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BACKGROUND P-glycoprotein, the gene product of MDR1, confers multidrug resistance against antineoplastic agents but also plays an important role in the bioavailability of common drugs in medical treatment. Various polymorphisms in the MDR1 gene were recently identified. A silent mutation in exon 26 (C3435T) was correlated with intestinal P-glycoprotein(More)
Infections are a leading cause of death in stroke patients. In a mouse model of focal cerebral ischemia, we tested the hypothesis that a stroke-induced immunodeficiency increases the susceptibility to bacterial infections. 3 d after ischemia, all animals developed spontaneous septicemia and pneumonia. Stroke induced an extensive apoptotic loss of(More)
OBJECTIVE According to in vitro data, the polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) may be the major S-ibuprofen hydroxylase. In humans, there are 2 variants of CYP2C9 with a high population frequency. We studied their impact on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenases 1 and 2. METHODS Kinetics of an oral dose of 600 mg(More)
AIMS The cytochrome P450 enzyme CYP2C9 catalyses the 4'-hydroxylation of the nonsteroidal analgesic drug diclofenac in humans. We studied the influences of the known amino acid variants, CYP2C9*2 (Arg144Cys) and CYP2C9*3 (Ile359Leu), on diclofenac pharmacokinetics after a 50-mg oral dose of diclofenac in healthy volunteers. As a surrogate marker of(More)
RATIONALE Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death. OBJECTIVES In the first controlled biomarker-guided immunostimulatory trial in sepsis, we tested whether granulocyte-macrophage colony-stimulating factor (GM-CSF) reverses monocyte deactivation, a hallmark of(More)
Tolerance of monocytes/macrophages to endotoxin (lipopolysaccharide [LPS]) can be induced both in vivo and in vitro by LPS itself. Exposure to LPS, even at a very low dose, induces a downregulation of cytokine response to a second high dose LPS challenge. To learn more about the unknown mechanisms of this phenomenon, we studied the role of antiinflammatory(More)
Tolbutamide is known to be metabolized by cytochrome P450 2C9 (CYP2C9), and the effects of the CYP2C9 amino acid polymorphisms *2 (Arg144Cys) and *3 (Ile359Leu) could be important for drug treatment with tolbutamide and for use of tolbutamide as a CYP2C9 test drug. Tolbutamide pharmacokinetics and plasma insulin and glucose concentrations were studied in 23(More)
It is well established that endotoxin [lipopolysacharide (LPS)] induces pro-inflammatory cytokine production in monocytes, which is followed by secretion of the anti-inflammatory cytokine, IL-10. IL-10 down-regulates inflammatory response [tumor necrosis factor (TNF)-alpha, IL-1, IL-6, IL-8] as well as IL-10 synthesis itself. We wondered whether(More)
In-vitro data indicate major effects of the genetically polymorphic cytochrome P450 enzyme 2C9 (CYP2C9) on the pharmacokinetics of celecoxib, a nonsteroidal anti-inflammatory drug acting as selective cyclooxygenase-2 inhibitor. Human studies report decreased clearance in heterozygous carriers of the CYP2C9 variant Ile359Leu (*3), but results appeared(More)
Infarction size and infections are important determinants of stroke outcome in humans. Bacterial infections are promoted by stroke-induced immunodeficiency which in experimental stroke is mainly characterized by extensive lymphocyte apoptosis and dysfunction. Pharmacological inhibition of caspases may improve stroke outcome not only by reducing apoptotic(More)