The glucagon-like peptide 1 (GLP) receptor as a therapeutic target in Parkinson's disease: mechanisms of action

Growing evidence suggests that agonists of the glucagon-like peptide 1 (GLP-1) receptor provide neuroprotection across a range of experimental models of Parkinson's disease (PD) and, recently, a small proof-of-concept, open-label human trial of exenatide in the treatment moderate severity PD appeared to show persistent improvements in motor and cognitive function. The underlying mechanisms of action remain unclear, but as evidence for the potential use of GLP-1 agonists in treating several neurodegenerative disease mounts, and with several clinical trials of GLP-1 analogues in PD and Alzheimer's disease (AD) currently underway, here we review the molecular mechanisms underlying the neuroprotective effects of GLP-1 analogues in the laboratory and their potential therapeutic utility with particular relevance to PD and PD dementia (PDD)

Challenges in detecting disease modification in Parkinson's disease clinical trials.

Despite the wealth of encouraging data from numerous compounds that demonstrate "neuroprotection" in pre-clinical studies of Parkinson's disease, and despite numerous clinical trials, to date, no intervention has been demonstrated to able to modify the course of disease progression. While this "failure to translate" is likely due to numerous factors including our incomplete understanding of the pathogenic mechanisms underlying PD together with excessive reliance on data from the toxin-based animal models of PD, here we will discuss the "structural issues" pertaining to inadequate clinical trial design, selection of inappropriate endpoints and poor patient selection which are often not addressed following failed disease modification trials. Future directions to overcome these challenges such as reducing the heterogeneity of patient cohorts, identifying and utilising a pre-diagnostic population, embracing a personalised medicine approach and utilising novel trial designs may be required to ultimately fulfil the goal of conclusively demonstrating evidence of disease modification

Insulin resistance and Parkinson's disease: A new target for disease modification?

There is growing evidence that patients with Type 2 diabetes have an increased risk of developing Parkinson's disease and share similar dysregulated pathways suggesting common underlying pathological mechanisms. Historically insulin was thought solely to be a peripherally acting hormone responsible for glucose homeostasis and energy metabolism. However accumulating evidence indicates insulin can cross the blood-brain-barrier and influence a multitude of processes in the brain including regulating neuronal survival and growth, dopaminergic transmission, maintenance of synapses and pathways involved in cognition. In conjunction, there is growing evidence that a process analogous to peripheral insulin resistance occurs in the brains of Parkinson's disease patients, even in those without diabetes. This raises the possibility that defective insulin signalling pathways may contribute to the development of the pathological features of Parkinson's disease, and thereby suggests that the insulin signalling pathway may potentially be a novel target for disease modification. Given these growing links between PD and Type 2 diabetes it is perhaps not unsurprising that drugs used the treatment of T2DM are amongst the most promising treatments currently being prioritised for repositioning as possible novel treatments for PD and several clinical trials are under way. In this review, we will examine the underlying cellular links between insulin resistance and the pathogenesis of PD and then we will assess current and future pharmacological strategies being developed to restore neuronal insulin signalling as a potential strategy for slowing neurodegeneration in Parkinson's disease

Boosting the Opportunities of Open Learning (MOOCs) through Learning T heories

The recent evolution of computing technology has led to dramatic developments and changes in online learning. Open learning is a new form of online learning that allows learning materials to be freely available on the Internet and accessible to anyone who is interested. Different initiatives, which are based on the open learning concept, have been initiated by various prestigious institutions. Although all of these initiatives provide courses with free access to content, each has its own approach in terms of teaching, assessment and even their own goals of defining an open learning environment. Massive Open Online Courses is the term for courses provided in these open environments. These courses attract a large number of learners, however their success and efficacy in terms of the learning process has yet to be determined. The authors found that there is no clear model for open learning environments and therein lies our research objective. Many aspects still need to be considered and addressed in order to achieve a reliable and sustainable model. These aspects can be addressed with consideration to the principles of cognitive science so that better learning models can be obtained. This paper presents some learning theories that can be considered and applied to enhance open learning environments. The use of knowledge maps, as an approach to implement schema theory, was selected to present and organize the learning concepts. In addition, the Felder-Silverman learning styles theory was selected to personalize the learning environment and provide learning materials based on every learner’s needs and preferences

Protective effects of the GLP-1 mimetic exendin-4 in Parkinson's disease

There is increasing interest in the potential role of glucagon-like peptide-1 (GLP-1) receptor agonists as neuroprotective treatments in neurodegenerative diseases including Parkinson's disease following the publication of the results of the Exenatide-PD trial. Of the current GLP-1 receptor agonists already licensed to treat Type 2 diabetes several including exenatide, liraglutide and lixisenatide are the subject of ongoing clinical trials in PD. The underlying rationale for using drugs licensed and effective for T2DM in PD patients therefore needs to be scrutinized, and the results obtained to date critically reviewed. We review the relationship between insulin resistance and Parkinson's disease, the implications on pathogenesis and the efforts to reposition GLP-1 agonists as potential treatments for Parkinson's disease and give an overview of the pre-clinical and clinical data supporting the use of exenatide in Parkinson's disease with a discussion regarding possible mechanisms of action

