At present, the best dose and duration of treatment with acetylcholinesterase inhibitors is determined by the balance between improvement in symptoms and adverse effects. This varies over time and depends on other types of treatment that are given at the same time to switch off the underlying autoimmune response. This is the second update of this review, which was first published in The evidence is current to July Except for one small and inconclusive trial of intranasal neostigmine, no other randomised controlled trials have been conducted on the use of acetylcholinesterase inhibitors in myasthenia gravis.
The response to acetylcholinesterase inhibitors in observational studies is so clear that a randomised controlled trial depriving participants in a placebo arm of treatment would be difficult to justify.
Acetylcholinesterase inhibitors provide temporary symptomatic treatment of muscle weakness but there is controversy about their long-term efficacy, dosage and side effects.
This is the second update of a review published in The Cochrane Library Issue 2, Two authors scanned the articles for any study eligible for inclusion. We also contacted the authors and known experts in the field to identify additional published or unpublished data and searched clinical trials registries for ongoing trials. The types of studies were randomised or quasi-randomised trials. Participants were myasthenia gravis patients diagnosed by an internationally accepted definition.
The intervention was treatment with any form of acetylcholinesterase inhibitor. One author MMM extracted the data, which were checked by a second author. We contacted study authors for extra information and collected data on adverse effects from the trials. Despite the promising in vitro information, none of the five compounds are suitable for AChE inhibition against AD [ 27 ]. Both tacrine and PBT2 an 8-hydroxyquinoline derivative are known for ChE inhibition and decreasing beta-amyloid concentrations, respectively.
Fernandez-Bachiller et al. The drug has also demonstrated antioxidant and copper-complexing properties. With all the properties that these hybrids possess, it could be a possible therapeutic drug treatment in vivo as well [ 3 ].
Samadi et al. It also displays antioxidant and neuroprotective properties. Compounds 3, 4, 21—23, 25, 26 were shown to be highly selective for hAChE. Compounds bearing small groups such as the N, N 0 -dimethylamino or the pyrrolidino preferentially inhibit AChE. Compounds 3, 17, 22, 24, and 26 showed the highest neuroprotection values.
These compounds could be further developed to have multifaceted approach against cholinergic dysfunction and oxidative stress [ 23 ]. The hybrids are composed of a 6-unit chlorotacrine and a multicomponent reaction-derived pyrano [3,2-c]-quinoline scaffold as the active and peripheral sites interacting moieties, respectively.
Due to the dual binding site activity, both hybrids demonstrate the ability to inhibit AChE-induced beta-amyloid aggregation and self-induced beta-amyloid aggregation. Some of compounds can also inhibit BACE These hybrids also have the ability to permeate the BBB.
Hybrid 27 emerged as the most promising therapeutic as it was able to target both AChE and beta-amyloid production and aggregation [ 28 ].
Synthetic analogues are under development because, with targeted pharmacological development, class-specific hepatotoxicity and known gastrointestinal side effects may be avoided. The risk of developing synthetic analogs is that they might not have the potency and BBB permeability as naturally derived ChEIs or they may have unanticipated pharmacological properties. Ali et al. Their data showed that the majority of the compounds had moderate AChE inhibitory effects.
The study suggests that having an OCH 3 group substituted phenyl ring at diketone derivatives creates a vast improvement in AChE inhibition [ 29 ]. Compounds 9, 10, and 14 were found to be ineffective against hAChE. The structure-activity relationship findings point at the C6-C7 N-alkyl chains for cholinesterase inhibition [ 30 ]. It has neuroprotective and antioxidant activities in cellular models at much lower concentrations than those inhibiting MAO or AChE.
Ladostigil also prevented the age-related reduction in cortical AChE activity and the increase in butyrylcholinesterase activity in the hippocampus, in association with the reduction in gliosis. The immunological and enzymatic changes in aged rats were associated with improved spatial memory.
Ladostigil treatment had no effect on memory, glial, or proNGF immunoreactivity in young rats [ 32 ]. Physostigmine was the first ChEI investigated for AD, but it was discarded due to a number of disadvantages. Although phenserine, a physostigmine derivative, has failed the Phase II clinical trials, there are other derivatives in development. In addition, metrifonate also has a profound effect on those with AD.
A metrifonate derivative with the same or better efficacy and a lesser side effect profile would be a promising therapeutic drug. Naturally derived AChEIs are also a promising area of interest. HupA is the drug of choice in China [ 16 ]. Many hybrids are also being created. Some hybrids have completely new materials, but other hybrids are using the older AChEI and are trying to improve upon them.
The synthetic analogues have only been tested in vitro at this time, but it is an area that can help direct future treatment options for AD. Although the majority of the drugs discussed in this paper have not yet been tested in animals or humans, each of these areas will continue to develop because this class of drugs has demonstrated its value in symptomatic therapy. This class of drugs will continue to be developed because it is a proven symptomatic therapy with a recognized target.
Drugs in the class have a proven track of CNS permeability, known side effect profile, and demonstrated efficacy. It is logical to consider further development of novel agents in this class.
Challenges to development include potency, safety, and side effects as well as comparison to current ChEIs, many of which are generic. Many compounds developed to date have no human or animal data.
Thus, safety, efficacy, and toxicity have not been established. Further, this class of medications has not been established to possess disease-modifying properties. The risk of developing newer ChEIs is that they will need to be more effective than donepezil, rivastigmine, and galantamine to garner approval since these three drugs are FDA approved. Future research in this class will need to focus on whether ChEIs directly affect the pathophysiology of AD. The authors wish to thank Dawn Humay for her assistance in obtaining references.
