Unveiling the Potential of C Factor Applied to Pilot Bioavailability/Bioequivalence Studies-A Case Study with Pazopanib Drug Products.

When companies are uncertain about the potential of a new formulation to be bioequivalent to a Reference product, it is common practice to carry out downsized pilot studies as a gatekeeping in vivo strategy to decide whether to move forward or not with a full-size pivotal study. However, due to the small study size, these studies are inarguably more sensitive to variability. To address and mitigate the uncertainty of the conclusions of pilot studies concerning the maximum observed concentration (C), the factor was proposed as an alternative approach to the average bioequivalence statistical methodology.

Association of Gut Microbiome and Dipeptidyl Peptidase 4 in Immune-Mediated Inflammatory Bowel Disease: A Rapid Literature Review.

Immune-mediated inflammatory diseases (IMIDs) are characterized by dysregulated immune responses and chronic tissue inflammation. In the setting of inflammatory bowel disease (IBD), dipeptidyl peptidase 4 (DPP4) and gut microorganisms have been proved to interplay, potentially influenced by dietary factors. This rapid review aimed to study the DPP4-gut microbiome link in IBD.

A 14-Year Retrospective Clinical Analysis of Ocular Manifestations of Syphilis in a Portuguese Tertiary Center.

Purpose: Syphilis is a re-emerging infectious disease with various systemic manifestations, including ocular involvement, which can lead to significant morbidity if untreated. This study aims to analyze the ocular manifestations of syphilis in patients treated at a Portuguese tertiary center over a 14-year period.

Patients And Methods: A retrospective review of patients diagnosed with syphilis who presented with ocular symptoms from 2010 to 2023 was conducted.

Discovery of a Potent, Selective, and Blood-Brain Barrier Permeable Non-nitrocatechol Inhibitor of Catechol--methyltransferase.

A new library of non-nitrocatechol compounds (HetCAMs) was developed and their efficacy was compared to tolcapone, a standard COMT inhibitor for PD. Compound emerged as the most potent inhibitor, showing selective inhibition of brain (IC = 24 nM) and liver (IC = 81 nM) MB-COMT over liver S-COMT (IC = 620 nM) isoforms. Although compound presented higher IC values than tolcapone, it was more selective for brain MB-COMT than liver S-COMT.

Metabolism and disposition of zamicastat in rats.

The metabolism and disposition of zamicastat, a reversible dopamine β-hydroxylase (DβH) inhibitor, developed for treatment of Pulmonary Arterial Hypertension (PAH), were investigated in rats after oral and intravenous administration of [C]-zamicastat.Zamicastat was rapidly absorbed and widely distributed to peripheral tissues, with total radioactivity almost completely recovered 168 h post-dose. Its main route of excretion was via faeces, whilst urine and expired air had minor roles.

Evidence of Browning and Inflammation Features in Visceral Adipose Tissue of Women with Endometriosis.

Background: Patients with endometriosis tend to have a low body mass index, suggesting an inverse relationship between body fat and risk of disease. This is supported by evidence that miRNAs differentially expressed in endometriosis induce browning of pre-adipocytes in vitro. Thus, we hypothesize that endometriosis may underlie adipose tissue (AT) dysfunction and browning.

Could P2X7 receptor be a potencial target in neonatal sepsis?

The United Nations Inter-Agency Group for Child Mortality Estimation (UNIGME) estimates that every year 2.5 million neonates die in their first month of life, accounting for nearly one-half of deaths in children under 5 years of age. Neonatal sepsis is the third leading cause of neonatal mortality.

In silico analysis of aptamer-RNA conjugate interactions with human transferrin receptor.

The human transmembrane protein Transferrin Receptor-1 is regarded as a promising target for the systemic delivery of therapeutic agents, particularly of nucleic acid therapeutics, such as short double stranded RNAs. This ubiquitous receptor is involved in cellular iron uptake, keeping intracellular homeostasis. It is overexpressed in multiple cancer cell types and is internalized via clathrin-mediated endocytosis.

Brain Perception of Different Oils on Appetite Regulation: An Anorectic Gene Expression Pattern in the Hypothalamus Dependent on the Vagus Nerve.

(1) Background: We examined the effect of the acute administration of olive oil (EVOO), linseed oil (GLO), soybean oil (SO), and palm oil (PO) on gastric motility and appetite in rats. (2) Methods: We assessed food intake, gastric retention (GR), and gene expression in all groups. (3) Results: Both EVOO and GLO were found to enhance the rate of stomach retention, leading to a decrease in hunger.

Moderately intense physical exercise alleviates electrocardiographic changes induced by cisplatin in rats.

Introduction And Objective: Cisplatin induces many collateral effects such as gastrointestinal disorders, nephrotoxicity, and dysautonomia. Recently our group showed that cisplatin treatment induces gastric emptying delay and that physical exercise and treatment with pyridostigmine prevent this change. In the current study, we investigated the role of moderate exercise on cardiac activity and autonomic balance in rats treated with cisplatin.

