Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent health technology assessments have given us the go-ahead to use cholinesterase inhibitors, which, in combination with community services, are currently the most appropriate treatment for patients with Alzheimer's disease (AD). Initial research focused upon acetylcholinesterase (AChE)-selective agents, but it is now thought that dual inhibitors of AChE and butyrylcholinesterase (BuChE) may provide more sustained efficacy over the course of AD and may help to slow disease progression. Rivastigmine is a potent inhibitor of AChE and BuChE and has demonstrated broad benefits across the severity of AD and across the cognitive, functional and behavioural domains of AD. In addition, rivastigmine has shown cognitive and behavioural benefits in patients with dementia with the Lewy body variant of AD. These benefits may reflect the inhibition of both AChE and BuChE, as demonstrated by significant correlations between cognitive improvements and cholinesterase inhibition in rivastigmine-treated patients with AD. Rivastigmine shows a clear dose-response relationship, and physicians should aim to maintain patients on doses of 6 mg/day or higher, to a maximum of 12 mg/day. As with all cholinesterase inhibitors, rapid forced dose escalation may increase the incidence of typical cholinergic side-effects, resulting in lower maintenance doses. In a chronic disease such as AD, there is time to implement slow dose escalation and higher final maintenance doses. If used appropriately, the benefits of rivastigmine seen in clinical practice may prove to be even greater than those reported in clinical trials.
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PMID:The clinical benefits of rivastigmine may reflect its dual inhibitory mode of action: an hypothesis. 1201 28

Alzheimer's disease (AD) represents a major challenge to healthcare costs and to academic and pharmaceutical research efforts. The approval in 1996 of the first of the second generation acetylcholinesterase inhibitors, donepexil (Aricept, Eisai/Pfizer), has offered new hope, albeit palliative, to AD sufferers and care givers. Research has continued on the genetics of AD with the identification of the autosomal dominant inheritance of genetic defects in one of three distinct genes coding for the presensilins 1 and 2 and amyloid precursor protein (APP). While driving an ever increasing research effort related to the production, deposition and clearance of Abeta peptides, these mutations account for less than 10% of the AD cases reported, indicating that other causative factors, both genetic and environmental, may contribute to the pathophysiology of AD unrelated to familial cohorts. A newly developed transgenic mouse model and a broader appreciation of the multifactorial nature of this complex, chronic disease state may help provide a more objective approach to understanding the disease per se as opposed to amyloid neurotoxicity specifically which may or may not be causative.
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PMID:Alzheimer's disease and related dementias: prospects for treatment. 1598 38

Approximately half of all patients with multiple sclerosis (MS) experience cognitive impairment, most commonly with regard to new learning and memory. Cognitive dysfunction is a leading cause of disability in MS and it can have profound social and economic consequences for patients and their families. Research on treatment for cognitive impairment in MS is still in the early stages, as it is for most neurological conditions. The available disease-modifying therapies in MS may provide some modest benefit to cognition, but patients with MS clearly need better treatment for cognitive dysfunction. A number of studies have assessed symptomatic treatments of cognition in MS, and the results of these small, underpowered studies have been mixed. Regardless, acetylcholinesterase inhibitors (AChEIs) have been the most promising class of medications tested in MS to date. Seven of eight studies on AChEIs have shown positive results, although it is difficult to assess their adequacy since only three of the studies have been published in peer reviewed journals, with the rest appearing only as abstracts. The earliest AChEI studies in MS examined physostigmine, but the short half-life and prominent adverse effects of this medication may have limited its use compared with other AChEIs. All of the more recent AChEI studies have used donepezil, which, from the limited data available to date, appears to have been relatively well tolerated among MS patients. The largest randomized controlled trial of donepezil included 69 subjects and found that donepezil improved verbal learning and memory compared with placebo during neuropsychological testing. That study also found that patients receiving donepezil were more likely to report memory improvement than those receiving placebo, and the study clinician also noted a cognitive benefit among those on donepezil as opposed to placebo. There are still many unanswered questions regarding the use of AChEIs in MS, including the effects of their long-term use in a chronic disease such as MS. On the whole, to date the research on AChEIs in MS must be considered preliminary, and it is premature to recommend the clinical use of this class of medications at the present time.
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PMID:Treatment of cognitive impairment in multiple sclerosis: is the use of acetylcholinesterase inhibitors a viable option? 1819 21

