Combination Of Donepezil Research Articles

The combination of donepezil and cognitive training for improving treatment outcomes for alcohol use disorder: Design of a randomized controlled trial

BackgroundThe development of alcohol use disorder (AUD) is a major concern in public health, and cognitive impairments caused by alcohol are involved in this process. Emerging neurobiological evidence suggests that donepezil, an anticholinesterase agent, may improve AUD treatment outcomes by enhancing neurocognitive functioning. Previous research has also suggested that cognitive remediation therapy (CRT) could potentially improve cognitive function and AUD treatment outcomes. We present the rationale and design of a trial to evaluate the combination of donepezil and cognitive remediation therapy (donepezil + CRT) as an intervention for AUD. MethodsWe propose a 13-week, randomized, double-blind, placebo-controlled, between-subjects trial comparing 4 groups (donepezil + CRT vs. donepezil alone vs. CRT alone vs. placebos) as an intervention for AUD. The main goal of the study is to evaluate if donepezil + CRT is superior to placebo in reducing heavy drinking days and improving neurocognitive functioning. A total of 160 patients (4 groups, 40 per each group) with AUD between the ages of 18–80 years will be recruited at Yale University and the VA Connecticut Healthcare System. Primary outcome measures include 1) heavy drinking by Timeline Follow Back (TLFB) over 13 weeks and 2) global neurocognitive functioning by a global index of neurocognitive function score at 7 and 13 weeks. DiscussionThis protocol paper describes the rationale and proposed methods for the randomized controlled trial for improving AUD treatment outcomes. This project has significant clinical potential to help patients suffering from AUD by improving their cognition and reducing alcohol consumption.Trial Registration:NCT05042102

Outcome of resveratrol and resveratrol with donepezil combination on the β-amyloid plaques and neurofibrillary tangles in Alzheimer’s disease

The goal of this research was to study the effect of different doses of resveratrol (RS) and RS with donepezil (DPZ) on the deposition of amyloid beta (Aβ) and neurofibrillary tangles (NFTs) in colchicine-induced Alzheimer’s disease (AD) brain. The study included three months old male Albino Wistar rats and consisted of six animal groups: AD model (group 1), treatment groups, RS 10 mg/kg body weight (group 2), RS 20 mg/kg body weight (group 3), RS 10 mg/kg body weight along with DPZ 1 mg/kg body weight (group 6), prophylaxis groups, RS 10 mg/kg body weight (group 4) and RS 20 mg/kg body weight (group 5). In the treatment groups, RS was given for 7 consecutive days from the day of induction of AD, and in the prophylaxis groups, we started RS 7 days even before the induction of AD and continued for seven days after the induction. The number of Aβs and NFTs at the frontal region, cornu ammonis (CA) 1,2,3,4 and dentate gyrus regions of hippocampus were evaluated. The immunohistochemical analysis was performed by using mouse anti-β-amyloid antibody for the Aβ plaques and polyclonal rabbit anti-human tau for the tau-positive neurons. The present study observed the accumulation of Aβ plaques and tau-positive neurons in the AD model. However, their numbers were significantly decreased in the treatment groups (p < 0.001). The best results were observed when RS 10 mg was given prophylactically (p < 0.01) and RS along with DPZ (p < 0.001), suggesting the neuroprotective effect of RS and its synergistic effect with the DPZ.

Adverse event profile of memantine and donepezil combination therapy: a real-world pharmacovigilance analysis based on FDA adverse event reporting system (FAERS) data from 2004 to 2023.

