Old and new acetylcholinesterase inhibitors for Alzheimer’s disease

Introduction: To date, pharmacological treatment of Alzheimer’s disease (AD) includes Acetylcholinesterase Inhibitors (AChEIs) for mild-to-moderate AD, and memantine for moderate-to-severe AD. AChEIs reversibly inhibit acetylcholinesterase (AChE), thus increasing the availability of acetylcholine in cholinergic synapses, enhancing cholinergic transmission. These drugs provide symptomatic short-term benefits, without clearly counteracting the progression of the disease.

Areas covered: On the wake of successful clinical trials which lead to the marketing of AChEIs donepezil, rivastigmine and galantamine, many compounds with AChEI properties have been developed and tested mainly in Phase I-II clinical trials in the last twenty years. Here, we review clinical trials initiated and interrupted, and those ongoing so far.

Expert opinion: Despite many clinical trials with novel AChEIs have been carried out after the registration of those currently used to treat mild to moderate AD, none so far has been successful in a Phase III trial and marketed. Alzheimer’s disease is a complex multifactorial disorder, therefore therapy should likely address not only the cholinergic system but also additional neurotransmitters. Moreover, such treatments should be started in very mild phases of the disease, and preventive strategies addressed in elderly people.     

Pharmacological management of behavioral disturbances in patients with Alzheimer’s disease

ABSTRACT

Neuropsychiatric symptoms (NPS) inevitably occur during the course of Alzheimer’s disease (AD) including psychosis, aggression, and depression. The effectiveness of pharmacological treatments for NPS has been limited because of their lack of efficacy, discontinuation due to undesirable adverse events, or poor adherence. In recent consensus guidelines, non-pharmacological treatments for NPS have been prioritized as first-line management strategies. Pharmacological treatments for severe NPS should be administrated as a second-line approach, and have been suggested to be started at a lower dosage followed by titration to a minimum effective dosage and for a limited time period. However, recent studies have shown that some patients receiving pharmacological treatments do not exhibit treatment efficacy in comparison with placebo. The concurrence of several sub-symptoms in NPS makes it difficult to target one symptom exclusively. Therefore, the current review focuses on a strategy for such refractory NPS in patients with AD. Recent randomized controlled trials have shown that the severity of NPS gradually reduces in a time-dependent manner regardless of active treatments. Therefore, clinicians should consider potential causes of NPS sub-symptoms from multifactorial aspects and select alternative treatments (e.g. neuromodulation or relocation into specialized care units) during the long-term disease course.     

Donepezil (E2020): a new acetylcholinesterase inhibitor. Review of its pharmacology,pharmacokinetics, and utility in the treatment of Alzheimer’s disease

Donepezil is an acetylcholinesterase inhibitor under development for the treatment of mild-moderately Alzheimer's disease. In vitro, donepezil is about 10 times more potent than tacrine as an inhibitor of acetylcholinesterase. Donepezil is 500 - 1000 fold selective for acetylcholinesterase over butyrylcholinesterase. In animal models, donepezil produces positive effects on both working memory and long term memory. In man, donepezil is slowly absorbed from the gastrointestinal (GI) tract. The compound has a terminal elimination half-life of 50 - 70 h in young volunteers; in elderly volunteers, the half-life of the compound is extended to over 100 h. Donepezil is extensively metabolised after oral administration. The parent compound is 93% bound to plasma proteins. Results from two clinical trials with donepezil were published. The largest of these trials was a 12 week 161 patient Phase II investigation in the USA. Results from this investigation showed that donepezil produced dose-related improvements, with statistically significant effects occurring at doses of 3 and 5 mg/day. The results published to date suggest that donepezil will be a useful agent in the symptomatic treatment of Alzheimer’s disease.     

Current status and new developments with galantamine in the treatment of Alzheimer’s disease

Galantamine is a newly available cholinergic drug that offsets reductions in central cholinergic neurotransmission in Alzheimer's disease (AD) by specifically and reversibly inhibiting acetylcholinesterase (AChE) and by allosterically modulating nicotinic cholinergic receptors. The clinical impact of this latter mechanism of action has not been fully elucidated. Galantamine has favourable pharmacokinetic features including linear elimination kinetics, a relatively short half-life and high oral bioavailability. The efficacy of galantamine has been studied in an extensive clinical development program. During randomised, double-blind, placebo-controlled trials of up to 6 months duration, galantamine 16 and 24 mg/day consistently produced a broad spectrum of beneficial effects on cognitive and non-cognitive AD symptoms. Patients’ cognition, global function and abilities to perform both instrumental and basic activities of daily living were maintained, the emergence of behavioural symptoms was postponed and apparent reductions in caregiver burden were seen. In long-term studies (≥ 12 months), galantamine maintained cognitive and functional abilities at or near baseline levels for at least 12 months. Again, these benefits were associated with decreases in caregiver burden. The incidence of adverse events, which are typically mild or moderate in severity, is generally low with galantamine. Cholinergically mediated adverse events affecting mainly the gastrointestinal system can be minimised using the recommended slow dose-escalation regimen. Galantamine may therefore help reduce the overall burden and cost involved in caring for AD patients. Being approved for the treatment of mild-to-moderately severe AD in both the US and in Europe, with trials of its efficacy in other dementia types already yielding positive results, galantamine ranks as a first-line therapy for dementia.     

