Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

Acetylcholinesterase (AChE) reactivators (oximes) are compounds predominantly targeting the active site of the enzyme. Toxic effects of organophosphates nerve agents (OPNAs) are primarily related to their covalent binding to AChE and butyrylcholinesterase (BChE), critical detoxification enzymes in the blood and in the central nervous system (CNS). After exposure to OPNAs, accumulation of acetylcholine (ACh) overstimulates receptors and blocks neuromuscular junction transmission resulting in CNS toxicity. Current efforts at treatments for OPNA exposure are focused on non-quaternary reactivators, monoisonitrosoacetone oximes (MINA), and diacylmonoxime reactivators (DAM). However, so far only quaternary oximes have been approved for use in cases of OPNA intoxication. Five acetylcholinesterase reactivator candidates (K027, K075, K127, K203, K282) are presented here, together with pharmacokinetic data (plasma concentration, human serum albumin binding potency). Pharmacokinetic curves based on intramuscular application of the tested compounds are given, with binding information and an evaluation of structural relationships. Human Serum Albumin (HSA) binding studies have not yet been performed on any acetylcholinesterase reactivators, and correlations between structure, concentration curves and binding are vital for further development. HSA bindings of the tested compounds were 1% (HI-6), 7% (obidoxime), 6% (trimedoxime), and 5%, 10%, 4%, 15%, and 12% for K027, K075, K127, K203, and K282, respectively.

Although the information about Alzheimer’s disease (AD) etiology is still unclear; acetylcholinesterase inhibitors still play a major role in symptomatic treatment of AD. Unfortunately, a relevant argumentation is complicated since information about real drug concentration in the brain or time-dependent blood-brain barrier (BBB) distribution studies are still quite rare. In this in vitro study, high-performance liquid chromatography (HPLC) method with special (IAM – immobilized artificial membrane) column was used to determine the ability of cholinesterase inhibitors to penetrate through BBB. Set of 8 structurally different cholinesterase inhibitors applicable to AD treatment was evaluated throughout this study. According to our method, all molecules are able to penetrate BBB by passive transport. However, some molecules such as huperzine A and galanthamine have lower ability to penetrate the BBB directly. These molecules may be delivered into the brain via active transport. Other molecules probably use passive transport to permeate into the central nervous system; tacrine and 7-methoxytacrine exert the highest passive permeation from this set of compounds. Key words: Blood-brain barrier, central nervous system, acetylcholinesterase, Alzheimer disease.

Increasing life expectancy in modern society is undoubtedly due to improved healthcare, scientific advances in medicine, and the overall healthy lifestyle of the general population. However, this positive trend has led to an increase in the number of older people with a growing need for a sustainable system for the long-term care of this part of the population, which includes social and health services that are essential for a high quality of life. Longevity also brings challenges in the form of a polymorbid geriatric population that places financial pressure on healthcare systems. Regardless, one disease dominates the debate about financial sustainability due to the increasing numbers of people diagnosed, and that is Alzheimer’s disease (AD). The presented paper aims to demonstrate the economic burden of social and healthcare services. Data from two regions in the Czech Republic were selected to demonstrate the potential scope of the problem. The future costs connected with AD are calculated by a prediction model, which is based on a population model for predicting the number of people with AD between 2020 and 2070. Based on the presented data from the two regions in the Czech Republic and the prediction model, several trends emerged. There appears to be a significant difference in the annual direct costs per person diagnosed with AD depending on the region in which they reside. This may lead to a significant inequality of the services a person can acquire followed by subsequent social issues that can manifest as a lower quality of life. Furthermore, given the prediction of the growing AD population, the costs expressed in constant prices based on the year 2020 will increase almost threefold during the period 2020–2070. The predicted threefold increase will place additional financial pressure on all stakeholders responsible for social and healthcare services, as the current situation is already challenging.

Abstract: Cholinesterase inhibitors play an essential role in the treatment of Alzheimer’s disease. Since their first introduction over a decade ago, they are an indispensable part of Alzheimer’s disease therapy and remain at the forefront of scientific interest worldwide. In this manuscript new analogs of THA and 7-MEOTA were designed, synthesized, and evaluated for their inhibitory activity against both acetylcholinesterase and butyrylcholinesterase. Cholinergic properties were investigated and quantified with respect to their side chain residues (aromatic or alicyclic). All synthesized compounds proved to have potent inhibitory activity at micromolar range. Moreover, compound 4 demonstrated promising efficacy and appears to be an ideal candidate for further testing.