Oximes as pretreatment before acute exposure to paraoxon.

Organophosphates, useful agents as pesticides, also represent a serious danger due to their high acute toxicity. There is indication that oximes, when administered before organophosphate exposure, can protect from these toxic effects. We have tested at equitoxic dosage (25% of LD01 ) the prophylactic efficacy of five experimental (K-48, K-53, K-74, K-75, K-203) and two established oximes (pralidoxime and obidoxime) to protect from mortality induced by the organophosphate paraoxon. Mortalities were quantified by Cox analysis and compared with those observed after pretreatment with a strong acetylcholinesterase inhibitor (10-methylacridine) and after the FDA-approved pretreatment compound pyridostigmine. All nine tested substances statistically significantly reduced paraoxon-induced mortality. Best protection was conferred by the experimental oxime K-48, reducing the relative risk of death (RR) to 0.10, which was statistically significantly superior to pyridostigmine (RR = 0.31). The other oximes reduced the RR to 0.13 (obidoxime), 0.20 (K-203), 0.21 (K-74), 0.24 (K-75) and 0.26 (pralidoxime), which were significantly more efficacious than 10-methylacridine (RR = 0.65). These data support the hypothesis that protective efficacy is not primarily due to cholinesterase inhibition and indicate that the tested experimental oximes may be considered promising alternatives to the established pretreatment compound pyridostigmine.

Repetitive antidotal treatment is crucial in eliminating eye pathology, respiratory toxicity and death following whole-body VX vapor exposure in freely moving rats.

Exposure to the chemical warfare nerve agent VX is extremely toxic, causing severe cholinergic symptoms. If not appropriately treated, death ultimately ensues. Based on our previously described whole-body vapor exposure system, we characterized in detail the clinical outcome, including respiratory dynamics, typical of whole-body exposure to lethal doses of VX vapor in freely moving rats. We further evaluated the efficacy of two different antidotal regimens, one comprising a single and the other repeated administration of antidotes, in countering the toxic effects of the exposure. We show that a 15 min exposure to air VX concentrations of 2.34-2.42 mg/m3 induced a late (15-30 min) onset of obvious cholinergic signs, which exacerbated over time, albeit without convulsions. Marked eye pathology was observed, characterized by pupil constriction to pinpoint, excessive lacrimation with red tears (chromodacryorrhea) and corneal damage. Respiratory distress was also evident, characterized by a three-fourfold increase in Penh values, an estimate of lung resistance, and by lung and diaphragm histological damage. A single administration of TAB (the oxime TMB-4, atropine and the anticholinergic and antiglutamatergic benactyzine) at the onset of clinical signs afforded only limited protection (66% survival), with clinical deterioration including weight loss, chromodacryorrhea, corneal damage, increased airway resistance and late death. In contrast, a combined therapy of TAB at the onset of clinical signs and repeated administration of atropine and toxogonin (ATOX) every 3-5 h, a maximum of five i.m. injections, led to 100% survival and a prompt recovery, accompanied by neither the above-described signs of eye pathology, nor by bronchoconstriction and respiratory distress. The necessity of recurrent treatments for successful elimination of VX vapor toxicity strongly supports continuous penetration of VX following termination of VX vapor exposure, most likely from a VX reservoir formed in the skin due to the exposure. This, combined with the above-described eye and respiratory pathology and absence of convulsions, are unique features of whole-body VX vapor exposure as compared to whole-body vapor exposure to other nerve agents, and should accordingly be considered when devising optimal countermeasures and medical protocols for treatment of VX vapor exposure.

Efficacy of atropine sulfate/obidoxime chloride co-formulation against sarin exposure in guinea pigs.

