Dose Of Donepezil Research Articles

Joint administration of sub-threshold doses of the acetylcholinesterase inhibitor donepezil with those of the NMDA receptor antagonist ketamine improved rats’ recognition memory abilities

Alzheimer’s Disease (AD) is a serious progressive neurodegenerative illness conducting to the decay of cognitive functions. A few drugs have been approved for the therapy of AD, including the acetylcholinesterase inhibitors (AChEIs) like donepezil. Their efficiency, however, is modest and their application is associated with toxicity. Recently, the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine, a rapidly acting antidepressant, has been proposed as a potential agent for the treatment of AD. The present study was designed to investigate the effects exerted by the combination of sub-threshold doses of donepezil with those of ketamine on rats’ recognition memory abilities. For these experiments, the object recognition task (ORT) and the object location task (OLT), two procedures assessing non-spatial and spatial recognition memory respectively in rodents were used. Post-training acute administration of inactive doses of donepezil (0.3 mg/kg) and ketamine (1 mg/kg) counteracted non-spatial and spatial recognition memory impairments. The present findings, although preliminary, propose that the combined administration of ketamine and donepezil could represent a new strategy for the therapy of memory disorders, a common feature of AD patients.

Neuroprotective action of hordenine against the Aluminium Chloride (AlCl3) induced Alzheimer's diseases & associated memory impairment in experimental rats

ObjectiveTo investigate the neuroprotective action of hordenine against the cognitive dysfunction induced by aluminium chloride (AlCl3) in Wistar rats MethodologyRats were given oral doses of hordenine (25 and 50 mg/kg), donepezil (5 mg/kg), and AlCl3 (175 mg/kg) for 28 days. During the study, neurobehavioral parameters included Morris water maze (MWM), open field test (OFT), and novel object recognition test (NORT) to assess the cognitive effect. On the 29th day rats were sacrificed and brain tissues removed for biochemical and histopathological analyses. ResultsAlCl3 rats exhibited altered neurobehavioral patterns and cognitive impairment in experimental rats. Although AlCl3 raised the levels of mid-brain acetylcholinesterase (AChE), lipid peroxidation (LPO), nitrite, tumour necrosis factor-α (TNF-α), interleukin-β (IL-β), nuclear factor-kappa B (NF-κB), brain-derived neurotrophic factor (BDNF), and it decreased the levels of antioxidants including glutathione (GSH), catalase, superoxide dismutase (SOD), and body weight. In cortical and hippocampal slices, AlCl3 also revealed anatomical alterations that resulted in a decrease in the density of microglia. But donepezil and hordenine reversed these alterations to normal while demonstrating a neuroprotective effect against AD which is caused by AlCl3. ConclusionHordenine improved memory and other cognitive functions, demonstrating a neuroprotective effect against AlCl3-induced Alzheimer's disease. These findings imply that hordenine may be able to reverse the effects of oxidative stress and neuroinflammation, improve cognitive decline, and protect the brain's histological structure.

Oxyresveratrol-β-cyclodextrin mitigates streptozotocin-induced Alzheimer's model cognitive impairment, histone deacetylase activity in rats: in silico & in vivo studies

Alzheimer’s disease (AD) is associated with cognitive deficits and epigenetic deacetylation that can be modulated by natural products. The role of natural oxyresveratrol-β-cyclodextrin (ORV) on cognition and histone deacetylase activity in AD is unclear. Herein, in-silico docking and molecular dynamics simulation analysis determined that oxyresveratrol potentially targets histone deacetylase-2 (HDAC2). We therefore evaluated the in vivo ameliorative effect of ORV against cognitive deficit, cerebral and hippocampal expression of HDAC in experimental AD rats. Intracerebroventricular injection of STZ (3 mg/kg) induced experimental AD and the rats were treated with low dose (200 mg/kg), high dose (400 mg/kg) of ORV and donepezil (10 mg/kg) for 21 days. The STZ-induced AD caused cognitive and behavioural deficits demonstrated by considerable increases in acetylcholinesterase activity and escape latency compared to sham control. The levels of malondialdehyde (MDA) and HDAC activity were significantly increased in AD disease group comparison to the sham. Interestingly, the ORV reversed the cognitive-behavioural deficit and prominently reduced the MDA and HDAC levels comparable to the effect of the standard drug, donepezil. The findings suggest anti-AD role of ORV via antioxidant effect and inhibition of HDAC in the hippocampal and frontal cortical area of rats for AD.

