Therapeutic efficacy of chloroquine plus sulphadoxine/ pyrimethamine compared with monotherapy with either chloroquine or sulphadoxine/pyrimethamine in uncomplicated Plasmodium falciparum malaria in Laos

In a southern border province of Lao PDR, we compared the efficacy of antimalarial drug combinations in patients aged >or=1 year with uncomplicated Plasmodium falciparum malaria: monotherapy with either mefloquine (MQ), chloroquine (CQ), or sulphadoxine/pyrimethamine (SP) vs. the combination of both CQ and SP. Follow-up time was 14 days. Of 265 P. falciparum positive patients, 119 were enrolled in the drug trial. Significantly more patients treated with CQ than with SP developed early or late treatment failure [44.8%vs. 17.9%, relative risk (RR) = 2.51, 95% CI 1.03-6.12]. In the SP group, 82.1% were sensitive and 17.9% were treatment failures. The combination treatment CQ plus SP resulted in 83.3% sensitivity and 16.7% treatment failures. Combination treatment has no advantage over monotherapy with SP (RR = 1.01, 95% CI 0.8-1.3). All patients who received MQ for treatment (total dose 25 mg/kg) were cured within the 14 days of follow-up. The findings of this study suggest that use of CQ as first-line treatment of uncomplicated malaria in the Lao PDR has to be reconsidered. The combination of both CQ and SP has been discussed as a cost-effective alternative treatment, but in our patient population achieved no better results than single therapy with SP.     

Antipyretic, parasitologic, and immunologic effects of combining sulfadoxine/pyrimethamine with chloroquine or paracetamol for treating uncomplicated Plasmodium falciparum malaria

Sulfadoxine/pyrimethamine (SP) is increasingly used against malaria in sub-Saharan Africa because of chloroquine resistance. However, chloroquine may have a beneficial antipyretic effect. We therefore compared the combination of SP plus chloroquine, chloroquine alone, SP alone, and SP plus paracetamol in the treatment of uncomplicated Plasmodium falciparum malaria in 175 Tanzanian children (1-4 years old) in a randomized trial. Outcome variables were axillary temperatures every six hours, daily parasitemias, and serum levels of IgG antibodies to P. falciparum. Lower mean temperatures (6-48 hours) were achieved with SP plus chloroquine or paracetamol than with SP alone (P < 0.001) or chloroquine alone (P < 0.05). All three SP-treated groups showed high and similar parasite reduction (0-48 hours), whereas treatment with chloroquine alone was much less effective. Levels of IgG antibodies to P. falciparum increased significantly (P < 0.001) and similarly in the four treatment groups between days 0, 2, and 3. Thus, the addition of chloroquine or paracetamol to SP improved the clinical outcome, but did not affect the parasitologic response or antibody production.     

Efficacy of sulfadoxine/pyrimethamine in the treatment of uncomplicated Plasmodium falciparum malaria in Republic of Congo

Congo is facing frequent failures of treatment of Plasmodium falciparum malaria with chloroquine (CQ), which is still recommended and used as a first-line drug. In Pointe-Noire and Brazzaville, the two largest cities that contain approximately 60% of the population of Congo, we compared the efficacy of CQ versus sulfadoxine/pyrimethamine (SP) for treatment of uncomplicated malaria in children 6-59 months old (mean = 33 months) using the standard World Health Organization (WHO) 14-day in vivo test in two phases between 1999 and 2002. Patients enrolled were randomly assigned to receive SP (25 mg/kg of sulfadoxine and 1.25 mg/kg of pyrimethamine) or CQ (25 mg/kg). In the first phase of the study, 46 patients were assigned to the CQ (n = 23) or SP (n = 23) groups in Pointe-Noire and 52 children were assigned to the CQ (n = 26) or to SP (n = 26) groups in Brazzaville. Results were interpreted according to the WHO lot quality assurance sampling method, and treatment failure rates for SP versus CQ were < 25% versus > 25% in both cities. In the second phase of the study, we accurately determined the actual proportion of treatment failures for SP in Brazzaville. Thus, in 75 of the 80 children enrolled and followed-up until day 14, no clinical or parasitologic failure was recorded and no serious adverse reaction was observed. Since the CQ treatment failure rate exceeds the unacceptable upper limit, SP seems well to be an appropriate alternative for the first-line treatment of uncomplicated P. falciparum malaria, at least in the settings of the present study.     

