Is rivastigmine safe as pretreatment against nerve agents poisoning? A pharmacological, physiological and cognitive assessment in healthy young adult volunteers

• Rivastigmine induces mild adverse reactions with high inter-personal variability.
• Rivastigmine impairs 2 cognitive functions (perceptual speed and dynamic response).
• Rivastigmine has non-linear and highly variable pharmacological profile.
• Rivastigmine use as pretreatment in an operational population is problematic.

Rivastigmine, a reversible cholinesterase inhibitor, approved as a remedy in Alzheimer's disease, was suggested as pretreatment against nerve agents poisoning. We evaluated the pharmacokinetic, pharmacodynamic, physiologic, cognitive and emotional effects of repeated rivastigmine in young healthy male adults, in a double blind, placebo controlled crossover trial. Three groups completed 3 treatment periods: 0, 1.5 and 3 mg twice a day, for a total of 5 intakes. Parameters monitored were: vital signs, ECG, laboratory tests, sialometry, visual accommodation, inspiratory peak flow, and cognitive function tests. Adverse reactions were mild. Peak blood levels and peak cholinesterase inhibition increased with repeated intakes, and high variability and non-linear pharmacokinetics were demonstrated. In addition, two cognitive functions were affected (perceptual speed and dynamic tracking). The complicated pharmacological profile and the high inter-personal variability limit the potential use of rivastigmine as pretreatment for war fighters and first responders.