Synthesis and biological evaluation of Halogen-Substituted novel α-Ketoamides as potential protein aggregation modulators in Alzheimer’s disease

The escalating prevalence of Alzheimer's disease (AD) has prompted extensive research into potential therapeutic interventions, with a specific focus on molecular targets such as amyloid beta (Aβ) and tau protein aggregation. In this study, a series of α-ketoamide derivatives was synthesized from β,γ-unsaturated α-keto thioesters, achieving high purity and good yield. Thioflavin T based Aβ aggregation assay identified four promising compounds (BD19, BD23, BD24, and BD27) that demonstrated significant inhibitory effects on Aβ aggregation. BD23, selected for its better solubility (0.045 ± 0.0012 mg/ml), was further subjected to in vitro Parallel Artificial Membrane Permeability Assay to determine the Blood-Brain-Barrier permeability and emerged as BBB permeable with permeability rate (Pe) of 10.66 ± 8.11 × 10−6 cm/s. In addition to its Aβ inhibitory properties, BD23 exhibited significant inhibition of heparin-induced tau aggregation and demonstrated non-toxicity in SHSY5Y cell lines. Subsequent in vivo assays were conducted, administering compound BD23 to an Aβ induced mouse model of AD at various doses (1, 2, & 5 mg/kg). The results revealed a noteworthy enhancement in cognitive functions, particularly when BD23 was administered at a dosage of 5 mg/kg, comparable to the effects observed with the standard dose of Donepezil (DNP). In silico investigations, including molecular docking, molecular dynamics simulations, and Density Functional Theory calculations provided insights into BD23′s interactions with the targets and electronic properties. These analyses contribute to the understanding of the therapeutic potential of the lead compounds BD23 which further pave the way for further exploration of its therapeutic potential in the context of AD.

The importance of non-pharmacological approach versus pharmacological treatment of behavioral and psychological symptoms (bpsd) in patients with Alzheimer’s dementia (AD) in a geriatric institution

IntroductionBPSDs in patients with AD are present up to 90% and can cause serious complications in their overall health. A non-pharmacological approach and cognitive enhancers should be a priority in treatment in order to reduce the use of antipsychotics. In the pharmacological treatment of bpsd, additional therapy is inevitable in many casesObjectives the need for adequat educatation of the medical staff in a geriatric center for the nonfarmacological approach in patients with bpsd in AD. Polypharmacy is common in farmacological treatment.MethodsA cross-sectional study of 180 patients hospitalized at geriatric unit in period of January till May 2023 was conducted. 61(33.9%) were patients with AD, 44 or 72.1% were females and 17 or 27.9% were males, with mean age 78.6±5.6 years. 50 patients (82.0%) had potentiated BPSD in the first days of hospitalization and needed additional therapyResults: 19 od 61pts (31.1%) were on dual therapy, full doses of donepezil and memantine. 17 (89.5%) needed additional therapy for BPSD; 13 (68.4%) a short-term antipsychotic and 4 (21.1%) patients antidepressant therapy. 22 patients (36.1%) were admitted with donepezil only. 18 (81,8%) needed additional therapy. The remaining 20 (32,8%) were solely on memantine. 15 (75.0%) needed additional therapyConclusionsVast majority of patients AD (82.0%) manifested BPSD and needed additional therapy. Number of scientific papers it is found that cognitive stimulation in persons with moderate dementia has a benefit more than any pharmacological treatment. Education of caregivers of people with AD is inevitable.Opening of day care centers that will enable continuous support as well as individual access which would help delay institutionalization of people with BPSD at ADthe needDisclosure of InterestNone Declared

Strategies for managing patients with moderate to severe Alzheimer’s disease: high‐dose donepezil vs. memantine combination

