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Comparative efficacy of halofantrine, chloroquine and sulfadoxine-pyrimethamine for treatment of acute uncomplicated falciparum malaria in Nigerian children
TRANSACTIONS
OF THE
ROYAL
SOCIETY
OF TROPICAL
MEDICINE
AND
HYGIENE
(1997)
91,58-62
Comparative efficacy of halofantrine, chloroquine and sulfadoxine-pyrimethamine for treatment of acute uncomplicated malaria in Nigerian children
falciparum
C. 0. Falade1y2, L. A. Salako123, A. Sowunmi1~2, A. M. J. Oduola1y2 and I? Larcied ‘Department of Pharmacology and Therapeutics and 2Postgraduate Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria; 3Nigerian Institute of Medical Research,Yaba, Lagos, Nigeria;4SmithKline Beecham International, Ajiican Medical Department, Lagos, Nigeria Abstract One hundred and ten children aged 6 months to 11 years were randomly treated with halofantrine (HF), sulfadoxine-pyrimethamine (S-P) or chloroquine (CQ) f or acute uncomplicated Plasmodium falciparum malaria in an endemic area of south-western Nigeria. The resnonse of infection to treatment in each child was monitored for 14 d. The mean fever clear&ce times were 1.9 d (n=36), 1.6 d (n=27), and 1-7 d (n=28) for children treated with HF, S-P and CQ, respectively. The parasite clearance times were 3.4 d (n=39), 4.4 d (n=24) and 4.1 d (n=15) in the 3 groups of children.The cure rate at day 7 was 92.3% (36/ 39) in children treated with HF, 72.7% (24/33) in those treated with S-P, and 39.5% (15138) in those treated with CQ. By day 14,4 of 36 (11.1%) parasitologically cured patients treated with HF had experienced recrudescences. The corresponding figures among children treated with S-P or CQ were 83% and 13.3%, respectively. The 3 drugs were well tolerated. The results of the study showed a further decline in the sensitivity of I? falciparum infections to CQ, while HF and S-P remained relatively effective in the treatment of malaria in south-west Nigeria. Keywords: malaria, children, Nigeria
Plasmodium
fulciparum, chemotherapy, halofantrine, sulfadoxine-pyrimethamine,
Introduction Morbidity and mortality from malaria continue to be a major health problem in Nigeria. Malaria is the most common cause of out-patient clinic attendance among all age groups in the country and is responsible for an estimated 30bOOO deaths yearly in children less than 5 vears old ~NIGERIA. 1980-1983). Resistance to chloroquine (CQ), the drug of choice for the treatment of uncomplicated malaria in Nigeria, had been reported in several areas of the country (EKANEM et al., 1%; ODUOLA et al.. 1992: SOWUNMI & SALAKO, 1992). This has led to increasing use of alternative antimalarial drugs, particularly sulfadoxine-pyrimethamine (S-P) and halofantrine (HF). Although early studies showed full sensitivity of infection to S-P in the country (EWNEM et al., 1990; SALAKO et al., 1990a; SOWUNMI & SALAKO, 1992), there have been reports of failure of clinical response to treatment with this drug recently (SOWUNMI et al.. 1995). HF has been widelv available in the country in the ‘past 5 years. The drug has become the drug of choice for treatment of malaria among those patients attending private clinics who could afford it, particularlv in the major cities. Earlier studv of the efficacv of halofantrine before its introduction for general use in the country showed a 95-100% parasitological cure rate, and a 1 O-l 5% recrudescence rate 21 d or more after treatment (SALAKO et al., 1990b). In this report, the efficacy of HF after 5 years of general use in Nigeria is described. The efficacy of CQ, the first line antimalarial drug used in Nigeria, and S-P, a second line antimalarial drug, are also discussed in an effort to provide information useful in pragmatic management of malaria in Nigeria. Methods Patients The study was carried out at the University College Hospital, Ibadan, south-west Nigeria. The city of Ibadan has a population of 1.5 million. Malaria transmission in the city is intense. Children aged 6 months to 11 years with acute symptomatic uncomplicated falciparum malaria were recruited between November 1994 Address for correspondence: Dr A. Sowunmi, Department of Pharmacology andTherapeutics, College of Medicine, University of Ibadan, Ibadan, Nigeria.
chloroquine,
and February 1995. The children were enrolled after meeting recruitment criteria including Plasmodium falciparum asexual parasitaemia 21000 parasites per uL of blood, no history of antimalarial drug administration in the 2 weeks preceding presentation, negative urine tests for 4-aminoauinolines (Dill-Glazkol and sulnhonamides (ligninj, the presence or history’of fever w&in 24 h of presentation and signed informed consent by the parent or guardian. Children with severe or complicated malaria who needed parenteral therapy, a history of intolerance to any of the antimalarial drugs, additional causes of fever (bronchopneumonia), and/or concomitant chronic illness (sickle cell anaemia) were excluded from the study. Patients were withdrawn from the study for any of the following reasons: wish of the parent or guardian, clinical deterioration necessitating change of drug, inability to tolerate oral medication, lack of patient compliance, patient loss to follow-up, and protocol violation, including self-administration of other antimalarial drugs during the follow-up. Approval for the study protocol was obtained from the Toint Ethical Review Committee of the Universitv of IbadanAJniversity College Hospital, Ibadan before initiating the study. A careful history was taken from the parent or guardian of each patient and informed consent was signed before enrolment. The patients were examined by a physician, weighed, and their axillary temperature taken using a clinical thermometer. Thick and thin blood films were prepared from a finger-prick blood sample and stained with Giemsa’s stain. All findings were recorded on case record forms specifically provided for the study. The children were allocated into 3 groups for treatment with HF. S-P or CO accordine to a me-generated randomization schedule.- HF (Hsfan@, S&hKline Beecham) was administered orally at a dose of 8 mg/kg of body weight every 6 h for 3 doses (corresponding to a total dose of 24 mgikg). S-P (Fansidap, Roche), containing 500 mg sulfadoxine and 25 mg pyrimethamine per tablet, was given as a single dose treatment according to the following schedule: half a tablet for each child weighing 5-10 kg; one tablet for each child weighing 1 l-20 ke: 1 l/, tablets for each child weiahine 20-30 ke: and 2 t:blet: for each child weighing”30-20 kg. CQ (May & Baker), 25 mgfkg of body weight, was given orally over 3 d (10 mg/kg on days 0 and 1, and 5 mg/kg
COMPARISON
OF HALOFANTRINE,
CHLOROQUINE
AND
