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A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild to moderately severe Alzheimer's disease
Abstract
We evaluated the efficacy and safety of a new centrally acting acetycholinesterase inhibitor, ENA 713 (rivastigmine tartrate), for patients with Alzheimer's disease (AD). A total of 699 patients, between 45 and 90 years of age, with mild to moderately severe probable AD were randomly assigned to treatment with placebo (n = 235), relatively lower doses (1-4 mg/day) of ENA 713 (n = 233), or higher doses (6-12 mg/day) of ENA 713 (n = 231) for 26 weeks, followed by an open-label extension. The efficacy measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Clinician's Interview Based Impression of Change-Plus (CIBIC-Plus), and the Progressive Deterioration Scale (PDS). At 26 weeks, patients showed benefit from high-dose ENA 713 treatment on all outcome measures, including cognition (ADAS-Cog), global assessment of change (CIBIC-Plus), activities of daily living (PDS), and disease severity (Global Deterioration Scale, Mini-Mental State Examination). For both doses the mean changes from baseline on the ADAS-Cog and CIBIC-Plus were significantly different from those for placebo (P < 0.05) for all populations analyzed. On the ADAS-Cog, high-dose ENA 713 produced the largest drug-vs-placebo difference that has been reported to date for a dementia drug (4.94 points). On the PDS, the high-dose drug-vs- placebo difference was significant (P < 0.001). The proportion of clinically meaningful responders in both ENA 713 groups was significantly different from that of the placebo group on the ADAS-Cog and CIBIC-Plus (P < 0.05); only the high-dose group had a significantly greater number of responders on the PDS (P < 0.01). No differences were noted between groups regarding electrocardiograms, laboratory evaluations, or vital signs. A higher incidence of gastrointestinal adverse events, which were self-limited and of mild to moderate intensity, were noted with ENA 713. ENA 713 treatment is safe and effective with regard to cognition, global functioning, and activities of daily living in patients with mild to moderately severe AD.
... Ⅲ Rivastigmine Tartrate-In two 26-week trials involving patients with mild to moderate probable AD (N=1424), subjects receiving a daily dose of 6 mg to 12 mg rivastigmine demonstrated favorable and significant differences in ADAS-Cog and CIBIC-plus scores when compared with subjects in the placebo group (Table 2). 67,68 Doses of rivastigmine in these two trials consisted of a low daily dose that was between 1 mg and 4 mg (mean 3.5-3.6 mg/d) and a high daily dose between 6 mg and 12 mg (mean 9.7-10.4 ...
... The 4.9-point difference in overall ADAS-Cog score increases in favor of rivastigmine over placebo in this 26-week trial is the largest observed for any of the cholinesterase inhibitors. 67,68 Researchers found that improvements in the cognitive performance of subjects with mild to moderate AD receiving rivastigmine were significantly correlated with central inhibition of both AChE and BuChE. 42 Compared with subjects receiving placebo, approximately twice the number of subjects treated with high-dose rivastigmine had improved CIBICplus scores, resulting in overall CIBIC-plus score differences in favor of rivastigmine. ...
... After 6 months, subjects in the rivastigmine group demonstrated a 0.2-point decrease in mean ADAS-Cog scores (decreased impairment) compared with baseline, whereas subjects in the placebo group had an increase of 6.3 points the studies, the difference in PDS scores between the highdose rivastigmine and placebo groups reached 4.5 points (P Ͻ .001). 67 Such a difference would confirm the favorable effect of rivastigmine on overall clinical status, as measured on CIBIC-plus. ...
Dementia associated with probable Alzheimer's disease (AD) is one of the most common types of dementia. Patients with AD often have cholinergic deficits in association with the disease. The cholinesterase inhibitors donepezil hydrochloride, galantamine hydrobromide, and rivastigmine tartrate are the current mainstays of symptomatic treatment for patients with AD. In clinical trials for all three agents, beneficial effects on standard measures of cognitive and global function have been observed in patients with mild to moderate AD. Although none of the cholinesterase inhibitors has been approved for treatment of patients in advanced stages of AD, all three agents have had beneficial cognitive effects among patients with less severe forms of the disease. The author provides information on recommended dosing for all three medications, noting that cholinesterase inhibitors must be titrated carefully. When administered with caution, galantamine, rivastigmine, and donepezil are generally well-tolerated pharmacologic treatment options. The author notes that, after patients and their caregivers understand that no change in status is considered an “improvement” and a desirable clinical outcome for patients with AD, if no benefits are achieved with the use of one cholinesterase inhibitor, switching to another medication in this class might be beneficial. The author further suggests that the benefits found in cholinesterase inhibitors for patients with AD might also be applicable to patients with other types of dementia such as vascular dementia and dementia with Lewy bodies as cholinergic deficits have been reported in association with these types of dementia as well.
... are group of compounds from different chemical entities that inhibit breakdown of acetylcholine and thus increase both its level and duration of action in the synaptic cleft. Thus, rivastigmine [1], galantamine [2] and donepezil [3] were approved by the food and drug administration for treating the underline symptoms of Alzheimer's disease (AD) such as associated behavioural abnormalities and cognitive deficit. From a different proposed pathological hypothesis, the death of cholinergic neurons is widely recognised as the main pathological mechanism [4]. ...
... The crude material was washed with hot water (at 60°C) to give 2 (1.9 g, 95% yield). 1 3 mmol), bromoalkane (23.9 mmol), acetone (50 ml) and potassium carbonate (5 g) was heated with stirring for eight hours. After cooling, the mixture was vacuum filtered and the resultant solid was recrystallised from aqueous acetone (85%) to obtain a substantially pure product 3a-f. ...
... After cooling, the mixture was vacuum filtered and the resultant solid was recrystallised from aqueous acetone (85%) to a substantially pure product 4 (0.58 g, 90% yield). 1 , the corresponding amine (7.5 ml), was dissolved in THF (10 ml), aqueous sodium hydroxide (0.2%, 2 ml) was added, this mixture was stirred at 70°C for 6 h. After cooling to room temperature the organic substance was extracted with ether, and the solvent was evaporated under vacuum. ...
Xanthones from natural and synthetic origins have shown interesting diverse pharmacological activities. This study aims to assess the in silico and in vitro activities of new synthetic xanthones as inhibitors of acetylcholinesterase enzyme (AChE). A series of eight new xanthones were designed and synthesised, using an in house strategy, from a readily available starting material. Their inhibitory activities against AChE were assessed in vitro and presented as IC50 values. The binding mode of these compounds inside AChE was investigated using Auto-Dock 4.2.2. Additionally, molecular dynamics simulation was performed, using GROMACS 5.0.2, to explore the dynamics of the inhibitory mechanism and stability of xanthone 5a within the active site of AChE enzyme. All xanthones showed promising activities when tested in vitro and in silico with xanthone 5a being the most potent in terms of both binding energy (−12.32 kcal/mol) and IC50 (0.20 ± 0.04 µM). Molecular dynamics simulation revealed several interesting features responsible for the potency of xanthone 5a as an AChE inhibitor. Furthermore, the calculated Log P of xanthone (5a) was found to be 6.56 suggesting it to be a potential drug candidate for the management of AChE associated diseases such as Alzheimer’s disease and myasthenia gravis.
... These observations are also strongly supported by a recent meta-analysis using 11 independent studies [57]. The GDS stages have previously been used in the initial definition of MCI [4,40,45] (GDS stage 3), and in the pivotal trials associated with the initial approvals of 2 of the 3 most widely used medications for the treatment of AD at the present time, i.e., rivastigmine for mild to moderate dementia (GDS stages 4 and 5) [66,67], and memantine for moderate to severe dementia (GDS stages ≥ 5) [26,68]. A deriva-tive of the GDS staging, the FAST assessment [23], which is an expanded version of BCRS axis 5, has been used in the worldwide pivotal trial approvals of the remaining leading medication for the treatment of AD, donepezil [28][29][30][31][32]. Furthermore, it has previously been shown that after controlling for baseline demographic variables (subject age, gender, and education) and follow-up time, the hazard ratio of decline over a 7-year mean interval, is 4.5 times greater (confidence interval = 1.9 -10.3), for SCD(I) (GDS stage 2) subjects in comparison with NCI (GDS stage 1) persons [49]. ...
