The impact of malaria chemoprophylaxis in Africa with special reference to Madagascar, Cameroon, and Senegal

Bulletin of the World Health Organization, 62 (Suppl.): 41-48 (1984) © World Health Organization 1984 The impact of malaria chemoprophylaxis in Africa with special reference to Madagascar, Cameroon, and Senegal A. B. G. LAING' Some past and present experiences in the use of antimalarial drugs, particularly for chemoprophylaxis, are reviewed. The failure in the long term of mass chemoprophylaxis with weekly chloroquine in children in Madagascar, Cameroon, and Senegal is dis- cussed, the reasons for failure being an increasing lack of resources to ensure regular drug distribution and lack of supervision of dosage. The increasing number ofreports confirming chloroquine resistancefrom East Africa over the last decade poses a serious threat to the future usefulness of chloroquine as an antimalarial agent in Africa. There is now an urgent need for extensive drug sensitivity tests, which should also include alternative antimalarial drugs. To rely on mass chemo- prophylaxis as the main method of controlling malaria would appear to be no longer tenable. The sad story of the virtual failure of chemo- prophylaxis as a major method of controlling or pre- venting malaria in Africa is all too familiar: in the many trials of pyrimethamine, proguanil, and chlor- proguanil, the pattern of initial success in reducing malariometric indices was followed in the late 1950s and early 1960s by the development of parasite resist- ance (1). However, the continuing success obtained with the 4-aminoquinolines in the many mass chemo- prophylactic projects carried out in mainly franco- phone countries appeared promising; chloroquine particularly has been widely distributed to children and pregnant women and in some cases to village communities. Parasite resistance to chloroquine en- countered in South America and south-east Asia in the early 1960s did not appear to be a problem, and although reports of apparent failure of the drug came from Nigeria and Liberia, subsequent attempts at confirming emergent chloroquine resistance were un- successful (2). Then came further reports, usually of drug failure in individual cases, but although these began to cause some uneasiness the many attempts to prove resistance still failed. Eventually, but not until 1974, convincing evidence came from Ethiopia of what was then described as an increased tolerance to chloroquine, to be soon followed by reports of the unequivocal presence of chloroquine-resistant strains of Plasmodium falciparum in East Africa, Sudan, I Consultant, Malaria Action Programme, World Health Organ- ization, Geneva, Switzerland; Court Lodge Cottage, Star Lane, Chipstead, Surrey CR3 3RA, England. Requests for reprints should be sent to the address in England. Comoros, and Madagascar. Most of these reports were made as a result of observations on individual expatriates who had become infected while on short visits to these countries, but amongst indigenes chloroquine still appeared to be effective (2). However, incipient resistance of P. falciparum to chloroquine was found in a Tanzanian community who had been subjected to malaria control by the mass distribution of medicated salt. The chloro- quinized salt project was carried out regularly at Mto-wa-Mbu from 1961 to 1966 and irregularly up to 1978. When medicated salt became difficult to obtain, it was tentatively replaced by making chloro- quine tablets easily available, especially during the last five years. But chloroquine, when given at the standard dosage (25 mg base/kg body weight over a 3-day period) was still effective, the resistance re- ported being only at the RI stage (3). In a more recent study in Zanzibar (4) to evaluate the status of P. fal- ciparum sensitivity to chloroquine and amodiaquine by in vivo and in vitro test systems, "initial results indicated that a significant proportion of the indigen- ous population have P. falciparum with resistance to chloroquine at the RI and RII levels and both in pro- portion and degree this far exceeds any previous report from tropical Africa". This was an ominous conclusion in what was only an interim report. The potentiating combinations of pyrimethamine and sulfadoxine (Fansidar) or pyrimethamine and dapsone (Maloprim) were judged to be a significant advance in the treatment of drug-resistant malaria in the 1960s (5- 7), being completely effective against -41- A. B. G. LAING strains of P. falciparum resistant to all antimalarials except quinine. It was intended that these combin- ations