Parasitaemia and gametocytaemia after treatment with chloroquine, pyrimethamine/sulfadoxine, and pyrimethamine/sulfadoxine combined with artesunate in young Gambians with uncomplicated malaria

As part of a study to assess the infectivity of gametocytes after treatment with four antimalarial regimens, the efficacy of each treatment was also determined. From September to December 1998, 598 children with uncomplicated malaria were treated; 135 received chloroquine (CQ) alone, 276 received pyrimethamine/sulfadoxine (Fansidar, PSD) alone, 113 received PSD with a single dose of artesunate (PSD + 1ART) and 74 received PSD combined with three doses of artesunate (PSD + 3ART). On day 28 19/63 (30.2%; 95% C.I. 19.2% to 43.1%) of children treated with CQ alone, 5/134 (3.7%; 95% C.I. 1.2% to 8.5%) treated with PSD alone, 1/71 (1.4%, 95% C.I. 0.0% to 7.9%) treated with PSD + 1ART and 0/45 (0.0%; 95% C.I. 0.0% to 7.9%) treated with PSD + 3ART were parasitaemic. The proportion of children with gametocytes on day 7 after treatment with CQ alone was 16/89 (18.0%; 95% C.I. 10.6% to 27.6%), 98/174 (56.3%; 95% C.I. 48.6% to 63.8%) after treatment with PSD alone, 8/70 (11.4%; 95% C.I. 5.1% to 21.3%) after treatment with PSD + 1ART and 4/46 (8.7%; 95% C.I., 2.4% to 20.8%) after treatment with PSD + 3ART. CQ thus has a lower efficacy than PSD or either of the PSD and artesunate combinations. Use of PSD alone as an alternative first line treatment results in a very high post-treatment gametocyte prevalence that is likely to enhance transmission. There would be greater and more sustainable benefits from using PSD and artesunate combinations.     

In vitro sensitivity of Plasmodium falciparum to sulfadoxine and pyrimethamine

An in vitro microtechnique of Rieckmann et al., (1978) modified by Yisunsri and Rieckmann (1980) using 3 media; Waymouth, Waymouth plus 10% human serum, and RPMI was assessed to determine the sensitivity of P. falciparum to sulfadoxine, pyrimethamine and its combination. The study confirmed the synergism between sulfadoxine and pyrimethamine. There was no interaction between media and drug tested. MIC1 and MIC2 of sulfadoxine in different media showed significant difference (p less than 0.001). No significant difference was observed in MIC1 and MIC2 of pyrimethamine in the three media used (p greater than 0.05). For sulfadoxine-pyrimethamine combination, MIC1 and MIC2 in Waymouth alone and plus 10% human serum showed no significance (p greater than 0.05) while in RPMI showed positive correlation (p less than 0.001). MIC1 might be more applicable for clinical evaluation than MIC2. At present Waymouth medium with 5% patient serum, is considered to be the most suitable for testing sensitivity of malarial parasites.     

Plasmodium falciparum: effect of chloroquine, halofantrine and pyrimethamine on the infectivity of gametocytes for Anopheles stephensi mosquitoes.

The activity of chloroquine, halofantrine and pyrimethamine against the gametocytes and sporogonic stages of Plasmodium falciparum (strain NF54) was tested. Five-day-old gametocytes (stages I and II) from in vitro cultures were exposed to the drugs for 48 hours. The effect of the drugs on gametocyte development was assessed by counting gametocytes on days nine and 15 of culture and determining the infectivity of the drug-treated gametocytes to mosquitoes. Gametocytogenesis was partially inhibited by all three drugs; there were 71% of the number of gametocytes in drug-free control cultures in cultures with 3 x 10(-8) M chloroquine, 51% with 5 x 10(-8) M chloroquine, 78% with 5-7 x 10(-9) M halofantrine, and 48% with 10(-7) M pyrimethamine. Halofantrine- and pyrimethamine-treated gametocytes were found to be more infective to Anopheles stephensi than untreated controls. The three drugs were also administered to the mosquitoes, either in the first bloodmeal, which contained gametocytes from in vitro cultures, or in the second, parasite-free bloodmeal, given four days after infection. The sporontocidal activity of the drugs was evaluated by counting the number of oocysts on the midgut seven or eight days after infection, or the number of sporozoites in the salivary glands 15 days after infection. A sporontocidal effect was observed only when pyrimethamine was administered with the infective bloodmeal. Neither chloroquine nor halofantrine had any marked effect on sporogony at the concentrations tested.     

