Antidementia Agents Research Articles

β‐secretase inhibitory effects of furanocoumarins from the root of Angelica dahurica

In the course of screening antidementia agents from natural products, five beta-secretase (BACE1) inhibitors were isolated from the root extract of Angelica dahurica (Umbelliferae). They were identified as furanocoumarins, isoimperatorin (1), imperatorin (2), (+)-oxypeucedanin (3), (+)-byakangelicol (4) and (+)-byakangelicin (5). Among them, compounds 2 and 4 showed significant inhibitory activity against beta-secretase (BACE1) with IC(50) values of 91.8 +/- 7.5 and 104.9 +/- 2.4 microM, respectively. Compounds 1-5 inhibited BACE1 activity in a dose-dependent manner.

Potential Anti-Dementia Agents in Traditional Chinese Medicine

Dementia is becoming one of the biggest threats to human health. However, there is no efficient therapeutic approach so far. Thus, traditional medicines, which have accumulated certain experience in the treatment of dementia, are attracting more and more attention. Indeed, many anti-dementia drugs or drug candidates have been derived from these medicines. In this article, the profile of anti-dementia agents contained in traditional Chinese medicine (TCM) is described. It is indicated that TCM is not only a rich source of acetylcholinesterase inhibitors, but also of great potential to derive other kinds of anti-dementia agents which are either directly associated with ameliorating dementia or have complementary effects. These agents have apparent implications for anti-dementia drug discovery, especially for finding multicomponent anti-dementia drugs.

Price of Brand-Name Psychiatric Drugs on Steep Upward Course

Back to table of contents Previous article Next article Health Care EconomicsFull AccessPrice of Brand-Name Psychiatric Drugs on Steep Upward CourseMark MoranMark MoranSearch for more papers by this authorPublished Online:15 May 2009https://doi.org/10.1176/pn.44.10.0022aManufacturer prices for brand-name prescription drugs widely used by Medicare beneficiaries jumped by nearly 9 percent in 2008, according to the 2009 AARP “Rx Watchdog Report.”That increase was the largest annual increase in six years and greatly exceeded the general inflation rate of 3.8 percent. Major classes of psychiatric brand-name drugs—including antidepressants, antipsychotics, sedatives, antidementia agents—experienced price increases that exceeded general inflation. Grouped in a class and compared with all other therapeutic drug categories, two dosages of Wellbutrin (300 mg and 150 mg) experienced the greatest increase, rising in price by 21 percent (see chart).Meanwhile, manufacturer prices of widely used generic drugs continued to decrease in 2008, falling by an average of 10.6 percent. The majority of generics (83 percent) did not change in price in 2008, despite an increase in general inflation.And some of the generics that did drop in price did so very dramatically. For instance, the manufacturer price for the brand-name antidepressant Zoloft (50 mg and 100 mg tablets) increased by 12.3 percent in 2008, but the price for generic sertraline made by Teva Pharmaceuticals decreased by 45.1 percent, according to the report.“A person taking three brand-name prescription drugs could see his or her annual costs climb by more than $550 in just one year,” AARP Public Policy Director John Rother said in a statement released with the report.“ Switching to generic drugs whenever possible is one of the quickest and easiest ways to drastically reduce health care bills.”The list of prescription drugs widely used by Medicare beneficiaries is based on the 300 most widely dispensed drug products, the 300 drug products with the highest sales levels, and the 300 drug products with the highest number of days of therapy among the prescriptions provided by United Healthcare-PacificCare. (That company provides Medicare Part D coverage and is also the organization that insures the AARP Medicare Rx Plans.)Price changes were measured using changes in the wholesale acquisition cost as published by the Medi-Span Price-Chek PC Database.AARP's “Rx Watchdog Report” is posted at<http://assets.aarp.org/rgcenter/health/2009_07_rxq408.pdf>.▪ ISSUES NewArchived

Clinical practice with antidementia and antipsychotic drugs: Audit from a geriatric clinic in India.

