Organophosphorus esters (organophosphates and organophosphonates), which are used as pesticides and parasiticides, are amongst the most frequent causes of accidental and suicidal intoxications. Their acute toxicity is due to the inhibition of the enzyme acetylcholinesterase (AChE), which inactivates the neurotransmitter acetylcholine (ACh) at cholinergic synapses. Esterase inhibition results from phosphylation (i.e., either phosphorylation or phosphonylation) of the serine hydroxyl group in the active center of the enzyme and translates into an “endogenous acetylcholine poisoning.” The therapy of poisoning with organophosphorus compounds, which is summarized by the acronym A FLOP [Atropine, FLuids, Oxygen, Pralidoxime (aldoxime cholinesterase reactivator)], is generally disappointing.
Pyridinium oximes reactivate phosphylated AChE by interacting with the anionic site of the enzyme. An optimal orientation of the reactivator at the catalytic site of the enzyme is facilitated by the pyridinium moiety, which thus increases efficacy. It is generally accepted that nerve gas exposure can be treated with oximes; however, the therapeutic value of oximes in human organophosphate pesticide poisoning or nerve gas exposure is controversial. One possible reason for the disappointing efficacy may be the very limited ability of oximes (< 5%) to penetrate the blood-brain-barrier (Curr Med Chem. 2008;15:743-753).
Nanoized therapeutic agents display superior kinetic properties translating in enhanced efficacy (higher survival). Oxime nanoization was difficult to achieve due to the very high hydrophilicity of pyridinium alsoximes; recently small volume nanoxime synthesis was achieved possibly opening the way towards enhanced protection. We have recently shown that oxime administration prior to toxic agent exposure is superior to the US Army standard, which is prophylactic pyridostigmin (carbamate) administration.
These proposed investigations represent an organic continuation of past national and international collaborations. The work has the potential to shift the treatment paradigm of pesticide/nerve gas exposure towards the use of nanoized therapeutic agents.