AbstractBackgroundsWhen dementia patients who took already a maintenance dose of 10mg donepezil get worse to advanced stage, clinicians would consider and select which one is better between higher‐dose donepezil (23 mg/day) and memantine combination.ObjectivesTo compare the clinical benefits between high‐dose donepezil and memantine (20 mg/day) combination in moderate to severe Alzheimer’s diseaseMethodsA single center, retrospective, observational study was conducted. Patients with moderate to severe AD who were treated with a stable dose of donepezil were included. They started further treatments such as higher‐dose donepezil or memantine combination because they showed poor or waning response to a maintenance dose. After 6 months follow‐up, clinical efficacy and safety were compared between two groups, higher‐dose donepezil and memantine combination.ResultsA total of 108 patients, 35 with higher‐dose donepezil and 75 with memantine combination, were included. Baseline characteristics such as age, sex, education, MMSE, and CDR were similar between groups. After follow‐up, changes of MMSE and CDR were not different. Treatment responses measured as CGI‐C were as follows: 41.3% (improved 31, not changed 25, and worse 9) of patients improved after memantine combination and 22.9% (improved 8, not changed 12, and worse 15) improved after higher‐dose donepezil (p = 0.069). Adverse events were not different. Among patients with memantine combination, those who had no benefits to the initial donepezil showed better responses (27 vs. 48). Patients who had benefits to lower dose of donepezil showed better responses (24 vs. 11) after higher‐dose.ConclusionBoth of higher‐dose donepezil and memantine combination, which are approved as effective in moderate to severe AD, were not different in clinical benefits and safety. Although not statistically significant, treatment responses showed some differences. Patients who had shown good response at the time of the initial therapy of donepezil preferred higher‐dose donepezil over memantine combination, whereas those who did not respond to the initial donepezil had more effective after memantine was added. Further studies including randomized blind trials could strengthen these findings.

Cognitive Enhancer Donepezil Attenuates Heroin-Seeking Behavior Induced by Cues in Rats.

Opioid use disorder is a significant global problem. Chronic heroin use is associated with impairment of cognitive function and conscious control ability. The cholinergic system can be disrupted following heroin administration, indicating that activation of the cholinergic system may prevent chronic heroin misuse. Donepezil as an inhibitor of cholinesterase has been reported to clinically improve cognition and attention. In this study, the inhibition of heroin self-administration and heroin-seeking behaviours by donepezil were evaluated in rats. Rats were trained to self-administer heroin every four hours for 14 consecutive days under a fixed ratio 1 (FR1) reinforcement schedule, then underwent withdrawal for two weeks. A progressive ratio schedule was then used to evaluate the relative motivational value of heroin reinforcement. After withdrawal, a conditioned cue was introduced for the reinstatement of heroin-seeking behaviour. Donepezil (0.3-3 mg/kg, i.p.) was used during both the FR1 heroin self-administration and progressive ratio schedules. Immunohistochemistry was used to investigate the mechanism of action of donepezil in the rat brain. Pre-treatment with high dose donepezil (3 mg/kg) but not low doses (0.3-1 mg/kg) significantly inhibited heroin self-administration under the FR1 schedule. Donepezil decreased motivation values under the progressive ratio schedule in a dose-dependent manner. All doses of donepezil (1-3 mg/kg) decreased the reinstatement of heroin seeking induced by cues. Correlation analysis indicated that the inhibition of donepezil on heroin-seeking behaviour was positively correlated with an increased expression of dopamine receptor 1 (D1R) and dopamine receptor 2 (D2R) in the nucleus accumbens (NAc) and increased expression of choline acetyltransferase (ChAT) in the ventral tegmental area (VTA). The present study demonstrated that donepezil could inhibit heroin intake and heroin-seeking behaviour. Further, donepezil could regulate dopamine receptors in the NAc via an increase of acetylcholine. These results suggested that donepezil could be developed as a potential approach for the treatment of heroin misuse.

The measured CSF/plasma donepezil concentration ratio but not individually measured CSF and plasma concentrations significantly increase over 24 h after donepezil treatment in patients with Alzheimer’s disease

BackgroundThe 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.

Russian experience in using a combination of fixed doses of donepezil and memantine in the treatment of Alzheimer's disease as an observational non-interventional multicenter program

To evaluate the efficacy, safety, and compliance to therapy with Mioreol, first used as part of routine clinical practice in patients with moderate-to-severe dementia due to AD. The study was conducted as a non-interventional observational program. The work was performed on a group of 48 patients with moderate-to-severe AD aged from 60 to 90 years (median age 74 [69; 77]). The therapeutic dose of Mioreol was 10 mg donepezil + 20 mg memantine, the drug was taken orally, once a day at the same time, regardless of meals. The duration of the course of therapy was 24 weeks. The effects of the drug were assessed using the MMSE, ADAS-Cog, NPI, and CGI scales before the start of therapy and by the end of 12 and 24 weeks of treatment. The use of Mioreol in six-month therapy of AD patients with moderate-to-severe dementia improved not only cognitive but also a wide range of non-cognitive mental disorders. There was an improvement in the CGI-C scale in more than 50% of included patients, positive dynamics on the ADAS-cog scale (6.5 points reduction in total score) and reduction of non-cognitive mental disorders on the NPI scale (4 points reduction in total score). Fixed-dose combination therapy with Mioreol is an effective and well-tolerated treatment option for patients with moderate-to-severe AD. A combination of fixed-dose therapeutic doses of donepezil and memantine is potentially more appropriate than the simultaneous use of two recommended drugs for the treatment of AD, which will improve treatment adherence in patients with moderate to severe AD.

