Regular ArticlePlasmodium berghei Infection: Dichloroacetate Improves Survival in Rats with Lactic Acidosis
Abstract
The kinetics of Plasmodium berghei infection and the development of lactic acidosis, hypoglycemia, and anemia were defined in young Wistar rats. This model of metabolic dysfunction, which is similar to that of severe human malaria, was used to test the hypothesis that dichloroacetate, a treatment for lactic acidosis, prolonged survival in rats receiving a single antimalarial dose of quinine (20 mg/kg). Rats with hyperlactatemia (lactate >5 mmol/liter, N = 183) were randomized to receive either dichloroacetate (100 mg/kg, N = 99) or saline (N = 84) and were monitored for outcome (survival or death) for 50 hr. Logistic regression modeling adjusting for baseline venous lactate concentration demonstrated that dichloroacetate increases survival rates in rats with venous lactate concentrations between 5 and 8.9 mmol/liter (odds ratio > 2.2, P < 0.021). This is the first demonstration that specific intervention to treat lactic acidosis can prolong survival and suggests that dichloroacetate may be useful as adjunctive therapy in the management of lactic acidosis complicating severe falciparum malaria.
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Alterations in Blood Components
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Clinical Pathology of the Rat
2006, The Laboratory RatThis chapter provides a basis for how clinical pathology parameters are used to correctly diagnose toxicity and naturally occurring disease in the rat. Hematology data are generally collected by highly automated instrumentation that differentiates and quantifies the formed elements in blood based on their size, internal structures, staining, and/or biochemical characteristics. Such analyses then use species-specific algorithms to classify cells according to type. An evaluation of bone marrow cells is generally not necessary for the interpretation of peripheral blood changes. However, it is important to prepare bone marrow smears at the time of sacrifice for potential future examination. An examination of bone marrow alterations may provide additional information to the interpretation made from peripheral blood analyses, particularly in cases of unexplained cytopenias or malignancies. Routine clinical chemistry tests are run on automated clinical chemistry analyzers. These instruments use a variety of reagents to determine concentrations or activities of analytes in serum or plasma.
Malaria and fluids - Balancing acts
2005, Trends in ParasitologySevere malaria has many manifestations, of which coma and lactic acidosis are the best independent predictors of a fatal outcome. Most deaths from malaria occur within the first 24 h of admission, despite appropriate antimalarial chemotherapy. Adjunctive therapy for severe malaria has been seen as a way to improve survival by ‘buying time’ until antimalarials can act. Several adjunctive therapies have undergone clinical trials in the past 25 years but all of these trials showed worsened outcome or no benefit to patients receiving adjuncts compared with those receiving placebo. Although metabolic acidosis occurs in both hypovolaemia and malaria, the contribution of the former to the pathophysiology of severe malaria is unclear. I suggest that lactic acidosis due to malaria can be explained primarily by factors that are independent of volume depletion. Lactic acidosis in malaria can be treated safely with dichloroacetate. This intervention could prove useful as an adjunctive therapy aimed at reducing mortality rates in severe malaria.
Clinical Pathology of the Rat
2005, The Laboratory Rat, Second EditionThis chapter provides a basis for how clinical pathology parameters are used to correctly diagnose toxicity and naturally occurring disease in the rat. Hematology data are generally collected by highly automated instrumentation that differentiates and quantifies the formed elements in blood based on their size, internal structures, staining, and/or biochemical characteristics. Such analyses then use species-specific algorithms to classify cells according to type. An evaluation of bone marrow cells is generally not necessary for the interpretation of peripheral blood changes. However, it is important to prepare bone marrow smears at the time of sacrifice for potential future examination. An examination of bone marrow alterations may provide additional information to the interpretation made from peripheral blood analyses, particularly in cases of unexplained cytopenias or malignancies. Routine clinical chemistry tests are run on automated clinical chemistry analyzers. These instruments use a variety of reagents to determine concentrations or activities of analytes in serum or plasma.
Acidosis of severe falciparum malaria: Heading for a shock?
2005, Trends in ParasitologySevere Plasmodium falciparum malaria encompasses a complex syndrome affecting many organs and causing physiological perturbations that have many features in common with children with sepsis. Among these, metabolic acidosis has emerged as a central feature of severe malaria and is the best independent predictor of a fatal outcome in both adults and children. There is now clear evidence that intravascular hypovolaemia (shock) is common in children with malarial acidosis. How it should be treated presents a therapeutic dilemma because acidosis often coexists with impaired consciousness (cerebral malaria). We summarize the results of recent clinical trials examining the safety and efficacy of volume expansion in children with ‘cerebral malaria’ complicated by acidosis.
Nutritional lactate spikes: Quantitative antagonism by dichloroacetate
2001, Nutrition ResearchThis clinical study characterized nutritional lactate spikes, investigated their antagonism by dichloroacetate (DCA), quantitated that antagonism, and compared these with fasting lactate concentration responses. A secondary concern was the tolerability of DCA, including consequent oxaluria. We measured lactate and DCA concentrations simultaneously, using a double-blind, placebo-controlled protocol, and Schild analysis. Nutritional lactate spikes peaked at 2 mM, and lasted for about 2 h, and DCA was a non-competitive antagonist, with EC50 similar to that for reducing fasting lactate concentration. Oxaluria (up to 4-fold control) was complete by 24–36 h, linearly related to DCA dose, and without crystalluria. Conclusions: i) Nutritional lactate spikes are non-competitively antagonized by DCA (unlike exercise-induced spikes), ii) this is a method for comparison of pyruvate dehydrogenase activating drugs, and iii) consequent oxalate loads are well-tolerated.