Donepezil in combination with memantine is a widely used clinical therapy for moderate to severe dementia. However, real-world population data on the long-term safety of donepezil in combination with memantine are incomplete and variable. Therefore, the aim of this study was to analyze the adverse events (AEs) of donepezil in combination with memantine according to US Food and Drug Administration Adverse Event Reporting System (FAERS) data to provide evidence for the safety monitoring of this therapy. We retrospectively analyzed reports of AEs associated with the combination of donepezil and memantine from 2004 to 2023 extracted from the FAERS database. Whether there was a significant association between donepezil and memantine combination therapy and AEs was assessed using four disproportionality analysis methods, namely, the reporting odds ratio, proportional reporting ratio, Bayesian confidence propagation neural network, and multi-item gamma Poisson shrinker methods. To further investigate potential safety issues, we also analyzed differences and similarities in the time of onset and incidence of AEs stratified by sex and differences and similarities in the incidence of AEs stratified by age. Of the 2,400 adverse drug reaction (ADR) reports in which the combination of donepezil and memantine was the primary suspected drug, most of the affected patients were female (54.96%) and older than 65years of age (79.08%). We identified 22 different system organ classes covering 100 AEs, including some common AEs such as dizziness and electrocardiogram PR prolongation; fall, pleurothotonus and myoclonus were AEs that were not listed on the drug label. Moreover, we obtained 88 reports of AEs in men and 100 reports of AEs in women; somnolence was a common AE in both men and women and was more common in women, whereas pleurothotonus was a more common AE in men. In addition, we analyzed 12 AEs in patients younger than 18years, 16 in patients between 18 and 65years, and 113 in patients older than 65years. The three age groups had distinctive AEs, but lethargy was the common AE among all age groups. Finally, the median time to AE onset was 19days in all cases. In both men and women, most AEs occurred within a month of starting donepezil plus memantine, but some continued after a year of treatment. Our study identified potential and new AEs of donepezil in combination with memantine; some of these AEs were the same as in the specification, and some of the AE signals were not shown in the specification. In addition, there were sex and age differences in some of the AEs. Therefore, our findings may provide valuable insights for further studies on the safety of donepezil and memantine combination therapy, which are expected to contribute to the safe use of this therapy in clinical practice.

Anti-oxidant activity of coenzyme Q10 against AlCl3/D-galactose in albino rat induced cognitive dysfunctions: Behavioral, biochemical, and BACE-1/GSK-3β alterations.

The relationship between amyloid beta (Aβ) and oxidative stress (OS), both prominent factors in Alzheimer's disease-related neural degeneration, is deeply interconnected. The cleavage of the extracellular domain of Amyloid precursor protein (APP) and phosphorylating different substrates, respectively, the β-site amyloid precursor protein cleaving enzyme-1 (BACE-1) and Glycogen synthase kinase-3-beta (GSK-3β) enzymes initiate the synthesis of Aβ, which causes cognitive deficits in AD. This study aimed to explore the protective potential of Coenzyme Q10 (CoQ10). It also sought to uncover any synergistic effects when combined with donepezil, an acetylcholinesterase inhibitor, in treating Alzheimer's disease in male albino rats, focusing on the modulation of the BACE-1/GSK-3β pathway. The experiment involved 70 rats categorized into different groups: control, donepezil alone, CoQ10 alone, AD-model, donepezil co-treatment, CoQ10 co-treatment, and CoQ10+donepezil combination. Various assessments, such as cholinesterase activity, oxidative stress, serum iron profile, Brain Derived Neurotrophic Factor (BDNF), Tau protein, β-site amyloid precursor protein cleaving enzyme-1 (BACE-1), phosphatase and tensin homolog (Pten), and Glycogen synthase kinase-3-beta (GSK-3β), were conducted on behavioral and biochemical aspects. CoQ10 treatment demonstrated memory improvement, enhanced locomotion, and increased neuronal differentiation, mainly through the inhibition of the dual BACE-1/GSK-3β. These findings were substantiated by histological and immunohistological examinations of the hippocampus.

Comparative study of choline alfoscerate as a combination therapy with donepezil: A mixed double-blind randomized controlled and open-label observation trial.

