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Archives of Neurology Jun 2010
PubMed: 20558395
DOI: 10.1001/archneurol.2010.94 -
Alzheimer's Research & Therapy Apr 2010The amyloid hypothesis provides a basis for the development of new therapeutic strategies in Alzheimer's disease. Two large trials have recently been published. The...
The amyloid hypothesis provides a basis for the development of new therapeutic strategies in Alzheimer's disease. Two large trials have recently been published. The first is a phase 2 study of passive immunotherapy with bapineuzumab, a humanized anti-Abeta monoclonal antibody directed against the N-terminus of Abeta. This trial showed no differences within dose cohorts on the primary efficacy analysis. Exploratory analyses showed potential treatment differences on cognitive and functional endpoints in study completers and apolipoprotein E epsilon4 noncarriers. A safety concern was the occurrence of reversible vasogenic edema. The second study is a phase 3 trial of tarenflurbil, a modulator of the activity of gamma-secretase. Tarenflurbil had no beneficial effect on the primary or secondary outcomes. The tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections. Possible explanations for the negative results of these trials may be related to the study design or the choice of dosage. However, it may also be that these negative findings reflect our still incomplete understanding of, at least part of, the pathogenesis of Alzheimer's disease.
PubMed: 20388189
DOI: 10.1186/alzrt28 -
Current Alzheimer Research Nov 2010Recent studies of Alzheimer's disease (AD) and other neuropsychiatric drug developments raise questions whether failures of some drugs occur due to flaws in methods. In... (Review)
Review
Recent studies of Alzheimer's disease (AD) and other neuropsychiatric drug developments raise questions whether failures of some drugs occur due to flaws in methods. In three case studies of recent AD drug development failures with phenserine, metrifonate, and tarenflurbil we identified methodological lapses able to account for the failures. Errors in complex systems such as drug developments are both almost inescapable due to human mistakes and most frequently hidden at the time of occurrence and thereafter. We propose preemptive error management as a preventive strategy to exclude or control error intrusions into neuropsychiatric drug developments. We illustrate the functions we anticipate for a preemptive error management preventive strategy with a checklist and identify the limitations of this aspect of the proposal with three drug examples. This strategy applies core scientific practices to insure the quality of data within the current context of AD drug development practices.
Topics: Alzheimer Disease; Clinical Trials as Topic; Drug Evaluation; Humans; Neuroprotective Agents
PubMed: 20704560
DOI: 10.2174/156720510793499075 -
The American Journal of Geriatric... Jun 2009The aim of this article was to provide a survey of the clinical development of pharmacotherapy for Alzheimer's disease (AD). (Review)
Review
OBJECTIVE
The aim of this article was to provide a survey of the clinical development of pharmacotherapy for Alzheimer's disease (AD).
METHODS
A search of PubMed to identify pertinent English-language literature was conducted using the terms Alzheimer's disease AND clinical trials (2003-2008), dementia AND prevention AND clinical trials (2003-2008), and the chemical names of all compounds mentioned in articles on new drugs for AD published since 2005. www.ClinicalTrials.gov was searched for relevant trials. Abstracts of the 2008 International Conference on Alzheimer's Disease (ICAD) were reviewed for relevance, as were pharmaceutical company and AD advocacy Web sites. Articles selected for review were primary reports of data from preclinical studies and clinical trials.
RESULTS
A large number of drugs with differing targets and mechanisms of action are under development for the treatment of AD. Phase III trials of Ginkgo biloba, NSAIDs, phenserine, statins, tarenflurbil, tramiprosate, and xaliproden have been completed, none of them demonstrating adequate efficacy. Encouraging results from completed Phase II trials of dimebon, huperzine A, intravenous immunoglobulin, and methylthioninium chloride were reported at ICAD 2008. Nineteen compounds are currently in Phase II trials, and 3 compounds (AN1792, lecozotan SR, and SGS742) failed at this stage of development.
CONCLUSIONS
Despite disappointing results from recently completed Phase III trials of several novel compounds, the extent and breadth of activity at all phases of clinical development suggest that new pharmacotherapeutic options for the treatment of AD will become available within the next decade.
Topics: Alzheimer Disease; Animals; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Drug Delivery Systems; Drug Design; Humans; Randomized Controlled Trials as Topic
PubMed: 19616185
DOI: 10.1016/j.amjopharm.2009.06.003 -
JAMA Dec 2009Amyloid-beta peptide (Abeta(42)) has been implicated in the pathogenesis of Alzheimer disease (AD). Tarenflurbil, a selective Abeta(42)-lowering agent, demonstrated... (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Amyloid-beta peptide (Abeta(42)) has been implicated in the pathogenesis of Alzheimer disease (AD). Tarenflurbil, a selective Abeta(42)-lowering agent, demonstrated encouraging results on cognitive and functional outcomes among mildly affected patients in an earlier phase 2 trial.
