Donepezil Research Articles

Correction: Cognitive Improvement during Treatment for Mild Alzheimer's Disease with a Chinese Herbal Formula: A Randomized Controlled Trial.

[This corrects the article DOI: 10.1371/journal.pone.0130353.].

Higher levels of thyroxine may predict a favorable response to donepezil treatment in patients with Alzheimer disease: a prospective, case\u2013control study

BackgroundCholinergic hypothesis has been advanced as an etiology of Alzheimer disease (AD) on the basis of the presynaptic deficit found in the diseased brains, and cholinesterase inhibitors (ChEIs) are the treatment of choice for these patients. However, only about half of treatment efficacy was found. Because increasing evidence supports an extensive interrelationship between thyroid hormones (THs), cortisol level and the cholinergic system, the aim of the present study was to evaluate thyroid function and cortisol level in patients with mild to moderate AD before and after ChEIs treatment, and to identify possible variations in response. This was a prospective, case–control, follow-up study. Levels of cortisol and THs were evaluated in 21 outpatients with mild to moderate AD and 20 normal controls. All patients were treated with 5 mg/day of donepezil (DPZ) and were reevaluated after 24–26 weeks of treatment.ResultsThe patients had worse cognitive function, higher cortisol level, and lower levels of triiodothyronine (T3) and its free fraction than the controls. There were no significant differences in global cognitive function or cortisol level after treatment, however, significant reductions in T3 and thyroxin (T4) levels were observed. Responders had higher levels of T4 than non-responders, followed by a significant reduction after treatment.ConclusionsThese results suggest that relatively higher levels of T4 may predict a favorable response to DPZ treatment. Further studies are warranted to confirm the relationship between THs and ChEIs therapy in AD and to explore new therapeutic strategies. On the other hand, cortisol levels are more likely to respond to interventions for stress-related neuropsychiatric symptoms in patients with AD rather than ChEIs treatment. Further studies are warranted to investigate the association between cortisol level and the severity of stress-related neuropsychiatric symptoms in patients with AD.

1-Benzyl-4-methylpiperidinyl moiety in donepezil: The priority ticket across the blood-brain-barrier in rats

1-Benzyl-4-methylpiperidinyl moiety in donepezil: The priority ticket across the blood-brain-barrier in rats

In Depth Analysis of Pressure-Sensitive Adhesive Patch-Assisted Delivery of Memantine and Donepezil Using Physiologically Based Pharmacokinetic Modeling and in Vitro/in Vivo Correlations.

The objective of this work was to evaluate the feasibility of transdermal delivery of two widely prescribed dementia drugs for the Alzheimer's disease. In this regard, the drug in adhesive patches of memantine (ME) co-loaded with donepezil (DO) was prepared using an ethylene vinyl acetate polymer and characterized for drug content, the crystallinity of drugs in the polymer matrix, and in vitro permeation. To understand the different physical and chemical processes underlying the percutaneous absorption, it is required to employ a comprehensive model that accounts for the anatomy and physiology of the skin. A transdermal physiologically based pharmacokinetic (TPBPK) model was developed and was integrated in a compartmental pharmacokinetic model to predict the plasma drug concentrations in rats. The model predictions showed a good fit with the experimental data, as evaluated by the prediction error calculated for both drugs. It was evident from the simulations that the drug diffusivity and partition coefficient in the polymer matrix are the critical parameters that affect the drug release from the vehicle and subsequently influence the in vivo pharmacokinetic profile. Moreover, a correlation function was built between the in vitro permeation data and in vivo absorption for both ME and DO. A good point-to-point in vitro/in vivo correlation (IVIVC, Level A correlation) was achieved by predicting the plasma concentrations with convolution for the entire study duration. The results of our study suggested that the implementation of mechanistic modeling along with IVIVC can be a valuable tool to evaluate the relative effects of formulation variables on the bioavailability from transdermal delivery systems.

