Search

Introduction/Aim. In acute organophosphate poisoning the issue of special concern is the appearance of muscle fasciculations and convulsions that cannot be adequately antagonised by the use of atropine and oxime therapy. The aim of this study was to examine atidotal effect of obidoxime or HI-6 combinations with memantine in mice poisoned with soman, dichlorvos or heptenophos. Methods. Male Albino mice were pretreated intravenously (iv) with increasing doses of oximes and/or memantine (10 mg/kg) at various times before poisoning with 1.3 LD-50 of soman, dichlorvos or heptenophos, in order to determine the median effective dose and the efficacy half-time. In a separate experiment, cerebral extravasation of Evans blue dye (40 mg/kg iv) was examined after application of memantine (10 mg/kg iv), midazolam (2.5 mg/kg intraperitonealy - ip) and ketamine (20 mg/kg ip) 5 minutes before soman (1 LD-50 subcutaneously - sc). Results. Coadministration of memantine induced a significant decrease in median effective dose in null time of both HI-6 (7.96 vs 1.79 mmoL/kg in soman poisoning) and obidoxime (16.80 vs 2.75 mmoL/kg in dichlorvos poisoning; 21.56 vs 6.63 mmoL/kg in heptenophos poisoning). Memantine and midazolam succeeded to counteract the soman-induced proconvulsive activity. Conclusion. Memantine potentiated the antidotal effect of HI-6 against a lethal dose of soman, as well as the ability of obidoxime to antagonize the toxic effects of dichlorvos and heptenophos probably partly due to its anticonvulsive properties., Uvod/Cilj. Poseban problem pri trovanju organofosfornim jedinjenjima predstavljaju mišićne fascikulacije i konvulzije, koje se ne mogu u potpunosti antagonizovati primenom atropina i oksima. Cilj ovog rada bio je ispitivanje antidotskog efekta kombinacije memantina i oksima HI-6 kod trovanja somanom, kao i kombinacije memantina sa obidoksimom kod trovanja dihlorvosom i heptenofosom. Metode. Albino miševima, mužjacima, u repnu venu date su rastuće doze oksima i/ili memantina (10 mg/kg) u različitim vremenskim intervalima pre intravenskog (iv) davanja 1,3 LD-50 somana, dihlorvosa ili heptenofosa. Praćenjem stepena preživljanja, izračunate su srednje efektivne doze i poluvreme efikasnosti. U odvojenom eksperimentu praćena je cerebralna ekstravazacija boje Evans plavo (40 mg/kg iv) nakon primene memantina (10 mg/kg iv), midazolama (2,5 mg/kg intraoperitonealno - ip) i ketamina (20 mg/kg ip) 5 min pre davanja somana (1 LD-50 supkutano - sc). Rezultati. Primenom kombinacija sa memantinom srednje efektivne doze u nultom vremenu i HI-6 (7,96 vs 1,79 mmoL/kg kod trovanja somanom) i obidoksima (16,80 vs 2,75 mmoL/kg kod trovanja dihlorvosom; 21,56 vs 6,63 mmoL/kg kod trovanja heptenofosom) bile su višestruko niže u odnosu na dozu samog oksima. Memantin i midazolam uspešno su suprimirali prokonvulzivni efekat somana. Zaključak. Rezultati ove studije pokazuju da primena memantina u kombinaciji sa oksimima obezbeđuje bolji zaštitni efekat nego sam oksim, a u osnovi ovog efekta verovatno leži i njegov antikonvulzivni potencijal.