The efficacy and pharmacokinetics of the aqueous co-formulation contents of the Trobigard™ (atropine sulfate, obidoxime chloride) auto-injector were evaluated in a sarin exposed guinea pig model. Two subcutaneous (sc) sarin challenge doses were evaluated in guinea pigs instrumented with brain and heart electrodes for electroencephalogram (EEG) and electrocardiogram (ECG). Sarin challenge doses were chosen to reflect exposure subclasses with sublethal (moderate to severe clinical signs) and lethal consequences. The level of protection of intramuscular human equivalent doses of the co-formulation was defined by (1) the mitigation of signs and symptoms at a sublethal level and (2) the increase of survival time at the supralethal sarin dose levels. Pharmacokinetics of both atropine sulfate and obidoxime were proportional at 1 and 3 human equivalent doses, and only a small increase in heart rate was observed briefly as a side effect. At both sarin challenge doses, 54 µg/kg and 84 µg/kg, the co-formulation treatment was effective against sarin-induced effects. Survival rates were improved at both sarin challenge levels, whereas clinical signs and changes in EEG activity could not in all cases be effectively mitigated, in particular at the supralethal sarin challenge dose level. Reactivation of sarin inhibited cholinesterase was observed in blood, and higher brain cholinesterase activity levels were associated with a better clinical condition of the co-formulation treated animals. Although the results cannot be directly extrapolated to the human situation, pharmacokinetics and the effects over time related to plasma levels of therapeutics in a freely moving guinea pig could aid translational models and possibly improve prediction of efficacy in humans.

Brief isoflurane administration as a post-exposure treatment for organophosphate poisoning.

Organophosphate chemical threat agents (OP-CTA) exert toxic effects through cholinergic over-activation. However, after the initial cholinergic phase, the pathophysiology shifts to a non-cholinergic phase which leads to prolonged status epilepticus (SE), irreversible neuronal degeneration and long-term damage to the central nervous system. The efficacy of delayed treatments against OP-CTA is generally low due to the fact that most drugs fail to inhibit the later phase of non-cholinergic activation. Recently, we reported that intranasal brain delivery of obidoxime (OBD) provides complete neuroprotection against a lethal dose of paraoxon when administered 5min after intoxication. In follow-up studies, we examined the window of effectiveness and found that OBD lost effectiveness around 15min post-exposure, which corresponds to the onset of the non-cholinergic phase of intoxication. However, we observed that a brief isoflurane administration, the inhalation anesthetic used to facilitate intranasal drug administration, was effective against paraoxon-induced neurotoxicity. Thus, the present study aimed to investigate the time-course and dose-response efficacy of a brief 4min isoflurane administration as a treatment for neurotoxicity induced by OP-CTA. We found that isoflurane is a potent anti-seizure agent and neuroprotectant when administered between 20 and 30min after paraoxon exposure, stopping SE within 10min of administration and preventing acute neurodegeneration seen 24h later. We also found that the seizure blocking and neuroprotectant properties of isoflurane, when administered 30min after paraoxon, are dose-dependent. The effectiveness and current clinical use of isoflurane support its use as an innovative approach for post exposure treatment of organophosphate poisoning.

Reactivation of nerve agent-inhibited human acetylcholinesterase by obidoxime, HI-6 and obidoxime+HI-6: Kinetic in vitro study with simulated nerve agent toxicokinetics and oxime pharmacokinetics.

Despite extensive research for decades no effective broad-spectrum oxime for the treatment of poisoning by a broad range of nerve agents is available. Previous in vitro and in vivo data indicate that the combination of in service oximes could be beneficial. To investigate the ability of obidoxime, HI-6 and the combination of both oximes to reactivate inhibited human AChE in the presence of sarin, cyclosarin or tabun we adopted a dynamic in vitro model with real-time and continuous determination of AChE activity to simulate inhalation nerve agent exposure and intramuscular oxime administration. The major findings of this kinetic study are that the extent and velocity of reactivation is dependent on the nerve agent and the oxime-specific reactivating potency. The oxime-induced reactivation of inhibited human AChE in the presence of nerve agents is markedly impaired and the combination of obidoxime and HI-6 had no additive effect but could broaden the spectrum. In conclusion, these data indicate that a combination of obidoxime and HI-6 would be beneficial for the treatment of poisoning by a broad spectrum of nerve agents and could present an interim solution until more effective and broad-spectrum reactivators are available.