... These BCRS assessments have also been used as part of an outcome assessment known as the NYU-CIBIC-Plus (Clinician's Interview Based Impression of Change -Plus Caregiver Input, NYU version) [69]. The NYU-CIBIC-Plus has been employed as a primary outcome in the worldwide approvals of rivastigmine [66,67] and memantine [26]. More specifically, the NYU-CIBIC Plus is a syncretic scale comprised of 4 components [69]. ...
... The NYU-CIBIC-Plus also contains behavioral disturbance elements. Both rivastigmine and memantine showed efficacy on the NYU-CIBIC-Plus assessment in the pivotal trials [26,66,67]. Partially on the basis of other data from these trials, it is reasonable to assume that this efficacy was due to positive changes in the NYU-CIBIC-Plus cognitive component (represented by BCRS axes 1 to 4) and the functional component (represented by BCRS axis 5), with or without any contribution from the behavioral disturbance elements of the NYU-CIBIC-Plus, although no subanalyses were performed on this measure. ...
Background:
Little is known with respect to behavioral markers of subjective cognitive decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2.
Objective:
Two-year interval behavioral markers were investigated herein.
Methods:
Subjects from a published 7-year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years.
Results:
Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p < 0.001), with component declines in Remote memory (p < 0.01), and Functioning/self-care (p = 0.01).
Conclusion:
SCD(I) persons decline at an annual rate of approximately 6.7% /year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.
... These observations are also strongly supported by a recent meta-analysis using 11 independent studies [58]. The GDS stages have 26 previously been used in the initial definition of MCI [4,45,40], (GDS stage 3), and in the pivotal trials associated with the initial approvals of 2 of the 3 most widely used medications for the treatment of Alzheimer's disease at the present time, i.e., rivastigmine for mild to moderate dementia (GDS stages 4 and 5) [67,68], and memantine for moderate to severe dementia (GDS stages ≥ 5) [26,69]. A derivative of the GDS staging, the Functional Assessment Staging (FAST) assessment [23], which is an expanded version of BCRS axis 5, has been used in the worldwide pivotal trial approvals of the remaining leading medication for the treatment of Alzheimer's disease, donepezil [28,29,30,31,32]. ...
... These BCRS assessments have also been used as part of an outcome assessment known as the NYU-CIBIC-Plus (Clinician's Interview Based Impression of Change -Plus Caregiver Input, NYU version) [70]. The NYU-CIBIC-Plus has been employed as a primary outcome in the worldwide approvals of rivastigmine [67,68] and memantine [26]. ...
... The NYU-CIBIC-Plus also contains behavioral disturbance elements. Both rivastigmine and memantine showed efficacy on the NYU-CIBIC-Plus assessment in the pivotal trials [67,68,26]. Partially on the basis of other data from these trials, it is reasonable to assume that this efficacy was due to positive changes in the demographically matched "controls" without subjective symptoms [49]. ...
Background: Little is known with respect to behavioral markers of Subjective Cognitive Decline (SCD), a condition initially described in association with Global Deterioration Scale (GDS) stage 2. Objective: Two year interval behavioral markers were investigated herein. Methods: Subjects from a published 7 year outcome study of GDS stage 2 subjects were selected. This study had demonstrated a hazard ratio of 4.5 for progression of GDS stage 2, in comparison with GDS stage 1 (no subjective or objective cognitive decline) subjects, after controlling for demographic and temporal variables. Because GDS 2 subjects have previously demonstrated impairment in comparison with healthy persons free of complaints, we herein suggest the terminology "SCD(I)" for these persons. 98 SCD(I) persons, 63 women and 35 men, mean baseline age, 67.12±8.75 years, with a mean educational background of 15.55±2.60 years, and mean baseline MMSE scores of 28.9±1.24 were followed for 2.13±0.30 years. Results: Observed annual decline on the GDS was 6.701% per annum, very close to a 1986 published estimate. At follow up, the MMSE, and 7 of 8 psychometric tests did not decline significantly. Of 21 Hamilton Depression Scale items, 2 improved and the remainder were unchanged. Anxieties declined from multiple perspectives. The Brief Cognitive Rating Scale (BCRS) declined significantly (p<0.001), with component declines in remote memory (p<0.01), and functioning/self-care (p≤0.01). Conclusion: SCD(I) persons decline at an annual rate of approximately 6.7%/year from several recent studies. The BCRS assessments and the Digit Symbol Substitution Test can be sensitive measures for future studies of progression mitigation.
... Rivastigmine is a carbamate-type dual inhibitor of the brain cholinesterases, acetylcholinesterase (AChE) and butyl-cholinesterase (BuChE), with efficacy in the symptomatic treatment of mildto-moderate AD [40]. Previous research has identified greater improvements in APOE4 carriers than in non-APOE4 carriers following rivastigmine treatment [41]. ...
... Previous studies have, indeed, shown that increased NAP 226-90 concentration correlated well with cholinesterase inhibition [44,45]. Clinical trials of rivastigmine on patients with AD have suggested that increasing the therapeutic dosage would improve the clinical response due to evidence of dose-dependent effects [40,46]. Similar designs in other dose-related clinical studies on rivastigmine have found that only a few studies [44−46] addressed the plasma concentration of rivastigmine apart from the dosage. ...
Current treatment paradigm in Alzheimer’s disease (AD) involves multiple approaches combining pharmacological and nonpharmacological intervention to mitigate the clinical symptoms, slow the progressive loss of cognitive and functional abilities, or modify the disease course. So far, beyond anti-cholinesterase inhibitors (AChEIs), donepezil, rivastigmine, galantamine, and antagonist of N-methyl-D-aspartic acid (NMDA) receptor, there are no newly approved medicines to treat AD. Under pharmacological treatment, the personal characteristic and the intra-individual therapeutic evaluations to examine various cognitive domains, behavioral and psychological problems, and global function should be considered when choosing any of AChEIs. The use of optimal dosage referring to the expected clinical outcomes and currently reported deficits from patient with AD has become an important issue in clinical treatment. Establishing and maintaining a strong therapeutic alliance to physician, patient, and caregiver is crucial and central to the comprehensive care in AD.
... Rivastigmine is a carbamate-type dual inhibitor of the brain cholinesterases, acetylcholinesterase (AChE) and butyl-cholinesterase (BuChE), with efficacy in the symptomatic treatment of mildto-moderate AD [40]. Previous research has identified greater improvements in APOE4 carriers than in non-APOE4 carriers following rivastigmine treatment [41]. ...
... Previous studies have, indeed, shown that increased NAP 226-90 concentration correlated well with cholinesterase inhibition [44,45]. Clinical trials of rivastigmine on patients with AD have suggested that increasing the therapeutic dosage would improve the clinical response due to evidence of dose-dependent effects [40,46]. Similar designs in other dose-related clinical studies on rivastigmine have found that only a few studies [44−46] addressed the plasma concentration of rivastigmine apart from the dosage. ...
In this review article an overview of the current treatment paradigm in Alzheimer's disease, combing pharmacological and non-pharmacological interventions to mitigate the clinical symptoms, slow the progressive loss of cognitive and functional abilities, or modify the disease course.
... This effect may explain its unusually slow activation kinetics (32). rivastigmine has major side effects, including stomach pain, weight loss, diarrhoea, loss of appetite, nausea and vomiting (46). an overdose of rivastigmine may cause numerous symptoms, including irregular, fast or slow breathing, chest pain, and slow or irregular heartbeat (46). ...
... rivastigmine has major side effects, including stomach pain, weight loss, diarrhoea, loss of appetite, nausea and vomiting (46). an overdose of rivastigmine may cause numerous symptoms, including irregular, fast or slow breathing, chest pain, and slow or irregular heartbeat (46). The structure of rivastigmine is presented in Fig. 2d. ...
Alzheimer's disease (AD) is one of the most common forms of dementia. AD is a chronic syndrome of the central nervous system that causes a decline in cognitive function and language ability. Cholinergic deficiency is associated with AD, and various cholinesterase inhibitors have been developed for the treatment of AD, including naturally‑derived inhibitors, synthetic analogues and hybrids. Currently, the available drugs for AD are predominantly cholinesterase inhibitors. However, the efficacy of these drugs is limited as they may cause adverse side effects and are not able to completely arrest the progression of the disease. Since AD is multifactorial disease, dual and multi‑target inhibitors have been developed. The clinical applications and the limitations of the inhibitors used to treat AD are discussed in the present review. Additionally, this review presents the current status and future directions for the development of novel drugs with reduced toxicity and preserved pharmacological activity.