Effects of electroacupuncture on cognitive function in vascular cognitive impairment rats

Objective To investigate the effect of acupuncture at Baihui (DU20) and Zusanli (ST36) acupoints on the cognitive function and the oxidation protective mechanism of cortex in vascular cognitive impairment (VCI) rats, providing experimental evidence for the clinical treatment of VCI. Methods The VCI model was established by fluorescent microemboli injection through internal carotid artery. Randomly divided into the control group (n=12), the model group (n=12), the positive drug group (n=12), the acupuncture treatment group (n=12). Two weeks after modeling, the rats in the acupuncture treatment group were stimulated for 30 minutes with daily electroacupuncture at Baihui and Zusanli acupoints. The positive drug group was treated with donepezil hydrochloride 0.520 6 mg/kg orally daily for 30 days. After the treatment, the water maze test was used to test the cognitive learning ability of rats. The content of superoxide dismutase (SOD), malondialdehyde (MDA), glutathione peroxidase (GSH-Px) and hydrogen peroxide (H2O2) in the cortex of rats were detected by biochemical methods. Results Compared with the model group, the number of passing through the platform (7.5 ± 1.9, 6.8 ± 2.2 vs. 3.7 ± 1.0) of acupuncture treatment group and positive drug group were significantly higher (P 0.05). Conclusions Acupuncture at Baihui and Zusanli acupoints can improve the behavior scores of rats with VCI, increase the contents of total SOD and GSH-Px,decrease the content of MDA and H2O2 in brain,and enhance antioxidant effects, while inhibiting peroxidation, improve free radical metabolism. Key words: Cognition disorders; Acupuncture; Point GV20 (Baihui); Point ST36 (Zusanli); Cerebral cortex; Cognitive; Oxidative stress; Rats

Protective Effects of Donepezil Against Alcohol-Induced Toxicity in Cell Culture: Role of Caspase-3.

Ethanol (EtOH) is one of the most frequently abused drugs with heavy health, economic, and societal burdens. Although moderate to low EtOH may have some neuroprotective effects, heavy EtOH consumption associated with high blood alcohol level (BAL) can be quite detrimental. The brain is particularly vulnerable to the damaging effects of high BAL, leading to neuronal loss, cognitive, and behavioral deficits. Although the exact causes of these detriments are not fully elucidated, it is believed that damage to the cholinergic system is at least partially responsible for the cognitive impairment. Thus, high BAL may result in selective apoptotic damage to the cholinergic neurons. Donepezil (DON), a centrally acting, reversible and non-competitive acetylcholinesterase (AChE) inhibitor, approved for use in Alzheimer's disease (AD), may also attenuate EtOH-induced cognitive impairment. Cognitive effects of DON might be due to an anti-apoptotic activity as some AChE inhibitors have been shown to have this property. The aim of this study was to determine whether DON might protect against EtOH-induced toxicity and whether such protection might be apoptotically mediated. We exposed the human neuroblastoma-derived, SH-SY5Y cells to a relatively high concentration of EtOH (500mM) for 24h and evaluated the effects of two concentrations of DON (0.1 and 1.0μM) on alcohol-induced toxicity and caspase-3, an apoptotic marker. We found a dose-dependent protection of DON against EtOH-induced toxicity as well as dose-dependent attenuation of EtOH-induced increases in caspase-3 levels. Thus, DON may inhibit apoptosis as well as alcohol-induced toxicity.

A donepezil/cyclodextrin complexation orodispersible film: Effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption

The aim of this study was to develop a palatable donepezil (DP) orodispersible film (ODF) to facilitate the swallowing process and investigate the effect of cyclodextrin on taste-masking based on dynamic process and in vivo drug absorption. Complexation of DP with hydroxypropyl-β-cyclodextrin (HP-β-CD) was applied to mask the bitter taste then the prepared complexes were incorporated into ODF using solvent casting method. The taste-masking efficiency was evaluated by e-tongue; meanwhile the pharmacokinetic behavior of DP/HP-β-CD ODF was investigated by in vivo study. Results showed the optimized film was more palatable than donepezil hydrochloride (DH) film and was bioequivalent with DH. The molecular mechanism was revealed by phase solubility study, Fourier-transform infrared spectrometer (FT-IR), Differential scanning calorimeter (DSC), X-ray diffraction (XRD) and molecular modeling. Taste-masking was attributed to the formation of DP/HP-β-CD which was due to moderate interaction between DP and HP-β-CD. The stability of DP/HP-β-CD was decreased because of the acid environment in stomach, which facilitated the absorption of DP. These results extended our understanding about the application of cyclodextrin complexation and provided guidance for the design of ODF especially for drugs with disgusting taste.

