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Comparative efficacy of chloroquine plus chlorpheniramine and halofantrine in acute uncomplicated falciparum malaria in Nigerian children
TRANSACTIONS
OFTHE ROYAL SOCIETY OFTROPICAL
MEDICINE AND HYGIENE (1998) 92,441-445
441
Comparative efficacy of chloroquine plus chlorpheniramine and halofantrine acute uncomplicated falciparum malaria in Nigerian children A. Sowunmi, Therapeutics
F. A. Fehintola, and Postgraduate
0. A. T. Ogundahunsi
Institute for Medical
and A. M. J. Oduola
Research and Training,
Universiy
Department of Pharmacology ojIbadan, Ibadan, Nigeria
in
and
Abstract In the face of growing chloroquine resistance of Plasmodium.falciparum, efforts to prolong the clinical usefulness of the drug-have partly concentrated on its combination with potential resistance-reversing comnounds. However. , clinical studies on such combinations have been limited. We have comnared the -----r - ..~~~.~~~~ efficacy of halofantrine, an arylaminoalcohol effective in chloroquine resistant malaria, and a combination of chloroquine plus chlorpheniramine, a histamine Hl receptor antagonist which reverses chloroquine resistance of I? falciparum in vitro and in viva, in 100 children with acute symptomatic uncomplicated falciparum malaria in an area of Nigeria where the rate of chloroquine resistance is 3545%. Both chloroquine plus chlorpheniramine and halofantrine produced similar parasite and fever clearance times and cure rates (96%). Both treatment regimens were relatively well tolerated. Pruritus was commoner in patients treated with chloroquine plus chlorpheniramine than in those treated with halofantrine. Intravascular haemolysis occurred in one patient, and abdominal pain with or without diarrhoea occurred in 4 patients, treated with halofantrine. In vitro, the chloroquine resistance of I? jalciparum isolates obtained from the patients was reversed by verapamil. All patients with isolates which were chloroquineresistant in vitro were cured by either therapy. These results indicate that chloroquine plus chlorpheniramine is as effective as halofantrine and is without overt deleterious effect in treating acute uncomplicated chloroquine-resistant falciparum malaria in children, and may be a clinically useful alternative for this purpose in Nigeria. Keywords: malaria, iramine, halofantrine,
PZasmodium fulciparum, children, Nigeria
chemotherapy,
Introduction The spread of chloroquine-resistant falciparum malaria has created the need for alternative antimalarial drugs. In addition, it has led to renewed efforts to prolone the clinical usefulness of chloroquine. One such effor; involves the combination of *chloroquine with chlorpheniramine, a histamine Ht receptor antagonist which reverses chloroauine insensitivitv in Plasmodium jalciparum in vitro (OA~TOWO~U et al., -1992; BASCO & LE BRAS, 1994; SOVCTUNMI et al., 1997a) and in vivo (SOWUNMI et al., 1997a; SOWUNMI & ODUOLA, 1997).
In previous studies in an endemic area, we have shown that the combination of chloroquine with chlorpheniramine enhances the efficacy of chloroquine in chloroquine-resistant malaria, is superior to pyrimethamineisulfadoxine and is effective in pyrimethaminel sulfadoxine-resistant malaria in children (SOW~UMI et al., 1997a, 1998). In the present study, we have evaluated the efficacv of halofantrine, an arvlaminoalcohol effective in chloroquine resistant malaria, and the combination of chloroquine plus chlorpheniramine in a group of children suffering from acute symptomatic uncomnlicated falcinarum malaria in an endemic area whe;e the level of resistance to chloroquine is 3545% (FALADE et al.. 1997). Our results indicated that chloroquine plus chlorpheniramine was as effective as halofantrine and was without overt deleterious effect. Patients
and Methods
Studies in vivo Patients. One hundred
and four children aged 13 months to 13 years presenting with acute symptomatic uncomplicated P. jalciparum malaria were enrolled in the study between May and August 1997. The criteria for inclusion into the study were age l-l 3 years, symptoms compatible with acute falciparum malaria with fever or history of fever in the 24-48 h preceding presentation, pure I? falciparum parasitaemia > 1000 asexual forms/uL of blood, negative history of antimalarial drug administration in the 2 weeks preceding presentation, negative urine test for 4-aminoquinolines Address for correspondence: Professor A. Sowunmi, Clinical Pharmacology Unit, University College Hospital, Ibadan, Nigeria; e-mail [email protected]
chloroquine
resistance, chloroquine
plus chlorphen-
(Dill-Glazko) and sulphonamides (lignin), absence of concomitant illness, and consent of parents or guardians. A child was withdrawn from the study if a concomitant illness developed during the follow-up period or if desired by the parent or guardian. Children with sickle cell anaemia and severe or complicated malaria were excluded from the study. The study received ethical approval from the joint University of IbadaniUniversity College Hospital ethics committee. Before enrolment in the study, a history was obtained from an accompanying parent or guardian and a physical examination was performed. Body weight, height and oral or rectal temperature were recorded and thick and thin blood films were prepared from a finger-prick and Giemsa-stained for parasite identification and assessing peripheral parasitaemia. The children were randomly allotted to one of 2 treatment groups. One group, the combination group, received chloroquine base 30 mgikg of body weight over 3 d (i.e., 10 mgikg daily) plus chlorpheniramine maleate 6 mg at presentation, followed by 4 mg every 8 h for 7 d (days O-6) if the child was aged 5 years or less, or 8 mg at presentation followed by 6 mg every 8 h if the child was over 5 years of age (SOWCJNMI et al., 1998). The other group, the halofantrine group, received 8 mgi kg of halofantrine every 6 h for 3 doses (total dose 24 mgikg). All drugs were administered orally. Chloroquine, the first daily dose of chlorpheniramine, and the first 2 doses of halofantrine were administered by a physician and each child was observed for at least 3 h after supervised drug administration in order to ensure that the drug was not vomited; if it was, the child was excluded from the study. Subsequent doses of chlorpheniramine and the third dose of halofantrine were administered by the parent or guardian. Each parent or guardian gave an account of drug administration at home each time the child was seen for follow-up to ensure that the drug had been properly administered. Clinical observations were recorded daily for 8 d (days O-7) and on day 14. Thick and thin blood films for parasitaemia determination were prepared at these times. At each visit, the parents or guardians (and, when possible, the children) were questioned and the children examined for the presence of adverse reactions to the drugs. Additional management of some children in-
A. SOWUNMI ETAL.
442
mL), as previously described (ODUOLA et al., 1993; OAUTOWOJU et al., 1992; SOWUNMI et al., 1997a). Isolates were considered resistant if schizogony occurred in wells containing 33.08 ng/mL or more of chloroquine (WHO standard) or if the minimum inhibitory concentration (MIC) was reduced when chloroquine was combined with verapamil.
