Physostigmine and Hyoscine Improves Protection Against the Lethal and Incapacitating Effects of Nerve Agent Poisoning in the Guinea-Pig

Wetherell, Janet R.; Hall, Tracey E.; Passingham, Sarah

doi:10.1016/s0161-813x(02)00082-7

Cited by 65 publications

(38 citation statements)

References 29 publications

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“…Pretreatment with pyridostigmine prevents OP-induced irreversible AChE inhibition in the periphery, and it increases survival of animals acutely exposed to lethal doses of nerve agents, provided that atropine and oximes are administered promptly after an OP exposure (5,8,9). When used acutely before an OP exposure, reversible inhibitors of AChE that are capable of crossing the blood-brain barrier, including physostigmine, tacrine, and huperzine A (hereafter referred to as huperzine), afford better protection than pyridostigmine against OP toxicity, but generally this protection occurs at doses that produce significant incapacitation and central nervous system impairment (10-13).…”

mentioning

confidence: 99%

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Albuquerque

Pereira

Aracava

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

145

129

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The nerve agents soman, sarin, VX, and tabun are deadly organophosphorus (OP) compounds chemically related to OP insecticides. Most of their acute toxicity results from the irreversible inhibition of acetylcholinesterase (AChE), the enzyme that inactivates the neurotransmitter acetylcholine. The limitations of available therapies against OP poisoning are well recognized, and more effective antidotes are needed. Here, we demonstrate that galantamine, a reversible and centrally acting AChE inhibitor approved for treatment of mild to moderate Alzheimer's disease, protects guinea pigs from the acute toxicity of lethal doses of the nerve agents soman and sarin, and of paraoxon, the active metabolite of the insecticide parathion. In combination with atropine, a single dose of galantamine administered before or soon after acute exposure to lethal doses of soman, sarin, or paraoxon effectively and safely counteracted their toxicity. Doses of galantamine needed to protect guinea pigs fully against the lethality of OPs were well tolerated. In preventing the lethality of nerve agents, galantamine was far more effective than pyridostigmine, a peripherally acting AChE inhibitor, and it was less toxic than huperzine, a centrally acting AChE inhibitor. Thus, a galantamine-based therapy emerges as an effective and safe countermeasure against OP poisoning.galantamine ͉ guinea pig ͉ pyridostigmine ͉ soman ͉ sarin T he organophosphorus (OP) compounds soman, sarin, VX, and tabun, referred to as nerve agents, are among the most lethal chemical weapons ever developed (1). Some of them were used with catastrophic results in wars and also in terrorist attacks in Japan in the 1990s (2). The majority of insecticides are also OPs, and intoxication with these compounds represents a major public-health concern worldwide (3, 4). The possibility of further terrorist attacks with nerve agents and the escalating use of OP insecticides underscore the urgent need to develop effective and safe antidotes against OP poisoning.The acute toxicity of OPs results primarily from their action as irreversible inhibitors of acetylcholinesterase (AChE) (5). In the periphery, acetylcholine accumulation leads to persistent muscarinic receptor stimulation that triggers a syndrome whose symptoms include miosis, profuse secretions, bradycardia, bronchoconstriction, hypotension, and diarrhea. It also leads to overstimulation followed by desensitization of nicotinic receptors, causing severe skeletal muscle fasciculations and subsequent weakness. Central nervous system-related effects include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma.Current therapeutic strategies to decrease OP toxicity include atropine to reduce the muscarinic syndrome, oximes to reactivate OP-inhibited AChE, and benzodiazepines to control OPtriggered seizures (5). The limitations of these treatments are well recognized (4), and alternative therapies have been sought. Among these therapies are phosphotriesterases and butyrylcholinesterase (...

