Alzheimer's Disease Medications Research Articles

Nanotechnology for Alzheimer’s disease detection and treatment

In this paper, we present the role of nanotechnology in the development and improvement of techniques for early diagnosis and effective treatment of Alzheimer's disease (AD). Since AD pathology is almost irreversible and presentday medications for AD only lower its associated symptoms, application of diseasemodifying treatments could be successful only if AD early diagnosis is possible. The nanodiagnostic methods reported and compared in this paper include both of in vitro and in vivo nature. Of the in vitro approaches, the DNAnanoparticle conjugates (bioba rcode assay), nanoparticle surface plasmon resonance, scanning tunneling microscopy, and twophoton Rayleigh spectroscopy are presented here. Of the in vivo methods, µMRI and optical imaging techniques are discussed here. The nanotreatment methods for AD are numerous. They are categorized in this report under neuroprotective methods from toxicity of amyloid�β peptide (Aβ) oligomers , oxidative stress of free radicals and nanocarriers for targeted drug delivery. The important agents for neuroprotection include nanogels, fullerene, nanoceria, dendrimers, gold nanoparticles, and diamondoid derivatives. The major nanocarriers presented here include cholinesterase inhibitors nanocarriers, acetylcholine nanocarrier, metal chelator nanocarriers, (Iron chelators and copper chelators), curcuminoids nanocarrier, antioxidant nanocarriers, and gene nanocarriers. Considering that the AD is a multifactorial disease with several pathogenetic mechanisms and pathways, a multifunctional nanotechnology approach will be needed to target its main molecular culprits. These molecular targets must include, but not limited to, Aβ oligomers, reactive oxygen species (ROS), excessive metal ions, tau phosphorylating kinases and cell cycle proteins.

Treatment of Alzheimer Disease: The Past, the Present, and the Future

Can J Psychiatry. 2011;56(10):577-578. Many thanks to the editor-in-chief for this timely opportunity to provide the readers of The Canadian Journal of Psychiatry (The CJP) with an update on the fast-moving field of Alzheimer disease (AD). As detailed in the reviews by Dr Fadi Massoud and Dr Gabriel C Leger1 and by Dr Clive Ballard and colleagues2 in this issue of The CJP, the current symptomatic drugs are only 1 0 years old, cognitive training is still under development, and disease-modifying drugs are under study. This past spring alone you will have seen the publication, in Alzheimer 's & Dementia: the Journal of the Alzheimer 's Association, of revised diagnostic criteria for AD probable at the traditional dementia stage,3 for AD at the predementia stage,4 and even for AD in the presymptomatic stage,5 in Brain, of cognitive training-related plasticity in people with mild cognitive impairment,6 and in The Lancet, of a seminar on the epidemiology and pathophysiology of AD.7 How is Canada doing in the field of AD? The Canadian Study on Health and Aging8 gave us a good head start, with incidence and prevalence figures across the country for the late 1980s against which we will compare later this decade. When Cholinesterase inhibitors (ChEIs) first became available, family doctors were allowed to prescribe these medications and they are following evidence-based guidelines for diagnosis and treatment common to all interested physicians, the latest revision being done in 20069 and the next one scheduled for 2012. A network of specialized memory clinics was created in the early 1990s to facilitate randomized clinical trials for AD in Canada: the Consortium of Canadian Centres for Clinical Cognitive Research (commonly referred to as C5R). This network is 1 of 5, worldwide, currently planning for global prevention studies.10 More recently, the Canadian Institutes of Health Research initiated the International Collaborative Research Strategy for Alzheimer's Disease (commonly referred to as ICRSAD), including partnership with the United States in the Alzheimer Disease Neuro-Imaging (commonly referred to as ADNI) program, with Germany, the United Kingdom, and other European countries in biomarkers and other technical platforms, and with China for 5-year studies. The Alzheimer Society of Canada has been a strong supporter of AD research in Canada, particularly in training young people from different disciplines. The less positive side of treatment of AD in Canada has been the difficulty in obtaining reimbursement for AD medications across the country. The rivastigmine patch is reimbursed only in 1 province, despite the evidence for better tolerability than the oral formulation, which allows 1 0 mg (current maximal dose), compared with 1 5 mg dosing, in a randomized study about to be concluded. Memantine is reimbursed in only 2 provinces, despite the evidence for benefit on agitation and speech impairment, and even in that 1 province memantine is reimbursed only as monotherapy; for example, not with a ChEI, despite growing evidence for the value of combining the 2 drug classes.1112 In the United States and France, these 2 classes of drugs are routinely combined in the moderate stage of AD. There are even greater challenges ahead: if and when treatments become available to significantly slow down disease progression, how will we convince payers to reimburse them? We need to do a better job of finding responders to treatment during phases II and III of drug development: age at onset of symptoms and severity of symptoms may modify which drug to use, apoE genotype and possibly other genes - the pharmacogenomics of AD.13 Clear start and stopping rules will have to be established. It is conceivable that reimbursement will be conditional on positive biomarkers, such as amyloid deposition measured by positron emission tomography scanning or abnormal beta-amyloid and tau protein levels in cerebrospinal fluid. …

