https://research-information.bris.ac.uk/ws/files/259213304/PIIS0140673620309259.pdf

Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Alzheimer's disease drug development pipeline: 2018.

/pdf/alzheimer-s-disease-drug-development-pipeline-2019-4pg15jrq93.pdf

Alzheimer's disease drug development pipeline: 2019.

The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer's disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis "has all but supplanted the amyloid cascade." Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term.

The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade

Alzheimer disease (AD) accounts for 60–70% of dementia cases. Given the seriousness of the disease and continual increase in patient numbers, developing effective therapies to treat AD has become urgent. Presently, the drugs available for AD treatment, including cholinesterase inhibitors and an antagonist of the N-methyl-D-aspartate receptor, can only inhibit dementia symptoms for a limited period of time but cannot stop or reverse disease progression. On the basis of the amyloid hypothesis, many global drug companies have conducted many clinical trials on amyloid clearing therapy but without success. Thus, the amyloid hypothesis may not be completely feasible. The number of anti-amyloid trials decreased in 2019, which might be a turning point. An in-depth and comprehensive understanding of the contribution of amyloid beta and other factors of AD is crucial for developing novel pharmacotherapies. In ongoing clinical trials, researchers have developed and are testing several possible interventions aimed at various targets, including anti-amyloid and anti-tau interventions, neurotransmitter modification, anti-neuroinflammation and neuroprotection interventions, and cognitive enhancement, and interventions to relieve behavioral psychological symptoms. In this article, we present the current state of clinical trials for AD at clinicaltrials.gov. We reviewed the underlying mechanisms of these trials, tried to understand the reason why prior clinical trials failed, and analyzed the future trend of AD clinical trials.

/pdf/clinical-trials-of-new-drugs-for-alzheimer-disease-6bocufh04r.pdf

Clinical trials of new drugs for Alzheimer disease

Treatments are needed to address the growing prevalence of Alzheimer’s disease (AD). Clinical trials have failed to produce any AD drugs for Food and Drug Administration (FDA) approval since 2003, and the pharmaceutical development process is both time-consuming and costly. Drug repurposing provides an opportunity to accelerate this process by investigating the AD-related effects of agents approved for other indications. These drugs have known safety profiles, pharmacokinetic characterization, formulations, doses, and manufacturing processes. We assessed repurposed AD therapies represented in Phase I, Phase II, and Phase III of the current AD pipeline as registered on ClinicalTrials.gov as of February 27, 2020. We identified 53 clinical trials involving 58 FDA-approved agents. Seventy-eight percent of the agents in trials had putative disease-modifying mechanisms of action. Of the repurposed drugs in the pipeline 20% are hematologic-oncologic agents, 18% are drugs derived from cardiovascular indications, 14% are agents with psychiatric uses, 12% are drug used to treat diabetes, 10% are neurologic agents, and the remaining 26% of drugs fall under other conditions. Intellectual property strategies utilized in these programs included using the same drug but altering doses, routes of administration, or formulations. Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry. We compared our results to a European trial registry and found results similar to those derived from ClinicalTrials.gov. Drug repurposing is a common approach to AD drug development and represents 39% of trials in the current AD pipeline. Therapies from many disease areas provide agents potentially useful in AD. Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.

/pdf/repurposed-agents-in-the-alzheimer-s-disease-drug-2zumduzz9l.pdf

Repurposed agents in the Alzheimer’s disease drug development pipeline

Undergraduate medical education has evolved necessarily with the increasing utilization of technology and the availability of ancillary resources developed for medical students. However, medical educational resources are expensive and there have been few studies validating these resources for their ability to significantly modify student exam performance. A post-exam survey was devised to evaluate medical students for resource usage, student-perceived preparedness, and exam performance. Students who felt more prepared for exams performed better than students who felt less prepared (p = .017). Students who watched didactic lectures online and those who utilized peer-to-peer tutoring outperformed students who did not use these resources (p = .035, p = .008). Analyses of the data show that none of the purchased resources utilized significantly improved student exam performance. The majority of students used between six and eight resources for exam preparation. There may be a slightly negative association with the quantity of resources used and exam scores (p = .18). Contrary to traditional confidence studies that correlate overconfidence with underperformance, medical students who reported feeling more prepared for exams performed better than students who felt less prepared. Medical students may have a more complete grasp of their knowledge base and deficits, which may enable a more accurate match between exam expectations and academic performance. This post-exam survey method can be customized and applied to evaluate resource utility as it pertains to specific undergraduate medical education curricula at individual institutions.

