Pralidoxime chloride 1g powder for solution for injection vials

Introduction The benefits of atropine in the treatment of acute organophosphate (OP) poisoning has been well established, while that of oximes is still uncertain. Pralidoxime is the most often used oxime worldwide. In vitro experiments have consistently shown that oximes are effective reactivators of human acetylcholinesterase enzyme, inhibited by OP compounds. However, the clinical benefit of pralidoxime is still unclear. A recent meta-analysis has found that pralidoxime provides no significant improvement in outcome and rather may cause harm while increasing the economic burden in low-income communities where its use is the most prevalent. Objectives This study aimed to provide an updated evaluation of the efficacy of pralidoxime in addition to atropine alone in the treatment of patients with acute OP poisoning in terms of mortality, need for ventilator support, and the incidence of intermediate syndrome. The intermediate syndrome is a clinical syndrome that occurs 24 to 96 hours after the ingestion of an OP compound and is characterized by prominent weakness of neck flexors, muscles of respiration, and proximal limb muscles.  Materials and methods We searched MEDLINE, EMBASE, CENTRAL, and ClinicalTrials.gov databases until January 2019 for randomized controlled trials (RCTs) in the English language that evaluated the use of pralidoxime in individuals of any age, gender or nationality presenting with an alleged history of OP intake. The primary outcome was mortality. Secondary outcomes were the need for ventilator support and the incidence of intermediate syndrome. The risk of bias in included studies was assessed using the tool recommended by the Cochrane Handbook of Systematic Review of Interventions. Treatment/control differences in these outcomes across included studies were combined using risk ratios (RR). Results Six randomized controlled trials (n = 646) fulfilled the inclusion criteria, including one further trial missed from the most recent systematic review. The risk of bias varied across studies, with Eddleston 2009 being of the lowest risk and Cherian 2005 being of high risk. The risk of mortality (RR = 1.53, 95% confidence interval (CI) 0.97 to 2.41, P = 0.07) and the need for ventilator support (RR = 1.29, 95% CI 0.97 to 1.71, P = 0.08) were not significantly different between the pralidoxime and the control group. There was a significant increase in the incidence of intermediate syndrome in the pralidoxime group (RR = 1.63; 95% CI 1.01 to 2.62, P = 0.04). Conclusions Based on our meta-analysis of the available RCTs, pralidoxime was not shown to be beneficial in patients with acute OP poisoning. Our findings are consistent with the other literature.

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Some clinicians assess the efficacy of pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide, and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor pralidoxime treatment by studying its reactivation after pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) class II OP insecticide poisoning. Patient data were derived from 2 studies, a cohort study (using a bolus treatment of 1g pralidoxime chloride) and a randomized controlled trial (RCT) (comparing 2g pralidoxime over 20 min, followed by an infusion of 0.5 g/h, with placebo). Two grams of pralidoxime variably reactivated BuChE in patients poisoned by 2 diethyl OP insecticides, chlorpyrifos and quinalphos; however, unlike acetylcholinesterase reactivation, this reactivation was not sustained. It did not reactivate BuChE inhibited by the dimethyl OPs dimethoate or fenthion. The 1-g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO class II OP-poisoned patients according to the pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of pralidoxime treatment is unlikely to be clinically useful.

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A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.

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A library of 100 click-chemistry-derived oximes was evaluated as reactivators of butyrylcholinesterase (BChE) inhibited by the nerve agents (NAs) sarin, cyclosarin, VX, and tabun. While reactivation efficiency was highly dependent on the structure of both the NA and the oxime, for each NA-BChE conjugate, we identified reactivators more effective than currently approved oximes for NA poisoning. Detailed kinetic analysis indicated that this enhancement results from both improved molecular recognition-specifically, enhanced binding affinity of the phosphylated conjugates for the oximes-and increased maximal reactivation rates. Molecular modeling of oximes in a near-attack conformation within inhibited BChE revealed critical interactions for productive reactivation. Among all tested oximes, 5B [1-hexyl-2-((hydroxyimino)methyl)pyridinium chloride] emerged as a particularly efficient reactivator for BChE phosphorylated with cyclosarin, with the highest observed overall reactivation rate of 34,120 M-1 min-1, which is 525-fold and 44-fold higher than the reference oximes 2-PAM and HI-6, respectively. In general, three mono-pyridinium mono-oximes demonstrated more efficient recovery of BChE activity than bis-pyridinium triazole-annulated click-chemistry bis-oximes, which were previously identified as potent reactivators for inhibited acetylcholinesterase (AChE). Ex vivo assessment of reactivation potency demonstrated that the combined addition of BChE with one efficient reactivator for BChE and another for AChE achieved > 90% reactivation of cyclosarin-inhibited cholinesterases in whole blood (WB), demonstrating near-complete degradation of a 100-fold excess of cyclosarin within 6 min. These results confirm that oxime-assisted catalysis is feasible for NA bioscavenging in blood and underscore BChE's potential as a target for developing therapies against NA poisoning.

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Oximes play an essential role in the therapy of organophosphorus compound (OP) poisoning by reactivating inhibited acetylcholinesterase. Impairment of liver function was observed in OP poisoning and associated with obidoxime treatment by some reports. In this study human three-dimensional HepaRG spheroids were used as complex in vitro model to investigate oxime-induced liver toxicity. In this context, cold storage of liver spheroids at 4 °C in standard culture medium and in optimized tissue preservation solutions of up to 72 h was assessed. Cold storage in standard culture medium resulted in a complete loss of viability whereas an optimized tissue preservation solution preserved viability. Separately from that liver spheroids were exposed to the four oximes pralidoxime, obidoxime, HI-6, MMB-4 and cytotoxicity (effective concentration, EC50) was determined with an ATP-based assay at several time points. The release of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and albumin secretion was measured in supernatants. The same parameters were assessed with diclofenac as positive hepatotoxic control and with the OP pesticides malathion and malaoxon alone or in the presence of obidoxime. All individual tested oximes and OP showed a low cytotoxicity with effective concentrations mostly >2,000 μM. In contrast, the exposure to malaoxon in the presence of 1,000 μM obidoxime resulted in a marked decrease of viability and an increased release of AST indicating risk of liver injury only if oxime antidotes are strongly overdosed.

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