should be held in reserve for the treatment of drug-resistant falciparum malaria (8) but in fact the demand for their use for chemoprophylaxis has been high, backed up by drug company advertisements and more recently by officialdom (9). Now reports of varying degrees of resistance to these combinations are becoming more and more frequent, initially from Asia but recently also from Africa (10-12). Like the early reports of chloroquine resistance, these relate to individual isolated cases at present. Malaria control programmes using mass chloro- quine chemoprophylaxis have been in progress for many years in the francophone countries of Mada- gascar, Cameroon, and Senegal and are still con- tinuing. As little information has been available outside these countries, it was decided that I should visit them to evaluate at first hand past and present experience in malaria control, particularly using chloroquine chemoprophylaxis. 24 MADAGASCAR Despite the introduction of a malaria control pro- gramme in 1949 based on residual spraying with insecticides and weekly chloroquine prophylaxis in children up to the age of 15 years, malaria is still a major health problem throughout the country, par- ticularly in coastal areas. Virtually all malaria infec- tions were reported to be due to P. falciparum, but it is of interest that during the period 1965 to 1975 approximately 97o of 2058 slides found to be positive at the General Hospital of Antananarivo were in fact identified as P. vivax infections (13). Usually, in the figures for parasite indices available from school sur- veys, etc., P. vivax (like P. malariae and P. ovale) always accounts for less than lo of the total. The only drug used for chemoprophylaxis has been chloroquine sulfate or phosphate given weekly in a dosage of 5 mg of base per kg body weight. There were no records or suggestions of the use of any other antimalarials for chemoprophylaxis. 22 4 20 V 18 - 16 - 14 w 12 X 10 0- 8 6 4 2 0 1 7.04) / :66\ /.8.~/ \..8.42* Mean.,' 7.09 7.54.........-..... _/ .--- -_ _ _ - 1958-60 1961-62 1963 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 Slides C+ 162000 50180 34872 23025 39664 18956 15731 16742 17355 11660 6421 7560 10046 10184 examined C- 107000 23548 22149 12550 22048 14920 10269 7792 10866 8369 4315 4804 10288 6849 Fig. 1. Crude parasite rates for the entire population examined in Madagascar --- Subjects protected by chemoprophylaxis (C+) Subjects not protected by chemoprophylaxis (C-) Lb 42 IMPACT OF MALARIA CHEMOPROPHYLAXIS 43 Table 1. Morbidity and mortality from malaria in Madagascara Morbidity Mortality Provinces 1979 1980 1981 1979 1980 1981 Antananarivo 49 205 62 827 69 926 227 268 299 Tamatave 42 567 60 872 98 188 346 432 757 Fianarantsoa 34163 42 317 54 591 177 160 437 Mahajanga 83 784 85 426 73 807 86 51 105 Tulear 50 841 41 759 58 940 197 119 116 Diego-Suarez 46 902 55 933 45 934 163 130 126 Total 307 462 349 134 401 386 1196 1160 1840 a From the Annual Reports of the Institute of Social Hygiene, Madagascar. Details and evaluations of the effects of chemo- prophylaxis in the earlier years are given in reports by Noguera and Ralambosonb. These reports mainly outline data concerning population growth over the years, the number of children in different age groups, and the amount of chloroquine distributed in the different regions. Fig. 1 depicts crude parasite rates in schoolchildren examined in Madagascar and compares groups "pro- tected" and "unprotected" by chemoprophylaxis. The graph covers the period 1958 to 1974; no details concerning age groups, parasite species, or parasite densities appeared to be available, but the gradual increase in infection rates and the much smaller numbers of slides examined in the latter years would appear to indicate a progressive decline in the effi- cacy and/or application of chemoprophylaxis. This decline is also supported by available figures on malaria morbidity and mortality (Table 1). These figures are taken from annual reports of the Madagascar Institute of Social Hygiene and are based on data collected from clinics and hospitals. Mor- bidity figures have increased from approximately 300 000 in 1979 to 400 000 in 1981; mortality figures have increased over the same period from approxi- mately 1200 to 1800. Figures from earlier reports were difficult to assess accurately, although both morbidity and mortality from malaria appeared then to be much less, e.g., total mortality was given as 637 in 1977 and 943 in 1978. Many deaths, including those from malaria, are not officially reported to clinics or hospitals so