MC2 ASSESSING PREDICTORS OF MEDICATION ADHERENCE IN UNCONDITIONAL QUANTILE REGRESSION FRAMEWORK

Medication adherence has been linked to better health outcomes. Therefore, a comprehensive understanding of the predictors of adherence is essential for formulating adherence-improving strategies. Existing methods have not considered evaluation of heterogeneous impacts of predictors at different parts (quantiles) of the adherence distribution as defined by medication possession ratio. Using the novel econometric framework of unconditional quantile regression (UQR), this study assesses the heterogeneity of impacts of adherence predictors for an Alzheimer's disease (AD) population. This retrospective claims analysis identified AD patients from a large US health plan that initiated oral AD therapy (rivastigmine, donepezil, galantamine, or memantine) between 1/1/2006 and 12/31/2007. Baseline characteristics were assessed during the 6-month pre-index period; medication adherence was assessed during the 1-year post-index period. UQR was estimated at 10th, 20th, …, 90th quantiles. Predictors of adherence identified from the data included age, gender, indicator of mental health insurance coverage, region, commercial vs. Medicare insurance, log cost, comorbidity, and formulary tier for the AD medication. Baseline medication count was positively associated with adherence (p<0.05) in the upper half of the adherence distribution. Having mental health coverage is negatively associated with adherence in all but the 10th and 20th quantiles but the impact was substantially higher in the first half of the adherence distribution. Baseline (log) cost was positively associated with adherence in the 40th and upper quantiles of the adherence distribution. For patients in the 80th and 90th quantiles, the number of baseline office visits predicted lower adherence. Compared to patients from the East, patients from the South were less likely to be adherent in the 60th and 70th quantiles. The study results highlight the heterogeneity of impacts of various adherence predictors – a predictor may be statistically significant only in specific quantiles of the adherence distribution, and the impacts may vary substantially between quantiles.

Cognitive intervention in Alzheimer disease

Alzheimer disease (AD) is one of the most prevalent chronic medical conditions affecting the elderly population. The effectiveness of approved antidementia drugs, however, is limited-licensed AD medications provide only moderate relief of clinical symptoms. Cognitive intervention is a noninvasive therapy that could aid prevention and treatment of AD. Data suggest that specifically designed cognitive interventions could impart therapeutic benefits to patients with AD that are associated with substantial biological changes within the brain. Moreover, evidence indicates that a combination of pharmacological and non-pharmacological interventions could provide greater relief of clinical symptoms than either intervention given alone. Functional and structural MRI studies have increased our understanding of the underlying neurobiological mechanisms of aging and neurodegeneration, but the use of neuroimaging to investigate the effect of cognitive intervention on the brain remains largely unexplored. This Review provides an overview of the use of cognitive intervention in the healthy elderly population and patients with AD, and summarizes emerging findings that provide evidence for the effectiveness of this approach. Finally, we present recommendations for future research on the use of cognitive interventions in AD and discuss potential effects of this therapy on disease modification.

