Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
1.
Clin Pharmacol Drug Dev ; 8(4): 426-435, 2019 05.
Article in English | MEDLINE | ID: mdl-30934161

ABSTRACT

Azeliragon is an inhibitor of the receptor for advanced glycation end products being developed for the treatment of Alzheimer's disease. The objective of the current analysis was to evaluate the relationship between plasma azeliragon concentrations and QT interval. Simultaneous QT values and plasma concentrations were available from 711 subjects (6236 records), pooled from 5 studies in healthy volunteers, 2 studies in patients with mild to moderate Alzheimer's disease, and 1 study in patients with type 2 diabetes and persistent albuminuria. Nonlinear mixed-effects modeling was conducted to describe azeliragon concentration-related changes in QT interval, after correcting for heart rate, using Fridericia's criteria (QTcF) and sex-related differences in baseline QTcF. Azeliragon-related changes in QTcF were predicted using 2 methods: simulation and bias-corrected 90% confidence interval approaches. A small positive relationship between azeliragon plasma concentration and QTcF was noted with a slope of 0.059 ms/ng/mL. Simulations predicted mean (90% prediction interval) changes in QTcF of 0.733 milliseconds (0.32-1.66 milliseconds) with the phase 3 dose (5 mg once daily steady state) and 4.32 milliseconds (1.7-8.74 milliseconds) at supratherapeutic doses (20 mg once daily steady state or 60 mg once daily × 6 days). Bias-corrected upper 90% confidence intervals for therapeutic and supratherapeutic doses were 0.88 and 5.01 milliseconds, respectively. Model-based analysis showed a small, nonclinically meaningful, positive relationship between azeliragon plasma concentration and QTcF with a slope close to zero. Neither the prediction interval nor the upper bound of the 90% confidence interval reached 10 milliseconds, demonstrating no clinically meaningful drug-related effect on QTcF at expected therapeutic and supratherapeutic doses of azeliragon.


Subject(s)
Albuminuria/drug therapy , Alzheimer Disease/drug therapy , Diabetes Mellitus, Type 2/drug therapy , Imidazoles/adverse effects , Imidazoles/pharmacokinetics , Administration, Oral , Clinical Trials as Topic , Dose-Response Relationship, Drug , Drug Dosage Calculations , Electrocardiography , Heart Rate/drug effects , Humans , Imidazoles/administration & dosage , Imidazoles/pharmacology , Molecular Structure , Nonlinear Dynamics
2.
J Clin Psychopharmacol ; 35(1): 51-6, 2015 02.
Article in English | MEDLINE | ID: mdl-25422883

ABSTRACT

This randomized, double-blind, placebo-controlled trial evaluated the efficacy of CP-601,927, an α4ß2 nicotinic acetylcholine receptor partial agonist and an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to selective serotonin reuptake inhibitors (SSRIs). After open-label treatment with an SSRI for 8 weeks, subjects with a Hamilton Depression Scale 17 score greater than or equal to 16 were entered into a double-blind phase and randomized to CP-601,927 2 mg twice daily or placebo for 6 weeks. The primary end point was the change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from double-blind baseline to week 14. There was no significant difference in change from baseline to week 14 in the MADRS score for CP-610,927 versus placebo (least square mean difference [80% confidence interval], -1.30 [-3.32-0.71]). Post hoc analyses revealed that the drug-placebo difference in change from baseline (SE) to week 14 in MADRS score was greater in subjects with body mass index (BMI) less than or equal to 35 kg/m (-3.43 [1.87], P = 0.069) than those with BMI greater than 35 kg/m (3.37 [2.8], P = 0.230). Analysis of biomarkers associated with increased BMI suggests that baseline leptin had a significant effect on treatment outcome. P values for the effect of treatment on mean change in MADRS score for subjects with baseline leptin levels below and above the median were 0.055 and 0.0055, respectively. CP-601,927 was equivalent to placebo as an augmenting agent of antidepressants in major depressive disorder patients with insufficient response to SSRIs. However, post hoc analyses suggest that BMI, particularly elevated leptin levels, may have affected the response to CP-601,927; however, further study may be needed to confirm these results.


