Preclinical development

Résumé

In drug development, preclinical development, also termed preclinical studies or nonclinical studies, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals. The main goals of preclinical studies are to determine a starting, safe dose for first-in-human study and assess potential toxicity of the product, which typically include new medical devices, prescription drugs, and diagnostics. Companies use stylized statistics to illustrate the risks in preclinical research, such as that on average, only one in every 5,000 compounds that enters drug discovery to the stage of preclinical development becomes an approved drug. Types of preclinical research Each class of product may undergo different types of preclinical research. For instance, drugs may undergo pharmacodynamics (what the drug does to the body) (PD), pharmacokinetics

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https://en.wikipedia.org/wiki/Preclinical_development

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Cardiac ablation, How Contact Force influences lesion quality

Olivier Frémont

Cardiac ablation is a worldwide accepted minimally invasive procedure to treat Atrial Fibrillation (AF). It consists in creating lesions with a catheter in the cardiac tissue in order to cut off specific electrical pathways. During this project, based on preclinical studies, we investigated and modeled the lesion formation process. This led first to identify and quantify the different mechanisms which take place in the heating process. The model developed gave rise to a Lesion Depth Index to quantify the lesion depth based on clinical parameters used to treat patient: Force Power and Duration. Another part of this project was the analysis of the clinical study EFFICAS 1 focused on the local outcome of the Pulmonary Veins Isolation (PVI). Combining the lesion depth model with the clinical analysis permitted to upgrade the analysis and confirmed that the model developed was relevant for clinical analysis. Moreover, this clinical study, allowed us to discover that the smallest lesion performed in a given microscopic area is a key predictor for isolation defect in PVI. Therefore, we showed that performing transmural ablation at the first shot is essential for a good PVI.

2010

Chargement

Molecular imaging advances our understanding of cellular and molecular functions within complex biological systems. The development of novel imaging probes that can be applied to answer fundamental biological questions, diagnose and monitor disease progression and the efficacy of therapy in vivo is essential to the field of molecular imaging. Bioluminescence imaging is a powerful technique that allows to study and follow biological processes of interest noninvasively in real-time in living animals. Activatable bioluminescent probes can be designed according to the target of interest and can provide imaging signal in response to the specific stimuli. A strategy called "caged luciferin" can be used to design new bioluminescent probes for imaging of enzymatic activity, the presence of small molecules or metabolite uptake in vivo. In Chapter 1 we present an overview of bioluminescence imaging, with a focus on firefly luciferase-luciferin system. The caged luciferin approach is discussed and examples of existing caged luciferin probes are presented. In Chapter 2 we describe the development of a bioluminescent probe for imaging of bacterial nitroreductase activity and show the potential for its application in different areas of research. Bacterial nitroreductases have been widely utilized in the gene-directed enzyme prodrug therapy (GDEPT) approach for cancer therapy that reached clinical trials. However, both preclinical and clinical development of NTR-based GDEPT systems has been hampered by the lack of imaging tools that allow in vivo evaluation of transgene expression. We developed the NTR caged luciferin (NCL) probe and demonstrated its application for sensitive bioluminescence imaging of NTR in vitro, in bacteria and cancer cells, as well as in vivo in mouse models of bacterial infection and NTR-expressing tumor xenografts. We anticipate that this probe would significantly accelerate the development of cancer therapy approaches based on GDEPT and other fields where evaluation of NTR expression is important. In Chapter 3 we describe the development of a bioluminescent probe for imaging of hydrogen sulfide (H2S) using the caged luciferin approach. The objective of the research was to develop a probe that can detect endogenously produced H2S noninvasively in real-time in living animals. We present a series of caged luciferin probes that were evaluated on their ability to rapidly and selectively detect H2S in in vitro assays, in cells and in bacterial culture. The two selected probes were applied for imaging of exogenous H2S in the gastrointestinal tract in living mice. We anticipate further applications of the best performing probe (Az-CL) for imaging of H2S production by gut microbiota in mice. In Chapter 4 we present the overall conclusion followed by the outlook and future perspectives.

EPFL2016

Chargement

Monitoring tumor response to radiation therapy with longitudinal and multimodal molecular imaging

Jessica Perez

Purpose: Metabolic changes induced by radiation therapy (RT) provide a biological measure of tumor response to treatment beyond anatomic changes. In this preclinical study we investigated these changes through longitudinal monitoring of tumor response to varying doses of RT with 18F-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET) and Computed Tomography (CT), as well as bioluminescence imaging (BLI). We sought to establish the metabolic alterations in irradiated tumors at early timepoints following treatment. Materials & Methods: Human HT-29 colon carcinoma cells were inoculated subcutaneously on both sides of the back of nude mice. Tumors were grown for two or three weeks. One tumor per animal was treated with 10 or 20 Gy of RT on day 0. The first ten mice were imaged with both FDG-PET and CT on day -1, 1, 3, 9, and 14. The other 10 mice were imaged with BLI once a week during tumor growth and on the same days as the PET-CT study. These findings were correlated with histology. Results: At the beginning of treatment tumors exhibited low FDG uptake. The volume of the treated tumors (TT) determined by CT images, remained stable or decreased (for dose of 20 Gy), whereas the untreated tumors (UT) continued growing. Surprisingly, 9 days after RT, the FDG-uptake increased in the TT and remained low in the UT. We observed a clear decrease in BLI signal in TTs appearing also 9 days after RT. Conclusion: We have applied preclinical imaging and radiotherapy methods to study tumor response to treatment. The surprising rise in FDG uptake at day 9 after RT could be the result of several mechanisms including in inflammation, that still remains to be determined with immunohistochemistry. This study raises the possibility of FDG PET producing false negatives for early response. The preliminary data reported here will be used to establish future technical and biological approaches towards monitoring cancer therapies

2010

Chargement

EPFL2016

Monitoring tumor response to radiation therapy with longitudinal and multimodal molecular imaging

Jessica Perez

2010