/pdf/the-impact-of-educational-resources-and-perceived-o8hz017lkb.pdf

The Impact of Educational Resources and Perceived Preparedness on Medical Education Performance.

Who funds Alzheimer's disease drug development?

Remdesivir is an antiviral drug used to treat coronavirus disease 2019 (COVID-19) with a relatively obscure cardiac effect profile. Previous studies have reported bradycardia associated with remdesivir, but few have examined its clinical characteristics. The objective of this study was to investigate remdesivir associated bradycardia and its associated clinical characteristics and outcomes.This is a single-institution retrospective study that investigated bradycardia in 600 patients who received remdesivir for treatment of COVID-19. A total of 375 patients were included in the study after screening for other known causes of bradycardia (atrioventricular [AV] nodal blockers). All patients were analyzed for episodes of bradycardia from when remdesivir was initiated up to 5 days after completion, a time frame based on the drug's putative elimination half-life. Univariate and multivariate statistical tests were conducted to analyze the data.The mean age of the sample was 56.63 ± 13.23 years. Of patients who met inclusion criteria, 49% were found to have bradycardia within 5 days of remdesivir administration. Compared to the cohort without a documented bradycardic episode, patients with bradycardia were significantly more likely to experience inpatient mortality (22% vs 12%, p = 0.01). The patients with bradycardia were found to have marginally higher serum D-dimer levels (5.2 vs 3.4 µg/mL, p = 0.05) and were more likely to undergo endotracheal intubation (28% vs 14%, p = 0.008). Male sex, hyperlipidemia, and bradycardia within 5 days of completing remdesivir were significant predictors of inpatient mortality. No significant differences in length of stay were found.Bradycardia that occurs during or shortly after remdesivir treatment in COVID-19 patients may be associated with an increased rate of in-hospital mortality. However, COVID-19 and its cardiac complications cannot be excluded as potential contributors of bradycardia in the present study. Future studies are needed to further delineate the cardiac characteristics of COVID-19 and remdesivir. 

/pdf/clinical-characteristics-and-implications-of-bradycardia-in-1d3dn04q.pdf

Clinical Characteristics and Implications of Bradycardia in COVID-19 Patients Treated with Remdesivir: A Single-Center Retrospective Cohort Study

Background: Retrospective chart review studies may be delayed by inability to export clean clinical data from an electronic medical record (EMR) or data repository. Macros are pre-programmed procedures that can be used in Microsoft Excel to help streamline the process of cleaning clinical datasets. Objectives: To demonstrate how macros may be useful for researchers at community hospitals and smaller academic health centers that lack informatics support. Methods: Using an intrinsic function of our institution's EMR, vital signs and lab results from 20 individual hospitalizations were exported to a spreadsheet. Two macros were developed to sort through these datasets and output them into a specified format. The speed of macro-assisted data cleaning was compared to manual transcription. Results: Time spent on data cleaning was significantly reduced when using macro-assisted sorting compared to the manual approach for both vital signs (46.5 seconds versus 12.3 minutes per record, a 94% reduction; P < 0.001) and labs (13.7 seconds versus 2.6 minutes per record, a 91% reduction; P < 0.001). Conclusions:Macros offer a flexible and efficient tool for cleaning large sets of clinical data, particularly when an institution lacks informatics support or EMR functionality to export clinical data in an analysis-ready format.

https://www.tandfonline.com/doi/pdf/10.1080/20009666.2021.1954282

Justin Bauzon

Papers

Repurposed agents in the Alzheimer’s disease drug development pipeline

The Impact of Educational Resources and Perceived Preparedness on Medical Education Performance.

Who funds Alzheimer's disease drug development?

Clinical Characteristics and Implications of Bradycardia in COVID-19 Patients Treated with Remdesivir: A Single-Center Retrospective Cohort Study

Using macros in microsoft excel to facilitate cleaning of research data.