Background:Dementia is one of the most disabling disorders afflicting the elderly, with a staggering emotional and economic impact. Antidementia agents have been used for delaying cognitive decline. Antipsychotics are commonly prescribed for behavioral symptoms associated with dementia.Objectives:To explore the use of anti-dementing agents and antipsychotics used in patients with a diagnosis of dementiaMaterials and Methods:A retrospective chart review method; geriatric clinic of tertiary care setting.Results:The study sample included 51 consecutive patients with a diagnosis of dementia. The commonest subtype of dementia that was diagnosed was Alzheimer's disease (45%), followed by Frontotemporal dementia (25%).The commonest antidementia drug that was used was donepezil, which alone was prescribed in 27 patients (52%). The commonest antipsychotic used was quetiapine, which was used in 24 patients (47%).Conclusions:The study found donepezil to be the most commonly prescribed antidementia drug and quetiapine to be the most commonly used antipsychotic in a tertiary care geriatric clinic, in a developing country. There is a need to study the cost-effectiveness of antidementia and antipsychotic drugs in patients with dementia, in developing countries.

Syringin from Fraxinus rhynchophylla Hance inhibit the apoptotic neuronal cell death induced by Aβ25–35

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive degeneration and loss of neuronal cells in the brain. β-Amyloid peptide (Aβ) is produced by proteolysis of amyloid precursor protein (APP), and its accumulation in the senile plaque is the major hallmark of AD pathogenesis [1, 2, 3]. Various experimental evidence support that Aβ plaque can induce neurotoxic effect on neuronal cells [4]. In the course of screening of anti-dementia agents from medicinal plants, the ethanolic extract of Fraxinus rhynchophylla Hance showed neuroprotective effect against Aβ25–35-induced cytotoxicity in cultured B103 cells. The extract was partitioned with dichloromethane (CH2Cl2), n-butanol (n-BuOH), and water, successively. The repeated chromatographic separation afforded an active compound, and its chemical structure was elucidated as syringin by 1H- and 13C-NMR and LC-MS. Its effects on apoptotic cell death were determined by MTT, H2DCF-DA and caspase-3 activity assay. As results, syringin significantly increased B103 cell viability up to 79.16% at 20µM in the presence of 12.5µM of Aβ25–35, and it remarkably decreased Aβ25–35-induced reactive oxygen species (ROS) generation up to 92.87% at the same concentration. In addition, the activity of caspase-3, an enzymatic major marker of apoptosis, was decreased up to 39.75% at 25µM. These results indicate that syringin and ethanolic extracts from Fraxinus rhynchophylla Hance could be a promising agent for anti-dementia.

Extracts and constituents of Leontopodium alpinum enhance cholinergic transmission: Brain ACh increasing and memory improving properties

Leontopodium alpinum (‘Edelweiss’) was phytochemically investigated for constituents that might enhance cholinergic neurotransmission. The potency to increase synaptic availability of acetylcholine (ACh) in rat brain served as key property for the bioguided isolation of cholinergically active compounds using different chromatographic techniques. The dichlormethane (DCM) extract of the root, fractions and isolated constituents were injected i.c.v. and the effect on brain ACh was detected via the push–pull technique. The DCM extract enhanced extracellular ACh concentration in rat brain and inhibited acetylcholinesterase (AChE) in vitro. The extracellular level of brain ACh was significantly increased by the isolated sesquiterpenes, isocomene and 14-acetoxyisocomene, while silphiperfolene acetate and silphinene caused a small increasing tendency. Only silphiperfolene acetate showed in vitro AChE inhibitory activity, thus suggesting the other sesquiterpenes to stimulate cholinergic transmission by an alternative mechanism of action. Isocomene was further investigated with behavioural tasks in mice. It restored object recognition in scopolamine-impaired mice and showed nootropic effects in the T-maze alternation task in normal and scopolamine-treated mice. Additionally, this sesquiterpene reduced locomotor activity of untreated mice in the open field task, while the activity induced by scopolamine was abolished. The enhancement of synaptic availability of ACh, the promotion of alternation, and the amelioration of scopolamine-induced deficit are in accordance with a substance that amplifies cholinergic transmission. Whether the mechanism of action is inhibition of AChE or another pro-cholinergic property remains to be elucidated. Taken together, isocomene and related constituents of L. alpinum deserve further interest as potential antidementia agents in brain diseases associated with cholinergic deficits.

