Our library of drug research abstracts drawn from the medical literature is updated on a regular schedule, and you can be assured that new aricept research articles will be listed here shortly after becoming available to us.
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Medical research on aricept
Arzneimittelforschung. 2008; 58(5): 255-8
Erkent U, Koytchev R
The bioequivalence of long terminal half-life drugs, donepezil (CAS 120014-06-4) 10 mg and memantine (CAS 19982-08-2) 10 mg, was evaluated by comparing the results obtained for the total areas under the concentration time curves (AUC(0-inf)) with those for partial AUCs: AUC(0-216h), AUC(0-72h) and AUC(0-48h). Pharmacokinetic endpoints were determined by standard formulas from the concentration-time courses of the parent compounds donepezil and memantine. The results of the bioequivalence assessment based on the 90% confidence intervals calculated by means of ANOVA for logarithmically transformed values (ANOVA log) led to exactly the same decision irrespective of the type of AUC used. The 90% confidence intervals for all types of AUCs were practically identical within each product. These results prove that truncated AUCs, e.g. AUC(0-72h) or even AUC(0-48h), can be adequately used in assessing the relative bioavailability of long terminal half-life drugs. The findings suggest that even for drugs with half-lives between 24 and 60 h and thus shorter than those of donepezil and memantine an AUC truncated to 48 h post dose can be successfully used for the assessment of bioequivalence as this sample collection time ensures a proper comparison of the absorption process as recommended in the CPMP Note for Guidance on the Investigation of Bioavailability and Bioequivalence.
J Palliat Med. 2008 Jun; 11(5): 738-45
Weschules DJ, Maxwell TL, Shega JW
ABSTRACT Objectives: To describe acetylcholinesterase inhibitor (AChEI) and memantine use among persons over the age of 65 admitted to hospice with a primary diagnosis of dementia and identify patient and hospice program characteristics associated with the use of these agents. Design: Retrospective, cross-sectional study. Setting: Administrative database of a national hospice pharmacy provider. Participants: A total of 10,065 persons with end-stage dementia admitted to one of 441 U.S. hospices in 2004. Measurements: The frequency of AChEI and memantine use was determined and utilized as the unit of analysis for bivariate and multivariate comparisons with patient and hospice program characteristics. Results: Twenty-one percent (2148/10,065) of patients were prescribed AChEI and/or memantine therapy at the time of hospice enrollment. Of these, 49.5% were prescribed donepezil. Odds of receiving AChEI and/or memantine therapy were less likely if the patient was female, (odds ratio [OR] 0.68, 0.62-0.76), died while enrolled in hospice (OR 0.75, 0.67-0.85), received care at home (0.80, 0.71-0.89), or had a hospice length of stay (LOS) less than 7 days (0.53, 0.45-0.62). Patients who had a LOS of at least 60 days were significantly more likely to have received such therapies (OR 1.41 [1.24-1.60] for 61-180 days and 1.33 [1.15-1.54] for over 180 days). Conclusion: A notable number of hospice enrollees with a primary diagnosis of dementia were prescribed AChEI and/or NMDA receptor antagonist therapy. Studies are needed to better define the role of these agents as well as the impact of medication discontinuation in persons with end-stage dementia.
Psychiatr Danub. 2008 Jun; 20(2): 168-73
Zivin M, Pregelj P
OBJECTIVE: Acetylcholinesterase (AChE), an enzyme catalysing rapid hydrolysis of acetylcholine is the major enzyme in the metabolism of this neurotransmitter in the central nervous system and in the skeletal and smooth muscles. Donepezil is a reversible, primarily non-competitive, selective inhibitor of AChE used in patients with Alzheimer's disease for the improvement of cognitive deficits. We hypothesized that prolonged treatment with donepezil could increase AChE mRNA levels and AChE activity in the central nervous system. METHODS: The levels of AChE mRNA and AChE activity in the brain sections of 6 animals treated for 28 days with donepezil (2 mg/kg s.c.) were visualized by an autoradiographic method of in situ hybridization and by Koelle histochemical staining, respectively, and compared with 6 control animals treated with physiologic saline. The images of autoradiograms and of AChE-stained brain sections were densitometrically analysed with a computerized imaging analysis system. RESULTS: We observed that 28-day treatment with donepezil in comparison to control treatment increased hippocampal AChE mRNA levels and AChE activity. CONCLUSIONS: Our data suggest that AChE up-regulation induced by prolonged treatment with AChE inhibitors may be the rationale for up-titration of AChE inhibitors during the treatment of AD. Further preclinical and clinical data are needed to evaluate the relative impact of the up-regulation of AChE activity on the outcome of prolonged treatment of AD patients with donepezil.