Effect of zamicastat on blood pressure and heart rate response to cold pressor test: A double-blind, randomized, placebo-controlled study in healthy subjects.

Aims: Dopamine beta-hydroxylase (DβH) inhibitors, like zamicastat, hold promise for treating pulmonary arterial hypertension. This study aimed to validate the mechanism of action of zamicastat by studying its effect on the overdrive of the sympathetic nervous system (SNS).

Methods: A single-centre, prospective, double-blind, randomized, placebo-controlled, crossover study evaluated the effect of 400 mg zamicastat in 22 healthy male subjects.

Drug-Drug Interaction between Oral Zamicastat and Continuous Epoprostenol Infusion at Steady-State Conditions in Healthy Subjects.

This study intended to evaluate the interactions between zamicastat and epoprostenol in healthy human subjects. This was a single-center, open-label, two-period study. In period 1, epoprostenol 8 ng/kg/min was administered alone.

Mechanical stimulation-induced purinome priming fosters osteogenic differentiation and osteointegration of mesenchymal stem cells from the bone marrow of post-menopausal women.

Background: Mechanical stimulation (MS) significantly increases the release of adenine and uracil nucleotides from bone marrow-derived mesenchymal stem cells (BM-MSCs) undergoing osteogenic differentiation. Released nucleotides acting via ionotropic P2X7 and metabotropic P2Y purinoceptors sensitive to ATP and UDP, respectively, control the osteogenic commitment of BM-MSCs and, thus, bone growth and remodelling. Yet, this mechanism is impaired in post-menopausal (Pm)-derived BM-MSCs, mostly because NTPDase3 overexpression decreases the extracellular accumulation of nucleotides below the levels required to activate plasma membrane-bound P2 purinoceptors.

Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives.

Nitrocatechols are the standard pharmacophore to develop potent tight-binding inhibitors of catechol -methyltransferase (COMT), which can be used as coadjuvant drugs to manage Parkinson's disease. Tolcapone is the most potent drug of this class, but it has raised safety concerns due to its potential to induce liver damage. Tolcapone-induced hepatotoxicity has been attributed to the nitrocatechol moiety; however, other nitrocatechol-based COMT inhibitors, such as entacapone, are safe and do not damage the liver.

2,4,5-Triaminopyrimidines as blue fluorescent probes for cell viability monitoring: synthesis, photophysical properties, and microscopy applications.

Monitoring cell viability is critical in cell biology, pathology, and drug discovery. Most cell viability assays are cell-destructive, time-consuming, expensive, and/or hazardous. Herein, we present a series of newly synthesized 2,4,5-triaminopyrimidine derivatives able to discriminate between live and dead cells.

Molecular pathways underlying sympathetic autonomic overshooting leading to fear and traumatic memories: looking for alternative therapeutic options for post-traumatic stress disorder.

The sympathoadrenal medullary system and the hypothalamic-pituitary-adrenal axis are both activated upon stressful events. The release of catecholamines, such as dopamine, norepinephrine (NE), and epinephrine (EPI), from sympathetic autonomic nerves participate in the adaptive responses to acute stress. Most theories suggest that activation of peripheral β-adrenoceptors (β-ARs) mediates catecholamines-induced memory enhancement.

Glucose may Contribute to Retrieval and Reconsolidation of Contextual Fear Memory Through Hippocampal Nr4a3 and Bdnf mRNA Expression and May Act Synergically with Adrenaline.

Adrenaline (Ad) and glucose released into the bloodstream during stress may strengthen contextual fear memory. However, no previous studies have detached the effects of glucose from Ad in this paradigm. Using Ad-deficient mice, we aimed to evaluate the effect of glucose on contextual fear memory when endogenous Ad is absent.

The Carcinogenic Potential of Bisphenol A in the Liver Based on Transcriptomic Studies.

Bisphenol A (BPA) is an environmental toxin widely used in the production of polycarbonate plastics. A correlation exists between BPA tissue contamination and the occurrence of pathological conditions, including cancer. First-passage detoxification of high BPA amounts in the liver promotes hepatotoxicity and morphological alterations of this organ, but there is a lack of knowledge about the molecular mechanisms underlying these phenomena.

Phase angle values and ultra-processed food consumption are associated with changes in oxidative stress in inflammatory bowel disease patients.

Background & Aims: Changes in dietary habits including increased intake of refined sugars and fats and decreased intake of fiber have been suggested as potential risk factors for the development of inflammatory bowel diseases (IBD). Bioelectrical impedance analysis-derived phase angle (PhA) has been gaining attention in the clinical evaluation of nutritional status. In this study, we for the first time investigated the relationship of PhA and ultra-processed food intake with oxidative stress, body composition and biochemical parameters in adult patients with IBD.