Oral Pretreatment with Galantamine Effectively Mitigates the Acute Toxicity of a Supra-Lethal Dose of Soman in Cynomolgus Monkeys Post-treated with Conventional Antidotes

The present study was designed to evaluate the effectiveness of galantamine administered orally as a pre-treatment to mitigate the acute toxicity of 4.0xLD50 soman in Cynomolgus monkeys post-treated with atropine, 2-PAM, and midazolam. Pharmacokinetic experiments revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr were quickly absorbed and produced plasma concentrations of galantamine that generated approximately 20% to 40% reversible inhibition of blood acetylcholinesterase (AChE) activity. This degree of reversible AChE inhibition has been shown to be safe and sufficient to protect AChE from the irreversible inhibition by nerve agents, and, thereby, suppress the acute toxicity of these agents. Thus, in subsequent experiments, adult male Cynomolgus monkeys were pretreated orally with 1.5 or 3.0 mg/kg galantamine, challenged intramuscularly with 4.0xLD50, and post-treated with intramuscular injections of 0.4 mg/kg atropine, 30 mg/kg 2-PAM, and 0.32 mg/kg midazolam. All animals subjected to these treatments survived the soman. By contrast, none of the animals that were pretreated with saline and only 40% of the animals that were pretreated with pyridostigmine survived the soman challenge when post-treated with the same conventional antidotal therapy as that delivered to the galantamine-pretreated, soman-challenged monkeys. In addition, large numbers of degenerating neurons were visualized in the hippocampi of soman-challenged monkeys that had been pretreated with pyridostigmine or saline, but not in the hippocampi of animals that had been pretreated with galantamine. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supra-lethal doses of soman in non-human primates.

Antidotes Against Methanol Poisoning: A Review

Methanol is the simplest alcohol. Compared to ethanol that is fully detoxified by metabolism. Methanol gets activated in toxic products by the enzymes, alcohol dehydrogenase and aldehyde dehydrogenase. Paradoxically, the same enzymes convert ethanol to harmless acetic acid. This review is focused on a discussion and overview of the literature devoted to methanol toxicology and antidotal therapy. Regarding the antidotal therapy, three main approaches are presented in the text: 1) ethanol as a competitive inhibitor in alcohol dehydrogenase; 2) use of drugs like fomepizole inhibiting alcohol dehydrogenase; 3) tetrahydrofolic acid and its analogues reacting with the formate as a final product of methanol metabolism. All the types of antidotal therapies are described and how they protect from toxic sequelae of methanol is explained.

Fatality from potassium gold cyanide poisoning

While potassium cyanide poisoning has been well described, the toxicity of potassium gold cyanide is less well understood. This case describes an 84-year-old man who presented after an intentional ingestion of 0.5–1 teaspoons of potassium gold cyanide. Despite antidotal therapy, the patient rapidly developed severe lactic acidosis, multiorgan dysfunction and ultimately expired. While the patient’s clinical findings were consistent with acute cyanide poisoning, a serum cyanide level was below the toxic threshold. Previous reports have suggested that gold toxicity may also contribute to the effects of potassium gold cyanide, and may have played a role in the patient’s rapid decline. In addition to treatment of cyanide toxicity, management of acute gold toxicity should also be considered in potassium gold cyanide ingestion.

Therapy for acute nerve agent poisoning

Purpose of reviewAcute nerve agent poisoning was last reviewed in the neurology literature in 2004. As neurologists may expect to be called upon by non-neurologist colleagues as local experts, it is timely to update the 2004 review.Recent findingsAcute antidotal therapy for nerve agent poisoning has been rendered simpler and faster by the FDA approval and introduction of the dual-dose autoinjector. Although there are no truly new fielded antidotes, midazolam recently received FDA approval for treatment against seizures, and will replace diazepam in most acute situations when the FDA approves it in the autoinjector form. Information on acute therapy is much more easily accessed in real time now than in 2004, thanks to efforts by the National Library of Medicine and the American College of Medical Toxicology.SummarySince 2004, there have been changes in antidotal therapy and a robust expansion in familiarity with nerve agent management principles in the civilian sector. These advances are somewhat offset by the increased use of nerve agents for nefarious purposes.

PECULIARITIES OF METABOLITES TOXICOKINETICS OF G-TYPE ORGANOPHOSPHORUS NERVE AGENTS IN BIO FLUIDS OF RATS SUBECTED TO ANTIDOTE THERAPY

The effect of the Pelixim antidote on the possibility to detect markers of G type nerve agents sarin and soman was studies in bio probes obtained in an acute in vivo experiment after exposure of rats to organophosphorus nerve agents in doses of 0.5LD50. It was found out that the intake of equitoxic doses of soman and sarin leads to a decrease of acetylcholinesterase erythrocyte membrane (AChE) activity for up to 7 days after exposure. The effect of Pelixim on the recovery of erythrocyte AChE activity is mostly pronounced a day after sarin poisoning. The fluoride regeneration of nerve agents from blood plasma protein adducts was possible for up to 7 days after soman poisoning without antidotal therapy and for 3 days after with antidotal therapy; in case of sarin intoxication, fluoride regeneration was possible for 3 days regardless of the use of antidotal therapy . The antidote strongly affected the excretion of hydrolytic metabolite of sarin О-isopropyl methylphosphonic acid (IMPA) and had no effect on the excretion of hydrolytic metabolite of soman О-pinacolyl methylphosphonic acid (PMPA). A day after poisoning and Pelixim injection, IMPA was detected in urine at a level of 15.3 ng/ml, whereas its level in the urine samples of animals in the absence of antidotal therapy was 55.0 ng/ml; 3 days after poisoning, IMPA was detected at a level of 4.9 ng/ml exclusively in the urine of animals subjected to antidotal therapy. The urine levels of PMPA in animals subjected and not subjected to antidotal therapy were respectively 44 and 53 ng/ml a day after poisoning and 12 and 14 ng/ml respectively 3 days after poisoning. Thus, the antidote impact on the excretion profile of hydrolytic metabolites is more significant for sarin than that of soman.