Predictors of adherence among Alzheimer's disease patients receiving oral therapy

Objectives:Treatment effectiveness depends upon administering medications as prescribed, and adherence is critical for Alzheimer's disease (AD) patients to receive optimal benefit from therapy. The objective of this study was to investigate factors associated with adherence to AD oral medications.Methods:This retrospective claims analysis identified AD patients who initiated oral AD therapy (rivastigmine, donepezil, galantamine, or memantine) between January 1, 2006 and December 31, 2007 from a large US health plan. Patient baseline characteristics were assessed during the 6-month pre-index period; outcomes were assessed during the 1-year post-index period. Pill burden was measured as a count of unique units of medication/day. Adherence was measured by medication possession ratio (MPR), with MPR ≥80% defined as adherent. Multivariate logistic regression was used to assess how potential covariates affect adherence probability.Results:A total of 3091 AD patients (36% male; mean age 80 [8.25 SD]) were identified. Only 58% of patients were adherent to oral AD medications. Compared to patients <75 years, patients ≥86 years were likely to be more adherent (OR = 1.401, p < 0.001). Other factors found to be positively associated with the probability of adherence to AD medications were male gender (OR = 1.175, p < 0.05), overall pill burden (OR = 1.192, p < 0.001), and a lower formulary tier status of the AD medication (OR = 1.332, p < 0.001).Conclusion:Among the several variables assessed, being male, ≥86 years of age, having a greater overall daily pill burden, or using a lower formulary tier AD medication was associated with better adherence to oral AD medication in patients diagnosed with AD. The database had no information on caregiver support, medication management interventions, or use of adherence aids that may have affected adherence in this cohort, yet, a substantial proportion of patients (42%) remained non-adherent. A better understanding of the causes of non-adherence is necessary, and methods to improve adherence, such as transdermal medications and educational programs, should be considered.

Rethinking Alzheimer's Disease Therapy: Are Mitochondria the Key?

The number of people suffering from Alzheimer's disease (AD) is constantly increasing worldwide since humans live longer and age is the strongest risk factor for AD. Currently available medications for AD do not interfere with the progressive loss of synapses and neurons in the AD brain. Therefore, the development of disease modifying therapies is a major future goal. Mitochondria provide cellular energy and are crucial for proper neuronal activity and survival. Mitochondrial dysfunction is evident in early stages of AD and is involved in AD pathogenesis. The development of drugs that protect mitochondria from damage is therefore a promising strategy for AD therapy. In this review, we will discuss current available medications for AD, drugs under clinical testing, and mitochondria as a novel drug target.

Cognition-Enhancing Properties of Dimebon in a Rat Novel Object Recognition Task Are Unlikely to Be Associated with Acetylcholinesterase Inhibition orN-Methyl-d-aspartate Receptor Antagonism

Dimebon (dimebolin) treatment enhances cognition in patients with Alzheimer's disease (AD) or Huntington's disease. Although Dimebon was originally thought to improve cognition and memory through inhibition of acetylcholinesterase (AChE) and the N-methyl-d-aspartate (NMDA) receptor, the low in vitro affinity for these targets suggests that these mechanisms may not contribute to its clinical effects. To test this hypothesis, we assessed whether Dimebon enhances cognition in rats and if such an action is related to either mechanism or additional candidate mechanisms. Acute oral administration of Dimebon to rats (0.05, 0.5, and 5 mg/kg) enhanced cognition in a novel object recognition task and produced Dimebon brain concentrations of 1.7 +/- 0.43, 14 +/- 5.1, and 172 +/- 94 nM, respectively. At these concentrations, Dimebon did not alter the activity of recombinant human or rat brain AChE. Unlike the AChE inhibitors donepezil and galantamine, Dimebon did not change acetylcholine levels in the hippocampus or prefrontal cortex of freely moving rats. Dimebon displays affinity for the NMDA receptor (K(i) = 105 +/- 18 microM) that is considerably higher than brain concentrations associated with cognition enhancement in the novel object recognition task and 200-fold weaker than that of memantine (K(i) = 0.54 +/- 0.05 microM). Dimebon did not block NMDA-induced calcium influx in primary neuronal cells (IC(50) > 50 microM), consistent with a lack of significant effect on this pathway. The cognition-enhancing effects of Dimebon are unlikely to be mediated by AChE inhibition or NMDA receptor antagonism, and its mechanism of action appears to be distinct from currently approved medications for AD.