Choline alfoscerate (alpha-glycerylphosphorylcholine) is a phospholipid that includes choline, which increases the release of acetylcholine. The ASCOMALVA trial, a combination of donepezil and choline alfoscerate, slowed cognitive decline in Alzheimer disease. This study aims to replicate the effect by combining donepezil with other nootropics currently used in South Korea. The 119 patients with cognitive decline who were eligible to use donepezil, with an mini-mental state examination (MMSE) score of 26 or less, were assigned to: donepezil alone (DO); donepezil and choline alfoscerate (DN); donepezil and acetyl-l-carnitine (DA); or donepezil and ginkgo biloba extract (DG). Cognitive evaluations such as MMSE, clinical dementia rating, Alzheimer disease assessment scale-cognitive subscale (ADAS-Cog), and Alzheimer disease assessment scale-noncognitive subscale were performed at the 12th and 24th weeks from the baseline time point. At the 12th week, the MMSE score increased 3.52% in the DN group, whereas it increased by 1.36% in the DO group. In the DA + DG group, it decreased by 2.17%. At the 24th week, the MMSE score showed an increase of 1.07% in the DO group and 1.61% in the DN group, but decreased by 5.71% in the DA + DG group. ADAS-Cog decreased by 0.9% in the DO group, while it improved by 13.9% in the DN group at the 12th week. At the 24th week, ADAS-Cog showed improvement in the DN group by 18.5%, whereas it improved by 9.4% in the DO group. Alzheimer disease assessment scale-noncognitive subscale also revealed better performance in the DN group than in the DO group at the 12th and 24th weeks. Choline alfoscerate exhibits additional cognitive improvement in both cognitive and noncognitive domains, supporting the findings of the ASCOMALVA trial.

Inhibitory effect of galantamine and donepezil combination against cholinesterase: An in silico and in vitro study.

This study aimed to evaluate the in silico and in vitro inhibitory effect of the combined use of galantamine (GAL) and donepezil (DON) against acetylcholinesterase and butyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysis were carried out for GAL and DON alone and combined. Molecular modeling studies were carried out (docking analysis, molecular dynamics simulation, and quantum theory of atoms in molecules). Cholinesterase's inhibitory activities by modified Ellman's method and the drug combination effect using the Chou-Talalay method were assayed. GAL/DON combination showed the co-occupancy of the ligands in both enzymes through in silico studies. Regarding in vitro BuChE inhibition analyses, three of five combinations showed an interaction between GAL and DON at the threshold of additive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higher concentrations. This is the first report showing the efficacy of the GAL/DON combinations inhibiting BuChE, showing the importance of analyzing the behavior of different ligands when co-occupancy into the active site is possible. These combinations might be a possible therapy to improved efficacy, reduced doses, minor side effects, and high levels of the neurotransmitter in the synaptic space for Alzheimer's disease.

Amnesiac (AMN) gene and cnc/Nrf2-redox responses in fruit fly model of memory impairment co-administered Solanum leaves and donepezil

BackgroundConsidering that Alzheimer disease (AD) is a disease of multiple etiological theories, there is a continuous quest for multitarget approach for its management. In view of this, combinatory approach using therapeutic drugs and functional foods is gaining wide popularity. Leaves of Solanum spp such as S. nigrum and S. macrocarpon which are cultivated across the world including Southeast Asia and Africa has several health-promoting benefits. While we have previously reported that both S. nigrum and its relative of African origin S. macrocarpon has neuroprotective properties, however, there is dearth of information on their possible interaction with anti-amnesic drugs which suggests a possible novel therapeutic hypothesis. PurposeThis study investigated the effects of combining Black Nightshade (BN; S. nigrum) and African eggplant (AE; S. macrocarpon) dietary inclusions with donepezil, to gain insights into the molecular mechanisms underlying any synergistic effects resulting from the interaction between these food components and the drug, with the ultimate goal of developing comprehensive intervention. MethodsSix to eight-day-old flies were grouped into five. The treatment lasted for seven days and the survival rate of the flies was recorded. Thereafter, acetylcholinesterase (AChE) activity and antioxidant status of the head tissue were assayed. Also, the level of expression of amnesiac gene (AMN) and nuclear factor erythroid 2–related factor 2 (Nrf2) gene, as well as phytochemical present in the samples were quantified. ResultsThe phytochemical screening results revealed abundance of quercetin and kaempferol. Furthermore, the induced group exhibited impaired cholinergic system, increased mortality rate and oxidative stress, as well as reduced catalase activity compared to the control. Treatment with donepezil and the combinations improved flies survival rate and ameliorated the impaired cholinergic system and oxidative stress levels. Similarly, the downregulated expression of AMN and cnc/Nrf2 genes observed in the induced flies was upregulated in the treated groups. The HPLC result revealed the abundance of quercetin in both samples, which could be attributed to their neuroprotective and antioxidant properties. ConclusionsThe administration of donepezil with the consumption of AE but not the combination of donepezil with BN, significantly improved the memory impairment through interactions with the AMN and cnc/Nrf2 genes but not AChE activity.

