The Effect of Pyridostigmine Pretreatment on Oxime Efficacy Against Intoxication by Soman or VX in Rats

Anderson, Dana R.; Harris, Larrel W.; Woodard, Claude L.; Lennox, Willard J.

doi:10.3109/01480549209014158

Cited by 29 publications

(11 citation statements)

References 10 publications

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“…An improvement was found in pyridostigmine pretreated animals but in sarin and VX poisoning in particular, pyridostigmine reduced the efficacy of oxime-atropine treatment. 4,33,34 Concerning survival data in tabun poisoning, the studies directly comparing the effect of pretreated and non-pretreated animals report an improvement by pyridostigmine.4,5 In one of the studies 2-PAM was investigated in guinea-pigs, and in the other 2-PAM and HI 6 in rabbits. However, one has to take into account that in the studies mentioned a model of subacute (s.c.) poisoning and i.m.…”

Section: Discussionmentioning

confidence: 98%

Effect of pyridostigmine pretreatment on cardiorespiratory function in tabun poisoning

1995

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1 The effect of pyridostigmine on cardiorespiratory func tion after oxime+atropine injection was investigated in tabun poisoned guinea-pigs and without tabun poisoning. 2 The trachea, a carotid artery and jugular vein were can nulated in female urethane-anaesthetised Pirbright white guinea-pigs. After baseline measurements the ani mals received pyridostigmine (0.05 μmol kg-1) and 30 min later atropine (29.5 μmol kg-1) plus obidoxime, HI 6 or HL6 7 (30 or 100 μmol kg-1) or tabun (1.85 μmol kg-1 = 5 x LD50) followed by oxime+atropine treatment (all i.v.). Erythrocyte, brain and diaphragm acetyl cholinesterase (AChE) activity were determined. Similar groups without pretreatment were included for compar ison. 3 Pyridostigmine aggravated the oxime+atropine induced hypotension and prevented the increase in heart rate but not the respiratory stimulation. The pyridostigmine inhibited AChE recovered only in the 100 μmol kg-1 kg oxime groups at the end of the experiment. 4 In tabun poisoning, pyridostigmine reduced the oxime+atropine induced circulatory recovery and decreased the survival time and rate. It did not affect the therapeutic oxime+atropine effect on respiratory function. 5 These results suggest that pyridostigmine enhances oxime+atropine related circulatory depression which may be the reason for the reduced efficacy of oxime+atropine treatment in tabun poisoning. The pos sible mechanisms are discussed.

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Section: Discussionmentioning

confidence: 98%

Effect of pyridostigmine pretreatment on cardiorespiratory function in tabun poisoning

1995

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“…pyridostigmine or physostigmine, was proposed to improve antidotal treatment of nerve agent poisoning (Somani and Dube, 1989;Wolthuis et al, 1994;Dunn et al, 1997). In fact, carbamate pretreatment significantly improved the therapeutic efficacy of atropine/oxime treatment in soman poisoned animals (Dirnhuber et al, 1979;Gordon et al, 1978), whereas such an effect was doubted in the case of sarin and VX poisoning (Koplovitz et al, 1992;Anderson et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

et al. 2005

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The repeated misuse of highly toxic organophosphorus-type (OP) chemical warfare agents ('nerve agents') emphasizes the necessity for the development of effective medical countermeasures. The standard treatment with atropine and acetylcholinesterase (AChE) reactivators ('oximes') is considered to be ineffective with certain nerve agents due to low oxime efficacy. Therefore, pretreatment with carbamate-type compounds, e.g. pyridostigmine, was recommended to improve antidotal efficacy. Recently, the clinically used reversible AChE inhibitors metoclopramide (MCP) and ranitidine (RAN) were shown to exhibit some protective effect against the OP pesticide paraoxon in vitro and in vivo. The present study was undertaken to investigate a potential protective effect of MCP and RAN against inhibition of human AChE by the nerve agent VX (O-ethyl S-[2-(diisopropylamino)ethyl)methylphosphonothioate). Hemoglobin-free human erythrocyte membranes were incubated with various, human relevant MCP (0.5-2 microm) and RAN (0.5-5 microm) concentrations starting 1 min before addition of VX (1-40 nm). Both compounds failed to increase VX IC(50) values. In addition, human AChE was incubated with higher than human relevant therapeutic concentrations of MCP (1 microm-1 mm) and RAN (1 microm-2.0 mm) and inhibited by 40 nm VX. At concentrations higher than 100 microm MCP and RAN caused a concentration dependent increase of residual AChE activity 15 min after addition of VX. These data indicate that MCP and RAN may be ineffective in protecting human AChE against inhibition by the nerve agent VX at human relevant doses.

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“…The effectiveness of pyridostigmine as a pretreatment against nerve agent poisoning has been attributed to its ability to reversibly inhibit AChE and, consequently, protect a critical portion of the enzyme from irreversible inhibition by soman (Dinhurber et al, 1979;Gordon et al, 1978;Haigh et al, 2005;Heyl et al, 1980;Eckert et al, 2006). However, because pyridostigmine does not promptly cross the blood brain barrier, it does not protect AChE in the brain from irreversible inhibition by soman and, consequently, it does not prevent the CNSrelated toxic effects of this agent (Anderson et al, 1992). Although centrally acting, reversible AChE inhibitors, including galantamine and huperzine, are more effective pretreatments than pyridostigmine to prevent the acute toxicity of soman and other nerve agents (Albuquerque et al, 2006;Hilmas et al, 2009;Hamilton et al, 2017), concerns have been raised that effective doses of centrally acting reversible AChE inhibitors can be detrimental to executive brain functions.…”

Section: Discussionmentioning

confidence: 99%

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

Lane

Carter

Pescrille

et al. 2020

Preprint

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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 somanchallenged 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.

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The Effect of Pyridostigmine Pretreatment on Oxime Efficacy Against Intoxication by Soman or VX in Rats

Cited by 29 publications

References 10 publications

Effect of pyridostigmine pretreatment on cardiorespiratory function in tabun poisoning

Effect of pyridostigmine pretreatment on cardiorespiratory function in tabun poisoning

Effect of metoclopramide and ranitidine on the inhibition of human AChE by VXin vitro

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

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