eluded the administration of an antipyretic, for example paracetamol lo-15 mg/kg of body weight every 8 h for 36 h, and fanning and tepid sponging when necessary. Giemsa-stained blood films were examined by light microscopy under an oil immersion objective at x1000 magnification. Parasitaemia in thick films was estimated by counting parasites relative to leucocytes; 500 asexual forms of l? falcipamn or the number of such parasites corresponding to 1000 leucocytes were counted, whichever occurred first. from this figure, the parasite density was calculated using the patient’s known leucocyte count. Classification of response to drug treatment was according to World Health Organization criteria (WHO, 1973). Treatment was considered a failure if parasitaemia on day 3 was more than 25% of the day 0 value, if parasitaemia did not clear by day 7, or if parasitaemia cleared before day 7 but reappeared before day 14. The parasite clearance time was defined as the time elapsing between drug administration and disappearance of patent parasitaemia. The fever clearance time was defined as the time from drug administration until the oral or rectal temperature fell to 37.4”C or below and remained so for at least 72 h. This definition was necessary because of the routine use of paracetamol during the first 36 h of treatment in some children. The cure rite was defined as the proportion of patients who remained free of parasitaemia on day 14 of follow-up. All treatment failures were re-treated with the same drug or drug combination that they had been given at enrolment. Re-treatment was done on day 14 provided the patient was not symptomatic before that time. However, if the patients be&me symptomatic between days 7 and 14, thev were similarlv treated. Patients with nrofound clhicai and parasitological deterioration during follow-up were treated with artemether (total dose 9.6 mg/kg of body weight over 5 d) and were regarded as treatment failures (RIII) . Clinical investigations. Before initiation of treatment and on days 1 and 7 venous blood (5 mL) was obtained from all patients for a complete blood count, liver function tests, and determination of electrolytes, creatinine and blood sugar. In addition, in 42 randomly selected children, a 12-lead electrocardiogram was d&e before initiation of treatment and at 6. 24. 48. 72. 96. 120. 144, 168 and 336 h after initiafion ‘of treatmenf. The cardiac effects of these drugs will be reported elsewhere.
Statistical analysis Data were analysed using Epi-Info Version 6 (CDC & WHO, 1994). Proportions were compared by calculating x2 with Yates’s correction or by Fisher’s exact test. Normally distributed continuous data were compared by Student’s t test. Data not normally distributed were compared by the Mann-Whitney U test and the Kruskal-Wallis test. Values are given in the text and Tables as mean&SD and values of P less than 0.05 were taken as significant. Results Clinical features at presentation and therapeutic responses Of the one hundred and four children enrolled in the study, 5 1 were placed in the combination group and 53 in the halofantrine group. Four children, one in the chloroquine plus chlorpheniramine group and 3 in the halofantrine group, defaulted within 2 d of the commencement of the study and were excluded from the analysis. The clinical features at presentation of the children who completed the study are summarized in Table 1. These features were similar in the 2 groups. The therapeutic responses of the infections to drug treatment are shown in Table 2. These responses were also similar in the 2 groups. However, the proportion of children who cleared their parasitaemias on day 2 alone was significandy higher In the halofantrine group than in the cornbination arouv (34148 vs. 18147. P=O.O02). There was no relati&shfp ‘between parasite density & enrolment and parasite clearance time (chloroquineichlorpheniramine, r=0.203, 130.2; halofantrine, ~0.247, P=O. 10). Four children, 2 from each group, had an RI response to treatment. Re-treatment of these children with their initial treatment drugs resulted in complete clearance of their parasitaemias, with no recurrence during an additional 14 d of follow-up. Responsessf patients from household clusters sf i&ction Palciparum malaria patients often form ciusters in households (SNOW et al., 1993). We analvsed the response to treatment of siblings’from the same households presenting on the same say for treatment who had been allotted to different regimens. There were 19 children from 9 households, Fin the combination group and 10 in the halofantrine group. The fever clearance times were similar in the 2 treatment groups (1.2f0.7 d, ranee l-3, and 1.4kO.7 d, range l-3 in the chloroauine plus chlorpheniramine a& ha&fantrine groups, reipectively). Similarly, the parasite clearance times were 2.520.8 d (range 1-3) and 2.3f0.5 d (range 2-3), re-
Studies in vitro Venous blood (3 mL) was obtained from 50 randomly selected children at presentation and divided into 2 aliquots. One aliquot was used to evaluate parasite sensitivity to chloroquine alone and the other that to chloroquine in combination with verapamil, using a modification of the World Health Organization (WHO) schizont inhibition assay (RIECKMAN et al., 1978). The modification involved the addition of verapamil (l.oXl@M) as a resistance-reversing agent in wells containing serial dilutions of chloroquine (0.66-500 ngi Table 1. Enrohnent
clinical
characteristics
of patients
with acute Hasmodium
Chloroquine/chlorpheniramine Age (years) Weight (kgfa Duration of illness (d)a Body tempreature (OC), Parasitaemia (per &)b No. >25OOOO/~L Heart rate/mina Enlarged organ(s) Splenomegaly only Hepatomegaly only Hepatosplenomegaly aMe~nt~~
bGeometric
(range in parentheses). mean (range in parentheses).
malaria
falciparum
Halofantrine
6.3+3.6(1.1-13) 17.7+_6.3(7-7-34) 2.9+1.3(1-7) 38.5kO.8 (36.4-40.5) 3;0479(1677-531428) 2 116.9+21.3(84-144)
6.0?3.6(1.1-13) 16.9+_6.8(6-5-32:5) 3.0&1.4(1-7) 38.4kO.8 (36.5-40.5) 28048(2210-610430)
38 26
1: 23
119.6+25.:
(88-160)
CHLOROQUINE
PLUS CHLORPHENIRAMINE
FOR MALARIA
443
Table 2. Therapeutic responses of patients with acute uncomplicated chloroquine plus chlorpheniramine or halofantrine
Plasmodium
Chloroquine/chlorpheniramine Number Fever clearance time (d)a Parasite density (per uL) Day 1 Day 2 No. with increased parasitaemia on day 1 Parasite clearance time (d)a Response (no. of patients) Cured
1.3+0-5(lY)
1.450.6(1?)
[1.2-1.51
[1.2-I.61
5911 96
2.7kO.7 (Z&2.5-2.9]
2.3kO.5 (Z;j3[2.0-2.41
48 2 0 0 96
Cure rate at day 14 (%)
to
Halofantrine
7028 377
ZI RI11
malaria
falciparum
48 2 0 0 96
aMean?cSD (range in parentheses) [95% confidence interval in brackets].
Table 3. Adverse effects following treatment of falciparum malaria with chloroquine plus chlorpheniramine or halofantrine Chloroquine/ chlorpheniramine No. of patients No. with Pruritus Abdominal pain Diarrhoea Drowsiness Intravascular haemolysis
Halofantrine
50
50
8(16%) 0
1(2%) 4(8%)
3 (6%) &%)a 0
1 (2%)
aOnly after the first dose of chloroquine+chlorpheniramine.
