Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment

Shrot, Shai; Ramaty, Erez; Biala, Yoav; Bar‐Klein, Guy; Daninos, Moshe; Kamintsky, Lyna; Makarovsky, Igor; Statlender, Liran; Rosman, Yossi; Krivoy, Amir; Lavon, Ophir; Kassirer, Michael; Friedman, Alon; Yaari, Yoel

doi:10.1016/j.tox.2014.05.010

Cited by 35 publications

(27 citation statements)

References 30 publications

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“…In severe cases like this, as an adjunct to the standard therapy of atropine plus oxime, intranasal obidoxime treatment could be given at regular intervals until blood cholinesterase levels return to normal, providing protection for the CNS. Intranasal obidoxime could be used in place of, or in conjunction with second generation benzodiazepines such as midazolam to prevent seizures and subsequent brain damage (Shrot et al, 2014). Nasal inhalers with specific oximes or combinations of oximes may be practical additions to combat personnel emergency kits that include atropine/oxime auto-injectors for treating organophosphate poisoning.…”

Section: Discussionmentioning

confidence: 99%

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning

et al. 2016

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Intranasal delivery is an emerging method for bypassing the blood brain barrier (BBB) and targeting therapeutics to the CNS. Oximes are used to counteract the effects of organophosphate poisoning, but they do not readily cross the BBB. Therefore, they cannot effectively counteract the central neuropathologies caused by cholinergic over-activation when administered peripherally. For these reasons we examined intranasal administration of oximes in an animal model of severe organophosphate poisoning to determine their effectiveness in reducing mortality and seizure-induced neuronal degeneration. Using the paraoxon model of organophosphate poisoning, we administered the standard treatment (intramuscular pralidoxime plus atropine sulphate) to all animals and then compared the effectiveness of intranasal application of obidoxime (OBD) to saline in the control groups. Intranasally administered OBD was effective in partially reducing paraoxon-induced acetylcholinesterase inhibition in the brain and substantially reduced seizure severity and duration. Further, intranasal OBD completely prevented mortality, which was 41% in the animals given standard treatment plus intranasal saline. Fluoro-Jade-B staining revealed extensive neuronal degeneration in the surviving saline-treated animals 24 hours after paraoxon administration, whereas no detectable degenerating neurons were observed in any of the animals given intranasal OBD 30 min before or 5 min after paraoxon administration. These findings demonstrate that intranasally administered oximes bypass the BBB more effectively than those administered peripherally and provide an effective method for protecting the brain from organophosphates. The addition of intranasally administered oximes to the current treatment regimen for organophosphate poisoning would improve efficacy, reducing both brain damage and mortality.

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Section: Discussionmentioning

confidence: 99%

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning

et al. 2016

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“…In addition, the administration of diazepam is recommended for the relief of anxiety, agitation and to reduce muscle fasciculations (Eddleston & Chowdhury, ; Yang & Deng, ). Alternative benzodiazepines with anticonvulsant activity, midazolam and imidazenil, are now under research (Shrot et al, ).…”

Section: Oxidative Stress In Organophosphate Antidotal Therapymentioning

confidence: 99%

Oxidative stress in organophosphate poisoning: role of standard antidotal therapy

Váňová

Pejchal

Herman

et al. 2018

J of Applied Toxicology

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Despite the main mechanism of organophosphate (OP) toxicity through inhibition of acetylcholinesterase (AChE) being well known over the years, some chronic adverse health effects indicate the involvement of additional pathways. Oxidative stress is among the most intensively studied. Overstimulation of cholinergic and glutamatergic nervous system is followed by intensified generation of reactive species and oxidative damage in many tissues. In this review, the role of oxidative stress in pathophysiology of OP poisoning and the influence of commonly used medical interventions on its levels are discussed. Current standardized therapy of OP intoxications comprises live-saving administration of the anticholinergic drug atropine accompanied by oxime AChE reactivator and diazepam. The capability of these antidotes to ameliorate OP-induced oxidative stress varies between both therapeutic groups and individual medications within the drug class. Regarding oxidative stress, atropine does not seem to have a significant effect on oxidative stress parameters in OP poisoning. In a case of AChE reactivators, pro-oxidative and antioxidative properties could be found. It is assumed that the ability of oximes to trigger oxidative stress is rather associated with their chemical structure than reactivation efficacy. The data indicating the potency of diazepam in preventing OP-induced oxidative stress are not available. Based on current knowledge on the mechanism of OP-mediated oxidative stress, alternative approaches (including antioxidants or multifunctional drugs) in therapy of OP poisoning are under consideration.

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“…Many mouse and rat OP studies have recapitulated findings that were already made in NA models, such as the link between convulsions and brain damage, as well as the latent development of epilepsy following SE. 60,70 The similarities between OP and NA models suggest that mechanisms and treatments discovered in one model may be applicable to patients exposed to either type of organophosphate. Indeed, using OP animal models as a surrogate for NA exposure would be ideal, since OPs are safer for researchers to handle and more readily available.…”

Section: Pesticide Modelsmentioning

confidence: 99%

Anticonvulsant discovery through animal models of status epilepticus induced by organophosphorus nerve agents and pesticides

McCarren

McDonough

2016

Annals of the New York Academy of Sciences

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Organophosphorus pesticides (OPs) and nerve agents (NAs) are highly toxic chemicals that pose a significant threat to human health worldwide. These compounds induce status epilepticus (SE) by irreversibly blocking the ability of acetylcholinesterase to break down acetylcholine at neural synapses. Animal models of organophosphate-induced SE are a crucial resource for identifying new anticonvulsant therapies. Here, we describe the development of various animal models of SE induced by NA or OP exposure. Experiments in nonhuman primates, rats, mice, and guinea pigs have helped to identify novel therapeutic targets in the central nervous system, with particular success at modulating GABAergic and glutamatergic receptors. The anticonvulsants identified by NA- and OP-induced SE models are well poised for fast advancement into clinical development, and their potential utility in the broader field of epilepsy should make them all the more attractive for commercial pursuit.

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Prevention of organophosphate-induced chronic epilepsy by early benzodiazepine treatment

Cited by 35 publications

References 30 publications

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning

Intranasal delivery of obidoxime to the brain prevents mortality and CNS damage from organophosphate poisoning

Oxidative stress in organophosphate poisoning: role of standard antidotal therapy

Anticonvulsant discovery through animal models of status epilepticus induced by organophosphorus nerve agents and pesticides

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