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confidence: 99%

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Albuquerque

Pereira

Aracava

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

145

129

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“…For several years, 2 mg as the 'unit dose' of atropine in the MARK researchers in Israel, the UK and the Nether-I or ATNAA autoinjectors was established lands have demonstrated the effectiveness of because this amount of atropine can reverse the scopolamine or hyoscine as part of a pretreateffects of low or moderate exposures to nerve ment combination with the centrally active caragent. The associated side-effects of this dose bamate physostigmine against soman poisoning are well-tolerated, change in mental status is (Meshulam et al, 2001;Philippens et al, 2000;very unlikely and reasonable military perfor-Wetherell, 1994;Wetherell et al. 2002).…”

Section: Principles Of Treatment Ofmentioning

confidence: 96%

Atropine and Other Anticholinergic Drugs

McDonough¹,

Shih²

2007

Chemical Warfare Agents

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“…BChE can act as an endogenous scavenger for organophosphate compound, which is blocked by pyridostigmine. The inability of the compound to prevent central nervous system manifestations such as seizures may demand the inclusion of anticonvulsants into the treatment pattern [29,30] .…”

Section: Current Treatment Optionsmentioning

confidence: 99%

Can Galantamine Act as an Antidote for Organophosphate Poisoning? A Review

Indu¹,

Danasekaran²,

Manjunatha³

et al. 2016

ijps

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Indu, et al.: Galantamine in the Management of Organophosphate PoisoningOrganophosphate compounds are commonly used as insecticides in rural areas and powerful warfare agents by military personnel. These agents inhibit cholinesterases especially acetylcholinesterase and accumulate acetylcholine causing muscarinic, nicotinic and central nervous system manifestations. Currently, drugs such as atropine, oximes and benzodiazepine are used to treat these symptoms. But these drugs are associated with certain drawbacks and have found to be ineffective in preventing the delayed symptoms. This review analyses the rationalities in considering galantamine as an effective choice in the management of organophosphate toxicity. The mechanism is based on reversible competitive inhibiting property of galantamine on acetylcholinesterase without affecting butylcholinesterase. The drug can prevent the delayed cognitive effects and neurodegeneration by acting as a nicotinic allosteric potentiating ligand. It can cross the blood brain barrier and reversibly inhibit acetylcholinesterase in the brain and decrease the incidence of central nervous system manifestations such as convulsions. The drug is associated with good pharmacokinetic profile, minimal side effects and has been found to be effective as a pretreatment and post treatment agent. Thus, galantamine can be considered as an effective therapeutic agent in management of organophosphate toxicity.Key words: Acetylcholinesterase, galantamine, organophosphate compound, poisoning management, therapeutic approachesOrganophosphate compounds are used as insecticides and powerful warfare agents worldwide. The differences in the properties are based on the substituents attached to the basic moiety. The highly toxic compounds were developed as warfare agents and lesser toxic agents as insecticidal agents [1,2] . Among the commonly used agrochemicals, organophosphates were found to be the most preferred one due to their wide spectrum bioactivity and easy availability [3] . Parathion, fenthion, malathion, diazinon, chlorpyrifos (Dursban), terbufos, acephate, phorate, methyl parathion, phosmet, azinphos-methyl and dimethoate are the commonly used insecticidal agents. World Health Organization (WHO) has described that these agents belong to the extremely hazardous category, yet no law or policies exist to restrict their availability to the public [4][5][6] . Organophosphate compounds are responsible for large scale accidental poisoning and suicidal poisoning in developed countries [7] . Compounds such as soman (1,2,2-trimethyl propylmethyl phosphono fluoridate), sarin (isopropyl methyl phosphono fluoridate), tabun (ethyl dimethyl phosphoramidocyanidate) and VX (ethyl-S-diisopropylamino ethyl methyl phosphono thioate) are used as warfare agents, capable of causing mass destruction in war [8] . Thus, organophosphate poisoning became a major public health hazard to be therapeutically managed effectively. MECHANISM OF ACTION AND CLINICAL SYMPTOMSOrganophosphate compounds may enter into the human ...

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Physostigmine and Hyoscine Improves Protection Against the Lethal and Incapacitating Effects of Nerve Agent Poisoning in the Guinea-Pig

Cited by 65 publications

References 29 publications

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents

Atropine and Other Anticholinergic Drugs

Can Galantamine Act as an Antidote for Organophosphate Poisoning? A Review

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