Table 4. Parasite acute malaria Patient
no.
sensitivity
status
Treatment
in vitro
of isolates
giver?
dose of chlorpheniramine in 10 patients treated with the combination. Abdominal pain with or without diarrhoea was the commonest
adverse
drug reaction
in chil-
dren treated with halofantrine. One 12 years old boy had intravascular haemolysis on day 2 after initiation of halofantrine therapy. There was a mild increase in plasma creatinine level (15 lrmol) in this child, which returned to normal by day 7. The child was not glucose 6phosphate
dehydrogenase
Laboratory
investigations
deficient.
Before treatment, 12 and 18 children in the combination and halofantrine groups, respectively, were anaemic (haematocrit <30%). The group mean preof Plasmodium
from
falciparum
Chloroquine
children
with
MIC (ng/mL) b Chloroquine+verapamil
8197 1 l/97 20197 25197 27197 28197 35197 56197 59197 61197 62197
CQiCP HF CQiCl’ HF HF CQICP HF HF CQiCP ifi:
166.7 18.5 500 18.5 55.6 166.7 6.2 6.2 55.6 18.5 55.6
55.6c 18.5 166.7c 166.7 6.Zc 55.6c 18.5 6.2 55.6d 6.2 2.1c
68197 70197 85197 88197 141197
CQICP CQ/CP CQKP HF CQiCP
6.2 166.7 18.5 6.2 18.5
z:;C 18.5 5z
TQ/CP=chloroquine plus chlorpheniramine, HF=halofantrine; all patients were cured. bMIC=minimum inhibitory concentration (dataw derived from 3 observations). CResistance to chloroquine based on reversal phenomenon using verapamil. dResistant byWorld Health Organization criteria.
spectively. All children treated with the combination were cured, as were 9 of the 10 treated with halofantrine.
treatment haematocrits were 31.8+4.6% (range 23-40) and 28.5-16.2% (range 18-36) in the combination and halofantrine groups, respectively. On day 7, the group mean haematocrits were 28.1 rt3.7% (range 22-34) and
Adverse reactions to drug treatment
245.2f5.9%
Except in one child treated with halofantrine, all adverse reactions to both drugs were mild and did not necessitate discontinuation of therapy (Table 3). Itching, which subsided within 48 h of onset, was the most commonly reported adverse drug reaction in the combination group and disturbed the sleep of one child. Drowsiness lasting about l-2 h occurred after the first
halofantrine cant difference
(range
14-32)
in the
groups, respectively. between
combination
and
There was no signifi-
these values.
Before
treatment,
the total leucocyte counts were 6225f2328/mm3 (range 3500-l 1200) and 5595f2037imm’ (range ZZOO10 400) in the combination and halofantrine groups, respectively. On day 7, these values were 5477*1742/ mm3 (range 3200-8100) and 5867+2460/mm3 (range
444
2000-9300) in the combination and halofantrine groups, respectively. There was no significant difference between these values. Group mean neutrophil counts were 4200+1874/mm3 (range 2196-7560) and 3722f2289/mm3 (range 1764-l 1444) in the combination and halofantrine groups, res ectively. On day 7, these values were 3987f1147imm !?(range 1386- 5 184) and 3465+ 1605/mm3 (range 1180-5580) in the combination and halofantrine groups, respectively. There was no significant difference between the neutrophil counts. Pre-treatment creatinine concentrations were within normal limits in all patients. There was a mild increase in creatinine concentration in the patient with intravascular haemolysis in the halofantrine group following treatment (see above). Two children in the halofantrine group had mildly raised aspartate aminotransferase concentration (45 and 50 i.u.) before treatment which did not worsen following treatment.
Testsin vitro Seventeen isolates obtained from the patients were successfully evaluated for susceptibility in vitro. Treatment outcome could not be determined in one patient because the evaluation criteria were not met. The sensitivity data in vitro and the details of treatment outcome for the remaining 16 patients treated with the combination of chloroquine plus chlorpheniramine or halofantrine are shown in Table 4. Seven of the 16 isolates were resistant to chloroquine; 5 of these 7 isolates had been obtained from patients treated (successfully) with chloroquine plus chlorpheniramine. Discussion
In the present study, as we11as in previous studies, the combination of chloroquine plus chlorpheniramine was consistently effective in the treatment of falciparum malaria in an area where chloroquine, pyrimethamine/sulfadoxine and halofantrine resistance levels are close to 45%, 25% and 4-7%, respectively (FALADE et al., 1997‘1. The efficacv of the combination was similar to that of halofantrine: The latter finding is of interest in a number of ways. First, the combination is 50 times less expensive than halofantrine for the treatment of acute malaria and is certainly affordable by all patients. Second, apart from mefloquine which is superior to the combination (SOW~VMI & ODUOLA, 1997), a consequence of the inverse relationship between the sensitivity to mefloquine and chloroquine of West African isolates of p. fakipamnz (see SOWUNMI et al., 19%; WERNSDORFER et aZ., 1994), the combination has been shown in recent studies to be superior to many of the currently available antimalarial drugs in the area (SOWUNMI et al., 1997a, 1998). Third, it has become easier to determine the exact place of the combination in the treatment of malaria in the area as the third-line drug in the treatment of acute uncomplicated malaria in children (SOWUNMI et al., 1998). The use of chloroquine plus chlorpheniramine for the treatment of mild to moderate chloroquine-resistant and pyrimethamineisulfadoxine-resistant malaria is likely to increase in south-western Nigeria and elsewhere. When separately administered to the same individual, both chloroquine and chlorpheniramine are well tolerated. However, potential pharmacokinetic and pharmacodynamic interactions between these drugs when co-administered for the management of chloroquine-resistant malaria have been less frequently studNigerian volunteers, ied. In healthy adult chlorpheniramine reduced the plasma clearance of orally administered chloroquine and increased the area described by the plasma concentration-time curve (AUC) (SOWUNMI et al., 1997b). In the present study, apart from mild sedation and pruritus due to chlorpheniramine and chloroquine in 20% and 12% of the children, respectively, the combination was well tolerated. The limited duration of drowsiness in the patients treat-
