scholarly journals BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease

2014 ◽  
Vol 6 (9) ◽  
Author(s):  
Robert Vassar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Bace1 Inhibitor

Alzheimer's Disease and β-Secretase Inhibition: An Update With a Focus on Computer-Aided Inhibitor Design

2021 ◽  
Vol 22 ◽  
Author(s):  
Samuel Ugbaja ◽  
Isiaka Lawal ◽  
Hezekiel Kumalo ◽  
Monsurat Lawal
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trial ◽  
Clinical Trials ◽  
Drug Discovery ◽  
Inhibitor Design ◽  
Vitro Assay ◽  
Bace1 Inhibitor ◽  
In Silico Studies ◽  
Computer Aided

Introduction: Alzheimer's disease (AD) is an intensifying neurodegenerative illness due to its irreversible nature. Identification of β‐site amyloid precursor protein (APP) cleaving enzyme1 (BACE1) has been a significant medicinal focus towards AD treatment, and this has opened ground for several investigations. Despite the numerous works in this direction, no BACE1 inhibitor has made it to the final approval stage as an anti-AD drug. Method: We provide an introductory background of the subject with a general overview of the pathogenesis of AD. The review features BACE1 inhibitor design and development with a focus on some clinical trials and discontinued drugs. Using the topical keywords BACE1, inhibitor design, and computational/theoretical study in the Web of Science and Scopus database, we retrieved over 49 relevant articles. The search years are from 2010 and 2020, with analysis conducted from May 2020 to March 2021. Results and discussion: Researchers have employed computational methodologies to unravel potential BACE1 inhibitors with a significant outcome. The most used computer-aided approach in BACE1 inhibitor design and binding/interaction studies are pharmacophore development, quantitative structure-activity relationship (QSAR), virtual screening, docking, and molecular dynamics (MD) simulations. These methods, plus more advanced ones including quantum mechanics/molecular mechanics (QM/MM) and QM, have proven substantial in the computational framework for BACE1 inhibitor design. Computational chemists have embraced the incorporation of in vitro assay to provide insight into the inhibition performance of identified molecules with potential inhibition towards BACE1. Significant IC50 values up to 50 nM, better than clinical trial compounds, are available in the literature. Conclusion: The continuous failure of potent BACE1 inhibitors at clinical trials is attracting many queries prompting researchers to investigate newer concepts necessary for effective inhibitor design. The considered properties for efficient BACE1 inhibitor design seem enormous and require thorough scrutiny. Lately, researchers noticed that besides appreciable binding affinity and blood-brain barrier (BBB) permeation, BACE1 inhibitor must show low or no affinity for permeability-glycoprotein. Computational modeling methods have profound applications in drug discovery strategy. With the volume of recent in silico studies on BACE1 inhibition, the prospect of identifying potent molecules that would reach the approved level is feasible. Investigators should try pushing many of the identified BACE1 compounds with significant anti-AD properties to preclinical and clinical trial stages. We also advise computational research on allosteric inhibitor design, exosite modeling, and multisite inhibition of BACE1. These alternatives might be a solution to BACE1 drug discovery in AD therapy.

A Biomarker Combining Imaging and Neuropsychological Assessment for Tracking Early Alzheimer's Disease in Clinical Trials

2018 ◽  
Vol 15 (5) ◽  
pp. 429-442 ◽  
Author(s):  
Nishant Verma ◽  
S. Natasha Beretvas ◽  
Belen Pascual ◽  
Joseph C. Masdeu ◽  
Mia K. Markey ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Latent Variable ◽  
Brain Regions ◽  
Disease Assessment ◽  
Latent Variable Analysis ◽  
The Relationship ◽  
Selection Of

Background: Combining optimized cognitive (Alzheimer's Disease Assessment Scale- Cognitive subscale, ADAS-Cog) and atrophy markers of Alzheimer's disease for tracking progression in clinical trials may provide greater sensitivity than currently used methods, which have yielded negative results in multiple recent trials. Furthermore, it is critical to clarify the relationship among the subcomponents yielded by cognitive and imaging testing, to address the symptomatic and anatomical variability of Alzheimer's disease. Method: Using latent variable analysis, we thoroughly investigated the relationship between cognitive impairment, as assessed on the ADAS-Cog, and cerebral atrophy. A biomarker was developed for Alzheimer's clinical trials that combines cognitive and atrophy markers. Results: Atrophy within specific brain regions was found to be closely related with impairment in cognitive domains of memory, language, and praxis. The proposed biomarker showed significantly better sensitivity in tracking progression of cognitive impairment than the ADAS-Cog in simulated trials and a real world problem. The biomarker also improved the selection of MCI patients (78.8±4.9% specificity at 80% sensitivity) that will evolve to Alzheimer's disease for clinical trials. Conclusion: The proposed biomarker provides a boost to the efficacy of clinical trials focused in the mild cognitive impairment (MCI) stage by significantly improving the sensitivity to detect treatment effects and improving the selection of MCI patients that will evolve to Alzheimer’s disease.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

scholarly journals On the design of early-phase Alzheimer’s disease clinical trials with cerebrospinal fluid tau outcomes

