-
International Journal of Molecular... May 2023The extension of human life makes it more and more important to prevent and treat diseases of the elderly, including Alzheimer's disease (AD) and osteoporosis. Little is...
The extension of human life makes it more and more important to prevent and treat diseases of the elderly, including Alzheimer's disease (AD) and osteoporosis. Little is known about the effects of drugs used in the treatment of AD on the musculoskeletal system. The aim of the present study was to investigate the effects of donepezil, an acetylcholinesterase inhibitor, on the musculoskeletal system in rats with normal and reduced estrogen levels. The study was carried out on four groups of mature female rats: non-ovariectomized (NOVX) control rats, NOVX rats treated with donepezil, ovariectomized (OVX) control rats and OVX rats treated with donepezil. Donepezil (1 mg/kg p.o.) was administered for four weeks, starting one week after the ovariectomy. The serum concentrations of CTX-I, osteocalcin and other biochemical parameters, bone mass, density, mineralization, histomorphometric parameters and mechanical properties, and skeletal muscle mass and strength were examined. Estrogen deficiency increased bone resorption and formation and worsened cancellous bone mechanical properties and histomorphometric parameters. In NOVX rats, donepezil decreased bone volume to tissue volume ratio in the distal femoral metaphysis, increased the serum phosphorus concentration and tended to decrease skeletal muscle strength. No significant bone effects of donepezil were observed in OVX rats. The results of the present study indicate slightly unfavorable effects of donepezil on the musculoskeletal system in rats with normal estrogen levels.
Topics: Humans; Rats; Female; Animals; Aged; Donepezil; Rats, Sprague-Dawley; Acetylcholinesterase; Bone and Bones; Bone Density; Estrogens; Ovariectomy
PubMed: 37240337
DOI: 10.3390/ijms24108991 -
Scientific Reports Jun 2023An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in older children and adults. Acetylcholinesterase inhibitors (AChEI)... (Clinical Trial)
Clinical Trial
An elevated threshold for neuroplasticity limits visual gains with treatment of residual amblyopia in older children and adults. Acetylcholinesterase inhibitors (AChEI) can enable visual neuroplasticity and promote recovery from amblyopia in adult mice. Motivated by these promising findings, we sought to determine whether donepezil, a commercially available AChEI, can enable recovery in older children and adults with residual amblyopia. In this open-label pilot efficacy study, 16 participants (mean age 16 years; range 9-37 years) with residual anisometropic and/or strabismic amblyopia were treated with daily oral donepezil for 12 weeks. Donepezil dosage was started at 2.5 or 5.0 mg based on age and increased by 2.5 mg if the amblyopic eye visual acuity did not improve by 1 line from the visit 4 weeks prior for a maximum dosage of 7.5 or 10 mg. Participants < 18 years of age further patched the dominant eye. The primary outcome was visual acuity in the amblyopic eye at 22 weeks, 10 weeks after treatment was discontinued. Mean amblyopic eye visual acuity improved 1.2 lines (range 0.0-3.0), and 4/16 (25%) improved by ≥ 2 lines after 12 weeks of treatment. Gains were maintained 10 weeks after cessation of donepezil and were similar for children and adults. Adverse events were mild and self-limited. Residual amblyopia improves in older children and adults treated with donepezil, supporting the concept that the critical window of visual cortical plasticity can be pharmacologically manipulated to treat amblyopia. Placebo-controlled studies are needed.
Topics: Animals; Mice; Acetylcholinesterase; Amblyopia; Donepezil; Visual Acuity
PubMed: 37349338
DOI: 10.1038/s41598-023-34891-5 -
Carbohydrate Polymers Nov 2022A donepezil hydrochloride (DPZ)-reinforced cellulose nanocrystal (CNC) hydrogel structure with pH control was developed for sustained drug delivery through subcutaneous...
