Cholinesterase inhibitors as Alzheimer's therapeutics (Review).

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 naturally­derived 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 multi­target 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.

Acetylcholinesterase inhibitor insecticides related acute poisoning, availability and sales: trends during the post-insecticide-ban period of Anuradhapura, Sri Lanka.

BACKGROUND: Acetylcholinesterase inhibitor insecticides (AChEIIs) were used extensively in the agrarian region of Anuradhapura for the past few decades. As a result, the region faced a heightened risk of toxicity. Carbaryl, carbofuran, chlorpyrifos, dimethoate, and fenthion were the five hazardous AChEIIs banned from Anuradhapura in 2014. Assessment of post-ban trends in acute poisoning will reveal the impact of the ban. Data on availability and sales of remaining AChEIIs will guide towards preventive measures against related toxicities. METHODS: Cross-sectional surveys were conducted at Anuradhapura district of Sri Lanka. Details related to acute AChEII poisoning were sorted from the Teaching Hospital Anuradhapura. Main insecticide vendors in Anuradhapura were surveyed to find information on availability and sales of AChEIIs. Chi-square for goodness of fit was performed for trends in acute poisoning and sales. RESULTS: Hospital admissions related to acute AChEII poisoning have declined from 554 in 2013 to 272 in 2017. Deaths related to acute AChEII poisoning have declined from 27 in 2013 to 13 in 2017. Sales of all five banned AChEIIs had reduced by 100%. Sales of the remaining AChEIIs were declining, except for acephate, phenthoate, and profenofos. However, one of the top selling, most frequently abused carbosulfan, had the highest risk of toxicity. Chi-square for goodness of fit showed a significance (P < 0.001) between the trends of hospital admissions for acute AChEII poisoning and the sales related to AChEIIs. CONCLUSIONS: Hospital admissions related to acute poisoning was declining along with the overall sales of remaining AChEIIs, during the post-AChEII ban period. Nevertheless, future vigilance is needed on the remaining AChEIIs to predict and prevent related toxicities.

Alkaloid profiles and acetylcholinesterase inhibitory activities of Fumaria species from Bulgaria.

GC-MS analysis of alkaloid profiles of five Fumaria species, naturally grown in Bulgaria (F. officinalis, F. thuretii, F. kralikii, F. rostellata and F. schrammii) and analysis of acetylcholinesterase inhibitory activity of alkaloid extracts were performed. Fourteen isoquinoline alkaloids were identified, with the principle ones being protopine, cryptopine, sinactine, parfumine, fumariline, fumarophycine, and fumaritine. Protopine contents, defined by HPLC analysis varied between 210.6 ± 8.8 µg/g DW (F. schrammii) and 334.5 ± 7.1 µg/g DW. (F. rostellata). While all of the investigated alkaloid extracts significantly inhibited acetylcholinesterase activity, the F. kralikii demonstrated the highest level of inhibition (IC(50) 0.13 ± 0.01 mg extract/mL).

Classification of acetylcholinesterase inhibitors and decoys by a support vector machine.

Acetylcholinesterase has long been considered as a target for Alzheimer disease therapy. In this work, several classification models were built for the purpose of distinguishing acetylcholinesterase inhibitors (AChEIs) and decoys. Each molecule was initially represented by 211 ADRIANA.Code and 334 MOE descriptors. Correlation analysis, F-score and attribute selection methods in Weka were used to find the best reduced set of descriptors, respectively. Additionally, models were built using a Support Vector Machine and evaluated by 5-, 10-fold and leave-one-out cross-validation. The best model gave a Matthews Correlation Coefficient (MCC) of 0.99 and a prediction accuracy (Q) of 99.66% for the test set. The best model also gave good result on an external test set of 86 compounds (Q=96.51%, MCC=0.93). The descriptors selected by our models suggest that H-bond and hydrophobicity interactions are important for the classification of AChEIs and decoys.

[Antidementia drugs]. / Antidementiva.

The pharmacological treatment of dementias aims to improve cognitive deficits, activities of daily living and behavioural and psychiatric symptoms. The weighting of theses therapeutic aims varies with disease progression. Behavioural symptoms may dominate especially in the more severe stages of the disease and may further deteriorate global functional level of the patient. Today there is no causal therapy for Alzheimer's disease (AD). Based on preclinical disease models novel therapeutic approaches are under development that target the beta-amyloid and tau protein metabolism. Some of them aim to inhibit the formation, aggregation and toxicity of beta-amyloid peptides or promote their clearance from the brain. Others inhibit the formation of neurofibrillary tangles or have neuroprotective effects. Active or passive immunisation against beta-amyloid may be a very specific and effective approach. The efficacy of acetylcholine esterase inhibitors (AchEI) in the treatment of mild to moderate AD is well documented. They are first line therapeutics in the treatment of the disease and lead to a delay of symptomatic progression. Memantine is effective in the treatment of moderate to severe stages of AD. The evidence for the treatment of vascular dementia is comparatively weak. However, positive effects have been shown for all available AchEI and memantine. Non pharmacological therapy is an indispensable part of the treatment of dementia patients and should be adapted to the individual needs of the patient in the respective stage of the disease. The efficacy of antipsychotics in the treatment of behavioural and psychiatric symptoms of dementia is limited. These drugs are associated with increased morbidity and mortality in dementia patients. Therefore, their application should be based on a critical and individual evaluation of risks and benefits.