Eur J Pharmacol. 2008 Jun 12;
Takada-Takatori Y, Kume T, Ohgi Y, Fujii T, Niidome T, Sugimoto H, Akaike A
alpha7-nicotinic acetylcholine receptors are one of the most abundant subtypes of nicotinic receptors in the brain and have been shown to be involved in the neuroprotective effect of donepezil. Recently, we showed that in primary culture of rat cortical neurons, chronic donepezil treatment (10 muM, 4 days) (1) induces the up-regulation of alpha7-nicotinic receptors, (2) enhances the nicotine-induced increase in [Ca(2+)](i) and (3) enhances the sensitivity to the neuroprotective effect of donepezil. Here we demonstrate the involvement of alpha7-nicotinic receptors in these three effects. Concomitant treatment with nicotinic receptor antagonist inhibited the up-regulation of alpha7-nicotinic receptor, enhancement of the increase in [Ca(2+)](i) induced by nicotine, and enhancement of sensitivity to the neuroprotective effect of donepezil. Next, using inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase signaling pathways, we demonstrate the involvement of these pathways in the up-regulation of alpha7-nicotinic receptors and in making the neurons more sensitive to the neuroprotective effects of donepezil. Concomitant chronic donepezil treatment with inhibitors of phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways inhibited nicotinic receptor up-regulation and enhancement of the response to nicotine, and enhanced the sensitivity to donepezil. This study increases understanding of the less-studied mechanism of chronic donepezil treatment-induced nicotinic receptor up-regulation and increased sensitivity to donepezil.
Anesthesiology. 2008 Jul; 109(1): 124-9
Nakahata K, Kinoshita H, Hama-Tomioka K, Ishida Y, Matsuda N, Hatakeyama N, Haba M, Kondo T, Hatano Y
BACKGROUND: An acetylcholinesterase inhibitor donepezil currently is used to treat patients with Alzheimer disease. However, its direct effect on cerebral blood vessels has not been evaluated. The present study was designed to examine whether donepezil induces acute cerebral arteriolar dilation and whether neuronal nitric oxide synthase contributes to this vasodilator response. METHODS: Brain slices were obtained from neuronal nitric oxide synthase knock-out or C57BL/6J strain (control) mice as well as Wistar rats. Parenchymal arterioles were monitored using videomicroscopy. During constriction to prostaglandin F2alpha (5 x 10 m), donepezil (10-10 m) or acetylcholine (10-10 m) was added. In some experiments, brain slices were treated with a nonselective or a selective nitric oxide synthase inhibitor (N-nitro-L-arginine methyl ester [10 m] and S-methyl-L-thiocitrulline [10 m], respectively). An immunohistochemical analysis was performed using antibodies for neuronal nitric oxide synthase and acetylcholinesterase. RESULTS: Acetylcholine concentration-dependently dilated rat parenchymal arterioles, while S-methyl-L-thiocitrulline as well as N-nitro-L-arginine methyl ester completely abolished this response. Donepezil produced arteriolar dilation, which was inhibited by S-methyl-L-thiocitrulline or N-nitro-L-arginine methyl ester. Donepezil failed to induce arteriolar dilation in the brain slice from the neuronal nitric oxide synthase knock-out mice. Immunohistochemical analysis revealed spatial relationship between neuronal nitric oxide synthase and acetylcholinesterase in the arteriolar wall. CONCLUSIONS: Donepezil produces acute vasodilation induced by a selective activation of neuronal nitric oxide synthase in the cerebral parenchymal arterioles. This agent may be capable of enhancing this enzymatic activity directly or via acetylcholinesterase existing on the arteriolar wall.
The new approach in development of anti-Alzheimer's disease drugs via the cholinergic hypothesis.
