Search

Nerve agent exposure is generally treated by an antidote formulation composed of a muscarinic antagonist, atropine sulfate (ATR), and a reactivator of acetylcholinesterase (AChE) such as pralidoxime, obidoxime (OBI), methoxime, trimedoxime or HI-6 and an anticonvulsant. Organophosphates (OPs) irreversibly inhibit AChE, the enzyme responsible for termination of acetylcholine signal transduction. Inhibition of AChE leads to overstimulation of the central and peripheral nervous system with convulsive seizures, respiratory distress and death as result. The present study evaluated the efficacy and pharmacokinetics (PK) of ATR/OBI following exposure to two different VX dose levels. The PK of ATR and OBI administered either as a single drug, combined treatment but separately injected, or administered as the ATR/OBI co-formulation, was determined in plasma of naïve guinea pigs and found to be similar for all formulations. Following subcutaneous VX exposure, ATR/OBI-treated animals showed significant improvement in survival rate and progression of clinical signs compared to untreated animals. Moreover, AChE activity after VX exposure in both blood and brain tissue was significantly higher in ATR/OBI-treated animals compared to vehicle-treated control. In conclusion, ATR/OBI has been proven to be efficacious against exposure to VX and there were no PK interactions between ATR and OBI when administered as a co-formulation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24h after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30min before or 5min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality., (Published by Elsevier B.V.)

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.

The neuroprotective effects of a newly developed oxime K203 and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with sarin were studied. The sarin-induced neurotoxicity was monitored using a functional observatory battery at 2 hr after sarin challenge. The results indicate that the potency of a novel bispyridinium oxime K203 to counteract sarin-induced neurotoxicity is relatively low and roughly corresponds to the neuroprotective efficacy of obidoxime. Among tested oximes, the oxime HI-6 seems to be significanlty more efficacious to counteract acute neurotoxicity of sarin than commonly used obidoxime and a newly developed oxime K203. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with sarin in comparison with the oxime HI-6 that should be considered to be the best oxime for antidotal treatment of acute sarin poisonings., (© 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.)

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.

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., (© 2010 The Authors. Basic & Clinical Pharmacology & Toxicology © 2010 Nordic Pharmacological Society.)

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., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Reactivation of inhibited acetylcholinesterase (AChE) with oximes is a causal therapy of intoxication with organophosphorus compounds (OPs). Maximal oxime effects are expected when effective doses are administered as soon as possible and as long as reactivation can be anticipated. An obidoxime plasma level in the range of 10-20 microM was estimated as appropriate. The achievement of this target was assessed in 34 severely OP-poisoned patients., Methods: After admission to the intensive care unit (ICU) the obidoxime regimen (250 mg i.v. as bolus, followed by 750 mg/24h) was started and maintained as long as reactivation was possible. Plasma concentrations of obidoxime were determined by HPLC., Results: A total amount of 2269+/-1726 mg obidoxime was infused over 65 h+/-55 h resulting in a steady state plasma concentration of 14.5+/-7.3 microM. Obidoxime was eliminated with t(1/2(1)) 2.2 and t(1/2(2)) 14 h. The volumes of distribution amounted to 0.32+/-0.1L/kg (V((1))) and 0.28+/-0.12 (V((2)))L/kg. Postmortem examination of tissue in one patient showed obidoxime accumulation in cartilage, kidney and liver and pointed to brain concentrations similar to plasma concentration., Conclusions: Using the suggested obidoxime regimen, the targeted plasma concentration could be achieved. Obidoxime was eliminated biphasically and was well tolerated. This result allows the recommendation of using this definite regimen for adults also in case of mass casualties., ((c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Assessment of organophosphate poisoning could benefit from a safe, non-expensive, easy to perform, quick (< 1 hour) test, which evaluates the level of cholinesterase activity "in vitro" regarding to the capability of oximes to reactivate OF-blocked cholinesterase. In the proposed protocol, 0.5 mL of sample serum is incubated, prior to the evaluation of level of cholinesterase activity, with 5 microL of a Toxogonin dilution (0.125 mg) for 30 minutes at 37 degrees C. For the standardization of the newly proposed protocol, several important issues were documented in the present article. The new original method of assessing cholinesterase reactivability will consist in an advantage for the diagnosis, prognostic evaluation and therapeutic orientation in OF intoxication.