Repetitive obidoxime treatment induced increase of red blood cell acetylcholinesterase activity even in a late phase of a severe methamidophos poisoning: A case report.

Accidental self-poisoning or deliberate use in suicidal intent of organophosphorus pesticides (OPP), which are widely used in agriculture, represent a health problem worldwide. Symptoms of poisoning are characterized by acute cholinergic crisis caused by inhibition of acetylcholinesterase. A 75-year-old male patient ingested 20ml of an OPP solution containing 10% methamidophos in suicidal intent. In the course of poisoning typical clinical symptoms of cholinergic crisis (miosis, bradycardia, hypotension, hypersalivation and impairment of neurologic status) were evident. Butyryl (plasma) cholinesterase (BChE) and red blood cell acetylcholinesterase (RBC-AChE) revealed decreased activities, thus specific treatment with the enzyme reactivator obidoxime was started. Inhibitory activity of the patient's plasma indicated significant amounts of persisting methamidophos in the circulation and was still found on day 4 after ingestion. Due to missing spontaneous breathing on day 6, obidoxime was administered again. Afterwards a significant increase of RBC-AChE activity was found. The patient was extubated on day 10 and a restitution ad integrum was achieved. In conclusion, obidoxime is a potent reactivator of OPP-inhibited AChE. A repetitive and prolonged administration of obidoxime should be considered in cases of severe methamidophos poisoning and should be tailored with an advanced analytical biomonitoring.

Butyrylcholinesterase activity-biomarker for predicting the outcome in acute cholinesterase inhibitor poisoning--a 30-year retrospective analysis.

AIM: To assess the role of butyrylcholinesterase (BuChE) activity as a predictive biomarker in acute cholinesterase inhibitor poisoning in a cohort from a regional tertiary care hospital. MATERIAL AND METHODS: Plasma butyrylcholinesterase activity on admission and at regular intervals during admission and clinical outcomes of cases admitted to the Toxicology Clinic of "Sf. Spiridon" Emergency Hospital Iasi, Romania between 1983 and 2013 were evaluated. RESULTS: A total number of 606 patients were included in the study. The mean BuChE-activity level on admission was 1.54 ml NaOH N/100. A correlation between the amount of ingested organophosphates/carbamates (OPs/CMs) and low cholinesterase activity on admission was found. 66.66% of the patients were admitted to hospital within 8 hours after poisoning. The initial, daily and mean total atropine doses administrated were 9.65 mg, 10.51 mg and 69.39 mg, respectively. 67.16% of the investigated patients received Toxogonin for 6.41 days showing a slow increase in BuChE activity afterwards. The average number of hospital days was 11.22. The study revealed that complications occurred in patients with BuChE-activity levels below 1.4 mL NaOH N/100. A positive correlation between mortality rate (3.8% of patients) and the lowest BuChE-activity level on admission (0.89 mL NaOH N/100) was found. CONCLUSIONS: BuChE activity on admission and its level during hospital stay represent an important predictive factor for acute cholinesterase inhibitors poisoning.

[Antidotal effect of combinations obidoxime/HI-6 and memantine in mice poisoned with soman, dichlorvos or heptenophos].

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 gmoL/kg in soman poisoning) and obidoxime (16.80 vs 2.75 micromoL/kg in dichlorvos poisoning; 21.56 vs 6.63 micromoL/kg in heptenophos poisoning). Memantine and midazolam succeded 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.

A comparison of tabun-inhibited rat brain acetylcholinesterase reactivation by three oximes (HI-6, obidoxime, and K048) in vivo detected by biochemical and histochemical techniques.