OBJECTIVE
To determine the efficacy, safety, and tolerability of tarenflurbil.
DESIGN, SETTING, AND PATIENTS
A multicenter, randomized, double-blind, placebo-controlled trial enrolling patients with mild AD was conducted at 133 trial sites in the United States between February 21, 2005, and April 30, 2008. Concomitant treatment with cholinesterase inhibitors or memantine was permitted.
INTERVENTION
Tarenflurbil, 800 mg, or placebo, administered twice a day.
MAIN OUTCOME MEASURES
Co-primary efficacy end points were the change from baseline to month 18 in total score on the subscale of the Alzheimer Disease Assessment Scale-Cognitive Subscale (ADAS-Cog, 80-point version) and Alzheimer Disease Cooperative Studies-activities of daily living (ADCS-ADL) scale. Additional prespecified slope analyses explored the possibility of disease modification.
RESULTS
Of the 1684 participants randomized, 1649 were included in the analysis, and 1046 completed the trial. Tarenflurbil had no beneficial effect on the co-primary outcomes (difference in change from baseline to month 18 vs placebo, based on least squares means: 0.1 for ADAS-Cog; 95% CI, -0.9 to 1.1; P = .86 and -0.5 for ADCS-ADL; 95% CI, -1.9 to 0.9; P = .48) using an intent-to-treat analysis. No significant differences occurred in the secondary outcomes. The ADAS-Cog score decreased by 7.1 points over 18 months. The tarenflurbil group had a small increase in frequency of dizziness, anemia, and infections.
CONCLUSION
Tarenflurbil did not slow cognitive decline or the loss of activities of daily living in patients with mild AD.
TRIAL REGISTRATION
clinicaltrials.gov Identifier: NCT00105547.
Topics: Activities of Daily Living; Aged; Aged, 80 and over; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Cognition; Cognition Disorders; Double-Blind Method; Enzyme Inhibitors; Female; Flurbiprofen; Humans; Male; Middle Aged; Peptide Fragments
PubMed: 20009055
DOI: 10.1001/jama.2009.1866 -
Molecules (Basel, Switzerland) May 2021All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer's disease (AD). One focus in...
All over the world, societies are facing rapidly aging populations combined with a growing number of patients suffering from Alzheimer's disease (AD). One focus in pharmaceutical research to address this issue is on the reduction of the longer amyloid-β (Aβ) fragments in the brain by modulation of γ-secretase, a membrane-bound protease. -Flurbiprofen (tarenflurbil) was studied in this regard but failed to show significant improvement in AD patients in a phase 3 clinical trial. This was mainly attributed to its low ability to cross the blood-brain barrier (BBB). Here, we present the synthesis and in vitro evaluation of a racemic -carborane analogue of flurbiprofen. By introducing the carborane moiety, the hydrophobicity could be shifted into a more favourable range for the penetration of the blood-brain barrier, evident by a logD value of 2.0. Furthermore, our analogue retained γ-secretase modulator activity in comparison to racemic flurbiprofen in a cell-based assay. These findings demonstrate the potential of carboranes as phenyl mimetics also in AD research.
Topics: Amyloid Precursor Protein Secretases; Boron Compounds; Cell Death; Cell Line, Tumor; Cyclooxygenase Inhibitors; Flurbiprofen; Humans; Inhibitory Concentration 50
PubMed: 34064783
DOI: 10.3390/molecules26102843 -
Indian Journal of Psychiatry Jan 2009The prevention and treatment of cognitive impairment in the elderly has assumed increasing importance in an aging population. This article presents a qualitative review...
The prevention and treatment of cognitive impairment in the elderly has assumed increasing importance in an aging population. This article presents a qualitative review of recent research on experimental interventions for the prevention and treatment of mild cognitive impairment and Alzheimer's disease in elderly subjects. Interventions addressed range from lifestyle measures to pharmacological treatments. Epidemiological studies suggest that dietary measures, physical exercise, and mental activity may reduce the risk of cognitive impairment and Alzheimer's disease in elderly subjects. Statins may protect against incident dementia, and lithium may convey similar benefits to bipolar patients. Ginkgo appears ineffective as a primary preventive measure. Donepezil but not Vitamin E may benefit persons with mild cognitive impairment. Experimental treatments potentially useful for Alzheimer's disease include dimebon, PBT2 and etanercept; the safety and efficacy of the Alzheimer's vaccine remains to be proven, and growth hormone secretagogue and tarenflurbil are likely ineffective. Herbal treatments merit study in elderly subjects with cognitive syndromes.
