On the horizon: pathways for drug development in Alzheimer's disease.
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Aged↗
Biomedical subjects
Martin R Farlow
Publications and source records attributed to Martin R Farlow.
Utilizing combination therapy in the treatment of Alzheimer's disease.
Alzheimer's disease may not yet be curable, but it is treatable. Two classes of drugs with differing mechanisms of action have received Food and Drug Administration approval for the treatment of Alzheimer's disease: the cholinesterase inhibitors and the N-methyl-D-aspartate receptor antagonist memantine (Ebixa, Lundbeck; Namenda, Forest Laboratories). Alzheimer's disease research directed at increasing the understanding of the underlying disease process has led to the identification of several other potential targets for drug development strategies. Due to the complexity of the disease, it is possible that combination therapy -- concomitant use of agents with nonoverlapping or even synergistic mechanisms of action -- may represent the best means available to enhance treatment effectiveness. This review evaluates the available data on combination therapy in Alzheimer's disease and provides an expert opinion on the use and implementation of combination therapy in clinical practice.
Alzheimer Disease↗
NMDA receptor antagonists. A new therapeutic approach for Alzheimer's disease.
Research into Alzheimer's disease (AD) pathology has identified several underlying disease processes that are potential targets for drug discovery and development. One strategy targets glutamatergic neurotransmission mediated by the N-methyl-D-aspartate (NMDA) receptor. Therapeutic intervention with high-affinity NMDA receptor antagonists, such as phencyclidine (PCP) and MK-801, is not practical due to adverse side effects; however, a low-moderate affinity, uncompetitive and strongly voltage-dependent NMDA receptor antagonist, memantine (NamendaTM), is well tolerated and recently has been approved by the U.S. Food and Drug Administration for the treatment of moderate to severe AD. Clinical results support NMDA receptor antagonism as a viable therapeutic strategy for AD and suggest that this novel pharmacologic approach, either alone or in combination with other drugs, is likely to significantly impact the current AD treatment paradigm.
Alzheimer Disease↗
Effects of rofecoxib or naproxen vs placebo on Alzheimer disease progression: a randomized controlled trial.
CONTEXT: Laboratory evidence that inflammatory mechanisms contribute to neuronal injury in Alzheimer disease (AD), along with epidemiological evidence, suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) may favorably influence the course of the disease. OBJECTIVE: To determine whether treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD. DESIGN: Multicenter, randomized, double-blind, placebo-controlled, parallel group trial, with 1-year exposure to study medications. SETTING: Forty ambulatory treatment centers affiliated with the Alzheimer's Disease Cooperative Study consortium. PARTICIPANTS: Participants with mild-to-moderate AD (Mini-Mental State Examination score of 13-26) were recruited from December 1999 to November 2000 using clinic populations, referrals from community physicians, and local advertising. Stable use of cholinesterase inhibitors, estrogen, low-dose aspirin, and vitamin E was allowed. Participants with inflammatory diseases that might respond to the study medications were excluded. Of 474 participants screened, 351 were enrolled. INTERVENTIONS: Once-daily rofecoxib, 25 mg, or twice-daily naproxen sodium, 220 mg, or placebo. MAIN OUTCOME MEASURES: The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale-Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). RESULTS: The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group. CONCLUSION: The results of this study indicate that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild-to-moderate AD.
Activities of Daily Living↗
Update on rivastigmine.
BACKGROUND: Rivastigmine is a carbamate drug designed to inhibit both acetylcholinesterase and butyrylcholinesterase by reversibly covalently bonding to these enzymes. Butyrylcholinesterase in-creases as Alzheimer disease progresses, so its inhibition may become more important as the disease worsens. Metabolism of rivastigmine occurs at the synapse rather than at the liver and previous studies have demonstrated no drug-drug interactions. Rivastigmine has a half-life at the synapse of 9 hours allowing for bid dosing. REVIEW SUMMARY: Effective therapy requires up-titration from initial dosage of 3 mg/d to 6 mg/d with additional increases to 9 mg or 12 mg/d giving additional benefits in some patients. Beneficial effects with rivastigmine therapy in the functioning of activities of daily living, behavior, cognition, and global functioning have been demonstrated in patients with mild to moderate Alzheimer disease in 4 large double-blind, placebo-controlled multicenter clinical trials. Potential adverse effects of nausea, vomiting, or diarrhea in these original Alzheimer trials with rapid (every week) dosage increases occurred in up to 34% of patients and can be minimized by slower monthly up-titrations. Rivastigmine also was proven effective in decreasing psychiatric symptoms and cognitive deficits in a large double-blind, placebo-controlled trial in patients with diffuse Lewy body disease. Other studies have suggested that rivastigmine improves symptoms in nursing home patients with more severe stage Alzheimer disease, Parkinson dementia, and subcortical dementia. Follow-up studies have suggested that rivastigmine may delay disease progression and, in patients discontinuing the drug, no withdrawal effects were seen. CONCLUSION: Rivastigmine is an effective therapeutic agent for treating cognitive and behavioral symptoms in Alzheimer disease and diffuse Lewy body disease and may also have beneficial effects in vascular and Parkinson dementias.