An Investigation on Cognitive and Behavioral Effects of Donepezil on Autistic Children in Winter 2020 in Gorgan's Taleghani Pediatric Hospital.

The present investigation has been done to study the behavioral effects of donepezil in autistic children, given that not much research has been carried out concerning using this drug for treating autism. A cross-sectional and analytic-descriptive study was done on twenty patients with autism, aged 4-17, who visited the neurology clinic of Gorgan's Taleghani Pediatric Hospital and Yasha Pediatric Autism Clinic, Iran from 2019 to 2020. Demographic information, including sex, age, father's education, mother's education ,patient's education, family status, other problems, and ethnicity, were documented using a checklist, having been filled in during interviews with the parents. Before the trial, ABC cognitive and behavioral tests were taken to determine the children's current status. After the tests, these children received a daily dose of donepezil (10mg) before sleep for three months. At the end of the three months, the cognitive and behavioral tests were taken from the children once again. In order to analyze the effects of different factors on the studied variables, including irritability, lethargy, stereotypic behavior, hyperactivity, and inappropriate speech before and after the administration of donepezil in patients, a generalized linear model and to test the effects of donepezil on the studied variables, paired t-test was used. In this study, twenty patients were registered for the investigation, 12 (60%) male and eight (40%) female. Age groups 5-6 had the highest frequency, and age group 17 had the lowest. Regardingthe parents' education, the highest frequency was for bachelor's degrees, and the lowest was for less-than-high school education and master's degree. The highest frequency for the patients' education was kindergarten (60%), and then groups without education (20%) and elementary school-level education (15%). Most of the studied patients (80%) did not have other problems besides autism, and only 20% had other problems besides autism. The family status of 15% of the families was 'separated,' and ethnically, most patients (80%) were Fars, while the rest (20%) were Turkmen. None of the analyzed factors (age, sex, father's education, mother's education, patient's education, other problems, family status, and ethnicity) had a significant effect on the studied variables after the administration of donepezil. Among the studied variables prior to the administration of donepezil and among the analyzed factors, the father's education, the patient's education, other problems, and family status had only a significant effect on stereotypic behavior. The present research findings of the present research indicated that all the studied variables, including irritability, lethargy, stereotypic behavior, hyperactivity, and inappropriate speech, were significantly decreased toward the desired goal. The decreased amounts in irritability, lethargy, stereotypic behavior, hyperactivity, and inappropriate speech after the administration of donepezil were, respectively, 38%, 44%, 54%, 41%, and 54% and on average, these behaviors were reduced by 46%. The present investigation has shown that all the studied variables, including irritability, lethargy, stereotypic behavior, hyperactivity, and inappropriate speech, were significantly decreased towards the desired goal by 46%. This significant decrease is indicative of the effectiveness of the treatment of autism patients with donepezil, and therefore, this drug can be placed as a prominent and essential part of the medical therapy of autism.

