TY  - JOUR
AU  - Antonijević, Biljana
AU  - Maksimović, Matej
AU  - Kilibarda, Vesna
AU  - Stojiljković, Miloš P.
AU  - Nedeljković, Mirjana
AU  - Milovanović, Zoran A.
AU  - Bokonjić, Dubravko
PY  - 2001
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/305
AB  - The aim of this study was to investigate the efficacy of four pyridinium oximes - pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LuH-6) and HI-6 - alone or in combination with memantine and its principal metabolite 1-amino-3-hydroxymethyl-5-methyl adamantane (Mrz 2/373) against soman in mice. Male Albino mice were pretreated iv with oximes and adamantanes at various times before 1.3 LD-50 of soman iv in order to obtain their ED-50t. In a separate experiment, the brain, dia­phragmai and erythrocytic acetylcholinesterase and plasma carboxylesterase activities were determined after sacrificing mice 5 min after soman 0.75 LD-50. Oxime HI-6 (ED-50 value at 5 min before soman) and adamantanes were administered 5 min before soman. In the combination regimens and in the biochemical experiments the dose of memantine and Mrz 2/373 was fixed at 10 mg/kg iv. Along the tested time intervals, HI-6 afforded the best protection of experimental animals, and calculated EDSOo value of HI-6 was 7.96 µmol/kg. Memantine significantly (up to 9 times) de­creased ED-500 values of all the oximes used, with the exception of TMB-4. Among tested tis­sues, the highest recovery of inhibited acetylcholinesterase was obtained in the diaphragm. Co-administration of adamantanes (memantine, Mrz 2/373) produced a statistically significant in­crease in the erythrocyte acetylcholinesterase activity. It could be concluded that memantine antidotal efficacy could be ascribed to the protection of acetylcholinesterase activity. .
AB  - Pored činjenice daje oksim HI-6 najefikasniji u antagonizovanju toksičnih efekata somana, terapija trovanja ovim nervnim bojnim otrovom još nije u potpunosti zadovoljavajuća. Dosadašnji eksperimenti sa memantinom su pokazali da ovaj derivat adamantana potencira terapijski efekat standardnih antidota pri trovanju organofosfornim jedinjenjima. U ovom radu ispitivana je antidotska efikasnost piridinijumskih oksima - pralidoksima, trimedoksima, obidoksima i HI-6, kao i njihovih kombinacija sa memantinom ili njegovim aktivnim metabolitom Mrz 2/373 u miševa trovanih somanom. Radi dobijanja parametara zaštitne efikasnosti antidota, albino miševima mužjacima su iv aplikovane rastuće doze antidota u određenim vremenskim intervalima ( 1 -60 min) pre 1,3 LD-50 iv somana. Aktivnosti acetilholinesteraze mozga, dijafragme i eritrocita, kao i karboksilesteraza plazme, određivane su nakon iv primene adamantana (10 mg/kg) i/ili oksima HI-6 (3,1 mg/kg; 7,96 µmol/kg) datih 5 min pre 0,75 LD-50 iv somana. Primena oksima HI-6 je obezbedila najbolju zaštitu eksperimentalnih životinja, a srednja efektivna doza u nultom vremenu ED-500 iznosila je 7,96 µmol/kg. Kada je primenjen u kombinaciji sa oksimima, memantin je doveo do značajnog (oko 9 puta) smanjenja HD-500 vrednosti svih oksima, osim trimedoksima. ali je zato poluvreme efikasnosti trimedoksima povećano 4,82 puta. Značajan porast acetilholinesteraze dijafragme dobijen je primenom HI-6, memantina kao i njihove kombinacije. U odnosu na grupu koja je primila samo soman, aktivnost acetilholi­nesteraze eritrocita bila je značajno veća u grupama kojima su davani adamantani i/ili HI-6. Nijedan od primenjenih tretmana nije doveo do statistički značajnog povećanja aktivnosti acetilholinesteraze mozga i karboksilesteraza plazme. Bolji zaštitni efekt kombinacija oksima i memantina u odnosu na same oksime mogao bi se pripisati antikonvulzivnom potencijalu memantina, koji je nekompetitivni antagonista NMDA receptora, ali i izvesnoj zaštiti aktivnog centra acetilholinesteraze dijafragme.
PB  - Srpsko lekarsko društvo - Sekcija za toksikologiju, Beograd
T2  - Archives of Toxicology, Kinetics and Xenobiotic Metabolism
T1  - Potential beneficial action of adamantanes in mice poisoned with soman
T1  - Potencijalna uloga adamantana u trovanju miševa somanom
VL  - 9
IS  - 1-2
SP  - 13
EP  - 20
UR  - https://hdl.handle.net/21.15107/rcub_farfar_305
ER  - 