DESIGN AND CHARACTERIZATION OF DONEPEZIL HYDROCHLORIDE SUSTAINED RELEASE MATRIX TABLETS

The ultimate aim of the present study was to develop sustained release (SR) tablets of Donepezil Hydrochloride by employing natural polymers (Guar gum and Xanthan gum) as the matrix material in different proportion by wet granulation method. Initially drug-excipients compatibility studies were carried out using FTIR and DSC which showed no interaction between drug and excipients. Granules of prepared batches were evaluated for bulk density, tapped density, carr’s index, hausner’s ratio, angle of repose. Tablets were evaluated for various physicochemical parameters like hardness, thickness, friability, weight variation test, drug content and in vitro drug release. All the formulation showed compliance with pharmacopoeial standards. 3 2 full factorial design was applied in which Guar gum (X 1 ) and Xanthan gum (X 2 ) were taken as independent factor and %CDR at 2hr (Y 1 ) and at 12hr (Y 2 ) were taken as response. In-vitro drug release study revealed that as the amount of polymers increased, % CDR decreased. Contour plots as well as response surface plots were constructed to show the effect of X 1 and X 2 on %CDR and predicted at the concentration of independent variables X 1 (40mg) and X 2 (40mg) for maximized response. The kinetic release treatment showed that korsmeyer peppas equation has shown of r 2 0.9517 which was close to one indicating that the dissolution profile fits in Korsmeyer-Peppas model and the mechanism of drug release from these tablets was by non-fickian diffusion mechanism. The optimized batch was kept for stability study at 40 ± 2 o C/ 75 ± 5 % RH for a period of 1 month according to ICH guidelines and found to be stable after 1 month of study. Keywords: Sustained release matrix tablet, Donepezil hydrochloride, Guar gum, Xanthan gum, 3 2 full factorial design.

Novel coumarin derivatives as potent acetylcholinesterase inhibitors: insight into efficacy, mode and site of inhibition

The inhibitory efficacy of two substituted coumarin derivatives on the activity of neurodegenerative enzyme acetylcholinesterase (AChE) was assessed in aqueous buffer as well as in the presence of human serum albumin (HSA) and compared against standard cholinergic AD drug, Donepezil (DON). The experimental data revealed the inhibition to be of non-competitive type with both the systems showing substantial inhibitory activity on AChE. In fact, one of the tested compounds Chromenyl Coumarate (CC) was found to be better inhibitor (IC50 = 48.49 ± 5.6 nM) than the reference drug DON (IC50 = 74.13 ± 8.3 nM), unequivocally amplifying its importance. The structure of the compound was found to play a vital role in the inhibitory efficiency, validating previous Structure Activity Relationship (SAR) reviews for coumarin. The mechanism of inhibition remained impervious when the experimental medium was switched from aqueous buffer to HSA, albeit noticeable change in the inhibition potency of the compound 3, 3′- Methylene-bis (4-hydroxy coumarin) (MHC) (38%) and CC (35%). Both the coumarin derivatives were observed to bind to the peripheral anionic site (PAS) of AChE and also found to displace the fluorescence marker thioflavinT (ThT) from AChE binding pocket. All experimental observations were seconded by molecular docking and MD simulation results. The inferences drawn in this study form a foundation for further investigation on these compounds; magnifying the probability of their usage as AD drugs and re-emphasizes the significance of drug delivery media while considering the inhibition potencies of targeted drugs.

Development of a Nasal Donepezil-loaded Microemulsion for the Treatment of Alzheimer's Disease: in vitro and ex vivo Characterization.

Donepezil (DPZ) is widely prescribed as a specific and reversible acetylcholinesterase inhibitor for the symptomatic treatment of mild to moderate Alzheimer's disease (AD). Considering the therapeutic potential of DPZ and the advantages offered by the intranasal route as an alternative for drug administration, the aim of this study was the development and characterization of a DPZ microemulsion (ME) for nose-to-brain delivery. The ME was developed by construction of pseudoternary phase diagrams and characterized by dynamic light scattering and transmission electron microscopy. Flow properties and viscosity, as well as optical stability and stability under storage at different temperatures were evaluated. Finally, in vitro release and ex vivo permeation studies through porcine nasal mucosa were accomplished. A transparent and homogeneous DPZ-ME (12.5 mg/ml) was obtained. The pH and viscosity were 6.38 and 44.69 mPa·s, respectively, indicating nasal irritation prevention and low viscosity. The mean droplet size was 58.9±3.2 nm with a polydispersity index of 0.19±0.04. The morphological analysis revealed the spherical shape of droplets, as well as their smooth and regular surface. Optical stability evidenced no destabilization processes. DPZ release profile indicated that the ME followed a hyperbolic kinetic model while the ex vivo permeation profile showed that the highest permeation occurred during initial 4 h and the maximum permeated amount was approximately 2000 µg, which corresponds to 80% of the starting amount of drug. We conclude that our nasal ME could be considered as a new potential tool for further investigation in the AD.