Sensitivity in vivo of Plasmodium falciparum to chloroquine and pyrimethamine/sulfadoxine in a coastal area of Tanzania

The in vivo response of Plasmodium falciparum to chloroquine and to pyrimethamine/sulfadoxine was studied for seven days in schoolchildren from two villages 30 to 40 km north of Dar es Salaam. Standard therapeutic regimen of chloroquine (25 mg base kg-1) failed to clear parasitaemia in 17 of 62 (27%) treated subjects. In contrast, standard treatment with pyrimethamine/sulfadoxine cleared the parasitaemia in all 44 treated subjects within five days. Hence, in the studied area, the therapeutic effect of sulfadoxine/pyrimethamine was superior to that of chloroquine.     

A randomized comparison of chloroquine and chloroquine plus ketotifen in the treatment of acute,uncomplicated, Plasmodium falciparum malaria in children

The increasing resistance of Plasmodium falciparum to chloroquine (CQ) has created urgent needs for the evaluation of alternative antimalarial drugs that are effective, safe, readily available and affordable. Ketotifen, a histamine H(1)-receptor antagonist that reverses CQ resistance in P. falciparum in vitro, may potentially enhance the effects of CQ in vivo. The effects of oral treatment with CQ alone (30 mg/kg base given over 3 days) were compared with those of this CQ regimen combined with ketotifen fumarate (0.25 mg at presentation followed by 0.125 mg/kg every 8 h for 5 days). The subjects were 145 children aged 1-10 years who were suffering from acute, symptomatic, uncomplicated, P. falciparum malaria: 74 given CQ alone and 71 given CQ plus ketotifen (CQK). Although the mean fever-clearance time was significantly shorter following treatment with CQK than after treatment with CQ alone, all other therapeutic responses were similar in the two treatment groups. Among siblings in whom there was clustering of infections, the likelihood of cure was also similar in the two treatment groups. Retreatment of 17 CQ-treatment failures with CQK produced a cure in six children, and retreatment of 22 CQK-treatment failures with CQK produced a cure in eight children. Retreatment of all drug failures with a combination of amodiaquine plus pyrimethamine-sulfadoxine resulted in complete clearance of parasitaemia and symptoms within 2-3 days and a cure 'rate' of 100% on day 28. The prevalences and intensities of gametocytaemias on day 3 or days 3, 7 and/or 14 combined were similar in the two groups. Adverse drug reactions were always tolerable, and limited to pruritus, gastro-intestinal disturbances, drowsiness and weight gain; the latter two adverse effects were significantly more frequent in those treated with CQK than in those given CQ alone. Haematological and biochemical parameters were not adversely affected by either treatment regimen. The findings indicate that - at least at the dosing regimen used in the present study and among children with acute, uncomplicated, P. falciparum malaria from Ibadan - the addition of ketotifen to CQ produced little or no significant enhancement of the antimalarial effect of CQ.     

Proguanil plus sulfamethoxazole in the treatment of uncomplicated Plasmodium falciparum malaria

In a malaria endemic area of Brazil where P. falciparum is highly resistant to chloroquine and Fansidar, we conducted an in vivo study to evaluate the therapeutic response of proguanil plus sulfametoxazole against Plasmodium falciparum malaria. Twenty-five adult subjects with uncomplicated P. falciparum malaria received supervised drug administration and were followed for 28 days in an inpatient hospital or in a malaria free-transmission area. The therapeutic regimen was proguanil 100 mg BID plus sulfamethoxazole 1,000 mg BID for 7 days. Of those who took all medications (n=21), 17 (81%) were cured. Recrudescent parasitemia during follow-up occurred in four (19%) patients on days 14, 19, 20 and 21 after beginning of treatment. The remaining four (16%) subjects did not complete their therapeutic regimen because the incidence of side effects. Considering the shortage of falciparum malaria therapeutic options and the urgent need for new regimens to deal with the spread of drug resistant P. falciparum, one might consider the study results as a lead to study analogous compounds, hopefully with fewer adverse reactions.     

Cross resistance of pyrimethamine and sulfadoxine to their related compounds in Plasmodium falciparum

Cross resistance of pyrimethamine and amethopterin, sulfadoxine and the other sulfonamides in Plasmodium falciparum culture lines was studied. Our results indicate some evidence of a cross resistance between pyrimethamine to amethopterin a drug sharing the same mode of action but never been used as an antimalarial before. Studies on sulfonamides revealed that the minimal inhibitory concentration for sulfadoxine was lower than for sulfadiazine and sulfisoxasole, and that a cross resistance between sulfadoxine and the other sulfonamides may not occur.     

