The effects of donepezil in Alzheimer's disease - Results from a multinational trial

Donepezil has been shown to be well tolerated and to improve cognition and global function in patients with mild to moderately severe Alzheimer's disease (AD). The current trial was undertaken to investigate further the efficacy and safety of donepezil, in a multinational setting, in patients with mild to moderately severe AD. This 30-week, placebo-controlled, parallel-group study consisted of a 24-week, double-blind treatment phase followed by a 6-week, single-blind, placebo washout. Eight hundred and eighteen patients with mild to moderately severe AD were randomly allocated to treatment with single, daily doses of 5 or 10 mg donepezil, or placebo. The two primary efficacy measures were: a cognitive performance test, the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and a global evaluation, the Clinician's Interview-Based Impression of Change with caregiver input (CIBIC plus). Secondary outcome measures included the Sum of the Boxes of the Clinical Dementia Rating Scale (CDR-SB), a modified Interview for Deterioration in Daily living activities in Dementia (IDDD) and a patient-rated quality of life assessment. Statistically significant improvements in cognitive and global function were observed, as evaluated by ADAS-cog and CIBIC plus, respectively, in both the 5 and 10 mg/day donepezil groups, compared with placebo. Treatment-associated changes were also observed in functional skills, as shown by improved scores on the CDR-SB and the complex-tasks component of the IDDD. A dose-response effect was evident, with the 10 mg/day donepezil group demonstrating greater benefits in all outcome measures than the 5 mg/day group. Donepezil was well tolerated by this patient population and did not produce any clinically significant laboratory test abnormalities. The results of this study confirm that donepezil is effective and well tolerated in treating the symptoms of mild to moderately severe AD

Beyond Cholinesterase Inhibition. Anti-Inflammatory Role and Pharmacological Profile of Current Drug Therapy for Alzheimer's Disease

Inflammation is a common response of an individual against either exogenous or endogenous damage. The role of inflammation and of inflammatory cells recently emerged also in the pathogenesis of neurodegenerative disorders. Experimental evidences show how neurotransmitters, besides their role in the synapses, play a modulatory role during immune response. Drugs used for treatment of dementia symptoms are able to increase neurotransmitters levels, and likely to have a modulatory role during immune response. Aim of this review is to discuss the most recent advances on inflammation role during neurodegeneration and also to individuate the potential anti-inflammatory role played by drugs currently used for Alzheimer's disease treatment

Nootropics use in the workplace. Psychiatric and ethical aftermath towards the new frontier of bioengineering

OBJECTIVE: The authors have sought to expound upon and shed a light on the rise of nootropics, which have gradually taken on a more and more relevant role in workplaces and academic settings. MATERIALS AND METHODS: Multidisciplinary databases have been delved into by entering the following keys: "nootropics", "cognitive enhancement", "workplace", "productivity", "ethics", "bioengineering". In addition, a broad-ranging search has been undertaken on institutional websites in order to identify relevant analysis and recommendations issued by international institutions and agencies. Papers and reports have been independently pored over by each author. This search strategy has led to the identification of 988 sources but only 64 were considered appropriate for the purposes of the paper after being selected by at least 3 of the authors, independently. RESULTS: The notion of an artificially enhanced work performance - carried out by the 'superworker' - is particularly noteworthy and resonates with the conception of contemporary work on so many different levels: the rising need and demands for higher degrees of flexibility and productivity on the job, the implications of a '24/7' society, where more and more services are available at any time, the ever greater emphasis on entrepreneurial spirit, individual self-reliance and self-improvement, and last but not least, the impact of an ageing society on economic standards and performance. CONCLUSIONS: Moreover, it is worth mentioning that human enhancement technologies will predictably and increasingly go hand in hand with gene editing, bioengineering, cybernetics and nanotechnology. Applications are virtually boundless, and may ultimately affect all human traits (physical strength, endurance, vision, intelligence and even personality and mood)

NICE 2011 recommendations on the management of Alzheimer’s disease by acetylcholinesterase inhibitors and memantine

The National Institute of Clinical Excellence (NICE) has lately overturned its decision to restrict the use of acetycholinesterase inhibitors and memantine in patients diagnosed with Alzheimer’s disease (AD). It is estimated that such a policy U-turn will offer access to a significant number of individuals who were previously denied these medications. This short article will focus on the latest developments and recommendations by NICE on the use of these pharmacological agents in the managment of AD.peer-reviewe

Beneficial effects of pharmacological treatment in post-stroke dynamic aphasia: a behavioural and neuroimaging study