Clinical limitations of acetylcholinesterase antagonists.

Administration of a nondepolarizing neuromuscular blocking drug (muscle relaxant) is a standard practice in many anesthetic scenarios. These muscle relaxants work by competitive antagonism of the neurotransmitter acetylcholine at nicotinic cholinergic receptors within the neuromuscular junction of skeletal muscle (Martyn et al; Neuromuscular physiology and pharmacology, anesthesia. Edited by RD Miller, Philadelphia, Churchill Livingstone, 2000). At the conclusion of the procedure for which the muscle relaxant was administrated, there will be a greater or lesser degree of residual muscle weakness. It is usually necessary to pharmacologically reverse this residual weakness to restore full function to the patient's muscles. Indeed, failure to reverse neuromuscular block is associated with increased perioperative morbidity and mortality (Arbous et al; Impact of anesthesia management characteristics on severe morbidity and mortality. Anesthesiology 2005;102:257-268; quiz 491-2). Pharmacologic reversal currently relies on the administration of an anticholinesterase drug, which decreases the metabolism of acetylcholine at the neuromuscular junction and allows its concentration to increase and hopefully overcome the effect of the muscle relaxant. This approach to reversal has significant limitations; the mechanism of reversal is indirect, the efficacy is limited and unpredictable, and undesirable autonomic responses occur. This review will address these limitations.

Classification of drug molecules considering their IC50 values using mixed-integer linear programming based hyper-boxes method.

BACKGROUND: A priori analysis of the activity of drugs on the target protein by computational approaches can be useful in narrowing down drug candidates for further experimental tests. Currently, there are a large number of computational methods that predict the activity of drugs on proteins. In this study, we approach the activity prediction problem as a classification problem and, we aim to improve the classification accuracy by introducing an algorithm that combines partial least squares regression with mixed-integer programming based hyper-boxes classification method, where drug molecules are classified as low active or high active regarding their binding activity (IC50 values) on target proteins. We also aim to determine the most significant molecular descriptors for the drug molecules. RESULTS: We first apply our approach by analyzing the activities of widely known inhibitor datasets including Acetylcholinesterase (ACHE), Benzodiazepine Receptor (BZR), Dihydrofolate Reductase (DHFR), Cyclooxygenase-2 (COX-2) with known IC50 values. The results at this stage proved that our approach consistently gives better classification accuracies compared to 63 other reported classification methods such as SVM, Naïve Bayes, where we were able to predict the experimentally determined IC50 values with a worst case accuracy of 96%. To further test applicability of this approach we first created dataset for Cytochrome P450 C17 inhibitors and then predicted their activities with 100% accuracy. CONCLUSION: Our results indicate that this approach can be utilized to predict the inhibitory effects of inhibitors based on their molecular descriptors. This approach will not only enhance drug discovery process, but also save time and resources committed.

Construction of the pharmacophore model of acetylcholinesterase inhibitor.

Based on ninety three acetylcholinesterase inhibitors (AChEIs) which have the same mechanism of action but are different in structural characteristics, the pharmacophore model for acetylcholinesterase inhibitor was constructed by the CATALYST system. The optimal pharmacophore model with three hydrophobic units, a ring aromatic unit and a hydrogen-bond acceptor unit were confirmed (Weight = 3.29, RMS = 0.53, total cost-null cost = 62.75, Correl = 0.93, Config = 19.05). This pharmacophore model will act on the double active site of acetylcholinesterase and is able to predict the activity of known acetylcholinesterase inhibitors that are used for clinical treatment of Alzheimer's disease (AD), and can be further used to identify structurally diverse compounds that have higher activity treating with Alzheimer's disease (AD) by virtual screening.

Anticholinergic activity of 107 medications commonly used by older adults.

The objective of this study was to measure the anticholinergic activity (AA) of medications commonly used by older adults. A radioreceptor assay was used to investigate the AA of 107 medications. Six clinically relevant concentrations were assessed for each medication. Rodent forebrain and striatum homogenate was used with tritiated quinuclidinyl benzilate. Drug-free serum was added to medication and atropine standard-curve samples. For medications that showed detectable AA, average steady-state peak plasma and serum concentrations (C(max)) in older adults were used to estimate relationships between in vitro dose and AA. All results are reported in pmol/mL of atropine equivalents. At typical doses administered to older adults, amitriptyline, atropine, clozapine, dicyclomine, doxepin, L-hyoscyamine, thioridazine, and tolterodine demonstrated AA exceeding 15 pmol/mL. Chlorpromazine, diphenhydramine, nortriptyline, olanzapine, oxybutynin, and paroxetine had AA values of 5 to 15 pmol/mL. Citalopram, escitalopram, fluoxetine, lithium, mirtazapine, quetiapine, ranitidine, and temazepam had values less than 5 pmol/mL. Amoxicillin, celecoxib, cephalexin, diazepam, digoxin, diphenoxylate, donepezil, duloxetine, fentanyl, furosemide, hydrocodone, lansoprazole, levofloxacin, metformin, phenytoin, propoxyphene, and topiramate demonstrated AA only at the highest concentrations tested (patients with above-average C(max) values, who receive higher doses, or are frail may show AA). The remainder of the medications investigated did not demonstrate any AA at the concentrations examined. Psychotropic medications were particularly likely to demonstrate AA. Each of the drug classifications investigated (e.g., antipsychotic, cardiovascular) had at least one medication that demonstrated AA at therapeutic doses. Clinicians can use this information when choosing between equally efficacious medications, as well as in assessing overall anticholinergic burden.