Dissociating the pro‐cognitive effects of donepezil and an M1 PAM

AbstractBackgroundDonepezil, an FDA approved drug for dementia in Alzheimer’s disease, increases the extracellular concentration of acetylcholine non‐selectively stimulating cholinergic receptors indiscriminately leading to dose‐limiting side effects. Muscarinic M1 sub‐receptor specific positive allosteric modulators (PAMs) have shown promise in addressing symptoms in Alzheimer’s disease, Schizophrenia and more1. M1 PAMs have little to no agonistic properties, avoiding peripheral side effects, and are mostly centrally located allowing for the modulation of endogenous signaling of the brain2.MethodWe tested non‐human primates in two tasks measuring cognitive flexibility and attentional control3 at varying doses of donepezil and an M1 PAM (VU0453595). Attentional control was measured with a visual search task requiring animals to search for a learned target object among distractors of variable number and similarity to the target object. Cognitive flexibility was measured with a feature‐reward learning task that required animals to learn the value of objects of varying feature complexity by trial and error. Flexibility was indexed as the speed of learning, the degree of latent inhibition and the amount of target perseveration after switching the rewarded feature.ResultDonepezil enhanced attention control at a high dose (0.3 mg/kg) but enhance flexibility only moderately at a lower dose (0.06 mg/kg). In contrast, VU0453595 did not modulate attention, but at 0.1 mg/kg enhanced flexible learning, reduced target perseverations, and increased reaction time measures of decision confidence. At the dose with the most pronounced cognitive benefits donepezil resulted in gastrointestinal side effects, while VU0453595 did not cause side effects.ConclusionThese results suggest that donepezil engages the brain networks underlying cognitive flexibility and interference control at different doses4, while the M1 receptor plays a major role in facilitating flexible behavioral adaptation but with no role in controlling interference. Such receptor specific results can be used to better curate to patient‐specific needs in order to address the most debilitating symptoms with the highest efficacy.1. Melancon, B. J. et al. (2013) Drug Discovery Today https://doi.org/10.1016/j.drudis.2013.09.005.2. Ghoshal, A. et al. (2016) Neuropsychopharmacology doi:10.1038npp.2015.189 3. Womelsdorf, T. et al. (2021) Frontiers in Behavioral Neuroscience https://doi.org/10.3389/fnbeh.2021.721069 4. Hassani, S.A. et al. (2021) Biological Psychiatry Global Open Science https://doi.org/10.1016/j.bpsgos.2021.11.012.

RETRACTED ARTICLE: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

BackgroundRecent investigations suggested that anticancer agents may inhibit the progression of Alzheimer's disease (AD) pathology. Conyza dioscoridis (L.) was demonstrated to have anticancer, antioxidant, anti-inflammatory and antidiabetic effects. This study was carried out to investigate the efficacy of polyphenols from Conyza dioscoridis (L.) extract (PCDE) on AD.MethodsImpacts of 3 doses of PCDE and donepezil, a reference drug, on the features of Alzheimer's disease in two animal models were investigated.ResultsPCDE ameliorated the memory and learning impairment shown in rats following a single dose of scopolamine (scopolamine model) or 17 weeks of high-fat/high-fructose(HF/Hfr) diet coupled with a single dose of streptozotocin, (25 mg/kg) (T2D model). They reduced significantly the high hippocampal cholinesterase activity in the two models of rats. Administration of PCDE for 8 weeks in the T2D model showed a significant reduction in hippocampal GSK-3β, caspase-3 activity and increase in the inhibited glutamate receptor expression (AMPA GluR1 subunit and NMDA receptor subunits NR1, NR2A, NR2B). A significant reduction of HOMA-insulin resistance and serum hypercholesterolemia was observed. The Tau hyperphosphorylation and Aβ 1–42 generation in the hippocampal of T2D rats were significantly decreased by PCDE. Modulation of the oxidative stress markers, (rise in GH and SOD; decrease in MDA levels) and a significant reduction of TNF-α and IL-1β in the hippocampus of T2D rats treated by PCDE extract were important findings in this study. The highest dose tested was 4% of the highest safe dose.ConclusionOur study suggests that PCDE is multi-targeting agent with multiple beneficial activities in combating features of AD. This study may provide a novel therapeutic strategy for AD treatment that warrants clinical studies.

Curcumin improves the ability of donepezil to ameliorate memory impairment in Drosophila melanogaster: involvement of cholinergic and cnc/Nrf2-redox systems

One of the well-established models for examining neurodegeneration and neurotoxicity is the Drosophila melanogaster model of aluminum-induced toxicity. Anti-cholinesterase drugs have been combined with other neuroprotective agents to improve Alzheimer’s disease management, but there is not much information on the combination of anti-cholinesterases with dietary polyphenols to combat memory impairment. Here, we assess how curcumin influences some of the critical therapeutic effects of donepezil (a cholinesterase inhibitor) in AlCl3-treated Drosophila melanogaster. Harwich strain flies were exposed to 40 mM AlCl3 – alone or in combination with curcumin (1 mg/g) and/or donepezil (12.5 µg/g and 25 µg/g) – for seven days. The flies’ behavioral evaluations (memory index and locomotor performance) were analyzed. Thereafter, the flies were processed into homogenates for the quantification of acetylcholinesterase (AChE), catalase, total thiol, and rate of lipid peroxidation, as well as the mRNA levels of acetylcholinesterase (ACE1) and cnc/NRF2. Results showed that AlCl3-treated flies presented impaired memory and increased activities of acetylcholinesterase and lipid peroxidation, while there were decrease in total thiol levels and catalase activity when compared to the control. Also, the expression of ACE1 was significantly increased while that of cnc/NRF2 was significantly decreased. However, combinations of curcumin and donepezil, especially at lower dose of donepezil, significantly improved the memory index and biochemical parameters compared to donepezil alone. Thus, curcumin plus donepezil offers unique therapeutic effects during memory impairment in the D. melanogaster model of neurotoxicity.