Tabun belongs to the most toxic nerve agents. Its mechanism of action is based on acetylcholinesterase (AChE) inhibition at the peripheral and central nervous systems. Therapeutic countermeasures comprise administration of atropine with cholinesterase reactivators able to reactivate the inhibited enzyme. Reactivation of AChE is determined mostly biochemically without specification of different brain structures. Histochemical determination allows a fine search for different structures but is performed mostly without quantitative evaluation. In rats intoxicated with tabun and treated with a combination of atropine and HI-6, obidoxime, or new oxime K048, AChE activities in different brain structures were determined using biochemical and quantitative histochemical methods. Inhibition of AChE following untreated tabun intoxication was different in the various brain structures, having the highest degree in the frontal cortex and reticular formation and lowest in the basal ganglia and substantia nigra. Treatment resulted in an increase of AChE activity detected by both methods. The highest increase was observed in the frontal cortex. This reactivation was increased in the order HI-6 < K048 < obidoxime; however, this order was not uniform for all brain parts studied. A correlation between AChE activity detected by histochemical and biochemical methods was demonstrated. The results suggest that for the mechanism of action of the nerve agent tabun, reactivation in various parts of the brain is not of the same physiological importance. AChE activity in the pontomedullar area and frontal cortex seems to be the most important for the therapeutic effect of the reactivators. HI-6 was not a good reactivator for the treatment of tabun intoxication.

Percutaneous exposure to the nerve agent VX: Efficacy of combined atropine, obidoxime and diazepam treatment.

The nerve agent VX is most likely to enter the body via liquid contamination of the skin. After percutaneous exposure, the slow uptake into the blood, and its slow elimination result in toxic levels in plasma for a period of several hours. Consequently, this has implications for the development of toxic signs and for treatment onset. In the present study, clinical signs, toxicokinetics and effects on respiration, electroencephalogram and heart rate were investigated in hairless guinea pigs after percutaneous exposure to 500 microg/kg VX. We found that full inhibition of AChE and partial inhibition of BuChE in blood were accompanied by the onset of clinical signs, reflected by a decline in respiratory minute volume, bronchoconstriction and a decrease in heart rate. Furthermore, we investigated the therapeutic efficacy of a single dose of atropine, obidoxime and diazepam, administered at appearance of first clinical signs, versus that of repetitive dosing of these drugs on the reappearance of signs. A single shot treatment extended the period to detrimental physiological decline and death for several hours, whereas repetitive administration remained effective as long as treatment was continued. In conclusion, percutaneous VX poisoning showed to be effectively treatable when diagnosed on time and when continued over the entire period of time during which VX, in case of ineffective decontamination, penetrates the skin.

Adsorption of obidoxime onto human serum albumin nanoparticles: drug loading, particle size and drug release.

The standard treatment of poisoning by organophosphorous compounds such as paraoxon includes the administration of oximes. Due to their inability to rapidly cross the blood-brain barrier (BBB) in therapeutically relevant concentrations, these drugs possess insufficient activity in the central nervous system. Since human serum albumin (HSA) nanoparticles enable the delivery of a variety of drugs across the BBB into the brain, in the present study the antidote obidoxime was bound to these particles by adsorption. The resulting sorption isotherms showed a best fit to Langmuir isotherms indicating that obidoxime adsorbs to HSA nanoparticles forming a monolayer. A maximum drug loading of 93.5 microg obidoxime/mg of nanoparticles at pH 8.3 was calculated. At higher concentrations the particle diameter increased significantly with obidoxime concentration leading to instable particle systems. The in vitro release of obidoxime from HSA nanoparticles showed a rapid release of the drug from the nanoparticles within 3 h.

A comparison of neuroprotective efficacy of the oxime K203 and its fluorinated analogue (KR-22836) with obidoxime in Tabun-poisoned rats.

The ability of the newly developed bispyridinium compound K203 and its fluorinated analogue KR-22836 to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the currently available reactivator of acetylcholinesterase-obidoxime. Tabun-induced neurotoxicity and the neuroprotective effects of all tested oximes in combination with atropine in rats poisoned with tabun at a sublethal dose (200 µg/kg intramuscularly (i.m.); 80% of LD(50) value) were monitored by a functional observational battery at 24 hr after tabun challenge. The results indicate that all tested oximes combined with atropine were able to survive tabun-poisoned rats 24 hr after tabun challenge while one non-treated tabun-poisoned rat died within 24 hr after tabun poisoning. All tested oximes combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisoning but they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. While the ability to reduce tabun-induced acute neurotoxicity of obidoxime and K203 was similar, the neuroprotective efficacy of KR-22836 was slightly higher compared to other tested oximes. Thus, the newly developed fluorinated analogue of K203, called KR-22836, is able to slightly increase the neuroprotective effectiveness of antidotal treatment of acute tabun poisonings compared to K203 and currently available obidoxime.

