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

• Published in: Neurotoxicology (Park Forest South) Vol. 49; pp. 36 - 44
• Main Authors: Lavon, Ophir, Eisenkraft, Arik, Blanca, Merav, Raveh, Lily, Ramaty, Erez, Krivoy, Amir, Atsmon, Jacob, Grauer, Ettie, Brandeis, Rachel
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-07-2015
• Subjects: Acetylcholinesterase - metabolism; Adolescent; Adult; Cholinesterase inhibitors; Cognition - drug effects; Cross-Over Studies; Double-Blind Method; Emotions - drug effects; Follow-Up Studies; Healthy Volunteers; Humans; Male; Nerve agents; Neuroprotective Agents - blood; Neuroprotective Agents - pharmacology; Organophosphates; Psychometric evaluation; Rivastigmine; Rivastigmine - blood; Rivastigmine - pharmacology; Saliva - metabolism; Time Factors; Vision, Ocular - drug effects; Visual Acuity - drug effects; Young Adult; Psychometric evaluation; Rivastigmine; Cholinesterase inhibitors; Nerve agents; Organophosphates
• ISSN: 0161-813X; 1872-9711
• DOI: 10.1016/j.neuro.2015.05.003

•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 3mg 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.