Premium
P4–277: Evaluation of beta‐amyloid‐lowering efficacy of a novel BACE1 inhibitor in multiple species
Author(s) -
Nolan Charles,
Atchison Kevin,
Robshaw Ashley,
Pustilnik Leslie,
Noell Stephen,
Ambroise Claude,
Gonzales Cathleen,
Pan Feng,
Oborski Christine,
HajosKorcsok Eva,
Chang Cheng,
Lu Yasong,
Liu JianHua,
Doran Shawn,
Negahban Andre,
Brodney Michael,
O'Neill Brian,
Butler Christopher,
Beck Elizabeth,
Riddell David
Publication year - 2013
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2013.05.1670
Subject(s) - ic50 , in vivo , beagle , chemistry , pharmacology , in vitro , cmax , ex vivo , potency , pharmacokinetics , medicine , biochemistry , biology , microbiology and biotechnology
subjects, aged 18-45. Bloodsamples 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, stabilityand pharmaco-EEG (Table 1). Results: 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) tracking (respectively -2.7 (CI -5.1 -0.3), -3.6 (CI -5.9 -1.4), -7.7 (CI -10.1 -5.4)) and adaptive tracking (respectively -1.89 (CI -3,90 0.12), -2.06 (CI -3.97 -0.16), -10.38 (CI 12.38 -8.39)), a test for attention. However, mecamylamine did not have sedative effects, contrary to scopolamine. This is illustrated by the simple reaction time task (respectively 7.0 (CI -0.8 15.5), 3.8 (CI -3.5 11.7), 26.8 (CI 17.6 36.8)), a subjective visual analogue scale (VAS) 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 sacadic peak velocity (respectively -14.3 (CI33.5 4.8), -10.9 (CI -29.0 7.1), -25.4 (CI -44.2 -6.6)), a marker for sedation (Figure 1). Conclusions: 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 f or proof of pharmacology and dose finding studies of nicotinic receptor agonists than the frequently used scopolamine model.