Br J Dermatol 2002 Jan;146(1):2-6
Skin Therapy Research Unit, St John's Institute of Dermatology, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
Systemic therapies are increasingly used in the management of common skin diseases, and drug toxicity and relative lack of efficacy remain significant problems. In addition, we are unable to predict life-threatening adverse reactions such as toxic epidermal necrolysis. Pharmacogenetics, the study of how genetic differences influence the variability of individual patient responses to drugs, aims to distinguish responders from non-responders and predict those in whom toxicity is likely. Successful application of pharmacogenetics should lead to rationalized drug therapy. Recent advances in molecular genetic techniques such as high-throughput genotyping and microarrays have the potential to provide a practicable and economical approach to future pharmacogenetic testing. Pharmacogenetics will change not only the way drugs are selected but will also impact on clinical trial design and the costs of healthcare delivery.
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PMID: 11841360, UI: 21830395
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J Hepatol 2001 Oct;35(4):539-41
PMID: 11682043, UI: 21539753
J Hepatol 2001 Oct;35(4):490-7
Department of Molecular Biology, Flanders Interuniversity Institute for Biotechnology and University of Ghent, Belgium.
BACKGROUND/AIMS: Tumor necrosis factor (TNF) plays an essential role in several types of acute and chronic hepatitis. Our aims in the present study were to elucidate the mechanism by which TNF leads to acute lethal hepatitis, thereby focusing on the role of serine proteases and platelet-activating factor (PAF). METHODS: All experiments were performed in a model of acute hepatitis, induced by TNF in combination with D-(+)-galactosamine (GalN). Neutrophil elastase (NE)-deficient mice, generated by gene targeting were used in the studies. RESULTS: We found that a serine protease plays an essential mediating role in the in vivo TNF effect as alpha1-antitrypsin (alpha1-AT), soybean trypsin inhibitor (STI) and turkey trypsin inhibitor (TTI), confer complete protection. alpha1-AT and TTI, but not STI, reduce PAF blood levels, induced by TNF/GalN, which is compatible with an elastase-like serine protease involvement in PAF synthesis. In our search for relevant serine proteases we believed that NE was an excellent candidate protease. However, we found that TNF/GalN-induced lethality is not attenuated in mice deficient in NE. CONCLUSIONS: The data suggest that TNF-induced lethal hepatitis is accompanied by increases in circulating PAF and plasma clotting time, and mediated by a serine protease, but not by NE.
PMID: 11682033, UI: 21539743
JAMA 2002 Mar 6;287(9):1103
PMID: 11879090, UI: 21872290
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