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Efficacy of Trimedoxime in Mice Poisoned with Dichlorvos, Heptenophos Or Monocrotophos

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Efficacy of Trimedoxime in Mice Poisoned with Dichlorvos, Heptenophos Or Monocrotophos CORE Metadata, citation and similar papers at core.ac.uk Provided by FarFar - Repository of the Faculty of Pharmacy, University of Belgrade C Basic & Clinical Pharmacology & Toxicology 2005, 96, 111–117. Printed in Denmark . All rights reserved Copyright C ISSN 1742-7835 Efficacy of Trimedoxime in Mice Poisoned with Dichlorvos, Heptenophos or Monocrotophos Biljana Antonijevic´1, Dubravko Bokonjic´2, Milosˇ P. Stojiljkovic´2, Vesna Kilibarda2, Zoran A. Milovanovic´2, Mirjana Nedeljkovic´1 and Matej Maksimovic´1 1Institute of Toxicological Chemistry, School of Pharmacy, University of Belgrade, Vojvode Stepe 450, and 2National Poison Control Centre, Military Medical Academy, Crnotravska 17; 11000 Belgrade, Serbia and Montenegro (Received June 18, 2004; Accepted September 3, 2004) Abstract: The aim of the study was to examine antidotal potency of trimedoxime in mice poisoned with three direct dimethoxy-substituted organophosphorus inhibitors. In order to assess the protective efficacy of trimedoxime against dichlorvos, heptenophos or monocrotophos, median effective doses and efficacy half-times were calculated. Trimedoxime (24 mg/kg intravenously) was injected 5 min. before 1.3 LD50 intravenously of poisons. Activities of brain, diaphragmal and erythrocyte acetylcholinesterase, as well as of plasma carboxylesterases were determined at different time intervals (10, 40 and 60 min.) after administration of the antidotes. Protective effect of trimedoxime decreased according to the following order: monocrotophos Ͼ heptenophos Ͼ dichlorvos. Administration of the oxime produced a significant reacti- vation of central and peripheral acetylcholinesterase inhibited with dichlorvos and heptenophos, with the exception of erythrocyte acetylcholinesterase inhibited by heptenophos. Surprisingly, trimedoxime did not induce reactivation of mon- ocrotophos-inhibited acetylcholinesterase in any of the tissues tested. These organophosphorus compounds produced a significant inhibition of plasma carboxylesterase activity, while administration of trimedoxime led to regeneration of the enzyme activity. The same dose of trimedoxime assured survival of experimental animals poisoned by all three organ- ophosphorus compounds, although the biochemical findings were quite different. The primary molecular mechanism of action of the organ- are: weak ability to inhibit cholinesterase, direct reaction ophosphorus compounds is inhibition of acetylcholine- with organophosphates, anticholinergic effect similar to sterase (AChE, EC 3.1.1.7.) (Koelle 1975). Inhibition of that of atropine, sympathomimetic effect potentiating the AChE results in accumulation of acetylcholine (ACh) at the pressor effect of adrenaline, depolarising effect at the neuro- synaptic cleft of the cholinergic neurones, leading to oversti- muscular junction and direct influence on synaptic trans- mulation of cholinergic receptors. In addition to the inhi- mission by mechanisms that are not clear at present (Bosˇ- bition of AChE, organophosphorus compounds clearly kovic´ & Stern 1963; Clement 1981; Busker et al. 1991; Mel- have a potential to interact with other esterases such as car- chers et al. 1991; Van Helden et al. 1991 & 1996; Becker et boxylesterases (EC 3.1.1.1.). Carboxylesterases play an im- al. 1997). However, some failures of the standard therapy in portant role in the detoxification of organophosphorus organophosphate poisoning are due to the unequal effec- compounds via hydrolysis of ester bond in these compounds tiveness of oximes in the treatment of intoxications caused and binding of the compounds at the active site of carboxyl- by different organophosphorus compounds (Bismuth et al. esterases that reduces the free concentration of organophos- 1992; Dawson 1994; Thiermann et al. 1999; Worek et al. phate potentially available to inhibit acetylcholinesterase 1996, 1997, 1998, 1999, 2002 & 2004). Many in vitro and in (Jokanovic´ et al. 1996; Sogorb & Vilanova 2002). vivo studies have been focused on the efficacy of the oximes Together with atropine pyridinium oximes (pralidoxime, in organophosphate poisoning. Although some of them trimedoxime, obidoxime, HI-6, HLö-7) represent the most were very difficult to interpret due to the differences in ex- important component of the specific therapy used against perimental design, it could be summarised that trimedoxime organophosphate poisoning (Bismuth et al. 1992; Karallied- (TMB-4) and obidoxime (LüH-6) were superior to the other de & Szinicz 2001). Since the resulting inhibited AChE is oximes used in organophosphorus insecticide poisoning generally considered very stable and is only slowly reactiv- (Sanderson & Edson 