Medication use in nursing home residents with advanced dementia

To describe medication usage in nursing home residents with advanced dementia, to identify how this usage changed as patients advanced towards death, and to identify correlates of increased medication usage. Prospective cohort study (CareAD) during which data on medication prescription were extracted from medical records at regular intervals using standardized extraction procedures. Patients (n=125) were prescribed a mean of 14.6 medications during the 6 months prior to study enrollment. In a subgroup of patients who died during the study (n=88), as the time of death approached, the total number of medications prescribed did not vary but the types of medications prescribed did change, with an increase in palliative medications such as opiate analgesics and a decrease in other medication classes such as antibiotics, anti-dementia agents, cardiovascular agents, and psychotropic agents, among others. In linear regression analyses, total medication prescription at study entry was associated with study site, antibiotic treatment, presence of cardiovascular disease, and treatment of gastrointestinal or dermatological conditions. Nursing home residents with advanced dementia are prescribed a large number of medications from numerous medication classes and prescribing patterns change over time. Further study is needed to determine the ideal approach to treating chronic medical problems at the end of life in this patient population.

β-secretase (BACE1) inhibitors from Perilla frutescens var. acuta

In the course of screening for anti-dementia agents from natural products, two beta-secretase (BACE1) inhibitors were isolated from the methanolic extract of Perilla frutescens var. acuta and identified as luteolin (1) and rosmarinic acid (2) with IC50 values of 5.0 x 10(-7) M and 2.1 x 10(-5) M, respectively. They inhibited BACE1 in a non-competitive manner with a substrate in Dixon plots, suggesting that they might bind to either beta-secretase subsite or to another regulatory site. Kivalues of 1 and 2 were 6.2 x 10(-5) M and 3.9 x 10(-5) M, respectively. They were less inhibitory against other enzymes such as alpha-secretase (TACE), acetylcholine esterase (AchE), chymotrypsin, and elastase, indicating that they were relatively specific inhibitors of BACE1.

A Systematic Review of Assessment and Treatment of Moderate to Severe Alzheimer's Disease

The systematic, large-scale study of therapies for moderate to severe Alzheimer's disease (AD) is a relatively recent advancement in the field. This review describes for the general practitioner the characterization of moderate to severe AD, discusses the development of metrics sensitive to the constellation of symptoms in these patients, and critically evaluates the use of those measures in moderate to severe AD clinical trials. Published clinical trials obtained by MEDLINE searches used the following key words: moderate AD, severe AD, donepezil, rivastigmine, galantamine, memantine, and anti-dementia agents. Clinical trials were limited by language (English), study type (clinical trial), and publication dates (1990-2005). Nine clinical trials comprise the studies conducted to date in moderate to severe AD and include 5 prospective randomized clinical trials (3 for memantine, 2 for donepezil) and 4 retrospective subanalyses (2 for galantamine, 2 for rivastigmine) of primary datasets. Clinical trials are summarized and major findings are reviewed. The data reviewed support the decision to initiate and maintain treatment in moderate to severe AD patients. The development and implementation of improved metrics for moderate to severe AD patients has revealed that meaningful benefits are attainable in this patient population by treatment with the N-methyl-D-aspartate receptor antagonist memantine. Evidence also indicates a benefit from cholinesterase inhibitor treatment, although further study of these agents in this patient population is warranted.