The influence of the combination of oximes on the reactivating and therapeutic efficacy of antidotal treament of acute tabun poisoning was evaluated. The ability of two combinations of oximes (HI-6 + obidoxime and HI-6 + K203) to reactivate tabun-inhibited acetylcholinesterase and reduce acute toxicity of tabun was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, obidoxime, K203) 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 both combinations of oximes is higher than the reactivating efficacy of the most effective individual oxime in blood and diaphragm and comparable with the reactivating effects of the most effective individual oxime in brain. Moreover, both combinations of oximes were found to be slightly more efficacious in the reduction of acute lethal toxic effects in tabun-poisoned mice than the antidotal treatment involving individual oxime. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the newly developed oxime K203 is slightly more effective than commonly used obidoxime and both of them are markedly more effective than the oxime HI-6. Based on the obtained data, we can conclude that the antidotal treatment involving chosen combinations of oximes brings beneficial effects for the potency of antidotal treatment to reactivate tabun-inhibited acetylcholinesterase in rats and to reduce acute toxicity of tabun in mice.

Organophosphate poisoning is associated with a high mortality rate due to respiratory failure, dysrhythmias, and multi-organ failure. We report two cases of survival after "in-the field" antidote treatment of very severe organophosphate poisonings. Two patients orally ingested large amounts of the organophosphorous agent oxydemeton-methyl in suicide attempts, resulting in the hypercholinergic syndrome in both. Resuscitation included early administration of antidote by emergency medical personnel as well as high-dose atropine. Plasma levels of pseudo cholinesterase were initially very low in both patients. Long-term mechanical ventilation was necessary, and both patients developed aspiration pneumonia. At discharge, no major neurological deficits were present. Prompt antidote treatment and aggressive supportive emergency and intensive care unit therapy contribute to improved survival after acute organophosphate poisoning. We believe that in cases of mass poisonings--for example, terrorist activity--therapy must be available on the scene as soon as possible. This also may require decentralized antidote storage.

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.

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.

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.

The neuroprotective effects of newly developed oximes (K203, K206) and commonly used oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (180 microg/kg i.m.; 80% LD(50)) were studied. The tabun-induced neurotoxicity was monitored by using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 hours and 7 days following tabun challenge. The results indicate that K203 and obidoxime in combination with atropine allow all tabun-poisoned rats to survive within 7 days following tabun challenge, while 2 nontreated tabun-poisoned rats and 1 tabun-poisoned rat treated with K206 or HI-6 in combination with atropine died within 7 days. Only one of the newly developed oximes (K203) combined with atropine seems to be effective for a decrease in tabun-induced neurotoxicity within 24 hours after tabun sublethal poisoning, although it is not able to eliminate tabun-induced neurotoxicity completely. On the other hand, the neuroprotective efficacy of commonly used oximes (obidoxime and HI-6), as well as one of the new synthesized oximes (K206), is significantly lower in comparison with K203, according to the number of eliminated tabun-induced neurotoxic signs at 24 hours after tabun challenge. Due to its neuroprotective effects, K203 appears to be a suitable oxime for the antidotal treatment of acute tabun poisonings.

Study Objective: Unintentional pediatric exposure to insecticides is common in developing countries. A clinical decision aid could guide early triage decisionmaking., Methods: Study design was prospective observational data collection in a specialty poisoning hospital in Cairo, Egypt. Patients were children 2 months to 59 months of age, without pretreatment, presenting within 2 hours of an exposure to an organophosphate or carbamate insecticide. A resource-requiring course was defined as any occurrence of hypoxia, use of atropine or obidoxime, use of ICU care, or death. The goal of analysis was derivation of a clinical decision aid to predict a resource-requiring course with 100% sensitivity., Results: During the 21-month study, 197 children 2 months to 59 months of age exposed to an organophosphate or carbamate insecticide were treated at the center. One hundred two of these children met the study inclusion criteria: 95 had parental consent and completed the study observation period of which 65 used resources (4 died). All patients who ultimately met resource-requiring criteria initially did so at arrival. Pinpoint pupil alone identified 63 of 65 of these patients yet wrongly identified only 5 of 30 minimally ill patients. Pinpoint pupil or diarrhea identified 65 of 65 patients with a resource-requiring course while identifying 7 of 30 patients with a non-resource-requiring course (sensitivity 1.00; 95% confidence interval 0.95 to 1.00; specificity 0.77; 95% confidence interval 0.58 to 0.90)., Conclusion: Using 2 features, pinpoint pupils and diarrhea, we identified at presentation all patients who ultimately had a course using medications or advanced resources. According to this preliminary study, symptoms occur rapidly, so using an early triage aid may be feasible. A validation study is necessary.

