Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer's patients-an open-label trial
ABSTRACT Evidence suggests that dihydropyridine calcium channel blockers may be useful in preventing and treating Alzheimer's disease (AD).
In an open-label trial of safety and tolerability of nilvadipine in patients with AD, we examined cognition and executive function over a short time period to determine an influence of nilvadipine on these outcomes.
We investigated change in cognition using the Mini mental state examination and in executive function using the EXIT25 in 55 patients with AD who received nilvadipine 8 mg daily for 6 weeks compared with 30 non-treated subjects with AD. Apolipoprotein E genotyping was performed, and the study team and caregivers were kept blinded to APOE ε4 status during the trial.
Aside from differences in gender and education, both the treatment and the control groups were similar in general demographics and on baseline cognition status. After correction for potential confounders, APOE ε4 status, and use of other antihypertensive medications, a significant impact of study intervention was observed on MMSE (F = 8.67, p < 0.01) and EXIT (F = 8.77, p < 0.03) scores. An interaction between APOE ε4 carrier status and treatment (p ≤ 0.05) was observed for both outcome measures.
In this open-label trial, among APOE ε4 non-carriers, we observed stabilization of cognition and improvement in executive function among treated individuals compared with non-treated individuals. Among APOE ε4 carriers, cognitive stabilization was evident for treated individuals whereas a cognitive decline was observed in non-treated individuals. These findings provide additional evidence for potential therapeutic efficacy of nilvadipine in treating AD and warrant further investigation.
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ABSTRACT: We have previously shown that the L-type calcium channel (LCC) antagonist nilvadipine reduces brain Aβ accumulation by affecting both Aβ production and Aβ clearance across the blood-brain barrier (BBB). Nilvadipine consists of a mixture of two enantiomers, (+)-nilvadipine and (-)-nilvadipine, in equal proportion. (+)-nilvadipine is the active enantiomer responsible for the inhibition of LCC whereas (-)-nilvadipine is considered inactive. Both nilvadipine enantiomers inhibit Aβ production and improve the clearance of Aβ across the BBB showing that these effects are not related to LCC inhibition. In addition, treatment of P301S mutant human Tau transgenic mice (Tg Tau P301S) with (-)-nilvadipine reduces tau hyperphosphorylation at several AD pertinent epitopes. A search for the mechanism of action of (-)-nilvadipine revealed that this compound inhibits the spleen tyrosine kinase (syk). We further validated syk as a target regulating Aβ by showing that pharmacological inhibition of syk or downregulation of syk expression reduces Aβ production and increases the clearance of Aβ across the BBB mimicking (-)-nilvadipine effects. Moreover, treatment of transgenic mice overexpressing Aβ and Tg Tau P301S mice with a selective syk inhibitor respectively decreased brain Aβ accumulation and tau hyperphosphorylation at multiple AD relevant epitopes. We show that syk inhibition induces an increased phosphorylation of the inhibitory Ser9 residue of glycogen synthase kinase-3β, a primary tau kinase involved in tau phosphorylation, by activating protein kinase A, providing a mechanism explaining the reduction of tau phosphorylation at GSK3β dependent epitopes following syk inhibition. Altogether our data highlight syk as a promising target for preventing both Aβ accumulation and tau hyperphosphorylation in AD.Journal of Biological Chemistry 10/2014; 289(49). DOI:10.1074/jbc.M114.608091 · 4.60 Impact Factor
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ABSTRACT: Introduction This study is a European multicentre, randomised, double-blind, placebo-controlled trial investigating the efficacy and safety of nilvadipine as a disease course modifying treatment for mild-to-moderate Alzheimer's disease (AD) in a phase III study that will run for a period of 82 weeks with a treatment period of 78 weeks. Methods and analysis Adult patients, males and females over 50 years with mild-to-moderate AD as defined by the National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's disease and Related Disorders Association (NINCDS-ADRDA) criteria, will be included in the study. It aims to recruit a total of 500 patients with AD; 250 in the nilvadipine group and 250 in the placebo group. Participants will be randomised to receive nilvadipine, an 8 mg overencapsulated, sustained release capsule, or a matching overencapsulated placebo (sugar pill) for a period of 78 weeks of treatment. The primary efficacy outcome measure in this study is the change in cognitive function as assessed by the Alzheimer's disease Assessment Scale (ADAS-Cog 12) from baseline to the end of treatment duration (78 weeks). There are two key secondary outcome measures, the Clinical Dementia Rating Scale Sum of Boxes (CDR-sb) and the Disability Assessment for Dementia (DAD). If a statistically significant effect is seen in the primary outcome, CDR-sb will be considered to be a coprimary end point and only the DAD will contribute to the secondary outcome analysis. Ethics and dissemination The study and all subsequent amendments have received ethical approval within each participating country according to national regulations. Each participant will provide written consent to participate in the study. All participants will remain anonymised throughout and the results of the study will be published in an international peer-reviewed journal. Trial registration number EUDRACT Reference Number: 2012-002764-27.BMJ Open 10/2014; 4(10):e006364. DOI:10.1136/bmjopen-2014-006364 · 2.06 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.Journal of the American Society for Experimental NeuroTherapeutics 12/2014; 12(1). DOI:10.1007/s13311-014-0325-7 · 3.88 Impact Factor