Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment.
Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis,...
| Main Authors: | , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
1994
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| _version_ | 1797070161071570944 |
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| author | Krishna, S Supanaranond, W Pukrittayakamee, S Karter, D Supputamongkol, Y Davis, T Holloway, P White, N |
| author_facet | Krishna, S Supanaranond, W Pukrittayakamee, S Karter, D Supputamongkol, Y Davis, T Holloway, P White, N |
| author_sort | Krishna, S |
| collection | OXFORD |
| description | Lactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P > .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P < .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria. |
| first_indexed | 2024-03-06T22:35:01Z |
| format | Journal article |
| id | oxford-uuid:5997a45b-40b5-4a99-a236-f51e35755c9a |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:35:01Z |
| publishDate | 1994 |
| record_format | dspace |
| spelling | oxford-uuid:5997a45b-40b5-4a99-a236-f51e35755c9a2022-03-26T17:10:40ZDichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5997a45b-40b5-4a99-a236-f51e35755c9aEnglishSymplectic Elements at Oxford1994Krishna, SSupanaranond, WPukrittayakamee, SKarter, DSupputamongkol, YDavis, THolloway, PWhite, NLactic acidosis and hypoglycemia are potentially lethal complications of falciparum malaria. We have evaluated the pharmacokinetics and pharmacodynamics of dichloroacetate ([DCA], 46 mg/kg infused over 30 minutes), a stimulant of pyruvate dehydrogenase and a potential treatment for lactic acidosis, in 13 patients with severe malaria and compared the physiological and metabolic responses with those of a control group of patients (n = 32) of equivalent disease severity. The mean +/- SD peak postinfusion level of DCA was 78 +/- 23 mg/L, the total apparent volume of distribution was 0.75 +/- 0.35 L/kg, and systemic clearance was 0.32 +/- 0.16 L/kg/h. Geometric mean (range) venous lactate concentrations in control and DCA recipients before treatment were 4.5 (2.1 to 19.5) and 5.5 (2 to 15.4) mmol/L, respectively (P > .1). A single DCA infusion decreased lactate concentrations from baseline by a mean of 27% after 2 hours, 40% after 4 hours, and 41% after 8 hours, compared with decreases of 5%, 6%, and 16%, respectively, in controls (P = .032). These changes were preceded by rapid and marked decreases in pyruvate concentrations. Arterial pH increased from 7.328 to 7.374 (n = 10, P < .02) 2 hours after the infusion. Hypoglycemia was prevented by infusing glucose at 3 mg/kg/min. There was no clinical, electrocardiographic, or laboratory evidence of toxicity. These results suggest that DCA should be investigated further as an adjunctive therapy for severe malaria. |
| spellingShingle | Krishna, S Supanaranond, W Pukrittayakamee, S Karter, D Supputamongkol, Y Davis, T Holloway, P White, N Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. |
| title | Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. |
| title_full | Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. |
| title_fullStr | Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. |
| title_full_unstemmed | Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. |
| title_short | Dichloroacetate for lactic acidosis in severe malaria: a pharmacokinetic and pharmacodynamic assessment. |
| title_sort | dichloroacetate for lactic acidosis in severe malaria a pharmacokinetic and pharmacodynamic assessment |
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