A. SOWUNMI ETAL.
ed with the combination may be beneficial to anxious or excited patients, but it may also mask or mimic clinical deterioration. Chloroquine may cause cardiovascular collapse and sudden death, but this is more likely after parenteral administration (OLATUNDE, 1970; AEKJAISHA et al., 1979) and is very rarely encountered after oral chloroquine (SOWUNMI et al., 1997a). Antihistamines may also cause deleterious cardiovascular effects, but this is more likelv with non-sedating antihistamines such as terfenadrine and astemizole which may cause prolongation of the QTc (corrected QT) interval on the electrocardiogram, cardiac arrhythmia and sudden death (LINDOUIST & EDWARDS. 1997). and less likelv with sedating antihistamines such as xchlorpheniramine (A. Sowunmi, unpublished observations). Although chlorpheniramine and promethazine have been reported to cause neutropenia (BOWMAN & BAND, 1988), this adverse effect was not encountered in any of the children treated with the combination. Compared to halofantrine, the adverse effects reported in the combination group were less serious. In contrast to previous reports (SOWUNMI et al., 1989), halofantrine-induced pruritus was less common than in adults. It is, however, possible that under-reporting of adverse effects may occur with children since they may be unable accurately to describe adverse symptomatology. A serious adverse effect seen with halofantrine, but not with the combination, was intravascular haemolysis, which has been relatively more frequently reported in adults than in children (VACHON et al., 1992; MOJON et al., 1994). This adverse effect occurred in a child who was not glucose 6-phosphate dehydrogenase deficient and was associated with mild renal impairment of limited duration. The data obtained in vitro confirmed our previous findings (SOWUNMI et al., 1997a) and indicated that the use of the combination of chloroquine plus chlorpheniramine is beneficial in the treatment of malaria. However, compared with our earlier report in which a lower dose of chlorpheniramine was used (SOWUNMI et al., 1997a), the cure rate was significantly higher when a higher dose of chlorpheniramine was used-in the combination (SOWUNMI et al.. 1998). This indicates that. as with reversal in vitro of chloroquine-resistance by chlorpheniramine (BASCO & LE BRAS, 1994), the enhancement of the antimalarial efficacy of chloroquine by chlorpheniramine in chloroquine-resistant infections in vivo may be dose-related. In conclusion, the combination of chloroquine plus chlorpheniramine was as effective as halofantrine and was without overt deleterious effects in a group of children with acute symptomatic uncomplicated falciparum malaria in an endemic area where resistance to chloroquine is increasing. Acknowledgements The study received support from the UNDIVWorld Bank/ WHO Special Programme for Research and Training in Tropical Diseases. A.S. was in receipt of a WHOiTDR Career Development Grant. References Abu-Aisha, H., Abu-Sabaa, H. M. A. & Nur,T. (1979). Cardiac arrest after intravenous chloroquine injection. Journal of Tropical Medicine and Hygiene, f&36-37. Basco, L. K. & Le Bras, J. (1994). In piitro reversal of chloroquine resistance with chlorpheniramine in isolates of PZasmodium fakiparum. ‘fapanese .yournal of Medical Science and Biologj, 47, 59-63. Bowman, W. C. & Rand, M. J. (1988). Textbook of Pharmacology, 2nd edition. Oxford: Blackwell Scientific Publications. CDC &WHO (1994). Epi-Info I’,rstin 6. A word processing data base and statistics program for public health on IBM-compatible microcomputer. Atlanta, Georgia: Centers for Disease Control and Prevention & Geneva: World Health Omanization. Falade, C. O., Salako, L. A., Sowunmi, A., 0duola;A. M. J. & Larcier, P. (1997). Comparative efficacy of halofantrine, chloroquine and sulfadoxine-pyrimethamine for treatment
CHLOROQUINE
PLUS CHLOWHENI
RAMINE
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FOR MALARIA
of acute uncomplicated falciparum malaria in Nigerian children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91, 58-62. Falade, C. O., Salako, L. A., Sowunmi, A., Oduola, A. M. J. & Larcier, l? (1997). 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, 91, 58-62. Lindquist, M. & Edwards, I. R. (1997). Risks of non-sedating antihistamines. Lancet, 349, 1322. Mojon, M., Wallon, M., Gravey, A., Peaud, l? Y., Sartre, J. & Peyron, F. (1994). Intravascular haemolysis following halofantrine intake. Transactions of the Royal Society of Tropical Medicine and Hygiene, 88, 9 1. Oduola, A. M. J., Omitowoju, G. O., Gerena, L., Kyle, D. E., Milhous, W. K., Sowunmi, A. & Salako, L. A. (1993). Reversal of mefloquine resistance with penfluoridol in isolates of Plasmodium falciparum, from southwest Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87, 81-83. Olatunde, I. A. (1970). Parenteral chloroquine in children. WestAfrican Medical Journal, 19, 93-99. Omitoqoju, G. O., Ogundahunsi, 0. A. T., Milhous, W. K., Gerena, L., Sowunmi, A., Schuster, B. G. & Oduola, A. M. J. (1992). Chlorpheniramine: a resistance reversing agent with potential clinical application. American Journal of Tropical Medicine and Hygiene, 47, 175 [abstract]. Rieckman, K. H., Campbell, G. H., Sax, L. J. & Mrema, J. 9 1978). Drug sensitivity of Plasmodium falciparum: an in vitro microtechnique. Lance& i, 22-23. Snow, R. W., Armstrong Schellenberg, J. R. M., Peshu, N., Forster, D., Newton, C. R. J. C., Winstanley, P. A., Mwangi, I., Waruiru, C., Warn, l? A., Newbold, C. & Marsh, K. (1993). Periodicity and space-time clustering of severe childhood malaria on the coast of Kenya. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87,386-390. Sowunmi, A. & Oduola, A. M. J. (1997). Comparative efficacy of chloroquineichlorpheniramine combination and mefloquine for the treatment of chloroquine-resistant Plasmodium falciparum malaria in Nigerian children. Transactions of the
Royal Society of Tropical Medicine and Hygiene, 91, 689-693. Sowunmi, A., Walker, 0. & Salako, L. A. (1989). Pruritus and antimalarial drugs in Africans. Lancet, ii, 2 13. Sowunmi, A., Oduola, A. M. J., Salako, L. A., Ogundahunsi, 0. A. T., Laoye, 0. J. &Walker, 0. (1992). The relationship between the response of Pl~modium falciparum malaria to mefloquine in African children and its sensitivity in vitro. Transactions of the Royal Society of Tropical Medicine and Hygiene, 86, 368-371. Sowunmi, A., Oduola, A. M. J., Ogundahunsi, 0. A. T., Falade, C. O., Gbotosho, G. 0. & Salako, L. A. (1997a). Enhanced efficacy of chloroquine-chlorpheniramine combination in acute uncomplicated falciparum malaria in children. Transactions of the Royal Sociey of Tropical Medicine and Hygiene, 91, 63-67. Sowunmi, A., Oduola, A. M., Ogundahunsi, A., Fehintola, F. A. & Salako, L. A. (1997b). Pharmacokinetic interactions of chlorpheniramine and chloroquine in volunteers from Nigeria. American Journal of Tropical Medicine and Hygiene, 57, supplement, 102-l 03 [abstract]. Sowunmi, A., Oduola, A. M. J., Ogundahunsi, 0. A. T. & Sala1~0,L. A. (1998). Comparative efficacy of chloroquine plus chlorpheniramine and pyrimethamineisulfadoxine in acute uncomplicated falciparum malaria in Nigerian children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 92, 7778 1. Vachon, F., Fajac, J., Gacot, B., Coulaud, J. l? & Charrmol, G. (1992). Halofantrine and acute vascular haemolysis. Lancet, 340,909-910. Wernsdorfer, W. H., Landgraf, B., Wiedermann, G. & Kollaritsch, H. (1994). Inverse correlation of sensitivity in vitro of Plasmodium falciparum malaria to chloroquine and mefloquine in Ghana. Transactions of the Royal Society of Tropical Medicine and Hygiene, SS,443-444. WHO (1973). Chemotherapy of Malaria and Resistance to Antimalarials. Geneva: World Health Organization, Technical Report Series, no. 529. Received 5 January 1998; revised 16 March 2 April 1998
