Filip Zemek

Outcomes of Alzheimer's disease therapy with acetylcholinesterase inhibitors and memantine

Introduction: Alzheimers disease (AD) is a world-wide health problem with implications for an increasing number of people and countries. Populations suffering from AD financially strain the healthcare budgets of rich and poor countries alike. Moreover, no effective treatment is available and current drugs merely slow the progression of cognitive function deterioration and overall health status toward an inevitable end point. An increasing number of novel approaches have been tested in numerous clinical trials, but none of them has proved safe and effective for treating AD. Areas covered: This review summarizes all currently available compounds (donepezil, rivastigmine, galantamine, memantine) for the management of AD, concentrating on clinical aspects such as the mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. This review also considers the mechanisms and side effects to provide perspective on current treatment options. Expert opinion: Novel approaches in the treatment of AD are being intensively tested, but so far without any major success. Patients diagnosed with AD still mostly benefit from four compounds to significantly improve cognition functions and overall health and help manage other symptoms or even prolong the symptom-free period.

Synthesis and in vitro evaluation of N-alkyl-7-methoxytacrine hydrochlorides as potential cholinesterase inhibitors in Alzheimer disease

All approved drugs for Alzheimer disease (AD) in clinical practice ameliorate the symptoms of the disease. Among them, acetylcholinesterase inhibitors (AChEIs) are used to increase the cholinergic activity. Among new AChEI, tacrine compounds were found to be more toxic compared to 7-MEOTA (9-amino-7-methoxy-1,2,3,4-tetrahydroacridine). In this Letter, series of 7-MEOTA analogues (N-alkyl-7-methoxytacrine) were synthesized. Their inhibitory ability was evaluated on recombinant human acetylcholinesterase (AChE) and plasmatic human butyrylcholinesterase (BChE). Three novel compounds showed promising results towards hAChE better to THA or 7-MEOTA. Three compounds resulted as potent inhibitors of hBChE. The SAR findings highlighted the C(6)-C(7)N-alkyl chains for cholinesterase inhibition.

Adamantane – A Lead Structure for Drugs in Clinical Practice

The adamantane moiety is the structural backbone of numerous compounds and its discovery launched a new field of chemistry studying the approaches to the synthesis as well as the physicochemical and biological properties of organic polyhedral compounds with practical application in the pharmaceutical industry. Adamantane derivatives have proven to be very potent compounds in a wide range of applications from systemic to topical therapy. This review summarizes the currently available adamantane derivatives in clinical practice (amantadine, memantine, rimantadine, tromantadine, adapalene, saxagliptin, vildagliptin), focusing on mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. The adamantane-based compounds presented in this manuscript have been approved for a wide spectrum of indications (antivirals, antidiabetics and against Alzheimers and Parkinsons disease). Each of the compounds proved to be of vital importance in their therapeutic indication for numerous patients worldwide. This review also considers the mechanisms of side effects to deliver a complete perspective on current treatment options.

Passive diffusion of acetylcholinesterase oxime reactivators through the blood–brain barrier: Influence of molecular structure

In this in vitro study, high-performance liquid chromatography (HPLC) was used to determinate the penetration of 30 acetylcholinesterase (AChE) reactivators through the blood-brain barrier (BBB). According to our method, monoquaternary AChE reactivators were found to be able to penetrate the BBB. In addition to molecular structure, molecular weight appears to be an important factor for passive transport of oximes through the BBB. For bisquaternary reactivators, the connecting linker plays a key role in the ability to penetrate into the central nervous system (CNS): simple, short linkers tend to facilitate permeation. The location of groups on the pyridine ring also influences passive transport into the brain; the optimum position of the oxime group was found to be position four (para) and substitution of the oxime group on the pyridine ring by carbamoyl or amidoxime group markedly decreased penetration of AChE reactivators into the CNS.

Partition of bispyridinium oximes (trimedoxime and K074) administered in therapeutic doses into different parts of the rat brain

The penetration of acetylcholinesterase reactivators (oximes) into the central nervous system is typically restricted by the blood-brain barrier. Although oximes are highly hydrophilic compounds, some contradictory results confirming permeation into the brain exist. The aim of this study is to verify the penetration of oximes through the blood-brain barrier and to detect their levels achieved in different brain regions 60 min after the administration. It was confirmed that oximes are able to penetrate into the brain after injection of therapeutic doses corresponding with 5% of LD(50). The level in whole brain was 0.58% for trimedoxime and 0.85% for the experimental drug oxime K074 as the percentage of their plasma concentration. The highest concentration was found in frontal cortex (trimedoxime 2.27%; oxime K074 0.95%) and lowest in basal ganglia (trimedoxime 0.86%; oxime K074 0.42%). Entry of oximes into the brain is minimal, but some low reactivation effect should be expected. The reactivation potency of oximes might be higher or lower, depending on the real oxime concentration in a given area.

