Donepezil Research Articles

Efficacy of Donepezil Hydrochloride Treatment for "Regression of Social and Communication Skill in Down Syndrome" in a 14-year-old Girl

Efficacy of Donepezil Hydrochloride Treatment for "Regression of Social and Communication Skill in Down Syndrome" in a 14-year-old Girl

Efficacy of donepezil hydrochloride for patients with mild Alzheimer's disease

Objective To investigate the effect of donepezil hydrochloride tablets in the treatment of mild Alzheimer's disease(AD) patients with clinical effect. Methods Ninety two patients with mild Alzheimer's disease (AD) were enrolled from March 2013 to March 2015. Patients were randomly assigned in two groups with 46 cases in each: patients in study group were treated with donepezil hydrochloride tablets (4 mg, q. n) and patients in control group were treated with piracetam tablets (1.2 mg t. i.d). The Mini Mental State Scale (MMSE) and Montreal Cognitive Assessment Scale (MoCA), the Alzheimer's disease assessment component table Perception Scale (ADAS COG), Hamilton Anxiety Scale (HAMA) and Hamilton Depression Scale (HAMD) were applied for evaluation of cognitive, activity ability and mental state before and after treatment. Results Before treatment, there were no significant differences in MMSE, MoCA, ADAS-cog, HAMA and HAMD scores between study and control groups (all P>0.05). The MMSE, MoCA scores after treatment in study group were higher than those in control group [24.80±1.15 vs. 23.75±1.20(t=4.285, P=0.000) and 23.30±0.55 vs. 22.41±0.64(t=7.153, P=0.000)]; the ADAS-cog score in study group was lower than that in control group (26.0±1.7 vs. 27.6±1.5, t=2.884, P=0.035). There were no significant differences in HAMA, HAMD scores between two groups (7.1±1.9 vs. 7.4±1.7 and 6.6±2.0 vs. 7.1±2.2, all P>0.05]. After treatment, the visual-spatial ability to execute in study group was 3.81±0.65, pay attention to the ability was (4.30±0.66) points and delayed recall score was 3.20±0.35, which were significantly higher than those in control group (3.42±0.66, 3.78±0.69 and 2.85±0.34; t=2.864, P=0.036; t=3.900, P=0.000; t=2.991, P=0.032). Mild adverse reactions were observed in 4 cases of study group and 2 cases of control group, all patients had spontaneous remission. Conclusions Donepezil hydrochloride tablets is effective in treatment of patients with mild AD with low incidence of adverse reactions. Key words: Alzheimer disease; Donepezil hydrochloride tablets; Drug therapy

Synthesis of new donepezil analogues and investigation of their effects on cholinesterase enzymes

Donepezil (DNP), an acetylcholinesterase (AChE) inhibitor, is one of the most preferred choices in Alzheimer diseases (AD) therapy. In the present study, 38 new DNP analogues were synthesized. Structures of the synthesized compounds (1–38) were elucidated by IR, 1H NMR, 13C NMR and HRMS spectroscopic methods and elemental analysis. Inhibitory potential of the compounds on cholinesterase enzymes was investigated. None of the compounds displayed significant activity on butyrylcholinesterase (BChE) enzyme. On the other hand, compounds 26–29 indicated important inhibitory activity on AChE enzyme. Kinetic studies were performed in order to observe the effects of the most active compounds on substrate-enzyme relationship. Cytotoxicity studies and theoretical calculation of pharmacokinetic properties were also carried out to get an information about toxicity and pharmacokinetic profiles of the compounds. The compounds 26–29 were found to be nontoxic at their effective concentrations against AChE. A good pharmacokinetic profile was predicted for these compounds. Docking studies were performed for the most active compounds 26–29 and interaction modes with enzyme active sites were determined. Docking studies revealed that there is a strong interaction between the active sites of AChE enzyme and analyzed compounds.

