Inhaled therapy confers key advantages for the treatment of topical pulmonary diseases and offers potential for systemic delivery of medicines. Dry powder inhalers (DPIs) are generally the preferred devices for pulmonary delivery due to improved stability and satisfactory patient compliance. However, the mechanisms governing drug powder dissolution and availability in the lung and poorly understood.
View Article and Find Full Text PDFIn vitro absorption, distribution, metabolism and elimination (ADME) assays are widely used for profiling compounds in pharmaceutical drug discovery programs. Many compounds are screened in metabolic stability assays, using liver microsomes as a model of intrinsic hepatic clearance. Analysis of metabolic stability assays has relied on high throughput LC-MS/MS techniques to keep up with automated assays and compound profiling needs.
View Article and Find Full Text PDFA local sustained-release drug delivery system, or depot, for intra-articular injection offers the opportunity to release a therapeutic agent directly to the joint with limited need for reinjection. A successful system would provide more consistent efficacy and minimize systemic side effects. In this paper, we explore the potential use of diclofenac, a non-steroidal anti-inflammatory drug, for use in a polymer-conjugate depot system.
View Article and Find Full Text PDFDopamine transporter (SLC6A3) deficiency causes infantile Parkinson disease, for which there is no effective therapy. We have explored the effects of genetically deleting SLC6A3 in zebrafish. Unlike the wild-type, slc6a3-/- fish hover near the tank bottom, with a repetitive digging-like behavior.
View Article and Find Full Text PDFA hallmark of cancer is unbridled proliferation that can result in increased demand for de novo synthesis of purine and pyrimidine bases required for DNA and RNA biosynthesis. These synthetic pathways are frequently upregulated in cancer and involve various folate-dependent enzymes. Antifolates have a proven record as clinically used oncolytic agents.
View Article and Find Full Text PDFProstaglandin (PG) E2 plays a critical role in eliciting inflammation. Nonsteroidal anti-inflammatory drugs and selective inhibitors of cyclooxygenase, which block PGE2 production, have been used as key agents in treating inflammation and pain associated with arthritis and other conditions. However, these agents have significant side effects such as gastrointestinal bleeding and myocardial infarction, since they also block the production of prostanoids that are critical for other normal physiologic functions.
View Article and Find Full Text PDFAs part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold.
View Article and Find Full Text PDFInsulin-degrading enzyme (IDE, insulysin) is the best characterized catabolic enzyme implicated in proteolysis of insulin. Recently, a peptide inhibitor of IDE has been shown to affect levels of insulin, amylin, and glucagon in vivo. However, IDE(-/-) mice display variable phenotypes relating to fasting plasma insulin levels, glucose tolerance, and insulin sensitivity depending on the cohort and age of animals.
View Article and Find Full Text PDFAGPAT6 is a member of the 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) family that appears to be important in triglyceride biosynthesis in several tissues, but the precise biochemical function of the enzyme is unknown. In the current study, we show that AGPAT6 is a microsomal glycerol-3-phosphate acyltransferase (GPAT). Membranes from HEK293 cells overexpressing human AGPAT6 had higher levels of GPAT activity.
View Article and Find Full Text PDFA quantitative method for the determination of a partially modified, 2'-ribose alkoxy 18-mer phosphorothioate oligonucleotide, in liver tissue has been developed. A liquid:liquid extraction, ion-pair reverse phase chromatographic separation, and tandem mass spectrometry were used to achieve a quantitation range of 125 to 10,000 ng g(-1) mouse liver tissue. A total cycle time of 5 min was obtained while maintaining separation of three potential impurities.
View Article and Find Full Text PDFThis study examines the role of steric hindrance near the stereogenic centers of four glutamic acid based polymeric surfactants. The single amino acid surfactants of glutamic acid, glutamic acid methyl ester, glutamic ethyl ester, and glutamic acid tert-butyl ester were investigated. The micellar electrokinetic chromatography (MEKC) separation of three binaphthyl derivatives and three benzodiazepines were used to study these steric factors.
View Article and Find Full Text PDFThis study examined the effect of steric factors near the stereogenic center on polymerized surfactants, sodium N-undecyl-L-leucine, sodium N-undecyl-L-norleucine, sodium N-undecyl-L-tert.-butyl leucine, sodium N-undecyl-L-isoleucine. sodium N-undecyl-L-valine, sodium N-undecyl-L-norvaline.
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