on day 2). Each drug was administered with an ample amount of water and the mouth was inspected after administration to ensure that it had been swallowed. The children were observed for at least 3 h after drug administration, and any who vomited were withdrawn from the study. A 14 d modification of the World Health Organization extended field test was used for the study, as the intense malaria transmission in the area made it difficult to differentiate between reinfection and recrudescence beyond 14 d. The patients were seen daily from the day of presentation (day 0) to day 3 or until parasitaemia cleared and subsequently on days 7 and 14. Haematological variables, including haematocrit, total white blood cell count, differential count, and platelet count were determined. Serum sodium, potassium, creatinine, and urea levels were measured and tests of liver function and urinalysis (for glucose, protein and blood) were also done. Giemsa-stained blood films were examined under an oil immersion objective at xl000 magnification. Parasitaemia was determined by counting the number of asexual parasites relative to 500 leucocytes in each thick Table
1. Clinical
Presenting
features
with
malaria
enrolment criteria completed the study. Of the 21 children who did not complete the study, 2 were withdrawn at the request of their parents, one developed mumps parotitis, and the disease progressed to severe malaria in another one within 4 h of enrolment. The remaining 17 children were lost to follow-up. Nine of the 17 were aparasitaemic by the time they defaulted, while 8 still had patent parasitaemia. Thirty-nine of the children who completed the study were treated with HF, 33 with S-P and 38 with CQ. The clinical features and therapeutic responses to treatment with the 3 antimalarial drugs are summarized in Tables 1 and 2. There was no preceding history of any antimalarial drug treatment in those who presented with itching, and the symptoms subsided with-specific antimalarial treatment onlv. Couahinn subsided within 48 h of instituting antimalarial thevapy-in all those who presented with a cough. The patients had no clinical evidence of pneumonia or any other respiratory tract infection. Clinical response Improvement in clinical symptoms
24 h
110 (100%) 84(76.4%) 62 (56.4%) 62 (56.4%) 57(51.8%) 54(49.1%) 48 (43.6%) 31(28.2%) 25 (22.7%) 16(14.5%) 10 (9.1%) 8 (7.3%)
blood film and assuming a mean leucocyte count of 8000 per pL of blood. Parasitological and clinical examinations were done twice daily (8-10 h apart during daytime) for the first 4 d and once daily on subsequent follow-up days. Patient monitoring Patients whose parasitaemia on day 3 was greater than the value on day 0 were regarded as treatment failures. Each was subsequently re-treated with halofantrine or mefloquine. Patients in whom parasitaemia on day 3 was between 25% and 100% of the presenting value were treated as treatment failures if they remained symptomatic. However, those who were asymptomatic were followed-up daily until day 7. They were treated as treatment failures if parasitaemia remained unchanged and they became symptomatic. Patients with parasitaemia on day 3 <25% of the pretreatment value with or without symptoms were observed until day 7 and regarded as treatment failures only if parasitaemia persisted until day 7. Parasitological cure rate was determined as the percentage of patients who did not require re-treatment as described above and were without patent parasitaemia on day 7. Patients who had patent parasitaemia on day 14 after initial clearance on day 7 were regarded as suffering recrudescences. Fever clearance time (FCT) was defined as the time taken for the presenting raised temperature (>37.5”C) to decrease to 37.O”C and remain below 37.5”C for 24 h. The parasite clearance time (XT) was defined as the interval from beginning of treatment to the time asexual parasites were completely cleared from the blood and remained cleared till day 7. Results One hundred
and ten of 13 1 patients who satisfied the
preceded parasito-
at presentation
No. of children
complaints
Fever in the preceding Chills/rigors Palpitation Anorexia Headache Vomiting Nausea Abdominal pain Diarrhoea Itching Cough Dizziness
of children
59
SULFADOXINE-PYRIMETHAMINE
Halofantrine 39 29 24 27 21 16 16 12 6 4 0 4
Sulfadoxinepyrimethamine 33 29 17 18 18 8 8 7 5 3
Chloroquine 38 26 21 17 17 18 14 11 11 5 5 1
logical clearance in the patients (Table 2). Children treated with CQ showed significant clinical improvement despite persistent patent parasitaemia in 61% of the group. Parasitological data I? falciparum was the only species identified. Five of the 110 patients had hyperparasitaemia (parasite count >250 000 per pL; WHO, 1990). Two of the 3 hyperparasitaemic children treated with HF and one of the 2 treated with CQ were cured. Parasitaemia in each of the 17 children treated with HF who had patent parasitaemias on day 3 was less than 25% of the pretreatment value and they were all asymptomatic; no further treatment was therefore necessary. Of the 3 who had patent parasitaemia on day 7, one was treated with mefloquine (15 mg/kg of body weight, single dose), one with HF, and the third was cleared of his parasitaemia on day 14 without additional treatment. However, the boy with delayed parasite clearance became symptomatic with a parasite count of 22222lpL on day 19 and was treated with mefloquine. The cure rate for halofantrine among the children (36139) was 92.2%. Four of the 36 children cured with HF had recrudescences by day 14, a recrudescence rate of 11.1%. Three of the 16 children treated with S-P who had uatent parasitaemia on day 3 (18.7%) had a parasite density above 25% of the day 0 value; 2 of them were re-treated with HF on day 4 because of worsening clinical symptoms and increasing parasitaemia. Seven of the remaining 14 had parasitaemia by day 7 and were also retreated, 4 with HF and 3 with mefloquine. There were 9 treatment failures among children treated with S-P; 2 of the 24 parasitologically cured patients had recrudescences by day 14 and were cured with halofantrine. The total
60
C. 0. FALADE
recrudescence rate among the groups was 83%. Onlv 3 of the 27 children treated with chloroauine who had patent parasitaemia on day 3 (11’ 1%) had parasitaemia >25% of day 0 value; 2 of them needed retreatment before day 7 because of progression of their illness. Twentv-two of the CQ SOLID children had natent narasitaemia-on day 7, a parasitological cure rate of 56.8%. Five children who had patent parasitaemia on day 3 cleared their infection by day 7 and remained aparasitaemic up to day 14. Twenty children remained parasitaemic till day 7, while 2 who had cleared earlier had patent parasitaemia again on day 7. Two patients (13.3%) had recrudescences by day 14. Only 8 patients in the CQ group, of 15 whose parasitaemia had been cleared, were aparasitaemic bv day 3. - Eighteen of the children who failed to respond to treatment with CO were re-treated with HF and 6 were retreated with mefloquine. All re-treated patients were free of parasites by day 3. Only 2 of the children re-treated in Table 2. Presenting sulfadoxine-pyrimethamine
ETAL.