Effect of donepezil and kamikihito combination therapy on cognitive function in Alzheimer's disease: Retrospective study

ABSTRACTAimKamikihito (KKT) is a herbal drug used in traditional Japanese medicine (kampo medicine) to treat psychological symptoms such as insomnia, restlessness, and fear. The aim of this study was to investigate the effect of the combination of KKT extract and donepezil (DPZ) on the cognitive function of patients diagnosed with Alzheimer's disease (AD).MethodsThe effect of this combination therapy (CBT) was analyzed retrospectively using Mini‐Mental State Examination (MMSE). AD patients were treated with DPZ (5 mg/day). Those with psychological symptoms, such as insomnia, were also given the KKT extract (7.5 g/day), beginning 3 months after the initiation of DPZ.ResultsMedical records of patients who visited the outpatient department for the first time between May 2010 and January 2013 were retrospectively evaluated, and six patients from each group selected as candidates for this study. Changes in total MMSE score for the DPZ and CBT groups were unremarkable until 6 months; at 12 months the scores were markedly, but non‐significantly, different: cognitive function was maintained in the CBT group while it deteriorated in the DPZ group. On MMSE subscale analysis, delayed memory recall score in the CBT group was sustained in a statistically significant manner.ConclusionCBT may prolong the effect of DPZ and, thus, CBT may be more beneficial than monotherapy using DPZ.

Effect of Donepezil Hydrochloride on Cognitive Function Recovery of Rats with Alzheimer’s Disease

Objective: To explore the effect of donepezil hydrochloride on cognitive function recovery of rat with Alzheimer’s disease and the positive expression of nitric oxide synthase and acetylcholinesterase (NOS and AchE) in the brain tissues of rats with Alzheimer's disease (AD).Methods: Forty SD (Sprague Dawley) rats were randomly classified into a model group, a treatment group, a control group, and a sham operation group. Each group had 10 rats. AD rat models were prepared with Aβ1-40. Donepezil hydrochloride was orally administered to rats in the treatment group two weeks after modeling. Rat recognition function was assessed. The positive expression of NOS and AchE in rat brain tissues was observed via immunohistochemistry after administration of 28 days.Results: Rat escape latency was significantly longer after modeling (p < 0.010). Compared to the model group, treatment group escape latency was significantly shortened and the difference was significant (p < 0.05). NOS and AchE positive expression mainly reflects in hippocampus region tissue. Compared with the control, and sham, operation groups, NOS positive expression decreased and AchE positive expression increased in the model group. The difference was statistically significant (p < 0.01). Compared with the model group, NOS expression in the treatment group increased and AchE expression decreased. The difference was significant (p < 0.01).Conclusion: Donepezil hydrochloride can promote AD rat cognitive function recovery. Its effects are also associated with increased NOS protein expression in hippocampus neuron cells in addition to specifically inhibiting the AchE activities.

The dual-acting AChE inhibitor and H3 receptor antagonist UW-MD-72 reverses amnesia induced by scopolamine or dizocilpine in passive avoidance paradigm in rats

Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5.4μM on hAChE and hH3R antagonism with Ki of 2.54μM, respectively. In the current study, the effects of UW-MD-72 (1.25, 2.5, and 5mg/kg, i.p.) on memory deficits induced by the muscarinic cholinergic antagonist scopolamine (SCO) and the non-competitive N-methyl-d-aspartate (NMDA) antagonist dizocilpine (DIZ) were investigated in a step-through type passive avoidance paradigm in adult male rats applying donepezil (DOZ) and pitolisant (PIT) as reference drugs. The results observed show that SCO (2mg/kg, i.p.) and DIZ (0.1mg/kg, i.p.) significantly impaired learning and memory in rats. However, acute systemic administration of UW-MD-72 significantly ameliorated the SCO- and DIZ-induced amnesic effects. Furthermore, the ameliorating activity of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was partly reversed when rats were pretreated with the centrally-acting H2R antagonist zolantidine (ZOL, 10mg/kg, i.p.), but not with the CNS penetrant H1R antagonist pyrilamine (PYR, 10mg/kg, i.p.). Moreover, ameliorative effect of UW-MD-72 (1.25mg/kg, i.p.) in DIZ-induced amnesia was strongly reversed when rats were pretreated with a combination of ZOL (10mg/kg, i.p.) and SCO (1.0mg/kg, i.p.), indicating that these memory enhancing effects were, in addition to other neural circuits, observed through histaminergic H2R as well as muscarinic cholinergic neurotransmission. These results demonstrate the ameliorative effects of UW-MD-72 in two in-vivo memory models and provide evidence for the potential of dual-acting AChEI and H3R antagonists to treat cognitive disorders.

