A. Sowunmi

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.

Plasmodium falciparum gametocytaemia in Nigerian children: before, during and after treatment with antimalarial drugs

Summary We evaluated gametocyte carriage and intensities of gametocytaemia in 710 children presenting with acute, symptomatic, uncomplicated Plasmodium falciparum malaria who were treated with various antimalarial drug regimens: chloroquine (CQ); chloroquine plus chlorpheniramine, a histamine H1 receptor antagonist that reverses CQ resistance in P. falciparum in vitro and in vivo (CQCP); chloroquine plus ketotifen, a histamine H1 receptor antagonist that reverses CQ resistance in P. falciparum in vitro but not in vivo in the present study (CQK); chloroquine plus pyrimethamine–sulphadoxine (CQPS); amodiaquine (AQ); amodiaquine plus pyrimethamine–sulphadoxine (AQPS); and pyrimethamine–sulphadoxine (PS). On presentation, gametocyte carriage was significantly higher in CQ‐resistant (CQ‐R) than in CQ‐sensitive (CQ‐S) infections. Following CQ treatment, gametocyte carriage was significantly higher at all times after treatment and gametocyte density significantly higher on day 7 of follow‐up in children with CQ‐R than CQ‐S infections. CQ treatment of CQ‐R infections resulted in significantly higher density of gametocytaemia on day 7 compared with pre‐treatment (day 0), but similar treatment of CQ‐S infections resulted in significantly lower density of gametocytaemia on day 14 compared with day 0. Among children with CQ‐R infections, those with mild (RI) resistance carried gametocytes significantly more often than those with moderate (RII) resistance on days 5 and 7 of follow‐up (P = 0.04 and 0.01, respectively). Disposition kinetics of gametocytaemia using a non‐compartmental method showed that the half life of gametocytaemia was longer and the clearance slower in children with CQ‐R than in those with CQ‐S infections. PS treatment was associated with significantly higher gametocyte carriage at all times between days 1 and 14, and significantly higher gametocytaemias on days 7 and 14 than in the other treatment regimens. Combination of AQ with PS significantly decreased gametocyte carriage at all times between days 1 and 14 of follow‐up. Continuing use of CQ in CQ‐R infections may encourage transmission of CQ‐R infections; SP monotherapy is associated with significant gametocyte carriage and gametocytaemia and may encourage transmission of SP resistant infections as resistance to the drug increases.

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.

Congenital malaria in a hyperendemic area: a preliminary study

The prevalence of Plasmodium falciparum parasitaemia was evaluated in 59 neonates admitted to the University College Hospital, Ibadan in South-western Nigeria between August and December 1991--a period spanning part of both wet and dry seasons. Peripheral parasitaemia was present in 14 (23.7%) neonates; of these, four were preterm (4/26, 15%) and ten were term babies (10/33, 30.3%). The difference in the prevalence of P. falciparum parasitaemia in the two groups was not statistically significant (chi 2 = 1.78; p = 0.10). Parasite densities in all neonates were uniformly low (< 2000 asexual forms/microliters blood), and only four of the neonates had fever within 48 hrs of birth. Infected neonates weighed 200 g more than non-infected neonates, but the difference was not statistically significant. Maternal weekly pyrimethamine prophylaxis did not appear to be effective in preventing infection as six (21.4%) of the 28 neonates whose mothers had regular prophylaxis had parasitaemia compared with seven (26.9%) of the 26 neonates whose mothers had no prophylaxis (chi 2 = 0.22; p > 0.05). These data indicate that congenital malaria is not as uncommon as was previously thought and that the recent increase in reported cases may be due to an interplay of several factors.

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.

Risk factors for gametocyte carriage in uncomplicated falciparum malaria in children.

The risk factors associated with gametocytaemia at presentation and after treatment with different antimalarial drug regimens were evaluated in 767 children enrolled prospectively in 5 antimalarial drug trials between July 1996 and December 2002 in a hyperendemic area of southwestern Nigeria. The children were assigned to one of 6 treatment groups: chloroquine (CQ) only; pyrimethamine-sulfadoxine (PS) only; amodiaquine (AQ) only; CQ combined with chlorpheniramine (CQCP); or PS combined with CQ (CQPS) or AQ (AQPS). At enrolment, 115 (15%) of 767 children were gametocyte carriers. During follow-up, 15.6% of all patients (i.e. 120 patients) developed patent gametocytaemia, which in 85% (102 patients) had developed by day 7 following treatment. In a multiple regression model, 4 factors were found to be independent risk factors for the presence of gametocytaemia at enrolment: male gender (adjusted odds ratio [AOR] = 0.55, 95% confidence interval [CI] 0.36-0.83, P=0.005), absence of fever (AOR = 1.61, 95% CI 1.05-2.5, P=0.03), duration of illness >3 days (AOR=1.57, 95% CI 1.0-2.4, P=0.047), and asexual parasite densities less than 5000/microl (AOR=0.42, 95% CI 0.24-0.73, P=0.002). The presence of patent gametocytaemia at enrolment (AOR=0.04, 95% CI 0.02-0.07, P<0.001) and recrudescence of asexual parasites within 14 days were associated with the presence of gametocytaemia 7 or 14 days after enrolment (AOR=0.5, 95% CI 0.3-0.8, P=0.007). Delay in the time taken to clear the initial parasitaemia (>2 days) was associated with increased risk of subsequent gametocyte carriage. These findings may have implications for malaria control efforts in sub-Saharan Africa where control of the disease depends almost entirely on chemotherapy.

Open randomized study of artesunate-amodiaquine vs. chloroquine-pyrimethamine-sulfadoxine for the treatment of uncomplicated Plasmodium falciparum malaria in Nigerian children

Background  Artemisinin‐based combination antimalarials are currently considered effective alternatives for the treatment of malaria in Africa, but there are few studies of such combinations in Nigerian children. We assessed the safety, treatment efficacy and effects on gametocyte carriage of the combination of artesunate plus amodiaquine and chloroquine plus pyrimethamine‐sulfadoxine in children.

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.

Hepatomegaly in acute falciparum malaria in children

The characteristics of hepatomegaly in acute falciparum malaria were studied in 114 children presenting consecutively with the disease. Hepatomegaly was more common than splenomegaly and was significantly more frequent in younger than in older children. In children with hepatomegaly at presentation, there was an equal sex distribution, a negative correlation between liver size and age, and a positive correlation between liver enlargement and the reported duration of symptoms at presentation. Symptoms attributable directly to liver involvement were relatively uncommon. There was no correlation between liver and spleen size, presenting core temperature, or peripheral parasite density. Tender hepatomegaly and tender splenomegaly were rare during the acute illness; tenderness resolved within 72 h after commencement of antimalarial therapy. Complete resolution of hepatomegaly occurred in 41% of children after recovery from the acute illness (by days 7 or 14), varying degrees of resolution occurred in 48% and no reduction or an increase in liver size occurred in the remainder. In children with hepatomegaly who failed to clear parasitaemia by days 7 or 14, persistent hepatomegaly was common. These results suggest that hepatomegaly, like splenomegaly, may be assessed as a possible malariometric index of the intensity of transmission in children in an endemic area.