PW01-79 - Effect of memantine treatment in cognitive and behavioral symptoms of Alzheimer disease patients

PurposeThis study investigated the efficacy of memantine alone or in combination for the treatment of patients with Alzheimer's disease (AD) in a naturalistic setting, specifically for the cognitive and behavioural symptom domains.MethodsOpen-label, 6-month observational study, conducted at 110 sites in Greece. Efficacy was based on the MMSE and NPI scales at baseline, 3 months, and 6 months. Statistical analysis was made on a modified intent-to-treat dataset (ITT: at least one valid post-baseline measurement) using last observation carried forward (LOCF), and observed cases (OC, defined as patients assessed at all 3 visits).Results1,469 patients were enrolled. Their mean age was 75.7±6.5 years and the majority were women (52.7%). At baseline the average scores were 17.6 (±5.3) for the MMSE and 30.6 (±25.9) for the NPI. 285 patients (19.4%), received combination treatment (a second AD medication) during the observation period.Both cognitive and behavioral symptoms were improved at the end of the study, as measured by the MMSE and NPI scales (repeated measures analysis of variance Hotelling's test, p-value&lt; 0.001, both ITT, LOCF and OC analyses). After 3 and 6 months, cognitive function improved for 50.3% and 55.8% of the patients (ITT, LOCF), while behavioral symptoms improved for 56.8% and 62%, respectively.Memantine was well tolerated, with 3.5% (52) of patients withdrawing from the study for any reason and 7.6% reporting adverse events.ConclusionMemantine treatment resulted in significant improvement of cognitive and behavioral symptoms in patients with AD and was well tolerated based on patient withdrawals.

Adverse Events in Randomized Trials; Hepatitis Caused by Transdermal Medication for Alzheimer Disease; Mycophenolate Mofetil–Induced Colitis in Children; Severe Apnea in Infant Caused by Lamotrigine in Breast Milk; Aripiprazole-Associated Paroxysmal Supraventricular Tachycardia; Three Cases of Severe Hepatic Impairment Caused by Erlotinib

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers.

Support for a tax increase to provide unrestricted access to an Alzheimer's disease medication: a survey of the general public in Canada.

BackgroundPublic drug insurance plans provide limited reimbursement for Alzheimer's disease (AD) medications in many jurisdictions, including Canada and the United Kingdom. This study was conducted to assess Canadians' level of support for an increase in annual personal income taxes to fund a public program of unrestricted access to AD medications.MethodsA telephone survey was administered to a national sample of 500 adult Canadians. The survey contained four scenarios describing a hypothetical, new AD medication. Descriptions varied across scenarios: the medication was alternatively described as being capable of treating the symptoms of cognitive decline or of halting the progression of cognitive decline, with either no probability of adverse effects or a 30% probability of primarily gastrointestinal adverse effects. After each scenario, participants were asked whether they would support a tax increase to provide unrestricted access to the drug. Participants who responded affirmatively were asked whether they would pay an additional $75, $150, or $225 per annum in taxes. Multivariable logistic regression analysis was conducted to examine the determinants of support for a tax increase.ResultsEighty percent of participants supported a tax increase for at least one scenario. Support was highest (67%) for the most favourable scenario (halt progression - no adverse effects) and lowest (49%) for the least favourable scenario (symptom treatment - 30% chance of adverse effects). The odds of supporting a tax increase under at least one scenario were approximately 55% less for participants who attached higher ratings to their health state under the assumption that they had moderate AD and almost five times greater if participants thought family members or friends would somewhat or strongly approve of their decision to support a tax increase. A majority of participants would pay an additional $150 per annum in taxes, regardless of scenario. Less than 50% would pay $225.ConclusionsFour out of five persons in a sample of adult Canadians reported they would support a tax increase to fund unrestricted access to a hypothetical, new AD medication. These results signal a willingness to pay for at least some relaxation of reimbursement restrictions on AD medications.