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (180 micro g/kg i.m.; 80% LD(50)) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24h and 7 days following tabun challenge. The results indicate that all oximes studied in combination with atropine allow all tabun-poisoned rats to survive within 7 days following tabun challenge while two non-treated tabun-poisoned rats died within 2h. Both newly developed oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The oxime K075 showed a higher neuroprotective efficacy against tabun than K074 according to the number of eliminated tabun-induced neurotoxic signs at 24h as well as 7 days after tabun challenge. The neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly developed oxime K075 but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity is significantly lower at 24h as well as 7 days after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes (especially K075) appear to be more suitable oximes for the antidotal treatment of acute tabun poisonings than the oxime HI-6.

Objective: The status of oximes in human organophosphate poisoning is controversial. This analysis compares the outcomes of therapy with or without oximes., Design: Quantitative analysis using meta-analytic techniques., Methods: Controlled trials of oximes in human organophosphate poisoning were identified by search of MEDLINE and TOXLINE (1966 to May 2005) and review of published articles., Measurements and Main Results: Of the 3,122 articles on organophosphate poisoning identified by electronic search, 116 related to oxime use in human organophosphate poisoning. Seven trials, including two randomized controlled trials, compared oximes with standard medical care. Varying dosage schedules of pralidoxime or obidoxime were used. The effects of oxime therapy on mortality rate, mechanical ventilation, incidence of intermediate syndrome, and need for intensive care therapy were analyzed and expressed as risk difference (positive values indicating oxime harm). The random effects estimator was reported because of underlying heterogeneity of treatment effects between study types. No statistically significant association of oxime therapy was demonstrated for either mortality (risk difference 0.09, 95% confidence interval -0.08 to 0.27), ventilatory requirements (risk difference 0.16, 95% confidence interval -0.07 to 0.38), or the incidence of intermediate syndrome (risk difference 0.16, 95% confidence interval -0.12 to 0.45), although point estimates of effect suggested harm. An increased need for intensive care therapy (risk difference 0.19, 95% confidence interval 0.01 to 0.36) was apparent with oxime therapy., Conclusions: Based on the current available data on human organophosphate poisoning, oxime was associated with either a null effect or possible harm. The lack of current prospective randomized controlled trials, with appropriate patient stratification, mandates ongoing assessment of the role of oximes in organophosphate poisoning.

The mortality rate of suicidal parathion poisoning is particularly high, the onset of fulminant cholinergic signs, and the patients frequently present to the emergency physician with life-threatening symptoms. Despite this uniformity, subsequent clinical course differs significantly among patients, mostly not as a result of different delays in treatment or insufficiency of primary care. Probably, the differences depend on the amount of poison absorbed and/or the disposition of the active poison, paraoxon. We followed the toxicokinetics of parathion and tried to quantify the actual poison load. To this end, we monitored parathion-intoxicated patients (patients requiring artificial ventilation) for plasma levels of parathion and paraoxon along with the activity of erythrocyte acetylcholinesterase and its reactivatability. Plasma obidoxime concentrations were followed as well as the cumulative urinary para-nitrophenol conjugate excretion as a measure of total poison load. All patients received a standard obidoxime scheme of a 250 mg bolus dose intravenously, followed by continuous infusion with 750 mg per 24 hours as long as reactivation could be expected (usually 1 week). All other treatment was instituted as judged by the physician. It was recommended to use atropine at low doses to achieve dry mucous membranes, no bronchoconstriction and no bradycardia. Usually 1-2 mg/h were sufficient. Seven selected cases are presented exemplifying toxicokinetic peculiarities. All patients were severely intoxicated, while the amount of parathion absorbed varied widely (between 0.12 and 4.4 g; lethal dose 0.02-0.1 g) and was generally much lower than anticipated from the reports of relatives. It remains open whether the discrepancies between reports and findings were due to exaggeration or to effective decontamination (including spontaneous vomiting, gastric lavage and activated charcoal). Absorption of parathion from the gastrointestinal tract was sometimes retarded, up to 5 days, resulting in fluctuating plasma profiles. The volume of distribution at steady-state (Vdss) of parathion was around 20 L/kg. Post-mortem analysis in one patient revealed a 66-fold higher parathion concentration in fat tissue compared with plasma, 16 days after ingestion. Biotransformation of parathion varied widely and was severely retarded in one patient receiving fluconazole during worsening of renal function, while phenobarbital (phenobarbitone) sedation (two cases) had apparently no effect. The proportion of plasma parathion to paraoxon varied from 0.3-30, pointing also to varying paraoxon elimination, as illustrated by one case with particularly low paraoxonase-1 activity. Obidoxime was effective at paraoxon concentrations below 0.5 microM, provided aging was not too advanced. This concentration correlated poorly with the paration concentration or the poison load. The data are discussed in light of the pertinent literature.

