A. M. J. Oduola

Enhanced efficacy of chloroquine-chlorpheniramine combination in acute uncomplicated falciparum malaria in children

Chlorpheniramine, a histamine H1 receptor antagonist, reverse chloroquine resistance in Plasmodium falciparum in vitro. However, the clinical significance of this remains unclear. We have evaluated the efficacy of chloroquine and a chloroquine-chlorpheniramine combination in 112 consecutive children with acute symptomatic uncomplicated falciparum malaria. There was no significant difference in the parasite and fever clearance times in the 2 treatment groups. However, the proportion of patients in whom parasitaemia increased 24 h after commencement of treatment was significantly higher in the chloroquine group than in the chloroquine-chlorpheniramine group (28.5% vs. 8.3%, chi 2 = 6.61, P < 0.01). There was also a higher proportion of children with RII and RIII responses to treatment in the chloroquine than in the chloroquine-chlorpheniramine group but the difference was not statistically significant. The cure rate on day 14 was higher in the chloroquine-chlorpheniramine group than in the chloroquine group. Chloroquine and its combination with chlorpheniramine were well tolerated, the only prominent adverse effect being pruritus, with equal incidence in both groups. Chlorpheniramine reversed chloroquine resistance in vitro in a similar manner to verapamil in isolates of P. falciparum obtained from the patients. Failure of a response in vivo to chloroquine correlated with resistance in vitro in patients treated with this drug. In contrast, all but one patient with isolates which were chloroquine resistant in vitro were successfully treated with chloroquine-chlorpheniramine combination. These data suggest the enhanced efficacy of chloroquine-chlorpheniramine combination in treating acute uncomplicated P. falciparum infection in children from an endemic area of Nigeria.

Comparative efficacy of halofantrine, chloroquine and sulfadoxine-pyrimethamine for treatment of acute uncomplicated falciparum malaria in Nigerian children

One hundred and ten children aged 6 months to 11 years were randomly treated with halofantrine (HF), sulfadoxine-pyrimethamine (S-P) or chloroquine (CQ) for acute uncomplicated Plasmodium falciparum malaria in an endemic area of south-western Nigeria. The response of infection to treatment in each child was monitored for 14 d. The mean fever clearance 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% (15/38) 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 8.3% and 13.3%, respectively. The 3 drugs were well tolerated. The results of the study showed a further decline in the sensitivity of P. falciparum infections to CQ, while HF and S-P remained relatively effective in the treatment of malaria in south-west Nigeria.

Reversal of mefloquine resistance with penfluridol in isolates of Plasmodium falciparum from south-west Nigeria

The susceptibilities of isolates of Plasmodium falciparum from Nigeria and two reference cloned strains (D6 and W2) to mefloquine or chloroquine alone and in combination with either penfluridol, a piperidine analogue, or verapamil were determined using a modification of the semiautomated microdilution technique. Six of the isolates showed reduced susceptibility to mefloquine in vitro. The response of the 6 isolates was similar to that of the mefloquine resistant reference clone D6, with 50% inhibitory concentration (IC50) values = 3.29-9.72 ng/ml. Only 2 of the Nigerian isolates were sensitive to mefloquine (IC50 = 1.16 ng/ml and 2.62 ng/ml) and were similar to the reference mefloquine sensitive clone W2 (IC50 = 1.78 ng/ml). All the isolates tested were sensitive to chloroquine, with IC50 values = 1.5-3.04 ng/ml. Simultaneous incubation of the parasites with a constant sub-inhibitory concentration of penfluridol (5.0 x 10(-7)M) and mefloquine increased the susceptibility of the resistant parasites to mefloquine. Addition of the neuroleptic drug penfluridol did not alter the response of sensitive parasites to mefloquine or chloroquine. Similarly, addition of 1.0 x 10(-6)M verapamil did not affect the activity of mefloquine against the sensitive or resistant parasites.

Innate resistance to new antimalarial drugs in Plasmodium falciparum from Nigeria

The rapid dissemination of chloroquine-resistant Plasmodium falciparum in West Africa has been well documented and represents a significant health threat to autochthonous populations. The methodical development of alternative chemotherapeutic agents demands that dispensing new antimalarial drugs (mefloquine, halofantrine, and artemisinine [qinghaosu]) be closely monitored in order to protect their clinical utility. Indeed, mefloquine-resistant strains of P. falciparum have been reported. We present data from experiments in vitro on the innate resistance of P. falciparum isolates to mefloquine as well as a disturbing observation of transient resistance to artemisinine. The implications for the extended efficacy of these new antimalarial drugs are addressed.