... Rivastigmine has lower activity at the periphery and has central activity at acetyl cholinesterase and butyl cholinesterase. The approval of rivastigmine indicate that doses of 6-12mg/day are efficacious (79)(80)(81). The initial dose of rivastigmine is 1.5mg Bid and titrated upward at a minimum of 2 weeks intervals to a maximum daily dose of 12 mg. ...
... The initial dose of rivastigmine is 1.5mg Bid and titrated upward at a minimum of 2 weeks intervals to a maximum daily dose of 12 mg. Rivastigmine has cholinergic side effects but it was well tolerated in clinical studies (79)(80)(81). Rivastigmine has low peripheral side effects (78). Because of the low protein binding, potential drug interactions are low (82). ...
Alois Alzheimer, a German psychiatrist and pathologist characterized Alzheimer's disease in 1907; chronic neurodegenerative disorder that progresses gradually affecting cognition and behavior earliest symptom is short term memory loss. With the progression of the disease, symptoms include mood swings, disorientation, problem with language, loss of motivation, behavioral issues. Gradually losing the body functions which ultimately lead to death. In the year 2015, 1.9 million Deaths resulted due to dementia. The most common cause of Alzheimer’s disease is the combination of genetic, environmental factors and lifestyle that affects the brain over time. 5% of the Alzheimer’s disease is caused by specific genetic changes which will develop the disease. Alzheimer's disease is caused by brain cell death. In Alzheimer’s disease the total brain size reduces and the nerve cells, connections progressively decrease in the tissue. The brain affected with Alzheimer’s disease cannot be seen or tested in living conditions but, the small inclusions in the nerve
tissue called plaques and tangles are shown in postmortem/autopsy. With the progress of Alzheimer’s disease to its last stages changes in the brain starts to affect physical functions such as swallowing bowel and bladder control and balance.
... The cholinesterase inhibitors donepezil, galantamine, and rivastigmine can cause side effects, including sometimes severe vomiting; cardiac symptoms, such as arrhythmia and conduction disturbances; bradycardia; collapse; and syncope. In addition, donepezil can cause compulsive sexual behavior [18,19]. Memantine, an NMDA glutamate receptor antagonist, can cause neuropsychiatric symptoms such as hallucinations and confusion, sometimes leading to violent behavior, seizures, psychotic disorders, and heart failure or bradyarrhythmia [20]. ...
In 2017, the Lancet Commission on Dementia Prevention, Intervention, and Care included air pollution in its list of potential risk factors for dementia; in 2018, the Lancet Commission on Pollution concluded that the evidence for a causal relationship between fine particulate matter (PM) and dementia is encouraging. However, few interventions exist to delay or prevent the onset of dementia. Air quality data are becoming increasingly available, and the science underlying the associated health effects is also evolving rapidly. Recent interest in this area has led to the publication of population-based cohort studies, but these studies have used different approaches to identify cases of dementia. The purpose of this article is to review recent evidence describing the association between exposure to air pollution and dementia with special emphasis on fine particulate matter of 2.5 microns or less. We also summarize here the proposed detailed mechanisms by which air pollutants reach the brain and activate the innate immune response. In addition, the article also provides a short overview of existing limitations in the treatment of dementia.
... Rivastigmine provides meaningful management of symptoms, maintains cognitive ability and daily function, and prevents some behavioural problems in AD [428][429][430]. ...
The sigma-1 receptor is a 223 amino acid-long protein with a recently identified structure. The sigma-2 receptor is a genetically unrelated protein with a similarly shaped binding pocket and acts to influence cellular activities similar to the sigma-1 receptor. Both proteins are highly expressed in neuronal tissues. As such, they have become targets for treating neurological diseases, including Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), multiple sclerosis (MS), Rett syndrome (RS), developmental and epileptic encephalopathies (DEE), and motor neuron disease/amyotrophic lateral sclerosis (MND/ALS). In recent years, there have been many pre-clinical and clinical studies of sigma receptor (1 and 2) ligands for treating neurological disease. Drugs such as blarcamesine, dextromethorphan and pridopidine, which have sigma-1 receptor activity as part of their pharmacological profile, are effective in treating multiple aspects of several neurological diseases. Furthermore, several sigma-2 receptor ligands are under investigation, including CT1812, rivastigmine and SAS0132. This review aims to provide a current and up-to-date analysis of the current clinical and pre-clinical data of drugs with sigma receptor activities for treating neurological disease.
... The distance between Trp-84 and Trp-279 is 12 Å. [37][38][39] Galantamine binds at the base of the active site gorge of Tc-AChE; Therefore, it will interact with the acyl-binding pocket and the indole ring of Trp-84 [ Figure 6]. The third group of amine galantamine has no interaction with Trp-84. ...
Genus Galanthus (Amaryllidaceae) is an early spring flowering bulbous plant. Galanthus species contain alkaloids that have shown pharmacological activity. Galanthamine is an alkaloid that was extracted from Galanthus and other Amaryllidaceae. Owing to its acetylcholinesterase (AChE) inhibitory activity, galanthamine is used and marketed to treat Alzheimer's disease (AD). The aim of the present study, while introducing the botanical and pharmacological characteristics and various aspects of the medicinal plant Galanthus, is to emphasize the effect of this plant in the treatment of AD. In this web-based study in 2021, articles indexed in scientific databases in English language, including ISI Web of Knowledge, PubMed, Scopus, MedLib, Medknow, SID, ISC, and also articles and e-books published in Springer, Elsevier, John Wiley and Sons, and Taylor and Francis were evaluated from 1990 to 2021, using the following keywords: "Galanthus" "galanthamine," "Alzheimer's disease." Amaryllidaceae-type alkaloids possess an anticholinesterase activity. The most studied Galanthus alkaloid, galanthamine, is a long-acting, selective, reversible, competitive inhibitor of AChE and an allosteric modulator of the neuronal nicotinic receptor for acetylcholine (ACh). Owing to its AChE inhibitory activity, galanthamine is used to treat certain stages of AD. Galantamine can act as a parasympathomimetic agent, especially as a reversible cholinesterase inhibitor. Galantamine is not structurally associated with other AChE inhibitors. Hence, its proposed mechanism of action involves the reversible inhibition of AChE, preventing hydrolysis of ACh that results in an increased concentration of ACh at cholinergic synapses.
... These drugs elicit improvement in certain cognitive and behavioral symptoms in mild to moderate AD, but do not treat the underlying problem of cholinergic neuronal degeneration or prevent disease progression [197,198]. In addition, they have several drawbacks such as (1) low efficacy, which wanes further as the disease progresses, and (2) severe adverse side effects such as cardiac arrhythmia, nausea, diarrhea, vomiting, and muscle cramps [199][200][201]. ...
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that leads to dementia and patient death. AD is characterized by intracellular neurofibrillary tangles, extracellular amyloid beta (Aβ) plaque deposition, and neurodegeneration. Diverse alterations have been associated with AD progression, including genetic mutations, neuroinflammation, blood–brain barrier (BBB) impairment, mitochondrial dysfunction, oxidative stress, and metal ion imbalance.Additionally, recent studies have shown an association between altered heme metabolism and AD. Unfortunately, decades of research and drug development have not produced any effective treatments for AD. Therefore, understanding the cellular and molecular mechanisms underlying AD pathology and identifying potential therapeutic targets are crucial for AD drug development. This review discusses the most common alterations associated with AD and promising therapeutic targets for AD drug discovery. Furthermore, it highlights the role of heme in AD development and summarizes mathematical models of AD, including a stochastic mathematical model of AD and mathematical models of the effect of Aβ on AD. We also summarize the potential treatment strategies that these models can offer in clinical trials.
... Cholinesterase Inhibitor Prevent the breakdown of ACh and BuCh in the Brain. (Ray et al., 2020;Enz et al., 1998;Corey-Bloom et al., 1998;Winblad et al., 2007) (Cox et al., 2010;Winrow et al., 2011;Qaseem et al., 2016;Brasure et al., 2016;Krystal et al., 2019) adverse events (AEs) were reported. The ECG, physical examination parameters, and C-SSRS evaluations did not show any suicide attempts or behavioral changes (Boinpally et al., 2015). ...
Alzheimer's disease (AD) is a multivariate and diversified disease and affects the most sensitive areas of the brain, the cerebral cortex, and the hippocampus. AD is a progressive age-related neurodegenerative disease most often associated with memory deficits and cognition that get more worsen over time. The central theory on the pathophysiological hallmark features of AD is characterized by the accumulation of amyloid β (Aβ) peptides, also associated with tau proteins (τ) dysfunctioning which leads to distorted microtubular structure, affects the cholinergic system, and mitochondrial biogenesis. This review emphasizes how simple it is to find novel treatments for AD and focuses on several recently developed medications through repurposing that can speed up traditional drug development.