1998; accepted
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OFTHE ROYAL SOCIETY OFTROPICAL
MEDICINE AND HYGIENE (1998) 92,441-445
441
Comparative efficacy of chloroquine plus chlorpheniramine and halofantrine acute uncomplicated falciparum malaria in Nigerian children A. Sowunmi, Therapeutics
F. A. Fehintola, and Postgraduate
0. A. T. Ogundahunsi
Institute for Medical
and A. M. J. Oduola
Research and Training,
Universiy
Department of Pharmacology ojIbadan, Ibadan, Nigeria
in
and
Abstract In the face of growing chloroquine resistance of Plasmodium.falciparum, efforts to prolong the clinical usefulness of the drug-have partly concentrated on its combination with potential resistance-reversing comnounds. However. , clinical studies on such combinations have been limited. We have comnared the -----r - ..~~~.~~~~ efficacy of halofantrine, an arylaminoalcohol effective in chloroquine resistant malaria, and a combination of chloroquine plus chlorpheniramine, a histamine Hl receptor antagonist which reverses chloroquine resistance of I? falciparum in vitro and in viva, in 100 children with acute symptomatic uncomplicated falciparum malaria in an area of Nigeria where the rate of chloroquine resistance is 3545%. Both chloroquine plus chlorpheniramine and halofantrine produced similar parasite and fever clearance times and cure rates (96%). Both treatment regimens were relatively well tolerated. Pruritus was commoner in patients treated with chloroquine plus chlorpheniramine than in those treated with halofantrine. Intravascular haemolysis occurred in one patient, and abdominal pain with or without diarrhoea occurred in 4 patients, treated with halofantrine. In vitro, the chloroquine resistance of I? jalciparum isolates obtained from the patients was reversed by verapamil. All patients with isolates which were chloroquineresistant in vitro were cured by either therapy. These results indicate that chloroquine plus chlorpheniramine is as effective as halofantrine and is without overt deleterious effect in treating acute uncomplicated chloroquine-resistant falciparum malaria in children, and may be a clinically useful alternative for this purpose in Nigeria. Keywords: malaria, iramine, halofantrine,
PZasmodium fulciparum, children, Nigeria
chemotherapy,
Introduction The spread of chloroquine-resistant falciparum malaria has created the need for alternative antimalarial drugs. In addition, it has led to renewed efforts to prolone the clinical usefulness of chloroquine. One such effor; involves the combination of *chloroquine with chlorpheniramine, a histamine Ht receptor antagonist which reverses chloroauine insensitivitv in Plasmodium jalciparum in vitro (OA~TOWO~U et al., -1992; BASCO & LE BRAS, 1994; SOVCTUNMI et al., 1997a) and in vivo (SOWUNMI et al., 1997a; SOWUNMI & ODUOLA, 1997).
In previous studies in an endemic area, we have shown that the combination of chloroquine with chlorpheniramine enhances the efficacy of chloroquine in chloroquine-resistant malaria, is superior to pyrimethamineisulfadoxine and is effective in pyrimethaminel sulfadoxine-resistant malaria in children (SOW~UMI et al., 1997a, 1998). In the present study, we have evaluated the efficacv of halofantrine, an arvlaminoalcohol effective in chloroquine resistant malaria, and the combination of chloroquine plus chlorpheniramine in a group of children suffering from acute symptomatic uncomnlicated falcinarum malaria in an endemic area whe;e the level of resistance to chloroquine is 3545% (FALADE et al.. 1997). Our results indicated that chloroquine plus chlorpheniramine was as effective as halofantrine and was without overt deleterious effect. Patients
and Methods
Studies in vivo Patients. One hundred
and four children aged 13 months to 13 years presenting with acute symptomatic uncomplicated P. jalciparum malaria were enrolled in the study between May and August 1997. The criteria for inclusion into the study were age l-l 3 years, symptoms compatible with acute falciparum malaria with fever or history of fever in the 24-48 h preceding presentation, pure I? falciparum parasitaemia > 1000 asexual forms/uL of blood, negative history of antimalarial drug administration in the 2 weeks preceding presentation, negative urine test for 4-aminoquinolines Address for correspondence: Professor A. Sowunmi, Clinical Pharmacology Unit, University College Hospital, Ibadan, Nigeria; e-mail [email protected]
chloroquine
resistance, chloroquine
plus chlorphen-
(Dill-Glazko) and sulphonamides (lignin), absence of concomitant illness, and consent of parents or guardians. A child was withdrawn from the study if a concomitant illness developed during the follow-up period or if desired by the parent or guardian. Children with sickle cell anaemia and severe or complicated malaria were excluded from the study. The study received ethical approval from the joint University of IbadaniUniversity College Hospital ethics committee. Before enrolment in the study, a history was obtained from an accompanying parent or guardian and a physical examination was performed. Body weight, height and oral or rectal temperature were recorded and thick and thin blood films were prepared from a finger-prick and Giemsa-stained for parasite identification and assessing peripheral parasitaemia. The children were randomly allotted to one of 2 treatment groups. One group, the combination group, received chloroquine base 30 mgikg of body weight over 3 d (i.e., 10 mgikg daily) plus chlorpheniramine maleate 6 mg at presentation, followed by 4 mg every 8 h for 7 d (days O-6) if the child was aged 5 years or less, or 8 mg at presentation followed by 6 mg every 8 h if the child was over 5 years of age (SOWCJNMI et al., 1998). The other group, the halofantrine group, received 8 mgi kg of halofantrine every 6 h for 3 doses (total dose 24 mgikg). All drugs were administered orally. Chloroquine, the first daily dose of chlorpheniramine, and the first 2 doses of halofantrine were administered by a physician and each child was observed for at least 3 h after supervised drug administration in order to ensure that the drug was not vomited; if it was, the child was excluded from the study. Subsequent doses of chlorpheniramine and the third dose of halofantrine were administered by the parent or guardian. Each parent or guardian gave an account of drug administration at home each time the child was seen for follow-up to ensure that the drug had been properly administered. Clinical observations were recorded daily for 8 d (days O-7) and on day 14. Thick and thin blood films for parasitaemia determination were prepared at these times. At each visit, the parents or guardians (and, when possible, the children) were questioned and the children examined for the presence of adverse reactions to the drugs. Additional management of some children in-
A. SOWUNMI ETAL.
442
mL), as previously described (ODUOLA et al., 1993; OAUTOWOJU et al., 1992; SOWUNMI et al., 1997a). Isolates were considered resistant if schizogony occurred in wells containing 33.08 ng/mL or more of chloroquine (WHO standard) or if the minimum inhibitory concentration (MIC) was reduced when chloroquine was combined with verapamil.