Alzheimer Disease↗
Review: cholinesterase inhibitors have a modest effect on neuropsychiatric and functional outcomes in Alzheimer's disease.
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Comment↗
A collaborative study of the emergence and clinical features of the major depressive syndrome of Alzheimer's disease.
OBJECTIVE: This report provides a description of the prevalence and clinical features of the major depressive syndrome of Alzheimer's disease using data derived from structured diagnostic assessments of 243 patients with probable Alzheimer's disease and 151 nondemented elderly comparison subjects. METHOD: Subjects were characterized by a consortium of four Alzheimer's disease research centers and the Geriatric Psychiatry Branch of the National Institute of Mental Health. All sites administered the Clinical Assessment of Depression in Dementia, a structured, anchored diagnostic interview that was developed to reliably diagnose and characterize major depressive episodes in this population. RESULTS: Despite the use of a common, reliable methodology for the assessment and diagnosis of major depressive episodes, the prevalence of major depression in Alzheimer's disease ranged widely from 22.5% to 54.4% across the recruitment sites. The prevalence of major depressive episodes among Alzheimer's disease patients in the aggregate sample exceeded that for elderly comparison subjects and reached nearly 50% among the most severely demented patients. Alzheimer's disease patients with a current major depressive episode had earlier mean ages at onset, a higher mean Hamilton Depression Rating Scale score, and were more likely to be experiencing psychotic symptoms than those who had not developed a major depressive episode. Although the major depressive episodes of Alzheimer's disease patients and nondemented elderly comparison subjects included similar numbers of depressive symptoms, patients with Alzheimer's disease were more likely to report a diminished ability to concentrate or indecisiveness and less likely to experience sleep disturbances and feelings of worthlessness or excessive guilt during their major depressive episodes. None of the clinical features of major depression differed significantly in frequency among depressed Alzheimer's disease patients with mild, moderate, or severe dementia. Concurrent psychotic symptoms progressively increased with dementia severity. CONCLUSIONS: The high rate of major depressive episodes that occur after the onset of cognitive impairment among patients with Alzheimer's disease (the majority of whom had no premorbid history of major depression), common emergence in the early stages of dementia when symptoms of cognitive impairment are least likely to contribute to the syndromal diagnosis of major depression, and differences in the clinical presentations of the major depressive episodes of Alzheimer's disease patients and nondemented elderly comparison subjects, all support the validity of the major depressive syndrome of Alzheimer's disease. Our findings suggest that the major depressive syndrome of Alzheimer's disease may be among the most common mood disorders of older adults.
Age of Onset↗
Strategies for continued successful treatment of Alzheimer's disease: switching cholinesterase inhibitors.
Cholinesterase (ChE) inhibitors represent the standard therapeutic approach to the treatment of Alzheimer's disease (AD). However, a proportion of patients experience lack or loss of therapeutic benefit with an initial agent, or discontinue due to safety/tolerability issues. In many instances, no alternative treatment is offered once the initial agent has been stopped. Thus, for many patients, the total duration of treatment is relatively short in comparison with the chronic nature of AD. Switching medications is a common therapeutic strategy within many drug classes across many clinical areas following a lack/loss of efficacy or safety/tolerability problems, and is also an increasingly important concept in the management of AD with ChE inhibitors. A number of open-label studies, where patients were switched from donepezil to rivastigmine, have indicated that approximately 50% of patients experiencing a lack/loss of efficacy with donepezil (a selective acetylcholinesterase [AChE] inhibitor) respond to subsequent treatment with rivastigmine (a dual AChE and butyrylcholinesterase inhibitor). In these studies, rivastigmine was well tolerated, and the occurrence of safety/tolerability problems with donepezil was not predictive of similar problems with rivastigmine. In the summer of 2002, leading neurologists and psychiatrists attended a medical experts meeting to discuss the clinical importance of switching ChE inhibitors in AD. The expert panel examined available clinical data, shared clinical experiences, and discussed current clinical guidelines for switching. The panel also aimed to reach consensus on 'whom to switch', 'when to switch' and 'how to switch'. The key findings from that meeting are reported in this review.
Alzheimer Disease↗
Clinical pharmacokinetics of galantamine.
