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Membrane transporters can be major determinants of the pharmacokinetic, safety and efficacy profiles of drugs. This presents several key questions for drug development, including which transporters are clinically important in drug absorption and disposition, and which in vitro methods are suitable for studying drug interactions with these transporters. In(More)
BACKGROUND Angiogenesis is a promising treatment strategy for patients who are not candidates for standard revascularization, because it promotes the growth of new blood vessels in ischemic myocardium. METHODS AND RESULTS We conducted a randomized, double-blind, placebo-controlled study of basic fibroblast growth factor (bFGF; 10 or 100 microg versus(More)
Thromboxane A2 (TxA2) causes contraction of vascular smooth muscle and aggregation of platelets; paradoxically, it also induces formation of the vasodilator and antiaggregant prostacyclin by human endothelium. To determine if the molecular structure of the endothelial TxA2 receptor differs from that of the previously characterized receptor from placenta, we(More)
Sulfasalazine is used in the treatment of ulcerative colitis, Crohn's disease, and rheumatoid arthritis. When administered orally, sulfasalazine is poorly absorbed with an estimated bioavailability of 3-12%. Recent studies using the T-cell line (CEM) have shown that sulfasalazine is a substrate for the ATP-binding cassette (ABC) efflux pump ABCG2. ABCG2 is(More)
The clinical pharmacokinetics and in vitro inhibition of digoxin were examined to predict the P-glycoprotein (P-gp) component of drug-drug interactions. Coadministered drugs (co-meds) in clinical trials (N = 123) resulted in a small, <or=100% increase in digoxin pharmacokinetics. Digoxin is likely to show the highest perturbation, via inhibition of P-gp,(More)
Activation of the protein kinase C (PKC) family with phorbol esters induces endothelial proliferation and angiogenesis, but which of the events that constitute angiogenesis are affected by individual members of the PKC family is unknown. In rat capillary endothelial (RCE) cells, serum stimulation increased expression of a single PKC isoenzyme, PKCtheta, and(More)
Vascular endothelial growth factor (VEGF) is an important patho-physiological mediator of angiogenesis. VEGF-induced endothelial cell (EC) migration and angiogenesis often occur in complicated environments containing multiple agents capable of modifying the response. Thromboxane (TX) A2 is released from multiple cell types and is a prime mediator of(More)
Although protein kinase C (PKC) activation is required for endothelial cell (EC) growth, migration, adhesion, and vessel formation, the role of individual PKC isoenzymes in these events is not defined. Because PKCalpha has been previously linked with enhanced EC migration and response to angiogenic growth factors, we characterized a specific(More)
The mitogen-activated protein kinase signaling cascade is used by many G protein-coupled receptors to initiate functional events. In this study, activation of the Gq/G11-coupled thromboxane A2 (TxA2) receptor (TP) by the TxA2 mimetic IBOP in ECV304 cells was found to induce extracellular regulated kinase (ERK) phosphorylation and tyrosine phosphorylation of(More)
A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM,(More)