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Toxicology - Articles and news items
Clinical development costs are rising at an alarming rate. There is a decreasing success rate for new drug candidate approval and the duration of development is increasing. In other words, industry is spending more and getting less from current drug development efforts. In 2010, 21 new drugs were approved in the U.S., the fewest since 2007, as the Food and Drug Administration showed more willingness to delay or reject medicines with potential safety risks1. Along these lines and according to a study conducted by the Biotechnology Industry Organisation and BioMedTracker, the success rate in bringing new drugs to market has fallen. The study looked at drugs moving from early stage Phase I clinical trials to Food and Drug Administration approval between 2004 and 2010. The researchers found that the overall success rate is about one in 10, down from one in five to one in six, seen in reports involving earlier years2.
Toxicology is the study of the harmful interactions between chemicals and biological systems. Man, as well as other animals and plants, is increasingly exposed to a huge variety of chemicals. These range from metals to large complex organic molecules, all of which are potentially toxic. A toxicologist must understand pathology, biochemistry, chemistry and physiology as these disciplines all contribute to the impact of a given chemical’s toxicity. Indeed the multidisciplinary nature of toxicology makes the area of toxicology a challenging yet rewarding area for research and learning. To gain a true understanding of how a chemical can disrupt a biological system and cause toxic consequences is no easy matter.
Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction which accounts for a significant amount of patient suffering, including death. Currently, idiosyncratic DILI is unpredictable and as a result arises late in the drug development process or even post-marketing. The prediction of idiosyncratic DILI based on preclinical or early clinical data is a formidable challenge and this short review will discuss why and how new initiatives in systems biology and dynamic computational simulations can meet this challenge and predict the ‘unpredictable’.
Segregation of molecular mechanisms of genotoxicity and carcinogenicity across human, yeast and Salmonella species
Screening assays for in vitro toxicity are the way to reduce the attrition rates in the preclinical development of new drugs. Here a test battery is presented for screening of genotoxic and carcinogenic compounds by means of VitotoxTM, RadarScreen, and four human liver HepG2 cell lines with two different promoters as well as responsive element (RE) settings in combination with a luminescent read-out. The VitotoxTM assay in Salmonella is a substitute for the Ames test and the RadarScreen assay for in vitro clastogenicity. Moreover, HepG2 assays with RAD51C and Cystatin A promoters, and p53-RE are more predictive for in vivo clastogenicity. The Nrf2-RE can be used for analysis of reactive oxygen species production. The validity of this battery is checked for 62 compounds of an ECVAM list for genotoxicity and for 190 other references or in house drugs.
Neurotoxicology is not a discipline that can expect to be popular in pharmaceutical circles. It is a not unreasonable prejudice amongst people working in drug development that even a suggestion that a candidate drug might be neurotoxic is enough to halt development, or at the least to stimulate a highly motivated search for an alternative. There are several good reasons for this. Firstly, neurotoxicity can be highly disabling and irreversible. Secondly, it is hard to detect (or rather to exclude) via high throughput systems. Thirdly, it is often hard to understand.
Drug discovery relies on massive screening of compound libraries with in vitro cell-based target assays. These pharmacological screens have been well accepted. For in vitro toxicological screening, this privilege has only been obtained for the Ames, chromosomal aberration and eye irritation tests. At the moment, a number of cellular assays for cytotoxicity, genotoxicity, embryotoxicity, cellular metabolic activation processes and endocrine disruption await general acceptance. From that point onwards, tools will become available to identify unwanted pharmacological or toxicological effects at a much earlier stage in the drug development process.
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