A5111953272- Neuroscience and Neuropharmacology Research
- Drug Transport and Resistance Mechanisms
- Alzheimer's disease research and treatments
- Computational Drug Discovery Methods
- Diet and metabolism studies
- Cardiac electrophysiology and arrhythmias
- Receptor Mechanisms and Signaling
- Liver Disease Diagnosis and Treatment
- Metabolomics and Mass Spectrometry Studies
- Pharmacological Effects and Toxicity Studies
- Treatment of Major Depression
- Asthma and respiratory diseases
- Cholinesterase and Neurodegenerative Diseases
- Pharmacogenetics and Drug Metabolism
- Healthcare Policy and Management
- Optimal Experimental Design Methods
- Dermatology and Skin Diseases
- Acute Ischemic Stroke Management
- Blood Pressure and Hypertension Studies
- Metabolism and Genetic Disorders
- Stroke Rehabilitation and Recovery
- Neurological Disorders and Treatments
- Cholesterol and Lipid Metabolism
- Neuropeptides and Animal Physiology
- Phenothiazines and Benzothiazines Synthesis and Activities
Pfizer (United States)
2015-2025
University of Arizona
2014-2024
Banner Sun Health Research Institute
2014
Yale University
2014
Stony Brook University
2001
State University of New York
2001
To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD).Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD Mini-Mental State Examination score 14-26 were randomized PF-04494700 60 mg/day × 6 days, then 20 mg daily (high dose); 15 5 (low or placebo, 18 months. Clinical laboratory measures used evaluate safety tolerability. The...
Objective To evaluate the efficacy and safety of PF‐06651600 (ritlecitinib), an irreversible inhibitor JAK3 tyrosine kinase expressed in hepatocellular carcinoma (TEC) family, comparison with placebo patients rheumatoid arthritis (RA). Methods An 8‐week, phase II, double‐blind, parallel‐group study was conducted. Seventy who were seropositive for anti–citrullinated protein antibodies and/or factor randomized 3:2 to receive oral (200 mg once daily) or 8 weeks. Eligible had inadequate response...
Chronic pain conditions affect nearly 20% of the population in United States. Current medical interventions, such as opioid drugs, are effective at relieving but accompanied by many undesirable side effects. This is one reason increased numbers chronic patients have been turning to Cannabis for management. contains bioactive chemical compounds; however, current research looking into lesser-studied minor cannabinoids lacks uniformity between experimental groups and/or excludes female mice...
The objective of our study was to determine the QTc effects tolterodine. A crossover-design thorough QT recommended (2 mg twice daily) and supratherapeutic (4 doses tolterodine, moxifloxacin (400 once daily), placebo performed. Electrocardiograms (ECGs) pharmacokinetic samples were obtained on days 1-4; time-matched baseline ECGs taken day 0. Mean placebo-subtracted change from Fridericia-corrected (QTcF) during peak drug exposure 4 primary end point. QTcF prolongation 8.9 ms (machine-read)...
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), systematic structure-activity relationship (SAR) study was conducted with specific focus on balancing pharmacological potency physicochemical and pharmacokinetic (PK) properties. This effort led to the discovery 1-methyl-3-(4-methylpyridin-3-yl)-6-(pyridin-2-ylmethoxy)-1H-pyrazolo[3,4-b]pyrazine (PF470, 14) highly potent, selective,...
Previous publications suggest that interstitial fluid compound concentrations (<i>C</i><sub>ISF</sub>) best determine quantitative neurotherapeutic pharmacology relationships, although confirming large animal <i>C</i><sub>ISF</sub> remains elusive. Therefore, this work primarily evaluated using respective acute dose, rat-derived unbound brain concentration-to-unbound plasma concentration ratios (<i>C</i><sub>b,u</sub>/<i>C</i><sub>p,u</sub>) to project accurately dog and nonhuman primate...
Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer's disease (AD) trials. SAM-760 is a potent and selective antagonist that has demonstrated central saturation humans at dose of 30 mg. This was randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy safety mg once daily (QD) 12 weeks subjects with AD on stable regimen donepezil 5 to 10 QD. The study included an interim analysis stopping rules futility or after...
γ-Secretase modulators (GSMs) represent a promising therapy for Alzheimer's disease by reducing pathogenic amyloid-β (Aβ) peptide production. Three phase I studies (NCT02316756, NCT02407353, and NCT02440100) investigated the safety/tolerability, pharmacokinetics (PKs), pharmacodynamics (PDs) of oral GSM, PF-06648671. A PK/PD indirect-response model was developed (using biomarker data) to simultaneously characterize differential effects PF-06648671 on multiple Aβ species in cerebrospinal...