Benzoate fraction from Gentiana rigescens Franch alleviates scopolamine-induced impaired memory in mice model in vivo

Ethnopharmacological relevanceG. rigescens Franch (Long Dan Cao in Chinese) is a well-known TCM herb. It is clinically used with other drugs for the treatment of brain diseases such as epilepsy, postherpetic neuralgia in China. Aim of studyIn our previous study, the 11 dihydroxybenzoates compounds with NGF mimicking activity from G. rigescens Franch were found. In the present study, the neurogenesis and neuroprotection of a mixture of benzoates ( n-GS) were investigated in animal level. Materials and methodsThe NGF mimicking activity of n-GS from G. rigescens Franch was examined in PC12 cells. The neurogenesis effects of n-GS were investigated in ICR mice with 5-bromo-2-deoxyuridine (BrdU) and neuronal neclei (NeuN) double immunostaining. Furthermore, the neuroprotection effects of n-GS on the memory in a scopolamine (SCO)-induced mouse model were evaluated with animal behavior tests. ResultsThe NGF-mimicking function and neurogenesis of n-GS were observed in PC12 cells and in normal mice. Subsequently, we investigated the effects of n-GS on the memory in a SCO-induced mouse model. In Y-maze test, SCO significantly lowered the alternation. This finding was reversed by n-GS and donepezil (DONE). SCO significantly impaired the mice's performance in novel object recognition (NOR) and Morris water maze (MWM) tests. The time spent to explore the novel object was longer in the n-GS- and DONE-treated groups than in the SCO control group. In the MWM test, the escape latency of n-GS- and DONE-treated groups was shorter than that of the SCO control group. Mechanism study showed that SCO significantly reduced superoxide dismutase (SOD) but increased the activities of acetylcholinesterase (AChE) and the levels of malondialdehyde (MDA) in the hippocampus and cerebral cortex, which all can be improved by n-GS and DONE. Additionally, the phosphorylation of type 1 insulin-like growth factor (IGF-1) receptor, extracellular signal-regulated kinase (ERK), and cAMP responsive element-binding (CREB) protein in the hippocampus was significantly up-regulated in the treatment group compared with that in the SCO group. Conclusionsn-GS could alleviate impaired memory of the SCO-induced mice model by inhibiting AChE activity and oxidative stress, and regulating the IGF-1R/ERK signaling pathway.

FINANCIAL AVAILABILITY OF IN-HOME MEDICAL TREATMENT OF PATIENTS WITH ALZHEIMER’S DISEASE

SUMMARY Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and presents a great burden for the person, family and society as a whole. Since 2012, in Bulgaria, AD is accepted as a disorder of a great socioeconomic significance and the drugs for home treatment are included in the reimbursement list of the National Health Insurance Fund (NHIF). Objective: To trace the access to treatment of Alzheimer’s in-home patients, as a result of generic substitution on the base of share distribution of the original and generic products. Methods: We collected data for the sales of pharmaceutical products (PP’s), containing donepezil hydrochloride and memantine hydrochloride from a distributor for the Northeast region of Bulgaria (Varna) in the period 20142015. An analysis of the percentage share distribution of the original and generic products was conducted. Results: According to our results original product Aricept accounts for only 4%, while the market share for its generics is 96%. In this group the share to be paid from NHIF is 25%, the remaining 75% from the cost is paid by the patients. The original product Axura occupies 8% market share, the generics- 92%. In this group the share to be paid from NHIF is 50% for generics, while Axura was removed from the Positive reimbursement list. We comment the significant differences in the sale shares in several directions. Conclusion: The reduction of expenses, with the use of generics, would help more patients to receive an optimal treatment and the savings could be redirected for other costly treatments.

