Search results for "regulator"
showing 10 items of 1009 documents
Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Metformin Hydrochloride.
2021
Abstract Data are examined regarding possible waiver of in vivo bioequivalence testing (i.e. biowaiver) for approval of metformin hydrochloride (metformin) immediate-release solid oral dosage forms. Data include metformin's Biopharmaceutics Classification System (BCS) properties, including potential excipient interactions. Metformin is a prototypical transporter-mediated drug and is highly soluble, but only 50% of an orally administered dose is absorbed from the gut. Therefore, metformin is a BCS Class III substance. A BCS-based approval approach for major changes to marketed products and new generics is admissible if test and reference dosage forms have the identical active pharmaceutical …
Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Cephalexin Monohydrate.
2019
Literature data and results of experimental studies relevant to the decision to allow waiver of bioequivalence studies in humans for the approval of immediate release solid oral dosage forms containing cephalexin monohydrate are presented. Solubility studies were performed in accordance with the current biowaiver guidelines of the Food and Drug Administration, World Health Organization and European Medicines Agency, taking the degradation at some pH values into consideration. Together with solubility and permeability data for cephalexin monohydrate from the literature, it was demonstrated to be a Biopharmaceutics Classification System Class 1 drug. The pharmacokinetic behavior, results of b…
Toward a Rationale for the PTC124 (Ataluren) Promoted Readthrough of Premature Stop Codons: A Computational Approach and GFP-Reporter Cell-Based Assay
2014
The presence in the mRNA of premature stop codons (PTCs) results in protein truncation responsible for several inherited (genetic) diseases. A well-known example of these diseases is cystic fibrosis (CF), where approximately 10% (worldwide) of patients have nonsense mutations in the CF transmembrane regulator (CFTR) gene. PTC124 (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)-benzoic acid), also known as Ataluren, is a small molecule that has been suggested to allow PTC readthrough even though its target has yet to be identified. In the lack of a general consensus about its mechanism of action, we experimentally tested the ability of PTC124 to promote the readthrough of premature termination c…
Inferring slowly-changing dynamic gene-regulatory networks
2015
Dynamic gene-regulatory networks are complex since the interaction patterns between their components mean that it is impossible to study parts of the network in separation. This holistic character of gene-regulatory networks poses a real challenge to any type of modelling. Graphical models are a class of models that connect the network with a conditional independence relationships between random variables. By interpreting these random variables as gene activities and the conditional independence relationships as functional non-relatedness, graphical models have been used to describe gene-regulatory networks. Whereas the literature has been focused on static networks, most time-course experi…
Hub-Centered Gene Network Reconstruction Using Automatic Relevance Determination
2012
Network inference deals with the reconstruction of biological networks from experimental data. A variety of different reverse engineering techniques are available; they differ in the underlying assumptions and mathematical models used. One common problem for all approaches stems from the complexity of the task, due to the combinatorial explosion of different network topologies for increasing network size. To handle this problem, constraints are frequently used, for example on the node degree, number of edges, or constraints on regulation functions between network components. We propose to exploit topological considerations in the inference of gene regulatory networks. Such systems are often…
Pathway network inference from gene expression data
2014
[EN] Background: The development of high-throughput omics technologies enabled genome-wide measurements of the activity of cellular elements and provides the analytical resources for the progress of the Systems Biology discipline. Analysis and interpretation of gene expression data has evolved from the gene to the pathway and interaction level, i.e. from the detection of differentially expressed genes, to the establishment of gene interaction networks and the identification of enriched functional categories. Still, the understanding of biological systems requires a further level of analysis that addresses the characterization of the interaction between functional modules. Results: We presen…
PED Mediates AKT-Dependent Chemoresistance in Human Breast Cancer Cells
2005
Abstract Killing of tumor cells by cytotoxic therapies, such as chemotherapy or gamma-irradiation, is predominantly mediated by the activation of apoptotic pathways. Refractoriness to anticancer therapy is often due to a failure in the apoptotic pathway. The mechanisms that control the balance between survival and cell death in cancer cells are still largely unknown. Tumor cells have been shown to evade death signals through an increase in the expression of antiapoptotic molecules or loss of proapoptotic factors. We aimed to study the involvement of PED, a molecule with a broad antiapoptotic action, in human breast cancer cell resistance to chemotherapeutic drugs–induced cell death. We show…
Genetic ablation of macrohistone H2A1 leads to increased leanness, glucose tolerance and energy expenditure in mice fed a high-fat diet.
2015
Contains fulltext : 155347.pdf (Publisher’s version ) (Closed access) BACKGROUND/OBJECTIVES: In the context of obesity, epigenetic mechanisms regulate cell-specific chromatin plasticity, perpetuating gene expression responses to nutrient excess. MacroH2A1, a variant of histone H2A, emerged as a key chromatin regulator sensing small nutrients during cell proliferation and differentiation. Mice genetically ablated for macroH2A1 (knockout (KO)) do not show overt phenotypes under a standard diet. Our objective was to analyse the in vivo role of macroH2A1 in response to nutritional excess. METHODS: Twelve-week-old whole-body macroH2A1 KO male mice were given a high-fat diet (60% energy from lard…
The Strategic Use of Innovation to Influence Environmental Policy: Taxes versus Standards
2015
Abstract This paper evaluates the strategic behavior of a polluting monopolist to influence environmental policy, either with taxes or with standards, comparing two alternative policy games. The first of the games assumes that the regulator commits to an ex-ante level of the policy instrument. The second one is the time-consistent policy game. We find that the strategic behavior of the firm is welfare improving and leads to more environmental innovation than under regulatory commitment if a tax is used to control pollution. However, the contrary occurs if an emission standard is used. Under commitment, it is shown that both policy instruments are equivalent. We conclude that the optimal env…
IL-12 family members in experimental colitis
2008
Interleukin (IL)-12 p35/p40 is a heterodimeric cytokine that plays an important role in T helper (Th) cell polarization and Th1 T-cell differentiation. Recent findings have shown that both p35 and p40 can form other cytokines with different proteins (IL-23: p19/p40; IL-35: p35/EBI3). Furthermore, the cytokine IL-27 (EBI3/p28) has been identified as a member of the IL-12 family. Here, we discuss the recent findings on the role of IL-12 family members in experimental colitis. In particular, the role of IL-23 as a master regulator of effector T-cell activation is highlighted. These findings have important implications for the design of new therapeutic approaches in chronic intestinal inflammat…