@article{
author = "Antonijević, Biljana and Maksimović, Matej and Kilibarda, Vesna and Stojiljković, Miloš P. and Nedeljković, Mirjana and Milovanović, Zoran A. and Bokonjić, Dubravko",
year = "2001",
abstract = "The aim of this study was to investigate the efficacy of four pyridinium oximes - pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LuH-6) and HI-6 - alone or in combination with memantine and its principal metabolite 1-amino-3-hydroxymethyl-5-methyl adamantane (Mrz 2/373) against soman in mice. Male Albino mice were pretreated iv with oximes and adamantanes at various times before 1.3 LD-50 of soman iv in order to obtain their ED-50t. In a separate experiment, the brain, dia­phragmai and erythrocytic acetylcholinesterase and plasma carboxylesterase activities were determined after sacrificing mice 5 min after soman 0.75 LD-50. Oxime HI-6 (ED-50 value at 5 min before soman) and adamantanes were administered 5 min before soman. In the combination regimens and in the biochemical experiments the dose of memantine and Mrz 2/373 was fixed at 10 mg/kg iv. Along the tested time intervals, HI-6 afforded the best protection of experimental animals, and calculated EDSOo value of HI-6 was 7.96 µmol/kg. Memantine significantly (up to 9 times) de­creased ED-500 values of all the oximes used, with the exception of TMB-4. Among tested tis­sues, the highest recovery of inhibited acetylcholinesterase was obtained in the diaphragm. Co-administration of adamantanes (memantine, Mrz 2/373) produced a statistically significant in­crease in the erythrocyte acetylcholinesterase activity. It could be concluded that memantine antidotal efficacy could be ascribed to the protection of acetylcholinesterase activity. ., Pored činjenice daje oksim HI-6 najefikasniji u antagonizovanju toksičnih efekata somana, terapija trovanja ovim nervnim bojnim otrovom još nije u potpunosti zadovoljavajuća. Dosadašnji eksperimenti sa memantinom su pokazali da ovaj derivat adamantana potencira terapijski efekat standardnih antidota pri trovanju organofosfornim jedinjenjima. U ovom radu ispitivana je antidotska efikasnost piridinijumskih oksima - pralidoksima, trimedoksima, obidoksima i HI-6, kao i njihovih kombinacija sa memantinom ili njegovim aktivnim metabolitom Mrz 2/373 u miševa trovanih somanom. Radi dobijanja parametara zaštitne efikasnosti antidota, albino miševima mužjacima su iv aplikovane rastuće doze antidota u određenim vremenskim intervalima ( 1 -60 min) pre 1,3 LD-50 iv somana. Aktivnosti acetilholinesteraze mozga, dijafragme i eritrocita, kao i karboksilesteraza plazme, određivane su nakon iv primene adamantana (10 mg/kg) i/ili oksima HI-6 (3,1 mg/kg; 7,96 µmol/kg) datih 5 min pre 0,75 LD-50 iv somana. Primena oksima HI-6 je obezbedila najbolju zaštitu eksperimentalnih životinja, a srednja efektivna doza u nultom vremenu ED-500 iznosila je 7,96 µmol/kg. Kada je primenjen u kombinaciji sa oksimima, memantin je doveo do značajnog (oko 9 puta) smanjenja HD-500 vrednosti svih oksima, osim trimedoksima. ali je zato poluvreme efikasnosti trimedoksima povećano 4,82 puta. Značajan porast acetilholinesteraze dijafragme dobijen je primenom HI-6, memantina kao i njihove kombinacije. U odnosu na grupu koja je primila samo soman, aktivnost acetilholi­nesteraze eritrocita bila je značajno veća u grupama kojima su davani adamantani i/ili HI-6. Nijedan od primenjenih tretmana nije doveo do statistički značajnog povećanja aktivnosti acetilholinesteraze mozga i karboksilesteraza plazme. Bolji zaštitni efekt kombinacija oksima i memantina u odnosu na same oksime mogao bi se pripisati antikonvulzivnom potencijalu memantina, koji je nekompetitivni antagonista NMDA receptora, ali i izvesnoj zaštiti aktivnog centra acetilholinesteraze dijafragme.",
publisher = "Srpsko lekarsko društvo - Sekcija za toksikologiju, Beograd",
journal = "Archives of Toxicology, Kinetics and Xenobiotic Metabolism",
title = "Potential beneficial action of adamantanes in mice poisoned with soman, Potencijalna uloga adamantana u trovanju miševa somanom",
volume = "9",
number = "1-2",
pages = "13-20",
url = "https://hdl.handle.net/21.15107/rcub_farfar_305"
}