Laboratory data Haematocrit data are shown in Table 2. Thirty-seven of the 110 children were anaemic (packed cell volume ~30%). Anaemia was related to the age of the children rather than the level of parasitaemia. The mean age of children with anaemia was 3.9 years (s~k2.74) while the mean age of the total study population was 5.6 years (SDk3.3). Twenty-seven percent of the children who received HF, 39% of those treated with S-P, and 54% of those treated with CQ were anaemic. The pretreatment white blood cell count in all the children ranged from 4300 to 138OO/pL, with a mean of 7700 uL (~~+2400). Biochemical results were available for 102 patients before treatment and 76 after treatment. Serum urea and creatinine were within normal limits in all the patients. The most common biochemical abnormality was an increase in serum alkaline phosphatase in 19 children; 6 of these children had been treated with HF. 7 with S-P. and 6 with CQ. Serum alkaline phosphatase remained high in 3
features and clinical response or chloroquine for uncomplicated Halofantrine
No. 39 Presenting features 6.3+3.4(1.3-11.0) Age (years)a 20.62k7.9 (7-38) Weight (kg)a Male:female ratio 19:2d ’ Persistence of symptoms after treatment (d)a 1.72_+1*85(1-4) Initial body temperature (“C)a All children 36.3-40.2 Febrile children 38.6f 1.1(36.340.2) 44875(1641456000) Parasitaemia (per l.tL)b No. with >250000 UL 3 Haematocrit (%)” ’ 32.2f4.58(21-41) Clinical response Fever clearance time (d)a>c I-9f0.94 (14) Geometric mean parasite density (per FL) 27 Day 3 Day 7 39 3.4_+ 1.01 Parasite clearance time (d)d No. with parasitaemia Day 1 39 (100%) Day 3 17(43.6%) 3 (7.7%) Day 7 5(12.8%) Day 14 Cure rate 92.3% Day 7 Day 14 82.1% Persistence of symptoms after treatment (d)a 1*7*1*9(1-4) Haematocrit at day 14 (%)a 34.6f2.5 (27-39)
of
children falciparum
treated malaria
Sulfadoxinepyrimethamine 33 5.3_+2.9(0.9-10.5) 16.5+ 6.5 (5-27) 17:16 ’ 1.91&1.3(1-5)
with
halofantrine, Chloroquine 38
4.7+3.2(0.5-l 1.0) 14.3f5.5 (7-23) 22:16 ’ 2.26f2.1 (l-7)
36-40 36.241 38.2f 1.0 3.81f 1.0 19409(1082-236667)30479(2079-333533) 0 31.3?3.7(25-39) 29.03k3.522 (22-37) 1.6f0.86(14)
1.7+1.23(1-7)
183 64 4.4f 1.93
263 98 4.1k1.50
33 (100%) 16(48.5%) 7 (21.2%) 8 (24.2%)
38 (100%) 27(71.1%) 22 (57.9%) 20 (52.6%)
72.7% 69.7% 1*9f1.3(1-5) 34*4f 1.8 (27-38)
39.5% 36.8% 2.3f2.1 (l-7) 33.7+ 1.9 (30-37)
aMeankSD (range in parentheses). bGeometric mean (range in parentheses). %=36 for halofanaine, n=27 for sulfadoxine-pyrimethamine, 72~28 for chloroquine. dMeatiSD; n=39 for halofantrine, n=24 for sulfadoxine-pyrimerhamine, n=15 for chloroquine.
this group complied with follow-up; both were treated with HF and remained free of parasites up to day 14 following re-treatment. The others were lost to follow-up as soon as their parasitaemia had been cleared. Side effects Only one patient developed pruritus following treatment with CQ. One patient treated with HF had mild diarrhoea for 48 h. In the child who had pruritus, itching was reported 24 h after instituting therapy and persisted for 72 h; it was not severe enough to stop therapy. The relatively low incidence of pruritus (2.6%) in this study was probably due to the fact that allergy to any antimalarial drug was an exclusion criterion. The patient with diarrhoea needed only oral fluids.
of the children who were treated with HF, 4 of those treated with S-P, and 4 of those receiving CQ. Two children who received S-P and 3 who received CQ had raised alkaline phosphatase levels at the end of the study which had not been present at the outset. None of the children in the study had any clinical manifestation of jaundice. Only 3 of the children with raised serum alkaline phosphatase levels had a concomitant rise in serum glutamic oxaloacetic acid and pyruvic acid transaminases. This combination was observed in one patient at enrolment, and that natient was treated with S-P. The other 2 cases occurred at the end of the study, after treatment with CO. Two of the children. one treated with S-P and one with CQ, were clinically’and parasitologically cured. The third patient failed to respond to CQ treatment.
COMPARISON
OF HALOFANTRINE,
CHLOROQUINE
AND
Discussion This study revealed a decline in the sensitivity ofP. falciparum to S-P and a continued deterioration in the efflcacy of CQ in south-west Nigeria. Earlier studies in the area (EKANEM et al., 1990; SOVVUNMI & SAw(0, 1992) reported better efficacy, with no patient parasitaemic on days 7 and 14 after treatment with either CQ or S-P. The Table 3. Progressive decline in the antimalarial halofantrine between 1990 and 1995
parasite clearance patterns in children treated with HF and S-P showed much less disparity. These properties probably contribute in part to the retention of CQ for treatment of uncomplicated falciparum malaria in Nigeria. It remains the drug of choice because of its easy availability and affordability, despite the marked decline in the sensitivity of P. fulciparum. However, it should be em-
efficacy
of chloroquine, Proportion
Day 3 Chloroquine Ekanem et al. (1990) Sowunmi & Salako (1992) This studya Sulfadoxine-pyrimethamine Ekanem et al. (1990) Sowunmi et al. (1993) Sowunmi et al. (1995) This studya Halofantrine Salako et al. (1990b) This study aNovember 1994-February
61
SULFADOXINE-PYRIMETHAMINE
sulfadoxine-pyrimethamine
and
with patent parasitaemia Day 7 Day 14
19.6%<9/46) 55.3% (21138)
6.5%&46) 57.9% (22138)
15.2&7146) 52.35 (20138)
7.4% (15/202) 48.5% (16133)
5.9% (121202) 21.2% (7133)
6.7%(12/30) 1.9% (4/202) 24.3% (8133)
7.7&39)
43.6%:17/39)
12+&5/39)
1995.