Experience of using the combined drug Mioreol in patients with Alzheimer's disease and mixed dementia

The aim of the study was to evaluate the clinical efficacy, safety, and tolerability of a fixed-dose combination of donepezil and memantine (Mioreol) in patients with Alzheimer's disease (AD) and AD with cerebrovascular pathology. 497 patients with moderate to severe dementia, average age 75.4+6.81 years, received Mioreol (donepezil 10 mg+memantine 20 mg). Treatment efficacy was assessed using the MMSE, clock drawing, Sandoz Clinical Geriatric Scale, and Clinical Global Impressions after 3 months of therapy. All adverse events during treatment were recorded. The transition to Mioreol was accompanied by a reliable improvement in cognitive functions, emotional-behavioral indicators and neuropsychiatric status in general. Mioreol demonstrated clinical efficacy, safety and good tolerability in patients with AD and AD with cerebrovascular pathology with moderate to severe dementia syndrome.

Antinociceptive Effect of the Combination of a Novel α4β2* Agonist with Donepezil in a Chronic Pain Model.

Chronic pain presents a major challenge in contemporary medicine, given the limited effectiveness and numerous adverse effects linked to available treatments. Recognizing the potential of the cholinergic pathway as a therapeutic target, the present work evaluates the antinociceptive activity of a combination of Cris-104, a novel α4β2* receptor agonist, and donepezil, a central anticholinesterase agent. Isobolographic analysis revealed that equimolar combination was approximately 10 times more potent than theoretically calculated equipotent additive dose. Administration of Cris-104 and donepezil combination (3 μmol/kg) successfully reversed hyperalgesia and mechanical allodynia observed in rats subjected to spinal nerve ligation (SNL). The combination also modulated neuroinflammation by reducing astrocyte activation, evident in the decreased expression of glial fibrillary acidic protein (GFAP) in the spinal cord. The observed synergism in combining a nicotinic receptor agonist with an anticholinesterase agent underscores its potential for treating chronic pain. This alternative therapeutic distinct advantage, including dose reduction and high selectivity for the receptor, contribute to a more favorable profile with minimized adverse effects.

Comparative efficacy of cholinesterase inhibitors and memantine on cognition in AD patients with application of network meta‐analysis

AbstractBackgroundThis study aimed to assess the comparative efficacy of monotherapy and combined therapy of cholinesterase inhibitors plus memantine on cognition in AD and determine efficacy across doses for these pharmacological drugs.MethodThe screening of 2,113 articles were initiated. Finally, forty randomized controlled trials (RCTs) from PubMed, Web of Science, and Scopus databases inception to the end of Dec. 2022 were finally included in this review. The included RCTs contain donepezil, rivastigmine, galantamine and memantine alone or in any combination of them were compared with placebo in terms of MMSE score. The mean difference (MD) in MMSE score was considered as the effect size of efficacy. The quality of the RCTs were appraised using the Cochrane risk‐of‐bias tool (RoB‐2). An additive network meta‐analysis (NMA) was applied to compare the efficacy of the drugs. Trends of efficacy across doses for each available treatment were checked using a dose‐response modeling. Finally, P‐score as a probability of being the most effective treatment, was used to rank the treatments. All statistical analyses were done using netmeta and dosresmeta R packages. The study protocol was registered in the PROSPERO (CRD42022358469).ResultThese RCTs included 16,785 AD patients with mean age 73 (SD = 3.5) yrs., and weight 64.5 (SD = 5.55) kg. Of these patients, 65.15% were women. The median follow‐up time was 6 (range = 3‐48) months. The main NMA results showed that galantamine 32mg/day (MD = 3.71; 95% CI = 2.21, 5.21; P‐score = 0.89), donepezil 10mg/day combined with memantine 20mg/day (MD = 3.27; 95% CI = 1.79, 4.76; P‐score = 0.83), and then galantamine 24mg/day (MD = 3.02; 95% CI = 2.19, 3.84; P‐score = 0.79) were significantly the most effective treatments compared with placebo, respectively. According to the sub‐group analysis of stages, donepezil 10mg/day combined with memantine 20mg/day (MD = 4.78; 95% CI = 2.86, 6.71) and galantamine 32mg/day (MD = 3.81; 95% CI = 2.20, 5.34) were recommended for moderate to severe and mild to moderate AD patients, respectively. Moreover, we found there was a significant positive linear trend of efficacy across doses of galantamine.ConclusionMonotherapy with a high dose of galantamine or the combination of donepezil plus memantine have the most favorable effects on cognition for 6 months follow up in AD patients.

