Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol11Issue3abst205P.pdf PK and PD of a Nicotinic Anti-Cholinergic Challenge with Mecamylamine and Comparison to Scopolamine AC Baakman, R Rissmann, E Klaassen, JMA van Gerven, GJ Groeneveld. Centre for Human Drug Research, Leiden, The Netherlands Cholinesterase inhibitors are frequently prescribed to patients with Alzheimer’s Disease. The increase in acetylcholine level has effect on both muscarinic and nicotinic acetylcholine receptors, causing cognitive enhancement, mostly via the nicotinic receptors, and peripheral side effects, mostly via the muscarinic receptors. Therefore, nicotinic receptor specific agonists are currently being developed. For proof of pharmacology studies with these compounds, an anti-cholinergic pharmacological challenge with the nicotinic antagonist mecamylamine was developed. With the current study we aimed to gain more and time-dependent information on pharmacodynamic effects of mecamylamine. This was a double-blind, double-dummy, placebo-controlled, randomized four-way crossover study with mecamylamine 10 mg or 20 mg p.o. or scopolamine 0.5 mg i.v. in 12 non-smoking healthy subjects, aged 18-45. Blood samples were taken for pharmacokinetic and neuro-endocrine measurements. Pharmacodynamic measurements consisted of computerised tests for memory, attention, psychomotor speed, eye movements, subjective scales for mood and alertness, stability (body sway) and pharmaco-EEG. Mecamylamine was well tolerated and had linear pharmacokinetics over the dose range tested. Mecamylamine appeared to more selectively affect memory than sedation compared to scopolamine 0.5 mg iv. Mecamlyamine 10mg, mecamylamine 20mg and scopolamine all affected the visual verbal learning test (VVLT) and adaptive tracking, a test for attention (see figure 1 and 2). However, mecamylamine did not have sedative effects, contrary to scopolamine. This is illustrated by the simple reaction time task (see figure 3), a subjective visual analogue scale for alertness (respectively -1.3 (CI-3.7 – 1.2), -2.5 (CI -4.8 - -0.2), -5.3 (CI -7.7 - -2.9)) and saccadic peak velocity (respectively -14.3 (CI-33.5 – 4.8), -10.9 (CI -29.0 – 7.1), - 25.4 (CI -44.2 - -6.6)), a marker for sedation. The pharmacological challenge model with mecamylamine 20 mg in healthy subjects leads to a reproducible pattern of cognitive disturbance that is nicotinic receptor specific. This model may be more suitable for proof of pharmacology and dose finding studies of nicotinic receptor agonists than the frequently used scopolamine model. .