943-P: Role of Model-Informed Drug Development in Confirming Additional Clinical Benefits of Dulaglutide

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 943-P
Author(s):  
LAI-SAN THAM ◽  
JEANNE GEISER ◽  
CHENG CAI TANG ◽  
KAREN SCHNECK ◽  
DAVID COX ◽  
...  
Keyword(s):  
Drug Development ◽  
Clinical Benefits

Redox State in Atrial Fibrillation Pathogenesis and Relevant Therapeutic Approaches

2019 ◽  
Vol 26 (5) ◽  
pp. 765-779 ◽  
Author(s):  
Alexios S. Antonopoulos ◽  
Athina Goliopoulou ◽  
Evangelos Oikonomou ◽  
Sotiris Tsalamandris ◽  
Georgios-Angelos Papamikroulis ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Clinical Studies ◽  
Redox State ◽  
Redox Balance ◽  
Therapeutic Approaches ◽  
Critical Determinant ◽  
Electrophysiological Properties ◽  
Antioxidant Agents ◽  
Clinical Benefits

Background: Myocardial redox state is a critical determinant of atrial biology, regulating cardiomyocyte apoptosis, ion channel function, and cardiac hypertrophy/fibrosis and function. Nevertheless, it remains unclear whether the targeting of atrial redox state is a rational therapeutic strategy for atrial fibrillation prevention. Objective: To review the role of atrial redox state and anti-oxidant therapies in atrial fibrillation. Method: Published literature in Medline was searched for experimental and clinical evidence linking myocardial redox state with atrial fibrillation pathogenesis as well as studies looking into the role of redoxtargeting therapies in the prevention of atrial fibrillation. Results: Data from animal models have shown that altered myocardial nitroso-redox balance and NADPH oxidases activity are causally involved in the pathogenesis of atrial fibrillation. Similarly experimental animal data supports that increased reactive oxygen / nitrogen species formation in the atrial tissue is associated with altered electrophysiological properties of atrial myocytes and electrical remodeling, favoring atrial fibrillation development. In humans, randomized clinical studies using redox-related therapeutic approaches (e.g. statins or antioxidant agents) have not documented any benefits in the prevention of atrial fibrillation development (mainly post-operative atrial fibrillation risk). Conclusion: Despite strong experimental and translational data supporting the role of atrial redox state in atrial fibrillation pathogenesis, such mechanistic evidence has not been translated to clinical benefits in atrial fibrillation risk in randomized clinical studies using redox-related therapies.

scholarly journals Cathepsin L plays a key role in SARS-CoV-2 infection in humans and humanized mice and is a promising target for new drug development

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Miao-Miao Zhao ◽  
Wei-Li Yang ◽  
Fang-Yuan Yang ◽  
Li Zhang ◽  
Wei-Jin Huang ◽  
...  
Keyword(s):  
Drug Development ◽  
Cathepsin L ◽  
Human Cells ◽  
New Drugs ◽  
Disease Course ◽  
Promising Target ◽  
First Time

AbstractTo discover new drugs to combat COVID-19, an understanding of the molecular basis of SARS-CoV-2 infection is urgently needed. Here, for the first time, we report the crucial role of cathepsin L (CTSL) in patients with COVID-19. The circulating level of CTSL was elevated after SARS-CoV-2 infection and was positively correlated with disease course and severity. Correspondingly, SARS-CoV-2 pseudovirus infection increased CTSL expression in human cells in vitro and human ACE2 transgenic mice in vivo, while CTSL overexpression, in turn, enhanced pseudovirus infection in human cells. CTSL functionally cleaved the SARS-CoV-2 spike protein and enhanced virus entry, as evidenced by CTSL overexpression and knockdown in vitro and application of CTSL inhibitor drugs in vivo. Furthermore, amantadine, a licensed anti-influenza drug, significantly inhibited CTSL activity after SARS-CoV-2 pseudovirus infection and prevented infection both in vitro and in vivo. Therefore, CTSL is a promising target for new anti-COVID-19 drug development.

scholarly journals The Role of Network Science in Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1045
Author(s):  
Marta B. Lopes ◽  
Eduarda P. Martins ◽  
Susana Vinga ◽  
Bruno M. Costa
Keyword(s):  
Personalized Medicine ◽  
Drug Development ◽  
Information Flow ◽  
Clinical Studies ◽  
Network Science ◽  
Cancer Genomics ◽  
High Dimensional ◽  
Network Discovery ◽  
Software Implementations

Network science has long been recognized as a well-established discipline across many biological domains. In the particular case of cancer genomics, network discovery is challenged by the multitude of available high-dimensional heterogeneous views of data. Glioblastoma (GBM) is an example of such a complex and heterogeneous disease that can be tackled by network science. Identifying the architecture of molecular GBM networks is essential to understanding the information flow and better informing drug development and pre-clinical studies. Here, we review network-based strategies that have been used in the study of GBM, along with the available software implementations for reproducibility and further testing on newly coming datasets. Promising results have been obtained from both bulk and single-cell GBM data, placing network discovery at the forefront of developing a molecularly-informed-based personalized medicine.

