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Proteomics of cerebrospinal fluid (CSF) of acitretin treated patients

ABSTRACT: Acitretin has been shown to increase ADAM10 expression. In a phase II clinical trial, Alzheimer's disease patients were treated with acitretin or placebo to increase ADAM10 levels to counteract amyloid beta production. Analysis of the cerebrospinal fluid of from 18 AD patients treated with the synthetic retinoid acitretin or placebo were analyzed by label-free quantitative LC-MS/MS analysis.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Stefan F. Lichtenthaler

PROVIDER: MSV000098351 | MassIVE | Fri Jun 27 03:57:00 BST 2025

SECONDARY ACCESSION(S): PXD010756

REPOSITORIES: MassIVE

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Project description:Lockwood2006 - AlzheimersDisease PBPK model A mathematical model to predict the effectiveness of CI-1017 (muscarinic agonist) for Alzheimer's disease by evaluating changes in ADAS-cog score. This model is described in the article: Application of clinical trial simulation to compare proof-of-concept study designs for drugs with a slow onset of effect; an example in Alzheimer's disease. Lockwood P, Ewy W, Hermann D, Holford N. Pharm. Res. 2006 Sep; 23(9): 2050-2059 Abstract: OBJECTIVE: Clinical trial simulation (CTS) was used to select a robust design to test the hypothesis that a new treatment was effective for Alzheimer's disease (AD). Typically, a parallel group, placebo controlled, 12-week trial in 200-400 AD patients would be used to establish drug effect relative to placebo (i.e., Ho: Drug Effect = 0). We evaluated if a crossover design would allow smaller and shorter duration trials. MATERIALS AND METHODS: A family of plausible drug and disease models describing the time course of the AD assessment scale (ADAS-Cog) was developed based on Phase I data and literature reports of other treatments for AD. The models included pharmacokinetic, pharmacodynamic, disease progression, and placebo components. Eight alternative trial designs were explored via simulation. One hundred replicates of each combination of drug and disease model and trial design were simulated. A 'positive trial' reflecting drug activity was declared considering both a dose trend test (p < 0.05) and pair-wise comparisons to placebo (p < 0.025). RESULTS: A 4 x 4 Latin Square design was predicted to have at least 80% power to detect activity across a range of drug and disease models. The trial design was subsequently implemented and the trial was completed. Based on the results of the actual trial, a conclusive decision about further development was taken. The crossover design provided enhanced power over a parallel group design due to the lower residual variability. CONCLUSION: CTS aided the decision to use a more efficient proof of concept trial design, leading to savings of up to US 4 M dollars in direct costs and a firm decision 8-12 months earlier than a 12-week parallel group trial. This model is hosted on BioModels Database and identified by: BIOMD0000000673. To cite BioModels Database, please use: Chelliah V et al. BioModels: ten-year anniversary. Nucl. Acids Res. 2015, 43(Database issue):D542-8. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Proteomics of cerebrospinal fluid (CSF) of acitretin treated patients

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