Efficacy and Safety of Woohwangchungsimwon Combined with Donepezil in Behavioral and Psychological Symptoms of Dementia in Patients with Probable Alzheimer's Disease: Study Protocol for a Randomized Controlled Trial.

Behavioral and psychological symptoms of dementia are a major factor in the burden of care and medical expenses. Conventional pharmacological treatments do not exert a distinct effect on the benefits versus the risks. The herbal medicine woohwangchungsimwon is frequently prescribed for neuropsychiatric disorders. An effect of woohwangchungsimwon on behavioral and psychological symptoms of dementia has been previously reported; however, no clinical studies have been conducted. We aim to evaluate the efficacy and safety of woohwangchungsimwon combined with donepezil for alleviating these symptoms in probable Alzheimer's disease. In this randomized, assessor-blinded, parallel-group clinical trial, 74 participants with probable Alzheimer's disease will be divided via block randomization into a woohwangchungsimwon + donepezil combination group (n = 37) or a donepezil single group (n = 37). Participants will include patients under donepezil treatment for at least a month. We will perform the study for 24 weeks. The Neuro-Psychiatric Inventory subscale scores will be the primary outcome. Secondary outcomes will include cognitive function, dementia severity, physical function, quality of life, depression, anxiety, and insomnia. For safety evaluation, we will assess adverse reactions, measure vital signs, and conduct laboratory tests. This is the first trial aiming to confirm the efficacy and safety of woohwangchungsimwon combined with donepezil for alleviating behavioral and psychological symptoms of dementia. Its findings could provide a basis for their co-administration to control these symptoms in probable Alzheimer's disease.

Donepezil combined with traditional Chinese medicine has promising efficacy on mild cognitive impairment: a systematic review and meta-analysis.

Prior research has shown mixed results regarding the effectiveness of combining donepezil and traditional Chinese medicine (TCM) to treat mild cognitive impairment (MCI). In light of this, our study aims to examine the efficacy and safety of this treatment approach for patients with MCI. We conducted a comprehensive search of various databases, including Medline (via PubMed), Cochrane, Embase, Web of Science, Chinese National Knowledge Infrastructure, Chinese Biomedical Literature Database, Chinese Scientific Journal Database, and Wanfang Database from their inception to November 16, 2022. The selection of studies, risk of bias assessment, and data extraction were carried out independently by two authors. The statistical analysis was performed using STATA. Our meta-analysis included a total of 35 studies with 2,833 patients, published between 2008 and 2022, with intervention durations ranging from 4 weeks to 12 months. However, most of the studies had a high risk of detection bias. Our findings indicated that the combination of donepezil and TCM significantly improved the Montreal Cognitive Assessment (MoCA) score (weighted mean difference [WMD] = 2.79, 95% confidence interval [CI]: 1.82 to 3.75) and the Barthel Index score (WMD = 9.20, 95% CI: 5.39 to 13.00) compared to donepezil alone. However, subgroup analyses showed that the MoCA score did not increase significantly in patients with MCI resulting from cerebrovascular disease (WMD = 1.47, 95% CI: -0.02 to 2.96). The combination of donepezil and TCM may have a more positive effect on cognitive function and activities of daily living in patients with MCI compared to the use of donepezil alone. However, due to the limited quality of the studies included in our analysis, these findings should be interpreted with caution.