that the real figures for malaria mortality are almost certainly much higher. At present, chemoprophylaxis with weekly doses of chloroquine is still being recommended for pregnant a NOGUER, A. Evaluation de la lutte antipaludique a Madagas- car. Unpublished WHO document, AFR/MAL/122-1973. bRALAMBOSON, D. Distribution of chloroquine to children aged 0- 6 years as a malaria control measure. Unpublished WHO docu- ment, MAL/TRC/72.24-1972. women and for all infants and children under the age of 15 years. The drug is distributed under the auspices of the Department of Education by lady volunteers, whose main concern appears to be with problems of nutrition in the peripheral health clinics. In the schools, the distribution of chloroquine is apparently the responsibility of school teachers. According to the 1980 Annual Report of the Institute of Social Hygiene, of the 8 700 000 population of Madagascar, 407o are under the age of 15 years (and therefore subject to chemoprophylaxis). No official figures were made available for the numbers of pregnant women taking chemoprophylaxis, but figures for pre- school children and schoolchildren aged 6-15 years showed that the percentage coverage (i.e., those con- sidered to be on regular chemoprophylaxis), which was already less than 4007o in 1977, had declined to less than 15%o in 1982 (Table 2). "Nivaquinization" (prophylaxis with chloroquine sulfate) is now virtually a national policy and, al- though mainly unsupervised, is still considered the primary malaria control measure in Madagascar. The initially extensive programme of residual insecticide spraying of houses has gradually diminished over the years and has now almost ceased. Again, the reason would appear to be a general lack of resources. The officially recommended treatment in Mada- gascar for acute malaria in an adult is a five-day course of chloroquine (a total of 2.1 g of chloroquine base), not the generally recommended 1.5 g over 3 days. The rationale for the extended course is not clear, except that apparent recrudescence has some- times occurred with the three-day course. Also in recent years, quinine by intramuscular injection has become increasingly popular, particularly in coastal regions. No other antimalarials appear to be used officially for treatment, although brands of amo- diaquine and also pyrimethamine-sulfadoxine are available in some pharmacies. At no time has there been any mention of chloro- 44 A. B. G. LAING Table 2. Chemoprophylaxis with chloroquine (5 mg/kg body weight weekly) in Madagascar children, 1 977-82° Children 0- 5 years Schoolchildren 6-1 5 years Years No. Coverage 1%) No. Coverage (%) 1977 1 256 100 39.39 1 971 100 35.92 1978 1 378770 37.06 1 929056 34.91 1979 1 757 800 31.34 2089 570 33.87 1980 1 721 150 31.47 1 975 850 40.35 1981 1 804 635 19.49 2 050 058 26.14 1982 1 786612 14.79 2 106698 12.29 ° Figures from the Malaria Division, Institute of Social Hygiene, Madagascar. quine resistance as a possible cause of the decline in efficiency of the chemoprophylaxis programme, but a recent report (14) has unequivocally proved the presence of chloroquine-resistant P. falciparum, the first report of chloroquine resistance from Mada- gascar. Following this report, a French team directed by Dr J. Le Bras is involved in an extensive country- wide programme in an attempt to define the extent of chloroquine resistance in the country, but as yet no details have been made available and investigations are still continuing. The team has, however, already reported findings concerning the sensitivity of chloro- quine-sensitive and chloroquine-resistant strains of P. falciparum to three other 4-aminoquinolines (amodiaquine, dichlorquinazine, and piperaquine), which could have important bearings on malaria chemoprophylaxis in future (15). CAMEROON The trials in Cameroon of synthetic antimalarials for chemoprophylaxis date from 1956 when, follow- ing a recommendation of the WHO Malaria Confer- ence in Lagos the previous year, a controlled trial of weekly doses of a combination of chloroquine and pyrimethamine were given to groups of children in a hyperendemic area in northern Cameroon (16). Parasite indices for trophozoites were soon reduced to zero, but after three months rose again and sub- sequently this was considered to be due to the early development of resistance to pyrimethamine. This would appear to be the only published work on ex- perimental chemoprophylaxis. Other trials of chloro- quine were carried out about that time by Chastang and by Swarte. Neither of them published their re- sults but they were