PASS assisted prediction and pharmacological evaluation of hesperidin against scopolamine induced amnesia in mice

Alzheimer's disease (AD) is a neurodegenerative disorder that leads to memory impairment. However, the exact etiology of AD is not clear but cholinergic dysfunction and oxidative stress are considered to play an important role in its pathogenesis. Because of this reason, antioxidant compounds are expected to play potential beneficial role in this disease. Among number of antioxidant compounds, hesperidin (HSD) was selected for this study on the basis of its reported antioxidant and neuroprotective effects. Moreover, it has shown higher probable activity value for scavenging free radical along with anti-dementia effects, predicted by PASS online computer program. Current study was designed to evaluate the nootropic and antioxidant effects of HSD. The different groups of animals received scopolamine (2mg/kg) along with co-treamtment of HSD (100, 200mg/kg) and donepezil HCl (3mg/kg) i.p. for consecutive 10 days. Behavioral tests were carried out, 30min after respective treatment on 2nd, 5th and 9th day for memory evaluation. On 10th day of treatment, the animals were sacrificed and the homogenates of brain hippocampus and cortex were used for biochemical estimation. Co-treatment with HSD at both doses significantly reversed the changes in memory and biochemical alterations, induced by scopolamine administration. It can be concluded that HSD has strong memory enhancing and anti-oxidant effects, therefore, it can be considered as a potential candidate for its further pharmacological evaluation for AD-induced dementia.

Donepezil modulates the endogenous immune response: implications for Alzheimer's disease.

Donepezil (DNPZ) is a drug commonly used for Alzheimer's disease (AD) that may favour a T helper 2 phenotype leading to increased naturally occurring auto-antibodies (NAb) against beta-amyloid (Aβ). We hypothesized the involvement of the cholinergic receptors [α7-nicotnic acetylcholine receptor (α7nAChR)] expressed on peripheral blood mononuclear cells (PBMC). Fifty patients with mild-to-moderate AD, DNPZ treated (DNPZ+, n = 25) or not (DNPZ-, n = 25), and 25 matched controls were enrolled and PBMC extracted for both in vitro cultures, and real-time polymerase chain reaction and chromatin immunoprecipitation assay. Plasma samples were also obtained for Aβ and NAb determination. Donepezil increased in vitro the expression of the transcription factor GATA binding protein 3 (GATA3) through α7nAChR, because prevented by the specific antagonist methyllycaconitine. Ex vivo PBMC α7nAChR mRNA expression was increased in both AD groups, while GATA3 expression was not. A significant increase in the GATA3/interleukin 5 promoter association was found in DNPZ+ patients. Finally, DNPZ+ patients showed both significantly higher plasma levels of anti-Aβ NAb with respect to DNPZ- patients and Aβ 1-42 with respect to normal controls. Donepezil might modulate a T helper 2 bias via α7nAChR leading to increased expression of NAb. Further studies on the role of the modulation of the immune response against Aβ may pave the way to innovative therapeutic strategies for AD. Copyright © 2016 John Wiley & Sons, Ltd.

Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer’s disease

Donepezil hydrochloride (DPH) is often used in the treatment of Alzheimer’s disease. A new treatment method was developed by encapsulating high DPH content in the tips of dissolving microneedles for rapid, transdermal delivery of a predetermined dose of DPH. The microneedles were prepared by a micromolding method using a hydroxy-propyl-methyl-cellulose (HPMC)-ethanol/water mixture (80:20, v/v) for the tips and carboxy-methyl cellulose (CMC)-water for the base of the needles. The micromolding method involved centrifuging a DPH-HPMC-ethanol/water mixture at 10°C to obtain tips with sufficient mechanical strength. To test their mechanical strength, microneedles with different DPH content were inserted into porcine skin. Then the amount of DPH encapsulated in the microneedles was measured using high-performance liquid chromatography. The efficiency of administering DPH tip-loaded microneedles was investigated using four administrations of a pharmacokinetic test: (1) two oral administration groups (283μg/kg and 692μg/kg) and (2) two microneedle administration groups (283μg/kg and 692μg/kg). High DPH content (up to 78%, w/w) was encapsulated in the microneedle tips without serious loss of mechanical strength by using a mixture of hydroxy-propyl-methyl-cellulose (HPMC) and ethanol/water mixture (80:20, v/v). Because of the distribution of DPH in the tips, 95% of the DPH was delivered into porcine skin after 5min of insertion. As measured by Cmax and AUC, transdermal delivery of DPH tip-loaded microneedles was more effective compared to oral administration of the same dose of DPH. Transdermal delivery could replace oral administration of DPH.