Neuroprotective properties of memantine in different in vitro and in vivo models of excitotoxicity

The pathogenesis of stroke, trauma and chronic degenerative diseases, such as Alzheimer's disease (AD), has been linked to excitotoxic processes due to inappropriate stimulation of the N-methyl-D-aspartate receptor (NMDA-R). Attempts to use potent competitive NMDA-R antagonists as neuroprotectants have shown serious side-effects in patients. As an alternative approach, we were interested in the anti-excitotoxic properties of memantine, a well-tolerated low affinity uncompetitive NMDA-R antagonist presently used as an anti-dementia agent. We explored in a series of models of increasing complexity, whether this voltage-dependent channel blocker had neuroprotective properties at clinically relevant concentrations. As expected, memantine protected neurons in organotypic hippocampal slices or dissociated cultures from direct NMDA-induced excitotoxicity. However, low concentrations of memantine were also effective in neuronal (cortical neurons and cerebellar granule cells) stress models dependent on endogenous glutamate stimulation and mitochondrial stress, i.e. exposure to hypoxia, the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+) or a nitric oxide (NO) donor. Furthermore, memantine reduced lethality and brain damage in vivo in a model of neonatal hypoxia-ischemia (HI). Finally, we investigated functional rescue (neuronal capacity to migrate along radial glia) by memantine in cerebellar microexplant cultures exposed to the indirect excitotoxin 3-nitropropionic acid (3-NP). Potent NMDA-R antagonists, such as (+)MK-801, are known to block neuronal migration in microexplant cultures. Interestingly, memantine significantly restored the number of neurons able to migrate out of the stressed microexplants. These findings suggest that inhibition of the NMDA-R by memantine is sufficient to block excitotoxicity, while still allowing some degree of signalling.

Treatments for behavioural disorders in neurodegenerative diseases: drug development strategies

Neuropsychiatric symptoms and behavioural alterations are common in neurodegenerative diseases, and effective treatment of these changes represents an important unmet public health need. Imaging, neuropathological, neurotransmitter and molecular genetic studies increasingly identify specific mechanisms that mediate behavioural changes in neurodegenerative disorders and provide a platform for seeking effective therapeutic interventions. Measuring behavioural outcomes in clinical trials of antidementia agents represents an important means of evaluating treatment effectiveness, and clinical trial methodologies and behavioural instrumentation are evolving to facilitate drug development in this important therapeutic target area.

β-Secretase(BACE1) inhibitors from pomegranate (Punica granatum) husk

In the course of screening for anti-dementia agents from natural products, two beta-secretase (BACE1) inhibitors were isolated from the husk of pomegranate (Punica granatum) by activity-guided purification. They were identified as ellagic acid and punicalagin with IC50 values of 3.9 x10(-6) and 4.1x10(-7) M and Ki values of 2.4x10(-5) and 5.9x10(-7) M, respectively. The compounds were non-competitive inhibitors with a substrate in the Dixon plot. Ellagic acid and punicalagin were less inhibitory to alpha-secretase (TACE) and other serine proteases such as chymotrypsin, trypsin, and elastase, thus indicating that they were relatively specific inhibitors of BACE1.

β-Secretase (BACE1) inhibitors from Sanguisorbae Radix

In the course of screening anti-dementia agents from natural products, two beta-secretase (BACE1) inhibitors were isolated from the ethyl acetate soluble fraction of Sanguisorbae Radix by the activity-guided purification using silica gel, Sephadex LH-20, and RP-HPLC. They were identified as 1,2,3-trigalloyl-4,6-hexahydroxydiphenoyl-beta-D-glucopyranoside (Tellimagrandin II, 1) and 1,2,3,4,6-pentagalloyl-beta-D-glucopyranoside (2) and were shown to non-competitively inhibit beta-secretase (BACE1) with the IC50 values of 3.10x10(-6) M and 3.76x10(-6) M, respectively. The Ki values of 1 and 2 were 6.84x10(-6) M and 5.13x10(-6) M. They were less inhibitory to alphasecretase (TACE) and other serine proteases such as chymotrypsin, trypsin, and elastase, suggesting that they were relatively specific inhibitors of BACE1.