Antonijević, B., Maksimović, M., Kilibarda, V., Stojiljković, M. P., Nedeljković, M., Milovanović, Z. A.,& Bokonjić, D.. (2001). Potential beneficial action of adamantanes in mice poisoned with soman. in Archives of Toxicology, Kinetics and Xenobiotic Metabolism
Srpsko lekarsko društvo - Sekcija za toksikologiju, Beograd., 9(1-2), 13-20.
https://hdl.handle.net/21.15107/rcub_farfar_305

Antonijević B, Maksimović M, Kilibarda V, Stojiljković MP, Nedeljković M, Milovanović ZA, Bokonjić D. Potential beneficial action of adamantanes in mice poisoned with soman. in Archives of Toxicology, Kinetics and Xenobiotic Metabolism. 2001;9(1-2):13-20.
https://hdl.handle.net/21.15107/rcub_farfar_305 .

Antonijević, Biljana, Maksimović, Matej, Kilibarda, Vesna, Stojiljković, Miloš P., Nedeljković, Mirjana, Milovanović, Zoran A., Bokonjić, Dubravko, "Potential beneficial action of adamantanes in mice poisoned with soman" in Archives of Toxicology, Kinetics and Xenobiotic Metabolism, 9, no. 1-2 (2001):13-20,
https://hdl.handle.net/21.15107/rcub_farfar_305 .

TY  - JOUR
AU  - Jokanović, Milan
AU  - Maksimović, Matej
AU  - Stepanović-Petrović, Radica
PY  - 1995
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/121
AB  - Phosphamidon (PSM) is an organophosphorus insecticide widely used in agriculture. This study was undertaken to examine the interaction of PSM with acetylcholinesterase (AChE) and neuropathy target esterase (NTE) of hen brain in vitro and in vivo. PSM was a potent inhibitor of AChE, with an I50 of 2.9μM and second-order rate constant (ka) of 1.2×104 M-1 min-1 at 37°C. PSM-inhibited AChE aged rapidly (t1/2=1.9h). Pyridinium oximes pralidoxime, trimedoxime, obidoxime and HI-6 were effective reactivators of PSM-inhibited AChE, providing up to 75% reactivation. PSM was one of the weakest inhibitors of NTE among organophosphorus compounds, with an I50 of 19 mM and ka of 1.8 M-1 min-1 at 37°C. Inhibited NTE did not reactivate spontaneously and KF-induced reactivation was not obtained even at the earliest tested moments, so it was not clear whether aging of PSM-inhibited NTE occurred very quickly or the KF molecule could not affect the stability of phosphoryl-NTE bond. From the ratio of kas for NTE and AChE (0.00015) it was predicted that delayed neuropathic effects of PSM in vivo would appear only at doses far above the acute LD50. The LD50 value of PSM p.o. for hens was 9 mg/kg. Hens were treated with a single oral dose of PSM, combined with standard antidotal treatment which included atropine, physostigmine, pralidoxime and anticonvulsant midazolam. Doses of 90 and 250 mg/kg caused up to 27% and 45% NTE inhibition 48h after poisoning, respectively. Clinical signs of neuropathy were not seen up to 25 days after treatment, which could be expected, since the proposed level (>70%) of NTE inhibition necessary for the occurrence of delayed neuropathy was not achieved. The results suggest that PSM, at doses tested, has no ability to cause delayed neuropathy in hens without showing signs of severe cholinergic intoxication.
PB  - Springer-Verlag
T2  - Archives of Toxicology
T1  - Interaction of phosphamidon with neuropathy target esterase and acetylcholinesterase of hen brain
VL  - 69
IS  - 6
SP  - 425
EP  - 428
DO  - 10.1007/s002040050195
ER  - 