Donepezil ameliorates oxygen-glucose deprivation/reoxygenation-induced brain microvascular endothelial cell dysfunction via the SIRT1/FOXO3a/NF-κB pathways

ABSTRACT Ischemic stroke is a disease in which brain tissue is damaged by a sudden rupture or blockage of a blood vessel in the brain that prevents blood from flowing to the brain. Extensive literature has demonstrated the neuroprotective effect of donepezil on brain injury, and this paper attempts to further reveal the effect of donepezil on brain microvascular endothelial cells dysfunction. Human brain microvascular endothelial cells (HBMECs) were treated with oxygen-glucose deprivation/reoxygenation (OGD/R) to induced brain microvascular endothelial cell dysfunction. The OGD/R-induced cell were added with different doses of donepezil with or without Sirtuin-1 (SIRT1) inhibitor EX527. Cell viability of HBMECs was examined by cell counting kit (CCK)-8 assay. OGD/R-treated cell migration was assessed by wound healing assay while angiogenesis in HBMECs was examined by tube formation assay and Western blot analysis. Endothelial cell dysfunction was assessed employing fluorescein isothiocyanate-dextran assay and Western blotting. SIRTI/FOXO3a/NF-kB signaling pathway-related protein expressions were detected using Western blotting. After pretreatment with SIRT1 inhibitor EX527, the above experiments were done again. Donepezil increased cell viability of OGD/R-induced HBMECs, promoted cell migration and angiogenesis, decreased cell permeability, and upregulated the expressions of tight junction proteins. In addition, donepezil regulated the expressions of SIRT1/FOXO3a/NF-κB signaling pathways. However, pretreatment with the SIRT1 inhibitor EX527 reversed the protective effect of donepezil on OGD/R-induced HBMECs. In summary, Donepezil ameliorates OGD/R-induced brain microvascular endothelial cell dysfunction via the SIRT1/FOXO3a/NF-κB pathways.

A Multinational, Multicenter, Randomized, Double-Blind, Active Comparator, Phase III Clinical Trial to Evaluate the Efficacy and Safety of Donepezil Transdermal Patch in Patients With Alzheimer's Disease.

Background and PurposeOral administration of cholinesterase inhibitors is often associated with adverse gastrointestinal effects, and so developing an alternative administration route, such as transdermal, is urgently needed. The primary objective of this study was to determine the efficacy and safety of the IPI-301 donepezil transdermal patch compared with donepezil tablets (control) in mild-to-moderate probable Alzheimer’s disease (AD).MethodsThis prospective, randomized, double-blind, double-dummy, two-arm parallel, multicenter trial included 399 patients, among whom 303 completed the trial. For randomization, the patients were stratified based on previous treatment and donepezil dose; patients in each stratum were randomized to the test and control groups at a 1:1 ratio.ResultsThe difference between the control group and the IPI-301 group, quantified as the Hodges–Lehmann estimate of location shift, was 0.00 (95% confidence interval: -1.00 to 1.33), with an upper limit of less than 2.02. The change in Alzheimer’s Disease Cooperative Study–Activities of Daily Living (ADCS-ADL) score differed significantly between the IPI-301 and control groups (p=0.02). However, the changes in the full-itemized ADCS-ADL scores at week 24 did not differ significantly between the two groups. There were no differences between the two groups regarding the scores for the Clinician Interview-Based Impression of Change (p=0.9097), Mini-Mental State Examination (p=0.7018), Neuropsychiatric Inventory (p=0.7656), or Clinical Dementia Rating (p=0.9990). Adverse events, vital signs, and laboratory test results were comparable between the two groups.ConclusionsIPI-301 was safe and efficacious in improving cognitive function in patients with mild-to-moderate AD.

A phase 1b/2a multicenter study of the safety and preliminary pharmacodynamic effects of selective muscarinic M1 receptor agonist HTL0018318 in patients with mild-to-moderate Alzheimer's disease.