declining sensitivity of l? falciparum infections to S-P is a continuation of a trend: SOWUNMI et al. (1993, 1995) reported recrudescence rates of 6.5% and 7.4% followed treatment with the drug. The presence of CQ-resistant l? falcipawn in Nigeria is well documented (SALAKO & ADEROUNMU, 1987; EKANEM et al., 1990; SOWUNMI et al., 1990). The 60.5% failure rate in children treated with CQ in this study, however, showed an increasing level of CQ-resistance in this area of Nigeria. Previous studies in the area reported only 14.3% and 275% in 1990 and 1992, respectively (SALAKO et al., 199Oa; SOWUNMI & SALAKO, 1992). The progressive decline in the efficacy of CQ in the area is manifested by delayed initial parasite clearance and increasing lack of responsiveness over the last 5 years. This pattern seems to follow trends observed in other endemic areas of south-east Asia and East Africa with established CQ-resistant malaria (HARINASUTA et al., 1965; KHOROMANA et al., 1986). A cure rate of 92.3% by day 7 in children treated with HF shows that this drug remains effective for the treatment of acute falciparum malaria in Nigeria. This confumed previous studies in Nigeria (SALAKO et al., 1990b) and other endemic areas (KRISHNA et al., 1993; WILDLING et al., 1993), but also revealed some decline in efficacy. The decline in sensitivity of P. falciparum to HF, however, was not as significant as that with CQ, and was manifested only by recrudescence of parasitaemia in 4 children (11.1%) by day 14, and by a delay in parasite clearance (mean=3.4 d). An earlier study (SALAKO et al., 1990b), involving 50 patients from the same area, reported no parasite in any patient by day 3, no recrudescence by day 14, and a mean parasite clearance time of 1.4 d. However, the ages of patients in the 2 studies were different: patients in the earlier study were older (12-45 years) (SALAKO et al., 1990b); the age of the children in the present study ranged from 6 months to 11 years. Better developed immunity to malaria in the older children could have contributed to their better response to HF. These observations are summarized in Table 3. Alleviation of symptoms in patients treated with CQ is of interest; it occurred despite persistent patent parasitaemia. Fever clearance preceded parasite clearance by a significant margin. Only 27% and 23% of the children treated with CQ had fever on days 1 and 2 despite patent parasitaemia on both days in all the children. Fever and
phasized that, in the absence of parasitological diagnosis, as is common in private clinics and rural areas in Nigeria, the appearance of fever which had earlier subsided should suggest the substitution of alternative therapy or referral to an established health centre capable of managing drug-resistant malaria. The increasing CQ-resistance and the decline in sensitivity of infections to S-P and HF (Table 3) observed in this study may have far reaching implications for malaria chemotherapeutic decision making in Nigeria. The appearance of recrudescences and delayed parasite clearance in patients treated with HF within 5 years of its introduction for general use also raises some questions. It is important to develop a pragmatic approach in utilizing these drugs and to make a concerted effort to preserve their efficacy. This approach will provide a rational basis for the choice of drugs for the treatment of the individual patient while protecting the population, and may help to develop national malaria drug treatment guidelines. Acknowledgements This study We appreciate
received support from SmithKline Beecham Ltd. the assistance of Drs F. A. Fehintola and A. Ade-
dapo and Mrs. Adedoja, and we are grateful fo the medical nursing staff of the paediatric
ward for assisting
with patient
care.
References Ekanem, 0. J., Weisfeld, J. S., Salako, L. A., Nahlen, B. L., Ezedinachi, E. N. U., Walker, O., Breman, J. G., Laoye, 0. J. & Hedberg, K. (1990). Sensitivity of PZ~modium falciparum to chloroquine and sulphadoxine-pyrimethamine in Nigerian children. Bulletin of the World Health Organization, 68,45-5 1. Harinasuta,T., Sunthtarasami, I? &Viravan, C. (1965). Chloroquine-resistant falciparum malaria in Thailand. Lancet, ii, 657-660. Khoromana, C. O., Campbell, C. C., Wirima, J. J. & Heymann, D. (1986). In viva efficacy of chloroquine treatment for Plusmodium falciparum in Malawian children under five years of age. American Journal of Tropical Medicine and Hygiene, 35, 4655471.
Krishna, S., ter Kuile, F., Supanaranond, W., Putrittayakamee, S., Pega-Isavadharm, l?, Kyle, D. &White, N. J. (1993). Pharmacokinetics, efficacy and toxicity of parenteral halofantrine in uncomplicated malaria. British Journal of Clinical Pharmacology, 36,-582-591. Nigeria (1980-1983). Annual Reports. Lagos: Federal Ministrv Gf He&h. Oduola, A. M. J., Sowunmi, A., Milhous, W. K., Kyle, D. E., Martin, R. K., Walker, 0. & Salako, L. A. (1992). Innate re-
62
C.O.FALADE ETAL.
sistance to new antimalarial drugs in Plasmodium
falciparum from Nigeria. Transactions of the Royal Society of Tropical Medicine a&Hygiene, 86, 123--126. Salako, L. A. & Aderounmu, A. F. (1987). In-vitro chloroquine and mefloquine resistant Plasmodium falciparum in Nigeria. Lancet, ii, 572-573. Salako, L. A., Adio, R. A., Sowunmi, A. &Walker, 0. (1990a). Parenteral sulphadoxine-pyrimethamine (Fansida*): an effective and safe but under-used method of antimalaria treatment. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84,641-643. Salako, L. A., Sowunmi, A. &Walker, 0. (1990b). Evaluation of the clinical efficacy and safety of halofantrine in falciparum malaria in Ibadan, Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84,644-647. Sowunmi, A. & Oduola, A. M. J. (1995). Open comparison of mefloquine, mefloquine/sulfadoxine/pyrimethamine and chloroquine in acute uncomplicated falciparum malaria in children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 89,303-305. Sowunmi, A. & Salako, L. A. (1992). Evaluation of the relative efficacy of various antimalarial drugs in Nigerian children under five years of age suffering from acute uncomplicated falciparum malaria. Annals of Tropical Medicine and Parasitol-
( Announcement
ogy,86, l-8. Sowunmi, A., Salako, L. A., Walker, 0. & Ogundahunsi, 0. A. T. (1990). Clinical efficacy of mefloquine in children suffering from chloroquine-resistant Plasmodium falciparum malaria in Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene,84,761-764. Sowunmi, A., Akindele, J. A., Omitowoju, G. O., Omigbodun, A. O., Oduola, A. M. J. & Salako, L. A. (1993). Intramuscular sulfadoxine-pyrimethamine in uncomplicated chloroquine-resistant malaria during pregnancy. Transactions of the Royal So&y of Tropical Medicine and Hygiene, 87,472. Sowunmi, A., Oduola, A. M. J. & Salako, L. A. (1995). Artemether treatment of sulfadoxine/pyrimethamine-resistant Plasmodium falciparum malaria in children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 89, 435436. WHO (1990). Severe and complicated malaria, 2nd edition. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84, supplement 2. Wildling, E., Winkler, S., Brandts, C. & Jenne, L. G. (1993). Halofantrine sensitivity. Lance& 342, 55-56. Received publication