Predictors of the failure of treatment with chloroquine plus chlorpheniramine, in children with acute, uncomplicated, Plasmodium falciparum malaria

Resistance to chloroquine in Plasmodium falciparum can be reversed, both in vitro and in vivo, by chlorpheniramine, a histamine H(1) receptor antagonist. This reversal raises the possibility of using chlorpheniramine to prolong the clinical usefulness of chloroquine in resource-poor communities. The factors that identify children at risk of treatment failure after being given chloroquine plus chlorpheniramine have now been evaluated in 281 children with uncomplicated, P. falciparum malaria. The children, who had taken part in six trials of antimalarial drugs between February 1996 and September 1999, in a hyper-endemic area of south-western Nigeria, were enrolled prospectively for the present study. Following treatment with chloroquine plus chlorpheniramine, 13 (5%) of the children failed treatment by day 7 or 14. In a multivariate analysis, an age of < or =3 years (adjusted odds ratio = 11.1; 95% confidence interval = 2.2-55.3; P = 0.003) and a parasitaemia that took >3 days to clear (adjusted odds ratio=7.9; 95% confidence interval = 1.3-49.4; P = 0.027) were found to be independent predictors of treatment failure. In addition, compared with the children who had a lower axillary temperature then, the children who had an axillary temperature of > or =38 degrees C 2 days after commencing treatment were significantly more likely to be treatment failures.In resource-poor communities using chloroquine plus chlorpheniramine, the easily identifiable predictors of treatment failure might be used to identify children requiring alternative antimalarial drugs.     

Anti-NANP antibody and treatment efficacy in patients with acute uncomplicated falciparum malaria attacks

African patients originating from the hypoendemic, urban area of Greater Dakar (Senegal, West Africa) who presented with an acute Plasmodium falciparum infection were studied using an in-vivo chloroquine sensitivity assay for 28 days. Forty-seven patients with acute malaria infections were treated with 25 mg/body weight of chloroquine. Adequate responses to treatment were observed in 24 patients (51%), whereas 23 (49%) were resistant. On the day of admission, these two groups of patients were comparable with respect to age, level of parasitemia and delay before initiation of treatment, but not with respect to gametocyte prevalence which was higher in patients resistant to therapy (48%) than in those who responded to treatment (17%). In order to evaluate whether the therapeutic response was associated with any given specific immune response, antibody activities against different stages of the parasite cycle were evaluated: anti-NANP repeats (i.e. antisporozoite stage antigen), anti-Pfs 45 kDa (i.e. antigametocyte stage antigen), and anti-MSP3 (i.e. antimerozoite stage antigen) antibodies were measured by ELISA at day 0 (i.e. on the day of admission and before initiation of treatment), day 7 and day 28. No significant differences between treatment-sensitive and treatment-resistant infections were observed for antibody prevalences and optical densities, except at day 0, when the prevalence of antibodies against NANP repeats was 2.4 times more frequent in the group of patients with a propitious response to treatment: 62.5% of the patients with an infection sensitive to chloroquine had anti-NANP antibodies, whereas only 26.1% of the patients resistant to chloroquine treatment had such a humoral response. These observations are discussed in relation to (1) the finding that gametocyte prevalence was markedly increased at a time when resistance to antimalarial treatment was observed; (2) the possibility that the efficacy of the therapeutic response could be the result of the combined effects of treatment and the individual immune status of the patients at the time of drug cure; and (3) the presence of detectable anti-NANP activity as potential indicator of the level of premunition acquired in an area of low and seasonal malaria transmission.     

Efficacy of artesunate plus amodiaquine, artesunate plus sulfadoxine-pyrimethamine, and chloroquine plus sulfadoxine-pyrimethamine in patients with uncomplicated Plasmodium falciparum in the Comoros Union

Health policy makers in Comoros Union have considered a policy change recommending combination treatment to control malaria. We evaluated the efficacy of three antimalarial drug combinations, taken orally, to enable the authorities to make an evidence-based choice. The study was carried out in patients of 2-70 years old in Moroni, Moheli and Anjouan in 2003. We enrolled 168 patients with uncomplicated malaria from 1097 outpatients screened at the health centres. One hundred and fifty-eight patients, of whom half were under five years old, (mean age=11.1+/-13.9 years), were followed up for 14 days. According to PCR adjusted outcome, the therapeutic efficacy of artesunate+amodiaquine (AS+AQ) (n=54) and artesunate+sulfadoxine-pyrimethamine (AS+SP) (n=53) was 100%, whereas that of chloroquine+sulfadoxine-pyrimethamine (CQ+SP) was 98% (50/51). The key difference between these treatments was the higher parasite clearance rate on Day 2 obtained with artesunate-containing combinations (P<0.001). These results provide a baseline for monitoring changes in the susceptibility of Plasmodium falciparum to artesunate+amodiaquine and artesunate+sulfadoxine-pyrimethamine (ACTs) in the Comoros Union. Health policy changes involving the replacement of chloroquine in the Indian Ocean subregion are discussed.     