This report presents a non-lethal method for estimating a range of therapeutic doses of bisquaternary oximes that serve as antidotes against organophosphorus poisoning. We have estimated therapeutic oxime doses that are equivalent in their relative toxicity rather than selecting arbitrary fractions of their LD(50). Thus, toxic signs of the oximes HI-6, HLö-7, Toxogonin, AB-8 and AB-13 were monitored quantitatively in baboon monkeys and beagle dogs. Using Toxogonin as a reference oxime, a calculated unit of equivalent dose (CED) was defined as the oxime dose equal to the ratio between its minimal toxic dose (MTD) and the therapeutic ratio (TR) of Toxogonin i.e. CED = MTD/TR. Assuming that the tails of dose-response curves of toxicity for bisquaternary oximes are shallow and similar to one another, one could substitute the ED(10) for the MTD. The ED(10) values for bisquaternary oximes were estimated using the log-log model following experimental observations and quantitative scoring of toxic signs in dogs and monkeys. The MTD values then were calculated using the ED(10) values and the experimental therapeutic dose of the reference oxime Toxogonin. The following CED values were obtained for AB-8, AB-13, Toxogonin, HI-6 and HLö-7 in dogs (d) and monkeys (m): 98.7, 74.2, 30.0, 14.5 and 12.1 (d) and 281.9, 232.1, 41.7, 192.9 and 92.9 (m) micromol kg(-1), respectively. The antidotal efficacy of these oximes against poisoning by the nerve agent tabun was determined in dogs and monkeys. These dose-dependent efficacy data were obtained at 0.3 x CED, 1 x CED and 3 x CED of oximes in combination with atropine. These data provide comparative therapeutic values using oxime doses based on their relative toxicity. The highest antidotal efficacy against tabun in dogs was obtained for toxogonin, whereas HLö-7 and AB-13 were most efficacious in monkeys., (Copyright 2001 John Wiley & Sons, Ltd.)

Considering the various microscopic reactions as well as toxicokinetic and pharmacokinetic principles in therapy of organophosphate poisoning, the administration of obidoxime by an initial bolus dose followed by continuous infusion appears rational. Using this protocol, six patients each with parathion or oxydemeton methyl poisoning were treated. In parathion poisoning, reactivation was possible up to 7 days. At paraoxon concentrations > 0.1 microM obidoxime only partially reactivated acetylcholinesterase (AChE) of erythrocytes in vivo although reactivation could be assessed in vitro, which roughly fitted theoretical calculations. AChE-inhibitory material was detected up to 5 days. Cholinergic signs soon subsided when AChE was above 20% of normal, and atropine plasma levels could be kept below 7 ng/ml. In one patient brain damage persisted. Oxydemeton methyl poisoning responded to obidoxime therapy only when the oxime was instituted shortly after poisoning. Out of six patients one died. No intermediate syndrome and no signs of permanent hepatic dysfunction were found in the 12 patients.

Organophosphate (OP) compounds have been used as pesticides and in chemical warfare (nerve agents). Two nerve agents, tabun and sarine, were used by the Iraqi army against Iranian troops and innocent people. Hundreds of the exposed combatants died in the field. Atropine sulphate has been used successfully in large doses to counteract the muscarinic effects of OP poisoning. The effects of oximes in human OP poisoning have not been well studied. Our aim was to study the effects of obidoxime and pralidoxime in OP pesticide poisoning. The patients were divided into three groups: atropine (A), obidoxime + atropine (OA) and pralidoxime + atropine (PA). Sixty-three patients (33 males, 30 females) with a mean age of 25 years were studied in different groups (43 A, 22 OA and 8 PA). There were no statistical significant differences in major clinical findings and acetylcholinesterase (AChE) activity on admission between the groups. Significant changes were observed during the treatment. Notwithstanding the severity of intoxication--particularly respiratory complications were more observed in the OA and PA groups--there were no fatalities in the PA group, whereas 4 (9%) and 6 (50%) patients in the A and OA groups died, respectively. AChE reactivation was only observed in the PA group, although it was not statistically significant (r = 0.4747). There was a good relationship between the AChE reactivation and outcome of the patients. High doses of obidoxime (8 mg/kg followed by 2 mg/kg/h) were found to be hepatotoxic and should be avoided. High doses of pralidoxime (30 mg/kg followed by 8 mg/kg/h) did not induce serious side effects and may be effective in some OP pesticides poisoning.

