Oral Pretreatment with Galantamine Effectively Mitigates the Acute Toxicity of a Supralethal Dose of Soman in Cynomolgus Monkeys Posttreated with Conventional Antidotes

Abstract

Earlier reports suggested that galantamine, a drug approved to treat mild-to-moderate Alzheimer's disease (AD), and other centrally acting reversible acetylcholinesterase (AChE) inhibitors can serve as adjunct pretreatments against poisoning by organophosphorus (OP) compounds, including the nerve agent soman. The present study was designed to determine whether pretreatment with a clinically relevant oral dose of galantamine HBr mitigates the acute toxicity of 4.0xLD50 soman (15.08 µg/kg) in Macaca fascicularis posttreated intramuscularly with the conventional antidotes atropine (0.4 mg/kg), 2-PAM (30 mg/kg), and midazolam (0.32 mg/kg). The pharmacokinetic profile and maximal degree of blood AChE inhibition (~ 25-40%) revealed that the oral doses of 1.5 and 3.0 mg/kg galantamine HBr in these non-human primates (NHPs) translate to human equivalent doses that are within the range used for AD treatment. Subsequent experiments demonstrated that 100% of NHPs pretreated with either dose of galantamine, challenged with soman, and posttreated with conventional antidotes survived 24 h. By contrast, given the same posttreatments, 0% and 40% of the NHPs pretreated, respectively, with vehicle and pyridostigmine bromide (1.2 mg/kg, oral), a peripherally acting reversible AChE inhibitor approved as pretreatment for military personnel at risk of exposure to soman, survived 24 h after the challenge. In addition, soman caused extensive neurodegeneration in the hippocampi of saline-or pyridostigmine-pretreated NHPs, but not in the hippocampi of galantamine-pretreated animals. To our knowledge, this is the first study to demonstrate the effectiveness of clinically relevant oral doses of galantamine to prevent the acute toxicity of supralethal doses of soman in NHPs.

Treating disorders across the lifespan by modulating cholinergic signaling with galantamine

“…Brain cholinergic signaling is implicated in the neurobiology of lucid dreaming—a state of consciousness of being aware that one is dreaming while dreaming (Baird et al., 2019; LaBerge et al., 2018). As previously reviewed, lucid dreaming can be explored in the treatment of persistent nightmares, narcolepsy, to establish brain activity markers of self‐awareness, and to provide unique insights into neuropsychiatric conditions (Baird et al., 2019).…”

“…As previously reviewed, lucid dreaming can be explored in the treatment of persistent nightmares, narcolepsy, to establish brain activity markers of self‐awareness, and to provide unique insights into neuropsychiatric conditions (Baird et al., 2019). Pre‐sleep treatment with galantamine (4 mg or 8 mg per day) dose‐dependently increases the frequency of lucid dreams compared with placebo in a double blind study with 121 participants (LaBerge et al., 2018). While the exact mechanism(s) by which galantamine stimulates lucid dreams are unclear, activating of brain cholinergic mechanisms that results in stimulation of REM sleep intensity and phasic activation, and enhanced cognitive processing may play a role (Baird et al., 2019; LaBerge et al., 2018).…”

“…Pre‐sleep treatment with galantamine (4 mg or 8 mg per day) dose‐dependently increases the frequency of lucid dreams compared with placebo in a double blind study with 121 participants (LaBerge et al., 2018). While the exact mechanism(s) by which galantamine stimulates lucid dreams are unclear, activating of brain cholinergic mechanisms that results in stimulation of REM sleep intensity and phasic activation, and enhanced cognitive processing may play a role (Baird et al., 2019; LaBerge et al., 2018).…”

The Amaryllidaceae alkaloids: an untapped source of acetylcholinesterase inhibitors

“…OPs are commonly used as insecticides in agriculture, causing environmental pollution, health risks to humans and non-target animals and reducing the biodiversity in the treated areas. OPs are also used as therapeutic agents in ophthalmology or as nerve agents in chemical weapons (sarin, tabun, soman, cyclosarin and VX, Lane et al 2020).…”

“…The allosteric potentiating effects of galanthamine (1) on nicotinic receptors also affect monoamine-, glutamate-, and c-aminobutyric acid (GABA) neurotransmitter systems, improving cognitive dysfunction and psychiatric illness in schizophrenia, major depression, bipolar disorder and alcohol abuse (Ago et al 2011). A clinically relevant oral dose of galanthamine effectively prevents lethality and neuropathology induced by a supralethal dose of the nerve agent soman in Cynomolgus monkeys posttreated with conventional antidotes (Lane et al 2020). There is no evidence that any of donepezil (2), rivastigmine (3) and galanthamine (1) is superior in terms of efficacy, however, donepezil is better tolerated.…”