1,2,4-trisubstituted cyclopentanes as platforms for diversity.

Despite their simplicity, relatively few examples of 1,2,4 (1,3,4)-amino-, azido-, and hydroxy-substituted cyclopentanes are reported in the literature. We found that cyclopent-3-en-1-ol can be transformed into a significant variety of compounds of this class by relatively common and efficient synthetic procedures. Stereochemical control of epoxidation of the cyclopentene double bond can be achieved by varying the substitutents at C4.

Conformational flexibility of transmembrane helix VII of the human serotonin transporter impacts ion dependence and transport.

The serotonin transporter (SERT) regulates the serotonin concentration in the synapse and is a target of several antidepressant and psychostimulant drugs. Previous work suggested that the middle transmembrane helices (TMHs) of the biogenic amine transporters (TMHs) play a role in substrate and ion recognition. We focused our present studies on exploring the role of TMH VII in transporter function and ion recognition.

Activation of TRPC6 channels promotes endocannabinoid biosynthesis in neuronal CAD cells.

Calcium influx activates biosynthesis of the endogenous cannabinoids 2-arachidonyl glycerol (2-AG) and anandamide (AEA). The calcium channel involved with endocannabinoid synthesis and release in neurons is still unknown. The canonical TRP (TRPC) channels are calcium-permeable channels that are a homology-based subdivision of the broader class of TRP channels.

Structural analysis of the extracellular entrance to the serotonin transporter permeation pathway.

Neurotransmitter transporters are responsible for removal of biogenic amine neurotransmitters after release into the synapse. These transporters are the targets for many clinically relevant drugs, such as antidepressants and psychostimulants. A high resolution crystal structure for the monoamine transporters has yet to be solved.

Evolving novel anti-HER2 strategies.

The approval of trastuzumab for use in metastatic breast cancer marked a breakthrough in the understanding of the biology of the disease. However, like most cancer therapies, the disease finds a way to advance despite the treatments developed to eradicate it. Although trastuzumab has had a large effect on the treatment of early and advanced-stage disease, a substantial proportion of patients with HER2-positive breast cancer still progress after receiving the drug.

Laboratory session to improve first-year pharmacy students' knowledge and confidence concerning the prevention of medication errors.

Objectives: To implement a laboratory session into the first-year pharmacy curriculum that would provide active-learning experiences in the recognition, resolution, and prevention of medication errors.

Design: Students participated in medication error-prone prescription processing and counseling simulations, role-played communication strategies after a medication error occurred, and discussed an introductory pharmacy practice experience focused on prescription processing and prevention of medication errors.

Assessment: Students completed an assessment prior to and after completion of the laboratory on their knowledge of and confidence in identifying medication errors.

Collaborative partnership for clinical pharmacy services in Kenya.

Purpose: A collaborative partnership for clinical pharmacy services in Kenya is described.

Summary: Purdue University School of Pharmacy and Pharmaceutical Sciences (PUSOPPS) agreed to collaborate with the United States Agency for International Development-Academic Model for Providing Access to Healthcare (USAID-AMPATH) partnership to provide pharmacy services necessary for patients infected with human immunodeficiency virus (HIV) in Kenya. In addition to assisting Kenyan collaborators, the full-time, onsite faculty member from PUSOPPS serves as a preceptor to pharmacy clerkship students from PUSOPPS and the University of Nairobi in the delivery of clinical pharmacy services in inpatient and outpatient settings.

Intestinal dipeptide absorption is preserved during thermal injury and cytokine treatment.

Background: Intestinal barrier function is impaired during thermal injury; however, the effects of thermal injury on the absorption of dietary peptides are not well characterized. The purpose of this study was to determine the impact of thermal injury on dipeptide absorption in rats and to describe the influence of inflammatory cytokines on the expression of the oligopeptide transporter PEPT1 and dipeptide permeability in cultured intestinal cells (Caco-2 cells).

Methods: Sprague Dawley rats were assigned to 30% body surface area burn (n = 7) or sham (n = 8) groups.

Interferon-gamma increases expression of the di/tri-peptide transporter, h-PEPT1, and dipeptide transport in cultured human intestinal monolayers.

The di/tri-peptide transporter h-PEPT1 plays an important role in the oral absorption of di/tri-peptides and numerous drugs. Inflammatory conditions may influence intestinal xenobiotic transporter function; however, the effects of inflammation on h-PEPT1 have not been well described. This study was conducted to determine the effects of the inflammatory cytokine interferon-gamma (IFN-gamma) on h-PEPT1 mediated dipeptide absorption.