2021 ◽  
pp. 174077452110344
Author(s):  
Michelle M Nuño ◽  
Joshua D Grill ◽  
Daniel L Gillen ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cerebrospinal Fluid ◽  
Phosphorylated Tau ◽  
Inclusion Criteria ◽  
Eligibility Criteria ◽  
Total Tau ◽  
Prodromal Alzheimer’S Disease ◽  
Study Power

Background/Aims: The focus of Alzheimer’s disease studies has shifted to earlier disease stages, including mild cognitive impairment. Biomarker inclusion criteria are often incorporated into mild cognitive impairment clinical trials to identify individuals with “prodromal Alzheimer’s disease” to ensure appropriate drug targets and enrich for participants likely to develop Alzheimer’s disease dementia. The use of these eligibility criteria may affect study power. Methods: We investigated outcome variability and study power in the setting of proof-of-concept prodromal Alzheimer’s disease trials that incorporate cerebrospinal fluid levels of total tau (t-tau) and phosphorylated (p-tau) as primary outcomes and how differing biomarker inclusion criteria affect power. We used data from the Alzheimer’s Disease Neuroimaging Initiative to model trial scenarios and to estimate the variance and within-subject correlation of total and phosphorylated tau. These estimates were then used to investigate the differences in study power for trials considering these two surrogate outcomes. Results: Patient characteristics were similar for all eligibility criteria. The lowest outcome variance and highest within-subject correlation were obtained when phosphorylated tau was used as an eligibility criterion, compared to amyloid beta or total tau, regardless of whether total tau or phosphorylated tau were used as primary outcomes. Power increased when eligibility criteria were broadened to allow for enrollment of subjects with either low amyloid beta or high phosphorylated tau. Conclusion: Specific biomarker inclusion criteria may impact statistical power in trials using total tau or phosphorylated tau as the primary outcome. In concert with other important considerations such as treatment target and population of clinical interest, these results may have implications to the integrity and efficiency of prodromal Alzheimer’s disease trial designs.

scholarly journals Saffron for mild cognitive impairment and dementia: a systematic review and meta-analysis of randomised clinical trials

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Zahra Ayati ◽  
Guoyan Yang ◽  
Mohammad Hossein Ayati ◽  
Seyed Ahmad Emami ◽  
Dennis Chang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Cognitive Function ◽  
Daily Living ◽  
Randomised Clinical Trials ◽  
Disease Assessment ◽  
Significant Difference

Abstract Background Saffron (stigma of Crocus sativus L.) from Iridaceae family is a well-known traditional herbal medicine that has been used for hundreds of years to treat several diseases such as depressive mood, cancer and cardiovascular disorders. Recently, anti-dementia property of saffron has been indicated. However, the effects of saffron for the management of dementia remain controversial. The aim of the present study is to explore the effectiveness and safety of saffron in treating mild cognitive impairment and dementia. Methods An electronic database search of some major English and Chinese databases was conducted until 31st May 2019 to identify relevant randomised clinical trials (RCT). The primary outcome was cognitive function and the secondary outcomes included daily living function, global clinical assessment, quality of life (QoL), psychiatric assessment and safety. Rev-Man 5.3 software was applied to perform the meta-analyses. Results A total of four RCTs were included in this review. The analysis revealed that saffron significantly improves cognitive function measured by the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) and Clinical Dementia Rating Scale-Sums of Boxes (CDR-SB), compared to placebo groups. In addition, there was no significant difference between saffron and conventional medicine, as measured by cognitive scales such as ADAS-cog and CDR-SB. Saffron improved daily living function, but the changes were not statistically significant. No serious adverse events were reported in the included studies. Conclusions Saffron may have the potential to improve cognitive function and activities of daily living in patients with Alzheimer’s disease and mild cognitive impairment (MCI). However, due to limited high-quality studies there is insufficient evidence to make any recommendations for clinical use. Further clinical trials on larger sample sizes are warranted to shed more light on its efficacy and safety.

Non-Ceruloplasmin Copper as a Stratification Biomarker of Alzheimer’s Disease Patients: How to Measure and Use It

2021 ◽  
Vol 18 ◽  
Author(s):  
Rosanna Squitti ◽  
Mariacarla Ventriglia ◽  
Alberto Granzotto ◽  
Stefano L. Sensi ◽  
Mauro Ciro Antonio Rongioletti
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Cognitive Impairment ◽  
Cost Effective ◽  
The Elderly ◽  
The Body ◽  
Eligibility Criterion ◽  
Growing Body ◽  
Proper Balance

: Alzheimer’s disease (AD) is a type of dementia very common in the elderly. A growing body of recent evidence has linked AD pathogenesis to copper (Cu) dysmetabolism in the body. In fact, a subset of patients affected either by AD or by its prodromal form known as Mild Cognitive Impairment (MCI) have been observed to be unable to maintain a proper balance of Cu metabolism and distribution and are characterized by the presence in their serum of increased levels of Cu not bound to ceruloplasmin (non-ceruloplasmin Cu). Since serum non-ceruloplasmin Cu is a biomark- er of Wilson's disease (WD), a well-known condition of Cu-driven toxicosis, in this review, we pro- pose that in close analogy with WD, the assessment of non-ceruloplasmin Cu levels can be exploit- ed as a cost-effective stratification and susceptibility/risk biomarker for the identification of some AD/MCI individuals. The approach can also be used as an eligibility criterion for clinical trials aim- ing at investigating Cu-related interventions against AD/MCI.

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