A donepezil hydrochloride (DPZ)-reinforced cellulose nanocrystal (CNC) hydrogel structure with pH control was developed for sustained drug delivery through subcutaneous injection. In the present study, an aggregated CNC gel was fabricated by reducing the electrostatic repulsion between CNC particles by incorporating DPZ and adjusting the pH value to 7.7. The crosslinked CNC/DPZ (cCNC/DPZ) gel exhibited immediate gelation, injection capability through a single syringe, improved viscoelasticity, and shear-thinning properties. Interactions between the CNCs and DPZ and pH regulation were assessed using several solid-state studies, and a sustained release profile of the DPZ from the cCNC/DPZ gel was also observed. In the pharmacokinetic study, a higher half-life and mean residence time and lower maximum drug concentration values were obtained in the cCNC/DPZ group than in the DPZ solution and CNC/DPZ groups after subcutaneous injection. Drug salt form-incorporated and pH-controlled CNC hydrogel systems can be safely applied to the subcutaneous delivery of DPZ.
Topics: Cellulose; Donepezil; Hydrogels; Nanoparticles; Static Electricity
PubMed: 36088017
DOI: 10.1016/j.carbpol.2022.119887 -
JAMA May 2022
Topics: Administration, Cutaneous; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Humans; Indans; Nootropic Agents; Rivastigmine; Transdermal Patch
PubMed: 35503362
DOI: 10.1001/jama.2022.6662 -
Journal of Pharmacological Sciences Jul 2019Oxaliplatin induces severe peripheral neuropathy. The effect of donepezil, a drug used for treatment of Alzheimer's disease, on oxaliplatin-induced peripheral neuropathy...
Oxaliplatin induces severe peripheral neuropathy. The effect of donepezil, a drug used for treatment of Alzheimer's disease, on oxaliplatin-induced peripheral neuropathy was investigated using both in vivo and in vitro models. Donepezil effectively attenuated oxaliplatin- and cisplatin-induced inhibition of neurite outgrowth in cultured PC12 cells. In a rat model, repeated oral administration of donepezil (5 times/week for 4 weeks) ameliorated oxaliplatin-induced mechanical allodynia (von Frey test) and sciatic nerve axonal degeneration. Moreover, donepezil did not inhibit the anti-tumor activity of oxaliplatin in any cultured cancer cell line. Therefore, donepezil may be useful for managing oxaliplatin-induced peripheral neuropathy.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Donepezil; Male; Mice; Neuroprotective Agents; Oxaliplatin; PC12 Cells; Peripheral Nervous System Diseases; Rats; Rats, Sprague-Dawley; Sciatic Nerve
PubMed: 31377017
DOI: 10.1016/j.jphs.2019.05.009 -
Expert Opinion on Investigational Drugs May 2009Anorexia nervosa is a serious, multifactorial disease, characterized by psychiatric and neurological disturbances, which would appear to be similar to the manifestations... (Review)
Review
Anorexia nervosa is a serious, multifactorial disease, characterized by psychiatric and neurological disturbances, which would appear to be similar to the manifestations of dementia. Patients with anorexia nervosa present compromised affectivity, characterized by hypomanic, manic and depressive symptoms, and their cholinergic system is altered with a decrease in the release of acetylcholine. Donepezil is a drug that been proven to be effective in the treatment of dementia, including Alzheimer's; it has been used for affective disorders and its mechanism of action is to inhibit the acetylcholinesterase enzyme to increase acetylcholine. Therefore, donepezil could be effective in treating anorexia nervosa.
Topics: Animals; Anorexia Nervosa; Donepezil; Humans; Indans; Piperidines; Treatment Outcome
PubMed: 19388874
DOI: 10.1517/13543780902810360 -
International Journal of Clinical... Feb 2019Donepezil is an acetylcholinesterase inhibitor (AChI) that improves cognitive function in Alzheimer's disease (AD) patients. However, AChIs are usually associated with...
OBJECTIVE
Donepezil is an acetylcholinesterase inhibitor (AChI) that improves cognitive function in Alzheimer's disease (AD) patients. However, AChIs are usually associated with peripheral adverse reactions. Here, we investigated the cardiac outcomes in elderly AD patients treated with donepezil.
