Review of the Value of Huperzine as Pretreatment of Organophosphate Poisoning

Lallement, G.; Baille, Valérie; Baubichon, Dominique; Carpentier, Pierre; Collombet, Jean-Marc; Filliat, Pierre; Foquin, Annie; Four, Elise; Masqueliez, Catherine; Testylier, Guy; Tonduli, L.; Dorandeu, Frédéric

doi:10.1016/s0161-813x(02)00015-3

Cited by 87 publications

(64 citation statements)

References 22 publications

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“…All other centrally acting AChE inhibitors studied to date, including huperzine, acutely prevent OP toxicity when used at doses that decrease blood AChE activity by Ͼ70% (10-13). However, brain AChE activity is inhibited to a similar extent (Ϸ70%) by these drugs (13). Therefore, a high degree of reversible and selective AChE inhibition in the blood appears to be necessary to counteract the peripheral toxic effects of OPs acutely.…”

Section: Discussionmentioning

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.

140

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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Section: Discussionmentioning

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.

140

129

View full text Add to dashboard Cite

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“…Similarly, in primates (Chinese rhesus monkeys), HupA by itself has been shown to protect animals against the toxic signs and lethality induced by the injection of 1.3 LD 50 of soman [151] . When compared with pyridostigmine (PYR) [153,154] , the cumulative dose of soman needed to produce convulsions and epileptic activity was 1.5-fold greater in animals that received HupA compared with the group of primates pretreated with PYR. HupA also selectively inhibited red cell AChE activity , whereas PYR also inhibited plasma BuChE.…”

Section: Toxicology and Detoxificationmentioning

confidence: 99%

Progress in studies of huperzine A, a natural cholinesterase inhibitor from Chinese herbal medicine1

Rui

Yan

Tang

2006

Acta Pharmacologica Sinica

411

223

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Huperzine A (HupA), a novel alkaloid isolated from the Chinese herb Huperzia serrata, is a potent, highly specific and reversible inhibitor of acetylcholinesterase (AChE). Compared with tacrine, donepezil, and rivastigmine, HupA has better penetration through the blood-brain barrier, higher oral bioavailability, and longer duration of AChE inhibitory action. HupA has been found to improve cognitive deficits in a broad range of animal models. HupA possesses the ability to protect cells against hydrogen peroxide, β-amyloid protein (or peptide), glutamate, ischemia and staurosporine-induced cytotoxicity and apoptosis. These protective effects are related to its ability to attenuate oxidative stress, regulate the expression of apoptotic proteins Bcl-2, Bax, P53, and caspase-3, protect mitochondria, upregulate nerve growth factor and its receptors, and interfere with amyloid precursor protein metabolism. Antagonizing effects of HupA on N-methyl-D-aspartate receptors and potassium currents may also contribute to its neuroprotection as well. Pharmacokinetic studies in rodents, canines, and healthy human volunteers indicated that HupA was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate with the property of slow and prolonged release after oral administration. Animal and clinical safety tests showed that HupA had no unexpected toxicity, particularly the dose-limiting hepatotoxicity induced by tacrine. The phase IV clinical trials in China have demonstrated that HupA significantly improved memory deficits in elderly people with benign senescent forgetfulness, and patients with Alzheimer disease and vascular dementia, with minimal peripheral cholinergic side effects and no unexpected toxicity. HupA can also be used as a protective agent against organophosphate intoxication.

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“…Pyridostigmine, an AChE carbamylating compound that has been used as prophylaxis, calls for a replacement that will provide better protection 21,27 . In addition to carbamylation, the AChE catalytic site can also be protected by ligands that reversibly bind to AChE, such as huperzine A, SAD, and decamethonium, due to direct competition between the ligand and the phosphorylating agent [28][29][30][31] . A new approach to reduce the in vivo toxicity of chemical warfare nerve agents is the use of bioscavengers-enzymes that react with a nerve agent before it inhibits AChE at physiologically important target sites (i.e.…”

Section: Discussionmentioning

confidence: 99%