Comparative efficacy of chloroquine plus chlorpheniramine and pyrimethamine/sulfadoxine in acute uncomplicated falciparum malaria in Nigerian children

The efficacy of pyrimethamine/sulfadoxine (PS) and chloroquine plus chlorpheniramine, a histamine H1 receptor blocker which reverses chloroquine insensitivity in Plasmodium falciparum in vitro, was evaluated in 100 consecutive children with acute symptomatic uncomplicated falciparum malaria. Parasitaemia on day 3 following initiation of treatment, fever and symptom clearance times were significantly lower in the chloroquine/chlorpheniramine (CQ/CP) combination group than in the PS group. The cure rate was also significantly higher in the combination group. The combination cured all children who had failed PS treatment. Gametocytaemia and the gametocyte carrier rate following therapy were significantly lower in the combination group than in those receiving PS. Both treatments were well tolerated but adverse drug reactions were commoner in the children given PS. CQ/CP is effective in PS treatment failure in Nigerian children and may be useful for this condition in African children in general.

Randomised trial of artemether versus artemether and mefloquine for the treatment of chloroquine/sufadoxine-pyrimethamine-resistant falciparum malaria during pregnancy.

The efficacy of artemether and artemether followed by mefloquine was evaluated in 45 pregnant women with drug resistant Plasmodium falciparum malaria during the second and third trimesters. There was prompt clinical response to both treatment regimens. The parasite and fever clearance times and the cure rate were similar in both groups. Except for the correlation between initial parasite density and fever clearance time in the artemether-mefloquine group, there was no correlation between initial parasite density and parasite or fever clearance times in the two groups. Similarly, there was no correlation between parasite and fever clearance. Both treatment regimens were well tolerated. All newborn babies of the participating women were normal at birth. Physical and neurodevelopmental assessment of the newborn babies followed up for a period varying between 6 and 36 months were within normal limits. Artemether alone or with mefloquine are effective and do not produce undue deleterious effects in pregnant patients with drug-resistant falciparum malaria during the second and third trimesters.

Enhancement of the antimalarial effect of chloroquine by chloropheniramine in vivo

SummaryThe efficacy of chloroquine and chloroquine plus chloropheniramine, a histamine H1 receptor blocker which reverses chloroquine insensitivity in Plasmodium falciparum in vitro, was studied in 96 children with acute symptomatic uncomplicated falciparum malaria. The chloroquine/chloropheniramine combination produced a significantly higher cure rate than chloroquine alone and cured 77% of children with chloroquine treatment failures. Children with chloroquine treatment failure had mean plasma chloroquine concentrations above the minimum therapeutic concentration for the area. Chloroquine concentrations in plasma and red blood cells and ratio of red cell to plasma chloroquine concentrations on days 3 and 7 after initiation of therapy were not significantly different in the two groups. Chloroquine/chloropheniramine produces a higher cure rate than chloroquine alone and reverses chloroquine insensitivity in Plasmodium falciparum in vivo. It may be a useful way of optimising the antimalarial effect of chloroquine.

Open randomized study of pyrimethamine-sulphadoxine vs. pyrimethamine-sulphadoxine plus probenecid for the treatment of uncomplicated Plasmodium falciparum malaria in children

Background  Increasing drug resistance in Plasmodium falciparum has necessitated renewed search for cheap, effective alternatives to commonly available antimalarials, chloroquine and pyrimethamine–sulphadoxine, for the treatment of malaria in Africa. Probenecid, an inhibitor of organic anion transporters and multiresistance‐associated proteins, can chemosensitize P. falciparum to pyrimethamine and sulphadoxine in vitro, but the clinical significance is unclear. We assessed the safety, treatment efficacy, and effects on gametocyte carriage of adding probenecid to pyrimethamine–sulphadoxine.

Comparative efficacy of chloroquine plus chlorpheniramine and halofantrine in acute uncomplicated falciparum malaria in Nigerian children

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 compounds. However, clinical studies on such combinations have been limited. We have compared the efficacy of halofantrine, an arylaminoalcohol effective in chloroquine resistant malaria, and a combination of chloroquine plus chlorpheniramine, a histamine H1 receptor antagonist which reverses chloroquine resistance of P. falciparum in vitro and in vivo, in 100 children with acute symptomatic uncomplicated falciparum malaria in an area in Nigeria where the rate of chloroquine resistance is 35-45%. 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 P. falciparum isolates obtained from the patients was reversed by verapamil. All patients with isolates which were chloroquine-resistant 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.

Open comparison of mefloquine, mefloquine/sulfadoxine/pyrimethamine and chloroquine in acute uncomplicated falciparum malaria in children

The susceptibility in vivo of Plasmodium falciparum to mefloquine, mefloquine/sulfadoxine/pyrimethamine and chloroquine was investigated in 115 children with acute uncomplicated falciparum malaria. Susceptibility of P. falciparum isolates to mefloquine and chloroquine in vitro was also investigated. Mefloquine alone and mefloquine/sulfadoxine/pyrimethamine showed similar response rates and both reduced parasitaemia and fever more rapidly than chloroquine. Mefloquine also promptly reduced parasitaemia and fever within 48 h in all chloroquine treatment failures. In vitro, 10% of isolates showed reduced susceptibility to mefloquine and 18% were resistant to chloroquine. These results suggest that the addition of sulfadoxine/pyrimethamine does not have a significant therapeutic advantage over mefloquine alone in the treatment of acute uncomplicated falciparum malaria in children from this endemic area.