... Tacrine, Donepezil and Rivastigmine, three of the most recent medications, act by increasing the levels of acetylcholine available. Whilst these drugs seem to offer a temporary boost to cognitive function for some, (Knapp, Knopman DS, & Soloman PR 1994), (Rogers et al. 2000), (Corey-Bloom, Anand, & Veach 1998), their cost has led to inconsistencies in prescribing. ...
p>Many people try to present their best side to the pubic world; people with dementia are no exception. Carers may find this infuriating as doctors, nurses or social workers may never see the person’s more ‘difficult’ side.
Researchers, too, may only spend short periods of time observing or questioning people with dementia and their carers. This thesis sets out findings from a different approach to exploring their day-to-day lives. Here the researcher made extended stays of up to three days with people with dementia and their carers and repeated these visits several times over the course of 30 months. Using a case study approach for analysis the researcher looked at psychosocial aspects which may affect the person with dementia’s well-being, in particular interactions with their carer, verifying previous findings reported in the literature. As well as using pre-existing measures for well-being the researcher also employed Dementia Care Mapping, for the first time, in a community setting.
As well as studying interactions, this thesis questions the motivation behind the carer’s style of care. In particular the carer’s perception of what it may be like to have dementia is explored. Here the notion of social health, death of the ‘person’ before biological death, is investigated as a possible causal factor. As previous work on social death was limited a measured was devised by drawing on a thematic analysis of six biographies written by carers of a relative with dementia.
The reader is introduced and immersed in the lives of five couples who have been affected by dementia. Such an emotionally charged subject cannot fail to touch the researcher or reader alike. Reflexivity in research is one way of dealing with this. Throughout the thesis the researcher lays bare her thoughts and feelings and how they affect her research for the reader to make the ultimate decision.</p
... Since the Food and Drug Administration (FDA) approved memantine in 2003, no new drugs for AD treatment entered the market before aducanumab was approved (Figure 1) [14][15][16][17][18][19][20][21][22][23]. Clinically available treatments are mainly designed to attenuate cognitive decline, either with acetylcholinesterase inhibitors such as donepezil, which delays the breakdown of acetylcholine, or N-methyl-d-aspartate receptor antagonists such as memantine, which blocks the receptor's excitotoxic effects. ...
... Cholinesterase (ChE) inhibitors have been major treatment of Alzheimer's disease. Rivastigmine a member of Cholinesterase (ChE) inhibitors family have been shown to be effective in improving cognitive and global functioning in AD patients 9,10,11 . Rivastigmine is a selective, reversible acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitor. ...
Back ground: Treatment compliance in patients with Alzheimer’s disease is particularly important as patients receiving regular treatment have a greater chance of slowing or delaying disease progression. Transdermal delivery has the potential for providing continuous drug delivery and steady plasma levels. Current study aimed to evaluate safety and tolerability of rivastigmine patch, to assess patient compliance and to assess the efficacy of treatment in patients with dementia (with probable Alzheimer’s disease). Methods: A total of 112 dementia patients (with a diagnosis of probable Alzheimer’s disease) from 12 centers were enrolled who were residing with someone in the communities throughout the study. After eligibility, and baseline assessments, patients were entered a 24-week open label treatment phase. All patients were started with application of one 5 cm² patch, followed by an up-titration to the target dose of 10 cm² patch size. Efficacy assessments were performed at weeks 12 and 24 in terms of MMSE and GDS score. Safety was monitored at all assessment points based mainly on the frequency of adverse events. Results: Analysis of baseline and available data until the drop out revealed no significant differentials. Around 95% of the study participants could receive 10 cm² patch size, showing a very high tolerability of the patch. Concurrent medication use also showed significant reduction to 16.3% patient in the end from 25% at baseline. The average MMSE score increased to 19.3 (±3.1) at 12th week and to 20.6(±3.4) at 24th week from 16.8 (±3.2) at baseline. GDS score reduced to 3.7 (±1.4) at 12th week and to 3.2 (±1.3) at 24th week from 4.3 (±1.5) at baseline. Only eight occasions of adverse event was reported (8.2%); no serious adverse event (SAE) were reported. Lost to follow up in the study was 14 (12.5%). Analysis of baseline data shows no significant difference. Their withdrawal seems to be unrelated to the adverse events and treatment outcome. Among the lost to follow up only one 1 (7.1%) had some side effect. Conclusion: Our study supports the pharmacokinetic rationale for the rivastigmine patch, indicating that smooth and continuous delivery of rivastigmine translates into an improved tolerability profile versus conventional oral administration, while maintaining clinical effectiveness. Bangladesh Journal of Neuroscience 2013; Vol. 29 (1) : 5-14
... Features of different disease entities comprising dementia are listed in Table 4. Treatment with rivastigmine for 6 months resulted in significant differences compared with placebo in cognition and on a clinician's global assessment and an activities of daily living scale 22,23,24 . Higher doses (6 to 12 mg per day) yielded better outcomes than lower doses (1 to 4 mg per day), which were no better than placebo in one study. ...
... Oral and patch rivastigmine, were significantly better than placebo in delaying functional impairment based on network meta-analysis (NMA) of 19 trials with 7445 J o u r n a l P r e -p r o o f patients (Mercier, 2007;Corey-Bloom et al., 1998;Rosler et al., 1999). Using imaging techniques such as PET and magnetic resonance imaging (MRI) it was demonstrated that treatment of patients with mild-to-moderate AD with rivastigmine (3, 6, or 9 mg/day) for 6 months, significantly increased brain hippocampal metabolism. ...
Alzheimer's disease (AD), the most common cause of adult-onset dementia is characterized by a progressive decline of cognitive functions accompanied by behavioral manifestations. The main class of drugs currently used for the treatment of AD are acetylcholinesterase/cholinesterase inhibitors (ChE-Is). The first ChE-I licensed for symptomatic treatment of AD was tacrine. The ChE-Is currently available in the market are donepezil, rivastigmine and galantamine as tacrine is no longer in use, due to its hepatotoxicity. According to mechanism of action the ChE-Is are classified as short-acting or reversible agents such as tacrine, donepezil, and galantamine, as intermediate-acting or pseudo-irreversible agent such as rivastigmine. Overall, the efficacy of the three ChE-Is available in the market is similar and the benefit of administration of these compounds is mild and may not be clinically significant. Due to gastrointestinal side effects of these drugs, medicinal chemistry and pharmaceutical delivery studies have investigated solutions to improve the pharmacological activity of these compounds. In spite of the limited activity of ChE-Is, waiting for more effective approaches, these drugs still represent a pharmacotherapeutic resource for the treatment of AD. Other approaches in which ChE-Is were investigated is in their use in combination with other classes of drugs such as cholinergic precursors, N-methyl-d-aspartate (NMDA) receptor antagonists and antioxidant agents. After many years from the introduction in therapy of ChE-Is, the combination with other classes of drugs may represent the chance for a renewed interest of ChE-Is in the treatment of adult-onset dementia disorders.
... 23 In our patient, oxcarbazepine was chosen for this reason, but also given the lack of previous response to other mood stabilizers and the sedating effect of this drug. Rivastigmine is a cholinesterase inhibitor widely employed in the treatment of mild to moderate AD and PD, 7,8,24,25 with a good efficacy in psychiatric symptoms frequently co-occurring in these neurological disorders. 26 In addition, scattered data would also suggest its possible use in visual hallucinations of schizophrenic patients. ...
This paper reports the case of a 46‐year‐old woman suffering from bipolar disorder of type I with mixed features with initial fronto‐temporal atrophy. Although considered treatment‐resistant to conventional strategies, she successfully responded to a combination of rivastigmine, clozapine, and oxcarbazepine. This paper reports the case of a 46‐year‐old woman suffering from bipolar disorder of type I with mixed features with initial fronto‐temporal atrophy. Although considered treatment‐resistant to conventional strategies, she successfully responded to a combination of rivastigmine, clozapine, and oxcarbazepine.
... Over the past years, efforts have been done in order to allow for an efficient AD treatment, e.g., with the development of cholinesterase inhibitors, choline precursors, among others [62]. Experimental investigations have shown significant symptomatic benefits through the administration of the cholinesterase inhibitors, bringing about improvements in cognitive, functional and behavioral symptoms in AD [63][64][65][66]. ...
