Safety, pharmacokinetics and pharmacodynamics of TAK-418, a novel inhibitor of the epigenetic modulator lysine-specific demethylase 1A.

Aims: Dysregulation of histone methylation epigenetic marks may result in intellectual and developmental disability, as seen in Kabuki syndrome. Animal data suggest that increasing histone methylation by inhibiting lysine-specific demethylase 1A (LSD1) may improve cognitive outcomes in a model of Kabuki syndrome. TAK-418 is a novel LSD1 inhibitor, developed as a potential therapeutic agent for central nervous system disorders such as Kabuki syndrome.

The pathway to secondary prevention of Alzheimer's disease.

Alzheimer's disease (AD) is a continuum consisting of a preclinical stage that occurs decades before symptoms appear. As researchers make advances in investigating the continuum, the importance of developing drugs for secondary prevention is garnering increased discussion. For efficacious drug development for secondary prevention it is important to define what are the earliest biological stages of AD.

Combination therapy for Alzheimer's disease and related dementias.

The failure to date of all disease modifying therapies for Alzheimer's disease and related dementias requires a serious rethinking of the field's approach to therapeutic interventions. This begins with the acknowledgement that the great majority of sporadic neurodegenerative dementias are the result of more than one toxic protein/species. While there are challenges to the initiation of clinical trials targeting more than one mechanism, there is an urgent need for a paradigm shift where a pleotropic and personalized approach is implemented to address the devastating personal and societal consequences of neurodegenerative dementias.

Immunotherapy with ponezumab for probable cerebral amyloid angiopathy.

Objective: Cerebral amyloid angiopathy (CAA) is caused by cerebrovascular deposition of -amyloid fragments leading to cerebrovascular dysfunction and other brain injuries. This phase 2, randomized, double-blind trial in patients with probable CAA assessed the efficacy and safety of ponezumab, a novel monoclonal antibody against A .

Methods: Thirty-six participants aged 55-80 years with probable CAA received intravenous placebo ( = 12) or ponezumab ( = 24).

Current state of Alzheimer's fluid biomarkers.

Alzheimer's disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment.

Ponezumab in mild-to-moderate Alzheimer's disease: Randomized phase II PET-PIB study.

Introduction: The safety, pharmacokinetics, and effect on peripheral and central amyloid β (Aβ) of multiple doses of ponezumab, an anti-Aβ monoclonal antibody, were characterized in subjects with mild-to-moderate Alzheimer's disease treated for 1 year.

Methods: Subjects were aged ≥50 years with Mini-Mental State Examination scores 16 to 26. Cohort Q was randomized to ponezumab 10 mg/kg ( = 12) or placebo ( = 6) quarterly.

Multiple-dose ponezumab for mild-to-moderate Alzheimer's disease: Safety and efficacy.

Introduction: Multiple intravenous doses of ponezumab, an anti-amyloid antibody, were evaluated in subjects with mild-to-moderate Alzheimer's disease (AD).

Methods: In part A, 77 subjects were randomized to ponezumab 0.1, 0.

Phosphodiesterase-5 Inhibitor PF-03049423 Effect on Stroke Recovery: A Double-Blind, Placebo-Controlled Randomized Clinical Trial.

Background: The therapeutic potential of phosphodiesterase-5 inhibitor PF-03049423 was evaluated in a phase 2, multicenter, randomized, double-blind, placebo-controlled study of subjects with acute ischemic stroke (

Clinical Trial Registration Information: http://www.clinicaltrials.gov, unique identifier: NCT01208233; http://www.

The Safety and Efficacy of PF-04958242 in Age-Related Sensorineural Hearing Loss: A Randomized Clinical Trial.

Importance: To our knowledge, this is the first study to assess the potential to pharmacologically improve auditory function in adults with age-related sensorineural hearing loss.

Objective: To explore the potential for the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid potentiator mechanism to affect auditory function in individuals with mild to moderate age-related sensorineural hearing loss.

Design, Setting, And Participants: A randomized, double-blind, placebo-controlled, single-dose, 3-way crossover study was conducted in 3 academic ear, nose, and throat clinics and 2 private clinical research centers between December 22, 2011, and February 26, 2013.

Safety and pharmacokinetics of PF-04360365 following a single-dose intravenous infusion in Japanese subjects with mild-to-moderate Alzheimer's disease: a multicenter, randomized, double-blind, placebo-controlled, dose-escalation study.

Objective: PF-04360365 is a humanized IgG(2)Δa anti-amyloid β (Aβ) antibody designed to improve outcome in Alzheimer's disease (AD). Single doses of 0.1 - 10 mg/kg were safe and well tolerated in Western (mostly Caucasian) subjects with mild-to-moderate AD.

Safety and pharmacology of a single intravenous dose of ponezumab in subjects with mild-to-moderate Alzheimer disease: a phase I, randomized, placebo-controlled, double-blind, dose-escalation study.

