7196 research outputs found
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Novel roles of cardiac-derived erythropoietin in cardiac development and function.
No full textThe role of erythropoietin (EPO) has extended beyond hematopoiesis to include cytoprotection, inotropy, and neurogenesis. Extra-renal EPO has been reported for multiple tissue/cell types, but the physiological relevance remains unknown. Although the EPO receptor is expressed by multiple cardiac cell types and human recombinant EPO increases contractility and confers cytoprotection against injury, whether the heart produces physiologically meaningful amounts of EPO in vivo is unclear. We show a distinct circadian rhythm of cardiac EPO mRNA expression in adult mice and increased mRNA expression during embryogenesis, suggesting physiological relevance to cardiac EPO production throughout life. We then generated constitutive, cardiomyocyte-specific EPO knockout mice driven by the Mlc2v promoter (EPOfl/fl:Mlc2v-cre+/-; EPO). During cardiogenesis, cardiac EPO mRNA expression and cellular proliferation were reduced in EPO hearts. However, in adult EPO mice, total heart weight was preserved through increased cardiom
End points in clinical trials in diffuse large B-cell lymphoma: time for more dialogue?
No full textWe observed lack of clarity and consistency in end point definitions of large randomized clinical trials in diffuse large B-cell lymphoma. These inconsistencies are such that trials might, in fact, address different clinical questions. They complicate interpretation of results, including comparisons across studies. Problems arise from different ways to account for events occurring after randomization including absence of improvement in disease status, treatment discontinuation or the initiation of new therapy. We call for more dialogue between stakeholders to define with clarity the questions of interest and corresponding end points. We illustrate that assessing different end point rules across a range of plausible patient journeys can be a powerful tool to facilitate such a discussion and contribute to better understanding of patient-relevant end points
Development of an experimental dead-end microfiltration layout and process repeatability analysis
No full textThe article covers the instrumentalization and process control of a laboratory scale dead-end microfiltration layout. It focuses on process parameters and their influence on the repeatability of pressure oscillations caused by valve opening. Several filters in sizes between 3.5 cm^2 and 6900 cm^2 were tested and some recommendations suggested for repeatability improvement
Characterization of Surfactant Spheroidal Micelle Structure for Pharmaceutical Applications: A Novel Analytical Framework.
No full textWe introduce an innovative theoretical framework tailored for the analysis of Pair Distribution Function (PDF) data derived from Small-Angle X-ray Scattering (SAXS) measurements of core-shell micelles. The new approach involves the exploitation of the first derivative of the PDF and the derivation of analytical equations to solve the core-shell micelle structure under the hypothesis of a spheroidal shape. These analytical equations enable us to determine the micelle's aggregation number, degree of ellipticity, and contrast in electron density between the core-shell and shell-buffer regions after having determined the whole micelle size and its shell size from the analysis of the first derivative of the PDF. We have formulated an overdetermined system of analytical equations based on the unknowns that characterize the micelle structure. This allows us to establish a Figure of Merit, which is utilized to identify the most reliable solution within the system of equations
Process Mass Intensity (PMI): A holistic analysis in current peptide manufacturing processes, informing sustainability in peptide synthesis
No full textSmall molecule therapeutics represent the majority of FDA-approved drugs. Yet, many attractive targets are poorly tractable by small molecules, generating a need for new therapeutic modalities. Due to their biocompatibility profile and structural versatility, peptide-based therapeutics are potentially a possible solution. Additionally, in the past two decades, advances in peptide design, delivery, formulation and devices have occurred making therapeutic peptides an attractive modality. However, peptide manufacturing is often limited to Solid Phase Peptide Synthesis (SPPS), liquid phase peptide synthesis (LPPS) and to a lesser extent hybrid SPPS/LPPS, with SPPS emerging as a common platform technology for peptide synthesis. SPPS involves the use of excess solvents and reagents which have negative impact on the environment, thus highlighting the need for newer technologies for reduction of environmental footprint.