Alzheimer’s disease (AD) is a neurodegenerative disease that is usually accompanied by aging, increasingly being the most common cause of dementia in the elderly. This disorder is characterized by the accumulation of beta amyloid plaques (Aβ) resulting from impaired amyloid precursor protein (APP) metabolism, together with the formation of neurofibrillary tangles and tau protein hyperphosphorylation. The exacerbated production of reactive oxygen species (ROS) triggers the process called oxidative stress, which increases neuronal cell abnormalities, most often followed by apoptosis, leading to cognitive dysfunction and dementia. In this context, the development of new therapies for the AD treatment is necessary. Antioxidants, for instance, are promising species for prevention and treatment because they are capable of disrupting the radical chain reaction, reducing the production of ROS. These species have also proven to be adjunctive to conventional treatments making them more effective. In this sense, several recently published works have focused their attention on oxidative stress and antioxidant species. Therefore, this review seeks to show the most relevant findings of these studies.
... This means that it is unlikely to interact with other drugs, a key consideration given that elderly patients may take several drugs for various purposes 81 . In two studies which were performed on mild to moderate AD patients, 6-12 mg/day dosing of rivastigmine for 26 weeks improved the cognitive functions in a dose-related fashion 58,82,83 . It is currently available in the market under different names and in the form of oral capsule, oral solution, and transdermal patch at different doses 84 . ...
Alzheimer’s Disease (AD) is one of the most challenging diseases faced by humankind. AD is still not classified as curable because of the complex structure of pathologies underlying it. As the mean life expectancy of the world population constantly increases, the prevalence of AD and treatment costs for AD also grow rapidly. Current state of the art for AD treatment mainly consists of palliative therapy aimed at providing symptomatic relief and improving the standard of living in patients with AD. However, different research groups are working on more effective and safe drug delivery options aimed at both symptomatic relief and treatment of the underlying mechanisms. In this review, the current prevalence of AD, health costs, pathologies, and available treatment options including the ones in the market and/or under trial have been reviewed. Data in the existing literature have been presented, and future opportunities have been discussed. It is our belief that these nanotechnological products provide the required efficacy and safety profiles to enable these formulations go through phase studies and enter the market after regulatory authority approval, as with cancer. Last, but not the least the metabolomic studies will be providing useful informative data on the early diagnosis of AD, thus may be clinical implications might be delayed with the administration of therapeutic agents at the initial state of the disease.
... It is also important to highlight that clinical investigations demonstrated that the employment of precursors for the presynaptic releasing agent and muscarinic agonists did not present any efficacy due to the lack of efficiency and unacceptable side effects [118][119][120]. On the other hand, other works have described important and beneficial outcomes of cholinesterase inhibitors in relation to cognitive, functional, and behavioral symptoms in AD [121][122][123][124]. ...
Introduction: Alzheimer’s disease (AD) is the most common cause of dementia. Clinical progress in this pathogenesis field has drawn the attention of researchers, stimulating the investigation of novel treatment methods. Current therapies that deal with cholinesterase inhibitors and/or NMDA antagonists have shown a modest symptomatic potential, increasing the need for research into more efficient therapeutics. The goal of this review is to summarize the advances in, and the potential of, non-conventional therapies in AD treatment.
Areas covered: In this review, the authors describe the current status of unusual therapies in AD treatment, evaluating the modern scientific contexts in which these therapies have been developed. The authors also highlight the usage of methylene blue, natural products, organophosphorus compounds and Chinese medicine, along with the employment of nanotechnology.
Expert opinion: The potential therapies discussed in this review will play increasingly important roles in the prevention and treatment of AD, improving disease management and quality of life for AD patients. Given the annual increasing number of people with dementia, it is crucial to invest in the search for novel therapeutics. In addition, more sophisticated diagnosis techniques are also essential, to allow for an early diagnosis and treatment.
... Elle est connue par une bonne sélectivité pour le cholinestérase cérébral ainsi que son métabolisme indépendant du système enzymatique hépatique permettent une action ciblée(Polinsky, 1998). Quelques effets secondaires ont été enregistrés tels que les nausées et les vomissements(Corey-Bloom et al., 1998) (Figure 84).3 ème Partie: Résultats et discussions ...
Ce travail de recherche est centré sur la valorisation de deux Euphorbiacées : Ricinus communis et Jatropha curcas. La première est une espèce autochtone connue comme plante dont l’huile des graines est utilisée pour ses vertus cosmétiques quant à la deuxième, c’est une espèce allochtone récemment introduite à titre expérimental en Tunisie et connue comme plante bioénergetique. Pour le ricin huit populations Tunisiennes ont été étudiées: Riadh Andalous, Nefza, Béja, Nabeul, Hammamet, Bouficha, Khanguet Hajej et Aouled Amer. Quant au jatropha, le matériel végétal est récolté dans la station expérimentale de Nabeul (Tunisie). Il s’agit de huit populations qui proviennent d’Arusha en Tanzanie, de Mozambique, de Suriname et de Brésil à partir de cinq provenances à savoir : Paranà, Norte de Minas, Mato Grosso, Regiao sudeste et Vale do Jequitinhonha. Le travail comprend une première partie consacrée à une étude bibliographique. Une deuxième partie est consacrée aux matériels et méthodes utilisés et une dernière partie qui montre l’ensemble des résultats obtenues. Ainsi, les résultats montrent que les extraits des feuilles des populations des deux espèces étudiées sont plus riches en composés phénoliques que les extraits des racines. L’étude phytochimique a montré que le ricin contient surtout de l’acide gentisique. Quant au jatropha, il contient surtout de l’épicatechine et de la naringine. L’étude chimique des huiles fixes des deux espèces montrent que l’huile de ricin renferme essentiellement d’acide ricinoléique. Quant à l’huile de jatropha, elle contient deux acides gras en proportions majeures qui sont l’acide oléique et l’acide linoléique. L’évaluation des activités anti-oxydantes des extraits des deux espèces indique une corrélation positive entre ces activités et les teneurs en composés phénoliques. Par ailleurs, l’étude de l’activité anti-acétylcholinestérase des extraits testés montrent que ces extraits sont des inhibiteurs de l’AChE plus puissants que la galanthamine utilisée comme contrôle positif. Notre étude a confirmé que les différents extraits de ricin et de jatropha, autres que les huiles fixes, peuvent donc être exploités pour d’autres activités biologiques, parmi les quelles l’action inhibitrice de l’AChE une des principales cibles des traitements contre la maladie l’Alzheimer et le piégeage des radicaux libres, en raison de leur richesse en composés phénoliques
... Hoy se acepta que mejorar la neurotransmisión colinérgica es invertir en memoria [24]. De hecho, los inhibidores de la acetilcolinesterasa donepecilo [25], rivastigmina [26] y galantamina [27], que ya están en la clínica, han demostrado mejorar la memoria y retrasar el DC en pacientes con EA, lo que se apoya en ese deterioro de la neurona colinérgica como dato neuroquímico causal del DC [28]. El antagonista no competitivo del receptor glutamatérgico NMDA (N-metil-D-aspartato) memantina, demuestra también eficacia para mejorar el DC del paciente demenciado [29]. ...
... Large-scale, doubleblind, placebo-controlled trials have shown greater efficacy of rivastigmine over placebo. 11 Donepezil is a piperidine essentially metabolized by the liver, with a long half-life of around 70 hours, allowing administration in a single night-time dose. Large-scale, double-blind, placebo-controlled trials have shown greater efficacy of donepezil compared to placebo. ...