1959; Jokanovic´ & Maksimovic´ 1995; ated by spontaneous hydrolysis of the phosphate ester, the Worek et al. 1996, 1997 & 1999). It is also well known that essential role of the oximes is their ability to reactivate in- TMB-4 and LüH-6 (differing only in the structure of the hibited AChE (Worek et al. 1997; Thiermann et al. 1999). bridge between the two pyridinium rings) have a great react- Other effects attributed to the oximes (in very high doses) ivating potential, which explains their antidotal efficacy against a number of organophosphorus insecticides (Hob- biger & Vojvodic´ 1966; De Jong et al. 1982; Worek et al. Author for correspondence: Biljana Antonijevic´, Institute of Toxi- 1996). Generally, the antidotal effect is highly dependent on cological Chemistry, School of Pharmacy, University of Belgrade, Vojvode Stepe 450, 11000 Belgrade, Serbia and Montenegro (fax the type of the anticholinesterase and the oxime used. π381 11 3972 840, e-mail abiljana/pharmacy.bg.ac.yu). Concerning all these data on oxime efficacy, the aim of 112 BILJANA ANTONIJEVIC´ ET AL. the present study was (1) to examine and compare antidotal Table 1. potency of TMB-4 in mice poisoned with three direct dime- Intravenous median lethal doses of TMB-4 and organophosphorus thoxy-substituted inhibitors: dichlorvos, heptenophos and compounds. monocrotophos, and (2) to correlate the protective efficacy LD50 value 95% confidence and reactivating ability of TMB-4 in central and peripheral Compounds (mmol/kg) interval tissues of experimental animals. TMB-4 238.61 199.92–284.78 Monocrotophos 20.34 15.60–25.95 Dichlorvos 22.17 16.24–30.22 Materials and Methods Heptenophos 196.68 163.72–208.41 Experimental animals. Male albino mice (18–24 g) were obtained from the Military Medical Academy, Belgrade. The animals were rested at least one week before the experiment and received food in mice treated with organophosphorus compounds (table 2) was and tap water ad libitum. calculated by means of 2¿2 assay (Pharm-Pharmacological Calcu- The study protocol was based on the Guidelines for Animal lation System, v.4.0, Springer-Verlag, New York, USA, 1986). Study no. 282-12/2002 (Ethics Committee of the Military Medical Statistical significance between groups was determined by Mann- Academy, Belgrade, Serbia and Montenegro). Whitney U-test (fig. 2) and Student’s t-test (fig. 3, 4 & 5). The differ- ences were considered significant when P value was less than 0.05. Chemicals. Trimedoxime (1,1ø-trimethylene bis(4-hydroxyimino Statistical analyses were performed with commercial statistical soft- methyl) pyridinium dichloride), was obtained from the Military ware for PC, Stat for Windows R. 5.0. Medical Academy, Belgrade and was 99% pure when examined by HPLC. Dichlorvos (2,2-dichlorovinyldimethylphosphate) (94.0%), Results heptenophos ((7-chlorobicyclo[3.2.0]hepta-2,6-dien-6-yl)dimethyl- phosphate) (92.0%) and monocrotophos (O,O-dimethyl-O-(1- Intravenous LD50s of investigated compounds are given in methyl-2-methyl-carbamoylvinyl) phosphate) (82.8%) were pur- table 1. It is evident that LD50 of heptenophos is about chased from the domestic commercial sources. Structural formulae are presented in fig. 1. 10 times higher than in the other two organophosphorus Stock solutions of organophosphates were prepared in isopro- compounds tested. This finding should be ascribed to com- panol. Oxime was dissolved in distilled water and diluted to the plex interactions of numerous factors such as electronic ef- required concentration immediately before use. All the solutions fects, hydrophobicity, steric effects, ionic bonds, toxicoki- were administered intravenously via the tail vein at a volume of 0.1 ml/20 g of body mass. netic properties and non-anticholinesterase effects (Max- well & Lenz 1992). Experimental procedures. Toxicity signs were typical of cholinesterase inhibition. Protection. In the studies of antidotal protection, experimental ani- Time to their onset was short and death usually occurred mals were pretreated intravenously with increasing doses of TMB- within 5–10 min. after administration of a lethal dose. This 4 at different time intervals (5–60 min.) before 1.3 LD50 intra- venously of organophosphates. Median lethal doses of the tested very short survival of mice that were not pretreated with compounds (LD50) and median effective doses of oxime (ED50t) TMB-4 imposed use of an experimental model based on were calculated according to the method of Litchfield & Wilcoxon administration of the oxime at various times before intra- (1949), with 95% confidence limits. Median effective doses of the venous injection of organophosphorus compounds. oxime along with the corresponding time intervals were used to cal- Use of TMB-4 against monocrotophos protected success- culate ED50 at null time (ED500) and efficacy half-time (t1/2 effi- cacy) (Schoene et al. 1988). Biochemistry. In the biochemical
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