This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Read the winning articles.
Journal overview. Special Issues. Academic Editor: Anton P. Received 31 Jul Revised 06 Nov Accepted 07 Nov Published 15 Dec Abstract Acetylcholinesterase AChE remains a highly viable target for the symptomatic improvement in Alzheimer's disease AD because cholinergic deficit is a consistent and early finding in AD. Older Cholinesterase Inhibitors 2.
Tacrine Tacrine was the first drug approved for treatment of AD in [ 2 ]. Donepezil Donepezil was approved in for the treatment of mild-to-moderate AD. Rivastigmine Rivastigmine is a small molecule and has easy BBB permeability. Galantamine The therapeutic action of galantamine has been reported to be mainly produced by its sensitizing action on nAChRs rather than by general cholinergic enhancement due to cholinesterase inhibition.
Metrifonate Metrifonate is a long-acting irreversible ChEI that was originally used to treat schistosomiasis. Older ChEIs Summary Dozens of short-term clinical trials, open-label extension studies, and long-term clinical cohort observational studies generally point to the following a current ChEIs donepezil, rivastigmine, and galantamine reduce cognitive, functional, and behavioral decline in AD, b their efficacies appear similar there is no level 1 grade data that shows otherwise , c their benefits are sustained with treatment persistence, d their benefits are generally dose-related until limited by side-effects at very high doses , and e they appear to be relatively safe and well-tolerated see Table 1.
Drug Disposition Physostigmine First drug investigated; however, it is no longer used due to side effects, short half-life, and better treatment options.
Approved for mild, moderate, and severe AD. Approved for mild-to-moderate AD. Patch formulation has reduced cholinergic-related side effects. Despite a good safety profile, it did not achieve significant efficacy during Phase II trials. Tolserine A physostigmine derivative, has shown promise in the preclinical stages. It has not entered clinical trials. NS tesofensine Robust preclinical efficacy and safety data.
Early Phase II studies showed a positive signal on cognition. It is currently being investigated as a treatment for obesity treatment. It acts as a ChEI. It is drug of choice for AD in China. Himatanthus lancifolius A shrub with multiple medicinal purposes. The uliene in Himatanthus lancifolius is what is likely responsible for the significant AChE inhibitory effects.
Galangin Galangin is a flavonoid that demonstrated significant inhibition of AChE. It has not been tested in human trials. Donepezil hybrids 1 Of the series of hybrids derived from Donepezil and AP, compounds 15, 21, and 22 demonstrated the most potential. On the other hand, a weeks randomized, double-blind, multicenter trial, including 54 individuals suffering from mild-to-moderate AD, showed that daily intake of Crocus sativus L.
A recent systematic review and meta-analysis of 43 randomized placebo-controlled clinical trials showed that AChEi improved cognitive function, global symptomatology, and functional capacity, as well as decreased patients' mortality Blanco-Silvente et al. However, patients taking AChEi presented higher discontinuation due to adverse events, denoting an important issue on anti-AChE therapy.
As showed in Table 1 , the majority of the plant extract-based studies mentioned in this mini-review has not assessed their toxicity in animals or humans, although species like S. Amongst the main natural AChEi compounds herein mentioned, berberine and safranal seem to ally more advantages than disadvantages. Nevertheless, berberine has been shown to cause mild gastrointestinal reactions, including diarrhea and constipation, besides other less frequent side effects Imenshahidi and Hosseinzadeh, ; and safranal has toxic effects on hematological and biochemical indices, as well as induced embryonic malformation in animal's models at high doses Bostan et al.
The present mini-review demonstrated that during last decade several plant species and their potentially active compounds have been screened for anti-AChE activity. Amongst the most active extracts Table 1 , it is noticeable the use of extracting solvents of distinct polarities, which suggests that their active compounds might pertain to a wide range of secondary metabolites classes. However, having a look at the isolated substances summarized in Figure 1B , most high potent compounds assessed during this period pertain to alkaloid class, exception made to the highest potent decursinol, a dihydropyranocoumarin.
Alkaloids indisputably are the most studied class of natural AChEi, what seemly has trapped the researcher's attention in this class when in pursuit of new potential AChEi candidates, a vision that urges to be changed. Notwithstanding, the search for secondary AD-relevant pharmacological properties, such as antioxidant, deserves experimental approaches addressing their capacity to prevent oxidants generation and oxidative damage, instead of their mere scavengering capacity.
Finally, despite the undoubted relevance of new AChEi discovery for AD palliative pharmacotherapy, there is scanty knowledge on their structure-activity relationships, as well as toxicological assessments that would enable them to phase II studies.
For instance, berberine and related protoberberine alkaloids have been consistently assessed for their anti-AChE activity, but no phase II study has been conducted so far. Such knowledge is capital both to promote higher safety and to guide the design of new semi- synthetic AChEi.
Thus, given the plethora of plant species and compounds already described, their assessment through clinical trials certainly represent the main barrier to be transposed in order to expand and improve the pharmacological care of AD patients. TS conceived the proposal, discussed mini-review's structure, surveyed and selected relevant articles, tabulated the data and drafted the manuscript.
TG surveyed and selected relevant articles, tabulated the data. BP supervised articles selection, analysis and data tabulation. AC discussed mini-review's structure, supervised articles selection, analysis and data tabulation. AP conceived the proposal, discussed mini-review's structure, oriented the selection of relevant articles, analyzed tabulated data, and drafted the manuscript.
All authors read and approved the final format of the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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