Antidotal efficacy of newly synthesized oximes K203 and K027 in rats acutely exposed to dichlorvos

Standardna terapija akutnog trovanja ljudi organofosfornim (OF) jedinjenjimasastoji se od leka sa antiholinergičkim efektom (atropin) i reaktivatora inhibirane acetilholinesteraze(AChE)(oksim). Međutim, eksperimentalne i kliničke studije pokazale su nezadovoljavajuću i/ili nejednaku efikasnost postojećih oksima kod strukturno različitih OF. Među eksperimentalnim oksimima po svojoj efikasnostiizdvojili su se oksimi K203 i K027,koji do sada nisu in vivo testirani na modelu pesticida. Stoga je cilj istraživanja bio da se ispita njihova potencijalnaterapijska i reaktivatorska efikasnost, kao i antioksidativni kapacitet kod pacova akutno trovanih dihlorvosom.U cilju poređenja, ispitivanja antidotske efikasnosti sprovedena su pod istim eksperimentalnim uslovima i sa standardnim oksimima.Najbolji antidotski efekat dobijen je nakon primene oksima K027. Efikasnost drugih ispitivanih oksima opadala je sledećim redosledom obidoksim>K203> trimedoksim>pralidoksim>azoksim. Oksim K027 je sam i u kombinaciji sa atropinom jedini doveo do značajne reaktivacije AChE eritrocita i dijafragme.Ekviefektivne doze oksima K027 bile su niže od ekviefektivnih doza oksima K203,dok jenajniža doza oksima K027 bila potrebnaza reaktivaciju AChE dijafragme. Analizom dozne zavisnosti antioksidativnog efekta dobijeno je da je oksim K203 značajno efikasniji u odnosu na oksim K027, pri čemu je najveća razlika u efikasnostiuočena za efekat smanjenja lipidne peroksidacijeu plazmi, iza efekat smanjenja superoksidnog anjonau dijafragmi i mozgu. Rezultati ove doktorske disertacijeukazuju na bolji antidotski potencijal oksima K027 u odnosu na oksim K203 što podržava hipotezu oobećavajućoj hemijskoj strukturi oksima K027, vrednoj budućih in vivoispitivanja kod strukturno različitih OF pesticida.Standard therapy for acute human poisoning with organophosphorus (OP) compounds consistsof anticholinergic drug (atropine)andreactivator of OP-inhibited acetylcholinesterase (AChE) (oxime). However, experimentalandclinical studies have shown insufficient and/or unequal efficacy of current oximes against poisonings caused by structurally differentOPs. Among the experimental oximes, oximes K203andK027, have shown promising results, but theyhave not yet been tested in vivousing pesticide model. Therefore, the aim of the study was to examine their potential therapeuticandreactivating efficacy as well as antioxidant capacity in rats acutely poisoned with dichlorvos. For the sake of comparison, the study was also carried out with standardly usedoximes under the same experimental protocol. The best antidotal effect was obtained after administration of oxime K027. The efficacy of other investigated oximes decreased in the following order: obidoxime>K203>trimedoxime>pralidoxime>asoxime. Oxime K027 aloneand in combination with atropine led to a significant reactivation of erythrocyteanddiaphragm AChE. The equieffective doses of oxime K027 were lower compared to oxime K203, while the lowest K027 dose was required for the reactivation of diaphragm AChE. Evaluation of dose-response relationship for antioxidant effect has shown that the oxime K203 was significantly more effective compared to K027, with the greatest difference in efficacy for the lipid peroxidation attenuation in plasmaandreduction of superoxide anion radicals in the diaphragmandbrain tissues. The results of this doctoral dissertation indicate a better antidotal potential of oxime K027 compared to oxime K203, supportingthe hypothesis on the promising chemical structure of oxime K027, worth of future in vivotesting withstructurally different OP pesticides