Randomized comparison of chloroquine and amodiaquine in the treatment of acute, uncomplicated, Plasmodium falciparum malaria in children.

The increasing resistance of Plasmodium falciparum to chloroquine (CQ) has created an urgent need for the evaluation of alternative, effective, safe, cheap, readily available and affordable antimalarial treatments. In the present study, the efficacy of amodiaquine (AQ) in the treatment of acute, symptomatic, uncomplicated, P. falciparum malaria was compared with that of CQ, each drug being given at 10 mg/kg per day for 3 days (days 0, 1 and 2). The 210 subjects (104 given AQ and 106 CQ) were Nigerian children aged 5 months-12 years. Fever-clearance times (FCT), parasite densities on days 1-4 and parasite-clearance times (PCT) were all significantly lower with AQ than with CQ. Mean (S.D.) PCT, for example, were 2.6 (0.8) days with AQ and 3.0 (1.0) days with CQ (P = 0.001). The cure rates obtained on days 14, 21 and 28 - 98.1% v. 79.3% (P =0.000), 97.1% v. 64.2% (P = 0.00001) and 95.2% v. 58.5% (P = 0.0000000) with AQ and CQ, respectively - were all also significantly higher with AQ. All but two of the 20 subjects who were considered CQ-treatment failures by day 14 (i.e. two RIII, two RII and 16 RI) responded to subsequent treatment with AQ, with PCT (but not FCT) significantly shorter than during their initial treatment with CQ. In siblings in whom there was clustering of infections, the cure rates were 100% with AQ (N =12) and 63.6% with CQ (N = 11; P = 0.03). Adverse reactions to CQ and AQ were similar and tolerable: pruritus in 10 and 11 children in the AQ and CQ groups, respectively, and gastro-intestinal disturbances which occurred in three children from each group. Haematological parameters were not adversely affected by either drug. At least in the setting of the present study, AQ appears more effective than CQ, effective against CQ-resistant infections, and well tolerated by children with acute, uncomplicated, P. falciparum malaria. It may therefore be useful as an alternative to CQ in areas of CQ resistance.

Clinical characteristics and disposition kinetics of the hepatomegaly associated with acute, uncomplicated, Plasmodium falciparum malaria in children.

The clinical characteristics and the kinetics of the disposition of the hepatomegaly associated with acute, uncomplicated Plasmodium falciparum malaria were investigated in 162 children in an endemic area of Nigeria. Hepatomegaly was significantly more common in the younger than in the older children. Complete resolution occurred in 48% following antimalarial chemotherapy. In the children in whom hepatomegaly did not resolve, a reduction in liver size of < 17% by the time parasitaemia was cleared (usually on day 3) was associated with non-resolution of hepatomegaly by days 7 or 14 of follow-up. An increase in liver size to at least 125% of the baseline value by day 4 or 5 was associated with a lack of therapeutic response, providing the child involved was aged < 5 years. In the children who had complete clearance of parasitaemia and resolution of hepatomegaly, there was no significant relationship between the parasitaemia-derived conventional indices of therapeutic response [i.e. time to clearance of 50% (PC50) or 90% (PC90) of the parasitaemia, and the parasite-clearance time (PCT)] and the corresponding parameters derived from measurement of liver size [i.e. time for resolution of 50% (HR50) or 90% (HR90) of the hepatomegaly and the hepatomegaly-resolution time (HRT)] in the same patients. However, as the HR50:PC50, HR90:PC90 and HRT:PCT ratios were similar (range = 1.6-2.1), the liver parameters may have therapeutic application. In the children with drug-sensitive P. falciparum infections and in whom hepatomegaly completely resolved, the area produced by plotting liver size against time (i.e. the area under the curve of hepatomegaly v. time, or AUChp) increased in proportion to the liver size below the costal margin (P = 0.02, from analysis of variance), but there was no significant difference in the half-lives of hepatomegaly (t1/2hp) or in the ratios of liver size to AUChp, indicating that the kinetics of the resolution of hepatomegaly were linear in the range examined. Comparison of the kinetic indices of hepatomegaly and parasitaemia showed that, although the half-lives of parasitaemia and hepatomegaly and the corresponding clearance values were similar, there was no correlation between these parameters among those in whom hepatomegaly completely resolved and parasitaemia completely cleared. These results indicate that routine clinical measurement of the liver size in children with hepatomegaly during acute, uncomplicated, P. falciparum malaria may have some use in evaluating and monitoring the therapeutic responses of infections. The resolution of hepatomegaly, a reflection of pathological changes, lags behind clearance of parasitaemia in children with P. falciparum malaria, and supports the use of the liver 'rate' as a malariometric index for assessing the intensity of transmission in endemic areas.

Comparative clinical characteristics and response to oral antimalarial therapy of children with and without Plasmodium falciparum hyperparasitaemia in an endemic area.

The clinical characteristics and the responses to oral antimalarial therapy of 104 children presenting consecutively with or without Plasmodium falciparum hyperparasitaemia (HP) were investigated in an endemic area. At presentation, although the 52 children with HP were significantly younger and had significantly higher heart rates than the 52 without, there were no significant differences between the two groups in their symptoms or in any other clinical feature of their malaria. Responses to oral antimalarial drugs were similar in both groups. Analysis of the disposition kinetics of parasitaemia, using a non-compartmental model similar to that used in characterizing drug disposition, showed that the two groups had similar half-lives of parasitaemia (t1/2pd), volumes of blood completely cleared of parasites per unit time (CLBpd), and parasite-clearance-time:t1/2pd ratios. Three children in the HP group, all aged < 3 years, progressed to cerebral malaria within 8 h of presentation, and another HP child presented with isolated trunkal ataxia, indicative of cerebellar involvement. No child in the non-HP group had any of the features of severe malaria. Although the clinical characteristics and responses to oral therapy of children with and without HP are therefore very similar, young children with HP appear to have an increased risk of developing other features of severe malaria.

Female dominant age-dependent deterministic population dynamics.

In this paper the study of a nonlinear deterministic model of an age/sex differentiated population is started with a proof of existence and uniqueness of solution of the governing equation. We also obtain time dependent upper bounds to the male and female populations as well as necessary and sufficient conditions for equilibrium.