MATERIALS AND METHODS
A total of 82 AD patients (age, 75.47 ± 6.53 years) received 5 mg or 10 mg donepezil (n = 41/group) once daily for 12 weeks. Next, we examined the heart rate (HR), cardiac rhythm, and PR, QRS, and QTc intervals.
RESULTS
Compared to the 5-mg donepezil-treated group, the HR was slower in the 10-mg donepezil-treated group at the 4, 8, and 12 weeks of treatment (p = 0.041, 0.026, 0.008, respectively). The PR interval was longer in the 10-mg donepezil-treated group at the 12 week of treatment (p = 0.022). Compared to the pretreatment values, the post-treatment HR and PR interval in the 10-mg donepezil-treated group were significantly slower and longer, respectively (p = 0.002, p = 0.005). Further, the HR was significantly correlated to the donepezil dosage (p = 0.014). Similarly, donepezil dosage and treatment interval were significantly correlated (p = 0.048).
CONCLUSION
Taken together, our findings suggest that 10 mg donepezil decreased the HR of elderly AD patients without inducing severe cardiac outcomes. Therefore, AD patients receiving donepezil should undergo regular cardiovascular monitoring. .
Topics: Aged; Aged, 80 and over; Alzheimer Disease; Cholinesterase Inhibitors; Donepezil; Heart Rate; Humans
PubMed: 30378536
DOI: 10.5414/CP203257 -
Journal of Alzheimer's Disease : JAD 2022Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Donepezil is approved for treatment of dementia of the Alzheimer type and is currently available only in tablet forms in the United States.
OBJECTIVE
To compare steady-state pharmacokinetics of once-weekly 10-mg/d and 5-mg/d Corplex™ donepezil transdermal delivery systems (TDS) with once-daily 10-mg oral donepezil.
METHODS
Open-label, randomized, crossover study (NCT04617782) enrolled healthy participants aged 18-55 years. All participants received 5-mg/d donepezil TDS during the 5-week Period 1, followed by 10-mg/d TDS or 10-mg/d oral donepezil in the 5-week Period 2; treatments were switched in Period 3. Bioequivalence was assessed at steady state on Week 5.
RESULTS
All 60 enrolled participants received 5-mg/d TDS, 55 received 10-mg/d TDS, and 56 received oral donepezil. Adjusted geometric mean ratio (% [90% CI]) for maximum plasma concentration and area under the plasma concentration versus time curve (0-168 h) were 88.7 (81.7-96.2) and 108.6 (100.5-117.4) for 10-mg/d and 86.1 (79.8-92.9) and 105.3 (97.6-113.6) for dose-normalized 5-mg/d TDS and were generally within the 80% -125% range for establishing bioequivalence with oral donepezil. Skin adhesion was similar for both TDSs (>80% of patches remaining ≥75% adhered throughout the wear period). Overall incidence of adverse events (AEs) was similar across treatments. Compared with 10-mg/d TDS, oral donepezil was associated with higher incidence of gastrointestinal and nervous system AEs (14.5% versus 53.6% and 14.5% versus 30.4%, respectively).
CONCLUSION
Donepezil TDSs are bioequivalent to oral donepezil at steady state and have a safety profile that supports their use in treating dementia of the Alzheimer type.
Topics: Adolescent; Adult; Humans; Middle Aged; Young Adult; Alzheimer Disease; Cross-Over Studies; Donepezil
PubMed: 36120781
DOI: 10.3233/JAD-220530 -
British Journal of Pharmacology Dec 2022Donepezil, a piperidine inhibitor of acetylcholinesterase (AChE) prescribed for treatment of Alzheimer's disease, has adverse neuromuscular effects in humans, including...