Extemporaneous combination of donepezil and memantine to treat dementia in Alzheimer disease: evidence from Italian real-world data

Objective Providing evidence on donepezil and memantine administration as extemporaneous combination (DM-EXT) to treat Alzheimer Disease (AD) in Italy, and describing demographic and clinical features of AD patients prescribed DM-EXT. Methods Retrospective observational study using IQVIA Italian LifeLink Treatment Dynamics (LRx) and Longitudinal Patient Database (LPD). Prevalent users of DM-EXT were identified on the databases (cohorts DMpLRx and DMpLPD) including patients with donepezil and memantine overlapping prescriptions during the selection period (DMpLRx: “July 2018–June 2021”; DMpLPD: “July 2012–June 2021”). Demographic and clinical profiles of patients were provided. Starting from cohort DMpLPD, new users of DM-EXT were selected to calculate treatment adherence. Three additional cohorts of prevalent users of DM-EXT were identified on IQVIA LRx over subsequent 12-month periods, from July 2018 to June 2021, to get national-level yearly estimates accounting for database representativeness. Results Cohorts DMpLRx and DMpLPD included 9862 and 708 patients, respectively. For both cohorts, two-third of patients were female, and more than half were aged 80+. Concomitant conditions and co-treatments prevalence was very high; most frequent comorbidities included psychiatric and cardiovascular diseases. An intermediate-to-high adherence was observed in 57% of DM-EXT new users. National-level yearly estimates showed an increasing trend (+4%) in DM-EXT prescription, which led to estimate about 10,000 patients being treated during the period “July 2020–June 2021”. Conclusions Prescription of DM-EXT is a common practice in Italy. Because the administration of fixed-dose (FDCs) instead of extemporaneous combinations improves treatment adherence, the introduction of an FDC containing donepezil and memantine might enhance AD patients’ management and reduce caregiver burden.

Combination of Donepezil and Memantine Attenuated Cognitive Impairment Induced by Mixed Endocrine-Disrupting Chemicals: an In Silico Study.

Little is known about the effects of endocrine-disrupting chemicals (EDCs) and the combination of memantine and donepezil on the pathogenesis of cognitive impairment. Here, we aimed to identify in silico the molecular mechanisms of the combination of memantine and donepezil that combat cognitive impairment induced by nine common EDCs using GeneMania, AutoDock Vina, Metascape, SwissADME, MIENTURNET, and miRNAsong. We observed that the mixture of memantine and donepezil had therapeutic effects on mixed EDC-induced cognitive impairment via five genes (TNF, ACHE, BAX, IL1B, and CASP3). With ACHE and TNF, donepezil and memantine both had a high docking score, respectively. The predominant connections among five mutual genes were physical interactions (77.6%). The major pathways associated with memantine and donepezil countering cognitive impairment generated by mixed EDCs were discovered to be "AGE-RAGE signaling pathway in diabetic complications," "pro-survival signaling of neuroprotectin D1," and "non-alcoholic fatty liver disease." The miRNAs and transcription factors implicated in memantine and donepezil protecting against mixed EDCs were hsa-miR-128-3p and hsa-miR-34a-5p, NFKB1, NFKB2, IRF8, and E2F4. The sponges' tertiary structure predictions for two major miRNAs were provided. The physicochemical and pharmacokinetic properties of memantine and donepezil highlighted the need for a therapeutic combination of these medications to treat cognitive impairment.

Early donepezil monotherapy or combination with metoprolol significantly prevents subsequent chronic heart failure in rats with reperfused myocardial infarction

Despite the presence of clinical guidelines recommending that β-blocker treatment be initiated early after reperfused myocardial infarction (RMI), acute myocardial infarction remains a leading cause of chronic heart failure (CHF). In this study, we compared the effects of donepezil, metoprolol, and their combination on the progression of cardiac remodeling in rats with RMI. The animals were randomly assigned to untreated (UT), donepezil-treated (DT), metoprolol-treated (MT), and a combination of donepezil and metoprolol (DMT) groups. On day 8 after surgery, compared to the UT, the DT and DMT significantly improved myocardial salvage, owing to the suppression of macrophage infiltration and apoptosis. After the 10-week treatment, the DT and DMT exhibited decreased heart rate, reduced myocardial infarct size, attenuated cardiac dysfunction, and decreased plasma levels of brain natriuretic peptide and catecholamine, thereby preventing subsequent CHF. These results suggest that donepezil monotherapy or combined therapy with β-blocker may be an alternative pharmacotherapy post-RMI.