Protein phosphatase 2A, a key player in Alzheimer’s disease

Protein phosphatase 2A (PP2A) is the predominant serine/threonine phosphatase in eukaryotic cells. In the brains of patients with Alzheimer’s disease (AD), decreased PP2A activities were observed, which is suggested to be involved in neuro.brillary tangle (NFT) formation, disturbed amyloid precursor protein (APP) secretion and neurodegeneration in AD brain. Based on our research and other previous findings, decreased PP2Ac level, decreased PP2A holoenzyme composition, increased level of PP2A inhibitors, increased PP2Ac Leu309 demethylation and Tyr307 phosphorylation underlie PP2A inactivation in AD. β-amyloid (Aβ) overproduction, estrogen deficiency and impaired homocysteine metabolism are the possible up-stream factors that inactivate PP2A in AD neurons. Further studies are required to disclose the role of PP2A in Alzheimer’s disease.     

Chlorzoxazone exhibits neuroprotection against Alzheimer’s disease by attenuating neuroinflammation and neurodegeneration in vitro and in vivo

Alzheimer’s disease (AD), a complex and an age-related brain disease, is induced by the accumulation of amyloid beta (Aβ) and neuroinflammation. Chlorzoxazone (CZ) is a classical FDA-approved drug, and shows anti-inflammatory effects. However, up until now, its regulatory role in AD has not been investigated. Therefore, in this study we attempted to explore if CZ could be an effective therapeutic strategy for AD treatment. At first, the in vitro study was performed to mimic AD using Aβ. We found that Aβ caused p65 nuclear translocation in both primary microglial cells and astrocytes, which were, however, restrained by CZ treatments. Meanwhile, CZ incubation markedly decreased the expression of pro-inflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin-1β (IL-1β). Aβ deposition was also markedly reduced in glial cells treated with CZ. Importantly, we found that glial activation and its-related pro-inflammation induced by Aβ led to obvious neurodegeneration and neuroinflammation, which were effectively attenuated by CZ pre-treatment in the isolated primary cortical neurons. Then, the in vivo study was performed using APP/PS1 mice with AD. Behavior tests showed that CZ administration effectively improved cognitive deficits in AD mice. Neuron death in hippocampus of AD mice was also inhibited by CZ. Aβ accumulation in brain was markedly decreased in CZ-treated AD mice. We finally found that hippocampal glial activation in AD mice was obviously blocked by CZ supplementation, along with remarkable decreases in TNF-α, IL-1β and p65 nuclear translocation. Together, these findings above demonstrated that CZ could inhibit glial activation and inflammatory response, contributing to the suppression of neurodegeneration and neuroinflammation. Therefore, CZ may be an effective therapeutic strategy for AD treatment.     

Advancements in the treatment of agitation in Alzheimer’s disease

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer’s disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks well-established long-term interventions that are both effective and safe. While non-pharmacological interventions are the suggested first-line treatment, it isn’t effective in managing symptoms for every patient. In such cases, clinicians turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants, where the efficacy doesn’t necessarily outweigh the associated risks.

Areas covered: Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials. A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of these clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram show promise in treating agitation.

Expert opinion: Neurobiological findings and enhanced trial designs have re-ignited the area of pharmacological treatment of NPS. Although further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to finding effective treatments for NPS such as agitation in patients with dementia is well underway.     

The role of inflammatory processes in Alzheimer’s disease

It has become increasingly clear that inflammatory processes play a significant role in the pathophysiology of Alzheimer's disease (AD). Neuroinflammation is characterized by the activation of astrocytes and microglia and the release of proinflammatory cytokines and chemokines. Vascular inflammation, mediated largely by the products of endothelial activation, is accompanied by the production and the release of a host of inflammatory factors which contribute to vascular, immune, and neuronal dysfunction. The complex interaction of these processes is still only imperfectly understood, yet as the mechanisms continue to be elucidated, targets for intervention are revealed. Although many of the studies to date on therapeutic or preventative strategies for AD have been narrowly focused on single target therapies, there is accumulating evidence to suggest that the most successful treatment strategy will likely incorporate a sequential, multifactorial approach, addressing direct neuronal support, general cardiovascular health, and interruption of deleterious inflammatory pathways.     