Polyurethane/hydroxypropyl cellulose electrospun nanofiber mats as potential transdermal drug delivery system: characterization studies and in vitro assays

Donepezil hydrochloride containing polyurethane/hydroxypropyl cellulose (PU/HPC) nanofibers were prepared by the electrospinning for transdermal drug delivery. PU/HPC nanofibers were characterized with SEM, DSC, and Pascal mercury porosimetry. Drug–excipient interaction was studied by ATR-FTIR. In vitro release of PU/HPC nanofiber mat (10:2:1) exhibited Korsmeyer–Peppas release kinetics controlled by the diffusion of drug. In vitro permeation studies across skin resembling synthetic membrane demonstrated the flux of model drug. The in vitro cytotoxicity data obtained via MTT assay indicated that PU/HPC nanofiber mat could be well tolerated by the skin and the components was not irritant for the skin.

Postmortem redistribution mechanism of donepezil in the rat

Population aging is rapidly advancing in numerous parts of the world and, accordingly, the prevalence of Alzheimer's disease (AD) is rising. The safety of donepezil (DPZ), which is used for AD treatment, has been established in clinical trials. However, some studies have indicated that DPZ may be associated with severe cardiac side effects, and excessive doses may induce toxicity-related symptoms or death. Therefore, the measurement of blood DPZ levels is important for the postmortem investigation of related causes of death. However, postmortem drug concentrations in the blood may not always reflect those obtained antemortem because of the postmortem redistribution (PMR) of drugs. Therefore, the aim of this study was to investigate the potential PMR of DPZ using a rat model. The DPZ concentration was measured using a validated HPLC/Q-TOF-MS system in cardiac and peripheral blood, and in the brain, lungs, myocardium, liver, and thigh muscle at different postmortem intervals (0, 1, 3, 6, 12, and 24h). Overall, the DPZ tissue to peripheral blood ratio decreased throughout the postmortem period. Furthermore, the DPZ concentration increased in the peripheral and cardiac blood but decreased in both of the lungs, postmortem. Furthermore, the blood pH was significantly lowered. We used a perfusion approach to examine the rat lung and heart to further investigate the relationship between the pH and DPZ release from the lungs. The outflow concentrations when the inflow pH changed from 7.4 to 5.5 were approximately 2-fold higher than the inflow pH fixed 7.4. These findings suggest that the antemortem accumulated DPZ in the lungs is released into the pulmonary blood owing to postmortem acidification of blood, and subsequently flows into the cardiac blood, leading to the observed increase in concentration. Although we could not determine the underlying mechanism, we confirmed that PMR occurs similarly in the cardiac and peripheral blood.

Microneedle-mediated delivery of donepezil: Potential for improved treatment options in Alzheimer’s disease

Transdermal drug delivery is an attractive route of drug administration; however, there are relatively few marketed transdermal products. To increase delivery across the skin, strategies to enhance skin permeability are widely investigated, with microneedles demonstrating particular promise. Hydrogel-forming microneedles are inserted into the skin, and following dissolution of a drug loaded reservoir and movement of the drug through the created channels, the microneedle array is removed intact, and can then be readily and safely discarded. This study presents the formulation and evaluation of an integrated microneedle patch containing the Alzheimer’s drug, donepezil hydrochloride. The integrated patch consisted of hydrogel-forming microneedles in combination with a donepezil hydrochloride containing film. Formulation and characterisation of plasticised films, prepared from poly(vinylpyrrolidone) or poly (methyl vinyl ether co-maleic anhydride/acid) (Gantrez®) polymers, is presented. Furthermore, in vitro permeation of donepezil hydrochloride across neonatal porcine skin from the patches was investigated, with 854.71μg±122.71μg donepezil hydrochloride delivered after 24h, using the optimum patch formulation. Following administration of the patch to an animal model, plasma concentrations of 51.8±17.6ng/mL were obtained, demonstrating the success of this delivery platform for donepezil hydrochloride.