T-2 mycotoxin, secondary metabolite of Fusarium fungi, is one of the most potent cytotoxic representatives of trichothecene mycotoxin type A. After ingestion, T-2 toxin affects actively dividing cells and irreversible post-mitotic cells. In our experiments, the best protective effects were produced by dexametasone (PI = 3.37) and different methylprednisolone formulations (PI = 2.43-2.64). Significant protective efficacy was shown by nimesulide (PI = 1.44) and N-acethyilcistein (PI = 1.29), but their values were higher in a combination with methylprednisolone (PI = 2.16-2.34). Radioprotector amifostine (WR-2721) expressed good protective effects (PI = 1.26) or/and different absorbent formulations, such as: activated charcoal (PI = 1.13) and various Min-a-zel® powder compounds, which are a well known zeolite clinoptilolite absorbents. Among the five zeolite regimens investigated, only Min-a-zel Plus® showed a significant protective effect (PI = 1.77). In summary, the steroidal anti-inflammatory drugs could be recommended as a regimen of choice for treatment of acute T-2 toxicosis while nonsteroidal anti-inflammatory compounds, different absorbent formulations and their combinations with antioxidants or radioprotectors could be important for the treatment of subacute and chronic T-2 toxin poisonings., T-2 mikotoksin, sekundarni metabolit gljivica iz roda Fusarium, jedan je od najtoksičnijih predstavnika trihotecenskih mikotoksina tipa A. Njegove osnovne osobine, prvenstveno velika stabilnost u prirodi, jeftina proizvodnja, teška detekcija i još uvek nepostojanje adekvatnog antidota čine ga veoma dobrim potencijalnim bojnim otrovom. Posle unošenja, u organizmu otrovane jedinke T-2 toksin se u ćelijama vezuje za receptore na ribozomima i pokreće seriju kaskadnih reakcija koje za posledicu imaju smanjenje stabilnosti gRNK i povećanu ekspresiju proinflamatornih gena koji su između ostalog odgovorni za nastanak anoreksije, gubitak telesne mase imunosupresiju, autoimunih efekata i oštećenje većine tkiva. Toksično oštećenje ciljnih organa, nastalo pod dejstvom T-2 toksina, posledica je njegovog citotoksičnog efekta na labilne ćelije i proinflamatornog efekta na stabilne ćelije u organizmu životinja i ljudi. S obzirom na napred iznete činjenice, jasno je što je u našim istraživanjima najbolji terapijski efekat, kod akutnog trovanja T-2 toksinom, postignut primenom antiinflamatornih lekova steroidne strukture, prvenstveno deksametazona (ZI = 3,37) i različitih oblika metilprednizolona (ZI = 2,43-2,64). Osim toga antiinflamatorni lekovi nesteroidne strukture ispoljili su značajan terapijski efekat, nimesulid (ZI = 1,44) i N-acetlilcistein (ZI = 1,29), ali se njihovo zaštitno dejstvo potencira u kombinaciji sa metilprednisolonom (ZI = 2,16-2,34). Terapijsku efikasnost ispoljili su radioprotektor amifostin (WR-2721) (ZI = 1,26) i/ili različiti apsorbensi. Od primenjenih apsorbenasa, kao što su aktivni ugalj (ZI = 1,13) i različiti oblici Min-a-zel-a®, najveći protektivni efekat ispoljio je Min-a-zel Plus® oblik klinoptiolinskog zeolita (ZI = 1,77). Na osnovu prikazanih rezultata, a u skladu sa činjenicom da je citotoksično i proinflamatorno dejstvo T-2 toksina u direktnoj srazmeri sa njegovom akutnom toksičnošću, u potpunosti je opravdano korišćenje visokih doza antiinflamat

The use of organophosphorus pesticides results in toxicity risk to non-target organisms. Organophosphorus compounds share a common mode of action, exerting their toxic effects primarily via acetylcholinesterase (AChE) inhibition. Consequently, acetylcholine accumulates in the synaptic clefts of muscles and nerves, leading to overstimulation of cholinergic receptors. Acute cholinergic crisis immediately follows exposure to organophosphate and includes signs and symptoms resulting from hyperstimulation of central and peripheral muscarinic and nicotinic receptors. The current view of the treatment of organophosphate poisoning includes three strategies, i.e. the use of an anticholinergic drug (e.g., atropine), cholinesterase-reactivating agents (e.g., oximes) and anticonvulsant drugs (e.g., benzodiazepines). Oximes, as a part of antidotal therapy, ensure the recovery of phosphylated enzymes via a process denoted as reactivation of inhibited AChE. However, both experimental results and clinical findings have demonstrated that different oximes are not equally effective against poisonings caused by structurally different organophosphorus compounds. Therefore, antidotal characteristics of conventionally used oximes can be evaluated regarding how close the certain substance is to the theoretical concept of the universal oxime. Pralidoxime (PAM-2), trimedoxime (TMB-4), obidoxime (LüH-6), HI-6 and HLö-7 have all been demonstrated to be very effective in experimental poisonings with sarin and VX.TMEM and LüH-6 may reactivate tabun-inhibited AChE, whereas HI-6 possesses the ability to reactivate the soman-inhibited enzyme. An oxime HLö-7 seems to be an efficient reactivator of AChE inhibited by any of the four organophosphorus warfare agents. According to the available literature, the oximes LüH-6 and TMB-4, although relatively toxic, are the most potent to induce reactivation of AChE inhibited by the majority of organophosphorus pesticides. Since there are no reports of control