Effects of an acetylcholinesterase inhibitor and an N-methyl-D-aspartate receptor antagonist on inflammation and degeneration of the nucleus pulposus.

The study aimed to examine the effects of two drugs, an acetylcholinesterase inhibitor (AChEI) and an N-methyl-D-aspartate receptor (NMDAR) antagonist, on degenerated annulus fibrosus (AF) and nucleus pulposus (NP) cells and the extracellular matrix (ECM) structure in vitro. Tissue samples were obtained from patients with intervertebral disc herniation (four males and four females; classified as Pfirmann stage IV) and used to prepare cell cultures. Untreated cell culture samples served as the control group. Study group samples were treated with donepezil, memantine or a combination of the two drugs. Cell viability, toxicity and proliferation were evaluated in all groups. Western blotting was used to examine changes in protein expression of signal transducer and activator of transcription 3 (STAT3), phospho-STAT3 (ser727), hypoxia-inducible factor (HIF)-1 alpha (HIF-1α) and nucleotide-binding oligomerisation domain (NOD) leucine-rich repeat (LRR)-containing proteins (NLR) family pyrin domain containing 3 (NLRP3) inflammasome. The alpha significance value was < 0.05. Analysis of the microscopy and commercial kit results revealed that cell proliferation was suppressed, and no cell death was observed. The protein expression levels of NLRP3, STAT3, ser727 and HIF-1α were lower in the samples treated with donepezil and memantine at 72 h (p < 0.05). The protein expression levels of NLRP3, STAT3, ser727 and HIF-1α were higher in the samples treated with the combination of donepezil and memantine (p < 0.05). The combined administration of memantine a NMDAR antagonist which can prevent neurodegeneration and donepezil an AChEI used for pain relief increased the protein expression levels in the anabolic pathway. However, it did not reduce the protein expression levels in the catabolic pathway. Therefore, further studies are needed to provide extensive insight into whether it may be among the potential targets for the therapy of intervertebral disc (IVD) diseases.

The involvement of inflammation in the effect of the administration of donepezil, galantamine, memantine and/or fluoxetine in an animal model of depression and dementia.

Alzheimer's disease (AD) and major depressive disorder (MDD) can share the same inflammatory theory in their pathophysiology, indicating that MDD may not only be a symptom, but a risk factor for AD. Therefore, the present study evaluated the levels of cytokines such as tumor necrosis factor alpha (TNF-α), interleukin (IL) -1β, IL-6 and IL-10 in the frontal cortex and hippocampus of Wistar rats subjected to chronic mild stress protocol (CMS) for induction of an animal model of depression and administration of intra-hippocampal β-amyloid (βA) oligomers for induction of the dementia model. 60-day-old Wistar rats went subjected to CMS protocol for 40 days. After the CMS, the animals were subjected to stereotaxic surgery for intra-hippocampal administration of βA or artificial cerebrospinal fluid (ACSF). The next day, it was started the treatment with water, memantine, galantamine, donepezil and/or fluoxetine orally for 17 days. On the 59th day of the experimental protocol, euthanasia was performed, and the frontal cortex and hippocampus were dissected for later measurements of the TNF-α, IL-1β, IL-6 and IL-10. The results of this study show that animals subjected to CMS and administration of βA showed increased levels of TNF-α and IL-1β in the frontal cortex and reduced IL-10 level in the hippocampus. Fluoxetine reversed the levels of TNF-α and IL-1β in the frontal cortex. In addition, the fluoxetine + donepezil combination reversed the reduction of IL-10 levels in the hippocampus. Galantamine was also effective in reversing TNF-α levels in the cortex, as well as its association with fluoxetine and the association of donepezil with fluoxetine. The animals treated with memantine, as well as their association with fluoxetine, association of galantamine and fluoxetine and the association of donepezil with fluoxetine had levels of IL-10 significantly increased in the frontal cortex. In the hippocampus, only treatments with donepezil were able to raise the levels of IL-1β and IL-10. The results obtained in the present study indicate that there is a pathophysiological interaction between diseases, and that the association of medications in the future may be a possible therapeutic strategy to reduce the inflammation, especially in association with fluoxetine.