Myasthenia gravis is the most common neuromuscular junction disorder and the best understood autoimmune disease of the nervous system. The autoimmune attack leads to decreased concentrations of the AChR and results in fatigability of skeletal muscles increasing with activity and improving with rest. The treatment of myasthenia has improved dramatically over the last few decades, with an increasing number of immunotherapies used in management although not all of them have been formally tested in double-blind, prospective trials. The principles of treatment consist in optimizing neuromuscular junction function by use of cholinesterase inhibitors, inducing an immunologic remission and then maintaining that remission by long-term immunotherapies. Prednisone and/or azathioprine are the most effective. Short-term immunotherapies, i.e. intravenous immunoglobulin or plasmapheresis, are indicated for disease exacerbation. For patients with nonthymomatous autoimmune myasthenia, the effectiveness of thymectomy remains uncertain. The overall objective of therapy is to enable patients to lead a normal life as rapidly as possible, while limiting side effects and costs if possible. Treatment should be individualized. The aggressiveness of therapy should be balanced against a number of factors including distribution of muscle involvement, rate of progression, degree of functional impairment, lifestyle choice, and coexisting disease. In all cases, adequate education, for the patient and the physician, is most helpful in facilitating management of this chronic disease.
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PMID:[Treatment of autoimmune myasthenia]. 1983 41

A large proportion of Gulf War Veterans suffer from Gulf War Illness (GWI) - a devastating chronic disorder characterized by heterogeneous fatigue, pain and neuropsychological symptoms. In their recent Brain, Behavior and Immunity publication entitled "Curcumin Treatment Leads to Better Cognitive and Mood Function in a Model of Gulf War Illness with Enhanced Neurogenesis, and Alleviation of Inflammation and Mitochondrial Dysfunction in the Hippocampus", Kodali and colleagues (2018) report that the polyphenol curcumin improves cognition and mood in a rat model of GWI, potentially by increasing the expression of antioxidant genes and by reversing the effects of chronic combined acetylcholinesterase inhibitor exposure on neuroinflammation, mitochondrial respiration and hippocampal neurogenesis. This preclinical work is encouraging for our veterans who suffer chronically from GWI as well as for developing strategies to protect our troops during future deployments in similar environments.
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PMID:The potential of treating Gulf War Illness with curcumin. 2945 81

Trypanosoma cruzi infection triggers an intense production of pro-inflammatory cytokines mediated by T helper 1 lymphocytes, inducing the anti-inflammatory reflex of acetylcholine (ACh). The ACh concentration modulation is associated to the two major esterases, the acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). AChE H353N protein polymorphism is related to low Chagas chronic disease prognostic. In order to evaluate the correlation of plasmatic BuChE concentration and the presence of AChE H353N polymorphism in Chagas disease patients and healthy individuals, we studied two groups of individuals, one of 61 Chagas disease patients and another of 74 healthy individuals. Plasma concentration of BuChE was measured by the chemiluminescent method and AChE H353N polymorphism was investigated by PCR-RFLP and sequencing of the respective encoding AChE gene fragment. The BuChE concentration was statistically higher in Chagas disease patients, with no AChE genotype significant influence. AChE genotypes YT*A/YT*A, YT*A/YT*B and YT*B/YT*B, respectively, were expressed in 53 (86.88%), 7 (11.46%) and one (1.64%) chagasic patients, and in 68 (91.89%), 6 (8.10%) and none healthy individuals. BuChE activity may represent an important marker for chronic Chagas disease inflammatory process and prognostic. Lower BuChE concentration correlated with AChE YT*B allele, although without statistical power.
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PMID:Correlation of plasma butyrylcholinesterase concentration with Acethylcholinesterase H353N polymorphism in the inflammatory response of Chagas disease patients. 3200 76