1. The influence of three oximes (obidoxime, HI-6 and the new asymmetric bispyridinium oxime BI-6) in combination with atropine on soman-induced cholinergic and stressogenic effects in rats was studied. 2. The oxime BI-6 produced significantly higher reactivation of soman-inhibited blood and diaphragm cholinesterases than obidoxime. On the other hand, its reactivating effect was not so high as the effect of the oxime HI-6. 3. There were not significant differences in the reactivation of soman-inhibited brain acetylcholinesterase among all three oximes tested. 4. The influence of the oxime BI-6 on soman-induced stressogenic effects was greater than the antistressogenic effects of HI-6 or obidoxime at 1 h or 3 h following soman poisoning. 5 These findings confirm that the oxime BI-6 has no definite advantages over HI-6 in the antidotal treatment of soman poisoning but BI-6 is significantly more effective in rats than obidoxime, one of the oximes presently in use.

1 The effectiveness of oxime therapy in organophosphate poisoning is still a matter of debate. It appears, however, that the often cited ineffectiveness of oximes may be due to inappropriate dosing. By virtue of in vitro findings and theoretical considerations we concluded in the preceding paper that oximes should preferably be administered by continuous infusion following an initial bolus dose for as long as reactivation of inhibited acetylcholinesterase (AChE) can be expected. This conclusion has called for a clinical trial to evaluate such oxime therapy on the basis of objective parameters. 2 Before transfer to the intensive care unit (ICU), 5 patients received primary care by an emergency physician. In the ICU, atropine sulphate was administered i.v. upon demand according to the endpoints: no bronchorrhoea, dry mucous membranes, no axillary sweating, heart rate of about 100/min. Obidoxime (Toxogonin) was given as an i.v. bolus (250 mg) followed by continuous infusion of 750 mg/24 h. 3 Intoxication and therapy were monitored by determining erythrocyte AChE (eryAChE) activity, reactivatability of the patient's eryAChE ex vivo, plasma cholinesterase activity, the presence of AChE inhibiting compounds, as well as the concentrations of obidoxime and atropine in plasma. 4 Obidoxime was effective in life-threatening parathion poisoning, in particular when the dose absorbed was comparably low. In mega-dose poisoning, net reactivation was not achieved until several days after ingestion, when the concentration of active poison in plasma had declined. Reactivatability in vivo lasted for a longer period than expected from in vitro experiments. 5 Obidoxime was quite ineffective in oxydemetonmethyl poisoning, when the time elapsed between ingestion and oxime therapy was longer than 1 day. When obidoxime was administered shortly after ingestion (1 h) reactivation was nearly complete. 6 Obidoxime levels of 10-20 microM were achieved by our regimen, and atropine could rapidly be reduced to approx. 20 microM, as attained by continuous infusion of 1 mg atropine sulphate/h. Maintenance of the desired plasma levels was not critical even when renal function deteriorated. 7 Signs of transiently impaired liver function were observed in patients who showed transient multiorgan failure. In the present stage of knowledge, we feel it advisable to keep the plasma concentration of obidoxime at 10-20 microM, although the full reactivating potential of obidoxime will not then be exploited. Still, the reactivation rate, with an apparent half-time of some 3 min, is twice that estimated for a tenfold higher pralidoxime concentration.

1 The toxicity of pinacolyl methylphosphonofluoridate (soman, GD), cyclohexyl methylphosphonofluoridate (cyclohe xylsarin, GF) and 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV) and the therapeutic efficacy of two oximes (obidoxime and HI-6) in combination with atropine against mentioned nerve agents were evaluated in mice. 2 The 24-h i.m. LD50 of GD was 101 micrograms/kg (99.5-104.0), LD50 of GF was 170 micrograms/kg (151.0-190.0 and LD50 of GV was 25.2 micrograms/kg (23.0-27.7). 3 The efficacy of two oximes, obidoxime (15 and 30 mg/kg) or HI-6 (15 and 30 mg/kg) in combination with atropine (21 mg/kg) was tested. HI-6 was significantly more effective in reducing mortality than obidoxime following poisoning with all three nerve agents. 4 Higher doses of both oximes showed significantly more effective therapeutic efficacy against all nerve agents studied.

