbed from the compound is extremely slow and plasma concen- alimentary tract, and appears localized in the Postgrad Med J: first published as 10.1136/pgmj.28.315.5 on 1 January 1952. Downloaded from

January 1952 MURGATROYD: The Chemotherapy of Malaria 9 erythrocytes, leucocytes, kidney and liver. Al- lungs and brain but is quickly metabolized. The though it is fairly quickly degraded and disappears plasma concentration is raised by the concurrent from the plasma after cessation of dosage, there is administration of quinine, mepacrine, or pro- some evidence that a part of it may be converted guanil, especially by that of the two latter. into a plasmodicidal product. Asexual erythro- Pentaquine resembles pamaquin in its effects, cytic parasites exposed to proguanil develop until but is perhaps a little less toxic and, as a phosphate, the early stage of their schizogony is reached; at is used in twice the dosage recommended for this point development is arrested and the para- pamaquin. sites then undergo degeneration. Although the drug appears to have no direct action on gameto- PENTAQUINE cytes, it nevertheless prevents their subsequent CH3O/\/\ development in the mosquito. The mode of NI action of proguanil is unknown, but it has been suggested that it may interfere with the utilization of pteroylglutamic acid or with the porphyrin NH-(CH2)5-NH.CH(CH3)2 metabolism of the parasite, or inhibit the oxidiza- 6 - methoxy - 8 - (5 - isopropylaminoamylamino) quinoline tion of glucose, pyruvate and lactate. Pamaquin (plasmochin, praequine) is used, as Practical Treatment of Non-Immune naphthoate or monohydrochloride, in doses of Persons o.oI g. base two or three times daily by mouth Acute falciparum malaria. Of the four species for 10-14 days. of human malarial parasites, P. falciparum pro- duces the most serious and dangerous illness, but PAMAQUIN fortunately, because of its response to drugs and CH30O\/\ the absence of any persisting exo-erythrocytic phase, it is the easiest infection to cure completely. The use of quinine is now declining becausecopyright. N although it will control most infections, its ulti- NH-CH--(CH2)3-N(C2H )2 mate action is inferior to that of some of the newer synthetic antimalarial drugs. Probably CH3 because of its incomplete action against falciparum 6 - methoxy - 8 - (4 -diethylamino - i -methylbutylamino) infections its use appears to be associated with a quinoline relatively high incidence of . At Its action on asexual erythrocytic parasites is the same time many prefer to use it initially in slight, and its usefulness the fact falciparum infections of grave urgency, but

depends upon http://pmj.bmj.com/ that it devitalizes exo-erythrocytic parasites which normally in acute attacks of falciparum malaria, would otherwise give rise to relapses in vivax, non-immune persons should be treated by one of quartan and ovale malaria; this effect seems to be the schizonticidal drugs, chloroquine, mepacrine, enhanced by the concurrent administration of a or proguanil, in the doses indicated. The schizonticidal drug, especially quinine. It is response is usually rapid. If the patient is not often said that the drug should not be given con- obviously under control within two or three days, with because in such circum- the absorption of the drug or the diagnosis should currently mepacrine be stances the toxicity of both drugs appears to be suspect. on October 1, 2021 by guest. Protected increased, but in many cases the combination has Acute vivax, quartan and ovale malaria. Acute been given without trouble. Pamaquin also attacks of these infections can be controlled by any destroys gametocytes, especially those of P. fali- of the schizonticidal drugs such as quinine, parum. It also has some action on sporozoites mepacrine, chloroquine or proguanil given in the and pre-erythrocytic parasites, but the necessary doses recommended, but these infections so concentration can only be attained by doses treated may relapse, because of their persisting bordering upon the toxic and consequently the exo-erythrocytic parasites which are unaffected by drug is of no practical use as a true causal these schizonticidal drugs alone. Consequently prophylactic agent. the schizonticidal drugs should be reinforced by The drug tends to give rise to abdominal dis- the additional use of pamaquin or pentaquine. comfort and it often produces methaemoglobin- It has been stated that pamaquin is most effective cythaemia, clinically manifest by cyanosis; occa- when given with quinine, but if quinine is to be sionally its use is associated with intravascular used the possibility of an accompanying although haemolysis, which may be acute, or with granulo- cryptic falciparum infection and the possible asso- cytopaenia. ciation of quinine with blackwater fever should be Pamaquin is found concentrated in the liver, kept in mind. If a patient proposes to carry on Postgrad Med J: first published as 10.1136/pgmj.28.315.5 on 1 January 1952. Downloaded from

Io POSTGRADUATE MEDICAL JOURNAL January 1952 indefinitely with suppressive treatment immedi- the schizonticidal drugs. Futhermore, it is argued ately following the control of the acute attack, that it is impossible on economic and administra- there may be no need to give the pamaquin or tive grounds to treat large indigenous populations pentaquine, because any blood infection from any of malarious areas sufficiently to keep them free persisting exo-erythrocytic reservoir will be from infection, and that anything short of this inhibited by the suppressive treatment before any tends to deprive them of the natural immunity symptoms can become manifest. and protection that they obtain from infection. Consequently, it is suggested that in partially Suppressive treatment. As quinine appears in- immune persons all that is desirable is to give one ferior to the newer antimalarial drugs, it is of the schizonticidal drugs in the doses recom- gradually falling out of favour for suppression. mended above, but only for a period sufficient to It does not always adequately suppress falciparum control the acute manifestations of the attack. infections or prevent low-grade infections, and Such treatment may only require one or two doses, consequently it allows patients to become con- and at the most does not usually take more than ditioned for the development of blackwater fever. two or three days. Where there is a well-marked The drugs most commonly now used are mepa- seasonal incidence of malaria it may be desirable crine or proguanil daily, or chloroquine weekly. in the case of These drugs are most efficient and where they are to treat each attack thoroughly, regularly employed the malarial incidence shows vivax or quartan infections using pamaquin or a striking fall, and blackwater fever practically pentaquine together with a schizonticidal drug, disappears. A certain number of failures of but the most desirable regime to be adopted in suppression are reported whatever drug is being any given circumstances can only be decided after used, and reference has already been made to the careful consideration of all the factors, including suggestion that certain African strains of P. fali- the effects of the infections on the health and parum are relatively resistant to proguanil. In economic balance of the community, the part individual cases, however, it is sometimes very played by immunity in the protection of the difficult to be sure that the drug has been taken population, and the cost of any proposed line ofcopyright. regularly. treatment. Suppressive treatment. In partially immune populations relatively less frequent doses of sup- Treatment of Partially Immune Persons pressive drugs may be used, for example, mepa- Acute attacks. Partially immune patients tend crine or proguanil once or twice a week, or small to suffer from only relatively mild and short doses of chloroquine once a week, but again the attacks of fever, and these attacks are usually exact regime that seems desirable depends upon a controlled a few doses of one of full consideration of all the factors involved. readily by very http://pmj.bmj.com/

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