Once-daily oral small-molecule glucagon-like peptide-1 receptor agonist lotiglipron (PF-07081532) for type 2 diabetes and obesity: Two randomized, placebo-controlled, multiple-ascending-dose Phase 1 studies.

Aim: To investigate the effects of lotiglipron (PF-07081532), a once-daily, oral small-molecule glucagon-like peptide-1 receptor agonist, in participants with type 2 diabetes (T2D) and/or obesity.

Materials And Methods: Two Phase 1 randomized, double-blind, placebo-controlled, multiple-ascending-dose studies were conducted to investigate the safety, tolerability, pharmacokinetics and pharmacodynamics of lotiglipron.

Results: Across the studies, 74 participants with T2D were treated for 28 or 42 days, and 26 participants with obesity without diabetes were treated for 42 days, following randomization to placebo or lotiglipron (target doses 10-180 mg/day, with dose titration to higher target doses).

Pharmacological Inhibition of CETP (Cholesteryl Ester Transfer Protein) Increases HDL (High-Density Lipoprotein) That Contains ApoC3 and Other HDL Subspecies Associated With Higher Risk of Coronary Heart Disease.

Objective: Plasma total HDL (high-density lipoprotein) is a heterogeneous mix of many protein-based subspecies whose functions and associations with coronary heart disease vary. We hypothesize that increasing HDL by CETP (cholesteryl ester transfer protein) inhibition failed to reduce cardiovascular disease risk, in part, because it increased dysfunctional subspecies associated with higher risk such as HDL that contains apoC3. Approach and Results: We studied participants in 2 randomized, double-blind, placebo-controlled trials of a CETP inhibitor on a background of atorvastatin treatment: ACCENTUATE (The Addition of Evacetrapib to Atorvastatin Compared to Placebo, High Intensity Atorvastatin, and Atorvastatin With Ezetimibe to Evaluate LDL-C Lowering in Patients With Primary Hyperlipidemia; 130 mg evacetrapib; n=126) and ILLUMINATE (Phase 3 Multi Center, Double Blind, Randomized, Parallel Group Evaluation of the Fixed Combination Torcetrapib/Atorvastatin, Administered Orally, Once Daily [Qd], Compared With Atorvastatin Alone, on the Occurrence of Major Cardiovascular Events in Subjects With Coronary Heart Disease or Risk Equivalents; 60 mg torcetrapib; n=80).

ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials.

Alterations in lipid metabolism might contribute to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, no pharmacological agents are currently approved in the United States or the European Union for the treatment of NAFLD. Two parallel phase 2a studies investigated the effects of liver-directed ACC1/2 inhibition in adults with NAFLD.

De novo lipogenesis is essential for platelet production in humans.

Acetyl-CoA carboxylase (ACC) catalyses the first step of de novo lipogenesis (DNL). Pharmacologic inhibition of ACC has been of interest for therapeutic intervention in a wide range of diseases. We demonstrate here that ACC and DNL are essential for platelet production in humans and monkeys, but in not rodents or dogs.

Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems.

Background & Aims: Disordered metabolism, steatosis, hepatic inflammation, and fibrosis contribute to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase (ACC) catalyzes the first committed step in de novo lipogenesis (DNL) and modulates mitochondrial fatty acid oxidation. Increased hepatic DNL flux and reduced fatty acid oxidation are hypothesized to contribute to steatosis.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304): A Three-Part Randomized Phase 1 Study.

PF-05221304 is a liver-targeted inhibitor of acetyl-CoA carboxylase, an enzyme that catalyzes the first committed step in de novo lipogenesis (DNL). This first-in-human study investigated safety/tolerability and pharmacokinetics of single and multiple ascending oral PF-05221304 doses, and fructose-stimulated DNL inhibition with repeated oral doses. Healthy subjects (n = 96) received single (1-240 mg) or repeated (2-200 mg daily) doses for 14 days or single 100-mg doses with and without food.

Targeting diacylglycerol acyltransferase 2 for the treatment of nonalcoholic steatohepatitis.