The effects of HI-6 (1-[[[(4-aminocarbonyl) pyridinio]methoxy] methyl]-2-(hydroxyimino)-methyl]pyridinium dichloride monohydrate) on the organophosphorus agent 2-dimethylaminoethyl-(dimethylamido)-phosphonofluoridate (GV) inhibited cholinesterases in blood, brain and diaphragm and the stressogenic effect of GV in rats were compared to the effects of obidoxime. In GV-poisoned rats, HI-6 had a significantly higher reactivating effect in blood and brain as well as diaphragm than had obidoxime. HI-6 also practically eliminated the stressogenic effect of the GV compound. On the other hand, hypercorticosteronaemia and increase of liver tyrosine aminotransferase activity during treatment of poisoning with obidoxime were observed. These findings demonstrate the importance of HI-6 for treatment of GV agent poisoning in rats.

The action of HI-6 (1-[[[(4-aminocarbonyl)pyridiniol]methoxy]methyl]-2-[ (hydroxyimino)methyl] pyridinium dichloride monohydrate) and obidoxime on soman-induced anticholinesterase and stressogenic effects was studied in rats. HI-6 significantly affected acetylcholinesterase inhibition in erythrocytes, brain and diaphragm and practically eliminated the stressogenic effects of soman, i.e. an increase in plasma corticosterone level and liver tyrosine amino-transferase activity, while obidoxime, on the other hand, had very little influence on soman-induced inhibition of acetylcholinesterase activity and the stressogenic effects of soman. These findings support a hypothesis that the effects of HI-6 are not solely due to reactivation of the enzyme. They also demonstrate its importance in the treatment of soman poisoning in rats.

Six patients with organophosphorus compound intoxications developed an intermediate syndrome (weakness and fasciculations) and obidoxime was given on eight occasions. The efficacy of the acetylcholinesterase (AChE) reactivator was monitored electrophysiologically by neuromuscular transmission studies using single and repetitive nerve stimulation (20 and 50 Hz) and the activity of the serum (butyryl) cholinesterase (ChE). Dramatic electrophysiologic improvement was seen when obidoxime was given early within 12 h in 3 patients, although evidence of AChE inhibition did not subside completely. When administration of obidoxime was delayed 26 h or more after intoxication on five occasions, electrophysiologic improvement was mild or absent. In one case, 66 h after intoxication with oxydemeton-S-methyl, the neuromuscular block worsened, indicating that aging of the AChE had been completed. The electrophysiologic improvement was always accompanied with better motor function but not necessarily with improvement of the overall clinical status. Serum ChE did not predict the oxime effect at the motor endplate. In humans, the efficacy of oximes in AChE reactivation can be determined rapidly using electrophysiologic studies.

A capillary gas-liquid chromatographic (GLC) and an ion-pair high performance liquid chromatographic (HPLC) method were developed for the assay of atropine sulphate and obidoxime chloride from a parenteral solution in commercial automatic injection devices. The injectors are aimed for the emergency treatment of poisoning by nerve agents. The two-step GLC method consists of extraction of atropine as a free base prior to GLC analysis using scopolamine as an internal standard. Obidoxime is determined directly in a diluted sample solution by reversed-phase HPLC using sodium 1-heptanesulphonate as a counter ion in the mobile phase. The relative standard deviation (R.S.D.) was 1.81% for the GLC procedure with injectors containing only atropine and 2.37% for the GLC of atropine in atropine-obidoxime injectors. The R.S.D. for the HPLC procedure of obidoxime in atropine-obidoxime injectors was 0.82%. The corresponding R.S.D.s for the sampling of atropine-obidoxime injectors were 0.36% and 0.27%. The coefficient of determination (r2) was 1.000 for both methods. The recoveries at the target concentration averaged 101.0% and 98.7% with a standard error of the mean of 0.30 for both methods. The retention times for atropine and obidoxime were 6.27 and 4.29 min, respectively.

