RT Journal Article
SR Electronic
T1 Oral Pretreatment with Galantamine Effectively Mitigates the Acute Toxicity of a Supra-Lethal Dose of Soman in Cynomolgus Monkeys Post-treated with Conventional Antidotes
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.120.265843
DO 10.1124/jpet.120.265843
A1 Malcolm Lane
A1 D'Arice Carter
A1 Joseph D. Pescrille
A1 Yasco Aracava
A1 William P. Fawcett
A1 G. William Basinger
A1 Edna F.R. Pereira
A1 Edson X. Albuquerque
YR 2020
UL http://jpet.aspetjournals.org/content/early/2020/08/05/jpet.120.265843.abstract
AB 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.SIGNIFICANCE STATEMENT This is the first study to demonstrate that a clinically relevant oral dose of galantamine effectively prevents lethality and neuropathology induced by a supralethal dose of the nerve agent soman in Cynomolgus monkeys posttreated with conventional antidotes. These findings are of major significance for the continued development of galantamine as an adjunct pretreatment against nerve agent poisoning.