Ion Channel Safety Issues in Drug Development

2006 ◽  
pp. 444-465 ◽  
Author(s):  
Armando A. Lagrutta ◽  
Joseph J. Salata
Keyword(s):  
Drug Development ◽  
Ion Channel ◽  
Safety Issues

Evaluation of drug-mediated arrhythmic changes in spontaneous beating cardiomyocytes by AFM

The Analyst ◽  
2016 ◽  
Vol 141 (22) ◽  
pp. 6303-6313 ◽  
Author(s):  
A. T. Chen ◽  
S. Zou
Keyword(s):  
Drug Development ◽  
Ion Channel ◽  
Channel Effects

An AFM-based approach to investigate compound-induced ion channel effects in cardiomyocytes for pre-screening drug development.

scholarly journals Cell-based approaches in drug development – a concise review

2020 ◽  
Vol 8 (1) ◽  
pp. 44-49
Author(s):  
Ievgeniia Kocherova ◽  
Bartosz Kempisty ◽  
Greg Hutchings ◽  
Lisa Moncrieff ◽  
Claudia Dompe ◽  
...  
Keyword(s):  
Drug Development ◽  
Development Process ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Cytotoxic Effects ◽  
Safety Issues ◽  
Third Phase ◽  
Concise Review

AbstractIn vitro models represent an alternative technique to in vivo or ex vivo studies in the drug development process. Cell-based assays are used to measure the level of proliferation and toxicity, as well as activation of signalling pathways and changes in morphology in cultivated cells. The studies conducted in vitro are aimed to estimate the newly synthesised drugs’ ability to permeate biological barriers and exert their therapeutic or cytotoxic effects. However, more than half of all studied drugs fail in the second or third phase of clinical trials due to a lack of confirmed efficacy. About a third of drugs fail because of safety issues, such as unacceptable levels of toxicity. To reduce attrition level in drug development, it is crucial to consider the implementation of translational phenotypic assays as well as to decipher various molecular mechanisms of action for new molecular entities. In this review, we summarise the existing cell-based methods most frequently used in the studies on drugs, taking into account their advantages and drawbacks.Running title: Cell-based approaches in drug development

scholarly journals Investigative safety strategies to improve success in drug development

2016 ◽  
Vol 2 (1) ◽  
pp. 2 ◽  
Author(s):  
Franck Atienzar ◽  
Annie Delaunois ◽  
Frédéric Brouta ◽  
Miranda Cornet ◽  
Renaud Fleurance ◽  
...  
Keyword(s):  
Drug Development ◽  
Hazard Identification ◽  
Attrition Rate ◽  
Drug Discontinuation ◽  
Clinical Safety ◽  
In Vivo Models ◽  
Safety Issues ◽  
Organ Systems ◽  
Safety Strategies

Understanding and reducing attrition rate remains a key challenge in drug development. Preclinical and clinical safety issues still represent about 40% of drug discontinuation, of which cardiac and liver toxicities are the leading reasons. Reducing attrition rate can be achieved by various means, starting with a comprehensive evaluation of the potential safety issues associated to the primary target followed by an evaluation of undesirable secondary targets. To address these risks, a risk mitigation plan should be built at very early development stages, using a panel of in silico, in vitro, and in vivo models. While most pharmaceutical companies have developed robust safety strategies to de-risk genotoxicity and cardiotoxicity issues, partly driven by regulatory requirements; safety issues affecting other organs or systems, such as the central nervous system, liver, kidney, or gastro-intestinal system are less commonly addressed during early drug development. This paper proposes some de-risking strategies that can be applied to these target organ systems, including the use of novel biomarkers that can be easily integrated in both preclinical and clinical studies. Experiments to understand the mechanisms’ underlying toxicity are also important. Two examples are provided to demonstrate how such mechanistic studies can impact drug development. Novel trends in investigative safety are reviewed, such as computational modeling, mitochondrial toxicity assessment, and imaging technologies. Ultimately, understanding the predictive value of non-clinical safety testing and its translatability to humans will enable to optimize assays in order to address the key objectives of the drug discovery process, i.e., hazard identification, risk assessment, and mitigation.

NSAIDs' Safety Issues May Spur Clinical Change

2005 ◽  
Vol 36 (9) ◽  
pp. 50-51
Author(s):  
BRUCE JANCIN
Keyword(s):  
Clinical Change ◽  
Safety Issues
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