Objective: (1) Retrospective evaluation of the clinical course of carbamate poisoning and the effect of oxime therapy in children. (2) In vitro study of the effect of oximes on the reactivation of carbamylated cholinesterase., Design: (1) Clinical survey: The records of 26 children intoxicated with carbamates were examined retrospectively. The poisoning agents in all cases were positively identified as methomyl or aldicarb by gas chromatography-mass spectrometry. (2) Laboratory study: The direct effect of obidoxime and of pralidoxime on acetylcholinesterase activity in vitro was investigated in normal human packed red blood cells pretreated with an organophosphate (paraoxon) or a carbamate (aldicarb or methomyl)., Clinical Setting: Pediatric intensive care unit of a teaching hospital., Patients: Twenty-six infants and young children (aged 1 to 8 years) admitted to the pediatric intensive care unit with severe carbamate intoxication., Interventions: All cases had been treated with repeated doses of atropine sulfate (0.05 mg/kg) administered every 5 to 10 minutes until muscarinic symptoms disappeared. Obidoxime chloride (Toxogonin, 6 mg/kg) was administered on admission, and again after 4 to 5 hours., Results: Predominant symptoms were related to central nervous system and nicotinic effects. All the patients showed marked improvement within several hours and recovered completely within 24 hours. None of the children deteriorated and none showed exacerbation of cholinergic symptoms after obidoxime treatment. In vitro, oximes reactivated acetylcholinesterase inhibited with paraoxon, whereas no significant effect of oximes on carbamylated enzyme activity was observed., Conclusions: Based on the recovery of all cases, as compared with other reports of carbamate poisoning treated with atropine alone, it is concluded that, in the case of aldicarb or methomyl poisoning, oxime therapy apparently does not contribute to the recovery of poisoned patients. In cases of poisoning by an unknown pesticide or of mixed poisoning, oxime therapy can prove beneficial because no negative effects of the therapy can be discerned.

Obidoxime is an oxime used in several countries as an antidote in organophosphate intoxication. Its pharmacokinetics were studied in a 20 year-old female with severe and complicated methamidophos intoxication. Obidoxime elimination half life was 6.9 h, volume of distribution 0.845 L/kg, total body clearance 85.4 mL/min, and renal clearance 69 mL/min (creatinine clearance 54 mL/min). Eighty percent of the dose was excreted in the urine over 5 h. Possible reasons for the different pharmacokinetic values as compared with values previously reported in healthy volunteers are discussed. Obidoxime dose should be adjusted according to renal function. More studies are needed to establish the therapeutic window of obidoxime in patients with organophosphate intoxication.

The pharmacokinetics and pharmacodynamics of the oxime obidoxime (Toxogonin, 50 mg/kg iv) were investigated in anesthetized normal rats and in sarin-poisoned (50 micrograms/kg iv) rats. The kinetics were described by a two-compartment open model. The elimination half-life ranged from 35 min in normal rats to 86 min in sarin-poisoned rats. Obidoxime excretion occurred predominantly by the renal route, amounting to 4.6% of the administered dose in normal rats and to 0.9% in sarin-poisoned rats within the first hour of administration. The significantly diminished glomerular filtration rate confirmed the retardation of obidoxime excretion in sarin poisoning. The mean arterial blood pressure (MAP) response to obidoxime, measured in normal rats, was a transient hypotension, but to sarin an immediate hypertension. In sarin-poisoned rats the therapeutic sequence of administration of obidoxime and atropine (5 mg/kg iv) seemed to be important: the administration of atropine 10 min after and of obidoxime 20 min after sarin poisoning exerted a stabilizing effect on MAP. No serum albumin binding was found for obidoxime. Competition experiments at the isolated nicotinic receptor demonstrated the anticholinergic activity of obidoxime. The affinity of obidoxime was 1000 times smaller than that of acetylcholine. It is concluded that obidoxime, due to its prolonged residence time in the organism in sarin poisoning, exerts a "curare-like" inhibition and protection of the nicotinic acetylcholine receptor and, combined with atropine, a synergistic effect on blood pressure normalization.

This paper was aimed at the observation of trimethadione therapeutic effects while this preparation was used as an agent supplementing the standard therapeutic mixture (cholinolytic and reactivator) for mice poisoning with phospholine--a compound of AO 217 and DEP. The studies covered 216 female mice of Balb C strain, body weight 18-24 g. After the determination of toxic doses of phosphoroorganic preparations administered subcutaneously, therapeutic effects of a mixture of atropine sulphate (10 mg/kg i.p.) and obidoxime (40 mg/kg i.p.) administered immediately after poisoning, were observed. Then trimethadione 300 mg/kg i.p. was of in a dose of 300 mg/kg i.p was added and the effects of that agent on the efficiency of basic medicines were observed. The studies were performed during 2 and 24 hr of observation. The observations prove that the efficiency of the basic therapeutic mixture during 24 hrs of observation of mice poisonings with AO 217 and DFP was respectively: 2.31 x and 2.64 x. In phospholine poisonings no increase in therapeutic effects were found.