Basic studies for the development of anticancer, antidementia, and taste modifier drugs

We developed various types of differentiation- and apoptosis-inducing agents against tumor cells and also studied the function and structure of synucleins and taste modifiers. Differentiation- and apoptosis-inducing agents are classified into DNA-damaging agents, Na(+), K(+)-ATPase inhibitors, agents affecting the redox states of tumor cells, agents affecting signal transduction pathways, isoprenoid compounds, and ATP-noncompetitive tyrosine kinase inhibitors. These include camptothecin, etoposide, cisplatin, transplantin, bufalin, arsenic trioxide, costunolide, C(2)- ceramide, daidzein, geranylgeranylacetone, geranylgeraniol, vitamin K(2), sophoranone, and beta-hydroxyisovalerylshikonin. The mechanisms of action of these differentiation- and apoptosis-inducing agents are described. The structure and function of synucleins are also reviewed for the development of potential antidementia agents. In addition, the structures of three purified taste modifiers are described.

A β-Secretase (BACE1) Inhibitor Hispidin from the Mycelial Cultures ofPhellinus linteus

In the course of screening for anti-dementia agents from natural products, a beta-secretase (BACE1) inhibitor was isolated from the culture broth of Phellinus linteus and identified as hispidin. It showed an IC (50) value of 4.9 x 10 (-6) M and a Ki value of 8.4 x 10 (-6) M. The compound was a non-competitive inhibitor. Hispidin also inhibited a prolyl endopeptidase (IC (50) = 1.6 x 10 (-5) M, Ki = 2.4 x 10 (-5) M), but it was less inhibitory to alpha-secretase (TACE) and other serine proteases such as chymotrypsin, trypsin, and elastase.

Neuroprotective role of phosphodiesterase inhibitor ibudilast on neuronal cell death induced by activated microglia

The phosphodiesterase inhibitor, ibudilast, has many effects on lymphocytes, endothelial cells, and glial cells. We examined the neuroprotective role of ibudilast in neuron and microglia co-cultures. Ibudilast significantly suppressed neuronal cell death induced by the activation of microglia with lipopolysaccharide (LPS) and interferon (IFN)-γ. To examine the mechanisms by which ibudilast exerts a neuroprotective role against the activation of microglia, we examined the production of inflammatory and anti-inflammatory mediators and trophic factors following ibudilast treatment. In a dose-dependent manner, ibudilast suppressed the production of nitric oxide (NO), reactive oxygen species, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α and enhanced the production of the inhibitory cytokine, IL-10, and additional neurotrophic factors, including nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-4 in activated microglia. Thus, ibudilast-mediated neuroprotection was primarily due to the inhibition of inflammatory mediators and the upregulation of neurotrophic factor. In the CA1 region of hippocampal slices, long-term potentiation (LTP) induced by high frequency stimulation (HFS) could be inhibited with LPS and interferon-γ stimulation. Ibudilast returned this LTP inhibition to the levels observed in controls. These results suggest that ibudilast may be a useful neuroprotective and anti-dementia agent counteracting neurotoxicity in activated microglia.

Tolerability of memantine in combination with cholinesterase inhibitors in dementia therapy

Memantine, a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to be effective in dementia, including Alzheimer disease (AD). Therefore, its combination with acetylcholinesterase inhibitors (AChEIs) is anticipated. We report a postmarketing surveillance study conducted among German physicians who, during routine clinical practice, treated demented patients with memantine in combination with an AChEI. Most of the 158 surveyed patients (mean age, 74 years) were diagnosed with AD but other dementias were included. Memantine was prescribed at a wide range of daily doses (median, 20 mg/day) and was combined with donepezil for most patients (84%). Combination therapy was well tolerated for nearly all patients (98%) for an average observation period of 4 months at stable doses of both antidementia agents. No serious adverse drug reaction (ADR) was reported. No ADR or change in blood chemistry was experienced by most patients (96% and 81%, respectively); the six reported ADRs resolved without sequelae and without drug discontinuation. Global clinical status of most patients was judged as improved (54%) or stable (39%) over the observation period. These findings particularly suggest that memantine in combination with AChEIs is safe and well tolerated.

Neuroimaging and early diagnosis of Alzheimer disease: a look to the future.