Galantamine is the most recently approved cholinergic drug for the treatment of Alzheimer's disease, the most common type of dementia. Vascular dementia and Alzheimer's disease with cerebrovascular disease are also common in older patients. Dementia affects cognition, causes losses in ability to perform activities of daily living and often results in the emergence of psychiatric and abnormal behavioural symptoms. Dementia also results in an ever-increasing burden and a decreased quality of life for caregivers. Treatments for dementia, particularly Alzheimer's disease, have focused on improving function in the cholinergic system. Vascular dementia and diffuse Lewy body dementia are also associated with significant defects in cholinergic function. Galantamine works by inhibiting acetylcholinesterase and by allosterically modulating nicotinic receptors. In clinical trials, galantamine has shown benefits in the domains of cognition, function in activities of daily living, and behaviour. Galantamine is about 90% bioavailable and displays linear pharmacokinetics. It has a relatively large volume of distribution and low protein binding. Metabolism is primarily through the cytochrome P450 system, specifically the CYP2D6 and CYP3A4 isoenzymes. Population pharmacokinetic modelling with galantamine has shown that the variables affecting clearance are age, sex, and bodyweight. Model simulations demonstrate the importance of a slower dose-escalation schedule in patients with moderate hepatic impairment. In several large trials, galantamine has been shown to be well tolerated, with most adverse events being mild-to-moderate and gastrointestinal in nature. Based on the literature and clinical trial experience, galantamine appears to be an excellent treatment option for patients with Alzheimer's disease, vascular dementia or Alzheimer's disease with cerebrovascular disease.
Adult↗
A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease.
Alzheimer's disease (AD), a progressive, degenerative disorder of the brain, is believed to be the most common cause of dementia amongst the elderly. AD is characterized by the presence of amyloid deposits and neurofibrillary tangles in the brain of afflicted individuals. AD is associated with a loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning. AD appears to have a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in one of several genes, such as the beta-amyloid precursor protein (APP) and presenilins (PS1, PS2). These proteins along with tau, secretases, such as beta-amyloid cleaving enzyme (BACE), and apolipoprotein E play important roles in the pathology of AD. On therapeutic fronts, there is significant research underway in the development of new inhibitors for BACE, PS-1 and gamma-secretase as targets for treatment of AD. There is also a remarkable advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. The development of vaccination strategies, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy are examples of new approaches for treating or slowing the progression of AD. In addition, nutritional, genetic and environmental factors highlight more effective preventive strategies for AD. Developments of early diagnostic tools and of quantitative markers are critical to better follow the course of the disease and to evaluate different therapeutic strategies. In this review, we attempt to critically examine recent trends in AD research from molecular, genetic to clinical areas. We discuss various neurobiological mechanisms that provide the basis of new targets for AD drug development. All these current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain in order to effectively diagnose and prevent their occurrence.
Alzheimer Disease↗
NF-kappaB mediates IL-1beta-induced synthesis/release of alpha2-macroglobulin in a human glial cell line.
Increasingly, inflammatory responses in localized areas of brain parenchyma in response to the extracellular deposition of the Abeta peptides are thought to play a causative role in Alzheimer's disease (AD) progression. Anti-inflammatory agents, in particular non-steroid anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, have been shown to be associated with a delayed onset or slowed rate of disease progression in several epidemiological studies. Activation of glial cells and the subsequent expression of a number of proteins including alpha(2)-macroglobulin (alpha(2)M) are associated with the induction of brain tissue inflammation. Additionally cytokines, such as interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) are co-localized to senile plaques, a neuropathological hallmark of AD. Alpha(2)M binds various cytokines, including IL-1beta, as well as Abeta. In this study, we demonstrate that IL-1beta induces alpha(2)M synthesis/release from a human astroglial cell line (U373) via the activation of the nuclear transcription factor NF-kappaB. Our data suggest that attenuation of IL-1beta-induced alpha(2)M synthesis/release by blocking NF-kappaB activation may potentially be 'protective' against the development of late-onset AD.
Alzheimer Disease↗
Safety and acceptability of the research lumbar puncture.
Three hundred forty-two subjects underwent 428 research lumbar punctures for studies of cerebrospinal fluid (CSF) biomarkers. Subjects were 67 Alzheimer disease or mild cognitive impairment (AD/MCI) patients and 275 cognitively normal adults aged 21 to 88. Lumbar puncture was performed in the lateral decubitus or sitting position using the Sprotte 24 g atraumatic spinal needle. Up to 34 ml of cerebrospinal fluid were collected. Anxiety and pain experienced during lumbar puncture were rated on a visual analog scale. The frequency of any adverse event (11.7%), clinically significant adverse events (3.97%), and typical post-lumbar puncture headache (PLPHA) (0.93%) was low. Risk of post-lumbar puncture headache was unrelated to age, gender, position during lumbar puncture, ml of cerebrospinal fluid collected, or minutes of recumbent rest following lumbar puncture. The frequency of post-lumbar puncture headache was lower in AD/MCI (P = 0.03) than any other subject group. Anxiety and pain ratings were low. Younger subjects reported more anxiety than old (P = 0.001) and AD/MCI subjects (P = 0.008) and more pain than older normal subjects (P = 0.013). Pain ratings for women were higher than those for men (P = 0.006). Using the Sprotte 24 g spinal needle, research lumbar puncture can be performed with a very low rate of clinically significant adverse events and with good acceptability in cognitively impaired persons and cognitively normal adults of all ages.
Adult↗