18 April 17July
1996; revised 1996
17 Jut)
1996;
accepted
1
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OF THE
ROYAL
SOCIETY
OF TROPICAL
MEDICINE
AND
HYGIENE
(1997)
91,58-62
Comparative efficacy of halofantrine, chloroquine and sulfadoxine-pyrimethamine for treatment of acute uncomplicated malaria in Nigerian children
falciparum
C. 0. Falade1y2, L. A. Salako123, A. Sowunmi1~2, A. M. J. Oduola1y2 and I? Larcied ‘Department of Pharmacology and Therapeutics and 2Postgraduate Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria; 3Nigerian Institute of Medical Research,Yaba, Lagos, Nigeria;4SmithKline Beecham International, Ajiican Medical Department, Lagos, Nigeria Abstract One hundred and ten children aged 6 months to 11 years were randomly treated with halofantrine (HF), sulfadoxine-pyrimethamine (S-P) or chloroquine (CQ) f or acute uncomplicated Plasmodium falciparum malaria in an endemic area of south-western Nigeria. The resnonse of infection to treatment in each child was monitored for 14 d. The mean fever clear&ce times were 1.9 d (n=36), 1.6 d (n=27), and 1-7 d (n=28) for children treated with HF, S-P and CQ, respectively. The parasite clearance times were 3.4 d (n=39), 4.4 d (n=24) and 4.1 d (n=15) in the 3 groups of children.The cure rate at day 7 was 92.3% (36/ 39) in children treated with HF, 72.7% (24/33) in those treated with S-P, and 39.5% (15138) in those treated with CQ. By day 14,4 of 36 (11.1%) parasitologically cured patients treated with HF had experienced recrudescences. The corresponding figures among children treated with S-P or CQ were 83% and 13.3%, respectively. The 3 drugs were well tolerated. The results of the study showed a further decline in the sensitivity of I? falciparum infections to CQ, while HF and S-P remained relatively effective in the treatment of malaria in south-west Nigeria. Keywords: malaria, children, Nigeria
Plasmodium
fulciparum, chemotherapy, halofantrine, sulfadoxine-pyrimethamine,
Introduction Morbidity and mortality from malaria continue to be a major health problem in Nigeria. Malaria is the most common cause of out-patient clinic attendance among all age groups in the country and is responsible for an estimated 30bOOO deaths yearly in children less than 5 vears old ~NIGERIA. 1980-1983). Resistance to chloroquine (CQ), the drug of choice for the treatment of uncomplicated malaria in Nigeria, had been reported in several areas of the country (EKANEM et al., 1%; ODUOLA et al.. 1992: SOWUNMI & SALAKO, 1992). This has led to increasing use of alternative antimalarial drugs, particularly sulfadoxine-pyrimethamine (S-P) and halofantrine (HF). Although early studies showed full sensitivity of infection to S-P in the country (EWNEM et al., 1990; SALAKO et al., 1990a; SOWUNMI & SALAKO, 1992), there have been reports of failure of clinical response to treatment with this drug recently (SOWUNMI et al.. 1995). HF has been widelv available in the country in the ‘past 5 years. The drug has become the drug of choice for treatment of malaria among those patients attending private clinics who could afford it, particularlv in the major cities. Earlier studv of the efficacv of halofantrine before its introduction for general use in the country showed a 95-100% parasitological cure rate, and a 1 O-l 5% recrudescence rate 21 d or more after treatment (SALAKO et al., 1990b). In this report, the efficacy of HF after 5 years of general use in Nigeria is described. The efficacy of CQ, the first line antimalarial drug used in Nigeria, and S-P, a second line antimalarial drug, are also discussed in an effort to provide information useful in pragmatic management of malaria in Nigeria. Methods Patients The study was carried out at the University College Hospital, Ibadan, south-west Nigeria. The city of Ibadan has a population of 1.5 million. Malaria transmission in the city is intense. Children aged 6 months to 11 years with acute symptomatic uncomplicated falciparum malaria were recruited between November 1994 Address for correspondence: Dr A. Sowunmi, Department of Pharmacology andTherapeutics, College of Medicine, University of Ibadan, Ibadan, Nigeria.
chloroquine,
and February 1995. The children were enrolled after meeting recruitment criteria including Plasmodium falciparum asexual parasitaemia 21000 parasites per uL of blood, no history of antimalarial drug administration in the 2 weeks preceding presentation, negative urine tests for 4-aminoauinolines (Dill-Glazkol and sulnhonamides (ligninj, the presence or history’of fever w&in 24 h of presentation and signed informed consent by the parent or guardian. Children with severe or complicated malaria who needed parenteral therapy, a history of intolerance to any of the antimalarial drugs, additional causes of fever (bronchopneumonia), and/or concomitant chronic illness (sickle cell anaemia) were excluded from the study. Patients were withdrawn from the study for any of the following reasons: wish of the parent or guardian, clinical deterioration necessitating change of drug, inability to tolerate oral medication, lack of patient compliance, patient loss to follow-up, and protocol violation, including self-administration of other antimalarial drugs during the follow-up. Approval for the study protocol was obtained from the Toint Ethical Review Committee of the Universitv of IbadanAJniversity College Hospital, Ibadan before initiating the study. A careful history was taken from the parent or guardian of each patient and informed consent was signed before enrolment. The patients were examined by a physician, weighed, and their axillary temperature taken using a clinical thermometer. Thick and thin blood films were prepared from a finger-prick blood sample and stained with Giemsa’s stain. All findings were recorded on case record forms specifically provided for the study. The children were allocated into 3 groups for treatment with HF. S-P or CO accordine to a me-generated randomization schedule.- HF (Hsfan@, S&hKline Beecham) was administered orally at a dose of 8 mg/kg of body weight every 6 h for 3 doses (corresponding to a total dose of 24 mgikg). S-P (Fansidap, Roche), containing 500 mg sulfadoxine and 25 mg pyrimethamine per tablet, was given as a single dose treatment according to the following schedule: half a tablet for each child weighing 5-10 kg; one tablet for each child weighing 1 l-20 ke: 1 l/, tablets for each child weiahine 20-30 ke: and 2 t:blet: for each child weighing”30-20 kg. CQ (May & Baker), 25 mgfkg of body weight, was given orally over 3 d (10 mg/kg on days 0 and 1, and 5 mg/kg
COMPARISON
OF HALOFANTRINE,
CHLOROQUINE
AND
