Antimicrobial resistance in hospital and community settings is growing at an alarming rate and has been attributed to such organisms as methicillin-resistant staphylococcus aureus, staphylococci with decreased susceptibility to vancomycin, vancomycin-resistant enterococci, multi-drug resistant pseudomonas spp., klebsiella spp., enterobacter spp, and acinetobacter spp., as well as Streptococcus pneumoniae with decreased susceptibility to penicillin and other antibacterials. To address the need for new therapies to combat resistant organisms, drug companies are refocusing their discovery efforts on developing novel agents with new mechanisms of action. The hope is that rapidly emerging technologies including combinatorial chemistry, high throughput screening, proteomics and microbial genomics will have a positive impact on antimicrobial drug discovery. These technologies should aid in the identification of novel drug targets and compounds with unique mechanisms of action other than those currently provided by the traditional antibiotics. Nucleosides are one class of compounds worthy of further investigation as antibacterials since some derivatives have shown moderate to good activity against specific bacterial strains. For example, 5'-peptidyl nucleoside derivatives can inhibit peptide deformylase, an enzyme essential for bacterial survival that is not vital to human cells. This review also includes a list of miscellaneous nucleosides that have been synthesized as potential antibacterials. More detailed investigations on structure, as it relates to the antimicrobial activity of the various classes of nucleosides, need to be conducted in order to maximize the potential of developing a potent nucleoside for the treatment of bacterial infections. This review begins with an introduction to terms followed by discussions regarding the general background and relevance for developing novel antimicrobial agents. Challenges facing the antimicrobial drug discovery process are discussed along with relevant drug targets. An overview of nucleoside chemistry as it relates to antimicrobial activity is presented, followed by a discussion of the evidence which supports the potential of this class of compounds to yield the novel antimicrobial therapies needed in the new millennium.
Introduction This Phase Ib trial investigated the safety, tolerability, and recommended phase 2 dose for the pan-PI3K/mTOR inhibitor, GSK2126458 (GSK458), and trametinib combination when administered to patients with advanced solid tumors. Patients and Methods Patients with advanced solid tumors received escalating doses of GSK458 (once or twice daily, and continuous or intermittent) and trametinib following a zone-based 3 + 3 design to determine the maximum tolerated dose (MTD). Assessments included monitoring for adverse events and response, and evaluating pharmacokinetic (PK) measures. Archival tissue and circulating free DNA samples were collected to assess biomarkers of response in the PI3K and RAS pathways. Results 57 patients were enrolled onto the continuous dosing cohort and 12 patients onto an intermittent BID dosing cohort. Two MTDs were established for the continuous daily dosing: 2 mg of GSK458 with 1.0 mg of trametinib or 1.0 mg of GSK458 with 1.5 mg of trametinib; no MTD was determined in the intermittent dosing cohort. The most frequent adverse events were rash (74 %) and diarrhea (61 %). Dose interruptions due to adverse events occurred in 42 % of patients. No significant PK interaction was observed. One patient achieved partial response and 12 patients had stable disease>16 weeks. Mutations in RAS/RAF/PI3K were detected in 70 % of patients, but no pattern emerged between response and mutational status. Conclusion GSK458 plus trametinib is poorly tolerated, due to skin and GI-related toxicities. Responses were minimal, despite enrichment for PI3K/RAS pathway driven tumors, which may be due to overlapping toxicities precluding sufficient dose exposure.
2-Deoxy-2-fluorocytidine (FdC) is a potent inhibitor of the hepatitis C virus RNA replicon in culture, and FdC-5-triphosphate is an effective inhibitor of the NS5B polymerase. Dynamic profiling of cell growth in an antiviral assay showed that FdC caused cytostasis due to an S-phase arrest. These observations demonstrate that FdC treatment is affecting both a viral target and a cellular target.Hepatitis C virus (HCV) infection is the leading cause of liver transplantation in the United States, with sequelae including fibrosis, cirrhosis, and hepatocellular carcinoma (1). In vivo, HCV replication occurs mainly in the cytoplasm of infected hepatocytes, but it has been difficult to demonstrate replication in vitro. Replicon-based systems have now been developed that sustain efficient replication of HCV RNA in cell culture. Initially, subgenomic replicons that expressed only nonstructural proteins were constructed; however, recent reports described replicons that can express the entire HCV polyprotein (5, 7).In addition to the currently approved standard treatment options for HCV infections that use interferon and ribavirin, several new antiviral agents are in preclinical or clinical development. Similar to the case with human immunodeficiency virus type 1 treatment, multiple drug targets (e.g., protease, helicase, polymerase, and entry) may be needed to limit the emergence of drug-resistant variants. The HCV subgenomic replicon provides an excellent system for evaluating HCV antiviral agents in cell culture (3,5,6,10,16,18). We report here the antiviral activity of 2Ј-deoxy-2Ј-fluorocytidine (FdC) (Fig. 1) measured in the HCV subgenomic replicon system and in the bovine viral diarrhea virus (BVDV)-Madin-Darby bovine kidney (MDBK) cell system. HCV-replicon RNA-containing Huh-7 cells (Clone A cells; Apath, LLC, St. Louis, Mo.) were kept in exponential growth as described previously (16). Antiviral assays were performed in medium without G418. Cells were seeded in a 96-well plate at 1,000 cells per well, and test compounds were added immediately after seeding. After 96 h of incubation, total cellular RNA was isolated (Rneasy 96 kit; Qiagen, Valencia, Ca.), and HCV replicon RNA and an internal control (TaqMan rRNA Control Reagents; Applied Biosystems, Foster City, Ca.) were amplified in a single-step multiplex reverse transcription-PCR protocol. FdC (obtained from the Pharmasset compound library) was tested in a concentration range of 0.1 to 200 M, and a 90% effective concentration (EC 90 ) for reducing the intracellular HCV replicon RNA levels of 5.0 M was found ( Fig. 2A). FdC was found to be more potent than ribavirin (EC 90 , ϳ100 M) and comparable in potency to -D-N 4 -hydroxycytidine (NHC) (EC 90 ϭ 5 M) (16). The cellular toxicity against Huh-7 and HepG2 cells was measured after 96 h of incubation by using the CellTiter 96 AQ ueous One solution cell proliferation assay (Promega, Madison, Wis.), and the concentration resulting in 50% reduction in cell growth (CC 50 ) was found to be greater than 100 M. This resul...
Both low-fat and high-fat food consumed 1 h before lapatinib administration increased lapatinib systemic exposure compared with lapatinib administration 1 h before a low-fat meal. In order to administer lapatinib in a fasted state, it is advised to administer the drug 1 h before a meal.
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