Abstract Co‐administration of clesacostat (acetyl‐CoA carboxylase inhibitor, PF‐05221304) and ervogastat (diacylglycerol O‐acyltransferase PF‐06865571) in laboratory models improved non‐alcoholic fatty liver disease (NAFLD)/non‐alcoholic steatohepatitis (NASH) end points mitigated clesacostat‐induced elevations circulating triglycerides. Clesacostat is cleared via organic anion‐transporting polypeptide‐mediated hepatic uptake cytochrome P450 family 3A (CYP3A); vitro identified as a potential...
Abstract Aims Two general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and preserved EF (HFpEF). To develop phenotype‐specific approaches to treatment, distinguishing biomarkers needed. The goal this study was utilize quantitative metabolomics on a large, diverse population replicate extend existing knowledge the plasma metabolic signatures in human HF. Methods Plasma proteomics conducted 787 samples collected by Penn Medicine BioBank from...
PF-06751979 is a selective inhibitor of the beta-site amyloid precursor protein cleaving enzyme-1, which key aspartyl protease in generation amyloid- (A) peptides, thought to be critical for cerebral degeneration observed Alzheimer's disease.Two Phase I studies (NCT02509117, NCT02793232) investigated safety/tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) PF-06751979.Single-ascending doses up 540 mg multipleascending 275 once daily (QD) healthy adults, multiple 50 or 125 QD...
A new cholesteryl ester (CE) transfer protein (CETP) inhibitor (CP-800,569) was evaluated. Doses of 30–1,800 mg were administered once daily to healthy subjects for 14 days. Serum CP-800,569 levels increased, and CETP activity decreased, in a dose-related manner. high-density lipoprotein (HDL) increased (by maximum 156%), those low-density (LDL) decreased 47%). also had the effect lowering postprandial triglyceride levels. Trough concentrations apolipoprotein E (apoE) increased: increases...
Two general phenotypes of heart failure (HF) are recognized: HF with reduced ejection fraction (HFrEF) and preserved EF (HFpEF). To develop disease phenotype-specific approaches to define guide treatment, distinguishing biomarkers needed. The goal this study was utilize quantitative metabolomics on a large, diverse population replicate extend existing knowledge the plasma metabolic signatures in human HF. Quantitative, targeted LC/MS conducted 787 samples collected by Penn Medicine BioBank...
PF-06817024 is a high affinity, humanized antibody that binds interleukin-33, proinflammatory type 2 cytokine, and thereby has the potential to inhibit downstream inflammation. This Phase 1, randomized, placebo-controlled study was conducted in 3 parts evaluate safety, tolerability, pharmacokinetics (PK), immunogenicity, pharmacodynamics of escalating single limited repeat doses healthy participants (Part 1), dose with chronic rhinosinusitis nasal polyps 2), moderate severe atopic dermatitis...
We previously observed a cutaneous type IV immune response in nonhuman primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated distinct series of NAMs. Increasing sp3 character high-throughput screening hit 40 afforded novel morpholinopyrimidone NAM series. Its prototype, (R)-6-neopentyl-2-(pyridin-2-ylmethoxy)-6,7-dihydropyrimido[2,1-c][1,4]oxazin-4(9H)-one (PF-06462894, 8), possessed favorable...
Abstract Methods of isotonic regression are proposed to increase the power common trend tests in situations where a monotonicity constraint is imposed upon dose‐response function. Isotonic versions Cochran–Armitage type for binary response data developed, and bootstrap method used finding empirical distributions test statistics their critical values. The likelihood ratio with survival adjustment also proposed. This can be applied either order‐restricted or unrestricted parameter cases. To...
SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT<sub>6</sub> antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, predominantly metabolized by CYP3A (∼85%). Based on these observations an expectation 5-fold magnitude interaction with moderate to strong inhibitors, clinical DDI study performed. presence ketoconazole, mean <i>C</i><sub>max</sub> area under...
Summary. Preclinical animal carcinogenicity studies are usually concerned with testing the statistical significance of a dose–response relationship. When response consists rare event such as development certain type tumor, exact methods often employed. The randomization trend test based on multivariate hypergeometric distribution is less powerful in presence treatment-related risks other than specified response. Particularly, loss power becomes more pronounced when competing cause...