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The burden of hepatotoxicity on the pharmaceutical industry
More than 600 drugs have been associated with hepatotoxicity. The clinical picture is diverse, even for the same drug when given to different patients. The manifestations range from mild, asymptomatic changes in serum transaminases, which occur at a relatively high frequency with a number of drugs, to fulminant hepatic failure, which although rare, is potentially life threatening and may necessitate a liver transplant (Park et al., 2005).
From a pharmaceutical viewpoint toxicology plays a major role during early drug development, from the initial pre-clinical development of lead compounds through to the late clinical evaluation (phase III trials). Between 1992 and 2002, 43%, 25%, and 35% of drugs undergoing Phase I, II, and III studies, respectively, were terminated due to the development of mostly hepatic injury (Schuster et al., 2005). Also, the most common cause of drug attrition is drug-induced liver injury and between 1992 and 2002, 27% of market withdrawals in the United States and the European Union were due to hepatotoxicity (Lasser et al., 2002; Schuster et al., 2005). The pharmaceutical industry spends more than US$ 20 billion on drug discovery and development per year, with approximately one fifth of this amount is being used in initial screening assays and toxicity testing. To alleviate this financial burden, knowledge concerning the early events in drug-induced toxicity is required to aid in the decision-making processes during the development of new therapeutic agents (Hakimelahi and Kodarahmi, 2005). It is desirable to detect toxicity as early as possible, preferably during the pre-clinical phase, which will aid lead optimisation and subsequently increase the successful output of the entire process. Boosting the output from drug development programs is a necessity as there is a global need for faster drug development and nowhere is this more urgent than in the pharmaceutical field of antibiotics. Resistance to currently available antibiotics is rising and the arsenal of drugs seems to be shrinking as the development of novel antibiotics is not able to keep up with the increasing rate of microbial resistance (Livermore, 2004; Finch and Hunter, 2006; Baiden et al., 2010). Market withdrawals due to hepatotoxicity of antibiotics like Temafloxacin and Trovafloxacin (Peters, 2005) are only contributing to the problem.
Toxicity testing during preclinical drug development is intended to identify target tissues and then assess potential risks prior to introduction of new molecular entities into the human population. The standard regimen is testing at different doses in at least two species of animals, one rodent (rats or mice) and one non-rodent (dogs, nonhuman primates, minipigs or rabbits) for at least two weeks of repeated dosing. Although experience has shown that this regimen “works” most of the time, in many cases hepatotoxicity is detected later in animal toxicity studies or clinical trials (Ballet, 1997). However, animal testing is financially burdensome and because hundreds of compounds are synthesized each year, the cost of animal testing, which may exceed several million dollars to test a single substance for safety assessment, needs to be reduced (Davila et al., 1998).
Chapter 1: Literature review
1.1. Introduction.
1.2. Safety evaluation
1.3. The burden of hepatotoxicity on the pharmaceutical industry
1.4. Hepatotoxicity .
1.5. Molecular mechanisms of hepatotoxicity
1.6. Need for improved cell-based hepatotoxicity screening
1.7. Model hepatotoxin
1.8. Hepatoprotective agent
1.9. Research topic
1.10. Aims of the study
Chapter 2: In Vitro Procedure
2.1. Introduction
2.2. Methods
Chapter 3: In Vitro Cytotoxicity
3.1. Background
3.2. Methods
3.3. Results
3.4. Discussion
Chapter 4: Phase I metabolism
4.1. Background .
4.2. Methods
4.4. Discussion
Chapter 5: Oxidative Stress .
5.1. Background
5.2. Methods
5.3. Results.
Chapter 6: Mitochondrial Toxicity
Chapter 7: Modes of Cell Death ..