The benefits and risks associated with cholinesterase inhibitor therapy in Alzheimer’s disease

The ‘second-generation’ cholinesterase inhibitors (ChEIs), donepezil, galantamine and rivastigmine, are a class of medications that are currently approved for the treatment of mild-to-moderate Alzheimer’s disease (AD). These medications have proven efficacy in improving cognition, behaviour, activities of daily living, and global functioning in mild-to-moderate AD. They have also been shown to reduce caregiver stress and to delay time to nursing home placement. Two separate meta-analyses have indicated that ChEIs confer a modest but significant therapeutic benefit in the treatment of AD, despite higher rates of treatment discontinuation and side effects than placebo. There is growing evidence to support their efficacy in treating moderate-to-severe AD. ChEIs are generally well-tolerated, with side effects that tend to be dose-related and are most problematic during dose titration. The most common adverse effects, related to cholinergic stimulation in the brain and peripheral tissues, include gastrointestinal, cardiorespiratory, extrapyramidal, genitourinary, and musculoskeletal symptoms, as well as sleep disturbances. Few clinically significant drug–drug interactions with ChEIs have been identified. Three head-to-head trials of ChEIs in the treatment of AD have been published to date, but are limited due to their open-label design, rates of titration, and the drug dosage levels utilised. Further study is needed to examine other indications for ChEIs, as well as their combination with newer treatments, such as memantine.     

The role of mitochondrial defects and oxidative stress in Alzheimer’s disease

Abstract

Alzheimer’s disease (AD) is a complex, progressive, and irreversible neurodegenerative disorder. Recent reports suggest that it affects more than 36 million people worldwide and accounts 60–80% of all cases of dementia. It is characterised by aberrations of multiple interactive systems and pathways, which ultimately lead to memory loss and cognitive dysfunction. The exact mechanisms and initial triggering factors that underpin the known pathological defects in AD remain to be fully elucidated. In addition, an effective treatment strategy to reduce the progression of AD is yet to be achieved. In the light of above-mentioned facts, our article deals with the exploration of the mitochondrial defect and oxidative stress leading to this devastating disease. In this communication, we have highlighted specific mitochondrial and antioxidant-directed approach to ameliorate and manage AD. Nonetheless, new approaches should also be investigated that could tackle various molecular events involved in AD pathogenicity.     

Review of rivastigmine and its clinical applications in Alzheimer’s disease and related disorders

Rivastigmine (Exelon?, Novartis) is a novel intermediate-acting reversible and non-competitive carbamate acetylcholinesterase (AChE) that was recently introduced for the treatment of Alzheimer’s disease (AD). Preclinical studies have shown that rivastigmine has many similarities to other currently available cholinesterase inhibitors (ChEIs) and some important differences. The drug has been evaluated for this use in two well designed, published, adequately powered, Phase III, 26 week clinical trials that included a total of more than 1500 rivastigmine and 700 placebo recipients. Most of these patients had concomitant disorders that were being treated with numerous other drugs. These studies indicate that rivastigmine (6 - 12 mg/day) usually produces cognitive, global and functional changes that indicate significantly less deterioration than was observed with placebo in patients with mild-to-moderate AD, with higher doses producing more benefits. Rivastigmine is beneficial in all three domains (namely cognition, daily activities and behaviour) of AD. Data on long-term efficacy support continued benefits of rivastigmine beyond 6 months. Rivastigmine is generally well-tolerated with no requirement for routine electrocardiogram (ECG) or blood monitoring. Rivastigmine causes adverse events that are generally those expected from a ChEI and mainly involve gastrointestinal system. They are usually mild-to-moderate, of short duration and responsive to dosage reduction. They occur mostly during the dosage titration phase and decrease during the maintenance phase. Clinically significant drug-drug interactions are unlikely. The consistent efficacy in treating all three domains (cognition, daily functioning and behaviour) and good tolerability, particularly with slow titration, makes rivastigmine a good first-line ChEI therapy for the treatment of AD. Therapeutic dose range is 6 - 12 mg/day. Rivastigmine should be started at 1.5 mg b.i.d. with meals and increased at 2 - 4 week intervals to achieve the highest tolerated dose.     

Effects of rivastigmine on common symptomatology of Alzheimer’s disease (EXPLORE)

Abstract

Objective:

To evaluate, in a real-world clinical setting, the efficacy of rivastigmine in the management of six symptoms commonly associated with Alzheimer's disease (AD).     

