The study objectives were 1) to test the hypothesis that the lack of P-glycoprotein (P-gp) and the inhibition of breast cancer resistance protein (Bcrp) at the blood-brain barrier after cassette dosing of potent P-gp and Bcrp inhibitors were due to low plasma concentrations of those inhibitors and 2) to examine the effects of P-gp on the unbound brain (C(u,brain)) and cerebrospinal fluid (CSF) ...

PURPOSE The purpose of this study was to use dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) to measure changes in tumor xenograft permeability produced by the antitumor thioredoxin-1 (Trx-1) inhibitor 1-methylpropyl 2-imidazolyl disulfide (PX-12) and to assess the relationship to Trx-1 and vascular endothelial growth factor (VEGF) levels. EXPERIMENTAL DESIGN DCE-MRI was used t...

Aliskiren (2(S),4(S),5(S),7(S)-N-(2-carbamoyl-2-methylpropyl)-5-amino-4-hydroxy-2,7-diisopropyl-8-[4-methoxy-3-(3-methoxypropoxy)phenyl]-octanamid hemifumarate) is the first in a new class of orally active, nonpeptide direct renin inhibitors developed for the treatment of hypertension. The absorption, distribution, metabolism, and excretion of [(14)C]aliskiren were investigated in four healthy ...

Imiquimod [1-(2-methylpropyl)-1H-imidazo[4,5c]quinolin-4-amine] is a compound of low molecular weight that, when administered p.o., induces interferon-alpha in several animal species and inhibits tumor growth in mice. To determine maximum tolerated dose, toxicity, and biological response in humans, a phase I clinical trial was conducted with 14 eligible cancer patients who received 100-500 mg i...

Understanding the potential for cytochrome P450-mediated drug-drug interactions (DDIs) is a critical step in the drug discovery process. DDIs of CYP3A4 are of particular importance because of the number of marketed drugs that are cleared by this enzyme. In response to studies that suggested the presence of several binding regions within the CYP3A4 active site, multiple probe substrates are ofte...

The synthesis and characterisation of two groups nonsymmetric dimers, the 1-(4-cyanobiphenyl-4‘−yloxy)-ω-(4-butyl, 4-(1-methylpropyl) or 4-t-butylanilinebenzylidene-4’−oxy)alkanes, 1-(4-cyanobiphenyl-4‘−yl)-ω-(4-butyl, are reported. length parity flexible spacer is varied. tert-butyl homologues show higher melting points than corresponding sec-butyl n-butyl substituted suggesting that chain bra...

As a promiscuous xenobiotic sensor, the constitutive androstane receptor (CAR; NR1I3) regulates the expression of multiple drug-metabolizing enzymes and transporters in liver. The constitutively activated nature of CAR in the cell-based transfection assays has hindered its use as a predictor of metabolism-based drug-drug interactions. Here, we have identified 1-(2-chlorophenylmethylpropyl)-3-is...

Opening of the permeability transition (PT) pore is a central feature of apoptosis induction by chemical stress. One component of the PT pore, the mitochondrial benzodiazepine receptor (mBzR), has recently received attention for its potential role in modulating PT pore function. Specifically, antagonistic ligands of the mBzR, such as 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline...

The purpose of this study was to investigate the chemical composition and biological activity of the volatile oils (VOs) from the flowers of three buckwheat species, Fagopyrum esculentum, Fagopyrum tataricum and Fagopyrum cymosum. The VOs were obtained from the fresh buckwheat flowers by hydrodistillation, and were analyzed for their chemical composition by gas chromatography-mass spectrometry ...

UNLABELLED Schizophrenia is a chronic and disabling brain disease characterized by psychotic episodes with unknown etiology. It is suggested that neuroinflammation plays a role in the pathophysiology of schizophrenia. Neuroinflammation is characterized by the activation of microglia cells, which show an increase in the expression of the peripheral benzodiazepine receptor. The isoquinoline (R)-N...