Neurotoxicity evaluation of the organofluorine pesticide etoxazole in the brain of Oreochromis niloticus.

Etoxazole is a new organofluorine pesticide that has been used worldwide as acaricide and insecticide since 1998. Almost no previous attempt has been made to evaluate the toxic effects of etoxazole in vertebrates. Using fish (Oreochromis niloticus) as a suitable model organism, the aim of this study was to indicate whether etoxazole affects acetylcholinesterase and sodium potassium-activated adenosine triphosphatase activities in the brain tissue in order to evaluate the impacts on neurotoxicity and ion transportation. Enzyme activities were determined using spectrophotometric methods. At the sublethal concentrations (0.27, 0.54, 0.81, 1.08, 1.35 mg/L) and exposure durations (1, 7, 15 days) tested, etoxazole has no inhibitory effect on the brain acetylcholinesterase and sodium potassium-activated adenosine triphosphatase activities. Our results suggest that etoxazole and/or its metabolites may not reach or penetrate the blood-brain barrier; therefore, they do not essentially alter the functions of these two important enzymes for the brain.

A review of studies describing the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia.

OBJECTIVE: To review the literature relating to the use of acetyl cholinesterase inhibitors in Parkinson's disease dementia (PDD). METHOD: MEDLINE (1966--December 2004), PsychINFO (1972--December 2004), EMBASE (1980--December 2004), CINHAL (1982--December 2004), and the Cochrane Collaboration were searched in December 2004. RESULTS: Three controlled trials and seven open studies were identified. Efficacy was assessed in three key domains: cognitive, neuropsychiatric and parkinsonian symptoms. CONCLUSION: Cholinesterase inhibitors have a moderate effect against cognitive symptoms. There is no clear evidence of a noticeable clinical effect against neuropsychiatric symptoms. Tolerability including exacerbation of motor symptoms--in particular tremor--may limit the utility of cholinesterase inhibitors.

A preclinical view of cholinesterase inhibitors in neuroprotection: do they provide more than symptomatic benefits in Alzheimer's disease?

The prevalence of Alzheimer's disease (AD), a neurodegenerative condition whose greatest risk factor is old age, is expected to rise dramatically during the next five decades, along with the trend for increased longevity. Early diagnosis and intervention with therapies that halt or slow disease progress are likely to represent an important component of effective treatment. Although much progress has been made in this area, there are currently no clinically approved interventions for AD that are classed as disease modifying or neuroprotective. Cholinesterase inhibitors are a drug class used for the symptomatic treatment of AD. Recent evidence from preclinical studies indicates that these agents can attenuate neuronal damage and death from cytotoxic insults, and therefore might affect AD pathogenesis. The mechanisms by which these actions are mediated might or might not be directly related to their primary mode of action.

Synthesis and structure activity relationships (SAR) of a new class of potent and selective butyrylcholinesterase inhibitors.

Reported here is the synthesis and SAR of novel group of highly potent and selective inhibitors of human plasma butyrylcholinesterase (BuChE; EC 3.1.1.8). The design is based on the discovery that isosorbide 2-esters are hydrolysed by BuChE at exceptionally rapid rates. Two families of carbamates were synthesised in which the vulnerable 2-ester was replaced with a carbamate or reversed carabamate. Several compounds in one of the families are among the most potent and selective BuChE inhibitors reported.

An overview of the current and novel drugs for Alzheimer's disease with particular reference to anti-cholinesterase compounds.

Several cellular processes could be targeted if the complex nature of Alzheimer's disease (AD) was already understood. Most of AD treatments have been focused on the inhibition of acetylcholinesterase (AChE) in order to raise the levels of its substrate, i.e. the neurotransmitter acetylcholine (ACh), to augment cognitive functions of affected patients. Effectiveness in AChE inhibition and side-effect issues of clinical (tacrine, donepezil, galanthamine and rivastigmine) as well as of novel inhibitors is reviewed here. Novel design methods for the inhibition of AChE include the use of in silico tools to predict the interactions between AChE and the desired compound, both at the active site of the enzyme, responsible of hydrolysing ACh and with the peripheral anionic site (PAS), which has been described as a promoting agent of the amyloid beta-peptide (A beta) aggregation present in the senile plaques of the brain of AD individuals.