Helix XI contributes to the entrance of the serotonin transporter permeation pathway.

The sodium-dependent transporters for dopamine, norepinephrine, and serotonin that regulate neurotransmission, also translocate the neurotoxin 1-methyl-4-phenylpyridinium (MPP(+)). Previous studies implicated residues in transmembrane helix (TMH) XI of DAT as important sites for MPP(+) transport. We examined the importance of TMH XI residues F551 and F556 for MPP(+) translocation by human SERT.

Cephalexin inhibits N-formylated peptide transport and intestinal hyperpermeability in Caco2 cells.

Purpose: Intestinal barrier integrity is diminished in critical illness and inflammatory bowel disease. Bacterial-derived N-formylated peptides, absorbed by the intestinal oligopeptide transporter, hPEPT1, are involved in the pathogenesis of disease-induced intestinal barrier dysfunction, via stimulation of polymorphonuclear leukocyte (PMN) migration. The purpose of this study was to determine if the hPEPT1 substrate, cephalexin, inhibits the absorption of the N-formylated peptide, N-formyl-L-methionyl-L-leucyl-L-phenylalanine ("fMLP"), thereby preventing hyperpermeability in Caco2 cells.

Role of xenobiotic efflux transporters in resistance to vincristine.

This study characterized interactions between efflux transporters (P-glycoprotein (MDR1) and multidrug resistance associated proteins (MRPs1-3)) and vincristine (VCR), using cell lines with differential transporter expression, and studied effects of P-glycoprotein inhibition on VCR transport and toxicity. Caco2 (express MDR1, MRPs 1-3), LS174T (express MDR1, MRPs 1, 3), and A549 (express MRPs 1-3) cells were used. To study VCR transport (effective permeability, P(eff)), VCR (1-500 nM) was added to the donor chambers of permeable supports containing Caco2 monolayers, and receiving chamber concentrations were measured.

Selection of a gyrA mutation and treatment failure with gatifloxacin in a patient with Streptococcus pneumoniae with a preexisting parC mutation.

An 81-year-old woman had pneumonia caused by Streptococcus pneumoniae (levofloxacin Etest minimum inhibitory concentration [MIC] 1.5 microg/ml) and was treated with intravenous gatifloxacin 200 mg/day. After 3 days of therapy, repeat sputum cultures were positive for S.

Comparative in vitro and bactericidal activities of telithromycin against penicillin-nonsusceptible, levofloxacin-resistant, and macrolide-resistant Streptococcus pneumoniae by time-kill methodology.

Broth microdilution MICs were determined for 14 antimicrobial agents against 296 clinical, non-duplicate isolates of Streptococcus pneumoniae collected at Methodist Hospital (Indianapolis, Indiana, USA) from January 2001 to December 2003. Isolates were categorized as susceptible, intermediate, or resistant using Clinical and Laboratory Standards Institute breakpoints. Time-kill studies were performed to evaluate the bactericidal activity of telithromycin at 1, 2, 4, and 8x MIC against 10 penicillin-nonsusceptible, levofloxacin-resistant, and macrolide-resistant (7 M-phenotype, 3 MLS(B)-phenotype) strains.

Engineered zinc-binding sites confirm proximity and orientation of transmembrane helices I and III in the human serotonin transporter.

The human serotonin transporter (hSERT) regulates neurotransmission by removing released serotonin (5-HT) from the synapse. Previous studies identified residues in SERT transmembrane helices (TMHs) I and III as interaction sites for substrates and antagonists. Despite an abundance of data supporting a 12-TMH topology, the arrangement of the TMHs in SERT and other biogenic amine transporters remains undetermined.

Effect of ensure on the oral bioavailability of gatifloxacin in healthy volunteers.

Study Objective: To determine the effect of Ensure on the relative oral bioavailability of gatifloxacin in healthy volunteers.

Design: Single-dose, randomized, crossover study.

Setting: University-affiliated research center.

Pharmacokinetics of intravenously administered levofloxacin in men and women.

Study Objective: To characterize and compare the pharmacokinetics of levofloxacin in men and women after systemic administration.

Design: Prospective, open-label, parallel group pharmacokinetic study.

Setting: University research center.