This article reports the recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the treatment of Alzheimer's disease (AD) in Brazil, with special focus on cognitive disorders. It constitutes a revision and broadening of the 2005 guidelines based on a consensus involving researchers (physicians and non-physicians) in the field. The authors carried out a search of articles published since 2005 on the MEDLINE, LILACS and Cochrane Library databases. The search criteria were pharmacological and non-pharmacological treatment of cognitive disorders in AD. Studies retrieved were categorized into four classes, and evidence into four levels, based on the 2008 recommendations of the American Academy of Neurology. The recommendations on therapy are pertinent to the dementia phase of AD. Recommendations are proposed for the treatment of cognitive disorders encompassing both pharmacological (including acetyl-cholinesterase inhibitors, memantine and other drugs and substances) and non-pharmacological (including cognitive rehabilitation, physical activity, occupational therapy, and music therapy) approaches. Recommendations for the treatment of behavioral and psychological symptoms of dementia due to Alzheimer's disease are included in a separate article of this edition. Tratamento da doença de Alzheimer no Brasil: I. Dos transtornos cognitivos Resumo-Esse texto apresenta as recomendações da Academia Brasileira de Neurologia, por intermédio do seu Departamento Científico de Neurologia Cognitiva e do Envelhecimento, para o tratamento da doença de Alzheimer (DA) no Brasil, enfocando os transtornos cognitivos. Trata-se de uma revisão ampliada das diretrizes publicadas em 2005, resultada de um consenso envolvendo pesquisadores da área, médicos e não médicos. Os autores realizaram uma busca de artigos publicados a partir de 2005 nas bases MEDLINE, LILACS e Cochrane Library. A busca foi direcionada para tratamento farmacológico e não farmacológico dos transtornos cognitivos da DA. Os estudos foram categorizados em quatro classes e as evidências em quatro níveis, com base nas recomendações da Academia Americana de Neurologia publicadas em 2008. As recomendações terapêuticas referem-se à fase demencial da DA. Apresentam-se recomendações para o tratamento dos transtornos cognitivos, tanto farmacológico (incluindo inibidores da acetilcolinesterase, memantina e outros fármacos e substâncias), como não farmacológico (incluindo reabilitação cognitiva, atividade física, terapia ocupacional e musicoterapia). As recomendações para o tratamento dos sintomas comportamentais e psicológicos da demência da DA são apresentadas em outro artigo desse fascículo. Palavras-chave: doença de Alzheimer, demência, transtornos cognitivos, tratamento.
... Large-scale, doubleblind, placebo-controlled trials have shown greater efficacy of rivastigmine over placebo. 11 Donepezil is a piperidine essentially metabolized by the liver, with a long half-life of around 70 hours, allowing administration in a single night-time dose. Large-scale, double-blind, placebo-controlled trials have shown greater efficacy of donepezil compared to placebo. ...
This article reports the recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the treatment of Alzheimer's disease (AD) in Brazil, with special focus on cognitive disorders. It constitutes a revision and broadening of the 2005 guidelines based on a consensus involving researchers (physicians and non-physicians) in the field. The authors carried out a search of articles published since 2005 on the MEDLINE, LILACS and Cochrane Library databases. The search criteria were pharmacological and non-pharmacological treatment of cognitive disorders in AD. Studies retrieved were categorized into four classes, and evidence into four levels, based on the 2008 recommendations of the American Academy of Neurology. The recommendations on therapy are pertinent to the dementia phase of AD. Recommendations are proposed for the treatment of cognitive disorders encompassing both pharmacological (including acetyl-cholinesterase inhibitors, memantine and other drugs and substances) and non-pharmacological (including cognitive rehabilitation, physical activity, occupational therapy, and music therapy) approaches. Recommendations for the treatment of behavioral and psychological symptoms of dementia due to Alzheimer's disease are included in a separate article of this edition. Tratamento da doença de Alzheimer no Brasil: I. Dos transtornos cognitivos Resumo-Esse texto apresenta as recomendações da Academia Brasileira de Neurologia, por intermédio do seu Departamento Científico de Neurologia Cognitiva e do Envelhecimento, para o tratamento da doença de Alzheimer (DA) no Brasil, enfocando os transtornos cognitivos. Trata-se de uma revisão ampliada das diretrizes publicadas em 2005, resultada de um consenso envolvendo pesquisadores da área, médicos e não médicos. Os autores realizaram uma busca de artigos publicados a partir de 2005 nas bases MEDLINE, LILACS e Cochrane Library. A busca foi direcionada para tratamento farmacológico e não farmacológico dos transtornos cognitivos da DA. Os estudos foram categorizados em quatro classes e as evidências em quatro níveis, com base nas recomendações da Academia Americana de Neurologia publicadas em 2008. As recomendações terapêuticas referem-se à fase demencial da DA. Apresentam-se recomendações para o tratamento dos transtornos cognitivos, tanto farmacológico (incluindo inibidores da acetilcolinesterase, memantina e outros fármacos e substâncias), como não farmacológico (incluindo reabilitação cognitiva, atividade física, terapia ocupacional e musicoterapia). As recomendações para o tratamento dos sintomas comportamentais e psicológicos da demência da DA são apresentadas em outro artigo desse fascículo. Palavras-chave: doença de Alzheimer, demência, transtornos cognitivos, tratamento.
... The GDS is one of the most commonly used global assessment scales for measuring patients' severity. It has been found to be advantageous to overall subject assessment in terms of utility in incipient and severe AD, reliability, sensitivity to AD course [2], and response to cognitive enhancers (e.g., rivastigmine [20]). Furthermore, as with other global assessment scales, it has been considered to be less influenced by demographic, cultural, and linguistic factors, patients' occupation, and personal background and practice effects [2]. ...
Background
Informant-based rating scales are widely used in dementia but patients' and caregivers' features influence the final scoring. We aimed to evaluate the role of patient- and caregiver-related factors in a caregiver rated Global Deterioration Scale (GDS) score in a sample of Greek patients with dementia.
Methods
We included 194 patients with dementia and 194 caregivers/family relatives; Mini-Mental State Examination (MMSE); Neuropsychiatric Inventory (NPI); Katz Index of Activities of Daily Living (K-IADL) were administered to (a) patients and Center for Epidemiologic Studies-Depression (CES-D) Scale; Zarit Burden Interview (ZBI) to (b) caregivers. Participants' demographics and patients' and caregivers' characteristics were entered into a 3-block regression analysis.
Results
The final model explained 55% of the total variance of the caregiver assessed GDS score. The following variables significantly contributed to the final model: MMSE (β=-0.524); K-IADL (β=-0.264); ZBI (β=0.145).
Conclusion
We herein confirm the contribution of patients' cognitive and functional status and caregivers' burden in caregiver rated GDS scoring irrespective of demographic-related characteristics.
Dementia is a major public health concern due to its increasing prevalence, substantial caregiver burden, and high financial costs. Currently, the anti-dementia drugs aim only at a symptomatic effect. The subject of prescribing these drugs in advanced stages is a matter of considerable debate, with different countries making distinct recommendations. In this review article, we analyzed the evidence regarding cognitive and functional outcomes, adverse events, health-related costs, and caregiver burden in patients with advanced Alzheimer disease (AD) and mixed dementia. We included 35 studies. Most studies are heterogeneous, focus exclusively on AD, and show small benefits in terms of cognitive and functional scales. The overall evidence seems to suggest a benefit in introducing or maintaining anti-dementia drugs in patients with advanced dementia, but clinical meaningfulness is difficult to ascertain. The issue of costs and caregiver burden is significantly underexplored in this field but also seems to favor treatment continuation, despite a reduced overall effect. The decision of introducing or withdrawing anti-dementia drugs in advanced stages of dementia should be individualized. Future studies with homogeneous designs and outcomes are warranted.
Neurodegenerative diseases and Alzheimer’s disease (AD), as one of the most common causes of dementia, result in progressive losses of cholinergic neurons and a reduction in the presynaptic markers of the cholinergic system. These consequences can be compensated by the inhibition of acetylcholinesterase (AChE) followed by a decrease in the rate of acetylcholine hydrolysis. For this reason, anticholinesterase drugs with reversible inhibition effects are applied for the administration of neurodegenerative diseases. Their overdosage, variation in efficiency and recommendation of an individual daily dose require simple and reliable measurement devices capable of the assessment of the drug concentration in biological fluids and medications. In this review, the performance of electrochemical biosensors utilizing immobilized cholinesterases is considered to show their advantages and drawbacks in the determination of anticholinesterase drugs. In addition, common drugs applied in treating neurodegenerative diseases are briefly characterized. The immobilization of enzymes, nature of the signal recorded and its dependence on the transducer modification are considered and the analytical characteristics of appropriate biosensors are summarized for donepezil, huperzine A, rivastigmine, eserine and galantamine as common anti-dementia drugs. Finally, the prospects for the application of AChE-based biosensors in clinical practice are discussed.