Synthesis and In Vitro Evaluation of N-(Bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine as a Cholinesterase Inhibitor with Regard to Alzheimer's Disease Treatment

A new tacrine based cholinesterase inhibitor, N-(bromobut-3-en-2-yl)-7-methoxy-1,2,3,4-tetrahydroacridin-9-amine (1), was designed and synthesized to interact with specific regions of human acetylcholinesterase and human butyrylcholinesterase. Its inhibitory ability towards cholinesterases was determined and compared to tacrine (THA) and 9-amino-7-methoxy-1,2,3,4-tetrahydroacridine (7-MEOTA). The assessment of IC50 values revealed 1 as a weak inhibitor of both tested enzymes.

Oximes: inhibitors of human recombinant acetylcholinesterase. A structure-activity relationship (SAR) study.

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.

Synthesis and in vitro evaluation of 7-methoxy-N-(pent-4-enyl)-1,2,3,4-tetrahydroacridin-9-amine-new tacrine derivate with cholinergic properties.

Cholinesterase inhibitors are, so far, the only successful strategy for the symptomatic treatment of Alzheimers disease. Tacrine (THA) is a potent acetylcholinesterase inhibitor that was used in the treatment of Alzheimers disease for a long time. However, the clinical use of THA was hampered by its low therapeutic index, short half-life and liver toxicity. 7-Methoxytacrine (7-MEOTA) is equally pharmacological active compound with lower toxicity compared to THA. In this Letter, the synthesis, biological activity and molecular modelling of elimination by-product isolated during synthesis of 7-MEOTA based bis-alkylene linked compound is described.

Asoxime (HI-6) impact on dogs after one and tenfold therapeutic doses: Assessment of adverse effects, distribution, and oxidative stress

Asoxime (HI-6) is a well known oxime reactivator used for counteracting intoxication by nerve agents. It is able to reactivate acetylcholinesterase (AChE) inhibited even by sarin or soman. The present experiment was aimed to determine markers of oxidative stress represented by thiobarbituric acid reactive substances and antioxidants represented by ferric reducing antioxidant power, reduced and oxidized glutathione in a Beagle dog model. Two groups of dogs were intramuscularly exposed to single (11.4 mg/kg.b.wt.) or tenfold (114 mg/kg.b.wt.) human therapeutically doses of HI-6. HI-6 affinity for AChE in vitro was evaluated in a separate experiment. Complete serum biochemistry and pharmacokinetics were also performed with significant alteration in blood urea nitrogen, creatine phosphokinase, glucose and triglycerides. Blood samples were collected before HI-6 application and after 30, 60, and 120 min. The overall HI-6 impact on organism is discussed.

Toxicological scoring of Alzheimer's disease drug huperzine in a guinea pig model.

Huperzine is a secondary metabolite in lycopods Huprzia and an inhibitor of acetylcholinesterase and antagonist of N-methyl-D-apartate receptor. Huperine is a suitable drug for the treatment of Alzheimer’s disease as it is a part of traditional Chinese medicine. Currently, it undergoes clinical trials in the European Union and United States. The toxicological data about huperzine are missing and link between huperzine and oxidative stress has not been extensively investigated. For the above mentioned reasons, we organized experiment on a guinea pig model aimed at the investigation of adverse effects caused by huperzine. Guinea pigs were exposed to (–)-huperzine A in doses 5–625 µg/kg. Animals were sacrificed one day after exposure. Ferric reducing antioxidant power, thiobarbituric acid reactive substances, glutathione reductase, caspase 3 activity and selected biochemical markers (e.g. transaminases, blood urea nitrogen and glucose) were assayed. In frontal, parietal, temporal lobes and cerebellum, we found increase of antioxidants, glutathione reductase and oxidative stress markers in a dose dependent manner. Effects on liver, kidney and spleen were milder. We discuss ambivalent action of huperzine in the body and judge the huperzine action owing to recently reported experiments.