Efficacy of chloroquine in the treatment of uncomplicated,Plasmodium falciparum malaria in northern Ghana

Chloroquine (CQ) resistance in Plasmodium falciparum contributes to growing malaria-attributable morbidity and mortality in sub-Saharan Africa. However, the extent and degree of such resistance vary considerably between endemic areas. Data on CQ resistance in northern Ghana are almost entirely lacking. The therapeutic efficacy of CQ in uncomplicated malaria was therefore assessed, in a standard, 14-day protocol, in 225 children aged <5 years in Tamale, in the Northern region of Ghana. Early treatment failure (ETF) was observed in 11% of the children and late treatment failure in 18%. High initial parasite density and young age were independent predictors for ETF. Resistant parasitological responses (RI-RIII) were seen in 57% of the cases that could be classified. More than half of these responses occurred in children fulfilling the criteria for adequate clinical response (ACR), indicating a considerable lack of agreement between parasitological and clinical outcome. During the follow-up period, haemoglobin levels increased by approximately 1g/dl not only in patients with ACR but also in those who experienced clinical failure more than 1 week post-treatment. As CQ-treatment failure occurred in >25% of the children and more than half of the parasitological responses indicated resistance, current recommendations for the treatment of uncomplicated malaria in young children in northern Ghana have to be reconsidered.     

Therapeutic efficacy of chloroquine against uncomplicated, Plasmodium falciparum malaria in south-western Saudi Arabia.

The results of annual random screening indicated that Plasmodium falciparum strains showing chloroquine (CQ) resistance in vitro became increasingly common in the Jazan region of south-western Saudi Arabia between 1986 and 1998 (chi(2) for trend = 50.027; P < 0.001). This worrying trend and the emergence of a micro-epidemic in 1997-1998 prompted an assessment of the therapeutic efficacy of CQ against uncomplicated, P. falciparum malaria in the area. The in-vivo testing of sensitivity to CQ was carried out in 291 clinically manifest, microscopically positive cases of P. falciparum malaria. Most of these patients (88%) were successfully treated with a single standard regimen of CQ therapy. The other 36 patients (12%) showed early treatment failure or a poor response to the CQ, although all of these were then successfully treated with a single standard dose of sulfadoxine-pyrimethamine (Fansidar), as a replacement therapy. Those unsuccessfully treated with CQ were generally younger (t = 2.625; P = 0.01) and tended to have higher body temperatures (t = -2.62; P = 0.012) and higher levels of parasitaemia at initial presentation (P > 0.000) than those who responded well to the drug. Although CQ remains a reasonably effective drug for the treatment of malaria in the Jazan region, and therefore will be kept as the first-line drug for the foreseeable future, failure of CQ efficacy must be carefully monitored in the area.     

Improved efficacy with amodiaquine instead of chloroquine in sulfadoxine/pyrimethamine combination treatment of falciparum malaria in Uganda: experience with fixed-dose formulation

Amodiaquine (AQ) is an affordable compound, chemically related to chloroquine (CQ) but often effective against CQ resistant Plasmodium falciparum. In Uganda, a pre-packed fixed-dose combination of CQ plus sulfadoxine/pyrimethamine (CQ+SP) called Homapak is used in the home based management of fever program (HBM). We performed a single blind randomized trial to determine the efficacy of AQ+SP in comparison with the fixed-dose CQ+SP (Homapak) in the treatment of uncomplicated falciparum malaria in Ugandan children aged 6 months to 5 years. The study was done in 2004 at Walkuba Health Center, a sub-urban area in Jinja district, Uganda. Primary outcome was the day 14 per protocol clinical and parasitological response according to the WHO. A total of 183 children were included (mean age 28 months) and 90% completed 28 days of follow up. The day 14 adequate clinical and parasitological response was 70.9% for CQ+SP and 97.4% for AQ+SP (p<0.001). In those given CQ+SP, treatment failure rates for the 6 months to 2 years age group were much higher (48.2%) than in the older children (18.2%, p=0.004). The day 28 PCR adjusted parasitological failure rates were also higher in the CQ+SP (31.3%) than in the AQ+SP group (13.1%) (p=0.003), with a higher gametocyte carriage among the CQ+SP group. We conclude that the efficacy of AQ+SP was significantly superior to the fixed-dose CQ+SP (Homapak), particularly among the youngest children. Thus, AQ could be used instead of CQ in combination with SP to improve the effectiveness against falciparum malaria in Uganda.     

