Development of antidotes for sodium monofluoroacetate (1080)

Baits containing sodium monofluoroacetate (1080) are commonly used in New Z ealand during feral pest control operations. However, each year, a number o f domestic dogs are unintentionally killed during these control operations, and a suitable antidote to 1080 intoxication is required. The primary toxi c mechanism of 1080 is well known. However, as with other pathologies where energy deprivation is the main effect of intoxication, the cascade of effe cts that arises from this primary mechanism is complex. At present, putativ e antidotes for 1080 are generally unable to address the primary mechanism of intoxication but such agents may be able to control the cascade of secon dary effects, which can result during intoxication. Part of the reason for this is that targeting the cascade can provide a longer window of time for antidote success. We have undertaken studies that identified some of the ce ntral nervous system (CNS) and systemic pathophysiological cascades caused by 1080 intoxication. Using this information we designed antidotes, on the basis of preventing different steps in this cascade. In the chicken model t argeting systemic changes, in particular reducing effects of nitric oxide d erivatives generated in cardiac muscle, proved successful in reducing fatal ity associated with 1080. In rats and sheep, targeting the CNS with a numbe r of compounds including: glutamate; calcium and dopamine antagonists; gamm a amino butyric acid agonists, and astressin-like compounds reduced fatalat ies. However, to be successful in the rat and sheep model a given antidote needed to move quickly from systemic circulation across the blood brain bar rier and into the CNS. The work also suggests ways in which specific biomar kers of 1080 exposure may be developed with respect to different species.