Chem Biol Interact. 2008 Jun 3;
Sugimoto H
A wide range of evidences show that cholinesterase (ChE) inhibitors can interfere with the progression of Alzheimer's disease (AD). The earliest known ChE inhibitors, namely, physostigmine and tacrine, showed modest improvement in the cognitive function of AD patients. However, clinical studies show that physostigmine has poor oral activity, brain penetration and pharmacokinetic parameters while tacrine has hepatotoxic liability. Studies were then focused on finding a new type of acetylcholinesterase (AChE) inhibitor that would overcome the disadvantages of these two compounds. During the study, by chance we found a seed compound. We then conducted a structure-activity relationship (SAR) study of this compound. After four years of exploratory research, we found donepezil hydrochloride (donepezil). Recently, acetylcholinesterase inhibitors (AChEIs) have been studied for other mechanisms of action, such as neuroprotective action and lowering of beta-amyloid (beta-amyloid). Donepezil also reduced beta-amyloid plaque in in vitro. The amyloid hypothesis is believed to be the most promising approach in the development of anti-AD drugs. We speculate the mechanism of lowering beta-amyloid by donepezil implicate alpha-secretase (alpha-secretase) enhancer.
Study of neuroprotection of donepezil, a therapy for Alzheimer's disease.
Chem Biol Interact. 2008 May 7;
Akasofu S, Kimura M, Kosasa T, Sawada K, Ogura H
Donepezil is a potent acetylcholinesterase inhibitor used for the treatment of Alzheimer's disease. Although acetylcholinesterase inhibitors are thought to be symptomatic treatment of Alzheimer's disease, it is not clear whether they are effective against progressive degeneration of neuronal cells. In this study, we investigated the neuroprotective effects of donepezil against ischemic damage, N-methyl-d-aspartate (NMDA) excitotoxicity, and amyloid-beta (Abeta) toxicity using rat brain primary cultured neurons. Lactate dehydrogenase (LDH) released into the culture medium was measured as a marker of neuronal cell damage. As an ischemic damage model, we used oxygen-glucose deprivation in rat cerebral cortex primary cultured neurons. Pretreatment with donepezil (0.1, 1 and 10muM) significantly decreased LDH release in a concentration-dependent manner. However, other acetylcholinesterase inhibitors (galantamine, tacrine and rivastigmine) did not significantly decrease LDH release. In a NMDA excitotoxicity model, pretreatment with donepezil (0.1, 1 and 10muM) decreased the LDH release in a concentration-dependent manner. In binding assay for glutamate receptors, donepezil at 100muM only slightly inhibited binding to the glycine and polyamine sites on NMDA receptor complex. We further examined the effect of donepezil on Abeta (1-40)- and Abeta (1-42)-induced toxicity in primary cultures of rat septal neurons. Pretreatment with donepezil (0.1, 1 and 10muM) significantly decreased LDH release induced by Abetas in a concentration-dependent manner. However, other acetylcholinesterase inhibitors (galantamine and tacrine) and NMDA receptor antagonists (memantine and dizocilpine (MK801)) did not significantly decrease LDH release. These results demonstrate that donepezil has protective effects against ischemic damage, glutamate excitotoxicity and Abeta toxicity to rat primary cultured neurons and these effects are not dependent on acetylcholinesterase inhibition and antagonism of NMDA receptors. Thus, donepezil is expected to have a protective effect against progressive degeneration of brain neuronal cells in ischemic cerebrovascular disease and Alzheimer's disease.
Chem Biol Interact. 2008 May 7;
García-Ayllón MS, Silveyra MX, Sáez-Valero J
The altered expression of acetylcholinesterase (AChE) in the brains of patients with Alzheimer's disease (AD) has raised much interest of late. Despite an overall decrease in the AD brain, the activity of AChE increases around beta-amyloid plaques and indeed, the beta-amyloid peptide (Abeta) can influence AChE levels. Such evidence stimulated our interest in the possibility that the levels of AChE and amyloid might vary together in AD. We previously found that the different AChE forms present in both the brain and in the cerebrospinal fluid (CSF) of AD patients varied in conjunction with abnormal glycosylation. Thus, the alterations in glycosylation are correlated with the accumulation of a minor subspecies of AChE monomers. We also recently analysed whether long-term exposure to the cholinesterase inhibitor (ChE-I) donepezil influences the AChE species found in AD CSF. The marked increase in CSF-AChE activity in AD patients following long-term treatment with donepezil was not paralleled by a rise in this subset of light variants. Hence, the correlation with the levels of CSF-Abeta is unique to these AChE species in patients receiving such treatment. The aim of this report is to review the links between AChE and beta-amyloid, and to discuss the significance of the responses of the distinct AChE species to ChE-I during the treatment of AD.