Obidoxime in acute organophosphate poisoning: 1 - clinical effectiveness.

OBJECTIVE: The effects of obidoxime in the treatment of organophosphate poisoning were assessed by comparing the clinical course with its effects on laboratory parameters relevant to poisoning. In this article we report clinical findings and activity of cholinesterase in plasma and acetylcholinesterase (AChE) in red blood cells. In a linked paper we describe changes in neuromuscular transmission and atropine concentrations in the same patient cohort. METHODS: We studied 34 atropinized patients with severe parathion, oxydemeton methyl, and dimethoate self-poisoning who were treated with obidoxime in a standard protocol. We measured the AChE activity in blood and related it to clinical features of organophosphate poisoning. RESULTS: Patients poisoned with parathion responded promptly to obidoxime (250 mg bolus followed by continuous infusion at 750 mg/day up to 1 week) with improvement of neuromuscular transmission and increased AChE activity. The effects were only transient in cases with the other poisons. Death (7/34) occurred late and was mostly due to complications rather than due to ongoing cholinergic crisis. CONCLUSIONS: Obidoxime appeared safe and reactivated AChE in parathion poisoning.

Obidoxime in acute organophosphate poisoning: 2 - PK/PD relationships.

OBJECTIVE: The effects of obidoxime in the treatment of organophosphate poisoning were assessed by biochemical and biological effect monitoring. In this article we report effects on neuromuscular function, oxime and atropine concentration, and relate them to acetylcholinesterase (AChE) activity. METHODS: We measured the activity of cholinesterase in plasma and AChE in red blood cells (RBC) and related these data with neuromuscular transmission analysis (ulnar nerve stimulation). Concomitantly, poison and oxon along with plasma obidoxime and atropine levels were measured at regular intervals. RESULTS: We found a close correlation between RBC-AChE activity and neuromuscular transmission and a reciprocal correlation between both the atropine maintenance dose and/or its plasma concentration. The steady state of RBC-AChE activity of reactivation and re-inhibition followed the course predicted by laboratory-determined reaction constants. CONCLUSIONS: Intense monitoring of organophosphate-poisoned patients allowed assessment of why a given obidoxime concentration was, or was not, able to counteract the re-inhibition of the RBC-AChE. RBC-AChE activity mirrors the function of n-receptor- and m-receptor-mediated cholinergic signaling as measured by neuromuscular transmission and atropine requirements.

Correlation of therapeutic effect of obidoxime and dosing time in the acute intoxication by chlorfenvinphos in rats.

The ability of obidoxime with atropine and diazepam mixture to reactivate acetylcholinesterase inhibited by the organophosphorus compound chlorfenvinphos was compared in the central nervous system and peripheral tissues of rats. The animals were intoxicated with chlorfenvinphos (6 mg/kg, p.o.) and treated immediately, 24 and 48 hrs later with obidoxime (50 mg/kg, i.p.), atropine (10 mg/kg, i.p.), and diazepam (10 mg/kg, i.p.) in a single dose, or in various combinations (with 2-3 drugs) simultaneously. Total tissue acetylcholinesterase activities were monitored at 2, 72, and 168 hrs after intoxication. Enzyme activity was determined using Ellman's colorimetric method. The results of the present study show that obidoxime administered separately and jointly with atropine and diazepam 24 hrs after intoxication was effective on reactivation of chlorfenvinphos-inhibited acetylcholinesterase in the central nervous system and in the peripheral tissues. However, the application of obidoxime alone or in combination with atropine and diazepam 48 hrs after chlorfenvinphos intoxication caused an increased unfavourable effect in rats. The results obtained also indicate an unfavourable interaction of obidoxime with diazepam in the course of chlorfenvinphos poisoning, when antidotes were administered immediately, 24 and 48 hrs after intoxication.

