| Autor: |
Kennedy, Dianne L., Uhl, Kathleen, Kweder, Sandra L. |
| Předmět: |
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| Zdroj: |
Drug Safety; 2004, Vol. 27 Issue 3, p145-172, 28p |
| Abstrakt: |
Drug-induced torsade de pointes (TdP) has proved to be a significant iatrogenic cause of morbidity and mortality and a major reason for the withdrawal of a number of drugs from the market in recent times. Enzymes that metabolise many of these drugs and the potassium channels that are responsible for cardiac repolarisation display genetic polymorphisms. Anecdotal reports have suggested that in many cases of drug-induced TdP, there may be a concealed genetic defect of either these enzymes or the potassium channels, giving rise to either high plasma drug concentrations or diminished cardiac repolarisation reserve, respectively. The presence of either of these genetic defects may predispose a patient to TdP, a potentially fatal adverse reaction, even at therapeutic dosages of QT-prolonging drugs and in the absence of other risk factors. Advances in pharmacogenetics of drug metabolizing enzymes and pharmacological targets, together with the prospects of rapid and inexpensive genotyping procedures, promise to individualise and improve the benefit/risk ratio of therapy with drugs that have the potential to cause TdP. The qualitative and the quantitative contributions of these genetic defects in clinical clinical cases of TdP are unclear because not all of the patients with TdP are routinely genotyped and some relevant genetic mutations still remain to be discovered. There are regulatory guidelines that recommend strategies aimed at uncovering the risk of TdP associated with new chemical entities during their development. There are also a number of guidelines that recommend integrating pharmacogenetics in this process. This paper proposes a strategy for integrating pharmacogenetics into drug development programmes to optimise association studies correlating genetic traits and endpoints of clinical interest, namely failure of efficacy or development of repolarisation abnormalities. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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