Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS.

Understanding the practical limitations of chemical reactions is critically important for efficiently planning the synthesis of compounds in pharmaceutical, agrochemical, and specialty chemical research and development. However, literature reports of the scope of new reactions are often cursory and biased toward successful results, severely limiting the ability to predict reaction outcomes for untested substrates. We herein illustrate strategies for carrying out large-scale surveys of chemical reactivity by using a material-sparing nanomole-scale automated synthesis platform with greatly expanded synthetic scope combined with ultrahigh-throughput matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS).

A General Small-Scale Reactor To Enable Standardization and Acceleration of Photocatalytic Reactions.

Photocatalysis for organic synthesis has experienced an exponential growth in the past 10 years. However, the variety of experimental procedures that have been reported to perform photon-based catalyst excitation has hampered the establishment of general protocols to convert visible light into chemical energy. To address this issue, we have designed an integrated photoreactor for enhanced photon capture and catalyst excitation. Moreover, the evaluation of this new reactor in eight photocatalytic transformations that are widely employed in medicinal chemistry settings has confirmed significant performance advantages of this optimized design while enabling a standardized protocol.

Development and optimization of a high-throughput micro-computed tomography imaging method incorporating a novel analysis technique to evaluate bone mineral density of arthritic joints in a rodent model of collagen induced arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease resulting in joint inflammation, pain, and eventual bone loss. Bone loss and remodeling caused by symmetric polyarthritis, the hallmark of RA, is readily detectable by bone mineral density (BMD) measurement using micro-CT. Abnormalities in these measurements over time reflect the underlying pathophysiology of the bone. To evaluate the efficacy of anti-rheumatic agents in animal models of arthritis, we developed a high throughput knee and ankle joint imaging assay to measure BMD as a translational biomarker. A bone sample holder was custom designed for micro-CT scanning, which significantly increased assay throughput. Batch processing 3-dimensional image reconstruction, followed by automated image cropping, significantly reduced image processing time. In addition, we developed a novel, automated image analysis method to measure BMD and bone volume of knee and ankle joints. These improvements significantly increased the throughput of ex vivo bone sample analysis, reducing data turnaround from 5 days to 24 hours for a study with 200 rat hind limbs. Taken together, our data demonstrate that BMD, as quantified by micro-CT, is a robust efficacy biomarker with a high degree of sensitivity. Our innovative approach toward evaluation of BMD using optimized image acquisition and novel image processing techniques in preclinical models of RA enables high throughput assessment of anti-rheumatic agents offering a powerful tool for drug discovery.

Late-stage functionalization of biologically active heterocycles through photoredox catalysis.

The direct CH functionalization of heterocycles has become an increasingly valuable tool in modern drug discovery. However, the introduction of small alkyl groups, such as methyl, by this method has not been realized in the context of complex molecule synthesis since existing methods rely on the use of strong oxidants and elevated temperatures to generate the requisite radical species. Herein, we report the use of stable organic peroxides activated by visible-light photoredox catalysis to achieve the direct methyl-, ethyl-, and cyclopropylation of a variety of biologically active heterocycles. The simple protocol, mild reaction conditions, and unique tolerability of this method make it an important tool for drug discovery.

Development of an integrated semi-automated system for in vitro pharmacodynamic modelling.

OBJECTIVES: The aim of this study was to develop an integrated system for in vitro pharmacodynamic modelling of antimicrobials with greater flexibility, easier control and better accuracy than existing in vitro models. METHODS: Custom-made bottle caps, fittings, valve controllers and a modified bench-top shaking incubator were used. A temperature-controlled automated sample collector was built. Computer software was developed to manage experiments and to control the entire system including solenoid pinch valves, peristaltic pumps and the sample collector. The system was validated by pharmacokinetic simulations of linezolid 600 mg infusion. The antibacterial effect of linezolid against multiple Staphylococcus aureus strains was also studied in this system. RESULTS: An integrated semi-automated bench-top system was built and validated. The temperature-controlled automated sample collector allowed unattended collection and temporary storage of samples. The system software reduced the labour necessary for many tasks and also improved the timing accuracy for performing simultaneous actions in multiple parallel experiments. The system was able to simulate human pharmacokinetics of linezolid 600 mg intravenous infusion accurately. A pharmacodynamic study of linezolid against multiple S. aureus strains with a range of MICs showed that the required 24 h free drug AUC/MIC ratio was approximately 30 in order to keep the organism counts at the same level as their initial inoculum and was about > or = 68 in order to achieve > 2 log(10) cfu/mL reduction in the in vitro model. CONCLUSIONS: The integrated semi-automated bench-top system provided the ability to overcome many of the drawbacks of existing in vitro models. It can be used for various simple or complicated pharmacokinetic/pharmacodynamic studies efficiently and conveniently.

Short-term economic impact associated with occupational needlestick injuries among acute care nurses.

PURPOSE: Recent survey data have reported the incidence rate of needlestick injuries (NIs) and NIs which draw blood sustained by nurses caring for patients with diabetes in an in-patient hospital setting. The purpose of this study was to deduce the potential short-term annual economic impact resulting from such NI, and to project the potential national economic burden of NI among this population of health care workers (HCWs). METHODS: Data were obtained from a recently published, IRB-approved, Internet-based survey in which nurses routinely treating patients with diabetes self-reported outcomes of their experience with NI (N = 400). A micro-costing approach was adopted. Direct costs comprised post-exposure testing (PET) for infection, post-exposure health care services utilization, and NI-induced post-exposure prophylactic (PEP) drug utilization. Indirect costs were derived from missed workdays and associated lost productivity. These data were combined with data related to the national epidemiology and total incidence of NIs among HCWs and risk-associated populations to project the national burden. RESULTS: Among 400 nurses, 110 sustained at least one NI in the past year, with 73 punctures drawing blood. The ensuing total short-term costs of these NIs were calculated to range from 25,896 US dollars to 36,066 US dollars. Indirect costs accounted for 44-62% of this total cost. Average short-term costs per NI ranged from 145 to 201 US dollars, and average short-term costs of NI per injured nurse ranged from 235 to 328 US dollars. Assuming mean values from published literature on the incidence and distribution of NI among nursing populations, an annual national burden of 65 million US dollars was calculated for costs in the immediate period following NI. CONCLUSIONS: These data suggest substantial economic burden immediately following NI on a national and individual hospital level occurring among acute-care nurses treating patients with diabetes. Long-term treatment costs would add to the overall economic burden.

Relief of symptoms in patients with group A beta-hemolytic streptococcus tonsillopharyngitis: comparison between telithromycin and penicillin V.

This study compared the resolution of symptoms in patients with group A beta-hemolytic streptococcus tonsillopharyngitis treated with 5 d of telithromycin 800 mg once daily, or 10 d of penicillin V 500 mg 3 times daily. At days 3-5 of treatment, the mean improvement in total symptom score was greater with telithromycin than with penicillin V (p = 0.042). Thus, telithromycin provided faster symptom relief than penicillin V.