PubMed: 19742190
DOI: 10.4103/0019-5545.44900 -
Primary Care Companion To the Journal... 2007To review the amyloid hypothesis as the predominant mechanistic theory of Alzheimer's disease and update the status of new disease-modifying, anti-amyloid treatments in...
OBJECTIVES
To review the amyloid hypothesis as the predominant mechanistic theory of Alzheimer's disease and update the status of new disease-modifying, anti-amyloid treatments in clinical development.
DATA SOURCES
Governmental Web sites and those of professional Alzheimer's disease associations and drug manufacturers were searched for new drugs in development. An English-language search of PubMed (January 2003-January 2006) was conducted using the search terms Alzheimer's disease and amyloid hypothesis and each of the drugs and immunotherapies from the 4 identified classes of anti-amyloid, disease-modifying therapies.
STUDY SELECTION AND DATA EXTRACTION
Studies and reports were selected on the basis of recent publication, adequate methodology, and completeness of data.
DATA SYNTHESIS
Immunotherapy, γ-secretase inhibitors, selective neurotoxic aggregated 42-amino acid peptide subspecies of amyloid β (Aβ₄₂)-lowering agents (tarenflurbil), inhibitors of amyloid aggregation (tramiprosate), and statins show promise in clinical trials. Safety remains an important factor. Disease-modifying drugs that specifically target the amyloid cascade and do not interact with essential biological pathways are expected to possess a lower rate of unintended adverse events.Agents that selectively target Aβ₄₂ production (e.g., tarenflurbil), block Aβ aggregation (e.g., tramiprosate), or enhance alpha-secretase activity (statins) offer hope for disease modification and prevention and do not appear to interfere with other biological pathways.
CONCLUSIONS
Discovery of safe and effective disease-modifying therapies will usher in a new age of Alzheimer's disease treatment.
PubMed: 17599166
DOI: 10.4088/pcc.v09n0106 -
JAMA Dec 2009
Topics: Aging; Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Comorbidity; Cost of Illness; Dementia; Enzyme Inhibitors; Flurbiprofen; Global Health; Humans; Leptin; Longevity; Peptide Fragments
PubMed: 20009062
DOI: 10.1001/jama.2009.1863 -
BMC Neuroscience Jul 2007Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain...
BACKGROUND
Long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced incidence of Alzheimer's disease (AD). We and others have shown that certain NSAIDs reduce secretion of Abeta42 in cell culture and animal models, and that the effect of NSAIDs on Abeta42 is independent of the inhibition of cyclooxygenase by these compounds. Since Abeta42 is hypothesized to be the initiating pathologic molecule in AD, the ability of these compounds to lower Abeta42 selectively may be associated with their protective effect. We have previously identified R-flurbiprofen (tarenflurbil) as a selective Abeta42 lowering agent with greatly reduced cyclooxygenase activity that shows promise for testing this hypothesis. In this study we report the effect of chronic R-flurbiprofen treatment on cognition and Abeta loads in Tg2576 APP mice.
RESULTS
A four-month preventative treatment regimen with R-flurbiprofen (10 mg/kg/day) was administered to young Tg2576 mice prior to robust plaque or Abeta pathology. This treatment regimen improved spatial learning as assessed by the Morris water maze, indicated by an increased spatial bias during the third probe trial and an increased utilization of a place strategy to solve the water maze. These results are consistent with an improvement in hippocampal- and medial temporal lobe-dependent memory function. A modest, though not statistically significant, reduction in formic acid-soluble levels of Abeta was also observed. To determine if R-flurbiprofen could reverse cognitive deficits in Tg2576 mice where plaque pathology was already robust, a two-week therapeutic treatment was given to older Tg2576 mice with the same dose of R-flurbiprofen. This approach resulted in a significant decrease in Abeta plaque burden but no significant improvement in spatial learning.
CONCLUSION
We have found that chronic administration of R-flurbiprofen is able to attenuate spatial learning deficits if given prior to plaque deposition in Tg2576 mice. Given its ability to selectively target Abeta42 production and improve cognitive impairments in transgenic APP mice, as well as promising data from a phase 2 human clinical trial, future studies are needed to investigate the utility of R-flurbiprofen as an AD therapeutic and its possible mechanisms of action.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Cyclooxygenase Inhibitors; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Encephalitis; Female; Flurbiprofen; Learning Disabilities; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Peptide Fragments; Plaque, Amyloid; Stereoisomerism; Treatment Outcome
PubMed: 17650315
DOI: 10.1186/1471-2202-8-54