Dose-response modeling of reactivating potency of oximes K027 and K203 against a direct acetylcholinesterase inhibitor in rat erythrocytes
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2018
Authors
Antonijević, EvicaMusilek, Kamil
Kuca, Kamil
Đukić-Ćosić, Danijela
Curcić, Marijana
Ćupić Miladinović, Dejana
Bulat, Zorica
Antonijević, Biljana
Article (Published version)
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Inhibition of acethylcholinesterase (AChE) as a key molecular event induced by organophosphate (OP) pesticides and nerve agents presents a human health concern. In efficacy testing of experimental oximes, potential antidotes in OP poisoning, reactivation of OP-inhibited AChE is used as specific endpoint. However, according to our best knowledge, so far oximes have not been quantitatively evaluated by comprehensive benchmark dose (BMD) approach, that would improve both identification and quantification of the effect and allow more rigorous comparison of efficacies. Thus, we have examined in vivo dose-response relationship for two promising experimental oximes, K203 and K027, concerning reactivation of erythrocyte AChE inhibited by dichlorvos (DDVP). Groups of Wistar rats were treated with six different doses of oximes (i.m) immediately after DDVP challenge (s.c) and AChE was measured 60 min later. Dose-response modeling was done by PROAST software 65.5 (RIVM, The Nederlands). BMD-covari...ate method resulted in four-parameter model from both exponential and Hill model families as the best estimate of relationship between AChE activity and oxime dose, with potency parameter being oxime-dependent. Oxime K027 was shown to be 1.929-fold more potent considering that 58% increase in AChE activity was achived with the dose BMD58-K027 = 52 mu mol/kg in contrast to BMD58-K203 = 100 mu mol/kg.
Keywords:
Dichlorvos / K027 vs K203 / Rat erythrocytes / Benchmark dose / PROASTSource:
Food and Chemical Toxicology, 2018, 121, 224-230Publisher:
- Pergamon-Elsevier Science Ltd, Oxford
Funding / projects:
- Improvement and development of hygienic and technological procedures in production of animal originating foodstuffs with the aim of producing high-quality and safe products competetive on the global market (RS-46009)
- Grant Agency of the Czech RepublicGrant Agency of the Czech Republic [18017345]
DOI: 10.1016/j.fct.2018.08.065
ISSN: 0278-6915
PubMed: 30176309
WoS: 000449242800023
Scopus: 2-s2.0-85052992924
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Institution/Community
Fakultet veterinarske medicineTY - JOUR AU - Antonijević, Evica AU - Musilek, Kamil AU - Kuca, Kamil AU - Đukić-Ćosić, Danijela AU - Curcić, Marijana AU - Ćupić Miladinović, Dejana AU - Bulat, Zorica AU - Antonijević, Biljana PY - 2018 UR - https://vet-erinar.vet.bg.ac.rs/handle/123456789/1566 AB - Inhibition of acethylcholinesterase (AChE) as a key molecular event induced by organophosphate (OP) pesticides and nerve agents presents a human health concern. In efficacy testing of experimental oximes, potential antidotes in OP poisoning, reactivation of OP-inhibited AChE is used as specific endpoint. However, according to our best knowledge, so far oximes have not been quantitatively evaluated by comprehensive benchmark dose (BMD) approach, that would improve both identification and quantification of the effect and allow more rigorous comparison of efficacies. Thus, we have examined in vivo dose-response relationship for two promising experimental oximes, K203 and K027, concerning reactivation of erythrocyte AChE inhibited by dichlorvos (DDVP). Groups of Wistar rats were treated with six different doses of oximes (i.m) immediately after DDVP challenge (s.c) and AChE was measured 60 min later. Dose-response modeling was done by PROAST software 