referred to by Dr Samuel, though without comment, in his report on the introduction of chloroquine chemoprophylaxis in schools in east- ern Cameroon.c The only other reported experi- mental chemoprophylactic trial (again unpublished) was one concerning the combined use of chloroquine and primaquine carried out by Schneider et al.' in 1958-59 with apparently beneficial results. The extensive countrywide programme of regular antimalarial chemoprophylaxis in schoolchildren be- tween the ages of 5 and 15 years was started in 1964, details being given in Dr Samuel's report. The dosage of chloroquine base was of the order of 5 mg/kg body weight given on the same day each week and the whole scheme was planned and carried out through the Ministry of Education. It is reported that 880 000 children received regular weekly chloroquine chemo- prophylaxis during the school terms and figures for parasite indices at the beginning and end of each school year between 1964 and 1967 are given in detail, district by district, the effects being evaluated by sur- veys from approximately 1 % of children (a summary is given in Table 3). The figures indicate much higher transmission in the northern region, as expected, but reflect an equally good response in both central and southern regions with considerable reductions (but never to zero) in parasite indices. Chemoprophylaxis was carried out only during school terms so that re- infection occurred during holidays, with generally high parasite rates at the beginning of each school term. Teachers also found that absenteeism due to illness was less and that children had an increased capacity for work and also improved physically. In 1967, chloroquine chemoprophylaxis was extended to include infants, preschool children, and pregnant women; education and propaganda highlighted the scheme as the main measure of malaria control and although statistics must have been recorded they could not be found at the time of my visit. c SAMUEL, A.M. La chimioprophylaxie antipaludique dans les ecoles du Cameroun Oriental. Unpublished document, WHO/ MAL/67.631 (1967). d SCHNEIDER, J. ET AL. Unpublished document, WP(Sc.GR/18) (1967). IMPACT OF MALARIA CHEMOPROPHYLAXIS 45 Table 3. The effects of chemoprophylaxis with weekly chloroquine (5 mg base per kg body weight) in school- children in Cameroon 1964/65 1965/66 1966/67 Before After Before After Before After treatment 3 months treatment 3 months treatment 3 months North Cameroon No. of children surveyed 2324 1952 2338 1955 2946 2842 Mean asexual parasite index 63.8 9.4 66.1 8.9 17.8 7.9 Central and No. of children surveyed - - 5175 5137 5216 4989 South Cameroon Mean asexual parasite index - - 44.4 2.7 38.4 9.3 A recent small study (17) of chloroquine pro- phylaxis in pregnant women indicated that monthly dosage of chloroquine effectively suppressed malaria clinically without detriment to the subject (including immunity), whereas weekly dosage had a significant effect on depressing immunity; the study included examinations for blood parasite forms, haematocrit, and maternal antibodies. The effect on maternal antibodies is of potential importance and could be included for evaluation in future discussions on the problem of pregnancy and malaria. The only further data concerning chemoprophy- laxis that appeared to be available were in an unpub- lished report by the Ministry of Health of a survey carried out in Garoua in the northern province in 1973, the results of which are summarized in Table 4. Regular chemoprophylaxis with chloroquine would still appear to have been effective, but the much higher numbers of children virtually unprotected indicates a considerable decline in the efficacy of the scheme and/or shortages of drugs available. Indeed, since 1973 the supply of chloroquine for chemopro- phylaxis did become increasingly curtailed so that over the last ten years the drug has been mainly reserved for treatment. Malaria is still, therefore, a major public health problem and transmission con- Table 4. Parasite rates in children aged 5-14 years in the northern town of Garoua, Cameroon, February- March, 1973a Parasite rates (%) Groups No. Trophozoite Gametocyte Regular chemoprophylaxis 388 8 0.5 Irregular chemoprophylaxis 1100 42 4.0 No chemoprophylaxis 109 72 6.0 Not attending school (no chemoprophylaxis) 1 597 74 5.0 a Ministry of Health report. tinues virtually unabated. A report by the Minister of Health in 1980e outlined a new, extensive malaria control programme based mainly on chloroquine chemoprophylaxis with the reintroduction of anti- mosquito measures in