Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima

Zorbaz, Tamara

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doctoral thesis

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New approach to the analysis of oximes designed to protect central nervous system in organophosphorus poisoning

Tamara Zorbaz (2019)

University of Zagreb
Faculty of Science
Department of Chemistry

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APA 6th Edition

Zorbaz, T. (2019). Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima (Doctoral thesis). Retrieved from https://urn.nsk.hr/urn:nbn:hr:217:451370

MLA 8th Edition

Zorbaz, Tamara. "Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima." Doctoral thesis, University of Zagreb, Faculty of Science, 2019. https://urn.nsk.hr/urn:nbn:hr:217:451370

Chicago 17th Edition

Harvard

Zorbaz, T. (2019). 'Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima', Doctoral thesis, University of Zagreb, Faculty of Science, accessed 24 March 2019, https://urn.nsk.hr/urn:nbn:hr:217:451370

Vancouver

Zorbaz T. Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima [Doctoral thesis]. Zagreb: University of Zagreb, Faculty of Science; 2019 [cited 2019 March 24] Available at: https://urn.nsk.hr/urn:nbn:hr:217:451370

IEEE

T. Zorbaz, "Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima", Doctoral thesis, University of Zagreb, Faculty of Science, Zagreb, 2019. Available at: https://urn.nsk.hr/urn:nbn:hr:217:451370

Cite this item: https://urn.nsk.hr/urn:nbn:hr:217:451370

Metadata

Title	Novi pristup analizi oksima dizajniranih za zaštitu središnjeg živčanog sustava pri trovanju organofosfornim spojevima
Title (english)	New approach to the analysis of oximes designed to protect central nervous system in organophosphorus poisoning
Author	Tamara Zorbaz
Mentor	Zrinka Kovarik (mentor)
Committee member	Ines Primožič (predsjednik povjerenstva)
Committee member	Maja Katalinić (član povjerenstva)
Committee member	Jasmina Rokov Plavec (član povjerenstva)
Granter	University of Zagreb Faculty of Science (Department of Chemistry) Zagreb
Defense date and country	2019-11-09, Croatia
Scientific / art field, discipline and subdiscipline	NATURAL SCIENCES Chemistry
Universal decimal classification (UDC)	54 NATURAL SCIENCES Chemistry. Crystallography. Mineralogy
Abstract	Toksični organofosforni spojevi inhibiraju acetilkolinesterazu (AChE; EC 3.1.1.7) u sinapsama perifernog i središnjeg živčanog sustava (SŽS) te uzrokuju smrt ili dugotrajne neurološke poremećaje. Današnja terapija jesu oksimski reaktivatori inhibirane AChE, ali oni ne postižu dovoljne koncentracije u SŽS-u. Učinkovitost novosintetiziranih hidroksipiridinskih i klorpiridinijevih oksima dizajniranih s ciljem prolaska u SŽS ispitana je detaljnim kinetičkim istraživanjima reaktivacije AChE i butirilkolinestereraze (EC 3.1.1.8) inhibirane sarinom, ciklosarinom, VX-om, tabunom i paraoksonom. Analize njihovih fizikalno-kemijskih svojstava bitnih za prolazak u SŽS, in vitro toksičnosti, metaboličke stabilnosti i farmakokinetičkog profila na modelu miša, poslužile su za racionalan odabir vodećeg oksima za daljnja istraživanja, oksima 2-[(hidroksiimino)metil]-6-[4-(morfolin-4-il)butil]piridin-3-ola, koji ima potencijal reaktivirati AChE u perifernim tkivima i mozgu. Ovaj pristup analizi omogućio je bolji probir vodećih reaktivatora od uobičajene analize bazirane na reaktivacijskoj učinkovitosti oksima. Stoga se preporuča da ovakva evaluacija reaktivatora prethodi in vivo antidotskim testiranjima u smislu uvažavanja općeprihvaćenih pravila za zaštitu životinja.
Abstract (english)	Toxic organophosphorus compounds inhibit acetylcholinesterase (AChE; EC 3.1.1.7) in the synapses of the peripheral and central nervous system (CNS) and cause death or long-term neurological impairments. Therapy includes oxime reactivators of the inhibited AChE, but they do not achieve sufficient concentrations in the CNS. The efficiency of newly-synthesized hydroxyl-pyridine and chloro-pyridinium oximes, designed with an aim to cross into the CNS, was evaluated here with a detailed kinetic investigation of the reactivation of AChE and butyrylcholinesterase (EC 3.1.1.8) inhibited by sarin, cyclosarin, VX, tabun and paraoxon. Analyses of physicochemical properties important for crossing into the CNS, in vitro toxicity, metabolic stability and pharmacokinetic profile in mouse model, were used for the rational determination of the lead oxime for further tests, 2-((hydroxyimino)methyl)-6-(4-(morpholin-4-yl)butyl)pyridin-3-ol oxime, that has potency to reactivate AChE in peripheral tissues and the brain. This approach enabled better screening for lead compounds in comparison to the standard analysis based on the reactivation efficiency of the oximes. Therefore, this kind of reactivatior evaluation is recommended before in vivo antidotal testing, as it would singificantly improve adherence to rules for animal welfare.
Keywords
Keywords (english)
Language	croatian
URN:NBN	urn:nbn:hr:217:451370
Study programme	Title: Kemija Study programme type: sveučilišni Study level: poslijediplomski doktorski Academic / professional title: doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija (doktor/doktorica znanosti, područje prirodnih znanosti, polje kemija)
Type of resource	text
Extent	162 str. ; 30 cm
File origin	Born digital
Access conditions	Open access
Terms of use
Repository	Repository of Faculty of Science
Created on	2019-01-09 10:40:24