Multiple Centrally Acting Antidotes Protect against Severe Organophosphate Toxicity

Sivilotti, Marco L.A.; Bird, Steven B.; Lo, Jean; Dickson, Eric W.

doi:10.1197/j.aem.2005.10.018

Cited by 8 publications

(4 citation statements)

References 42 publications

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“…In another study, 23/24 animals treated with injected or nebulised atropine, or diphenhydramine survived 24 hours, whilst mortality was >88% at 10 minutes for saline controls, glycopyrrolate and ipratropium treated animals 53 . Morphine and diazepam in a recent study again had similar protective effects 54 . These observations argue that early death in OP poisoning is at least in part centrally mediated.…”

Section: Diazepammentioning

confidence: 81%

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Adjuncts and Alternatives to Oxime Therapy in Organophosphate Poisoning—is There Evidence of Benefit in Human Poisoning? A Review

Peter

Moran

Pichamuthu

et al. 2008

Anaesth Intensive Care

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Organophosphate poisoning is common in developing countries. The morbidity and mortality with organophosphate poisoning is relatively high despite the use of atropine as specific antidotal therapy and oximes to reactivate acetylcholinesterase. Several adjunct and alternative therapies have been explored in animal and human studies. We reviewed the literature to ascertain if there was evidence of benefit of such therapies. Adjunct and alternative therapies included treatments to reduce poison absorption by topical application of creams, enhance toxin elimination by haemoperfusion or bioremediation and neutralise the poison by scavenging free organophosphate with cholinesterase-rich human plasma. In addition, magnesium, clonidine, diazepam, N-acetyl cysteine and adenosine receptor agonists have also been used to counteract poison effects. Detailed assessment was limited by the paucity of trials on adjunct/alternative therapies. The limited evidence from the review process suggested potential benefit from the use of human plasma infusion, early initiation of haemoperfusion and intravenous magnesium, in addition to standard therapy with atropine and pralidoxime. There appeared to be no additional benefit with alkalinisation or use of glycopyrrolate instead of atropine in human trials. Diazepam administration has been advocated by military authorities if symptoms developed following exposure to organophosphate. Bioremediation, clonidine, N-acetyl cysteine and adenosine receptor agonists have been evaluated only in animal models. The impact of adjunct and alternate therapies on outcomes in human poisoning needs to be further explored before implementation as standard treatment.

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Section: Diazepammentioning

confidence: 81%

“…Diazepam Survival benefit in animals 29,54 No studies in humans NATO mandates diazepam use post-exposure 55 Grade D Level 5…”

Section: Grade C Levelmentioning

confidence: 99%

Adjuncts and Alternatives to Oxime Therapy in Organophosphate Poisoning—is There Evidence of Benefit in Human Poisoning? A Review

Peter

Moran

Pichamuthu

et al. 2008

Anaesth Intensive Care

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“…As a consequence, the inhibition of AChE leads to this overstimulation and various phenomena, signs and symptoms occur as a result of this action (10,11). Clinical picture of anticholinesterase poisoning depends on the route of exposure (12) and on the quantity of the anticholinesterase in the organism, but includes miosis, bronchoconstriction, hypersalivation, bronchorrhoea, skeletal muscle fasciculations, bradycardia, hypotension, seizures and respiratory failure, the latter being the main cause of death (9,13).…”

Section: Anticholinesterases and Their Mode Of Actionmentioning

confidence: 99%

Mechanism and Clinical Importance of Respiratory Failure Induced by Anticholinesterases

Ivosevic

Miletić

Vulović

et al. 2017

Serbian Journal of Experimental and Clinical Research

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“…Current therapy for OP poisoning requires resuscitation with the use of oxygen and atropine, followed by administration of an oxime (such as pralidoxime (2-PAM)) to reactivate AChE, plus benzodiazepines to mitigate neurological impairment [6][7][8][9][10]. However, 2-PAM has a limited window of effectiveness and cannot regenerate functional AChE once the alkyl chains of the OP are removed by aging.…”

Section: Introductionmentioning

confidence: 99%

Non-muscarinic Therapeutic Targets for Acute Organophosphorus Poisoning

Rosenbaum

Bird

2010

J. Med. Toxicol.

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Organophosphorus (OP) pesticides are a broad class of acetylcholinesterase inhibitors that are responsible for tremendous morbidity and mortality worldwide, contributing to an estimated 300,000 deaths annually. Current pharmacotherapy for acute OP poisoning includes the use of atropine, an oxime, and benzodiazepines. However, even with such therapy, the mortality from these agents is as high as 40%. It is increasingly recognized that not all OPs are the same. Significant differences exist in their toxicity, lipophilicity, and response to oxime therapy. Other nonmuscarinic effects of OP pesticides exist, such as acute and chronic neuromuscular junction failure and central respiratory failure. In part because most of the mortality from these chemicals takes place in the developing world, little National Institutes of Health (NIH) research has been directed towards these agents. However, the similar mechanism of action of OP pesticides and the military nerve agents, along with increasing concerns about chemical terrorism has lead to the formation of the NIH Countermeasures Against Chemical Threats (CounterACT) Program. As part of the CounterACT Program, the NIH has recently designated six OP pesticides as "threat agents". This concept paper describes some of the knowledge gaps related to non-muscarinic effects of OP pesticides and highlights needed areas of further research. Leveraging the current NIH interest in these chemicals to medical necessities in the developing world offers the possibility of delivering new therapeutics where they are needed on a daily basis.

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Multiple Centrally Acting Antidotes Protect against Severe Organophosphate Toxicity

Abstract: Doses of diazepam, xylazine, and morphine below those used for deep sedation protect against severe dichlorvos poisoning, implying that several distinct central mechanisms are each sufficient to avert lethality. These findings suggest new possibilities for prophylaxis or therapy.

Cited by 8 publications

References 42 publications

Adjuncts and Alternatives to Oxime Therapy in Organophosphate Poisoning—is There Evidence of Benefit in Human Poisoning? A Review

Adjuncts and Alternatives to Oxime Therapy in Organophosphate Poisoning—is There Evidence of Benefit in Human Poisoning? A Review

Mechanism and Clinical Importance of Respiratory Failure Induced by Anticholinesterases

Non-muscarinic Therapeutic Targets for Acute Organophosphorus Poisoning

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