certain areas, but no action has as yet been taken. A further report has recently been prepared by Dr Iba Gueye, a WHO consultant who visited the Republic of Cameroon in the period January to February 1983, but has not been pub- lished. Like the previous report of the Minister of Health, it contains detailed recommendations for a malaria control programme over five years based on chloroquine chemoprophylaxis in pregnant women and children up to the age of five years and residual spraying of insecticides, together with antilarval measures where possible; considerable emphasis is put on upgrading infrastructure and the training of staff so that the programme can be incorporated in primary health care centres. Apart from chloroquine, no other antimalarials have been used recently for chemoprophylaxis, ex- cept by some individualls who obtain drugs privately from pharmacies, e.g., amodiaquine and combin- ations of sulfonamides or sulfone with pyrimetha- mine. The drug treatment of acute attacks of malaria is usually a 3-day course of chloroquine (1500 mg) but parenteral quinine is also commonly given; there has been no complaint of drug resistance nor any report that chloroquine-resistant strains of P. falci- parum have emerged. No testing for parasite sensi- tivity to drugs, either by in vivo or in vitro methods, has been carried out in Cameroon (the only exception being the 1956 trials of chloroquine and pyrimetha- mine mentioned earlier). SENEGAL Malaria in Senegal is seasonally endemic in both urban and rural areas, with the highest rate of trans- ' ETAME, O.A. Nouvelle strate'gie de lutte contre le paludisme au Cameroun. Unpublished WHO document, AFR/RC30/R17 (1980). 46 A. B. G. LAING mission sufficient to produce hyperendemic malaria during and after the wet season (June to November). As in all tropical countries south of the Sahara in West Africa, approximately 900o of infections are due to P. fakciparum and the primary vector is Ano- pheles gambiae. A pilot eradication project, started in 1953 under the direction and supervision of the Service de Lutte Anti-Paludique (SLAP) and based on WHO protocols, considerably reduced the inci- dence of the disease but failed to interrupt trans- mission. The 1961 report of SLAP gives the following reasons: exophily of vectors reducing the impact of the residual spraying of insecticides, poor coverage in 1959 of distribution of antimalarials to treat fever cases, and the development of resistance to insecti- cides in 1960. In 1963, a systematic programme of chemoprophy- laxis with weekly dosage of chloroquine (5 mg/kg body weight) was started for pregnant women and children up to the age of 14 years, the distribution of chloroquine being limited to the period July to December inclusive. The first three years of the pro- gramme were successful in reducing morbidity and mortality from the disease (18) but thereafter the high cost of chloroquine and falling off in the effi- ciency of drug distribution at the peripheral level, together with reductions in the budgets of the Min- istry of Health, greatly diminished the beneficial effects of chemoprophylaxis as a method of malaria control. In fact, a resurgence of malaria is recognized in two papers (19, 20). This is further reflected in the figures for malaria admissions over the period 1969-79 given to me on a visit to the Clinique des Maladies infectieuses du Centre hospitalier de Fann: out of 4466 patients admitted, 668 died (Table 5). Antimalarial drugs used for treatment were infusions Table 5. Malaria patients admitted to the infectious diseases clinic at the Fann Hospital Centre, Dakar, Senegal Mortality Year No. No. % 1969 443 77 17.4 1970 318 36 11.3 1971 367 47 12.8 1972 309 41 13.3 1973 389 38 9.6 1974 356 60 16.9 1975 687 102 14.9 1976 423 86 20.3 1977 246 58 23.6 1978 428 103 24.0 Total 4466 668 16.4 of quinine and oral chloroquine and latterly injec- tions of pyrimethamine-sulfadoxine; most patients came from the environs of Dakar and although infor- mation on age groups was not readily available, most patients were apparently children under 10 years of age. More than half of patients admitted were con- sidered to be pernicious, with heavy falciparum parasitaemias and with neurological signs of cerebral malaria. At no time has there been any hint from any source of parasite resistance to chloroquinef although the existence of a partial degree of pyrimethamine re- sistance has been reported (21) when this drug was used in support of the original pilot eradication scheme; also, later in a trial of the injectable depot antimalarial