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Exogenous, well-established antioxidant N-acetylcysteine can reduce or prevent the deleterious effects of pesticides. In this study, utilizing a mouse model of daily single dose of N-acetylcysteine administration, we investigated the impact of this adjuvant on the treatment with atropine and/or obidoxime as well as oxidative stress response in pyrimiphos-methyl-induced toxicity. We found that N-acetylcysteine significantly reduces the oxidative stress generated by pyrimiphos-methyl. The therapy consisting of atropine and/or obidoxime routinely used in organophosphorous insecticide poisonings, including pyrimiphos-methyl, had no effect on the antioxidant properties of N-acetylcysteine. Adjunctive treatment offered by N-acetylcysteine fills therapeutic gap and may provide the full potential against pyrimiphos-methyl-induced toxicity., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

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.)

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 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.)

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.

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.

The oxime HI 6 (in combination with atropine) is considered to be an effective antidote in soman intoxication but was shown to be less effective in tabun poisoning. In contrast to HI 6, first in vitro studies with HLö 7 demonstrated a reasonable reactivating potency at acetylcholinesterase (AChE) inhibited by soman and tabun. Therefore, the therapeutic efficacy of HLö 7, HI 6 and obidoxime (with and without atropine) was compared in tabun poisoned guinea-pigs. In addition, the therapeutic effect of atropine in guinea-pigs poisoned by various doses of tabun was investigated. Female Pirbright-white guinea-pigs were anaesthetized with urethane (1.8 g/kg) and the carotid artery, jugular vein and trachea were cannulated. After baseline measurements the animals received tabun, 60, 180 or 300 micrograms/kg, and 2 min later the antidotes (all i.v.): obidoxine, HLö 7, or HI 6 (30 or 100 mumol/kg, each) or atropine 10 mg/kg or a combination of atropine and one of the oximes. Respiratory and circulatory parameters were recorded for 60 min or until the death of the animal. Erythrocyte, brain and diaphragm AChE activity was determined in every animal after the experiment. Poisoning by tabun resulted in a rapid deterioration of respiratory function and respiratory arrest within 5 min. Atropine treatment was very effective in improving the respiratory function after tabun 60 micrograms/kg but was ineffective after tabun 300 micrograms/kg. However, circulatory parameters were restored almost completely in all atropine therapy groups. Therapy of tabun 300 microns/kg poisoned animals with atropine plus oxime (30 micromol/kg) improved respiration to a variable extent and restored circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Mice and guinea pigs were intoxicated by three different organophosphates: DFP, paraoxon, and OMPA. After onset of intoxication the animals were treated by either a mixture of atropine plus obidoxim or dexetimide plus obidoxim. The combination of dexetimide plus reactivator proved to be superior to the combination of atropine plus reactivator in case of DFP intoxication. In guinea pig the LD50 of DFP could be increased from about 20 to 1300 micrometers/kg b.wt. by dexetimide plus obidoxim when applied after the onset of intoxication. Concerning the paraoxon intoxication both antidote mixtures were found to be equally potent, whereas the purely peripheral intoxication induced by OMPA could only be influenced to a minor degree. The tissue distribution of atropine and dexetimide differs markedly, dexetimide being accumulated faster and to a higher degree. Thus the higher penetration rate of dexetimide into the central nervous system is considered to be the reason of its superiority in the treatment of an organophosphate intoxication of rapid onset.

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.