on day 2). Each drug was administered with an ample amount of water and the mouth was inspected after administration to ensure that it had been swallowed. The children were observed for at least 3 h after drug administration, and any who vomited were withdrawn from the study. A 14 d modification of the World Health Organization extended field test was used for the study, as the intense malaria transmission in the area made it difficult to differentiate between reinfection and recrudescence beyond 14 d. The patients were seen daily from the day of presentation (day 0) to day 3 or until parasitaemia cleared and subsequently on days 7 and 14. Haematological variables, including haematocrit, total white blood cell count, differential count, and platelet count were determined. Serum sodium, potassium, creatinine, and urea levels were measured and tests of liver function and urinalysis (for glucose, protein and blood) were also done. Giemsa-stained blood films were examined under an oil immersion objective at xl000 magnification. Parasitaemia was determined by counting the number of asexual parasites relative to 500 leucocytes in each thick Table
1. Clinical
Presenting
features
with
malaria
enrolment criteria completed the study. Of the 21 children who did not complete the study, 2 were withdrawn at the request of their parents, one developed mumps parotitis, and the disease progressed to severe malaria in another one within 4 h of enrolment. The remaining 17 children were lost to follow-up. Nine of the 17 were aparasitaemic by the time they defaulted, while 8 still had patent parasitaemia. Thirty-nine of the children who completed the study were treated with HF, 33 with S-P and 38 with CQ. The clinical features and therapeutic responses to treatment with the 3 antimalarial drugs are summarized in Tables 1 and 2. There was no preceding history of any antimalarial drug treatment in those who presented with itching, and the symptoms subsided with-specific antimalarial treatment onlv. Couahinn subsided within 48 h of instituting antimalarial thevapy-in all those who presented with a cough. The patients had no clinical evidence of pneumonia or any other respiratory tract infection. Clinical response Improvement in clinical symptoms
24 h
110 (100%) 84(76.4%) 62 (56.4%) 62 (56.4%) 57(51.8%) 54(49.1%) 48 (43.6%) 31(28.2%) 25 (22.7%) 16(14.5%) 10 (9.1%) 8 (7.3%)
blood film and assuming a mean leucocyte count of 8000 per pL of blood. Parasitological and clinical examinations were done twice daily (8-10 h apart during daytime) for the first 4 d and once daily on subsequent follow-up days. Patient monitoring Patients whose parasitaemia on day 3 was greater than the value on day 0 were regarded as treatment failures. Each was subsequently re-treated with halofantrine or mefloquine. Patients in whom parasitaemia on day 3 was between 25% and 100% of the presenting value were treated as treatment failures if they remained symptomatic. However, those who were asymptomatic were followed-up daily until day 7. They were treated as treatment failures if parasitaemia remained unchanged and they became symptomatic. Patients with parasitaemia on day 3 <25% of the pretreatment value with or without symptoms were observed until day 7 and regarded as treatment failures only if parasitaemia persisted until day 7. Parasitological cure rate was determined as the percentage of patients who did not require re-treatment as described above and were without patent parasitaemia on day 7. Patients who had patent parasitaemia on day 14 after initial clearance on day 7 were regarded as suffering recrudescences. Fever clearance time (FCT) was defined as the time taken for the presenting raised temperature (>37.5”C) to decrease to 37.O”C and remain below 37.5”C for 24 h. The parasite clearance time (XT) was defined as the interval from beginning of treatment to the time asexual parasites were completely cleared from the blood and remained cleared till day 7. Results One hundred
and ten of 13 1 patients who satisfied the
preceded parasito-
at presentation
No. of children
complaints
Fever in the preceding Chills/rigors Palpitation Anorexia Headache Vomiting Nausea Abdominal pain Diarrhoea Itching Cough Dizziness
of children
59
SULFADOXINE-PYRIMETHAMINE
Halofantrine 39 29 24 27 21 16 16 12 6 4 0 4
Sulfadoxinepyrimethamine 33 29 17 18 18 8 8 7 5 3
Chloroquine 38 26 21 17 17 18 14 11 11 5 5 1
logical clearance in the patients (Table 2). Children treated with CQ showed significant clinical improvement despite persistent patent parasitaemia in 61% of the group. Parasitological data I? falciparum was the only species identified. Five of the 110 patients had hyperparasitaemia (parasite count >250 000 per pL; WHO, 1990). Two of the 3 hyperparasitaemic children treated with HF and one of the 2 treated with CQ were cured. Parasitaemia in each of the 17 children treated with HF who had patent parasitaemias on day 3 was less than 25% of the pretreatment value and they were all asymptomatic; no further treatment was therefore necessary. Of the 3 who had patent parasitaemia on day 7, one was treated with mefloquine (15 mg/kg of body weight, single dose), one with HF, and the third was cleared of his parasitaemia on day 14 without additional treatment. However, the boy with delayed parasite clearance became symptomatic with a parasite count of 22222lpL on day 19 and was treated with mefloquine. The cure rate for halofantrine among the children (36139) was 92.2%. Four of the 36 children cured with HF had recrudescences by day 14, a recrudescence rate of 11.1%. Three of the 16 children treated with S-P who had uatent parasitaemia on day 3 (18.7%) had a parasite density above 25% of the day 0 value; 2 of them were re-treated with HF on day 4 because of worsening clinical symptoms and increasing parasitaemia. Seven of the remaining 14 had parasitaemia by day 7 and were also retreated, 4 with HF and 3 with mefloquine. There were 9 treatment failures among children treated with S-P; 2 of the 24 parasitologically cured patients had recrudescences by day 14 and were cured with halofantrine. The total
60
C. 0. FALADE
recrudescence rate among the groups was 83%. Onlv 3 of the 27 children treated with chloroauine who had patent parasitaemia on day 3 (11’ 1%) had parasitaemia >25% of day 0 value; 2 of them needed retreatment before day 7 because of progression of their illness. Twentv-two of the CQ SOLID children had natent narasitaemia-on day 7, a parasitological cure rate of 56.8%. Five children who had patent parasitaemia on day 3 cleared their infection by day 7 and remained aparasitaemic up to day 14. Twenty children remained parasitaemic till day 7, while 2 who had cleared earlier had patent parasitaemia again on day 7. Two patients (13.3%) had recrudescences by day 14. Only 8 patients in the CQ group, of 15 whose parasitaemia had been cleared, were aparasitaemic bv day 3. - Eighteen of the children who failed to respond to treatment with CO were re-treated with HF and 6 were retreated with mefloquine. All re-treated patients were free of parasites by day 3. Only 2 of the children re-treated in Table 2. Presenting sulfadoxine-pyrimethamine
ETAL.