Subject(s)
Antidepressive Agents/therapeutic use , Depressive Disorder, Major/blood , Drug Partial Agonism , Leptin/blood , Nicotinic Agonists/therapeutic use , Receptors, Nicotinic , Adult , Antidepressive Agents/chemistry , Biomarkers/blood , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/drug therapy , Double-Blind Method , Female , Follow-Up Studies , Humans , Male , Middle Aged , Nicotinic Agonists/chemistry , Treatment Outcome
3.
Curr Alzheimer Res ; 11(5): 413-21, 2014.
Article in English | MEDLINE | ID: mdl-24801218

ABSTRACT

BACKGROUND: PF-04447943 is a potent, selective phosphodiesterase 9A (PDE9A) inhibitor that elevates guanoscine 3',5' - cyclic monophosphate (cGMP) in brain and cerebrospinal fluid. PDE9A inhibition enhances synaptic plasticity and improves memory in preclinical cognition models, and prevents decreases in dendritic spine density in transgenic mice that overexpress amyloid precursor protein (APP) leading to high levels of amyloid beta (Aß) production (Tg2576). OBJECTIVE: This Phase 2 multicenter study was designed to assess the efficacy, safety and pharmacokinetics of PF-04447943 compared with placebo in mild to moderate probable Alzheimer's disease (AD). METHODS: Subjects in overall good health with Mini Mental State Examination (MMSE) scores of 14-26 were randomized to 12 weeks treatment with PF-04447943 25 mg q12h (n=91) or placebo (n=100). Concomitant acetylcholinesterase inhibitor or memantine use was excluded. The primary outcome was the Alzheimer's Disease Assessment Scale - cognitive subscale (ADAS-cog). The Neuropsychiatric Inventory (NPI), Clinical Global Impression-Improvement scale (CGI-I) and standard safety measures were secondary outcomes. RESULTS: Completion rates were similar, 87% PF-04447943 vs 92% placebo. At week 12 the mean (SE) baseline adjusted decrease from baseline in ADAS cog for PF-04447943-treated patients was -1.91 (0.54). Placebo treated patients had a change of -1.60 (0.50). The difference between treatments was -0.31 (90% CI of -1.52, 0.90). Corresponding values for the NPI were -2.86 (0.72) vs -2.70 (0.67) with a treatment difference of -0.16 (90% CI of -1.78, 1.48). Neither these changes nor the distribution of CGI-I scores were statistically significantly different between groups. The incidence of serious adverse events (AEs) was similar between groups with 2 deaths in the placebo group. The PF-04447943 group reported more gastrointestinal AEs including diarrhea (5.5% vs 3%) and nausea (5.5% vs 1%) and had a higher rate of discontinuation due to AEs (6.6% vs 2%). CONCLUSIONS: Although generally safe and well-tolerated, 12 weeks PF-04447943 treatment did not improve cognition, behavior, and global change compared with placebo.


Subject(s)
Alzheimer Disease/drug therapy , Phosphodiesterase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Pyrimidinones/therapeutic use , Aged , Aged, 80 and over , Alzheimer Disease/complications , Cognition Disorders/drug therapy , Cognition Disorders/etiology , Double-Blind Method , Female , Humans , Male , Mental Status Schedule , Middle Aged , Neuropsychological Tests , Outcome Assessment, Health Care , Treatment Outcome
4.
Alzheimer Dis Assoc Disord ; 16 Suppl 1: S1-8, 2002.
Article in English | MEDLINE | ID: mdl-12070355

ABSTRACT

Alzheimer disease (AD) is a neurodegenerative condition leading to progressive, irreversible loss of cognitive and behavioral function. Despite considerable investments in neuroscience research, only four drugs, all cholinesterase inhibitors, have been approved for the symptomatic management of AD in the United States. Although basically safe and modestly effective, these drugs are far from ideal, being neither universally efficacious nor disease modifying. AD exacts a considerable toll in direct medical costs, quality of life, and caregiver burden for persons and society. In addition to the obvious clinical benefit, therapeutic agents for AD and related dementias represent a considerable market opportunity for the pharmaceutical and biotechnology industries. There are currently 8-10 million AD sufferers in the seven major pharmaceutical markets. The market will grow rapidly in coming decades, as the developed world experiences an enormous increase in its elderly population. Given the great need for new therapeutic agents to manage and prevent AD, the Institute for the Study of Aging and the Fidelity Foundation organized a workshop, "Barriers to the Discovery and Development of Drugs for Alzheimer's Disease," to examine ways to expedite drug discovery and development. The identified barriers and potential solutions will be discussed here and in the accompanying articles in more detail.


Subject(s)
Alzheimer Disease/drug therapy , Technology, Pharmaceutical/methods , Alzheimer Disease/blood , Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/economics , Animals , Biomarkers/blood , Biomarkers/cerebrospinal fluid , Biotechnology/economics , Biotechnology/legislation & jurisprudence , Biotechnology/methods , Clinical Trials as Topic/methods , Disease Models, Animal , Humans , Technology, Pharmaceutical/economics , Technology, Pharmaceutical/legislation & jurisprudence
SELECTION OF CITATIONS
SEARCH DETAIL
...