Objectives: Ponezumab is a humanized antiamyloid beta (Aβ) monoclonal antibody designed to treat Alzheimer disease (AD).

Methods: This randomized, double-blind, single-dose-escalation study evaluated the safety, pharmacokinetics, and pharmacodynamics of 0.1, 0.

Safety and pharmacology of ponezumab (PF-04360365) after a single 10-minute intravenous infusion in subjects with mild to moderate Alzheimer disease.

Objective: Ponezumab (PF-04360365) is a humanized anti-amyloid beta (Aβ) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid Aβ.

Neurorestoration therapeutics for neurodegenerative and psychiatric disease.

Objective: Neurorestoration within the human central nervous system (CNS) is a concept that is barely a decade old. Despite this, there is significant clinical activity in this area, although there has not been any attempt to systematically identify these trials and organize them by disease area and phase of development. The objective of this investigation is to broadly review the current state of neurorestorative clinical trial activity ongoing worldwide.

Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer's Association Research Roundtable Workgroup.

Amyloid imaging related abnormalities (ARIA) have now been reported in clinical trials with multiple therapeutic avenues to lower amyloid-β burden in Alzheimer's disease (AD). In response to concerns raised by the Food and Drug Administration, the Alzheimer's Association Research Roundtable convened a working group to review the publicly available trial data, attempts at developing animal models, and the literature on the natural history and pathology of related conditions. The spectrum of ARIA includes signal hyperintensities on fluid attenuation inversion recoverysequences thought to represent "vasogenic edema" and/or sulcal effusion (ARIA-E), as well as signal hypointensities on GRE/T2* thought to represent hemosiderin deposits (ARIA-H), including microhemorrhage and superficial siderosis.

Iatrogenic risk factors for Alzheimer's disease: surgery and anesthesia.

Increasing evidence indicates that patients develop post-operative cognitive decline (POCD) following surgery. POCD is characterized by transient short-term decline in cognitive ability evident in the early post-operative period. This initial decline might be associated with increased risk of a delayed cognitive decline associated with dementia 3 to 5 years post-surgery.

Stroke: working toward a prioritized world agenda.

Background And Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.

Methods: Preliminary work was performed by seven working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.

Stroke: working toward a prioritized world agenda.

Background And Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.

Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.

Stroke: working toward a prioritized world agenda.

Background And Purpose: The aim of the Synergium was to devise and prioritize new ways of accelerating progress in reducing the risks, effects, and consequences of stroke.

Methods: Preliminary work was performed by 7 working groups of stroke leaders followed by a synergium (a forum for working synergistically together) with approximately 100 additional participants. The resulting draft document had further input from contributors outside the synergium.

Anti-amyloid antibody drugs in clinical testing for Alzheimer's disease.

Although far from validated, the 'amyloid hypothesis' remains the most compelling contemporary hypothesis to explain the cognitive decline observed in Alzheimer's disease (AD). Late-stage clinical trials with both small molecules and immunotherapeutics are ongoing to investigate the role of amyloid in the pathophysiology of AD. Anti-amyloid mAbs are diverse, both in terms of epitope (with affinity for the N- or C-terminus and/or the middle of the protein sequence) and isotype (eg, IgG1 or IgG2 ).

The role of sildenafil in the treatment of stroke.

The structural underpinning responsible for neuroplasticity and neurorestoration under physiological and pathophysiological conditions is only beginning to be elucidated. It is evident that life-long neurogenesis occurs in the human brain, with experimental data supporting its upregulation following an insult (eg, stroke) and/or in response to pharmacological therapy. Sildenafil, a PDE5 inhibitor currently marketed for the treatment of erectile dysfunction, enhances neurorestoration in rat models of stroke, as measured by neurogenesis, synaptogenesis and angiogenesis.

Interventions for heart disease and their effects on Alzheimer's disease.

Objectives: To review the contributions of cardiovascular disease to Alzheimer's disease and vascular dementia.

Methods: Review of the literature.

Results: Alzheimer's disease and vascular dementia both share significant risk attributable to cardiovascular risk factors.

Reversal of scopolamine-induced deficits with a single dose of donepezil, an acetylcholinesterase inhibitor.

Background: To develop a more rapid screening paradigm for novel cognitive enhancers, the authors sought to determine the utility of a well-known pharmacologic model of induced dementia (scopolamine challenge), paired with a sensitive neuropsychological test, for assessing the ability of a single oral dose of a current treatment for Alzheimer's disease (donepezil) to improve cognitive performance in healthy elderly subjects.

Methods: Thirty-two (4 groups of 8) healthy elderly volunteers were put randomly into a double-blind, placebo-controlled, modified crossover design study. In Part 1, 16 subjects received donepezil (5 mg) or placebo separately in a crossover fashion.