Dementias are among the most prevalent neurological and psychiatric diagnoses. Alzheimer’s disease is the most frequent subtype, followed by vascular dementia, mixed dementia (a combination of degenerative and vascular dementia), dementia associated with Parkinson’s disease/dementia with Lewy bodies, frontotemporal dementia, and other rare dementias. Until recently, only symptomatic pharmacologic therapies have been available in Alzheimer’s disease, vascular dementia, Parkinson dementia, and dementia with Lewy bodies. The therapeutic concept is to counteract the progressive decline of cortical and hippocampal cholinergic neurotransmission in Alzheimer‘s disease, Parkinson’s disease, and vascular dementia using cholinesterase inhibitors (donepezil, galantamine, rivastigmine), and to reduce neurodegeneration-related prolonged NMDA-receptor stimulation using a NMDA-receptor antagonist (memantine). The therapeutic effects on cognition, global functioning, activities of daily living, and neuropsychiatric symptoms are mild to moderate. After a maximum of 1 year, most outcome parameter scores return to baseline but remain above the level of persons without anti-dementive medication. Frontotemporal dementia is a major therapeutic challenge. Frontal lobe-type cognitive deficits do not respond to cholinesterase inhibitors or memantine and evidence of effects of neuroleptics, antidepressants, or sedatives on neuropsychiatric symptoms is sparse. There is hope for causal therapeutic improvements of clinical parameters, mainly cognition, using monoclonal antibodies and small molecules against Aß and hyperphosphorylated Tau. Aducanumab, a monoclonal antibody to Aß, is the first drug which has recently been licensed for treatment of patients with early Alzheimer’s disease.
In Alzheimer's disease, cognition now responds to several drugs. Anticholinesterases target the acetylcholine deficit. In mild-to-moderate Alzheimer's disease, they all provide significant benefit versus placebo on the Alzheimer's Disease Assessment ScheduleCognitive Section (ADAS-Cog), Side effects, in 5% to 15% of cases, include nausea, vomiting, diarrhea, anorexia, and dizziness. Tacrine, the leading anticholinesterase, caused frequent hepatic enzyme elevation and was withdrawn; once-daily donepezil spares the liver and improves global measures of change in severe dementia; rivasiigmine is indicated in comorbid vascular disease; while galaniamine modulates the cerebral nicotinic acetylcholine receptors that potentiate the response to acetylcholine. Alternative agents include the N-methyl-D-aspartate (NMDA) receptor antagonist, memaniine, licensed in Europe for moderately severe to severe Alzheimer's disease; it acts on a different neurotransmitter system present in 70% of neurons, protecting against pathologic glutamergic activation while preserving or even restoring physiologic glutamergic activation. The clinician's armamentarium in AD has never been greater.
The main focus of this section is to review the available information on ChEs (ChEs) and their inhibitors. The ChE enzymes cause damage to the cholinergic system by hydrolyzing the neurotransmitter acetylcholine (ACh). ChE inhibitors, playing an important role in the cholinergic system, are used in the treatment of Alzheimer’s disease (AD) because of their effects on maintaining ACh levels in brain regions and preventing Aβ accumulation by inhibiting ChE. In this context, it is important to develop many synthetic and natural origin ChE inhibitors for the treatment of abnormalities in the cholinergic system and disorders with neuropsychiatric symptoms. In this section, firstly, general information about ACh and its synthesis in the cholinergic system is given, then ChEs and their catalytic properties, their roles in AD, and their molecular forms are explained. In the following section, the active site of Cantis was defined. The anti-ChE activity of the developed inhibitors was discussed, and then the mechanism of their binding to the ChE active site was explained by molecular docking. In the final section, many types of ChE inhibitors are described and discussed in detail in this section, and the properties and binding mechanism of these inhibitors are summarized.
Alzheimer’s disease (AD) is one of the most devastating neurological disorders causing memory loss and impairment of cognitive functions. It is distinguished by the presence of extracellular amyloid beta peptides, intracellular neurofibrillary tangles, and substantial loss in the cortex and hippocampus region of the brain. AD is incurable and has significant social and economic impacts. The disease, therefore, essentially requires successful diagnostics and effective therapeutic approaches. It has been demonstrated that conventional approaches often fail to achieve excellent pharmacokinetic and pharmacodynamic properties at the target site and thus produce low therapeutic efficacy and high toxicity. Recent advances in the pharmaceutical domain have shown the development of nano-systems to overcome the limitations associated with conventional therapy. In addition, emergence of nanotechnology serves as a potential tool in understanding complex mechanisms as well as treatment strategies of AD. These nanosystems are site-specific and offer desired pharmacokinetic properties such as solubility, bioavailability, absorption, permeability across the blood-brain barrier, and better therapeutic effects. Nowadays, a plethora of nano-carriers including solid lipid carriers, liposomes, emulsions, and carbon nanotubes have been designed to attain greater therapeutic effect in AD. Furthermore, nanotechnology also contributes to the early diagnosis of AD. The current chapter encompasses latest developments in nanotechnology-based diagnosis and therapeutic strategies for AD.
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with neuronal loss in the hippocampus. Our aim was to evaluate the effects of Iranian thyme honey (single dose: 2gr/kg) vs rivastigmine (0.3mg/kg) in vivo on spatial memory and in vitro on important parameters of oxidative stress as well as quantitative and qualitative studies of hippocampal neurons of AD rat models with this design that 30 days after oral administration of 17mg/kg AlCl3, 20 AD rats were received that underwent a 6-weeks therapeutic period and another 20 rats underwent a 6-weeks preventive period and also 20 rats were as controls. Y-Maze test was performed to show memory deficiency as well as TBARS and FRAP assays to measure malondialdehyde (MDA) and total antioxidant, respectively. In addition, H&E staining was also done for cell counting and morphological changes. We observed that AD rats with hippocampal damage had more significant errors during the Y-maze test than the control and other rats. Likewise, MDA and neurodegeneration increased in the AD group while in all preventive and therapeutic group's especially Iranian thyme honey, they decreased and conversely, total antioxidant and number of normal cells elevated and healthy neurons were observed in all parts of the hippocampus and cortex. Our results despite the limitations showed the powerful antioxidant properties and cytoprotective effects of Iranian thyme honey vs rivastigmine on hippocampal neurons that consequently enhanced memory and if advanced diagnostic tests in human clinical patients show other more pronounced effects, we have certainly started a key and targeted strategy.
We evaluated the potential of nine vitamin B3 scaffold-based derivatives as acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors, as a starting point for the development of novel drugs for treating disorders with cholinergic neurotransmission-linked pathology. As the results indicate, all compounds reversibly inhibited both enzymes in the micromolar range pointing to the preference of AChE over BChE for binding the tested derivatives. Molecular docking studies revealed the importance of interactions with AChE active site residues Tyr337 and Tyr124, which dictated most of the observed differences. The most potent inhibitor of both enzymes with K i of 4 µM for AChE and 8 µM for BChE was the nicotinamide derivative 1-(4-phenylphenacyl)-3-carbamoylpyridinium bromide. Such a result places it within the range of several currently studied novel cholinesterase inhibitors. Cytotoxicity profiling did not classify this compound as highly toxic, but the induced effects on cells should not be neglected in any future detailed studies and when considering this scaffold for drug development.
Drugs for Alzheimer’s disease.
Importance
Early identification of cognitive impairment may improve patient and caregiver health outcomes.
Objective
To systematically review the test accuracy of cognitive screening instruments and benefits and harms of interventions to treat cognitive impairment in older adults (≥65 years) to inform the US Preventive Services Task Force.
Data Sources
MEDLINE, PubMed, PsycINFO, and Cochrane Central Register of Controlled Trials through January 2019, with literature surveillance through November 22, 2019.
Study Selection
Fair- to good-quality English-language studies of cognitive impairment screening instruments, and pharmacologic and nonpharmacologic treatments aimed at persons with mild cognitive impairment (MCI), mild to moderate dementia, or their caregivers.
Data Extraction and Synthesis
Independent critical appraisal and data abstraction; random-effects meta-analyses and qualitative synthesis.
Main Outcomes and Measures
Sensitivity, specificity; patient, caregiver, and clinician decision-making; patient function, quality of life, and neuropsychiatric symptoms; caregiver burden and well-being.