Laboratory data Haematocrit data are shown in Table 2. Thirty-seven of the 110 children were anaemic (packed cell volume ~30%). Anaemia was related to the age of the children rather than the level of parasitaemia. The mean age of children with anaemia was 3.9 years (s~k2.74) while the mean age of the total study population was 5.6 years (SDk3.3). Twenty-seven percent of the children who received HF, 39% of those treated with S-P, and 54% of those treated with CQ were anaemic. The pretreatment white blood cell count in all the children ranged from 4300 to 138OO/pL, with a mean of 7700 uL (~~+2400). Biochemical results were available for 102 patients before treatment and 76 after treatment. Serum urea and creatinine were within normal limits in all the patients. The most common biochemical abnormality was an increase in serum alkaline phosphatase in 19 children; 6 of these children had been treated with HF. 7 with S-P. and 6 with CQ. Serum alkaline phosphatase remained high in 3
features and clinical response or chloroquine for uncomplicated Halofantrine
No. 39 Presenting features 6.3+3.4(1.3-11.0) Age (years)a 20.62k7.9 (7-38) Weight (kg)a Male:female ratio 19:2d ’ Persistence of symptoms after treatment (d)a 1.72_+1*85(1-4) Initial body temperature (“C)a All children 36.3-40.2 Febrile children 38.6f 1.1(36.340.2) 44875(1641456000) Parasitaemia (per l.tL)b No. with >250000 UL 3 Haematocrit (%)” ’ 32.2f4.58(21-41) Clinical response Fever clearance time (d)a>c I-9f0.94 (14) Geometric mean parasite density (per FL) 27 Day 3 Day 7 39 3.4_+ 1.01 Parasite clearance time (d)d No. with parasitaemia Day 1 39 (100%) Day 3 17(43.6%) 3 (7.7%) Day 7 5(12.8%) Day 14 Cure rate 92.3% Day 7 Day 14 82.1% Persistence of symptoms after treatment (d)a 1*7*1*9(1-4) Haematocrit at day 14 (%)a 34.6f2.5 (27-39)
of
children falciparum
treated malaria
Sulfadoxinepyrimethamine 33 5.3_+2.9(0.9-10.5) 16.5+ 6.5 (5-27) 17:16 ’ 1.91&1.3(1-5)
with
halofantrine, Chloroquine 38
4.7+3.2(0.5-l 1.0) 14.3f5.5 (7-23) 22:16 ’ 2.26f2.1 (l-7)
36-40 36.241 38.2f 1.0 3.81f 1.0 19409(1082-236667)30479(2079-333533) 0 31.3?3.7(25-39) 29.03k3.522 (22-37) 1.6f0.86(14)
1.7+1.23(1-7)
183 64 4.4f 1.93
263 98 4.1k1.50
33 (100%) 16(48.5%) 7 (21.2%) 8 (24.2%)
38 (100%) 27(71.1%) 22 (57.9%) 20 (52.6%)
72.7% 69.7% 1*9f1.3(1-5) 34*4f 1.8 (27-38)
39.5% 36.8% 2.3f2.1 (l-7) 33.7+ 1.9 (30-37)
aMeankSD (range in parentheses). bGeometric mean (range in parentheses). %=36 for halofanaine, n=27 for sulfadoxine-pyrimethamine, 72~28 for chloroquine. dMeatiSD; n=39 for halofantrine, n=24 for sulfadoxine-pyrimerhamine, n=15 for chloroquine.
this group complied with follow-up; both were treated with HF and remained free of parasites up to day 14 following re-treatment. The others were lost to follow-up as soon as their parasitaemia had been cleared. Side effects Only one patient developed pruritus following treatment with CQ. One patient treated with HF had mild diarrhoea for 48 h. In the child who had pruritus, itching was reported 24 h after instituting therapy and persisted for 72 h; it was not severe enough to stop therapy. The relatively low incidence of pruritus (2.6%) in this study was probably due to the fact that allergy to any antimalarial drug was an exclusion criterion. The patient with diarrhoea needed only oral fluids.
of the children who were treated with HF, 4 of those treated with S-P, and 4 of those receiving CQ. Two children who received S-P and 3 who received CQ had raised alkaline phosphatase levels at the end of the study which had not been present at the outset. None of the children in the study had any clinical manifestation of jaundice. Only 3 of the children with raised serum alkaline phosphatase levels had a concomitant rise in serum glutamic oxaloacetic acid and pyruvic acid transaminases. This combination was observed in one patient at enrolment, and that natient was treated with S-P. The other 2 cases occurred at the end of the study, after treatment with CO. Two of the children. one treated with S-P and one with CQ, were clinically’and parasitologically cured. The third patient failed to respond to CQ treatment.
COMPARISON
OF HALOFANTRINE,
CHLOROQUINE
AND
Discussion This study revealed a decline in the sensitivity ofP. falciparum to S-P and a continued deterioration in the efflcacy of CQ in south-west Nigeria. Earlier studies in the area (EKANEM et al., 1990; SOVVUNMI & SAw(0, 1992) reported better efficacy, with no patient parasitaemic on days 7 and 14 after treatment with either CQ or S-P. The Table 3. Progressive decline in the antimalarial halofantrine between 1990 and 1995
parasite clearance patterns in children treated with HF and S-P showed much less disparity. These properties probably contribute in part to the retention of CQ for treatment of uncomplicated falciparum malaria in Nigeria. It remains the drug of choice because of its easy availability and affordability, despite the marked decline in the sensitivity of P. fulciparum. However, it should be em-
efficacy
of chloroquine, Proportion
Day 3 Chloroquine Ekanem et al. (1990) Sowunmi & Salako (1992) This studya Sulfadoxine-pyrimethamine Ekanem et al. (1990) Sowunmi et al. (1993) Sowunmi et al. (1995) This studya Halofantrine Salako et al. (1990b) This study aNovember 1994-February
61
SULFADOXINE-PYRIMETHAMINE
sulfadoxine-pyrimethamine
and
with patent parasitaemia Day 7 Day 14
19.6%<9/46) 55.3% (21138)
6.5%&46) 57.9% (22138)
15.2&7146) 52.35 (20138)
7.4% (15/202) 48.5% (16133)
5.9% (121202) 21.2% (7133)
6.7%(12/30) 1.9% (4/202) 24.3% (8133)
7.7&39)
43.6%:17/39)
12+&5/39)
1995.