Drug-induced cardiac toxicity: emphasizing the role of electrocardiography in clinical research and drug development

2004 ◽  
Vol 37 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Ihor Gussak ◽  
Jeffrey Litwin ◽  
Robert Kleiman ◽  
Scott Grisanti ◽  
Joel Morganroth
Keyword(s):  
Drug Development ◽  
Clinical Research ◽  
Cardiac Toxicity ◽  
Drug Induced

The Role of Surgery in IDH-Wild-Type Lower-Grade Gliomas: Threshold at a High Extent of Resection Should be Pursued

Neurosurgery ◽  
2021 ◽  
Author(s):  
Peng Wang ◽  
Chen Luo ◽  
Peng-jie Hong ◽  
Wen-ting Rui ◽  
Shuai Wu
Keyword(s):  
Cox Regression ◽  
Progression Free Survival ◽  
Extent Of Resection ◽  
Lower Grade ◽  
Wild Type ◽  
Cox Regression Analysis ◽  
Kaplan Meier ◽  
Lower Grade Glioma ◽  
Clinical Benefits

Abstract BACKGROUND While maximizing extent of resection (EOR) is associated with longer survival in lower-grade glioma (LGG) patients, the number of cases remains insufficient in determining a EOR threshold to elucidate the clinical benefits, especially in IDH-wild-type LGG patients. OBJECTIVE To identify the effects of EOR on the survival outcomes of IDH-wild-type LGG patients. METHODS IDH-wild-type LGG patients were retrospectively reviewed. The effect of EOR and other predictor variables on overall survival (OS) and progression-free survival (PFS) was analyzed using Cox regression models and the Kaplan-Meier method. RESULTS A total of 94 patients (median OS: 48.9 mo; median follow-up: 30.6 mo) were included in this study. In the multivariable Cox regression analysis, postoperative residual volume was associated with prolonged OS (HR = 2.238; 95% confidence interval [CI], 1.130-4.435; P = .021) and PFS (HR = 2.075; 95% CI, 1.113-3.869; P = .022). Thresholds at a minimum EOR of 97.0% or a maximum residue of 3.0 cm3 were necessary to impact OS positively. For the telomerase reverse transcriptase (TERT)p-wild-type group, such an association was absent. Significant differences in survival existed between the TERTp-wild-type and mutant patients who underwent relatively incomplete resections (residual ≥2.0 cm3 + TERTp wild type: median OS of 62.6 mo [95% CI: 39.7-85.5 mo]; residual ≥2.0 cm3 + TERTp mutant: median OS of 20.0 mo [95% CI:14.6-25.4 mo]). CONCLUSION Our results support the core role of maximal safe resection in the treatment of IDH-wild-type LGGs, especially for IDH-wild-type + TERTp-mutant LGGs. Importantly, the survival benefits of surgery could only be elucidated at a high EOR cut-off point.

scholarly journals ROLE OF EFFECTIVE PROJECT MANAGEMENT IN REDUCING DRUG DEVELOPMENT COST

2017 ◽  
Vol 10 (3) ◽  
pp. 53
Author(s):  
Faisal B A Zaidi ◽  
Salma Ahmed ◽  
Munish Makkad
Keyword(s):  
Project Management ◽  
Drug Development ◽  
Site Selection ◽  
Late Phase ◽  
Critical Role ◽  
Project Manager ◽  
Development Cost ◽  
The Cost ◽  
Patient Enrollment

ABSTRACTPharmaceuticals are passing through the difficult phase due to increasing numbers of patents expiry along with increasing cost of drug development.Protocol design, regulatory cycle time, site selection, patient enrollment and monitoring are some of the cost contributing elements for late phaseclinical trials. This paper applies the principles of project management and suggests means to reduce the cost of late phase drug development. It alsothrows light on the critical role that a project manager can play in overall drug development process.Keywords: Cost of drug development, Effective project management, Reduction in cost of drug development.

scholarly journals Towards Academic Drug Development Guidelines

2019 ◽  
Author(s):  
Christopher Southan
Keyword(s):  
Drug Development ◽  
Success Rate ◽  
Case Studies ◽  
Small Molecule ◽  
Research Productivity ◽  
Medicinal Chemistry ◽  
Academic Development ◽  
Commercial Development ◽  
Small Molecule Drug

This report covers academic small-molecule drug development with a view to distilling guidelines. The first section covers research productivity feeding into commercial development before reviewing the literature on statistics of academic development It then considers differences between probes and drugs before discussing the role of author guidelines in medicinal chemistry and pharmacology journals. Resources for comprehensive compound and target cross-checking are then covered followed by comparisons between public and commercial databases including case studies of selected compounds. It concludes with an outline of new scientific developments that could increase the success rate of academic drug development.

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