Introduction : Dynamic Aphasia (DA) is a rare form of language disorder characterized by reduced spontaneous speech with preservation of other language functions. Two types of DA have been described: language-specific type (type I DA) and domain-general type (type II DA). In type I DA, deficits are selective for word and sentence generation, whereas in type II DA impairments affect discourse generation, narrative, fluency, and non-verbal generation tasks. There is little information on the treatment of DA. Although treatment with a cognitive enhancing drug (bromocriptine) improved outcome in previous studies, pharmacological interventions combining two drugs acting on other neurotransmitter systems in DA have not been reported so far. Methods : We report an open-label pharmacological single case study (n = 1) in a male patient with a chronic type I/II DA secondary to an ischemic infarction in the left fronto-opercular and insular regions. After baseline evaluation, the patient received donepezil 5 mg/day (2 months), donepezil 10 mg/day (2 months), donepezil 10 mg/day plus memantine 20 mg/day (4½ months) followed by a washout period (1½ months). No speech-language therapy was used. A comprehensive cognitive and language evaluation was carried out at baseline and at different endpoints. 18FDG-PET was performed at the four timepoints. Results : Donepezil (5 mg/day) significantly improved type I DA features (normalization of verbs generation, p = 0.01), whereas donepezil (10 mg/day) improved some type II features (normalizing spontaneous speech, verbal fluency and improving generation of novel thoughts, p = 0.004), along with improvement of executive-attentional functioning. Combined therapy further enhanced cognitive function, but did not additionally improved DA. 18 FDG-PET revealed significant reductions of perilesional hypometabolic activity mainly after donepezil (10 mg/day) and washout. Discussion : Treatment with donepezil improved language deficits in a patient with chronic post-stroke type I/II DA. Combined therapy (donepezil plus memantine) further enhanced executive-attentional functioning. Beneficial changes were associated with improvements in perilesional metabolic activity. References : Luria AR et al.Acta Neurologica et Psychiatrica (1967). Robinson G et al. Brain (1998). Keywords : Language; patients; single case study; adults; cerebrovascular; behavioural, functional imaging.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Phase I and Phase II Therapies for Acute Ischemic Stroke: An Update on Currently Studied Drugs in Clinical Research.

Acute ischemic stroke is a devastating cause of death and disability, consequences of which depend on the time from ischemia onset to treatment, the affected brain region, and its size. The main targets of ischemic stroke therapy aim to restore tissue perfusion in the ischemic penumbra in order to decrease the total infarct area by maintaining blood flow. Advances in research of pathological process and pathways during acute ischemia have resulted in improvement of new treatment strategies apart from restoring perfusion. Additionally, limiting the injury severity by manipulating the molecular mechanisms during ischemia has become a promising approach, especially in animal research. The purpose of this article is to review completed and ongoing phases I and II trials for the treatment of acute ischemic stroke, reviewing studies on antithrombotic, thrombolytic, neuroprotective, and antineuroinflammatory drugs that may translate into more effective treatments

Bayesian Value-of-Information Analysis: An Application to a Policy Model of Alzheimer's Disease

A framework is presented which distinguishes the conceptually separate decisions of which treatment strategy is optimal from the question of whether more information is required to inform this choice in the future. The authors argue that the choice of treatment strategy should be based on expected utility and the only valid reason to characterise the uncertainty surrounding outcomes of interest is to establish the value of acquiring additional information. A Bayesian decision theoretic approach is demonstrated though a probabilistic analysis of a published policy model of Alzheimer’s disease. The expected value of perfect information is estimated for the decision to adopt a new pharmaceutical for the population of US Alzheimer’s disease patients. This provides an upper bound on the value of additional research. The value of information is also estimated for each of the model inputs. This analysis can focus future research by identifying those parameters where more precise estimates would be most valuable, and indicating whether an experimental design would be required. We also discuss how this type of analysis can also be used to design experimental research efficiently (identifying optimal sample size and optimal sample allocation) based on the marginal cost and marginal benefit of sample information. Value-of-information analysis can provide a measure of the expected payoff from proposed research, which can be used to set priorities in research and development. It can also inform an efficient regulatory framework for new health care technologies: an analysis of the value of information would define when a claim for a new technology should be deemed “substantiated” and when evidence should be considered “competent and reliable” when it is not cost-effective to gather anymore information.stochastic CEA; Bayesian decision theory; value of information.

Cholinergic regulation of mood: from basic and clinical studies to emerging therapeutics.

Mood disorders are highly prevalent and are the leading cause of disability worldwide. The neurobiological mechanisms underlying depression remain poorly understood, although theories regarding dysfunction within various neurotransmitter systems have been postulated. Over 50 years ago, clinical studies suggested that increases in central acetylcholine could lead to depressed mood. Evidence has continued to accumulate suggesting that the cholinergic system has a important role in mood regulation. In particular, the finding that the antimuscarinic agent, scopolamine, exerts fast-onset and sustained antidepressant effects in depressed humans has led to a renewal of interest in the cholinergic system as an important player in the neurochemistry of major depression and bipolar disorder. Here, we synthesize current knowledge regarding the modulation of mood by the central cholinergic system, drawing upon studies from human postmortem brain, neuroimaging, and drug challenge investigations, as well as animal model studies. First, we describe an illustrative series of early discoveries which suggest a role for acetylcholine in the pathophysiology of mood disorders. Then, we discuss more recent studies conducted in humans and/or animals which have identified roles for both acetylcholinergic muscarinic and nicotinic receptors in different mood states, and as targets for novel therapies