Agreement Could Shrink Part D 'Donut Hole'

Back to table of contents Previous article Next article Government NewsFull AccessAgreement Could Shrink Part D 'Donut Hole'Rich DalyRich DalySearch for more papers by this authorPublished Online:7 Aug 2009https://doi.org/10.1176/pn.44.15.0006APA has hailed an agreement by drug companies and the Obama administration to discount by 50 percent the cost of pharmaceuticals that fall within Medicare's drug coverage gap.The voluntary agreement by pharmaceutical companies, announced in June, will cut the cost of name-brand prescription medications by up to 50 percent when they fall into the so-called donut hole of Medicare's Part D prescription drug program that excludes coverage of drugs when their annual costs rise to between $2,700 and $6,154. Drug costs are reimbursed at 75 percent when they are less than $2,700 annually, and Medicare covers 100 percent of the cost of drugs once their accumulated cost rises above $6,154 annually.The agreement is predicted to provide up to $30 billion in discounts to seniors and save the federal government an additional $50 billion over 10 years in health care costs. Obama administration officials have not specified how these savings will occur.APA President Alan Schatzberg, M.D., hailed the development, calling the coverage gap “an excessive burden to those over 65 and those who are chronically disabled, including those suffering from mental illnesses.”“Although this is a first step, it is a step in the direction of providing high-quality, affordable health care to all Americans,” Schatzberg said. “APA recognizes that full prescription coverage is an integral part of any meaningful health care reform and applauds the effort to eliminate one of the most glaring deficiencies in Medicare.”The Obama administration described the agreement as part of the effort to enact major health care reform under consideration in Congress, because the details of the $50 billion projected savings in the agreement will be negotiated as part of final health care reform legislation. The deal is the latest high-profile voluntary agreement that the administration has announced with entities involved in the health care sector. The White House also has reached agreements for health care providers and hospitals to provide billions in savings to Medicare over the next 10 years, according to administration announcements. However, few details have been released on how those savings will be achieved, and some congressional leaders have said they will not honor the agreements in formulating health care reform measures.“The agreement by pharmaceutical companies to contribute to the health reform effort comes on the heels of the landmark pledge many health-industry leaders made to me last month, when they offered to do their part to reduce health spending $2 trillion over the next decade,” Obama said in a written statement issued in June.Those deals are important because the high cost of expanding insurance coverage to the nation's 47 million uninsured—estimated between $1 trillion and $2 trillion over 10 years—has slowed the pace of legislation in Congress to overhaul health care. Public-opinion polls also have consistently found that although most people support health reform, support is weak for any specific funding proposal.The impact of the latest agreement on people with serious mental illness could be significant.Roughly 3.5 million Medicare beneficiaries are projected to fall into the donut hole this year, according to congressional health reform advocates. According to a 2008 Kaiser Foundation study, about 500,000 Medicare beneficiaries—or 15 percent—stopped using their prescription drugs when they fell into the prescription costs range that comprises the donut hole. The study examined some beneficiaries with chronic illnesses, including people receiving treatment for depression, and found that 15 percent who were prescribed antidepressants stopped taking the medication when they reached the coverage gap in 2007. Another 8 percent stopped taking Alzheimer's medications when they reached the gap.Anita Everett, M.D., chair of APA's Council on Healthcare Systems and Financing, said the planned assistance would have a “tremendous impact” on fixed-income Medicare patients with mental illness.“Many individuals with mental illness depend on Medicare for access to psychiatric and other medications; the donut hole payment makes medications unaffordable to many who choose to go without rather than to pay hundreds of dollars each month for medications,” said Everett, in comments to Psychiatric News.Meanwhile, the pharmaceutical drug discount agreement drew some criticism from consumer advocates and liberal politicians, who said the total $80 billion in drug company price cuts are a tiny fraction of the $3.3 trillion in prescription drug spending that the Department of Health and Human Services estimates will occur over the next 10 years.The Kaiser Foundation report “The Medicare Part D Coverage Gap: Costs and Consequences in 2007” is posted at<http://www.kff.org/medicare/upload/7811.pdf>.▪ ISSUES NewArchived