IntroductionThis study examined the safety and pharmacodynamic effects of selective muscarinic M1 receptor orthosteric agonist HTL0018318 in 60 patients with mild‐to‐moderate Alzheimer's disease (AD) on background donepezil 10 mg/day.MethodsA randomized, double‐blind, placebo‐controlled 4‐week safety study of HTL0018318 with up‐titration and maintenance phases, observing exploratory effects on electrophysiological biomarkers and cognition.ResultsTreatment‐emergent adverse events (TEAEs) were mild and less frequently reported during maintenance versus titration. Headache was most commonly reported (7–21%); 0 to 13% reported cholinergic TEAEs (abdominal pain, diarrhea, fatigue, nausea) and two patients discontinued due to TEAEs. At 1 to 2 hours post‐dose, HTL0018318‐related mean maximum elevations in systolic and diastolic blood pressure of 5 to 10 mmHg above placebo were observed during up‐titration but not maintenance. Postive effects of HTL0018318 were found on specific attention and memory endpoints.DiscussionHTL0018318 was well tolerated in mild‐to‐moderate AD patients and showed positive effects on attention and episodic memory on top of therapeutic doses of donepezil.

Dose-Dependent Dissociation of Pro-cognitive Effects of Donepezil on Attention and Cognitive Flexibility in Rhesus Monkeys

BackgroundDonepezil exerts pro-cognitive effects by nonselectively enhancing acetylcholine (ACh) across multiple brain systems. Two brain systems that mediate pro-cognitive effects of attentional control and cognitive flexibility are the prefrontal cortex and the anterior striatum, which have different pharmacokinetic sensitivities to ACh modulation. We speculated that these area-specific ACh profiles lead to distinct optimal dose ranges for donepezil to enhance the cognitive domains of attention and flexible learning. MethodsTo test for dose-specific effects of donepezil on different cognitive domains, we devised a multitask paradigm for nonhuman primates that assessed attention and cognitive flexibility. The nonhuman primates received either vehicle or variable doses of donepezil before task performance. We measured intracerebral donepezil and its strength in preventing the breakdown of ACh within the prefrontal cortex and anterior striatum using solid phase microextraction neurochemistry. ResultsThe highest administered donepezil dose improved attention and made the subjects more robust against distractor interference, but it did not improve flexible learning. In contrast, only a lower dose range of donepezil improved flexible learning and reduced perseveration, but without distractor-dependent attentional improvement. Neurochemical measurements confirmed a dose-dependent increase of extracellular donepezil and decreases in choline within the prefrontal cortex and the striatum. ConclusionsThe donepezil dose for maximally improving attention differed from the dose range that enhanced cognitive flexibility despite the availability of the drug in two major brain systems supporting these functions. These results suggest that in our cohort of adult monkeys, donepezil traded improvements in attention for improvements in cognitive flexibility at a given dose range.

Effects of Donepezil and Medroxyprogesterone Versus Placebo on Weaning in Adult Patients With Non-Pulmonary Etiologies Receiving Invasive Mechanical Ventilation: A triple-blind Randomized Clinical Trial.

Background: Medroxyprogesterone and donepezil could be used as respiratory stimulants in ventilated patients. However, no randomized placebo-controlled trial is available to confirm this approach and compare these drugs. The aim of the current study was to evaluate the effects of donepezil or medroxyprogesterone compared to the placebo in improvement in respiratory status and weaning facilitation in critically ill adult patients receiving mechanical ventilation. Material and Methods: This randomized, triple-blind trial was conducted on 78 ventilated patients in intensive care units (ICU). Patients who were intubated due to pulmonary disorders were ruled out. Patients were randomized in a 1:1:1 ratio to receive 5 mg donepezil (n = 23) or 5 mg medroxyprogesterone (n = 26), or placebo (n = 24) twice a day until weaning (maximum 10 days). The primary endpoints were weaning duration, and duration of invasive mechanical ventilation. Secondary endpoints included rate of successful weaning, changes in arterial blood gas (ABG) parameters, GCS and sequential organ failure assessment (SOFA) score, hemoglobin (Hgb), ICU-mortality, and duration of ICU stay, were measured before and after the intervention and if successful weaning was recorded. Results: Of 78 studied patients who were randomized, 59 weaned successfully. 87% patients in donepezil and 88.5% patients in medroxyprogesterone groups were successfully weaned compared to 66.7% patients in the placebo group. However, this difference was not statistically significant (p-Value = 0.111). Changes in pH, mean duration of intubation, and weaning duration were statistically different in donepezil compared with the control group (p-Value < 0.05). No significant difference in ABG, Hgb, GCS and SOFA score, and duration of intubation were seen in the medroxyprogesterone group, but weaning duration was significantly reduced to 1.429 days compared with the control group (p-Value = 0.038). Conclusion: The results of this clinical trial have demonstrated that the administered dose of medroxyprogesterone and donepezil can expedite the weaning process by reducing the weaning duration compared to placebo. Furthermore, the total duration of invasive ventilation was significantly lower in the donepezil group compared to the control group. Future clinical trials with a larger sample size will determine the exact role of medroxyprogesterone and donepezil in mechanically ventilated patients. Clinical Trial Registration: https://irct.ir/IRCT20190810044500N2 (April 1, 2020).

