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| 026P London, UK Pharmacology 2016 |
Validation of a cognitive challenge model with mecamylamine
Introduction. Anti-cholinergic pharmacological challenges can induce cognitive disturbances in healthy subjects and can be used for proof of pharmacology of centrally acting cholinergic drugs. Scopolamine (anti-muscarinic) is mostly used, but for proof-of-pharmacology of nicotinic agonists that are currently developed, a nicotinic anti-cholinergic challenge would be more rational. Mecamylamine is a centrally acting nicotinic acetylcholine (nACh) receptor antagonist. We previously showed reversible cognitive disturbances in healthy subjects after administration of 10 and 20mg. In the current study a higher dose of 30mg was investigated and the potential of a nACh receptor agonist (nicotine) and a cholinesterase inhibitor (galantamine) to reverse the cognitive effects of mecamylamine were determined.
Methods. Randomized, double-blind, double-dummy placebo-controlled, four-way cross-over study in 28 healthy male volunteers (18-45 yrs), with oral mecamylamine (30mg) administered on three occasions, and transdermal nicotine (21mg) oral galantamine (16mg) or placebo. Safety, PK and PD assessments were performed. PD was measured using CNS tests (NeuroCart®), including adaptive tracking, finger tapping, reaction time, n-back (0/1/2-back), visual verbal learning (VVLT; 30 words), and Milner maze tests, pharmaco-EEG, pupillometry and visual analogue scales (VAS) Bond and Lader and VAS nausea.
Results. 30mg mecamylamine was well tolerated and safe. Primarily, cardiovascular AEs were observed. Most were mild, some moderate, all were transient of nature. Following administration of mecamylamine a 3.27% decrease in score on the adaptive tracking test was observed compared to placebo (95%CI -4.58- -1.97). Co-administration of mecamylamine and nicotine resulted in an increased score of 1.47% (95%CI 0.15-2.78). Mean reaction time (RT) on N-back (2-back condition) was increased following mecamylamine (28.3 msec, 95%CI 2.0-54.6). Co-administration of mecamylamine and nicotine resulted in decreased RT (-36.0 msec, 95%CI -62.2 - -9.7). On the quantitative EEG (qEEG), α power (Pz-Oz) was decreased by mecamylamine (-6.2%, 95%CI -13.4 – 1.6) compared to placebo. Co-administration with nicotine resulted in increase in α power (14.9%, 95%CI 6-24.6).
Conclusion. 30mg mecamylamine resulted in a significant disturbance of attention, executive functioning and a significant decrease in alpha power on EEG. This effect could be partially reversed by the co-administration of nicotine, but not of galantamine). qEEG results following mecamylamine were comparable to effects observed in AD, reversed by nicotine administration. Overall, compared to administration of 10 and 20mg mecamylamine, 30mg showed larger negative cognitive effects. Furthermore, these effects could be reversed by co-administration of the nACh receptor agonist nicotine, validating the mecamylamine model as a cognitive challenge model for diseases such as AD.