Treatment of falciparum malaria with quinne and tetracycline or combined mefloquine/sulfadoxine/pyrimethamine on the Thai-Kampuchean border

Three different regimens were compared for treatment of falciparum malaria in displaced Kampucheans living in encampments on the Thai-Kampuchean border in 1983: single dose 750 mg mefloquine, 1.5 g sulfadoxine, 75 mg pyrimethamine (MSP); 600 mg quinine 8-hourly for 3 days and 500 mg tetracycline 8-hourly for 7 days (Q3T7); or 600 mg quinine 8-hourly for 7 days and 500 mg tetracycline 8-hourly for 7 days (Q7T7). Radical cure rates were 98% (40/41) for MSP, 76% (32/42) for Q3T7 and 92% (33/36) for Q7T7. The criterion for treatment failure was reappearance of parasites by 35 days after commencement of treatment or no parasite clearance. Treatment failures comprised one case of reduction but no clearance of parasites (RII resistance) for MSP, 10 recrudescences (RI) for Q3T7 and 3 recrudescences (RI) for Q7T7. The radical cure rate for Q3T7 was significantly lower than that for MSP (P less than 0.01), whilst Q7T7 significantly from the other groups. Parasite clearance time was shorter (2.4 days) with MSP than with Q3T7 (3.5 days) and Q7T7 (3.3 days). There was little difference in side effects between the regimens, and tolerance was good. The MSP and Q7T7 regimens are both effective for treatment, but the single dose of MSP is much easier to manage than 7 days of quinine and tetracycline.     

The effects of chloroquine,amodiaquine and chloroquine plus chlorpheniramine on the disposition kinetics of the hepatomegaly associated with acute,uncomplicated, Plasmodium falciparum malaria in children

The effects of chloroquine (CQ), amodiaquine (AQ) and CQ plus chlorpheniramine (a histamine H(1) antagonist that reverses CQ resistance in vitro and in vivo) on the disposition of the enlarged liver associated with acute, symptomatic, uncomplicated, Plasmodium falciparum malaria were evaluated. The subjects, 131 children aged 0.6-12 years who lived in an endemic area of Nigeria, were randomly allotted to the three treatment groups. The cumulative proportions of the children with complete resolution of their enlarged livers at 48, 96, 168 or 336 and 504 h after commencement of treatment were significantly higher in those treated with CQ plus chlorpheniramine (CQCP) than in the other two treatment groups (with P-values of 0.02, 0.001, 0.00000 and 0.00002, respectively). Among those with complete resolution, however, the times to resolution of 50% (HR50) or 90% (HR90) of the liver enlargement were similar in all the treatment groups. Complete resolution of the enlarged liver within 168 h was associated with a sensitive response to each treatment. Overall, in children with complete or partial resolution of their enlarged livers, the area produced by plotting liver size against time (i.e. the area under the curve of hepatomegaly v. time, or AUC(hp)) and the half-life of the hepatomegaly (t(1/2hp)) were significantly lower in the CQCP group than in the other two groups. The volume of blood completely cleared of the 'hepatic pathological processes' which led to the hepatomegaly (CL(Bhp)) and the fractional reduction of AUC(hp) at 48 and 96 h (i.e. AUC(hpFr148) and AUC(hpFr96)) were significantly higher in the CQCP group than in the other treatment groups. When the children with complete resolution of their liver enlargement were considered separately, t(1/2hp) (P=0.0008) but not AUC(hp) was found to be significantly lower, and AUC(hpFr196) (P=0.01) and CL(Bhl) (P=0.002) were found to be significantly higher in the CQCP group than in the other groups. Among the children with only partial resolution of their enlarged livers, the indices of resolution and the kinetic parameters of disposition were similar in all three groups. The data indicate that the addition of chlorpheniramine to chloroquine had a beneficial effect on both the early and late stages of the resolution of the liver enlargement associated with acute, symptomatic, uncomplicated, P. falciparum malaria.