Nonalcoholic steatohepatitis (NASH) is characterized by the accumulation of hepatocyte triglycerides, the synthesis of which is catalyzed by diacylglycerol acyltransferases (DGATs). Here, we investigate DGAT2 as a potential therapeutic target using an orally administered, selective DGAT2 inhibitor, PF-06427878. Treatment with PF-06427878 resulted in the reduction of hepatic and circulating plasma triglyceride concentrations and decreased lipogenic gene expression in rats maintained on a Western-type diet.

Human sebum requires de novo lipogenesis, which is increased in acne vulgaris and suppressed by acetyl-CoA carboxylase inhibition.

Sebum plays important physiological roles in human skin. Excess sebum production contributes to the pathogenesis of acne vulgaris, and suppression of sebum production reduces acne incidence and severity. We demonstrate that sebum production in humans depends on local flux through the de novo lipogenesis (DNL) pathway within the sebocyte.

Decreased VMAT2 in the pancreas of humans with type 2 diabetes mellitus measured in vivo by PET imaging.

Aims/hypothesis: The progressive loss of beta cell function is part of the natural history of type 2 diabetes. Autopsy studies suggest that this is, in part, due to loss of beta cell mass (BCM), but this has not been confirmed in vivo. Non-invasive methods to quantify BCM may contribute to a better understanding of type 2 diabetes pathophysiology and the development of therapeutic strategies.

Pharmacokinetics and pharmacodynamics of PF-05190457: The first oral ghrelin receptor inverse agonist to be profiled in healthy subjects.

Aim: To evaluate safety, tolerability and pharmacokinetics of oral PF-05190457, an oral ghrelin receptor inverse agonist, in healthy adults.

Methods: Single (SAD) and multiple ascending dose (MAD) studies were randomised, placebo-controlled, double-blind studies. Thirty-five healthy men (age 38.

Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes.

Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections.

Downregulation of GPR83 in the hypothalamic preoptic area reduces core body temperature and elevates circulating levels of adiponectin.

The G protein-coupled receptor 83 (GPR83) was recently demonstrated in warm sensitive neurons (WSN) of the hypothalamic preoptic area (POA) that participate in temperature homeostasis. Thus, we investigated whether GPR83 may have a role in regulating core body temperature (CBT) by reducing its expression in the POA. Dissipation of energy in the form of heat is the primary mode of energy expenditure in mammals and can ultimately affect energy homeostasis.

High throughput object-based image analysis of β-amyloid plaques in human and transgenic mouse brain.

Advances in imaging technology have enabled automated approaches for quantitative image analysis. In this study, a high content object based image analysis method was developed for quantification of β-amyloid (Aβ) plaques in postmortem brains of Alzheimer's disease (AD) subjects and in transgenic mice over overexpressing Aβ. Digital images acquired from immunohistochemically stained sections of the superior frontal gyrus were analyzed for Aβ plaque burden using a Definiens object-based segmentation approach.

Early markers of choroidal neovascularization in the fellow eye of patients with unilateral exudative age-related macular degeneration.

Objective: To identify morphological and/or functional early markers of choroidal neovascularization (CNV) development in fellow eyes of patients with exudative age-related macular degeneration (AMD).

Design: This is a single-center, prospective, observational, longitudinal 2-year study.

Patients: Patients were enrolled with the diagnosis of neovascular AMD in 1 eye and early age-related maculopathy (ARM) in the fellow eye.

In vivo MRI assessment of knee cartilage in the medial meniscal tear model of osteoarthritis in rats.

We present a new approach for quantifying the degradation of knee cartilage in the medial meniscal tear (MMT) model of osteoarthritis in the rat. A statistical strategy was used to guide the selection of a region of interest (ROI) from the images obtained from a pilot study. We hypothesize that this strategy can be used to localize a region of cartilage most vulnerable to MMT-induced damage.

Pathology underrates colon cancer extranodal and nodal metastases; ex vivo radioimmunodetection helps staging.