65.5 (RIVM, The Nederlands). BMD-covariate method resulted in four-parameter model from both exponential and Hill model families as the best estimate of relationship between AChE activity and oxime dose, with potency parameter being oxime-dependent. Oxime K027 was shown to be 1.929-fold more potent considering that 58% increase in AChE activity was achived with the dose BMD58-K027 = 52 mu mol/kg in contrast to BMD58-K203 = 100 mu mol/kg. PB - Pergamon-Elsevier Science Ltd, Oxford T2 - Food and Chemical Toxicology T1 - Dose-response modeling of reactivating potency of oximes K027 and K203 against a direct acetylcholinesterase inhibitor in rat erythrocytes VL - 121 SP - 224 EP - 230 DO - 10.1016/j.fct.2018.08.065 ER -
@article{ author = "Antonijević, Evica and Musilek, Kamil and Kuca, Kamil and Đukić-Ćosić, Danijela and Curcić, Marijana and Ćupić Miladinović, Dejana and Bulat, Zorica and Antonijević, Biljana", year = "2018", abstract = "Inhibition of acethylcholinesterase (AChE) as a key molecular event induced by organophosphate (OP) pesticides and nerve agents presents a human health concern. In efficacy testing of experimental oximes, potential antidotes in OP poisoning, reactivation of OP-inhibited AChE is used as specific endpoint. However, according to our best knowledge, so far oximes have not been quantitatively evaluated by comprehensive benchmark dose (BMD) approach, that would improve both identification and quantification of the effect and allow more rigorous comparison of efficacies. Thus, we have examined in vivo dose-response relationship for two promising experimental oximes, K203 and K027, concerning reactivation of erythrocyte AChE inhibited by dichlorvos (DDVP). Groups of Wistar rats were treated with six different doses of oximes (i.m) immediately after DDVP challenge (s.c) and AChE was measured 60 min later. Dose-response modeling was done by PROAST software 65.5 (RIVM, The Nederlands). BMD-covariate method resulted in four-parameter model from both exponential and Hill model families as the best estimate of relationship between AChE activity and oxime dose, with potency parameter being oxime-dependent. Oxime K027 was shown to be 1.929-fold more potent considering that 58% increase in AChE activity was achived with the dose BMD58-K027 = 52 mu mol/kg in contrast to BMD58-K203 = 100 mu mol/kg.", publisher = "Pergamon-Elsevier Science Ltd, Oxford", journal = "Food and Chemical Toxicology", title = "Dose-response modeling of reactivating potency of oximes K027 and K203 against a direct acetylcholinesterase inhibitor in rat erythrocytes", volume = "121", pages = "224-230", doi = "10.1016/j.fct.2018.08.065" }
Antonijević, E., Musilek, K., Kuca, K., Đukić-Ćosić, D., Curcić, M., Ćupić Miladinović, D., Bulat, Z.,& Antonijević, B.. (2018). Dose-response modeling of reactivating potency of oximes K027 and K203 against a direct acetylcholinesterase inhibitor in rat erythrocytes. in Food and Chemical Toxicology Pergamon-Elsevier Science Ltd, Oxford., 121, 224-230. https://doi.org/10.1016/j.fct.2018.08.065
Antonijević E, Musilek K, Kuca K, Đukić-Ćosić D, Curcić M, Ćupić Miladinović D, Bulat Z, Antonijević B. Dose-response modeling of reactivating potency of oximes K027 and K203 against a direct acetylcholinesterase inhibitor in rat erythrocytes. in Food and Chemical Toxicology. 2018;121:224-230. doi:10.1016/j.fct.2018.08.065 .
Antonijević, Evica, Musilek, Kamil, Kuca, Kamil, Đukić-Ćosić, Danijela, Curcić, Marijana, Ćupić Miladinović, Dejana, Bulat, Zorica, Antonijević, Biljana, "Dose-response modeling of reactivating potency of oximes K027 and K203 against a direct acetylcholinesterase inhibitor in rat erythrocytes" in Food and Chemical Toxicology, 121 (2018):224-230, https://doi.org/10.1016/j.fct.2018.08.065 . .