Melatonin ameliorates brain oxidative stress and upregulates senescence marker protein-30 and osteopontin in a rat model of vascular dementia.

The aim of this study was to investigate the effect of melatonin on oxidative stress and senescence marker protein-30 (SMP30) as well as osteopontin (OPN) expression in the hippocampus of rats subjected to vascular dementia (VD). A total of 72 male rats were divided into six groups (n = 12 each) as follows: (i)untreated control (CON), (ii)sham-operated group, (iii)sham-operated + melatonin, (iv)rats exposed to VD induced by permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion, (v)rats exposed to VD + melatonin, and (vi)rats exposed to VD + donepezil (DON). At the end of experiment, the hippocampal levels of acetylcholine (ACh), norepinephrine (NE), and dopamine (Dop) were measured. Expression of OPN was determined using immunohistochemistry, and SMP30 expression was determined using real-time PCR in the hippocampus. Hippocampal thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) were evaluated. The BCCAO group showed significantly decreased TAC (p < 0.05) and significantly increased in TBARS levels compared with the CON group. In addition, BCCAO significantly decreased (p < 0.05) the expression of both OPN and SMP30 and the levels of ACh, NE, and Dop in the hippocampus compared with CON treatment. Treatment with melatonin significantly increased OPN and SMP30 expression and ACh, NE, and Dop levels in the hippocampus with amelioration of the oxidative stress compared with BCCAO rats. Melatonin might produce a neuroprotective effect through its antioxidant action and by increasing the expression of SMP30 and OPN that is not comparable with that of DON.

Association between ABCA1 gene polymorphisms and the therapeutic response to donepezil therapy in Han Chinese patients with Alzheimer’s disease

AimIt is reported that ABCA1, which plays a key role in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain, is related to Alzheimer’s disease. However, few studies have focused on the relationship between the ABCA1 gene and the therapeutic response to donepezil (DNP), which has been shown to be related to reduced sAPP production.This study evaluated the association between the ABCA1 gene polymorphism and the clinical response to donepezil therapy in Han Chinese patients with Alzheimer’s disease. MethodsWe examined ABCA1 gene polymorphisms in 88 Han Chinese patients with Alzheimer’s disease who were receiving DNP therapy. The Mini-Mental State Examination was conducted before and after DNP treatment, and the ABCA1 rs 2230806 and rs 2230808, APOE E3 genotypes of each patient were identified. ResultsWe found that patients with the ABCA1 rs2230806 GG genotype responded better to DNP treatment compared to those with the AA and AG genotypes (p = 0.001). Patients who were APOE E3 non-carriers and had the ABCA1 rs2230806 GG genotype tended to have a better clinical response to DNP therapy. ConclusionsThe ABCA1 rs 2230806 polymorphism and its combination with the APOE E3 allele may provide clinically relevant information for predicting the therapeutic response to DNP therapy.

Chemometrics-assisted spectrophotometric green method for correcting interferences in biowaiver studies: Application to assay and dissolution profiling study of donepezil hydrochloride tablets

A green, simple and cost effective chemometric UV–Vis spectrophotometric method has been developed and validated for correcting interferences that arise during conducting biowaiver studies. Chemometric manipulation has been done for enhancing the results of direct absorbance, resulting from very low concentrations (high incidence of background noise interference) of earlier points in the dissolution timing in case of dissolution profile using first and second derivative (D1 & D2) methods and their corresponding Fourier function convoluted methods (D1/FF& D2/FF). The method applied for biowaiver study of Donepezil Hydrochloride (DH) as a representative model was done by comparing two different dosage forms containing 5mg DH per tablet as an application of a developed chemometric method for correcting interferences as well as for the assay and dissolution testing in its tablet dosage form. The results showed that first derivative technique can be used for enhancement of the data in case of low concentration range of DH (1–8μgmL−1) in the three different pH dissolution media which were used to estimate the low drug concentrations dissolved at the early points in the biowaiver study. Furthermore, the results showed similarity in phosphate buffer pH6.8 and dissimilarity in the other 2pH media. The method was validated according to ICH guidelines and USP monograph for both assays (HCl of pH1.2) and dissolution study in 3pH media (HCl of pH1.2, acetate buffer of pH4.5 and phosphate buffer of pH6.8). Finally, the assessment of the method greenness was done using two different assessment techniques: National Environmental Method Index label and Eco scale methods. Both techniques ascertained the greenness of the proposed method.

