022-0222148-2139 Therapeutic Effect of Newly-synthesized Compounds in Organophosphorus Poisoning
MINISTRY OF SCIENCE, EDUCATION AND SPORTS OF THE REPUBLIC OF CROATIA (2007-2014)
Principal Investigator: Božica Radić (until 31 September 2010), Ana Lucić Vrdoljak (since 1 January 2011)
General toxicological effect of organophosphorus compounds (OPc) is based on irreversible inhibition of the hydrolytic enzymes; vitally important acetylcholinestrase (AChE) and butyrylcholinesterase (BuChE). These compounds primarily affect the cholinergic nerve system. Besides their wide and beneficial use in agriculture, public health, and in human and veterinary medicine, they are used as harmful nerve agents in chemical warfare. Despite numerous research efforts, there is no efficient antidote for OPc poisoning, especially by nerve agents. Therefore, the ultimate goal of our research is to contribute to the development of new, satisfactorily effective antidotes.
It has been known that compounds containing an oxime group (oximes) and primarily nucleophilic properties reactivate the inhibited AchE, and protect its inhibition. That is the main reason for synthetyzation of the new classes of oximes (imidazolium, imidazolium-pyridinium, pyridinium oximes), non-oxime compounds but also of other compounds that could protect or reduce the effects of OPc poisoning through some other mechanisms that cannot be attributed to AChE protection or reactivation (e.g. adamantane derivatives which are the antagonists for N-methyl-D-aspartate receptors). The research deals with basic toxicity of each new compound, their cytotoxicity, genotoxicity as well as with rapidity of achieving therapeutic levels in the blood, distribution and retention within, and elimination from the body. The research investigates possible synergistic effects of these new compounds when applied according to a modified therapeutic protocol (related to pretreatment, treatment, supplemental therapy), which has been a proven method to identify the most effective antidote. In order to determine whether the oxidative stress is involved in the mechanism of OPc toxic effects, we will examine the biomarkers of oxidative damage of lipids (malondyaldehide) and proteins (antioxidation enzymes), as well as of relieving effects of OPc poisoning by antioxidants. A part of the research will investigate the properties of BuChE as a natural antidote for OPc, but also the role of this enzyme in the lipid and lipoprotein metabolism. The research will be performed in vitro and in vivo on experimental animals.
The results of the proposed scientific research could be of great practical value for the use in clinical toxicology, and, consequently, of considerable commercial importance for the pharmaceutical industry.