BACKGROUND: Cholinesterase inhibitors (CEIs) have been shown to improve cognitive functioning in Alzheimer's Disease (AD) patients, but are associated with multiple side effects and only 20-40% of the patients clinically improve. In this study, we aimed to investigate the acute pharmacodynamic (PD) effects of a single dose administration of galantamine on CNS functioning in mild to moderate AD patients and its potential to predict long-term treatment response. METHODS: This study consisted of a challenge and treatment phase. In the challenge phase, a single dose of 16 mg galantamine was administered to 50 mild to moderate AD patients in a double-blind, placebo-controlled cross-over fashion. Acute PD effects were monitored up to 5 hours after administration with use of the NeuroCart CNS test battery and safety and pharmacokinetics were assessed. In the treatment phase, patients were treated with open-label galantamine according to regular clinical care. After 6 months of galantamine treatment, patients were categorized as either responder or as non-responder based on their MMSE, NPI and DAD scores. An analysis of covariance was performed to study the difference in acute PD effects during the challenge phase between responders and non-responders. RESULTS: A single dose of galantamine significantly reduced saccadic reaction time (-0.0099; 95%CI=-0.0195,-0.0003; p=.0430), absolute frontal EEG parameters in alpha (-14.9; 95%CI=-21.0,-8.3; p=.0002), beta (-12.6; 95%CI=-19.4,-5.3; p=.0019) and theta (-17.9; 95%CI=-25.0,-10.0; p=.0001) frequencies. Relative frontal (-1.669; 95%CI=-2.999,-0.339; p=.0156) and occipital (-1.856; 95%CI=-3.339,-0.372; p=.0166) EEG power in theta frequency and relative occipital EEG power in the gamma frequency (1.316; 95%CI=0.158,2.475; p=.0273) also increased significantly compared to placebo. Acute decreases of absolute frontal alpha (-20.4; 95%CI=-31.6,-7.47; p=.0046), beta (-15.7; 95% CI=-28.3,-0.93; p=.0390) and theta (-25.9; 95%CI=-38.4,-10.9; p=.0024) EEG parameters and of relative frontal theta power (-3.27%; 95%CI=-5.96,-0.58; p=.0187) on EEG significantly distinguished responders (n=11) from non-responders (n=32) after 6 months. CONCLUSIONS: This study demonstrates that acute PD effects after single dose of galantamine are correlated with long-term treatment effects and that patients who demonstrate a reduction in EEG power in the alpha and theta frequency after a single administration of galantamine 16 mg will most likely respond to treatment.
Introduction: Donepezil is a widely used cholinesterase inhibitor in the management of Alzheimer's disease. Despite large-scaled evidence for its efficacy, elevated peripheral ACh levels often lead to side effects and are dose limiting. The present exploratory study is designed to determine the potentiation of the effects of donepezil by cotreatment with EVP-6124, an alpha-7 nicotinic agonist, to reduce scopolamine-induced cognitive deficits in healthy elderly subjects. Secondary objectives are to explore safety and pharmacokinetic and pharmacodynamics effects of EVP-6124 alone and in combination with donepezil compared to placebo. Methods: A phase I randomized, single-center, placebo-controlled, double-blind, five-way, partial crossover study was performed with donepezil 2.5, 5 mg or placebo combined with EVP-6124 0.3, 1, 2, 4 mg or placebo in three cohorts of healthy elderly subjects in a scopolamine (0.3 mg i.v.) challenge test. Safety, pharmacokinetic, and pharmacodynamics outcomes were assessed. Results: A total of 36 subjects completed the study. Donepezil pharmacokinetic parameters were similar with and without EVP-6124. Effective dose combinations were donepezil/EVP-6124(5/2 mg) and donepezil/EVP-6124 (5/0.3 mg) and showed improvements of the delayed recall of the Visual Verbal Learning Test (1.2; CI = 0.1-2.3) and reaction time during the two-back condition of the N-back (-42; CI = -77, -8), respectively. Overall, no marked reversal of scopolamine effects was observed. Discussion: This study shows no synergistic effect of subtherapeutic doses of donepezil and EVP-6124 in a scopolamine challenge model in healthy elderly subjects. Dosing of scopolamine and the combination of donepezil and EVP-6124 requires further study.
INTRODUCTION: Gln-1062 (Memogain) is a pharmacologically inactive prodrug of galantamine. Owing to its lipophilic nature, it preferentially enters the brain, where it is cleaved into active galantamine. Gln-1062 is expected to have fewer peripheral side effects than other cholinesterase inhibitors, with improved effectiveness. METHODS: This was a double-blind, comparator and placebo-controlled, sequential cohort, single ascending dose study in 58 healthy subjects with Gln-1062 in doses of 5.5, 11, 22, 33, and 44 mg, compared with oral galantamine 16 mg and donepezil 10 mg. Safety, tolerability, pharmacokinetics, and pharmacodynamics were assessed. RESULTS: Gln-1062 doses up to 33 mg were well tolerated and induced a dose-dependent increase in the plasma concentrations of Gln-1062 and galantamine. Gln-1062 had a dose-dependent positive effect on verbal memory and attention, mainly in the first hours after drug administration. DISCUSSION: Gln-1062 was better tolerated than galantamine in doses with the same molarity and led to improved effects in cognitive tests. This is most likely caused by the more favorable distribution ratio between peripheral and central cholinesterase inhibition. These results give reason for further exploration of this compound.
