spacer
home > ebr > spring 2009 > in vivo alternatives
PUBLICATIONS
European Biopharmaceutical Review

In Vivo Alternatives

The development process of a new drug is long and expensive (1). The main causes of drug withdrawal in advanced preclinical or clinical phases are toxicological effects, especially cardiotoxic and hepatotoxic (2). Cardiotoxicity is often described as the risk of causing a ventricular arrhythmia called Torsade de Pointes (TdP) through the alteration of the electrocardiogram (ECG) by prolonging the QT interval. Heart toxicological studies have proved the existence of a strong correlation between drugs known to induce a QT prolongation in humans and the appearance of an arrhythmia type 2:1 in zebrafish (3,4). The main protein involved in drug-induced QT prolongation is a potassium channel encoded by the ether-a-go-go-related gene (ERG), and its homologue in zebrafish can lead to arrhythmia type 2:1 (5). In addition, several other ion channel proteins and regulatory pathways are involved in the process of depolarisation and repolarisation, and they can compensate for the inhibition of ERG. Therefore, a wide spectrum of biological and environmental parameters must be controlled in order to develop an automated system. Nowadays, the predominant technique in early cardiotoxicological screenings is the ‘patch clamp’. This technique measures the voltage current in the cell, revealing fundamental cell mechanisms, such as the probability of channels opening in response to depolarisation of the membrane. Unfortunately, this cellular based technique cannot reproduce the organism environment and has limitations when predicting the biological effect of drugs on heartbeat.

ZEBRAFISH MODEL

The zebrafish (Danio rerio) has become a popular model system to study human diseases and in the drug discovery research field. Since zebrafish embryos are small, transparent and undergo rapid development, in vivo analysis of different structures and dynamic processes, such as the heart, are feasible (6). At day two post-fertilisation (dpf) the zebrafish embryo already shows a functional circulatory system with cardiac tissues and structures analogous to those present in humans (7). Genetic studies have proven that they share common genes with a high degree of homology, involved in determining the heart morphology and its physiological activity (5). These characteristics have been exploited by researchers in developmental processes or disease studies and are powerful tools in understanding common molecular pathways in humans (8,9). Furthermore, the transparency and the ability to generate transgenics with fluorescent reporters have eliminated the need for invasive surgery and enabled an easier visualisation of drug effects in specific organs (10). Still, the development of zebrafish drug screenings has remained challenging in the last decade (11,12).


Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer

During her PhD project in Madrid (CIB-CSIC), Ainhoa Letamendia Urraca studied the role of endoglin in the TGF-beta pathway. This led her to work in the laboratory of Liliana Attisano in the University of Toronto, where she learned a variety of techniques such as protein expression, data analysis, ligand binding assays and microbiology techniques. She also made significant research findings by characterising the cooperation between Wnt and TGF-beta relevant transduction pathways. In 2004, she was offered a position as a research associate in the University of Toronto to collaborate in a small molecules screen project in an attempt to find new proteins involved in the Wnt pathway. At the moment, she holds a position as Project Leader in Biobide, a biotechnological company focused on drug screening services.

Carles Callol Massot is the Scientific Director of Biobide, and is responsible for developing new models of efficacy and safety using zebrafish. Prior to joining Biobide, he focused on studying zebrafish embryological processes involved in heart development at the Gene Expression Laboratory at the Salk Institute. He has been a researcher at the Laboratory of Integrative Biochemistry and Cancer Therapy at the University of Barcelona.

spacer
Ainhoa Letamendia Urraca
spacer
spacer
spacer
Carles Callol Massot
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

ERT Offers First Patient-Administered ECG Assessment for Continuation of Clinical Trials during COVID-19

ERT, a global data and technology company that captures critical endpoint data while minimizing uncertainty and risk in clinical trials, today announced a first-of-its-kind partnership with AliveCor, the leader in AI-based, personal ECG technology. The partnership enables ERT to capture digital cardiac safety data with KardiaMobile 6L, the only FDA-cleared personal ECG for patient-administered 6-lead data collection.
More info >>

White Papers

By Your Side for a Healthier World

West Pharmaceutical Services, Inc.

Every day, injectable drugs are administered to improve the lives of millions of patients around the world. And every day, West is working by your side to design and manufacture drug packaging and delivery systems that will bring our customers’ drugs from concept to the patient more efficiently, reliably and safely. West understands our customers’ challenges and helps with solutions every step of the way, with cutting-edge production technologies, an unmatched expertise in global regulatory compliance, and an ever-growing knowledge base of pharmaceutical drug product testing, development, packaging and delivery. Whether focused on one piece of the process or an end-to-end solution, West is by your side for a healthier world.
More info >>

 
Industry Events

12th World Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology

8-11 February 2021, Vienna, Austria

In continuation of the very successful scientific meetings in Budapest, Paris, Berlin, Florence, Geneva, Barcelona, Malta, Istanbul, Lisbon, Glasgow and Granada, the 12th PBP World will be held in Vienna from 8-11 Feb 2021. This every two year held conference has gained an ever increasing impact among the pharmaceutical scientists: With up to 1000 submitted abstracts and about 1300 participants it has become a well-established major meeting, attracting scientists from all over the world.
More info >>

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement