Selective COX-2 inhibitors were developed to minimise the adverse gastrointestinal effects seen with conventional NSAIDs and have provided effective pain relief for millions of arthritis patients. Long-term, high dosage use of some COX-2 inhibitors, however, was found to be associated with an increased risk of heart attacks and strokes, resulting in drug withdrawals. A clearer understanding of the mechanisms underlying the cardiovascular effects associated with COX-2 inhibitors would allow better risk/benefit assessment and could possibly lead to the development of safer inhibitors.
Researchers from the University of California, Davis and Beijing University have now shown that, in mice, oral administration of rofecoxib for 3 months leads to a more than 120-fold increase in the regulatory lipid, 20-hydroxyeicosatetraenoic acid (20-HETE) which correlates with a significantly shorter tail bleeding time. Further studies suggested that inhibition of COX-2-mediated 20-HETE degradation by rofecoxib may, at least in part, explain the increase in blood levels and shortened bleeding time and may also contribute to the cardiovascular side effects seen with rofecoxib. Although the relative importance of COX-2 in the metabolism of 20-HETE in man has not yet been determined, if it proves to be as important as in mice, blood levels of 20-HETE may be a good predictor of which patients are at higher risk of heart attack or stroke.
Drug-induced liver injury (DILI) is the most frequent cause of acute liver failure in the US and a major obstacle in the development of new medicines. It is therefore not surprising that prediction of liver toxicity is of considerable interest to healthcare professionals and drug companies alike.
The partnership supports the FDA’s Critical Path Initiative, which aims to reduce the time taken to develop and approve safe and effective medicines, and two FDA scientists will join the scientific advisory board for the project.
Entelos will use its clinically validated PhysioLab biosimulation platform to build a mathematical model of liver function using information from a variety of sources, incorporating The Hamner’s expertise in liver injury and systems biology. Additional important information will be supplied through Hamner research programs employing novel liver-derived cell models and special metabolism studies made possible by a new Hamner metabolomics laboratory. The objective of the collaboration is to develop a virtual liver that will account for the effects of genetic variations and other factors, such as patient sex, age, behavioural characteristics and environmental influences. In parallel, virtual rodents will be developed that will provide an improved means by which to evaluate preclinical drug effects and mechanisms of liver injury across species.
If successful, the platform will have many potential uses, including guiding the development of new diagnostic tests and new ways to test drug safety in the laboratory.