preparation, cycloguanil, P. falciparum infections were described in some cases as tolerant to pyrimethamine, proguanil, and cycloguanil (22). CONCLUSIONS The advisability of continuing with chloroquine chemoprophylaxis in Madagascar, Cameroon, Sen- egal, and other African countries where the drug has been in wide circulation for long periods of time must be a matter for serious re-evaluation. In Africa generally, chloroquine is still considered to be the drug of choice for the treatment of acute falciparum malaria, although pyrimethamine-sulfa- doxine is now becoming increasingly and unnecess- arily used. This situation contrasts with that in many parts of South America and Asia where chloroquine has been largely discredited therapeutically owing to the development of parasite resistance. It is therefore imperative that tests for parasite sensitivity to chloro- quine (and other antimalarials) be given priority in field research programmes envisaged in the near future. Each of the African countries where malaria is endemic has a different antimalaria problem, de- pending on its topography, ecology, and resources; there can be no blueprint for malaria control com- mon to all. As eradication is still impractical, the main purpose of controlling malaria can and must be the reduction of mortality without interference in the acquisition of immunity; there is scope for many variations in control programmes but baseline data individual to each country must be acquired first to enable problems to be evaluated and dealt with suc- cessfully. This necessarily demands considerable ex- pertise and resources but, unless tackled scientific- ally, malaria can only continue to be a major scourge in Africa south of the Sahara. f A successful in vitro selection, under chloroquine pressure, of a resistant line of P. falciparum from an isolate from Senegal is mentioned in the report of the 1981 Kuala Lumpur meeting on drug- resistant malaria, but no reference is given (23). IMPACT OF MALARIA CHEMOPROPHYLAXIS 47 ACKNOWLEDGEMENT The author wishes to thank the Ministries of Health of the governments of Madagascar, the Republic of Cameroon, and Senegal for access to departmental reports and data relating to malaria control programmes and for permission to publish references to them in this paper. RtSUME L'IMPACT DE LA CHIMIOPROPHYLAXIE ANTIPALUDIQUE EN AFRIQUE ET PLUS SPECIFIQUEMENT A MADAGASCAR, AU CAMEROUN ET AU SENEGAL L'article fait le bilan de 1'experience passee et presente en matiere d'antipaludeens, notamment ceux qui sont destines a la chimioprophylaxie. I1 etudie 1'echec a long terme de la chimioprophylaxie de masse au moyen de la chloroquine administree hebdomadairement a des enfants de Mada- gascar, du Cameroun, et du Senegal, cet echec s'expliquant par la penurie croissante des ressources indispensables a la distribution reguliere des medicaments et une surveillance insuffisante des dosages. A Madagascar, la chimioprophylaxie au moyen de la chloroquine (surnommee "Nivaquinisation") se pratique depuis 1950 et elle se poursuit encore officiellement, la chloroquine etant distribuee hebdomadairement aux dis- pensaires prenatals et aux ecoles; toutefois il apparait que la couverture reelle, qui n'atteignait deja que 40 % en 1977, est tombee a 15 7o en 1982. La mortalite due au paludisme est d'ailleurs en augmentation, ainsi qu'en temoignent les statistiques. Au Cameroun, la chimioprophylaxie par la chloroquine etait devenue la seule methode de lutte antipaludique depuis qu'en 1964 avaient cesse les pulverisations d'insecticides a effet remanent qui n'avaient pas reussi a stopper la transmission. Comme a Madagascar, le medicament etait distribue gratuitement dans les dispensaires et les ecoles chaque semaine et s'etait montre tres efficace au debut; mais la chimioprophylaxie a plus ou moins cesse en 1973 quand les approvisionnements ont e reduits pour des raisons economiques. Des projets sont a present sur pied pour reintroduire a grande echelle une chimioprophylaxie chloroquinienne ainsi que des mesures de lutte antivec- torielle. C'est egalement en 1964 qu'une chimioprophylaxie chloroquinienne avait ete instauree au Senegal A 1'echelle du pays pour les enfants et les femmes enceintes aprbs 1'echec d'un projet pilote destine a enrayer la transmission au moyen d'insecticides a effet remanent. Mais le paludisme etant saisonnier avec une hyperendemicite au second semestre de I'annee, la chimioprophylaxie n'avait porte que sur cette periode. La encore, apres un succes initial, et malgre une bonne couverture, semble-t-il, le paludisme est