The antidotal efficacy of pralidoxime iodide and obidoxime dichloride was investigated in goslings poisoned by a supralethal dose of the organophosphorus insecticide diazinon. Various doses of both drugs were administered by intramuscular injection when the poisoned birds were unable to walk. Pralidoxime at 100 mg/kg brought about a complete and speedy clinical recovery. Fifty mg/kg induced recovery in 4 of 6 poisoned goslings, and 25 mg/kg successfully trated only 1 of 6 birds. Obidoxime at 25 mg/kg showed no therapeutic properties whereas 50 and 100 mg/kg delayed the death of some birds by several hours. At 100 mg/kg, all goslings had transient signs of intoxication, which precluded the use of this compound as an antidote at higher doses. The mode of action of these antidotes in diazinon-poisoned goslings is discussed.

Out of 859 consecutive cases treated for exposure to organophosphate (PO) insecticides, 53 were included in the study. Criteria for inclusion were severe OP poisoning necessitating artificial ventilation, intensive care monitoring and treatment according to a standard protocol. The protocol was based on relatively high doses of obidoxime, relatively low doses of atropine and overriding with a pacemaker in cases of ventricular arrhythmias and prolonged Q-T interval. Seven patients died during hospitalization. Thirty-two patients (60%) had major central nervous system (CNS) involvement. Five (9.4%) presented severe psychiatric sequelae. Twenty-two patients (41.5%) presented cardiac arrhythmias. Five (9.4%) had liver dysfunction. High frequency of cardiac arrhythmias was observed in patients who received high cumulative doses of atropine and obidoxime; impairment of liver functions was significantly higher in patients who received high cumulative doses of obidoxime. We conclude that each drug should be titrated separately: atropine dosage should be adjusted to the severity of tracheobronchial secretions and bronchospasm, while full doses of obidoxime are justified for the period before "aging" sets in.

The bispyridinium oxime HI-6, 1-((((4-amino-carbonyl)pyridinio)methoxy) methyl)-2-(hydroxyimino)methyl)pyridinium dichloride monohydrate, combined with atropine is an effective treatment for soman (pinacolyl methylphosphonofluoridate) poisoning but is relatively ineffective against tabun (ethyl N-dimethyl phosphoroamidocyanidate) poisoning in mice. This contrasts with those results obtained using the bispyridinium oxime obidoxime[1,1'-(oxy bis(methylene)) bis(4-(hydroxyimino)methyl) pyridinium dibromide]. The purpose of this study was to investigate the efficacy of the combination of HI-6 and obidoxime plus atropine against poisoning by tabun and soman in mice. The combination of ineffective single doses of obidoxime (5 or 10 mg/kg) and HI-6 (25 or 50 mg/kg) improved the treatment of tabun poisoning over either oxime alone. Combinations employing higher concentrations of obidoxime (25 or 50 mg/kg) and HI-6 (100 or 200 mg/kg) resulted in significant toxicity in the absence of organophosphate poisoning. Against soman poisoning the addition of obidoxime to HI-6 did not attenuate the efficacy of HI-6. The half-life of elimination and peak serum concentrations of HI-6 and obidoxime were not altered following administration of the combined injection. Reactivation of tabun-inhibited acetylcholinesterase was found consistently in the diaphragm but not in the brain. Using response surface methods it was possible to estimate the optimal therapy against soman and tabun poisoning (74.5 mg/kg HI-6 + 31.9 mg obidoxime against 1052 microns/kg obidoxime against 390 microns/kg challenge of soman).(ABSTRACT TRUNCATED AT 250 WORDS)

The efficacies (ED50) of obidoxime and atropine against paraoxon poisoning in mice were determined by administering the antidotes 5, 20, 40 and 60 min before administration of the organophosphate. With increasing time intervals t between the administration of the antidote and paraoxon, the dose of antidote (ED50), that reduced the lethality of 2 LD50 of paraoxon to 50% increased. The standardized log ED50/t plot was linear and yielded the "efficacy half-life". In addition, the blood concentrations c of the antidotes were measured, resulting in a linear log c/t plot. The "efficacy half-life" was approximately twice the half-life of the antidote in blood. The possible reasons for this phenomenon are discussed.