The Future of Incretin-Based Approaches for Neurodegenerative Diseases in Older Adults: Which to Choose? A Review of their Potential Efficacy and Suitability

The current treatment options for neurodegenerative diseases in older adults rely mainly on providing symptomatic relief. Yet, it remains imperative to identify agents that slow or halt disease progression to avoid the most disabling features often associated with advanced disease stages. A potential overlap between the pathological processes involved in diabetes and neurodegeneration has been established, raising the question of whether incretin-based therapies for diabetes may also be useful in treating neurodegenerative diseases in older adults. Here, we review the different agents that belong to this class of drugs (GLP-1 receptor agonists, dual/triple receptor agonists, DPP-4 inhibitors) and describe the data supporting their potential role in treating neurodegenerative conditions including Parkinson’s disease and Alzheimer’s disease. We further discuss whether there are any distinctive properties among them, particularly in the context of safety or tolerability and CNS penetration, that might facilitate their successful repurposing as disease-modifying drugs. Proof-of-efficacy data will obviously be of the greatest importance, and this is most likely to be demonstrable in agents that reach the central nervous system and impact on neuronal GLP-1 receptors. Additionally, however, the long-term safety and tolerability (including gastrointestinal side effects and unwanted weight loss) as well as the route of administration of this class of agents may also ultimately determine success and these aspects should be considered in prioritising which approaches to subject to formal clinical trial evaluations

Design Strategy for a Scalable Virtual Pharmacy Patient

This paper reports on the completion of the first stage of research of a pilot study undertaken in collaboration by 3 Australian universities. The pilot involves the development of a virtual pharmacy patient (VPP) as a study of its effects on student learning when it is used as a formative assessment tool for pharmacy students in interviewing and diagnosing a patient. The design criteria that have been incorporated into the virtual patient system are described. The novelty of this system is in its ability to track and report on the style and appropriateness of student questioning of a virtual pharmacy patient. One of the main problems in this type of system is recognition of free-text student questions. An overview of the pragmatic solution to this and the systems potential as a tool to generate a lexicon for more complex question recognition is presented

Pathological regression of primary tumour and metastatic lymph nodes following chemotherapy in resectable OG cancer: pooled analysis of two trials

Background: No definitive largescale data exist evaluating the role of pathologically defined regression changes within the primary tumour and lymph nodes (LN) of resected oesophagogastric (OG) adenocarcinoma following neoadjuvant chemotherapy and the impact on survival. / Methods: Data and samples from two large prospective randomised trials (UK MRC OE05 and ST03) were pooled. Stained slides were available for central pathology review from 1619 patients. Mandard tumour regression grade (TRG) and regression of tumour within LNs (LNR: scored as present/absent) were assessed and correlated with overall survival (OS) using a Cox regression model. An exploratory analysis to define subgroups with distinct prognoses was conducted using a classification and regression tree (CART) analysis. / Results: Neither trial demonstrated a relationship between TRG score and the presence or absence of LNR. In univariable analysis, lower TRG, lower ypN stage, lower ypT stage, presence of LNR, presence of well/moderate tumour differentiation, and absence of tumour at resection margin were all associated with better OS. However, the multivariable analysis demonstrated that only ypN, ypT, grade of differentiation and resection margin (R0) were independent indicators of prognosis. Exploratory CART analysis identified six subgroups with 3-year OS ranging from 83% to 22%; with ypN stage being the most important single prognostic variable. / Conclusions: Pathological LN stage within the resection specimen was the single most important determiner of survival. Our results suggest that the assessment of regression changes within the primary tumour or LNs may not be necessary to define the prognosis further

Cisplatin Substitution with Carboplatin During Radical Chemoradiotherapy for Oesophagogastric Carcinoma: Outcomes from a Tertiary Centre.

Background/aim Cisplatin-based radical chemoradiotherapy (CRT) is utilised in oesophagogastric (OG) cancer but the toxicity profile of cisplatin limits its use. This study aimed to evaluate the clinical characteristics and outcomes of patients treated with either cisplatin or carboplatin based CRT at our institution.Materials and methods This is a retrospective analysis of patients with localised OG cancer undergoing CRT with cisplatin/fluoropyrimidine (CX/F) or carboplatin/fluoropyrimidine (CarboX/F) between January 2001 and December 2014.Results A total of 91 eligible patients were included. Median age was 65 years (IQR=57-75) for CX/F and 77 years (IQR=69-80) for CarboX/F. Adenocarcinoma histology and Charlson comorbidity index were higher in the CarboX/F group. Endoscopic complete response (CR) was achieved in 64% of CX/F group and 48% of CarboX/F group (p=0.19). The median PFS for CX/F was 31.0 months (95%CI=18.2-NE) vs. 18.7 months for CarboX/F (95%CI=13.5-30.4; HR=1.49, p=0.21).Conclusion Despite significant differences in baseline clinical characteristics, patients treated with carboplatin CRT demonstrated no significant difference in PFS or endoscopic CR rate, compared to those treated with cisplatin