Results
The review included 287 studies with more than 280 000 older adults. One randomized clinical trial (RCT) (n = 4005) examined the direct effect of screening for cognitive impairment on patient outcomes, including potential harms, finding no significant differences in health-related quality of life at 12 months (effect size, 0.009 [95% CI, –0.063 to 0.080]). Fifty-nine studies (n = 38 531) addressed the accuracy of 49 screening instruments to detect cognitive impairment. The Mini-Mental State Examination was the most-studied instrument, with a pooled sensitivity of 0.89 (95% CI, 0.85 to 0.92) and specificity of 0.89 (95% CI, 0.85 to 0.93) to detect dementia using a cutoff of 23 or less or 24 or less (15 studies, n = 12 796). Two hundred twenty-four RCTs and 3 observational studies including more than 240 000 patients or caregivers addressed the treatment of MCI or mild to moderate dementia. None of the treatment trials were linked with a screening program; in all cases, participants were persons with known cognitive impairment. Medications approved to treat Alzheimer disease (donepezil, galantamine, rivastigmine, and memantine) improved scores on the ADAS-Cog 11 by 1 to 2.5 points over 3 months to 3 years. Psychoeducation interventions for caregivers resulted in a small benefit for caregiver burden (standardized mean difference, –0.24 [95% CI, –0.36 to –0.13) over 3 to 12 months. Intervention benefits were small and of uncertain clinical importance.
Conclusions and Relevance
Screening instruments can adequately detect cognitive impairment. There is no empirical evidence, however, that screening for cognitive impairment improves patient or caregiver outcomes or causes harm. It remains unclear whether interventions for patients or caregivers provide clinically important benefits for older adults with earlier detected cognitive impairment or their caregivers.
In our study, Allium nigrum L. and Allium subhirsutum L. were investigated in terms of phenolic profile, acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and tyrosinase inhibitory potentials. The colorimetric analysis revealed that the highest levels of total phenol (45.6, 15.8 mg GAE/g extract, respectively) and total flavonoid contents (8.2, 5.7 mg QE/g extract, respectively) were found in the bulbs of both plants. About 30 compounds were determined by LC‐ESI‐MS/MS with validated method and 3‐hydroxybenzoic acid (2,188.4 μg/g extract) and p‐coumaric acid (1,700.8 μg/g extract) were major phenolic acids. (−)‐Epigallocatechin gallate (998.3 µg/g extract) and genistein (159.3 μg/g extract) which are neuroprotective compounds were the predominant flavonoids for A. nigrum and A. subhirsutum, respectively. Enzyme inhibitory activities of samples were performed by spectrophotometrically with 96‐well microplate reader. All samples showed anti‐AChE, anti‐BuChE, and anti‐tyrosinase activities and the aerial part of A. nigrum was the most potent (IC50 6.1, 3.27, 22.31 µg/ml, respectively).
Practical applications
Many Allium species, especially those cultivated, are consumed in different countries as food in different ways. In the literature, studies on these species have generally focused on organosulfur compounds of the species. In our present study, phenolic compounds having a wide range of biological activities were determined in different parts of the two Allium species consumed as food. We also investigated in vitro cholinesterases and tyrosinase inhibition activities of these species. A correlation was observed between phenolic compounds and enzyme inhibition activities. These results were further explored and confirmed by principal component analysis (PCA). PCA revealed that samples were discriminated from each other according to phenolic compounds and enzyme inhibitory potencies. Conclusively, this study determines that the chemical profiles and biological activities of A. nigrum and A. subhirsutum.
Aims: To facilitate regulatory learning, we evaluated similarities and differences in evidence requirements between regulatory and health technology assessment (HTA) bodies of Alzheimer's disease (AD) approved products.
Methods: The European marketing authorisation application dossiers and European public assessment reports (EPARs) of the licensed AD drugs were screened to identify the phase III randomised controlled trials (RCTs) and outcomes used. We also screened the assessment reports of the National Institute of Health and Care Excellence (NICE, England) and the National Health Care Institute (ZiN, the Netherlands) to identify the studies and outcomes used in HTA assessments.
Results: The application dossiers of donepezil, galantamine, rivastigmine, and memantine contained 16 phase III RCTs in total. These trials were also included in HTA assessments except that NICE excluded studies that were not published (n = 2) or trials that included patients with other types of dementia (n = 3). In the regulatory assessments the focus was on cognitive and global outcomes, and to some extent on function. In the HTA assessments of clinical effectiveness other domains were also covered including: function, behaviour and mood, and, occasionally, quality of life. In the economic analyses of NICE the domains cognition, function, and quality of life were included.
Conclusion: There was a large overlap in inclusion of trials in regulatory and HTA assessments, although the focus on specific outcomes slightly differed. Understanding the methods and perceptions of both authorities can stimulate regulatory and HTA cross-talk and further alignment, and therefore more rapid patient access to new treatments.
Background
Cholinesterase inhibitors (ChEIs) and memantine have been reported to provide modest benefits for cognition and aspects of functioning in Alzheimer’s disease (AD). Ginkgo biloba extract (EGb761), a phytomedicine, is widely used and expected to be well-tolerated. A few trials have compared EGb761 with ChEIs, and the results were inconclusive.
Objective
A network meta-analysis was conducted to evaluate the therapeutic benefits and tolerability of EGb761, three ChEIs (donepezil, galantamine, and rivastigmine), and memantine in mild-to-moderate AD patients.
Methods
Electronic databases were searched through 30 June 2017. We included randomized double-blinded trials with a minimum treatment duration of 22 weeks for EGb761 240 mg/day and 12 weeks for ChEIs or memantine. The study patients included AD or probable AD patients without other types of dementia or neurological disorders. Cognition, function, and behavior symptoms were compared between treatments using the standardized mean difference (SMD). Clinical global impression, treatment discontinuation, and adverse events were compared between treatments using the relative risk (RR). Statistical pooling of the individual trial results was conducted using a frequentist approach. The probability of being the best for a treatment was estimated using surface under the cumulative ranking.
Results
EGb761 and memantine showed no therapeutic benefits in all study outcomes. For cognition, all ChEIs were significantly better than placebo (SMD from − 0.52 to − 0.26), and galantamine was better than rivastigmine in the oral and patch forms, EGb761, and memantine (SMD [95% confidence interval (CI)]: − 0.22 [− 0.40 to − 0.05]; − 0.26 [− 0.45 to − 0.07]; − 0.34 [− 0.56 to − 0.12]; and − 0.42 [− 0.71 to − 0.13], respectively). Compared to placebo, galantamine, the rivastigmine patch, and oral rivastigmine provided modest functional benefits (SMD, from 0.21 to 0.24), and galantamine provided behavioral benefits (SMD [95% CI]: − 0.15 [− 0.26 to − 0.04]). All ChEIs provided a better improvement in clinical global impression than placebo (RR from 1.20 to 1.69). The global impression ratings were more improved with donepezil than with galantamine (RR [95% CI]: 1.40 [1.09–1.80]) or with EGb761 (RR [95% CI]: 1.40 [1.06–1.85]), with a 96% probability of donepezil being more effective than the other study agents. Rivastigmine in oral and patch forms, galantamine, and donepezil had a higher risk of being discontinued than placebo (RR [95% CI]: 2.14 [1.49–3.06]; 2.04 [1.30–3.20]; 1.79 [1.28–2.49]; 1.49 [1.03–2.17], respectively). Discontinuation of EGb761 was not statistically lower than that of the ChEIs, in which donepezil had the lowest probability (38%) of being discontinued.
Conclusion
EGb761 and memantine showed no treatment benefits compared to placebo and ChEIs. Galantamine provided the highest beneficial effect on cognition and behavioral symptoms. Donepezil provided a better clinical global impression and tolerability than the other ChEIs and EGb761, with a similar benefit for cognition as galantamine.
Alzheimer's Disease (AD), affecting a large population worldwide is characterized by the loss of memory and learning ability in the old population. The enzyme Acetylcholinesterase Enzyme (AChE) is the key enzyme in the hydrolysis of the neurotransmitter acetylcholine and is also the target of most of the clinically used drugs for the treatment of AD but these drugs provide only symptomatic treatment and have the limitation of loss of therapeutic efficacy with time. The development of different strategies targeting the AChE enzyme along with other targets like Butyl Cholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals antioxidant properties and free radical scavenging capacity has been focused in recent years. Literature search was conducted for the molecules and their rational design which have shown inhibition for AChE and the other abovementioned targets. Several hybrid molecules incorporating the main sub-structures derived from diverse chemotypes like acridine, quinoline, carbamates, and other heterocyclic analogs have shown desired pharmacological activity with a good profile in a single molecule. It is followed by optimization of the activity through structural modifications guided by structure-activity relationship studies. It has led to the discovery of novel molecules 17b, 20, and 23 with desired AChE inhibition along with desirable activity against other abovementioned targets for further pre-clinical studies.
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