Effect of Food Thickeners on the Disintegration, Dissolution, and Drug Activity of Rapid Oral-disintegrating Tablets

For patients with dysphagia in medical facilities and nursing homes, food thickeners are routinely used to aid the ingestion of medicines such as tablets. However, some types of thickeners affect the disintegration and dissolution of tablets, such as rapidly-disintegrating magnesium oxide tablets and donepezil hydrochloride orally disintegrating tablets. Additionally, delayed disintegration and dissolution of tablets affect a drug's efficacy. As an example, with Voglibose orally disintegrating tablets, marked differences are observed in changes in glucose levels during glucose tolerance testing. When using food thickeners to aid tablet ingestion, it is therefore necessary to select a product that has little effect on drug disintegration, dissolution, and activity.

The Histamine H3 Receptor Antagonist DL77 Ameliorates MK801-Induced Memory Deficits in Rats.

The role of Histamine H3 receptors (H3Rs) in memory, and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer disease (AD) is well-accepted. For that reason, the procognitive effects of the H3R antagonist DL77 on cognitive impairments induced with MK801 were tested in an inhibitory passive avoidance paradigm (PAP) and novel object recognition (NOR) task in adult male rats, using donepezil (DOZ) as a standard drug. Acute systemic pretreatment with DL77 (2.5, 5, and 10 mg/kg, i.p.) significantly ameliorated memory deficits induced with MK801 in PAP (all P < 0.05, n = 7). The ameliorative effect of most promising dose of DL77 (5 mg/kg, i.p.) was reversed when rats were co-injected with the H3R agonist R-(α)-methylhistamine (RAMH, 10 mg/kg, i.p.) (p = 0.701 for MK801-amnesic group vs. MK801+DL77+RAMH group, n = 6). In the NOR paradigm, DL77 (5 mg/kg, i.p.) counteracted long-term memory (LTM) deficits induced with MK801 (P < 0.05, n = 6–8), and the DL77-provided effect was similar to that of DOZ (p = 0.788, n = 6–8), and was reversed when rats were co-injected with RAMH (10 mg/kg, i.p.) (p = 0.877, n = 6, as compared to the (MK801)-amnesic group). However, DL77 (5 mg/kg, i.p.) did not alter short-term memory (STM) impairment in NOR test (p = 0.772, n = 6–8, as compared to (MK801)-amnesic group). Moreover, DL77 (5 mg/kg) failed to modify anxiety and locomotor behaviors of animals innate to elevated-plus maze (EPM) (p = 0.67 for percentage of time spent exploring the open arms, p = 0.52 for number of entries into the open arms, p = 0.76 for percentage of entries into the open arms, and p = 0.73 number of closed arm entries as compared to saline-treated groups, all n = 6), demonstrating that the procognitive effects observed in PAP or NOR tests were unconnected to alterations in emotions or in natural locomotion of tested animals. These results signify the potential involvement of H3Rs in modulating neurotransmitters related to neurodegenerative disorders, e.g., AD.

