Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to analyze the changes in blood pressure (BP) and heart rate (HR) during 14 days of treatment with two different acetylcholinesterase inhibitors - pyridostigmine (PYR) having only peripheral effects or donepezil (DON) with both peripheral and central effects. In addition, we studied their effects on the cardiovascular response to restraint stress and on sympathovagal control of HR in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). SHR were characterized by elevated BP and increased low-frequency component of systolic BP variability (LF-SBPV), but their cardiac vagal tone and HR variability (HRV) were reduced compared with WKY. Chronic treatment with either acetylcholinesterase inhibitor decreased HR and increased HRV in both strains. PYR treatment slightly decreased BP and LF-SBPV in the dark phase of the day. Neither drug significantly altered BP response to stress, but PYR attenuated HR increase during restraint stress. Regarding sympathovagal balance, acute methylatropine administration caused a greater increase of HR in WKY than in SHR. Chronic PYR or DON treatment enhanced HRV and HR response to methylatropine (vagal tone) in WKY, whereas PYR but not DON treatment potentiated HRV and vagal tone in SHR. In conclusion, vagal tone was lower in SHR compared with WKY, but was enhanced by chronic PYR treatment in both strains. Thus, chronic peripheral, but not central, acetylcholinesterase inhibition has major effects on HR and its variability in both normotensive and hypertensive rats.

• Klíčová slova
• Acetylcholinesterase inhibitors, Parasympathetic tone, Spontaneously hypertensive rats, Sympathetic tone, Sympathovagal control of heart rate, Wistar-Kyoto rats,
• MeSH
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory farmakologie   terapeutické užití   MeSH
• deriváty atropinu * MeSH
• donepezil farmakologie   MeSH
• hypertenze * farmakoterapie   MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• potkani inbrední SHR MeSH
• potkani inbrední WKY MeSH
• pyridostigmin-bromid * farmakologie   MeSH
• srdeční frekvence MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• deriváty atropinu * MeSH
• donepezil MeSH
• methylatropine MeSH Prohlížeč
• pyridostigmin-bromid * MeSH

Environmental screening is essential due to the increased occurrence of harmful substances in the environment. Open Meter Duo (OMD) is an open-source field photo/fluorimeter that uses an RGB diode that imitates a color according to the selected wavelength and uses a UV LED from the security kit diode as an excitation light source. The prepared PCB shield with a 3D-printed aperture was connected to Arduino UNO R4 WiFi. This system was used for the fluorescent detection of cholinesterase activity with the indoxyl acetate method. Carbofuran-a toxic pesticide-and donepezil-a drug used to treat Alzheimer's disease-were tested as model inhibitors of cholinesterase activity. The limit of detection of indoxyl acetate was 11.6 μmol/L, and the IC50 values of the inhibitors were evaluated. This system is optimized for wireless use in field analysis with added cloud support and power source. The time of analysis was 5 min for the fluorimetric assay and 20 min for the optional photometric assay. The time of field operation was approximately 4 h of continuous measurement. This system is ready to be used as a cheap and easy control platform for portable use in drug control and point-of-care testing.

• Klíčová slova
• 3D printing, Arduino, cholinesterase, fluorimetry, low cost, portable, remote sensing,
• MeSH
• Alzheimerova nemoc * MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• cholinesterasy terapeutické užití   MeSH
• donepezil terapeutické užití   MeSH
• fluorometrie MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH
• donepezil MeSH

BACKGROUND: The acetylcholinesterase inhibitor donepezil is administered as a treatment for Alzheimer's disease (AD). However, the appropriate donepezil dosage is still a matter of debate. METHODS: Forty AD patients receiving 10 mg/day of donepezil were randomly divided into four groups based on the time of plasma and cerebrospinal fluid (CSF) sampling: 6 h (n = 5), 12 h (n = 12), 18 h (n = 6) and 24 h (n = 17) after donepezil administration. High-performance liquid chromatography measured the donepezil concentration in plasma samples and CSF samples collected at 4-time points. RESULTS: Plasma and CSF levels among the groups were not significantly different. Conversely, the CSF/plasma donepezil concentration ratio considerably increased in the 24 h group compared to the 6 h (p < 0.005) and 12 h (p < 0.05) groups. CONCLUSION: The measurement of the CSF/plasma donepezil concentration ratio could be used to better evaluate the optimal dose of donepezil.

• Klíčová slova
• AChE-Is, Alzheimer’s disease, CSF, Donepezil, Plasma, Ratio,
• MeSH
• acetylcholinesterasa MeSH
• Alzheimerova nemoc * krev   mozkomíšní mok   farmakoterapie   MeSH
• cholinesterasové inhibitory * krev   mozkomíšní mok   terapeutické užití   MeSH
• donepezil * krev   mozkomíšní mok   terapeutické užití   MeSH
• indany terapeutické užití   farmakologie   MeSH
• lidé MeSH
• piperidiny farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory * MeSH
• donepezil * MeSH
• indany MeSH
• piperidiny MeSH