Controlling the past, owning the present, and future: cholinergic modulation decreases semantic perseverations in a person with post-stroke aphasia

ABSTRACT Background Perseverations in speech production tasks represent a pervasive symptom of chronic aphasia. Semantic perseverations (SPs) are defined as repetitive and unconscious production of specific linguistic forms previously produced, heard, or seen which share semantic relatedness with the target word. Neurochemically, SPs have been attributed to weakened activation of the target word due to the depletion of neurotransmitter systems (acetylcholine and dopamine) occurring in the context of activation of semantic competitors. Aims The present pilot study seeks to evaluate the effectiveness of a cholinergic enhancing drug combined with speech language therapy in reducing SPs and other non-perseverative semantic errors in a person with chronic post-stroke aphasia. Methods & Procedures Combined therapy of the cholinesterase inhibitor donepezil and conventional speech-language therapy (SLT) (2 hours/week) over 16 weeks was administered to a woman with chronic fluent post-stroke aphasia showing high rate of semantic errors. Aphasia and SPs assessments were performed at four different time-points across the study: at baseline, after donepezil 5 mg, donepezil 10 mg, and after 4-weeks of washout. The changes induced by the treatments on the occurrence of SPs and semantic paraphasias during a picture naming task were evaluated. By using a specific statistical methodology, we performed a fine-grained analysis of the frequency of SPs and their temporal course at the different time-points to dissect changes induced by the treatment. Results At baseline, there were significantly more SPs than expected by a random distribution, whereas a marked reduction of these errors was found in the three following evaluations. A significant reduction in aphasia severity was also found with high donepezil doses and this improvement maintained after a 4-week washout period. Everyday communication improved with low doses of donepezil. Conclusion Our findings suggest that decreased activity of the cholinergic system may exert a permissive role for the production of SPs and highlight the importance of combining cholinergic agents with speech-language therapy to reduce SPs in aphasia at the time that other language deficits are also improved.

Protective effect of andrographolide against STZ induced Alzheimer's disease in experimental rats: possible neuromodulation and Aβ(1-42) analysis.

STZ is a glucosamine-nitrosourea compound, causes dysfunctioning of insulin receptors in the brain and disrupts glucose metabolism, produces cognitive decline and AD-like symptoms. ICV injection of STZ causes accumulation of Aβ and cognitive dysfunctions. Andrographolide (ANDRO) is a major bioactive constituent of Andrographis paniculata, has various biological activities such as antioxidant, anti-inflammatory, anti-cholinesterase, and neuroprotective properties. The study aimed to evaluate the neuroprotective effect of ANDRO against ICV-STZ induced AD-like symptoms in rats. To conduct the study, the Wistar rat received two injections of STZ (3mg/kg) through the ICV route. Rats were treated with three different doses of ANDRO (15, 30, and 60mg/kg, p.o.) and donepezil (5mg/kg, p.o.) for 14days. The behavioral impairments were analyzed on weekly basis. Subsequently, rats were sacrificed for the assessment of biochemical (MDA, Nitrite, GSH, SOD, Catalase and AChE), neuroinflammatory markers (IL-1β, IL-16, and TNF-α), neurotransmitters (glutamate and GABA), level of Aβ1-42 and p tau in the hippocampus on day 21st. Our result indicated that ANDRO treatment provided a protective effect against STZ induced behavioral deficits and changes in the biochemical, neuroinflammatory mediators, and neurotransmitters of the hippocampus. Further, ANDRO also reduced the level of Aβ1-42 and p tau in the rat hippocampus. These findings suggested that the antioxidant, anti-inflammatory, anti-cholinesterase potential of ANDRO contributed to its neuroprotective effect as well as promising therapeutic candidate for the treatment of cognitive impairment and AD-like symptoms.