Protective effects of Alpinae Oxyphyllae Fructus extracts on lipopolysaccharide-induced animal model of Alzheimer's disease

Ethnopharmacological relevanceAlpinae Oxyphyllae Fructus (AOF) with warming and tonifying the kidney and spleen, anti-salivation, anti-polyuria and anti-diarrhea functions is the dried ripe fruits of Alpinia oxyphylla Miq. (Zingiberaceae). As a traditional Chinese medicine, its application history is very long. Aims of the studyThe purpose of our study is to investigate the effects of different solvent extracts from AOF on lipopolysaccharide (LPS)-induced animal model of Alzheimer's disease (AD) to elucidate the traditional medical theories with modern pharmacological methods and provide a reference for further clarifying its active components and mechanisms. Materials and methodsThe method of stepwise screening was adopted in this paper. The animals were divided into 9 groups, including control (CT) group, model (MD) group, donepezil (DPZ) group, total extract (TT) group, petroleum ether extract (PE) group, chloroform extract (CF) group, ethyl acetate extract (EA) group, n-butanol extract (NB) group and water extract (WT) group. The anti-amnesic effects of different solvent extracts from AOF were measured in LPS-induced memory deficits mice by Y maze test and Morris water maze (MWM) test. Hematoxylin eosin (HE) staining was applied to observe pathological changes in hippocampus and cerebral cortex tissue of different groups. Biochemical indicators including ionized calcium-binding adaptor molecule 1 (IBA-1), interleukin beta 1 (IL-1β), Aβ1–42 and hyperphosphorylated tau proteins (p-tau) in hippocampus and cortex after treatment with LPS were measured according to the manufacturer's instructions of ELISA kits. HPLC was used to evaluate the major components of different extracts. ResultsIt was found that successive intragastric administration of AOF (360 mg/kg) extracts for 14 days showed different degrees of improvement on LPS-induced AD model as measured by Y-maze test, Morris water maze test, and Histopathological examination. Moreover, the results of ELISA suggested petroleum ether (PE) extracts were worth recommending for inhibiting the high level of IBA-1, IL-1β, Aβ1–42 and p-tau in hippocampus and cortex after treatment with LPS. ConclusionsThe present study demonstrated for the first time that AOF attenuated LPS-induced learning and memory impairment, which may be associated with its inhibitory effect on neuroinflammation, amyloids-β (Aβ) deposition and p-tau. This research provided a theoretical basis for elucidating the traditional theory of AOF, and was also the stepping stone to the next step.

Systemic administration of donepezil attenuates the efficacy of environmental enrichment on neurobehavioral outcome after experimental traumatic brain injury.

The acetylcholinesterase inhibitor (AChEI) donepezil (DON) is recommended as a potential treatment for cognition after clinical traumatic brain injury (TBI) and therefore may be prescribed as an adjunct therapy during rehabilitation. However, a dose-response study evaluating DON after a controlled cortical impact (CCI) injury in rats did not reveal cognitive benefits. The aim of this study was to determine the effect of DON on behavioral and histological outcome when combined with environmental enrichment (EE), a preclinical model of neurorehabilitation. It was hypothesized that the combined treatments would produce a synergistic effect yielding improved recovery over neurorehabilitation alone. Isoflurane-anesthetized adult male rats received a CCI or sham injury and then were randomly assigned to EE or standard (STD) housing plus systemic injections of DON (0.25 mg/kg) or vehicle (VEH; 1.0 mL/kg saline) once daily for 19 days beginning 24 hr after injury. Function was assessed by established motor and cognitive tests on post-injury days 1-5 and 14-19, respectively. Cortical lesion volume was quantified on day 19. DON was ineffective when administered alone. In contrast, EE conferred significant motor and cognitive benefits, and reduced cortical lesion volume vs. STD (p < 0.05). Combining the therapies weakened the efficacy of rehabilitation as revealed by diminished motor and cognitive recovery in the TBI+EE+DON group vs. the TBI+EE+VEH group (p < 0.05). These data replicate previous findings showing that EE is beneficial and DON is ineffective after CCI and add to the literature a novel and unpredicted finding that supports neither the hypothesis nor the use of DON for TBI. Investigation of other AChEIs after CCI injury is necessary to gain further insight into the value of this therapeutic strategy.

Investigating effect of water of hydration on active pharmaceutical ingredients in a water-sensitive dosage form

