Plasmodium berghei Infection: Dichloroacetate Improves Survival in Rats with Lactic Acidosis

Holloway, Paul; Knox, Kenneth S.; Bajaj, Naresh; Chapman, Doug B.; White, Nicholas J.; OʼBrien, Ralph G.; Stacpoole, Peter W.; Krishna, Sanjeev

doi:10.1006/expr.1995.1078

Cited by 28 publications

(9 citation statements)

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“…In African children with Plasmodium falciparum malaria, hyperlactataemia is one of the strongest biochemical predictors of death and is associated with a mortality up to 40% 16. DCA rapidly decreases lactic acidosis in such patients17 and significantly improves survival in a rodent model of malaria associated lactic acidosis 18. This is the first and only experimental demonstration that any intervention favourably affects survival in lactic acidosis of any aetiology.…”

Section: Dichloroacetatementioning

confidence: 87%

Treatment of congenital lactic acidosis with dichloroacetate

Stacpoole

Barnes

Hurbanis

et al. 1997

Archives of Disease in Childhood

101

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Section: Dichloroacetatementioning

confidence: 87%

Treatment of congenital lactic acidosis with dichloroacetate

Stacpoole

Barnes

Hurbanis

et al. 1997

Archives of Disease in Childhood

101

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“…Hyperlactatemia can be treated with sodium dichloroacetate (DCA), which stimulates the aerobic consumption of lactate. Following of increased survival in P. berghei-infected rats with lactic acidosis treated with DCA 44 and a pharmacodynamic/pharmacokinetic assessment in adults with severe malaria, 21 Krishna and others conducted a randomized, double-blind study of DCA (single dose, 50 mg/kg) as adjunct treatment for lactic acidosis in children with severe malaria. 45 Throughout the first 4 hr after treatment, the mean plasma lactate concentrations in DCA-treated patients were significantly less than that in controls, but thereafter, the mean plasma lactate concentrations decreased in both groups.…”

Section: Pathophysiology Of Fatal Malariamentioning

confidence: 99%

“…54 Gluconeogenic precursors are present in sufficient concentrations to exclude starvation as an etiology; hepatic glycogen stores may be depleted, and gluconeogenesis may be impaired. 40,44,52 Regardless of the etiology, pretreatment hypoglycemia is consistently associated with a poor prognosis (22-37% mortality) in children with CM, 7,40,48 and children with recurrent hypoglycemia fare even worse (71% mortality). 40 The emergency treatment of hypoglycemia is an intravenous infusion of 50% dextrose (1 ml/kg).…”

Section: Pathophysiology Of Fatal Malariamentioning

confidence: 99%

Pathophysiology of fatal falciparum malaria in African children.

Newton¹,

Taylor²,

Whitten³

1998

The American Journal of Tropical Medicine and Hygiene

120

121

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Abstract. Children living in sub-Saharan Africa bear the brunt of the mortality from falciparum malaria, yet there is a dearth of relevant post-mortem data. Clinical studies from centers in Africa suggest that the pathophysiology of severe malaria is different in children and adults. Three overlapping clinical syndromes, metabolic acidosis manifesting as hyperpnea, cerebral malaria, and severe anemia, are responsible for nearly all the deaths in African children. Despite improvements in antimalarial treatment, there has not been a significant reduction in mortality. We review the pathology and pathophysiology of fatal falciparum malaria in African children. Many questions remain, the answers to which would facilitate the development and evaluation of new approaches to the management of this disease.Severe and complicated Plasmodium falciparum infections continue to threaten the survival of young children in sub-Saharan Africa: one in 15 children on the Kenyan coast will have experienced an episode of severe malaria before the age of five, 1 and 1% of Gambian children less than five years of age will die of malaria. 2 The annual death toll is estimated to be one million children across the continent; 90% of the annual worldwide malaria mortality. 3 Although most children die in the community, on the Kenyan coast it is estimated that more than 40% die in a hospital (Marsh K, unpublished data) and one-third of pediatric hospital admissions and one-third of pediatric hospital deaths in Malawi can be attributed to malaria. 4

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“…One of the most important risk factors that identify these children is the complication of lactic acidosis (plasma or whole blood lactate concentration of Ն5 mmol/liter) (11). Dichloroacetate (DCA) is a potential treatment for malaria-associated lactic acidosis (7).…”

mentioning

confidence: 99%

Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

Krishna

Nagaraja

Planche

et al. 2001

Antimicrob Agents Chemother

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We present the first population pharmacokinetic analysis of quinine in patients with Plasmodium falciparum malaria. Ghanaian children (n ‫؍‬ 120; aged 12 months to 10 years) with severe malaria received an intramuscular loading dose of quinine dihydrochloride (20 mg/kg of body weight). A two-compartment model with first-order absorption and elimination gave post hoc estimates for pharmacokinetic parameters that were consistent with those derived from non-population pharmacokinetic studies (clearance [CL] ‫؍‬ 0.05 liter/h/kg of body weight; volume of distribution in the central compartment [V 1 ] ‫؍‬ 0.65 liter/kg; volume of distribution at steady state ‫؍‬ 1.41 liter/kg; half-life at ␤ phase ‫؍‬ 19.9 h). There were no covariates (including age, gender, acidemia, anemia, coma, parasitemia, or anticonvulsant use) that explained interpatient variability in weightnormalized CL and V 1 . Intramuscular quinine was associated with minor, local toxicity in some patients (13 of 108; 12%), and 11 patients (10%) experienced one or more episodes of postadmission hypoglycemia. A loading dose of intramuscular quinine results in predictable population pharmacokinetic profiles in children with severe malaria and may be preferred to the intravenous route of administration in some circumstances.Although quinine is one of the oldest drugs in the pharmacopoeia, the optimum usage of quinine in children with severe malaria is still debated (12, 29). The choice of route and dose of quinine for children with severe malaria will vary depending on circumstances and particularly on the capability of administering intravenous infusions reliably. Quinine is the drug of choice for the management of severe malaria in most areas of the world, and it is frequently deployed in conditions where intravenous infusions cannot be rapidly established or reliably monitored.Recent pharmacokinetic studies using African children have revived the intramuscular route as an alternative, cheaper, practicable, and potentially safer route for quinine administration (15, 25,27). However, classical pharmacokinetic studies are not always applicable to populations at highest risk of death from Plasmodium falciparum infection. One of the most important risk factors that identify these children is the complication of lactic acidosis (plasma or whole blood lactate concentration of Ն5 mmol/liter) (11). Dichloroacetate (DCA) is a potential treatment for malaria-associated lactic acidosis (7).We recently conducted a randomized, double-blind, placebo-controlled investigation to test the hypothesis that treatment with the lactate-lowering drug DCA, given with quinine, significantly improved morbidity and mortality in Ghanaian children with lactic acidosis due to severe P. falciparum malaria infection. This report describes the population pharmacokinetics of a loading dose of intramuscular quinine dihydrochloride (20 mg/kg of body weight) in 120 patients. The size of this study also allows assessment of covariables that may be important in influencing quinine kinetics. The ...

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Plasmodium berghei Infection: Dichloroacetate Improves Survival in Rats with Lactic Acidosis

Cited by 28 publications

References 0 publications

Treatment of congenital lactic acidosis with dichloroacetate

Treatment of congenital lactic acidosis with dichloroacetate

Pathophysiology of fatal falciparum malaria in African children.

Population Pharmacokinetics of Intramuscular Quinine in Children with Severe Malaria

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