eluded the administration of an antipyretic, for example paracetamol lo-15 mg/kg of body weight every 8 h for 36 h, and fanning and tepid sponging when necessary. Giemsa-stained blood films were examined by light microscopy under an oil immersion objective at x1000 magnification. Parasitaemia in thick films was estimated by counting parasites relative to leucocytes; 500 asexual forms of l? falcipamn or the number of such parasites corresponding to 1000 leucocytes were counted, whichever occurred first. from this figure, the parasite density was calculated using the patient’s known leucocyte count. Classification of response to drug treatment was according to World Health Organization criteria (WHO, 1973). Treatment was considered a failure if parasitaemia on day 3 was more than 25% of the day 0 value, if parasitaemia did not clear by day 7, or if parasitaemia cleared before day 7 but reappeared before day 14. The parasite clearance time was defined as the time elapsing between drug administration and disappearance of patent parasitaemia. The fever clearance time was defined as the time from drug administration until the oral or rectal temperature fell to 37.4”C or below and remained so for at least 72 h. This definition was necessary because of the routine use of paracetamol during the first 36 h of treatment in some children. The cure rite was defined as the proportion of patients who remained free of parasitaemia on day 14 of follow-up. All treatment failures were re-treated with the same drug or drug combination that they had been given at enrolment. Re-treatment was done on day 14 provided the patient was not symptomatic before that time. However, if the patients be&me symptomatic between days 7 and 14, thev were similarlv treated. Patients with nrofound clhicai and parasitological deterioration during follow-up were treated with artemether (total dose 9.6 mg/kg of body weight over 5 d) and were regarded as treatment failures (RIII) . Clinical investigations. Before initiation of treatment and on days 1 and 7 venous blood (5 mL) was obtained from all patients for a complete blood count, liver function tests, and determination of electrolytes, creatinine and blood sugar. In addition, in 42 randomly selected children, a 12-lead electrocardiogram was d&e before initiation of treatment and at 6. 24. 48. 72. 96. 120. 144, 168 and 336 h after initiafion ‘of treatmenf. The cardiac effects of these drugs will be reported elsewhere.
Statistical analysis Data were analysed using Epi-Info Version 6 (CDC & WHO, 1994). Proportions were compared by calculating x2 with Yates’s correction or by Fisher’s exact test. Normally distributed continuous data were compared by Student’s t test. Data not normally distributed were compared by the Mann-Whitney U test and the Kruskal-Wallis test. Values are given in the text and Tables as mean&SD and values of P less than 0.05 were taken as significant. Results Clinical features at presentation and therapeutic responses Of the one hundred and four children enrolled in the study, 5 1 were placed in the combination group and 53 in the halofantrine group. Four children, one in the chloroquine plus chlorpheniramine group and 3 in the halofantrine group, defaulted within 2 d of the commencement of the study and were excluded from the analysis. The clinical features at presentation of the children who completed the study are summarized in Table 1. These features were similar in the 2 groups. The therapeutic responses of the infections to drug treatment are shown in Table 2. These responses were also similar in the 2 groups. However, the proportion of children who cleared their parasitaemias on day 2 alone was significandy higher In the halofantrine group than in the cornbination arouv (34148 vs. 18147. P=O.O02). There was no relati&shfp ‘between parasite density & enrolment and parasite clearance time (chloroquineichlorpheniramine, r=0.203, 130.2; halofantrine, ~0.247, P=O. 10). Four children, 2 from each group, had an RI response to treatment. Re-treatment of these children with their initial treatment drugs resulted in complete clearance of their parasitaemias, with no recurrence during an additional 14 d of follow-up. Responsessf patients from household clusters sf i&ction Palciparum malaria patients often form ciusters in households (SNOW et al., 1993). We analvsed the response to treatment of siblings’from the same households presenting on the same say for treatment who had been allotted to different regimens. There were 19 children from 9 households, Fin the combination group and 10 in the halofantrine group. The fever clearance times were similar in the 2 treatment groups (1.2f0.7 d, ranee l-3, and 1.4kO.7 d, range l-3 in the chloroauine plus chlorpheniramine a& ha&fantrine groups, reipectively). Similarly, the parasite clearance times were 2.520.8 d (range 1-3) and 2.3f0.5 d (range 2-3), re-
Studies in vitro Venous blood (3 mL) was obtained from 50 randomly selected children at presentation and divided into 2 aliquots. One aliquot was used to evaluate parasite sensitivity to chloroquine alone and the other that to chloroquine in combination with verapamil, using a modification of the World Health Organization (WHO) schizont inhibition assay (RIECKMAN et al., 1978). The modification involved the addition of verapamil (l.oXl@M) as a resistance-reversing agent in wells containing serial dilutions of chloroquine (0.66-500 ngi Table 1. Enrohnent
clinical
characteristics
of patients
with acute Hasmodium
Chloroquine/chlorpheniramine Age (years) Weight (kgfa Duration of illness (d)a Body tempreature (OC), Parasitaemia (per &)b No. >25OOOO/~L Heart rate/mina Enlarged organ(s) Splenomegaly only Hepatomegaly only Hepatosplenomegaly aMe~nt~~
bGeometric
(range in parentheses). mean (range in parentheses).
malaria
falciparum
Halofantrine
6.3+3.6(1.1-13) 17.7+_6.3(7-7-34) 2.9+1.3(1-7) 38.5kO.8 (36.4-40.5) 3;0479(1677-531428) 2 116.9+21.3(84-144)
6.0?3.6(1.1-13) 16.9+_6.8(6-5-32:5) 3.0&1.4(1-7) 38.4kO.8 (36.5-40.5) 28048(2210-610430)
38 26
1: 23
119.6+25.:
(88-160)
CHLOROQUINE
PLUS CHLORPHENIRAMINE
FOR MALARIA
443
Table 2. Therapeutic responses of patients with acute uncomplicated chloroquine plus chlorpheniramine or halofantrine
Plasmodium
Chloroquine/chlorpheniramine Number Fever clearance time (d)a Parasite density (per uL) Day 1 Day 2 No. with increased parasitaemia on day 1 Parasite clearance time (d)a Response (no. of patients) Cured
1.3+0-5(lY)
1.450.6(1?)
[1.2-1.51
[1.2-I.61
5911 96
2.7kO.7 (Z&2.5-2.9]
2.3kO.5 (Z;j3[2.0-2.41
48 2 0 0 96
Cure rate at day 14 (%)
to
Halofantrine
7028 377
ZI RI11
malaria
falciparum
48 2 0 0 96
aMean?cSD (range in parentheses) [95% confidence interval in brackets].
Table 3. Adverse effects following treatment of falciparum malaria with chloroquine plus chlorpheniramine or halofantrine Chloroquine/ chlorpheniramine No. of patients No. with Pruritus Abdominal pain Diarrhoea Drowsiness Intravascular haemolysis
Halofantrine
50
50
8(16%) 0
1(2%) 4(8%)
3 (6%) &%)a 0
1 (2%)
aOnly after the first dose of chloroquine+chlorpheniramine.
Table 4. Parasite acute malaria Patient
no.
sensitivity
status
Treatment
in vitro
of isolates
giver?
dose of chlorpheniramine in 10 patients treated with the combination. Abdominal pain with or without diarrhoea was the commonest
adverse
drug reaction
in chil-
dren treated with halofantrine. One 12 years old boy had intravascular haemolysis on day 2 after initiation of halofantrine therapy. There was a mild increase in plasma creatinine level (15 lrmol) in this child, which returned to normal by day 7. The child was not glucose 6phosphate
dehydrogenase
Laboratory
investigations
deficient.
