Dalbavancin in the treatment of complicated skin and soft-tissue infections: a review

Increasing rates of antimicrobial resistance among strains of Streptococcus, Staphylococcus, and Enterococcus spp. have been widely documented. At least 50% of nosocomial Staphylococcus aureus infections in intensive care units in the US and UK are due methicillin-resistant S. aureus (MRSA). Drug resistance is not confined to hospitals, and community-acquired MRSA (CA-MRSA) strains are now common causes of complicated skin and soft-tissue infections (cSSTIs) in many regions. Dalbavancin is a novel parenterally administered semisynthetic lipoglycopeptide similar to the naturally produced glycopeptides vancomycin and teicoplanin. Dalbavancin features a multifaceted mechanism of action that inhibits bacterial cell wall formation by two different mechanisms that enhances its activity against a wide range of gram-positive bacteria including staphylococci, streptococci, enterococci, and some anaerobes. Additionally, dalbavancin possesses unique pharmacokinetic properties, the most significant of which is a long terminal half-life that allows for once weekly dosing. This attribute may prove to yield clinical and cost benefit. Overall, clinical trials indicate that dalbavancin is a safe, well-tolerated, and effective antimicrobial agent. In the largest investigation evaluating dalbavancin for the treatment of cSSTIs, it appeared to be as effective as linezolid. Dalbavancin, which is expected to receive FDA approval in 2008, appears to be a promising new antimicrobial agent for the treatment of cSSTIs

An imaging neutron/gamma-ray spectrometer

We present the test results of a neutron/gamma-ray imaging spectrometer for the identification and location of radioactive and special nuclear materials. Radioactive materials that could be fashioned into a radiation dispersal device typically emit gamma rays, while fissile materials such as uranium and plutonium emit both neutrons and gamma rays via spontaneous or induced fission. The simultaneous detection of neutrons and gamma rays is a clear indication of the presence of fissile material. The instrument works as a double-scatter telescope, requiring a neutron or gamma ray to undergo an interaction in two detectors to be considered a valid event. While this requirement reduces the detector efficiency, it yields information about the direction and energy of the incident particle, which is then used to reconstruct an image of the emitting source. Because of this imaging capability background events can be rejected, decreasing the number of events required for high confidence detection and thereby greatly improving its sensitivity. The instrument is optimized for the detection of neutrons with energies from 1-20 MeV and gamma rays from 0.4 to 10 MeV. Images and energy spectra for neutron and gamma rays are reported for several sources including depleted uranium and plutonium. In addition, the effect of neutron source shielding is investigated

PET and optical imaging of caveolin-1 in gastric tumors

Previous studies have suggested tumoral caveolin-1 (CAV1) as a predictive biomarker for the response to anti-HER2 antibody drug therapies in gastric tumors. In this study, radiolabeled and fluorescently labeled anti-CAV1 antibodies were developed and tested as an immunoPET or optical imaging agent to detect CAV1 in HER2-positive/CAV1-high NCIN87 gastric tumors. The expression of CAV1 receptors in NCIN87 gastric tumors and nontumor murine organs was determined by Western blot. Binding assays were performed to validate the anti-CAV1 antibody specificity for CAV1-expressing NCIN87 cancer cells. Subcutaneous and orthotopic NCIN87 xenografts were used for PET imaging an

Building Blocks for the Construction of Bioorthogonally Reactive Peptides via Solid-Phase Peptide Synthesis

The need for post-synthetic modifications and reactive prosthetic groups has long been a limiting factor in the synthesis and study of peptidic and peptidomimetic imaging agents. In this regard, the application of biologically and chemically orthogonal reactions to the design and development of novel radiotracers has the potential to have far-reaching implications in both the laboratory and the clinic. Herein, we report the synthesis and development of a series of modular and versatile building blocks for inverse electron-demand Diels–Alder copper-free click chemistry: tetrazine-functionalized artificial amino acids. Following the development of a novel peptide coupling protocol for peptide synthesis in the presence of tetrazines, we successfully demonstrated its effectiveness and applicability. This versatile methodology has the potential to have a transformational impact, opening the door for the rapid, facile, and modular synthesis of bioorthogonally reactive peptide probes

Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab

The positron-emitting radionuclide (89)Zr (t(1/2) = 3.17 days) was used to prepare (89)Zr-radiolabeled trastuzumab for use as a radiotracer for characterizing HER2/neu-positive breast tumors. In addition, pharmacodynamic studies on HER2/neu expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted.Trastuzumab was functionalized with desferrioxamine B (DFO) and radiolabeled with [(89)Zr]Zr-oxalate at room temperature using modified literature methods. ImmunoPET and biodistribution experiments in female, athymic nu/nu mice bearing sub-cutaneous BT-474 (HER2/neu positive) and/or MDA-MB-468 (HER2/neu negative) tumor xenografts were conducted. The change in (89)Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 was evaluated by biodistribution studies, Western blot analysis and immunoPET. (89)Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity 104.3+/-2.1 MBq/mg (2.82+/-0.05 mCi/mg of mAb). In vitro assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87+/-0.07. In vivo biodistribution experiments revealed high specific BT-474 uptake after 24, 48 and 72 h (64.68+/-13.06%ID/g; 71.71+/-10.35%ID/g and 85.18+/-11.10%ID/g, respectively) with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by biodistribution studies and immunoPET of (89)Zr-DFO-trastuzumab. Expression levels of HER2/neu were modulated during the first 24 and 48 h post-administration (29.75+/-4.43%ID/g and 41.42+/-3.64%ID/g, respectively). By 72 h radiotracer uptake (73.64+/-12.17%ID/g) and Western blot analysis demonstrated that HER2/neu expression recovered to baseline levels.The results indicate that (89)Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/neu positive tumors, and has potential to be used to measure the efficacy of long-term treatment with Hsp90 inhibitors, like PU-H71, which display extended pharmacodynamic profiles

Exploring the reactivity of 2-trichloromethylbenzoxazoles for access to substituted benzoxazoles

The reactivity of 2-trichloromethylbenzoxazoles towards various nucleophiles, under metal free or iron-catalyzed conditions, for the synthesis of substituted benzoxazoles is described. These methods allow for selective substitution at either the 2- or 2’- position of the benzoxazoles using the same starting materials / reagents. This approach allows for the controlled synthesis of a variety of key derivatives from a single 2-trichloromethylbenzoxazole starting material

Analysis of Rock Varnish from the Mojave Desert by Handheld Laser-Induced Breakdown Spectroscopy

Laser-induced breakdown spectroscopy (LIBS) is a form of optical emission spectroscopy that can be used for the rapid analysis of geological materials in the field under ambient environmental conditions. We describe here the innovative use of handheld LIBS for the in situ analysis of rock varnish. This thinly laminated and compositionally complex veneer forms slowly over time on rock surfaces in dryland regions and is particularly abundant across the Mojave Desert climatic region of east-central California (USA). Following the depth profiling examination of a varnished clast from colluvial gravel in Death Valley in the laboratory, our in situ analysis of rock varnish and visually similar coatings on rock surfaces was undertaken in the Owens and Deep Spring valleys in two contexts, element detection/identification and microchemical mapping. Emission peaks were recognized in the LIBS spectra for the nine elements most abundant in rock varnish—Mn, Fe, Si, Al, Na, Mg, K, Ca and Ba, as well as for H, Li, C, O, Ti, V, Sr and Rb. Focused follow-up laboratory and field studies will help understand rock varnish formation and its utility for weathering and chronological studies