Effect of five acetylcholinesterase reactivators on tabun-intoxicated rats: induction of oxidative stress versus reactivation efficacy.

Oxime reactivators HI-6, obidoxime, trimedoxime, K347 and K628 were investigated as drugs designed for treatment of tabun intoxication. The experiments were performed on rats in order to simulate real conditions. Rats were intoxicated with one LD(50 )of tabun and treated with atropine and mentioned reactivators. Activities of erythrocyte acetylcholinesterase (AChE), plasma butyrylcholinesterase (BChE) and brain AChE were measured as markers of reactivation efficacy. An estimation of low molecular weight antioxidant levels using cyclic voltammetry was the second examination parameter. The evaluation of cholinesterases activity showed good reactivation potency of blood AChE and plasma BChE by commercially available obidoxime and newly synthesized K347. The potency of oximes to reactivate brain AChE was lower due to the poor blood-brain barrier penetration of used compounds. Commercially available reactivator HI-6 and newly synthesized K628 caused oxidative stress measured by cyclic voltammetry as antioxidant level. The oxidative stress provoked by HI-6 and K628 was found to be significant on probability level P = 0.05. The others reactivators did not affect antioxidant levels.

An evaluation of reactivating and therapeutic efficacy of newly developed oximes (K206, K269) and commonly used oximes (obidoxime, HI-6) in cyclosarin-poisoned rats and mice.

INTRODUCTION: The ability of currently available reactivators to reactivate cyclosarin is low. The aim of this study was to determine the reactivating and therapeutic efficacy of newly developed oximes (K206, K269) compared with currently available oximes against cyclosarin. METHODS: Rats and mice received atropine or atropine + oxime intramuscularly (i.m.) before or after an i.m. dose of cyclosarin. Acetylcholine activity levels in blood and tissues were measured to calculate the reactivation efficacy and potency. RESULTS AND DISCUSSION: In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase (AChE) in poisoned rats showed that the potency of both newly developed oximes (K206, K269) to reactivate cyclosarin-inhibited AChE is comparable with that of obidoxime in blood and diaphragm, but slightly higher than that of obidoxime in brain. Their reactivating efficacy is significantly lower compared with that of the oxime HI-6. K206 and K269 are relatively effective in reducing cyclosarin-induced lethal toxic effects in mice. Their therapeutic efficacies exceed the therapeutic potency of obidoxime but not that of HI-6. CONCLUSIONS: K206 and K269 are as effective in the reactivation of cyclosarin-inhibited AChE in rats and in the reduction of lethal toxic effects of cyclosarin in mice as obidoxime, but because their reactivating and therapeutic potency is significantly lower than that of HI-6, they are not suitable replacements for the currently available oximes for the treatment of cyclosarin poisoning.

An evaluation of therapeutic and reactivating effects of newly developed oximes (K156, K203) and commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice.

The potency of newly developed monoxime bispyridinium compounds (K156, K203) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K203 is comparable with obidoxime and trimedoxime in blood and higher than the reactivating potency of trimedoxime and obidoxime in diaphragm and brain, where the difference in reactivating efficacy of obidoxime, trimedoxime and K203 is significant. On the other hand, the potency of newly developed K156 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in diaphragm and brain. It is significantly lower than the reactivating efficacy of trimedoxime and obidoxime in blood. Moreover, both newly developed oximes were found to be relatively efficacious in the reduction of lethal toxic effects in tabun-poisoned mice. Especially, the oxime K203 is able to decrease the acute toxicity of tabun nearly two times. The therapeutic efficacy of K156 and K203 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in diaphragm and brain. In contrast to obidoxime and trimedoxime, the oxime HI-6 is not effective in reactivation of tabun-inhibited acetycholinesterase and in reducing tabun lethality. While the oxime K156 does not improve the reactivating and therapeutic effectiveness of currently available obidoxime and trimedoxime, the newly developed oxime K203 is markedly more effective in reactivation of tabun-inhibited acetylcholinesterase in rats, especially in brain, and in reducing lethal toxic effects of tabun in mice and, therefore, it is suitable for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.