Before treatment, 12 and 18 children in the combination and halofantrine groups, respectively, were anaemic (haematocrit <30%). The group mean preof Plasmodium
from
falciparum
Chloroquine
children
with
MIC (ng/mL) b Chloroquine+verapamil
8197 1 l/97 20197 25197 27197 28197 35197 56197 59197 61197 62197
CQiCP HF CQiCl’ HF HF CQICP HF HF CQiCP ifi:
166.7 18.5 500 18.5 55.6 166.7 6.2 6.2 55.6 18.5 55.6
55.6c 18.5 166.7c 166.7 6.Zc 55.6c 18.5 6.2 55.6d 6.2 2.1c
68197 70197 85197 88197 141197
CQICP CQ/CP CQKP HF CQiCP
6.2 166.7 18.5 6.2 18.5
z:;C 18.5 5z
TQ/CP=chloroquine plus chlorpheniramine, HF=halofantrine; all patients were cured. bMIC=minimum inhibitory concentration (dataw derived from 3 observations). CResistance to chloroquine based on reversal phenomenon using verapamil. dResistant byWorld Health Organization criteria.
spectively. All children treated with the combination were cured, as were 9 of the 10 treated with halofantrine.
treatment haematocrits were 31.8+4.6% (range 23-40) and 28.5-16.2% (range 18-36) in the combination and halofantrine groups, respectively. On day 7, the group mean haematocrits were 28.1 rt3.7% (range 22-34) and
Adverse reactions to drug treatment
245.2f5.9%
Except in one child treated with halofantrine, all adverse reactions to both drugs were mild and did not necessitate discontinuation of therapy (Table 3). Itching, which subsided within 48 h of onset, was the most commonly reported adverse drug reaction in the combination group and disturbed the sleep of one child. Drowsiness lasting about l-2 h occurred after the first
halofantrine cant difference
(range
14-32)
in the
groups, respectively. between
combination
and
There was no signifi-
these values.
Before
treatment,
the total leucocyte counts were 6225f2328/mm3 (range 3500-l 1200) and 5595f2037imm’ (range ZZOO10 400) in the combination and halofantrine groups, respectively. On day 7, these values were 5477*1742/ mm3 (range 3200-8100) and 5867+2460/mm3 (range
444
2000-9300) in the combination and halofantrine groups, respectively. There was no significant difference between these values. Group mean neutrophil counts were 4200+1874/mm3 (range 2196-7560) and 3722f2289/mm3 (range 1764-l 1444) in the combination and halofantrine groups, res ectively. On day 7, these values were 3987f1147imm !?(range 1386- 5 184) and 3465+ 1605/mm3 (range 1180-5580) in the combination and halofantrine groups, respectively. There was no significant difference between the neutrophil counts. Pre-treatment creatinine concentrations were within normal limits in all patients. There was a mild increase in creatinine concentration in the patient with intravascular haemolysis in the halofantrine group following treatment (see above). Two children in the halofantrine group had mildly raised aspartate aminotransferase concentration (45 and 50 i.u.) before treatment which did not worsen following treatment.
Testsin vitro Seventeen isolates obtained from the patients were successfully evaluated for susceptibility in vitro. Treatment outcome could not be determined in one patient because the evaluation criteria were not met. The sensitivity data in vitro and the details of treatment outcome for the remaining 16 patients treated with the combination of chloroquine plus chlorpheniramine or halofantrine are shown in Table 4. Seven of the 16 isolates were resistant to chloroquine; 5 of these 7 isolates had been obtained from patients treated (successfully) with chloroquine plus chlorpheniramine. Discussion
In the present study, as we11as in previous studies, the combination of chloroquine plus chlorpheniramine was consistently effective in the treatment of falciparum malaria in an area where chloroquine, pyrimethamine/sulfadoxine and halofantrine resistance levels are close to 45%, 25% and 4-7%, respectively (FALADE et al., 1997‘1. The efficacv of the combination was similar to that of halofantrine: The latter finding is of interest in a number of ways. First, the combination is 50 times less expensive than halofantrine for the treatment of acute malaria and is certainly affordable by all patients. Second, apart from mefloquine which is superior to the combination (SOW~VMI & ODUOLA, 1997), a consequence of the inverse relationship between the sensitivity to mefloquine and chloroquine of West African isolates of p. fakipamnz (see SOWUNMI et al., 19%; WERNSDORFER et aZ., 1994), the combination has been shown in recent studies to be superior to many of the currently available antimalarial drugs in the area (SOWUNMI et al., 1997a, 1998). Third, it has become easier to determine the exact place of the combination in the treatment of malaria in the area as the third-line drug in the treatment of acute uncomplicated malaria in children (SOWUNMI et al., 1998). The use of chloroquine plus chlorpheniramine for the treatment of mild to moderate chloroquine-resistant and pyrimethamineisulfadoxine-resistant malaria is likely to increase in south-western Nigeria and elsewhere. When separately administered to the same individual, both chloroquine and chlorpheniramine are well tolerated. However, potential pharmacokinetic and pharmacodynamic interactions between these drugs when co-administered for the management of chloroquine-resistant malaria have been less frequently studNigerian volunteers, ied. In healthy adult chlorpheniramine reduced the plasma clearance of orally administered chloroquine and increased the area described by the plasma concentration-time curve (AUC) (SOWUNMI et al., 1997b). In the present study, apart from mild sedation and pruritus due to chlorpheniramine and chloroquine in 20% and 12% of the children, respectively, the combination was well tolerated. The limited duration of drowsiness in the patients treat-