The development of effective antidotes against organophosphates such as dichlorvos has been a persistent challenge over the past decades. Therapy of organophosphate poisoning is based on the administration of atropine and oxime as standard antidotes. The present study was undertaken to evaluate the ability of sodium bicarbonate to improve protective effects of standard antidotes in rats poisoned with dichlorvos. The aim of this experiment was to establish the correlation between protective effects and biochemical parameters relevant for acid-base status. In order to examine the protective effect of both standard antidotes and their combinations, groups of experimental animals were poisoned subcutaneously with increasing doses of dichlorvos. Immediately thereafter, rats were treated with atropine 10 mg/kg intramuscularly, oximes 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally. These antidotes were administered either as single doses or in combinations. In the biochemical part of the experiments, rats were poisoned with dichlorvos 1.3 LD50 (10.64 mg/kg) subcutaneously and immediately thereafter treated with atropine 10 mg/kg intramuscularly, oximes (trimedoxime or obidoxime) 10 mg/kg intramuscularly and sodium bicarbonate 3 mmol/kg intraperitoneally either as single doses or in combinations. Parameters relevant for acid-base status were measured 10 minutes after the administration of antidotes. The results of our study indicate that addition of sodium bicarbonate to standard antidotes significantly improves protective effects of atropine, obidoxime and trimedoxime. Correlation between protection and biochemical outcome is clearly evident when sodium bicarbonate is being added to atropine.

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 > heptenophos > dichlorvos. Administration of the oxime produced a significant reactivation 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 monocrotophos-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 organophosphorus compounds, although the biochemical findings were quite different.

The aim of the present work was to examine potential beneficial role of sodium bicarbonate (3 mmol/kg ip) on protective potency of trimedoxime (10 mg/kg im), obidoxime (10 mg/kg im) and atropine (10 mg/kg im) in rats poisoned with dichlorvos. Special attention was paid to the influence of co-administration of sodium bicarbonate on acid-base status in experimental animals poisoned with dichlorvos (1.3 LD50 sc). Coadministration of sodium bicarbonate significantly increased protective effect of standard antidotes in rats poisoned with dichlorvos. Sodium bicarbonate given along with atropine/oxime produced an increase in blood pH value and correction of acidosis. In conclusion, correlation between protective effect and biochemical outcome was evident when sodium bicarbonate was added to antidotes., Cilj rada je bio da se ispita efekat natrijum bikarbonata (3 mmol/kg ip) na zaštitni potencijal trimedoksima (10 mg/kg im), obidoksima (10 mg/kg im) i atropina (10 mg/kg im) u pacova trovanih dihlorvosom. Posebna pažnja je posvećena uticaju kombinacija natrijum bikarbonata i antidota na acido-bazni status eksperimentalnih životinja trovanih dihlorvosom (1.3 LD50 ). Primena kombinacija sa natrijum bikarbonatom zna- čajno je povećala zaštitne efekte standardnih antidota, a došlo je i do porasta vrednosti pH krvi i korekcije acidoze. Takođe, moglo se zaključiti da kada je natrijum bikarbonat dat zajedno sa atropinom/oksimom postoji jasna korelacija između dobijenih zaštitnih efekata i testiranih biohemijskih parametara.

This study was aimed to investigate the possibility of modifying the rate of aging of diisopropylfluorophosphate-inhibited neuropathy target esterase (NTE) of hen blain. This reaction on NTE occurs with a half-time of 7.4 min. Atropine was effective in decreasing the rate of aging on DFP-inhibited NTE and this effect was time-and concentration-dependent. Atropine was also a weak but progressive inhibitor of NTE activity (I-50 = 80 mM) and this reaction appears to be reversible at lower atropine concentrations. Among compounds containing oxime functional groups only OPAB, having longer methylene chain and being more lipophylic than other oximes usually used in acetylcholinesterase (AChE) reactivation studies, was effective in decreasing the rate of aging on DFP-inhibited NTE. However, when atropine and oximes were used together we have obtained a potentiating and/or synergistic effect which was most significant with combination of atropine and TMB-4 giving up to a 15-fold decrease in the rate of aging reaction. The efficacy of this particular combination was concentration-dependent. We have also discussed similarities and differences in aging reaction occurring on NTE and AChE.