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Prophylactic phenobarbitone in young children with severe falciparum malaria: pharmacokinetics and clinical effects
P A Winstanley1, C R Newton, G Pasvol
1Kenya Medical Research Institute, Kilifi Research Unit.
Insights
Phenobarbitone (PB) disposition did not differ in children with malaria. This anticonvulsant showed no benefit in reducing seizures or coma duration in cerebral malaria, suggesting a need for further dose-finding studies.
Area of Science:
- Pharmacology
- Clinical Pharmacy
- Pediatrics
Background:
- Severe malaria in children can lead to cerebral malaria and seizures.
- Phenobarbitone (PB) is an anticonvulsant used for seizure prophylaxis.
- Understanding PB disposition is crucial for optimizing its use in pediatric malaria patients.
Purpose of the Study:
- To measure phenobarbitone (PB) concentrations in children with severe malaria.
- To compare PB disposition in children with malaria receiving quinine versus those without malaria.
- To evaluate the efficacy of prophylactic PB in reducing seizures in young children with cerebral malaria.
Main Methods:
- Developed a reversed-phase high-performance liquid chromatography (h.p.l.c.) method for measuring PB in dried blood samples.
- Contrasted PB disposition in children with malaria on quinine versus healthy controls.
- Conducted an open, dose-finding study of prophylactic PB (10 mg kg-1) in cerebral malaria.
Main Results:
- No significant differences in PB disposition were observed between children with malaria and controls.
- Peak blood PB concentrations generally exceeded 10 mg L-1 in both groups.
- Prophylactic PB at 10 mg kg-1 did not reduce the incidence or duration of seizures or coma in cerebral malaria.
Conclusions:
- Phenobarbitone (PB) disposition is similar in children with and without malaria.
- A prophylactic dose of 10 mg kg-1 phenobarbitone (PB) was ineffective for seizure control in cerebral malaria.
- Further controlled trials with higher phenobarbitone (PB) doses are warranted for pediatric cerebral malaria.
Abstract:
1. A method is described for the measurement of phenobarbitone (PB) by reversed phase high performance liquid chromatography (h.p.l.c.) from small samples of whole blood dried onto filter paper strips. 2. The disposition of PB given prophylactically to young children with severe malaria on parenteral quinine is contrasted with that in aparasitaemic Kenyan children on no antimalarial drugs. There were no differences in the disposition of PB between the two groups. 3. Peak blood PB concentrations were equal to or greater than 15 mg l-1 in 27% of the patients on quinine and 23% of those not on quinine; a concentration of 10 mg l-1 was achieved or exceeded by 100% and 92% of each group, respectively, and was maintained for 39 +/- 24 h (mean +/- s.d.), and 33 +/- 21 h, respectively. 4. In an open, dose-finding study, the progress of young children with cerebral malaria given prophylactic PB (10 mg kg-1), was contrasted with that of controls given no seizure prophylaxis. 5. The drug had no apparent effect on depth or duration of coma, but neither was the incidence of seizures reduced. 6. A controlled trial of prophylactic PB in young children with cerebral malaria is needed, but a larger dose than 10 mg kg-1 should be studied.