A. SOWUNMI ETAL.
ed with the combination may be beneficial to anxious or excited patients, but it may also mask or mimic clinical deterioration. Chloroquine may cause cardiovascular collapse and sudden death, but this is more likely after parenteral administration (OLATUNDE, 1970; AEKJAISHA et al., 1979) and is very rarely encountered after oral chloroquine (SOWUNMI et al., 1997a). Antihistamines may also cause deleterious cardiovascular effects, but this is more likelv with non-sedating antihistamines such as terfenadrine and astemizole which may cause prolongation of the QTc (corrected QT) interval on the electrocardiogram, cardiac arrhythmia and sudden death (LINDOUIST & EDWARDS. 1997). and less likelv with sedating antihistamines such as xchlorpheniramine (A. Sowunmi, unpublished observations). Although chlorpheniramine and promethazine have been reported to cause neutropenia (BOWMAN & BAND, 1988), this adverse effect was not encountered in any of the children treated with the combination. Compared to halofantrine, the adverse effects reported in the combination group were less serious. In contrast to previous reports (SOWUNMI et al., 1989), halofantrine-induced pruritus was less common than in adults. It is, however, possible that under-reporting of adverse effects may occur with children since they may be unable accurately to describe adverse symptomatology. A serious adverse effect seen with halofantrine, but not with the combination, was intravascular haemolysis, which has been relatively more frequently reported in adults than in children (VACHON et al., 1992; MOJON et al., 1994). This adverse effect occurred in a child who was not glucose 6-phosphate dehydrogenase deficient and was associated with mild renal impairment of limited duration. The data obtained in vitro confirmed our previous findings (SOWUNMI et al., 1997a) and indicated that the use of the combination of chloroquine plus chlorpheniramine is beneficial in the treatment of malaria. However, compared with our earlier report in which a lower dose of chlorpheniramine was used (SOWUNMI et al., 1997a), the cure rate was significantly higher when a higher dose of chlorpheniramine was used-in the combination (SOWUNMI et al.. 1998). This indicates that. as with reversal in vitro of chloroquine-resistance by chlorpheniramine (BASCO & LE BRAS, 1994), the enhancement of the antimalarial efficacy of chloroquine by chlorpheniramine in chloroquine-resistant infections in vivo may be dose-related. In conclusion, the combination of chloroquine plus chlorpheniramine was as effective as halofantrine and was without overt deleterious effects in a group of children with acute symptomatic uncomplicated falciparum malaria in an endemic area where resistance to chloroquine is increasing. Acknowledgements The study received support from the UNDIVWorld Bank/ WHO Special Programme for Research and Training in Tropical Diseases. A.S. was in receipt of a WHOiTDR Career Development Grant. References Abu-Aisha, H., Abu-Sabaa, H. M. A. & Nur,T. (1979). Cardiac arrest after intravenous chloroquine injection. Journal of Tropical Medicine and Hygiene, f&36-37. Basco, L. K. & Le Bras, J. (1994). In piitro reversal of chloroquine resistance with chlorpheniramine in isolates of PZasmodium fakiparum. ‘fapanese .yournal of Medical Science and Biologj, 47, 59-63. Bowman, W. C. & Rand, M. J. (1988). Textbook of Pharmacology, 2nd edition. Oxford: Blackwell Scientific Publications. CDC &WHO (1994). Epi-Info I’,rstin 6. A word processing data base and statistics program for public health on IBM-compatible microcomputer. Atlanta, Georgia: Centers for Disease Control and Prevention & Geneva: World Health Omanization. Falade, C. O., Salako, L. A., Sowunmi, A., 0duola;A. M. J. & Larcier, P. (1997). Comparative efficacy of halofantrine, chloroquine and sulfadoxine-pyrimethamine for treatment
CHLOROQUINE
PLUS CHLOWHENI
RAMINE
445
FOR MALARIA
of acute uncomplicated falciparum malaria in Nigerian children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 91, 58-62. Falade, C. O., Salako, L. A., Sowunmi, A., Oduola, A. M. J. & Larcier, l? (1997). 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, 91, 58-62. Lindquist, M. & Edwards, I. R. (1997). Risks of non-sedating antihistamines. Lancet, 349, 1322. Mojon, M., Wallon, M., Gravey, A., Peaud, l? Y., Sartre, J. & Peyron, F. (1994). Intravascular haemolysis following halofantrine intake. Transactions of the Royal Society of Tropical Medicine and Hygiene, 88, 9 1. Oduola, A. M. J., Omitowoju, G. O., Gerena, L., Kyle, D. E., Milhous, W. K., Sowunmi, A. & Salako, L. A. (1993). Reversal of mefloquine resistance with penfluoridol in isolates of Plasmodium falciparum, from southwest Nigeria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87, 81-83. Olatunde, I. A. (1970). Parenteral chloroquine in children. WestAfrican Medical Journal, 19, 93-99. Omitoqoju, G. O., Ogundahunsi, 0. A. T., Milhous, W. K., Gerena, L., Sowunmi, A., Schuster, B. G. & Oduola, A. M. J. (1992). Chlorpheniramine: a resistance reversing agent with potential clinical application. American Journal of Tropical Medicine and Hygiene, 47, 175 [abstract]. Rieckman, K. H., Campbell, G. H., Sax, L. J. & Mrema, J. 9 1978). Drug sensitivity of Plasmodium falciparum: an in vitro microtechnique. Lance& i, 22-23. Snow, R. W., Armstrong Schellenberg, J. R. M., Peshu, N., Forster, D., Newton, C. R. J. C., Winstanley, P. A., Mwangi, I., Waruiru, C., Warn, l? A., Newbold, C. & Marsh, K. (1993). Periodicity and space-time clustering of severe childhood malaria on the coast of Kenya. Transactions of the Royal Society of Tropical Medicine and Hygiene, 87,386-390. Sowunmi, A. & Oduola, A. M. J. (1997). Comparative efficacy of chloroquineichlorpheniramine combination and mefloquine for the treatment of chloroquine-resistant Plasmodium falciparum malaria in Nigerian children. Transactions of the
Royal Society of Tropical Medicine and Hygiene, 91, 689-693. Sowunmi, A., Walker, 0. & Salako, L. A. (1989). Pruritus and antimalarial drugs in Africans. Lancet, ii, 2 13. Sowunmi, A., Oduola, A. M. J., Salako, L. A., Ogundahunsi, 0. A. T., Laoye, 0. J. &Walker, 0. (1992). The relationship between the response of Pl~modium falciparum malaria to mefloquine in African children and its sensitivity in vitro. Transactions of the Royal Society of Tropical Medicine and Hygiene, 86, 368-371. Sowunmi, A., Oduola, A. M. J., Ogundahunsi, 0. A. T., Falade, C. O., Gbotosho, G. 0. & Salako, L. A. (1997a). Enhanced efficacy of chloroquine-chlorpheniramine combination in acute uncomplicated falciparum malaria in children. Transactions of the Royal Sociey of Tropical Medicine and Hygiene, 91, 63-67. Sowunmi, A., Oduola, A. M., Ogundahunsi, A., Fehintola, F. A. & Salako, L. A. (1997b). Pharmacokinetic interactions of chlorpheniramine and chloroquine in volunteers from Nigeria. American Journal of Tropical Medicine and Hygiene, 57, supplement, 102-l 03 [abstract]. Sowunmi, A., Oduola, A. M. J., Ogundahunsi, 0. A. T. & Sala1~0,L. A. (1998). Comparative efficacy of chloroquine plus chlorpheniramine and pyrimethamineisulfadoxine in acute uncomplicated falciparum malaria in Nigerian children. Transactions of the Royal Society of Tropical Medicine and Hygiene, 92, 7778 1. Vachon, F., Fajac, J., Gacot, B., Coulaud, J. l? & Charrmol, G. (1992). Halofantrine and acute vascular haemolysis. Lancet, 340,909-910. Wernsdorfer, W. H., Landgraf, B., Wiedermann, G. & Kollaritsch, H. (1994). Inverse correlation of sensitivity in vitro of Plasmodium falciparum malaria to chloroquine and mefloquine in Ghana. Transactions of the Royal Society of Tropical Medicine and Hygiene, SS,443-444. WHO (1973). Chemotherapy of Malaria and Resistance to Antimalarials. Geneva: World Health Organization, Technical Report Series, no. 529. Received 5 January 1998; revised 16 March 2 April 1998
1998; accepted
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