J Pharmacol Sci. 2008 Jun; 107(2): 167-74
Jia F, Mobarakeh JI, Dai H, Kato M, Xu A, Okuda T, Sakurai E, Okamura N, Takahashi K, Yanai K
The aim of this study was to investigate the effects of histamine H(1) and H(3) antagonists on learning and mnemonic dysfunction in mice. Two H(1) antagonists, pyrilamine and clozapine, and the prototypic H(3) antagonist thioperamide were used to study the role of histamine in mice with social isolation and repeated methamphetamine administration. Mice with social isolation and repeated methamphetamine administration showed significant disruption of prepulse inhibition as compared to both the socially-housed mice and isolation-housing mice. Furthermore, social isolation and repeated methamphetamine administration caused significant learning and mnemonic dysfunctions. Treatment with clozapine improved learning and mnemonic ability in all of the tasks. Pyrilamine treatment ameliorated performance in all the tests examined except for the passive avoidance test. Thioperamide, however, did not change the learning and mnemonic ability. Donepezil, an acetylcholinesterase inhibitor, reversed the learning and mnemonic dysfunction in all four tasks. The present study has shown that blockade of histamine H(1) receptor improved the learning and mnemonic ability in mice, raising the possibility that treatment with clozapine or pyrilamine may improve learning and mnemonic performance in certain patients with psychiatric diseases such as schizophrenic patients with cognitive dysfunction.
Clin Drug Investig. 2008; 28(7): 429-37
Gil P, Ayuso JL, Marey JM, Antón M, Quilo CG
BACKGROUND AND OBJECTIVES: There is frequently a degree of variability among different types of dementia specialists in clinical practice in both the clinical diagnosis and the management of patients with Alzheimer's disease and cerebrovascular disease (CVD). This variability may have an adverse effect on the use of medical resources as well as on patients' well-being. The main objective of this study was to describe the current diagnosis and management of patients with Alzheimer's disease and CVD in Spain. Other objectives were to determine whether there were significant differences in the diagnosis and management of these patients depending on physician characteristics and/or patient profile. METHODS: This was an epidemiological, cross-sectional, multicentre study in which 107 physicians participated and recruited patients with Alzheimer's disease and CVD. During a 1-month period, physicians collected data on diagnosis, treatment, follow-up, adverse events and other characteristics of these patients. This study was performed under naturalistic conditions, and no restrictions were imposed on the physicians. RESULTS: Physicians were mainly neurologists (76%), geriatricians (14%) and psychiatrists (8%) with a median age of 42 years. A total of 720 patients with a diagnosis of Alzheimer's disease and CVD were recruited. The median age of the patients was 78 years. Almost all patients were diagnosed by neuroimaging (98%) together with medical history (87%). The existence of a previous stroke coincident with cognitive deterioration was used as a diagnostic method in only 27% of patients. Among non-pharmacological treatment measures, diet was the most frequently recommended (61%), followed by cognitive stimulation (50%) and physical exercise (44%). The most commonly used pharmacological treatments were galantamine (59%), donepezil (14%) and rivastigmine (11%). The incidence of adverse events was low (3%), and all were considered non-severe. There were no significant correlations between physician age or physician years of practice and the diagnostic method used. The diagnostic method most frequently used by psychiatrists (100%) and geriatricians (97%) was medical history whereas this method was not used as much by neurologists (85%) [p = 0.0150]. Neuroimaging methods were more frequently used by neurologists (99%) and geriatricians (96%) compared with psychiatrists (84%) [p < 0.0001]. Patients with attention disorders had a higher frequency of follow-up visits (p = 0.0145) and were treated less frequently with donepezil (p = 0.0118). CONCLUSIONS: Several possible areas of improvement in the management of patients with Alzheimer's disease and CVD were identified. These included better control of cardiovascular risk factors, such as hypertension and hyperlipidaemia, which have a high prevalence in this population, as has been shown in the present study. These potentially modifiable risk factors may assist in the prevention of Alzheimer's disease. Also identified was the need to emphasize the role of general practitioners in decreasing the time to diagnosis of Alzheimer's disease. Development of well designed clinical practice guidelines may help physicians decide on the most appropriate ways of diagnosing and managing patients with Alzheimer's disease and CVD and reduce practice variations between different medical specialities.