Background: Donepezil is an acetylcholinesterase inhibitor used in Alzheimer's disease management. It improves clinical symptoms but carries risks of orthostatic hypotension and bradycardia. Uncommon severe bradyarrhythmias post-discontinuation deserve attention. In addition, there have been no previous case reports regarding severe bradyarrhythmias post donepezil discontinuation. Case presentation: We report a case of a 33-year-old woman with a history of recurrent fainting. She has dementia and regularly takes donepezil. She experienced severe bradyarrhythmia with heart rate of 45 beats per minute regular on dopamine 5 μg/kg/min and unresponsive to atropine. The discontinuation of donepezil did not improve asymptomatic bradycardia. The use of temporary pacemaker (TPM) improved the patient's condition, then permanent pacemaker (PPM) was implanted. Conclusions: This case report highlights donepezil's link to severe bradyarrhythmia in dementia patients. It stresses the challenges in managing adverse effects, suggesting that stopping donepezil and anticholinergic therapy may not always be sufficient and pacemaker implantation may be required.
- MeSH
- bradykardie * diagnóza terapie MeSH
- demence farmakoterapie komplikace MeSH
- donepezil * aplikace a dávkování škodlivé účinky MeSH
- dospělí MeSH
- elektrokardiografie MeSH
- hrudník diagnostické zobrazování patologie MeSH
- kardiostimulace umělá MeSH
- kazuistiky jako téma MeSH
- lidé MeSH
- nenasazení léčby MeSH
- synkopa etiologie MeSH
- závrať etiologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- kazuistiky MeSH
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.
- 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
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.
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.
- 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
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.
- 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
- MeSH
- bradykardie * chemicky indukované etiologie terapie MeSH
- butylskopolamin terapeutické užití MeSH
- cholinesterasové inhibitory škodlivé účinky terapeutické užití MeSH
- demence farmakoterapie komplikace MeSH
- donepezil škodlivé účinky MeSH
- lidé MeSH
- nootropní látky * škodlivé účinky MeSH
- senioři MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- kazuistiky 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.
- 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
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.
- 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
- MeSH
- donepezil terapeutické užití MeSH
- echokardiografie metody MeSH
- infarkt sleziny * diagnóza terapie MeSH
- kognitivní poruchy * diagnóza terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- neurozobrazování metody MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- kazuistiky 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.
- 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