Nerve agents pose a real threat to both the military and civil populations, but the current treatment of the poisoning is unsatisfactory. Thus, we studied the efficacy of prophylactic use of memantine alone or in combination with clinically used reversible acetylcholinesterase inhibitors (pyridostigmine, donepezil, rivastigmine) against soman. In addition, we tested their influence on post-exposure therapy consisting of atropine and asoxime. Pyridostigmine alone failed to decrease the acute toxicity of soman. But all clinically used acetylcholinesterase inhibitors administered alone reduced the acute toxicity, with donepezil showing the best efficacy. The combination of memantine with reversible acetylcholinesterase inhibitors attenuated soman acute toxicity significantly. The pretreatment administered alone or in combinations influenced the efficacy of post-exposure treatment in a similar fashion: (i) pyridostigmine or memantine alone did not affect the antidotal treatment, (ii) centrally acting reversible acetylcholinesterase inhibitors alone increased the antidotal treatment slightly, (iii) combination of memantine with reversible acetylcholinesterase inhibitors increased the antidotal treatment more markedly. In conclusion, memantine alone failed to decrease the acute toxicity of soman or increase post-exposure antidotal treatment efficacy. The combination of memantine with donepezil significantly increased post-exposure effectiveness (together 5.12, pretreatment alone 1.72). Both drugs, when applied together, mitigate soman toxicity and boost post-exposure treatment.

• Klíčová slova
• Donepezil, Memantine, Mice, Pyridostigmine, Rivastigmine, Soman,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antiparkinsonika aplikace a dávkování   MeSH
• cholinesterasové inhibitory aplikace a dávkování   toxicita   MeSH
• donepezil aplikace a dávkování   MeSH
• dopaminové látky aplikace a dávkování   MeSH
• kombinovaná farmakoterapie MeSH
• memantin aplikace a dávkování   MeSH
• myši MeSH
• preexpoziční profylaxe metody   MeSH
• soman toxicita   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antiparkinsonika MeSH
• cholinesterasové inhibitory MeSH
• donepezil MeSH
• dopaminové látky MeSH
• memantin MeSH
• soman MeSH

Gastrointestinal side effects of donepezil, including dyspepsia, nausea, vomiting or diarrhea, occur in 20-30% of patients. The pathogenesis of these dysmotility associated disorders has not been fully clarified yet. Pharmacokinetic parameters of donepezil and its active metabolite 6-O-desmethyldonepezil were investigated in experimental pigs with and without small intestinal injury induced by dextran sodium sulfate (DSS). Morphological features of this injury were evaluated by a video capsule endoscopy. The effect of a single and repeated doses of donepezil on gastric myoelectric activity was assessed. Both DSS-induced small intestinal injury and prolonged small intestinal transit time caused higher plasma concentrations of donepezil in experimental pigs. This has an important implication for clinical practice in humans, with a need to reduce doses of the drug if an underlying gastrointestinal disease is present. Donepezil had an undesirable impact on porcine myoelectric activity. This effect was further aggravated by DSS-induced small intestinal injury. These findings can explain donepezil-associated dyspepsia in humans.

• Klíčová slova
• 6-O-desmethyldonepezil, dextran sodium sulfate, donepezil, electrogastrography, experimental pigs, gastric myoelectric activity, organ distribution, pharmacokinetics, video capsule enteroscopy,
• MeSH
• donepezil chemie   farmakokinetika   farmakologie   MeSH
• gastrointestinální trakt účinky léků   patologie   patofyziologie   MeSH
• indany metabolismus   MeSH
• kapslová endoskopie MeSH
• metabolom * účinky léků   MeSH
• migrující myoelektrický komplex * účinky léků   MeSH
• piperidiny metabolismus   MeSH
• prasata MeSH
• síran dextranu MeSH
• žaludek účinky léků   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 6-O-desmethyl donepezil MeSH Prohlížeč
• donepezil MeSH
• indany MeSH
• piperidiny MeSH
• síran dextranu MeSH

Thanks to the widespread use and safety profile of donepezil (1) in the treatment of Alzheimer's disease (AD), one of the most widely adopted multi-target-directed ligand (MTDL) design strategies is to modify its molecular structure by linking a second fragment carrying an additional AD-relevant biological property. Herein, supported by a proposed combination therapy of 1 and the quinone drug idebenone, we rationally designed novel 1-based MTDLs targeting Aβ and oxidative pathways. By exploiting a bioisosteric replacement of the indanone core of 1 with a 1,4-naphthoquinone, we ended up with a series of highly merged derivatives, in principle devoid of the "physicochemical challenge" typical of large hybrid-based MTDLs. A preliminary investigation of their multi-target profile identified 9, which showed a potent and selective butyrylcholinesterase inhibitory activity, together with antioxidant and antiaggregating properties. In addition, it displayed a promising drug-like profile.