BackgroundPreparation of mini buccal tablets incorporating either of the Alzheimer’s drugs, rivastigmine tartrate or donepezil hydrochloride, were developed for patients who have difficulty swallowing as a source of effervescence, by pairing the less commonly used malic acid with sodium bicarbonate in an experimentally determined (1:2) stochiometirc ratio.MethodsTo avoid premature reaction of the acid and the base during compounding, the tablet ingredients were mixed in the following order: acid, sweetener, binder, drug, preservative, base, and anti-adherent/lubricant.ResultsAn accelerated thermal stability study at 40 °C and 25% relative humidity showed that the integrity of the effervescent tablets containing rivastigmine tartrate were superior to that of donepezil HCl tablets. FT-IR spectrometry confirmed the presence of water of hydrate in donepezil HCl crystals. This water was absent in the IR after one-month storage at accelerated thermal stability, but was present at room temperature. This behavior was not observed in the tablet made from rivastigmine tartrate powder. Differential scanning calorimetry of donepezil hydrochloride showed two thermal events: the first was associated with the loss of the water, and the second, at much higher temperature, was the melting of theanhydrous drug. Such behavior was not observed in the rivastigmine tartrate powder.ConclusionsHidden water which may function as catalyst to induce premature effervescence during storage.

Lifetime Expectancy in Dementia with Lewy Bodies: Effects of Donepezil Administration and Special Nursing Home Replacement. A Retrospective Analysis in the Tajiri Project

Objective: Cholinesterase inhibitors (ChEIs) can delay the progression of Alzheimer disease (AD). We previously demonstrated a positive effect of donepezil (DNP) administration and a Special Nursing Home (SNH) replacement on lifetime expectancy after the onset of AD. Recently DNP has been indicated for use in the treatment of dementia with Lewy Bodies (DLB); however, the effect on lifetime expectancy remains unclear. Herein, we analyzed the effects of DNP on DLB. Methods: All outpatients at the Tajiri Clinic with available medical records and death certificates from 1999- 2012 were included in this retrospective analysis. The entry criteria were a diagnosis of dementia based on DSM-IV criteria and diagnosis of DLB using the international consensus criteria; medical treatment for more than 3 months and follow up to less than 1 year before death. Results: We identified 510 subjects based upon medical records and death certificates, of which 360 had a diagnosis of dementia that met the entry criteria. Of 51 patients diagnosed with DLB, 23 had taken DNP and 28 patients had not undergone drug treatment due to treatment prior to the introduction of DNP in 1999 in Japan. The lifetime expectancies after onset were 6.4 years in the DNP group and 3.6 years in the non-DNP group; with a significant drug effect. However, in contrast with the previous AD data, no significant effect of SNH residency was noted. Conclusion: Although this report has the limitation that all analyses were retrospective and lacked randomization, we found a positive effect of DNP on lifetime expectancy after the onset of DLB. The lower life expectancy compared with that of AD and the lack of an effect of SNH residency suggest the cholinergic deficiency in DLB is greater than that in AD.

Impact of butylphthalide soft capsules on the related factors and quality of life of Parkinson patients with dementia

Objective To explore the impact of butylphthalide soft capsules on the related factors and quality of life of Parkinson patients with dementia. Methods 90 Parkinson patients with dementia were selected, and they were divided into the study group and the control group by the random number table method, 45 cases in each group.The control group was treated with donepezil hydrochloride combined with routine nursing method, and the study group was treated with butylphthalide soft capsules based on the treatment of the control group.Before and after treatment, the serum C-reactive protein(CRP), recombinant human Parkinson disease protein 7(PARK7), neurotrophic factor-3(NT-3) levels of all patients were detected.And the quality of life of patients at admission and discharge were evaluated by the scale of disease self management efficiency and quality of life scale WHO(WHO QOL-BREF), quality of life of the two groups was compared before and after treatment.The Parkinson's Disease Rating Scale(UPDRS) scores was compared between the two groups before and after treatment. Results Before treatment, the dementia related factors and quality of life score, UPDRS score of the two groups had no statistically significant differences(all P>0.05). After treatment, the dementia related factors of the two groups were all improved, which of the study group improved significantly[CRP: (3.24±0.78)mg/L vs.(6.02±0.95)mg/L, PARK7: (13.15±1.51)μg/L vs.(24.93±2.02)μg/L, NT-3: (34.16±3.47)μg/L vs.(26.23±2.97)μg/L, all P<0.05]. After treatment, the quality of life(QOL) and UPDRS score of the study group were significantly higher than those of the control group[(80.5±12.5)points vs.(66.0±10.3)points, (33.28±2.18)points vs.(41.26±2.54)points, all P<0.05]. Conclusion Butylphthalide soft capsules can effectively improve the dementia related factor of Parkinson patients with dementia, and enhance the quality of life with good effect. Key words: Dementia; Parkinson disease; Risk factors; Quality of life; Butylphthalide