Herein, twelve American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) member companies with peptide-based therapeutics in their portfolio, have compiled Process Mass Intensity (PMI) metrics to help inform the sustainability efforts in peptide synthesis. This includes PMI assessment on 40 synthetic peptide processes at various development stages in pharma, classified according to development phase. This is the most comprehensive synthetic peptide assessment of environmental metrics. The synthetic peptide manufacturing process was divided into stages (synthesis, purification, isolation) to determine their respective PMI. On average, the synthetic peptide SPPS (PMI ~ 13,000) does not compare favourably with other modalities such as small molecules (PMI median 168−308) and biopharmaceuticals (PMI ∼8300). Revealing that the high PMI for peptide synthesis warrants more environmentally friendly processes in peptide manufacturing
Decentralized clinical trials: scientific considerations through the lens of the estimand framework
No full textWhile the industry and regulators’ interest in decentralized clinical trials (DCTs) is long-standing, the Covid-19 pandemic accelerated and broadened the adoption and experience with these trials. The key idea in decentralization is bringing the clinical trial design, typically on-site, closer to the patient’s experience (on-site or off-site). Thus, potential benefits of DCTs include reducing the burden of participation in trials, broadening access to a more diverse population, or using innovative endpoints collected off-site.
This paper helps researchers to carefully evaluate the added value and the implications of DCTs beyond the operational aspects of their implementation. The proposed approach is to use the ICH E9(R1) estimand framework to guide the strategic decisions around each decentralization component. Furthermore, the framework can guide the process for clinical trialists to systematically consider the implications of decentralization, in turn, for each attribute of the estimand. We illustrate the use of this approach with a fully DCT case study and show that the proposed systematic process can uncover the scientific opportunities, assumptions and potential risks associated with a possible use of decentralization components in the design of a trial. This process can also highlight the benefits of specifying estimand attributes in a granular way. Thus, we demonstrate that bringing a decentralization component into the design will not only impact estimators and estimation but can also correspond to addressing more granular questions, thereby uncovering new target estimand
Advancing pharmacogenetics research in Africa: the "Project Africa GRADIENT" initiative.
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Non-clinical safety assessment of novel drug modalities: Genome safety perspectives on viral-, nuclease- and nucleotide-based gene therapies.
No full textGene therapies have emerged as promising treatments for various conditions including inherited diseases as well as cancer. Ensuring their safe clinical application requires the development of appropriate safety testing strategies. Several guidelines have been provided by health authorities to address these concerns. These guidelines state that non-clinical testing should be carried out on a case-by-case basis depending on the modality. This review focuses on the genome safety assessment of frequently used gene therapy modalities, namely Adeno Associated Viruses (AAVs), Lentiviruses, designer nucleases and mRNAs. Important safety considerations for these modalities, amongst others, are vector integrations into the patient genome (insertional mutagenesis) and off-target editing. Taking into account the constraints of in vivo studies, health authorities endorse the development of novel approach methodologies (NAMs), which are innovative in vitro strategies for genotoxicity testing. This review provides an overview of NAMs applied to viral and CRISPR/Cas9 safety, including next generation sequencing-based methods for integration site analysis and off-target editing. Additionally, NAMs to evaluate the oncogenicity risk arising from unwanted genomic modifications are discussed. Thus, a range of promising techniques are available to support the safe development of gene therapies. Thorough validation, comparisons and correlations with clinical outcomes are essential to identify the most reliable safety testing strategies. By providing a comprehensive overview of these NAMs, this review aims to contribute to a better understanding of the genome safety perspectives of gene therapies
Design Space and Control Strategy for the Manufacturing of Wet Media Milled Drug Nanocrystal Suspension by Adopting Mechanistic Process Modeling
No full textWet media milling is a fully industrialized technology for the manufacturing of drug-nanocrystal suspensions. This work describes the development of an advanced control strategy and an asso-ciated design space for a manufacturing process at a commercial scale. Full-scale experiments and mechanistic process modeling have been used to establish a physically reasonable control strategy of factors relevant to the quality attributes of the nanocrystal suspension. The design space has been developed based on a mature mechanistic process model of the wet media milling procedure. It presents the process–product attribute relationship between a multidimensional range of measured process parameters and a range of the product-quality attribute mean particle sizes. The control strategy allows for simple, robust, and sound scientific process control as well as the op-erational flexibility of the suspension batch size. This is an industrial case study of control strategy and design-space definition with the crucial contribution of mechanistic process modeling for an intended commercial manufacturing process