BACKGROUND AND PURPOSE
Donepezil, a piperidine inhibitor of acetylcholinesterase (AChE) prescribed for treatment of Alzheimer's disease, has adverse neuromuscular effects in humans, including requirement for higher concentrations of non-depolarising neuromuscular blockers during surgery. Here, we examined the effects of donepezil on synaptic transmission at neuromuscular junctions (NMJs) in isolated nerve-muscle preparations from mice.
EXPERIMENTAL APPROACH
We measured effects of therapeutic concentrations of donepezil (10 nM to 1 μM) on AChE enzymic activity, muscle force responses to repetitive stimulation, and spontaneous and evoked endplate potentials (EPPs) recorded intracellularly from flexor digitorum brevis muscles from CD01 or C57BlWld mice.
KEY RESULTS
Donepezil inhibited muscle AChE with an approximate IC of 30 nM. Tetanic stimulation in sub-micromolar concentrations of donepezil prolonged post-tetanic muscle contractions. Preliminary Fluo4-imaging indicated an association of these contractions with an increase and slow decay of intracellular Ca transients at motor endplates. Donepezil prolonged spontaneous miniature EPP (MEPP) decay time constants by about 65% and extended evoked EPP duration almost threefold. The mean frequency of spontaneous MEPPs was unaffected but the incidence of 'giant' MEPPs (gMEPPs), some exceeding 10 mV in amplitude, was increased. Neither mean MEPP amplitude (excluding gMEPPs), mean EPP amplitude, quantal content or synaptic depression during repetitive stimulation were significantly altered by concentrations of donepezil up to 1 μM.
CONCLUSION AND IMPLICATIONS
Adverse neuromuscular signs associated with donepezil therapy, including relative insensitivity to neuromuscular blockers, are probably due to inhibition of AChE at NMJs, prolonging the action of ACh on postsynaptic nicotinic acetylcholine receptors but without substantively impairing evoked ACh release.
Topics: Humans; Mice; Animals; Acetylcholinesterase; Donepezil; Neuromuscular Junction; Synaptic Transmission; Muscle, Skeletal
PubMed: 36028305
DOI: 10.1111/bph.15940 -
Journal of Chromatography. B,... May 2023Accumulated clinical and biomedical evidence suggests that abnormalities in systemic metabolic processes such as fatty acid and amino acid metabolism can affect the...
Accumulated clinical and biomedical evidence suggests that abnormalities in systemic metabolic processes such as fatty acid and amino acid metabolism can affect the brain function and behavior of various central nervous system diseases such as Alzheimer's disease (AD). In this study, metabolic profiling was used to investigate changes in plasma and urine metabolites following stereotactic injection of amyloid β (Aβ) and treatment with donepezil in rats. Aβ causes cognitive impairment, while donepezil treatment successfully improves memory impairment. Donepezil improves Aβ-induced plasma fatty acid and bile acid metabolism disorders, as well as Aβ-induced urine phenylalanine and tryptophan metabolism disorders in rats. More specifically, the plasma fatty acids improved by donepezil include alpha-linolenic acid, stearidonic acid, eicosapentaenoic acid, docosahexaenoic acid, linoleic acid, arachidonic acid, oleic acid, and palmitic acid, among others. Additionally, donepezil significantly restored the downregulation of bile acids such as ursodeoxycholic acid, cholic acid, and glycocholic acid caused by Aβ. As for urine metabolites, phenylacetylglycine, epinephrine, and other phenylalanine metabolites, as well as kynurenic acid, xanthurenic acid, and other tryptophan metabolites, were worsened by Aβ and improved by donepezil. These findings suggest that the cognitive impairment induced by Aβ and the improvement by donepezil are associated with changes in metabolic disorders in rats. This study provides basic data for the effects of Aβ and donepezil on plasma and urine metabolites in Aβ-induced AD rat models.
Topics: Rats; Animals; Alzheimer Disease; Amyloid beta-Peptides; Donepezil; Tryptophan; Fatty Acids; Disease Models, Animal
PubMed: 37263123
DOI: 10.1016/j.jchromb.2023.123766