Combination of donepezil and gallic acid improves antioxidant status and cholinesterases activity in aluminum chloride-induced neurotoxicity in Wistar rats.

The present study compared the effect of donepezil only and combination of donepezil and gallic acid on oxidative status and cholinesterase activity in the brain of Wistar rats administered AlCl3 for 60days. Twenty-eight rats (180 - 200g) were arbitrarily distributed into four groups of seven animals apiece. Group 1 served as normal control and received distilled water throughout the study. Group 2 animals received only AlCl3 throughout the study while animals in groups 3 and 4 were administered donepezil only (10mg/kg) and combination of donepezil (10mg/kg) and gallic acid (50mg/kg), respectively, in addition to AlCl3. Treatments were administered orally by gavage. At the end of the study, animals were sacrificed and activities of acetylcholinesterase, butyrylcholinesterase, superoxide dismutase (SOD) and catalase as well as levels of malondialdehyde (MDA), total thiol and nitric oxide (NO) were evaluated in the brain. Histopathological study was conducted on the hippocampus of experimental animals. Results showed that AlCl3 significantly (p < 0.05) increased brain activities of cholinesterases and levels of MDA and NO with a concomitant decrease in total thiol level as well as activities of SOD and catalase. Donepezil only and combination of donepezil and gallic acid reversed these alterations. Also, combination of donepezil and gallic acid significantly (p < 0.05) improved antioxidant status better than donepezil only. It could be concluded that a synergy might exist between gallic acid and donepezil especially in ameliorating oxidative stress associated with AlCl3-induced neurotoxicity.

Zastosowanie kwetiapiny i donepezilu w leczeniu otępienia u starszych pacjentów

The goals of the treatment of dementia is to slow down the progression of neurological changes and reduce the severity of symptoms. One of the early symptoms of the development of neurological diseases is late-onset depression, which is associated with impaired functioning of the prefrontal circuits, prefrontal-striatal dysfunction, which is responsible for cognitive-depressive dysfunction. This syndrome responds poorly to antidepressants and better to dopaminergic drugs. Based on the literature and clinical experience, we can conclude that the combination of donepezil and quetiapine may provide many benefits to patients with dementia and is well tolerated. Cholinesterase inhibitors (i.e. donepezil) have the best proven effect in the first stage of the disease, when cholinergic deficiency is most prevalent, and benefit from 30–50% of patients. Quetiapine has a lower potential for developing weight gain and metabolic complications, and for producing hyperprolactinaemia and extrapyramidal symptoms, and is better tolerated.

Influence of Acetylcholine Esterase Inhibitors and Memantine, Clinically Approved for Alzheimer's Dementia Treatment, on Intestinal Properties of the Mouse.

Four drugs are currently approved for the treatment of Alzheimer’s disease (AD) by the FDA. Three of these drugs—donepezil, rivastigmine, and galantamine—belong to the class of acetylcholine esterase inhibitors. Memantine, a NMDA receptor antagonist, represents the fourth and a combination of donepezil and memantine the fifth treatment option. Recently, the gut and its habitants, its microbiome, came into focus of AD research and added another important factor to therapeutic considerations. While the first data provide evidence that AD patients might carry an altered microbiome, the influence of administered drugs on gut properties and commensals have been largely ignored so far. However, the occurrence of digestive side effects with these drugs and the knowledge that cholinergic transmission is crucial for several gut functions enforces the question if, and how, this medication influences the gastrointestinal system and its microbial stocking. Here, we investigated aspects such as microbial viability, colonic propulsion, and properties of enteric neurons, affected by assumed intestinal concentration of the four drugs using the mouse as a model organism. All ex vivo administered drugs revealed no direct effect on fecal bacteria viability and only a high dosage of memantine resulted in reduced biofilm formation of E. coli. Memantine was additionally the only compound that elevated calcium influx in enteric neurons, while all acetylcholine esterase inhibitors significantly reduced esterase activity in colonic tissue specimen and prolonged propulsion time. Both, acetylcholine esterase inhibitors and memantine, had no effect on general viability and neurite outgrowth of enteric neurons. In sum, our findings indicate that all AD symptomatic drugs have the potential to affect distinct intestinal functions and with this—directly or indirectly—microbial commensals.