Alzheimer disease (AD), a progressive neurodegenerative disorder, is the most common cause of dementia in the elderly. Current consensus statements have emphasized the need for early recognition and the fact that a diagnosis of AD can be made with high accuracy by using clinical, neuropsychologic, and imaging assessments. Magnetic resonance (MR) or computed tomographic (CT) imaging is recommended for the routine evaluation of AD. Coronal MR images can be useful to document or quantify atrophy of the hippocampus and entorhinal cortex, both of which occur early in the disease process. Both volumetric and subtraction MR techniques can be used to quantify and monitor dementia progression and rates of regional atrophy. MR measures are also increasingly being used to monitor treatment effects in clinical trials of cognitive enhancers and antidementia agents. Positron emission tomography (PET) and single photon emission CT offer value in the differential diagnosis of AD from other cortical and subcortical dementias and may also offer prognostic value. In addition, PET studies have demonstrated that subtle abnormalities may be apparent in the prodromal stages of AD and in subjects who carry susceptibility genes. PET ligands are in late-stage development for demonstration of amyloid plaques, and human studies have already begun. Functional MR-based memory challenge tests are in development as well.

Clinically significant drug interactions with cholinesterase inhibitors: a guide for neurologists.

Cholinesterase inhibitors are the only pharmacological class indicated for the treatment of mild to moderate Alzheimer's disease. These drugs are also being used off label to treat severe cases of Alzheimer's disease or vascular dementia and other disorders. The widespread use of cholinesterase inhibitors raises the possibility of their use in combination regimens, with the subsequent risk of deleterious drug-drug interactions in high-risk populations. The purpose of this review is to present the possible sources of pharmacokinetic or pharmacodynamic drug-drug interactions involving cholinesterase inhibitors. The four cholinesterase inhibitors (tacrine, donepezil, rivastigmine and galantamine) that are currently available have different pharmacological properties that expose patients to the risk of several types of drug interactions of nonequivalent clinical relevance. The principal proven clinically relevant drug interactions involve tacrine and drugs metabolised by the cytochrome P450 (CYP) 1A2 enzyme, as well as tacrine or donepezil and antipsychotics (which results in the appearance of parkinsonian symptoms). The bioavailability of galantamine is increased by coadministration with paroxetine, ketoconazole and erythromycin. It is of interest to note that because rivastigmine is metabolised by esterases rather than CYP enzymes, unlike the other cholinesterase inhibitors, it is unlikely to be involved in pharmacokinetic drug-drug interactions. Care must be taken to reduce the risk of inducing central (excitation, agitation) or peripheral (e.g. bradycardia, loss of consciousness, digestive disorders) hypercholinergic effects via drug interactions with cholinesterase inhibitors. A review of the literature does not reveal any alarming data but does highlight the need for prudent prescription, particularly when cholinesterase inhibitors are given in combination with psychotropics or antiarrhythmics. Possible interactions involving other often coprescribed antidementia agents (e.g. memantine, antioxidants, cognitive enhancers) remain an open area requiring particularly prudent use.

Ethyl ether fraction of Gastrodia elata Blume protects amyloid β peptide-induced cell death

Alzheimer's disease is the most common cause of dementia in the elderly. Recently, it has been reported that Alzheimer's disease is associated with cell death in neuronal cells including the hippocampus. Amyloid β-peptide stimulates neuronal cell death, but the underlying signaling pathways are poorly understood. In order to develop anti-dementia agents with potential therapeutic value, we examined the effect of the herbal compound Gastrodia elata Blume (GEB) on neuronal cell death induced by amyloid β-peptide in IMR-32 neuroblastoma cells. The fractionation of GEB was carried out in various solvents. The hydroxyl radical scavenging effect of the ethyl ether fraction was more potent than any other fractions. In cells treated with amyloid β-peptide, the neuroprotective effect of the ethyl ether, chloroform, and butanol fractions was 92, 44, and 39%, respectively, compared with control. Taken together, these results suggest that the ethyl ether fraction of GEB contains one or more compounds that dramatically reduce amyloid β-peptide induced neuronal cell death in vitro .