declining sensitivity of l? falciparum infections to S-P is a continuation of a trend: SOWUNMI et al. (1993, 1995) reported recrudescence rates of 6.5% and 7.4% followed treatment with the drug. The presence of CQ-resistant l? falcipawn in Nigeria is well documented (SALAKO & ADEROUNMU, 1987; EKANEM et al., 1990; SOWUNMI et al., 1990). The 60.5% failure rate in children treated with CQ in this study, however, showed an increasing level of CQ-resistance in this area of Nigeria. Previous studies in the area reported only 14.3% and 275% in 1990 and 1992, respectively (SALAKO et al., 199Oa; SOWUNMI & SALAKO, 1992). The progressive decline in the efficacy of CQ in the area is manifested by delayed initial parasite clearance and increasing lack of responsiveness over the last 5 years. This pattern seems to follow trends observed in other endemic areas of south-east Asia and East Africa with established CQ-resistant malaria (HARINASUTA et al., 1965; KHOROMANA et al., 1986). A cure rate of 92.3% by day 7 in children treated with HF shows that this drug remains effective for the treatment of acute falciparum malaria in Nigeria. This confumed previous studies in Nigeria (SALAKO et al., 1990b) and other endemic areas (KRISHNA et al., 1993; WILDLING et al., 1993), but also revealed some decline in efficacy. The decline in sensitivity of P. falciparum to HF, however, was not as significant as that with CQ, and was manifested only by recrudescence of parasitaemia in 4 children (11.1%) by day 14, and by a delay in parasite clearance (mean=3.4 d). An earlier study (SALAKO et al., 1990b), involving 50 patients from the same area, reported no parasite in any patient by day 3, no recrudescence by day 14, and a mean parasite clearance time of 1.4 d. However, the ages of patients in the 2 studies were different: patients in the earlier study were older (12-45 years) (SALAKO et al., 1990b); the age of the children in the present study ranged from 6 months to 11 years. Better developed immunity to malaria in the older children could have contributed to their better response to HF. These observations are summarized in Table 3. Alleviation of symptoms in patients treated with CQ is of interest; it occurred despite persistent patent parasitaemia. Fever clearance preceded parasite clearance by a significant margin. Only 27% and 23% of the children treated with CQ had fever on days 1 and 2 despite patent parasitaemia on both days in all the children. Fever and
phasized that, in the absence of parasitological diagnosis, as is common in private clinics and rural areas in Nigeria, the appearance of fever which had earlier subsided should suggest the substitution of alternative therapy or referral to an established health centre capable of managing drug-resistant malaria. The increasing CQ-resistance and the decline in sensitivity of infections to S-P and HF (Table 3) observed in this study may have far reaching implications for malaria chemotherapeutic decision making in Nigeria. The appearance of recrudescences and delayed parasite clearance in patients treated with HF within 5 years of its introduction for general use also raises some questions. It is important to develop a pragmatic approach in utilizing these drugs and to make a concerted effort to preserve their efficacy. This approach will provide a rational basis for the choice of drugs for the treatment of the individual patient while protecting the population, and may help to develop national malaria drug treatment guidelines. Acknowledgements This study We appreciate
received support from SmithKline Beecham Ltd. the assistance of Drs F. A. Fehintola and A. Ade-
dapo and Mrs. Adedoja, and we are grateful fo the medical nursing staff of the paediatric
ward for assisting
with patient
care.
References Ekanem, 0. J., Weisfeld, J. S., Salako, L. A., Nahlen, B. L., Ezedinachi, E. N. U., Walker, O., Breman, J. G., Laoye, 0. J. & Hedberg, K. (1990). Sensitivity of PZ~modium falciparum to chloroquine and sulphadoxine-pyrimethamine in Nigerian children. Bulletin of the World Health Organization, 68,45-5 1. Harinasuta,T., Sunthtarasami, I? &Viravan, C. (1965). Chloroquine-resistant falciparum malaria in Thailand. Lancet, ii, 657-660. Khoromana, C. O., Campbell, C. C., Wirima, J. J. & Heymann, D. (1986). In viva efficacy of chloroquine treatment for Plusmodium falciparum in Malawian children under five years of age. American Journal of Tropical Medicine and Hygiene, 35, 4655471.
Krishna, S., ter Kuile, F., Supanaranond, W., Putrittayakamee, S., Pega-Isavadharm, l?, Kyle, D. &White, N. J. (1993). Pharmacokinetics, efficacy and toxicity of parenteral halofantrine in uncomplicated malaria. British Journal of Clinical Pharmacology, 36,-582-591. Nigeria (1980-1983). Annual Reports. Lagos: Federal Ministrv Gf He&h. Oduola, A. M. J., Sowunmi, A., Milhous, W. K., Kyle, D. E., Martin, R. K., Walker, 0. & Salako, L. A. (1992). Innate re-
62
C.O.FALADE ETAL.
sistance to new antimalarial drugs in Plasmodium
falciparum from Nigeria. Transactions of the Royal Society of Tropical Medicine a&Hygiene, 86, 123--126. Salako, L. A. & Aderounmu, A. F. (1987). In-vitro chloroquine and mefloquine resistant Plasmodium falciparum in Nigeria. Lancet, ii, 572-573. Salako, L. A., Adio, R. A., Sowunmi, A. &Walker, 0. (1990a). Parenteral sulphadoxine-pyrimethamine (Fansida*): an effective and safe but under-used method of antimalaria treatment. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84,641-643. Salako, L. A., Sowunmi, A. &Walker, 0. (1990b). Evaluation of the clinical efficacy and safety of halofantrine in falciparum malaria in Ibadan, Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84,644-647. Sowunmi, A. & Oduola, A. M. J. (1995). Open comparison of mefloquine, mefloquine/sulfadoxine/pyrimethamine and chloroquine in acute uncomplicated falciparum malaria in children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 89,303-305. Sowunmi, A. & Salako, L. A. (1992). Evaluation of the relative efficacy of various antimalarial drugs in Nigerian children under five years of age suffering from acute uncomplicated falciparum malaria. Annals of Tropical Medicine and Parasitol-
( Announcement
ogy,86, l-8. Sowunmi, A., Salako, L. A., Walker, 0. & Ogundahunsi, 0. A. T. (1990). Clinical efficacy of mefloquine in children suffering from chloroquine-resistant Plasmodium falciparum malaria in Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene,84,761-764. Sowunmi, A., Akindele, J. A., Omitowoju, G. O., Omigbodun, A. O., Oduola, A. M. J. & Salako, L. A. (1993). Intramuscular sulfadoxine-pyrimethamine in uncomplicated chloroquine-resistant malaria during pregnancy. Transactions of the Royal So&y of Tropical Medicine and Hygiene, 87,472. Sowunmi, A., Oduola, A. M. J. & Salako, L. A. (1995). Artemether treatment of sulfadoxine/pyrimethamine-resistant Plasmodium falciparum malaria in children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 89, 435436. WHO (1990). Severe and complicated malaria, 2nd edition. Transactions of the Royal Society of Tropical Medicine and Hygiene, 84, supplement 2. Wildling, E., Winkler, S., Brandts, C. & Jenne, L. G. (1993). Halofantrine sensitivity. Lance& 342, 55-56. Received publication
18 April 17July
1996; revised 1996
17 Jut)
1996;
accepted
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