DONEPEZIL HYDROCHLORIDE MITIGATES CONSEQUENCES OF ACUTE MYOCARDIAL INFARCTION IN MALE ALBINO RATS

Background Cholinesterase inhibitors are used for symptomatic treatment of mild to moderate Alzheimer’s disease. These drugs have vagomimetic and anti-inflammatory properties that could be of interest also with respect to cardiovascular diseases. Aim The aim of the present work is to assess effects of pretreatment with donepezil hydrochloride, one of cholinesterase inhibitors, on acute myocardial infarction induced by coronary artery ligation in rats. Methods Rats were randomly divided into control, sham-operated, untreated-myocardial infarction, and donepezil hydrochloride-pretreated myocardial infarction groups. Donepezil hydrochloride was administered orally, 1mg/kg/day, for six days then acute myocardial infarction was induced in 6th day by ligation of the left anterior descending coronary artery. ECG and blood pressure were recorded. Triphenyltetrazolium chloride (TTC) stained ventricular slices were examined. The plasma levels of tumor necrosis factor-α (TNF-α) and cardiac troponin I (cTnI) were assessed. Catalase activity and glutathione levels in the myocardium were determined. Results Coronary artery ligation increased T-wave voltage with appearance of pathological Q-wave, tachycardia, decreased mean arterial pressure and pale areas (infarcts) in TTC-stained ventricular slices. The plasma levels of TNF-α and cTnI were increased while the myocardial catalase activity and glutathione levels were decreased. In donepezil hydrochloride-pretreated group T-wave voltage and heart rate were decreased and pathological Q-wave disappeared with decrements in infarct size and plasma levels of TNF-α as well as cTnI, while catalase activity and glutathione levels were increased in relation to untreated myocardial infarction group. Conclusion Pretreatment with donepezil hydrochloride decreased myocardial infarct size. This effect could be related to its negative chronotropic, anti-inflammatory, and antioxidant actions.

Cognitive decline induced by cerebral radiotherapy: What to do?

Introduction Each year about 200 000 individuals undergo radiotherapy treatment to primary brain cancer or brain metastasis. The number of survivor has been rising with the improvement of treatment and techniques. The current evidence suggest a progressive cognitive decline in the years following brain irradiation, and show that 50% of the people that survive longer than 6months are most affected. Aim The authors propose to make a literature review, trying to expose the cognitive decline profile after cerebral brain therapy and how to choose the best therapeutic option. Methodology Literature review using the data base available in the Documentation Service of the Central Library of the Centro Hospitalar e Universitario de Coimbra. Results and conclusions The severity profile of cognitive decline influences the therapeutic options. The use of donepezile and memantine presents as good therapeutic option, showing improvement in several cognitive domains. Metilphenidate steel needs investigation but the evidence is that has positive impact in the improvement of fatigue and concentration. There are lack of studies using Gingko Biloba, but reveals high toxicity inducing gastrointestinal symptoms and risk of intracranial haemorrhage.

Quantitative estimation of Donepenzil hydrochloride tablet by HPLC

A simple, rapid, reliable and accurate HPLC method has been developed and validated as per the ICH guidelines for the quantitative determination of Donepezil HCl in bulk and tablets. The water HLC-10, high performance liquid chromatography system were used. The LOQ is detected at concentration 0.05mg/ml and the linearity range is 50-150g/ml. An optimum concentration scanned in the range 200-350 nm and ? max of the drug is 230 nm. No any interference at developed (R t = 8.22 min) and also the ? max peak is sharp. The Accuracy of the method was found to be in the range of 99.70% to 100.26%. The mean Inter and Intraday assay Relative Standard deviation (%RSD) were less than 0.69%. The Proposed method was found to be Linear, precise and accurate for the quantitative estimation of Donepezil in tablet formulations and can be used for commercial purposes.