Silibinin Attenuates Amyloid β25–35Peptide-Induced Memory Impairments: Implication of Inducible Nitric-Oxide Synthase and Tumor Necrosis Factor-α in Mice

In Alzheimer's disease (AD), the deposition of amyloid peptides is invariably associated with oxidative stress and inflammatory responses. Silibinin (silybin), a flavonoid derived from the herb milk thistle, has potent anti-inflammatory and antioxidant activities. However, it remains unclear whether silibinin improves amyloid beta (Abeta) peptide-induced neurotoxicity. In this study, we examined the effect of silibinin on the fear-conditioning memory deficits, inflammatory response, and oxidative stress induced by the intracerebroventricular injection of Abeta peptide(25-35) (Abeta(25-35)) in mice. Mice were treated with silibinin (2, 20, and 200 mg/kg p.o., once a day for 8 days) from the day of the Abeta(25-35) injection (day 0). Memory function was evaluated in cued and contextual fear-conditioning tests (day 6). Nitrotyrosine levels in the hippocampus and amygdala were examined (day 8). The mRNA expression of inducible nitric-oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in the hippocampus and amygdala was measured 2 h after the Abeta(25-35) injection. We found that silibinin significantly attenuated memory deficits caused by Abeta(25-35) in the cued and contextual fear-conditioning test. Silibinin significantly inhibited the increase in nitrotyrosine levels in the hippocampus and amygdala induced by Abeta(25-35). Nitrotyrosine levels in these regions were negatively correlated with memory performance. Moreover, real-time RT-PCR revealed that silibinin inhibited the overexpression of iNOS and TNF-alpha mRNA in the hippocampus and amygdala induced by Abeta(25-35). These findings suggest that silibinin (i) attenuates memory impairment through amelioration of oxidative stress and inflammatory response induced by Abeta(25-35) and (ii) may be a potential candidate for an AD medication.

Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer's disease: a randomized, double-blind, placebo-controlled, multicenter trial