@article{
author = "Jokanović, Milan and Maksimović, Matej and Stepanović-Petrović, Radica",
year = "1995",
abstract = "Phosphamidon (PSM) is an organophosphorus insecticide widely used in agriculture. This study was undertaken to examine the interaction of PSM with acetylcholinesterase (AChE) and neuropathy target esterase (NTE) of hen brain in vitro and in vivo. PSM was a potent inhibitor of AChE, with an I50 of 2.9μM and second-order rate constant (ka) of 1.2×104 M-1 min-1 at 37°C. PSM-inhibited AChE aged rapidly (t1/2=1.9h). Pyridinium oximes pralidoxime, trimedoxime, obidoxime and HI-6 were effective reactivators of PSM-inhibited AChE, providing up to 75% reactivation. PSM was one of the weakest inhibitors of NTE among organophosphorus compounds, with an I50 of 19 mM and ka of 1.8 M-1 min-1 at 37°C. Inhibited NTE did not reactivate spontaneously and KF-induced reactivation was not obtained even at the earliest tested moments, so it was not clear whether aging of PSM-inhibited NTE occurred very quickly or the KF molecule could not affect the stability of phosphoryl-NTE bond. From the ratio of kas for NTE and AChE (0.00015) it was predicted that delayed neuropathic effects of PSM in vivo would appear only at doses far above the acute LD50. The LD50 value of PSM p.o. for hens was 9 mg/kg. Hens were treated with a single oral dose of PSM, combined with standard antidotal treatment which included atropine, physostigmine, pralidoxime and anticonvulsant midazolam. Doses of 90 and 250 mg/kg caused up to 27% and 45% NTE inhibition 48h after poisoning, respectively. Clinical signs of neuropathy were not seen up to 25 days after treatment, which could be expected, since the proposed level (>70%) of NTE inhibition necessary for the occurrence of delayed neuropathy was not achieved. The results suggest that PSM, at doses tested, has no ability to cause delayed neuropathy in hens without showing signs of severe cholinergic intoxication.",
publisher = "Springer-Verlag",
journal = "Archives of Toxicology",
title = "Interaction of phosphamidon with neuropathy target esterase and acetylcholinesterase of hen brain",
volume = "69",
number = "6",
pages = "425-428",
doi = "10.1007/s002040050195"
}

Jokanović, M., Maksimović, M.,& Stepanović-Petrović, R.. (1995). Interaction of phosphamidon with neuropathy target esterase and acetylcholinesterase of hen brain. in Archives of Toxicology
Springer-Verlag., 69(6), 425-428.
https://doi.org/10.1007/s002040050195

Jokanović M, Maksimović M, Stepanović-Petrović R. Interaction of phosphamidon with neuropathy target esterase and acetylcholinesterase of hen brain. in Archives of Toxicology. 1995;69(6):425-428.
doi:10.1007/s002040050195 .

Jokanović, Milan, Maksimović, Matej, Stepanović-Petrović, Radica, "Interaction of phosphamidon with neuropathy target esterase and acetylcholinesterase of hen brain" in Archives of Toxicology, 69, no. 6 (1995):425-428,
https://doi.org/10.1007/s002040050195 . .