reapparu r6cemment entrainant une augmentation de la morbidite et de la mortalite. On a largement recours pour le traitement a l'amodiaquine et a la sulfadoxine-pyri- methamine. Depuis une decennie, on signale de plus en plus souvent en Afrique orientale des cas de resistance a la chloroquine qui hypothequent gravement l'avenir de ce produit comme agent antipaludeen en Afrique. On comprend des lors l'urgente necessite de proceder A des essais etendus de pharmacosensibilit6, qui porteront aussi sur d'autres anti- paludeens. On ne peut plus desormais s'en remettre a la seule chimiotherapie de masse pour maltriser le paludisme. REFERENCES 1. BRUCE-CHWATT, L. J. Chemoprophylaxis of malaria in Africa: the spent "magic bullet". British medical journal, 285: 674-676 (1982). 2. BRUCE-CHWATT, L. J. Resistance of P. falciparum to chloroquine in Africa: true or false? Transactions ofthe Royal Society of Tropical Medicine and Hygiene, 64: 776-784 (1970). 3. ONORI, E. ET AL. Incipient resistance of Plasmodium falciparum to chloroquine among a semi-immune population of the United Republic of Tanzania. 1. Results of in vivo and in vitro studies and of an ophthalmological survey. Bulletin of the World Health Organization, 60: 77-87 (1982). 4. SCHWARTZ, I.K. ET AL. In vivo and in vitro assessment of chloroquine-resistant Plasmodium falciparum in Zanzibar. Lancet, 1: 1004-1005 (1983). 5. CHIN, W. ET AL. The evaluation of sulfonamides alone or in combination with pyrimethamine in the treatment of multi-drug-resistant falciparum malaria. American journal of tropical medicine and hygiene, 15: 828 (1966). 6. LAING, A. B. G. Sulphonamides in malaria with special reference to sulphormethoxine and dapsone and combinations of these with pyrimethamine. Thesis, University of Edinburgh, 1969. 7. LUCAS, A. 0. ET AL. The suppression of malaria parasitaemia by pyrimethamine in combination with dapsone and sulphormethoxine. Transactions of the Royal Society of Tropical Medicine and Hygiene, 63: 216-229 (1969). 48 A. B. G. LAING 8. WHO Technical Report Series, No. 375, 1975 (Chemo- therapy of malaria: report of a WHO Scientific Group). 9. PUBLIC HEALTH LABORATORY SERVICE REFERENCE LABORATORY. Malaria prophylaxis. British medical journal, 286: 787-789 (1983). 10. STAHEL, E. ET AL. Pyrimethamine/sulfadoxine-resist- ant falciparum malaria acquired at Dar es Salaam, Tanzania. Lancet, 1: 1 118 -1119 (1982). 11. HERZOG, C. H. ET AL. Pyrimethamine/dapsone- resistant falciparum malaria imported from Kenya. Lancet, 1: 1119-1120 (1983). 12. EITHENLAUB, D. ET AL. Falciparum malaria despite pyrimethamine/sulfadoxine prophylaxis in five tourists to East Africa. Lancet, 2: 1041-1042 (1982). 13. RAKOTOSON, M. Z. Evolution de la politique de lutte antipaludique a Madagascar. Thesis, University of Madagascar, 1980. 14. ARONSSON, B. ET AL. Chloroquine-resistant falciparum malaria in Madagascar and Kenya. Annals of tropical medicine and parasitology, 75: 367 (1981). 15. LE BRAS, J. ET AL. In: Re'union conjointe: The Royal Society of Tropical Medicine et La Societe' de Patho- logie Exotique, Institut Pasteur, Paris, mai 1983. Paris, Pasteur Institute, 1983 (abstract). 16. SCHNEIDER, J. ET AL. Association chloroquine-pyri- methamine dans la chimioprophylaxie du paludisme: resultats apres 22 mois de traitement. Bulletin de la Societe de Pathologie Exotique, 51: 316 (1958). 17. NKWATE, C. & MARTIN, G. Malaria chemoprophylaxis in pregnancy: the use of a single monthly dose of 600 mg of chloroquine base for prevention of malaria in preg- nancy. In: Proceedings of the OCEAC Conference, Yaounde' (in press). 18. WONE, I. & MICHEL, R. Bilan de la chimioprophylaxie systemique par chloroquine au Sen6gal 1963-1966. Medecine d'Afrique noire, 14 (6): 267 (1967). 19. REY, M. ET AL. Paludisme pernicieux mortel chez un drepanocytaire. Bulletin de la Sociefte6 Medicale d'Afri- que Noire de Langue franVaise, 11: 802 (1966). 20. REY, M. ET AL. Le paludisme dans l'agglom6ration dakaroise (d'apres une experience hospitaliere). Bul- letin de la Societe Medicale d'Afrique Noire de Langue franvaise, 13: 353 (1968). 21. MICHEL, R. Resistance a la pyrimethamine dans la zone antipaludique de Thies. Meddecine tropicale, 21: 876 (1960). 22. MICHEL, R. ET AL. Tolerance de Plasmodium falci- parum a la pyrim6thamine, au proguanil et au CI-501 dans la region de Niayes, S6n6gal. Bulletin de la Societe de Pathologie Exotique et deses Filiales, 50: 797 (1966). 23. WERNSDORFER, W., ed., Drug-resistant malaria. Geneva, UNDP/World Bank/WHO Special Pro- gramme for Research and Training in Tropical Diseases, 1982, p.2.