New concepts in the drug therapy of Alzheimer’s disease

There are currently four compounds approved for use in the treatment of Alzheimer’s disease (AD). These drugs are all cholinesterase (ChE) inhibitors, which are thought to provide predominantly symptomatic benefits by increasing the level of acetylcholine (ACh) in the synapse. Although there are slight differences in the mechanisms of action of these compounds, it remains to be determined whether any one of them has a significant therapeutic advantage over the others. Several other drugs have also been investigated for their potential use as either symptomatic or disease-modifying agents in the treatment of AD, with mixed results. Current therapeutic research is focused on addressing the underlying pathology of AD, in the hope of arresting or reversing the course of the disease. This review will provide an overview of the ChE inhibitors and other drugs used for treating the symptoms of AD, summarise the results of recent therapeutic trials, discuss directions of future research and outline the current treatment recommendations for AD.     

GSK-3 inhibitors and their potential in the treatment of Alzheimer’s disease

Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed kinase that has emerged as a promising drug target for several diseases, including various neurological conditions, Type 2 diabetes and cancer. For this reason, a number of drug candidates are being developed to achieve very different goals, any of which could have therapeutic value in the treatment of Alzheimer’s disease (AD). The importance of GSK-3 in so many processes, however, also suggests that issues of side effects will need to be addressed before GSK-3 inhibitors can be used in the clinic. This review discusses the role of GSK-3 in the development of AD, the various approaches that have been used to inhibit GSK-3 activity and the patents describing the use of GSK-3 inhibitors in the treatment of AD.     

Therapeutic strategies and nano-drug delivery applications in management of ageing Alzheimer’s disease

In recent years, the incidental rate of neurodegenerative disorders has increased proportionately with the aging population. Alzheimer’s disease (AD) is one of the most commonly reported neurodegenerative disorders, and it is estimated to increase by roughly 30% among the aged population. In spite of screening numerous drug candidates against various molecular targets of AD, only a few candidates – such as acetylcholinesterase inhibitors are currently utilized as an effective clinical therapy. However, targeted drug delivery of these drugs to the central nervous system (CNS) exhibits several limitations including meager solubility, low bioavailability, and reduced efficiency due to the impediments of the blood-brain barrier (BBB). Current advances in nanotechnology present opportunities to overcome such limitations in delivering active drug candidates. Nanodrug delivery systems are promising in targeting several therapeutic moieties by easing the penetration of drug molecules across the CNS and improving their bioavailability. Recently, a wide range of nano-carriers, such as polymers, emulsions, lipo-carriers, solid lipid carriers, carbon nanotubes, metal based carriers etc., have been adapted to develop successful therapeutics with sustained release and improved efficacy. Here, we discuss few recently updated nano-drug delivery applications that have been adapted in the field of AD therapeutics, and future prospects on potential molecular targets for nano-drug delivery systems.     

Pharmacotherapeutic strategies for treating epilepsy in patients with Alzheimer’s disease

Introduction: Alzheimer’s disease (AD)-related epileptic comorbidity is now well documented and appears to have been previously underestimated. Prescribing antiepileptic drugs (AEDs) in AD patients aims at preventing seizure-related morbi-mortality and the occurrence of deleterious status epilepticus. At the earlier stages of the disease, some clinicians even expect a disease-modifying effect.

Areas covered: In this review, the author provides a brief overview of the epileptic comorbidity in AD, discusses the appropriate AEDs from a syndromic point of view, reviews the effectiveness and cognitive tolerability of the currently available drugs, and considers the influence of the comorbidities and the age of AD patients in the choice of an AED.

Expert opinion: Given the paucity of current empirical data, much remains to be done to provide good evidence of the efficacy and tolerability of AEDs in the area of AD-related seizures and epilepsy. To our knowledge, lamotrigine and levetiracetam are currently the two best therapeutic options as low-dose monotherapies.     

In silico pharmacophore model generation for the identification of novel butyrylcholinesterase inhibitors against Alzheimer’s disease

Butyrylcholinesterase present in the serum, heart, lung, intestine, liver, and kidney plays an important role in the metabolism of ester containing compounds. Several neuronal groups solely show the activity of BChE in the human brain, such as in the inhibition or the absence of AChE, BChE can replace AChE in the degradation of acetylcholine ACh. Such replacement in Alzheimer’s patient brains renders BChE as a more effective drug target than AChE and its inhibitors are useful in the treatment of Alzheimer’s disease. Ligand-based pharmacophore modeling is playing an important role for the identification of ligand features for the particular targets. In this study, we present a model for designing the ligand-based pharmacophore onto the set of ten compounds of five different classes. Pharmacophore model was generated using Ligand Scout with diverse classes of Butyrylcholinesterase inhibitors. The pharmacophore model with two HBA, one HBD, two HY/AR, and one positive ionizable was generated. The results obtained in this study can be considered to be useful and reliable tools in identifying structurally diverse compounds with desired biological activity.