Purpose: Colorectal carcinoma is frequently accompanied by small lymph nodes metastases that often escape pathologic examination. We evaluated whether ex vivo radioimmunodetection with the Affinity Enhancement System (AES) could improve detection of mesocolonic metastases.

Experimental Design: A bivalent 111In-labeled hapten was injected (16 patients) 4 days after a bispecific antibody (anticarcinoembryonic antigen, antihapten).

Differential loss of presynaptic dopaminergic markers in Parkinsonian monkeys.

Assessment of dopamine nerve terminal function and integrity is a strategy employed to monitor deficits in Parkinson's disease (PD) patients and in preclinical models of PD. Dopamine replacement therapies effectively replenish the diminished supply of endogenous dopamine and provide symptomatic benefit to patients. Tyrosine hydroxylase (TH), dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2), and amino acid decarboxylase (AADC) are widely used markers of dopaminergic neurons and terminals.

Effects of lasofoxifene on the pharmacokinetics and pharmacodynamics of single-dose warfarin.

Aim: To investigate the effect of steady-state lasofoxifene on the pharmacokinetics and pharmacodynamics of warfarin.

Methods: Twelve healthy postmenopausal women received warfarin (single 20-mg dose) alone and during lasofoxifene. R- and S-warfarin concentrations, prothrombin time (PT) and international normalized ratio (INR) were determined with each treatment.

Resistance to induced apoptosis in the human neuroblastoma cell line SK-N-SH in relation to neuronal differentiation. Role of Bcl-2 protein family.

Much evidence suggests that apoptosis plays a crucial role in cell population homeostasis that depends on the expression of various genes implicated in the control of cell life and death. The sensitivity of human neuroblastoma cells SK-N-SH to undergo apoptosis induced by thapsigargin was examined. SK-N-SH were previously differentiated into neuronal cells by treatments with retinoic acid (RA), 4 beta-phorbol 12-myristate 13-acetate (PMA) which increases protein kinase C (PKC) activity, and staurosporine which decreases PKC activity.

Screening human donor corneas during organ culture for the presence of guttae.

Aims: To detect the presence of guttae by means of light microscopy during organ culture and to evaluate the influence of the presence of guttae in the donor tissue on transplantation outcome.

Methods: Donor corneas were investigated for the presence of guttae by means of light microscopy at the end of organ culture. Recipient corneal buttons from patients with severe Fuchs' dystrophy and donor corneas with advanced guttae were first studied by light microscopy and subsequently by transmission electron microscopy.

Automated keratoconus detection using the EyeSys videokeratoscope.

Purpose: To evaluate the effectiveness of indices derived from the EyeSys System 2000 in detecting keratoconic corneas.

Setting: Department of Ophthalmology, Hôpital Saint Antoine, Paris VI University, Paris, France.

Methods: Topographies of 208 corneas were evaluated.

Prediction of spectacle-corrected visual acuity using videokeratography.

Purpose: Our aim was to improve prediction of spectacle-corrected visual acuity (SCVA) using indices derived from the EyeSys System 2000 data (version 3.1).

Methods: We studied corneal topography in 182 eyes from 8 groups of patients.

The triple procedure: in the bag placement versus ciliary sulcus placement of the intraocular lens.

Aims: To evaluate the influence of intraocular lens (IOL) placement on triple procedure clinical results and to investigate whether it is appropriate to use phacoemulsification in patients with large lens nucleus.

Methods: 40 consecutive penetrating keratoplasties combined with cataract extraction performed in a single institution were studied. Whenever possible a capsulorhexis was performed and the IOL was placed into the capsular bag.

The results of successful penetrating keratoplasty using donor organ-cultured corneal tissue.

Background: The aim of this study was identification of predictive factors for postoperative visual acuity in patients with a clear organ-cultured graft and to analyze the change in visual acuity between 12 and 24 months after transplantation.

Methods: The study design was a prospective cohort study. A total of 342 consecutive penetrating keratoplasties using donor organ-cultured grafts, performed in 324 patients, were included.