Neurotoxic chemical agents induce complex toxicological effects with major adverse effects for those who are exposed to them. Medical countermeasures include administering atropine, a cholinesterase reactivating oxime and an anticonvulsant. The purpose of this reseach is the optimization of an antidote-based treatment in the intoxication with organophosphates through the synthesis and toxicological testing of new compounds with a pyridin-isonitrosoacetanilide structure and their comparison with obidoxime as reference. The objective of this study was the in vitro/in vivo assessment of the antidote properties and acute toxicity of synthethic oximes active in the exposure to neuroparalytic organophosphates. The CT50 value for obidoxime was estimated, through calculus, to be 3.24 mg/ml and 9.33 ×10 -6 M respectively. The CT50 value for Bis1,3[2-hydroxyimino-N-(pyridyl)acetamide]oxapropandichloride (HIN 2) was estimated to be 2.72 mg/ml and 6.29 ×10 -6 M respectively. The studied compounds showed values close to cellular viability at low and moderate equimolecular concentrations, administered in vitro to a cellular culture of fibroblasts. Bis1,3[2-hydroxyimino-N-(piridyl)acetamide]oxapropandichloride (HIN 2) showed an in vitro cellular viability value smalled than obidoxime at higher equimolecular concentrations, proving itself to be more toxic than obidoxime at high concentrations. Taking into account the close values of CT50, the newly synthethized compound, having this particular characterization from a toxicological standpoint, qualifies for further studies as an antidote.
Object: The aim of the study is to select the most active new imidazolium-quinuclidinum- oxime, from some similar chemical compounds synthesized in our chemistry department, with sufficient efficacy to decrease the acute toxicity of neurotoxic organophosphates known as nerve agents. Method: The experimental study consist in vivo testing the antidotal efficacy of obidoxime and of selected imidazolium oximes synthesized in our chemistry department. Each oxime was included, by equimolar replacing the obidoxime, in an antidotal formula, which also contains atropine. The above mentioned formula containing atropine and obidoxime was used as reference. The protective ratio, defined as the ratio between the lethal median dose of the poisoned and treated study group and the median lethal dose (LD50) of the poisoned and untreated study groups was one of the used parameters in order to select a new active chemical structure in counteracting the neurotoxic organophosphorus compounds acute toxicity. Another studied parameter was the erythrocyte acetylcholinesterase value measured in whole blood 24 hours after exposure. Results: The protective ratio against an organophosphorus compound were the follow: obidoxime chloride: 2; 1,3- dimethyl-2-hydroxyethyl-imidazolyliodide: 1,75;3-oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)- 2oxapropyl]quinuclidin-dichl-oride: 2,5; 1-methyl-quinuclidin-3-iodide: 1,5. The erythrocyte acetycholinesterase main values were the following: the unpoisoned and untreated study group:3,45 ±0,13mmol/dl; the poisoned and untreated study group: 0,89 ±0,09 mmol/dl; the poisoned and 3- oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)-2oxapropyl]quinuclidindichloride study group:2,89 ±0,11 mmol/dl; the poisoned and obidoxime treated study group: 2,53±0,15 mmol/dl. Conclusions: quinuclidindichloride synthesized in our chemistry department, has shown a better protective ratio and a more prolonged surviving time than the reference (obidoxime). It has shown the best AChE reactivation of all the synthetized compounds. This compound can be a cheap and good option for replacing obidoxime in the antidotal formula active in nerve agent exposure. 3-oxime-[3-(2-hidroxyimino-methyl-1-imidazolyl-)-2oxapropyl] treated