Human serum albumin reduces the potency of acetylcholinesterase inhibitor based drugs for Alzheimer's disease

Human serum albumin (HSA) induced modulation of acetylcholinesterase (AChE) inhibition activity of four well-known cholinergic inhibitors like tacrine hydrochloride (TAC), donepezil hydrochloride monohydrate (DON), (−) Huperzine A (HuPA), eserine (ESE) was monitored quantitatively by Ellman's method. Kinetic analysis of enzyme hydrolysis reaction revealed that while the mechanism of inhibition does not change significantly, the inhibition efficiency changes drastically in presence of HSA, particularly for DON and TAC. However, interestingly, no notable difference was observed in the cases of HuPA and/or ESE. For example, the IC50 value of AChE inhibition increases by almost 135% in presence of ∼250 μM HSA (IC50 = 159 ± 8 nM) while comparing with aqueous buffer solution of pH 8.0 (IC50 = 68 ± 4 nM) in DON. On the other hand, the change is almost insignificant (<10%) in case of HuPA under the similar condition. The experimentally observed difference in the extent of modulatory effect was correlated with the sequestration ability of HSA towards different drugs predicted from molecular docking calculations. The result in this study demonstrates the importance to consider the plasma protein binding tendency of a newly synthesized AD drug before claiming its potency over the existing one. Further, development of new and intelligent delivery medium that shields the administered drugs from serum adsorption may reduce the optimal drug dose requirement.

The roles of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms in the predictability of responses to individualized therapy with donepezil in Han Chinese patients with Alzheimer's disease

AimPolymorphisms in the apolipoprotein E and CYP2D6 genes are widely reported to be related to Alzheimer's disease. However, few studies have focused on the relationship between polymorphisms in apolipoprotein E and CYP2D6 (rs1065852) genes and therapeutic responses to donepezil (DNP). This study explored the influence of apolipoprotein E3 and CYP2D6 (rs1065852) gene polymorphisms on therapeutic responses to donepezil in Han Chinese patients with Alzheimer's disease. Materials and methodsA total of 85 patients with mild to moderate Alzheimer's disease who were treated with 2.5–10mg of DNP per day for at least 3 months were enrolled. Mini-Mental State Examination scores were measured before and after DNP treatment, and the apolipoprotein E3 and CYP2D6 (rs1065852) genotypes of the patients were determined. ResultsWe found that ApoE E3 non-carriers responded better to DNP treatment than E3 carriers (p=0.000) and that CYP2D6*10/*10 patients (MMSE score change: 0.29±3.27) exhibited better therapeutic responses to DNP than did CYP2D6*1/*1 and CYP2D6*1/*10 patients (p=0.033). Patients who were ApoE E3 non-carriers and who had the CYP2D6*10/*10 genotype exhibited a trend toward better clinical responses to DNP therapy. ConclusionsThe ApoE E3 allele and the CYP2D6 rs1065852 polymorphism may provide clinically relevant information for predicting therapeutic responses to DNP therapy.

Neuroprotection against vascular dementia after acupuncture combined with donepezil hydrochloride: P300 event related potential.

Acupuncture can be used to treat various nervous system diseases. Here, 168 vascular dementia patients were orally administered donepezil hydrochloride alone (5 mg/day, once a day for 56 days), or combined with acupuncture at Shenting (DU24), Tianzhu (BL10), Sishencong (Extra), Yintang (Extra), Renzhong (DU26), Neiguan (PC6), Shenmen (HT7), Fengchi (GB20), Wangu (GB12) and Baihui (DU20) (once a day for 56 days). Compared with donepezil hydrochloride alone, P300 event related potential latency was shorter with an increased amplitude in patients treated with donepezil hydrochloride and acupuncture. Mini-Mental State Examination score was also higher. Moreover, these differences in P300 latency were identified within different infarcted regions in patients treated with donepezil hydrochloride and acupuncture. These findings indicate that acupuncture combined with donepezil hydrochloride noticeably improves cognitive function in patients with vascular dementia, and exerts neuroprotective effects against vascular dementia.