• Klíčová slova
• Alzheimer's disease, drug design, medicinal chemistry, multi-target drug discovery, polypharmacology,
• MeSH
• acetylcholinesterasa chemie   metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   MeSH
• amyloidní beta-protein antagonisté a inhibitory   metabolismus   MeSH
• antioxidancia chemie   metabolismus   farmakologie   MeSH
• cholinesterasové inhibitory chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• donepezil chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• hematoencefalická bariéra diagnostické zobrazování   metabolismus   MeSH
• indany chemie   MeSH
• lidé MeSH
• ligandy * MeSH
• nádorové buněčné linie MeSH
• neuroprotektivní látky chemie   metabolismus   farmakologie   terapeutické užití   MeSH
• oxidační stres účinky léků   MeSH
• proteinové agregáty účinky léků   MeSH
• racionální návrh léčiv MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• amyloidní beta-protein MeSH
• antioxidancia MeSH
• cholinesterasové inhibitory MeSH
• donepezil MeSH
• indacrinone MeSH Prohlížeč
• indany MeSH
• ligandy * MeSH
• neuroprotektivní látky MeSH
• proteinové agregáty MeSH

We describe herein the design, multicomponent synthesis and biological studies of new donepezil + chromone + melatonin hybrids as potential agents for Alzheimer's disease (AD) therapy. We have identified compound 14n as promising multitarget small molecule showing strong BuChE inhibition (IC50 = 11.90 ± 0.05 nM), moderate hAChE (IC50 = 1.73 ± 0.34 μM), hMAO A (IC50 = 2.78 ± 0.12 μM), and MAO B (IC50 = 21.29 ± 3.85 μM) inhibition, while keeping a strong antioxidant power (3.04 TE, ORAC test). Consequently, the results reported here support the development of new multitarget Donepezil + Chromone + Melatonin hybrids, such as compound 14n, as a potential drug for AD patients cure.

• Klíčová slova
• Antioxidant, MAO-A, MAO-B, ORAC, Ugi-4MCR, cholinesterases, donepezil,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• chromony chemie   farmakologie   MeSH
• donepezil chemie   farmakologie   MeSH
• inhibitory MAO chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• melatonin chemie   farmakologie   MeSH
• molekulární struktura MeSH
• monoaminoxidasa metabolismus   MeSH
• simulace molekulového dockingu MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• chromony MeSH
• donepezil MeSH
• inhibitory MAO MeSH
• melatonin MeSH
• monoaminoxidasa MeSH

BACKGROUND: Many factors are involved in Alzheimer's Disease (AD) such as amyloid plaques, neurofibrillary tangles, cholinergic deficit and oxidative stress. To counter the complexity of the disease the new approach for drug development is to create a single molecule able to act simultaneously on different targets. OBJECTIVE: We conceived eight drug likeliness compounds targeting the inhibition of cholinesterases and the scavenging of radicals. METHODS: We synthesised the new molecules by the Passerini multicomponent reaction and evaluated their inhibitory activities against acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) as well as their antioxidant activities by the Oxygen Radical Absorbance Capacity (ORAC) assay. The lipinski's rule for drug likeness and in silico ADME prediction was also performed. RESULTS: Compounds 4f [IC50 (EeAChE) = 0.30 μM; IC50 (eqBuChE) = 0.09 μM; ORAC = 0.64 TE] and 4h [IC50 (EeAChE) = 1 μM; IC50 (eqBuChE) = 0.03 μM; ORAC = 0.50 TE] were identified as hits for further development. CONCLUSION: The Passerini reaction allowed us the facile synthesis of ditarget molecules of interest for the treatment of AD.

• Klíčová slova
• Alzheimer disease, ORAC, antioxidants, cholinesterase, chromone, donepezil, passerini reaction.,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   farmakologie   MeSH
• chromony chemická syntéza   farmakologie   MeSH
• donepezil chemická syntéza   farmakologie   MeSH
• lidé MeSH
• preklinické hodnocení léčiv MeSH
• scavengery volných radikálů chemická syntéza   farmakologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• chromony MeSH
• donepezil MeSH
• scavengery volných radikálů MeSH

Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aβ) peptide. The targeting includes direct interaction of the compounds with Aβ, AChE-induced Aβ aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aβ assembly.

• Klíčová slova
• Acetylcholinesterase, Alzheimer`s disease, amyloid-β, beta-secretase 1, biometal, butyrylcholinesterase, multitarget directed ligands, neuroprotection.,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• amyloidní beta-protein metabolismus   MeSH
• cholinesterasové inhibitory farmakologie   terapeutické užití   MeSH
• donepezil analogy a deriváty   MeSH
• lidé MeSH
• patologická konformace proteinů farmakoterapie   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• amyloidní beta-protein MeSH
• cholinesterasové inhibitory MeSH
• donepezil MeSH

Alzheimer's Disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine. Donepezil was able to ameliorate the symptoms related to AD mainly via AChE, but also through reduction of β-amyloid burden. This review presents the overview of donepezilrelated compounds as potential anti-AD drugs developed on the basis of cholinergic hypothesis to act as solely AChE and butyrylcholinesterase (BChE) inhibitors.

• Klíčová slova
• Alzheimer’s disease, NMDA, acetylcholinesterase, butyrylcholinesterase, donepezil, inhibitor, treatment.,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc farmakoterapie   metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemie   farmakologie   terapeutické užití   MeSH
• donepezil chemie   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• molekulární struktura MeSH
• neuroprotektivní látky chemie   farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• systematický přehled MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• donepezil MeSH
• neuroprotektivní látky MeSH