BackgroundAlzheimer's disease (AD) is characterized by early and region-specific declines in cerebral glucose metabolism. Ketone bodies are produced by the body during glucose deprivation and are metabolized by the brain. An oral ketogenic compound, AC-1202, was tested in subjects with probable AD to examine if ketosis could improve cognitive performance.MethodsDaily administration of AC-1202 was evaluated in 152 subjects diagnosed with mild to moderate AD in a US-based, 90-day, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were on a normal diet and continued taking approved AD medications. Primary cognitive end points were mean change from Baseline in the AD Assessment Scale-Cognitive subscale (ADAS-Cog), and global scores in the AD Cooperative Study – Clinical Global Impression of Change (ADCS-CGIC). AC-1202 was compared to Placebo in several population groups, including: intention-to-treat (ITT), per protocol, and dosage compliant groups. Results were also stratified by APOE4 carriage status (a predefined analysis based on the epsilon 4 (E4) variant of the apolipoprotein E gene). This trial was registered with ClinicalTrials.gov, registry number NCT00142805, information available at ResultsAC-1202 significantly elevated a serum ketone body (β-hydroxybutyrate) 2 hours after administration when compared to Placebo. In each of the population groups, a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45: 1.9 point difference, p = 0.0235 in ITT; 2.53 point difference, p = 0.0324 in per protocol; 2.6 point difference, p = 0.0215 in dosage compliant. Among participants who did not carry the APOE4 allele (E4(-)), a significant difference was found between AC-1202 and Placebo in mean change from Baseline in ADAS-Cog score on Day 45 and Day 90. In the ITT population, E4(-) participants (N = 55) administered AC-1202 had a significant 4.77 point difference in mean change from Baseline in ADAS-Cog scores at Day 45 (p = 0.0005) and a 3.36 point difference at Day 90 (p = 0.0148) compared to Placebo. In the per protocol population, E4(-) participants receiving AC-1202 (N = 37) differed from placebo by 5.73 points at Day 45 (p = 0.0027) and by 4.39 points at Day 90 (p = 0.0143). In the dosage compliant population, E4(-) participants receiving AC-1202 differed from placebo by 6.26 points at Day 45 (p = 0.0011, N = 38) and 5.33 points at Day 90 (p = 0.0063, N = 35). Furthermore, a significant pharmacologic response was observed between serum β-hydroxybutyrate levels and change in ADAS-Cog scores in E4(-) subjects at Day 90 (p = 0.008). Adverse events occurred more frequently in AC-1202 subjects, were primarily restricted to the gastrointestinal system, and were mainly mild to moderate in severity and transient in nature.ConclusionAC-1202 rapidly elevated serum ketone bodies in AD patients and resulted in significant differences in ADAS-Cog scores compared to the Placebo. Effects were most notable in APOE4(-) subjects who were dosage compliant.

How do elderly spouse care givers of people with Alzheimer disease experience the disclosure of dementia diagnosis and subsequent care?

Objectives:To examine the experiences of spousal care givers of Alzheimer patients to disclosure of dementia diagnosis and subsequent care.Methods:A random sample of 1943 spousal care givers of people receiving medication...

Medicare Part D and Nursing Home Residents

The objective of this study was to analyze national Part D formulary data to assess adequacy of coverage across seven drug classes commonly used by nursing home residents and older people, focusing on individuals dually eligible for Medicare and Medicaid and plans in which they enroll. Focusing at the molecule level, reasonably broad coverage across drug classes and minimal prior authorization overall was found. Of nonprotected classes, 69% of plans cover at least four of five Alzheimer's medications, 76% cover at least three of four bisphosphonates, 86% cover at least three of five proton pump inhibitors, and 61% cover at least four of six 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Nevertheless, a minority of plans are less generous, and some drug formulations important to nursing home residents are covered less well. For example, 11% of plans cover only one or two of the six statins. Of protected drug classes, plans generally cover all molecules, as expected. The majority of plans require no prior authorization for covered medications in six of seven classes reviewed (excepting bisphosphonates). A minority of plans once again are more stringent. For example, 22% and 9% of Part D Plans nationally require prior authorization for all covered Alzheimer's drugs and proton pump inhibitors, respectively. Random assignment of dually eligible patients to below-benchmark plans means that some residents initially will be enrolled in these more-restrictive plans. Part D allows nursing home residents to switch plans at any time, but there are important barriers to residents' self-advocacy. Finally, it is unclear how well nursing homes and the pharmacies they work with will work across Part D plans, and vigilance will be required as the benefit proceeds.

