Sarah Piel
Childrens Hospital of Philadelphia
Philadelphia, Pennsylvania
Disclosure information not submitted.
Laurenson Ward
Scientist
The Children's Hospital of Philadelphia, United States
Disclosure information not submitted.
David Jang, MD, MSc
Assistant Professor
University of Pennsylvania, United States
Disclosure information not submitted.
Carly Clayman, PhD
Research Scientist
Children's Hospital of Philadelphia, Pennsylvania, United States
Disclosure information not submitted.
Piotr Janowska
Scientist
The Children's Hospital of Philadelphia, United States
Disclosure information not submitted.
Todd Kilbaugh, MD
Associate Professor of Anesthesia, Critical Care, & Pediatrics
Childrens Hospital of Philadelphia, United States
Disclosure information not submitted.
Title: Succinate as Treatment for Metabolic Crisis During Acute Sodium Fluoroacetate Poisoning
Introduction: Sodium Fluroacetate (FA) is a metabolic poison that systemically inhibits the TCA cycle, causing energy deficiency and ultimately multi-organ dysfunction. Because of its high toxicity, use as a chemical weapon and lack of effective antidotal therapy FA poses a significant threat to society. Therefore, further treatment development is warranted. The aim of this study was to evaluate cell-permeable prodrugs of succinate as a potential treatment for acute FA intoxication. Because succinate is directly metabolized by mitochondrial complex II we hypothesized that succinate prodrugs provide an alternative energy source, bypass the TCA cycle inhibition of FA and energetically support cells in a rat model of acute FA intoxication.
Methods: Rats were anesthetized, mechanically ventilated and temperature controlled. We first identified an IV dose of FA that induced a moderate but significant reduction in mean arterial pressure (MAP) without causing mortality. We then co-treated rats with a continuous infusion of the cell-permeable succinate prodrug candidate NV354 (25 mg/kg/h). Subsequently, brain and heart tissue were harvested and mitochondrial function and metabolic profiles were measured. Data are presented as median plus interquartile range. Parametric and non-parametric tests were applied as appropriate. P< 0.05 was considered to indicate significant difference.
Results: Acute intoxication with FA resulted in a decrease in MAP (-25%, p< 0.05), severe inhibition of the phosphorylation system control ratio (OXPHOSCI+II / ETSCI+II, -41%, p< 0.05) and caused significant changes in the metabolic profile of the heart (4-fold-fold accumulation of citrate, p< 0.05). Co-treatment with NV354 did not counteract the SF-induced changes in the phosphorylation system control ratio, metabolic profile or MAP. The same dose of FA did not induce any acute changes in mitochondrial function or metabolic profiles of the brain.
Conclusion: This study demonstrates no treatment effect in the heart by the cell-permeable succinate prodrug NV354 during acute intoxication with FA based on the molecular outcome metrics investigated in this study. The brain was unaffected during the acute phase of FA intoxication. Future directions will include dose titrations, alternative succinate prodrug candidates and other mitochondrial therapies.