Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase treatments in acute sarin intoxication

Tuovinen, Kai; Kaliste-Korhonen, Eila; Raushel, Frank M.; Hänninen, Osmo

doi:10.1016/s0300-483x(99)00029-3

Cited by 63 publications

(48 citation statements)

References 36 publications

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“…remaining intact AChE is a basic requirement for normal function of peripheral and central cholinergic nervous systems. Due to this pretreatment, the enzyme AChE became resistant to nerve agent-induced irreversible inhibition (18). It can be achieved by using reversible inhibitors (preferably carbamates) which are able to inhibit AChE reversibly with spontaneous recovery of the activity (decarbamylation).…”

Section: Discussionmentioning

confidence: 99%

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

Kassa

Korábečný

Nepovimová

2017

Acta Med. (Hradec Kralove, Czech Repub.)

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A B ST R AC T Aim: The ability of four newly prepared reversible inhibitors of acetylcholinesterase (6-chlorotacrine, 7-phenoxytacrine, compounds 1 and 2) and currently used carbamate pyridostigmine to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. Methods: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD 50 value and its 95% confidence limit using probitlogarithmical analysis of death occurring within 24 h after administration of soman. Results: 6-chlorotacrine was only able to markedly protect mice against acute toxicity of soman. In addition, the pharmacological pretreatment with 6-chlorotacrine or compound 2 was able to increase the efficacy of antidotal treatment (the oxime HI-6 in combination with atropine) of soman-poisoned mice. The other newly prepared reversible inhibitors of acetylcholinesterase (7-phenoxytacrine, compound 1) as well as commonly used pyridostigmine did not influence the efficacy of antidotal treatment. Conclusion: These findings demonstrate that pharmacological pretreatment of somanpoisoned mice can be promising and useful in the case of administration of 6-chlorotacrine and partly compound 2. K E Y WO R D S soman; reversible inhibitors of acetylcholinesterase; antidotes; pharmacological pretreatment; mice

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Section: Discussionmentioning

confidence: 99%

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

Kassa

Korábečný

Nepovimová

2017

Acta Med. (Hradec Kralove, Czech Repub.)

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“…remaining intact AChE is a basic requirement for normal function of peripheral and central cholinergic nervous systems. Due to this pharmacological pretreatment, the enzyme AChE became resistant to nerve agent-induced irreversible inhibition (21).…”

Section: Discussionmentioning

confidence: 99%

“…The maximum inhibition is achieved 2-3 hrs and lasts more than 8 hrs. The half-life of inhibition is about 20 hrs (21,24,25). The main reason for the widespread adoption of pyridostigmine as a prophylactic antidote against nerve agents is the fact that it does not influence the ability of the troops to perform the combat mission probably due to its inability to inhibit AChE in the central nervous system.…”

Section: Discussionmentioning

confidence: 99%

“…The doses of reversible inhibitors of AChE must be sufficiently safe to avoid peripheral as well as central adverse drug reactions and to maintain battle readiness of troops. Physostigmine is one of the most important representative of central inhibition of AChE (21). However, it produces marked behavioral impairment at doses sufficient to contribute to protection against a convulsant dose of soman (27).…”

Section: Discussionmentioning

confidence: 99%

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Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice

Kassa

Korábečný

2017

Acta Med. (Hradec Kralove, Czech Repub.)

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A B ST R AC T Aim: The influence of the dose on the ability of promising newly prepared reversible inhibitor of acetylcholinesterase (6-chlorotacrine) to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman-poisoned mice was evaluated. Methods: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman-induced toxicity that was evaluated by the assessment of its LD 50 value and its 95% confidence limit using probit-logarithmical analysis of death occurring within 24 hrs after administration of soman. Results: The dose of 6-chlorotacrine significantly influences the prophylactic efficacy of 6-chlorotacrine. Its highest dose was only able to significantly protect mice against acute toxicity of soman and increase the efficacy of antidotal treatment (atropine in combination with the oxime HI-6) of soman-poisoned mice. In addition, the highest dose of 6-chlorotacrine was significantly more effective to protect mice from soman poisoning than its lowest dose. Conclusion: These findings demonstrate the important influence of the dose of 6-chlorotacine on its prophylactic efficacy in the case of pharmacological pretreatment of soman poisoning in mice.

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“…Pretreatment with oral pyridostigmine followed by the conventional atropine plus oxime treatment increased the LD 50 of soman by at least one order of magnitude compared with atropine plus oxime. Pyridostigmine pretreatment is effective only when followed by atropine and oxime; pyridostigmine alone is not effective (Stitcher et al, 1978;Heyl et al, 1980;Tuovinen et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Protective agents in acute high‐dose organophosphate exposure: comparison of ranitidine with pralidoxime in rats

Petroianu

Al‐Hasan

Nurulain

et al. 2005

J of Applied Toxicology

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Weak and reversible inhibitors of cholinesterase, when coadministred in excess with a more potent inhibitor such as organophosphates, can act in a protective manner. Ranitidine (RAN) is a clinically widely used histamine type 2 (H2) receptor blocker. Ranitidine is also the most potent inhibitor of acetylcholinesterase among H2 blockers (inhibitory constant K in the low micromolar range) but roughly three orders of magnitude less potent than paraoxon. This study evaluates RAN-conferred protection in acute high-dose organophosphate (paraoxon, POX) exposure in rats in direct comparison with the therapeutic gold-standard pralidoxime (PRX). Group 1 received 1 microM POX, group 2 received 50 microM RAN, group 3 received 50 microM PRX, group 4 received 1 microM POX + 50 microM RAN and group 5 received 1 microM POX + 50 microM PRX. All substances were applied intraperitoneally. The animals were monitored for 48 h and mortality was recorded at 30 min and 1, 2, 3, 4, 24 and 48 h. Blood was taken for red blood cell acetylcholinesterase (RBC-AChE) measurements at baseline, 30 min and 24 and 48 h. Mortality occurred mainly in the fi rst 30 min after POX administration, with minimal changes occurring thereafter. Mortality (in %) at 30 min in groups 1, 4 and 5 was 52 +/- 18, 37 +/- 20 and 17 +/- 18, respectively, and mortality at 48 h was 59 +/- 12, 39 +/- 20 and 28 +/- 20, respectively. The RBC-AChE activities (in % of baseline values) at 30 min in groups 1, 4 and 5 were 18 +/- 16, 47 +/- 23 and 48 +/- 20, respectively. At 24 h the values were 46 +/- 16, 65 +/- 24 and 86 +/- 17, respectively, and at 48 h the values were 71 +/- 19, 78 +/- 21 and 110 +/- 27, respectively. Coadministration of PRX significantly decreases mortality in the described model at all points in time. Coadministration of RAN statistically significantly decreases mortality at 24 and 48 h. The extent of protection conferred by RAN is less (but not statistically significantly so) than that conferred by the gold-standard PRX. Coadministration of PRX statistically significantly increases RBC-AChE activities in the described model at all points in time. Ranitidine confers a statistically significant protection for the enzyme at 30 min only. We conclude that RAN is potentially of clinical use in reducing mortality in acute high-dose organophosphate exposure. Further studies involving different organophosphates and dosages, as well as different animal species, will be needed both to con fi rm these initial findings and to address the issue of the optimal timing for RAN preadministration.

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Success of pyridostigmine, physostigmine, eptastigmine and phosphotriesterase treatments in acute sarin intoxication

Cited by 63 publications

References 36 publications

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice

Protective agents in acute high‐dose organophosphate exposure: comparison of ranitidine with pralidoxime in rats

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