Treatment Guidelines for Alzheimer's Disease

Current treatment guidelines for Alzheimer's disease (AD) do not reflect more recently collected data on therapeutic outcomes other than cognitive function and memory, and this has led to a limited understanding of the value of drug therapy in AD. To evaluate the need to revise treatment guidelines for AD, to review data that have become available since the publication of current guidelines, and to communicate how existing guidelines and relevant new data can be valuable to the primary care provider who assesses and treats patients with AD. A MEDLINE search was conducted to identify existing treatment guidelines using the MeSH headings Alzheimer disease-drug therapy AND practice guidelines. The alternative terms treatment guidelines, practice parameter, and practice recommendation were also searched in conjunction with the MeSH term Alzheimer disease-drug therapy. Additionally, MEDLINE was searched using the term dementia and publication type "practice guideline." All searches were limited to articles published within the last 10 years, in English. A total of 116 articles were identified by these searches. Additional publications were identified by manually searching the reference lists of these articles and of published clinical trials of AD therapies. Current AD treatment guidelines and clinical trial results for AD treatment options were extracted, reviewed, and summarized to meet the objectives of this article. Current guidelines support the use of cholinesterase inhibitors in patients with mild to moderate AD. More recent clinical research indicates that cholinesterase inhibitor treatment provides effectiveness across a wide range of dementia severity and multiple symptom domains. These medications also significantly decrease caregiver burden and may lower the risk for nursing home placement. The expanding literature on AD medications suggests that treatment guidelines need to be reexamined. Recent data emphasize preservation of abilities and delay of adverse outcomes in AD patients rather than short-term improvements in cognitive test scores. Treatment appears to provide the greatest benefit when it is initiated early in the course of the disease and maintained over the long term. Revised treatment guidelines should address newer medications and more recent outcomes considerations, as well as provide guidance on how long to continue and when to discontinue pharmacotherapy for AD.

ALZHEIMER'S DISEASE MEDICATION: USE AND COST PROJECTIONS FOR MEDICARE PART D

ALZHEIMER'S DISEASE MEDICATION: USE AND COST PROJECTIONS FOR MEDICARE PART D

Actions of tacrine and galanthamine on histamine-N-methytransferase

Histamine-synthesizing neurons in the brain may play an important role in cognition, and a histaminergic deficit has been found in Alzheimer's disease (AD). The AD medication tacrine was previously shown to inhibit some forms of rodent histamine-N-methyltransferase (HNMT), but the effects of AD drugs have not been investigated on human HNMT activity. Presently, the effects of tacrine and galanthamine (another AD medication) were studied on the activity of several forms of human and rat HNMT. Tacrine (0.01-10 microM) inhibited both human and rat HNMT activity in a concentration-dependent manner, but was less potent on both human embryonic kidney and recombinant human brain HNMT than on rat kidney HNMT (IC50 values were 0.46 and 0.70 microM vs. 0.29 microM, respectively). Galanthamine (up to 10 microM) did not influence the activity of rat kidney or human HNMT. Tacrine, but not galanthamine, may achieve brain levels sufficient to influence histamine metabolism in some patients treated for AD.

Assessing current practice in Alzheimer's disease.

Alzheimer's disease (AD) is a debilitating condition currently affecting 4.5 million elderly citizens in the United States alone. It is the most common form of dementia and is associated with significant disability. For many years the prognosis of the disease has remained largely unchanged. Those patients who develop AD face progressive cognitive and functional decline that ultimately shortens their life expectancy and destroys their quality of life. At the same time, the disease has a significant adverse impact on the lives of those family members who serve as caregivers. With the aging of the baby-boomer generation and the expected associated increase in the number of patients with AD, clinicians who treat the elderly will clearly be in need of some new answers. Recent advances in assessment, diagnosis, and treatment offer some hope for relief from this bleak prognosis.Advances in AD include the establishment of clear diagnostic criteria, the validation of disease-specific assessment instruments, and pharmacologic and behavioral therapies for management of symptoms. A handful of medications that enhance cognition have obtained the approval of the Food and Drug Administration, and more are currently in development. Trials of existing medications have demonstrated benefit in the management of the psychiatric symptoms (eg, psychosis and agitation) typically associated with the disease. But much still remains to be done.In the first article in this supplement, Michael A. Rogawski, MD, PhD, explains what is known about the pathogenesis and the behavioral and psychological symptoms of AD. He discusses the scientific basis for empirical therapies currently being used to relieve the symptoms of this disease, focusing on drug therapies approved by the FDA, including the newest AD medication to market memantine.