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.
Sowunmi
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Department of Pharmacology and Therapeutics and Postgraduate Institute for Medical Research and Training, University of Ibadan, Ibadan, Nigeria. malaria.iba@alpha.linkserve.com
Adedeji
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AA
D000208:Acute Disease; D000293:Adolescent; D000655:Amodiaquine / Q000627:therapeutic use; D000962:Antimalarials / Q000627:therapeutic use*; D019540:Area Under Curve; D002648:Child; D002675:Child, Preschool; D002738:Chloroquine / Q000627:therapeutic use; D002744:Chlorpheniramine / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D006529:Hepatomegaly / Q000188:drug therapy / Q000469:parasitology; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000150:complications / Q000188:drug therapy*; D011446:Prospective Studies; D016896:Treatment Outcome
D000962:Antimalarials; D000655:Amodiaquine; D002744:Chlorpheniramine; D002738:Chloroquine