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A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer's disease.

ABSTRACT: Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer's disease (AD). Here, we design a dual-targeted Prussian blue nanoformulation (PTCN) that can cross the blood-brain barrier and target amyloid beta aggregates further exert antioxidant effects. An adjustable gradient dosing strategy with PTCN is used for the first time to design the preventive and therapeutic trials based on the severity of oxidative stress at different AD stages. The results show that PTCN could effectively ameliorate AD-related pathological processes, improve the cognitive decline, and rescue hippocampal atrophy of APP/PS1 mice in both preventive and therapeutic trials. Altogether, PTCN provided here is a successful combination of three traditional biomaterials with good biosafety, which has broad prospects for the early prevention, mild remission, and late treatment of AD, and is expected to be developed into personalized therapeutic drugs and healthcare products for clinical AD in the future.

SUBMITTER: Zhao D

PROVIDER: S-EPMC8640585 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer's disease.

Zhao Dongju D Tang Yuqing Y Suo Xinjun X Zhang Chaonan C Dou Yan Y Chang Jin J

Innovation (Cambridge (Mass.)) 20210901 4

Antioxidation and adjustable treatment strategies are critical for the effective treatment of Alzheimer's disease (AD). Here, we design a dual-targeted Prussian blue nanoformulation (PTCN) that can cross the blood-brain barrier and target amyloid beta aggregates further exert antioxidant effects. An adjustable gradient dosing strategy with PTCN is used for the first time to design the preventive and therapeutic trials based on the severity of oxidative stress at different AD stages. The results ...[more]

PMID: 34901904

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Project description:Dual antiplatelet therapy (DAPT) combining aspirin and a P2Y12 receptor inhibitor has been consistently shown to reduce recurrent major adverse cardiovascular events (MACE) in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) for stable coronary artery disease (CAD) compared with aspirin monotherapy, but at the expense of an increased risk of major bleeding. Nevertheless, the optimal duration of DAPT for secondary prevention of CAD remains uncertain, owing to the conflicting results of several large randomised trials. Among patients with stable CAD undergoing PCI with drug-eluting stents (DES), shorter durations of DAPT (3-6 months) were shown non-inferior to 12 or 24 months duration with respect to MACE, but reduced the rates of major bleeding. Contrariwise, prolonged DAPT durations (18-48 months) reduced the incidence of myocardial infarction and stent thrombosis, but at a cost of an increased risk of major bleeding and all-cause mortality. Until more evidence becomes available, the choice of optimal DAPT regimen and duration for patients with CAD requires a tailored approach based on the patient clinical presentation, baseline risk profile and management strategy. Future studies are however needed to identify patients who may derive benefit from shortened or extended DAPT courses for secondary prevention of CAD based on their individual ischaemic and bleeding risk. Based on limited evidence, 12 months duration of DAPT is currently recommended in patients with ACS irrespective of their management strategy, but large ongoing randomised trials are currently assessing the efficacy and safety of a short-term DAPT strategy (3-6 months) for patients with ACS undergoing PCI with newer generation DES. Finally, several ongoing, large-scale, randomised trials are challenging the current concept of DAPT by investigating P2Y12 receptor inhibitors as single antiplatelet therapy and may potentially shift the paradigm of antiplatelet therapy after PCI in the near future. This article provides a contemporary state-of-the-art review of the current evidence on DAPT for secondary prevention of patients with CAD and its future perspectives.

Project description:IntroductionPractice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome.MethodsWe investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline.ResultsOn average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design.DiscussionAssuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials.

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A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer's disease.

Publications

A dual-targeted multifunctional nanoformulation for potential prevention and therapy of Alzheimer's disease.

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