A Scientific Roadmap for Antibiotic Discovery: A Sustained and Robust Pipeline of New Antibacterial Drugs and Therapies is Critical to Preserve Public Health

In recent decades, the discovery and development of new antibiotics have slowed dramatically as scientific barriers to drug discovery, regulatory challenges, and diminishing returns on investment have led major drug companies to scale back or abandon their antibiotic research. Consequently, antibiotic discovery—which peaked in the 1950s—has dropped precipitously. Of greater concern is the fact that nearly all antibiotics brought to market over the past 30 years have been variations on existing drugs. Every currently available antibiotic is a derivative of a class discovered between the early 1900s and 1984.At the same time, the emergence of antibiotic-resistant pathogens has accelerated, giving rise to life-threatening infections that will not respond to available antibiotic treatment. Inevitably, the more that antibiotics are used, the more that bacteria develop resistance—rendering the drugs less effective and leading public health authorities worldwide to flag antibiotic resistance as an urgent and growing public health threat

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects.

AIM: The D2 /D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT). METHODS: This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period. RESULTS: The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5). CONCLUSIONS: Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose

Post-Harvest Residue Management Methods in Kentucky Bluegrass Seed Production on the Eastern Canadian Prairies

Studies were conducted to evaluate methods of crop residue management in seed production fields of Kentucky bluegrass (Poa pratensis L.). Five residue management systems were evaluated at two sites for effectiveness of maintaining seed yield in comparison to the traditional method of burning crop residues. At Selkirk, MB, open burning applied shortly after harvest was the most effective, followed closely by dethatching of the stand. A later implemented trial at Stead, MB indicated that late season burning of residues reduced the seed yield compared to baling the residue only. All residue removal methods increased the seed yield over bale only. Time of residue management can play an important role in determining the appropriate renovation method

Phase II Clinical Trial With Pegylated Liposomal Doxorubicin (CAELYX®/Doxil®) and Quality of Life Evaluation (EORTC QLQ-C30) in Adult Patients With Advanced Soft Tissue Sarcomas: A study of the Spanish Group for Research in Sarcomas (GEIS)

Background: Pegylated liposomal doxorubicin (PLD), a formulation with pharmacokinetic differences with respect to doxorubicin (DXR), might benefit patients with advanced soft tissue sarcoma (STS) pretreated with DXR

Wetland buffers are no substitute for landscape-scale conservation

Wetlands in farmland are at risk of contamination by fertilizers and pesticides. One recommendation for reducing wetland contamination is to maintain a buffer of contiguous uncropped land around the wetland (a wetland buffer). Many agricultural water protection policies around the world recommend 5 to 50-m wide uncropped buffers around water bodies, but it is unclear how large wetland buffers must be to effectively protect against these chemicals. In addition, it is unclear whether wetland buffers have similar—or stronger—effects on fertilizer and pesticide contamination than reducing the amount of cropped land within the larger landscape context around wetlands. Our study, conducted across 37 wetlands in eastern Ontario, Canada, addressed the following questions: (1) Does increasing buffer width, or increasing the amount of contiguous uncropped land within recommended buffer width guidelines, reduce nutrient and pesticide levels in agricultural wetlands? (2) Does increasing uncropped land cover in the broader landscape reduce nutrient and pesticide levels in agricultural wetlands? and (3) What is the relative importance of buffer size and landscape-scale uncropped cover for reducing nutrient and pesticide levels in agricultural wetlands? A rigorous site selection process was employed to minimize the correlation between buffer size and landscape-scale uncropped cover, minimize spatial gradients in these predictor variables, and minimize variation in potentially confounding variables. We obtained nutrient and pesticide data by collecting water samples from each wetland under similar weather conditions in June–July 2015. Nitrate concentrations were measured using ion chromatography, and atrazine and neonicotinoid (pesticide) concentrations using a combination of high-performance liquid chromatography and mass spectrometry. We found that nitrate, atrazine, and neonicotinoid concentrations in study wetlands were unaffected by wetland buffer size. However, concentrations of each chemical decreased with uncropped land cover in the surrounding 150 to 300-m radius landscapes. To effectively protect w

Liposomes in Biology and Medicine

Drug delivery systems (DDS) have become important tools for the specific delivery of a large number of drug molecules. Since their discovery in the 1960s liposomes were recognized as models to study biological membranes and as versatile DDS of both hydrophilic and lipophilic molecules. Liposomes--nanosized unilamellar phospholipid bilayer vesicles--undoubtedly represent the most extensively studied and advanced drug delivery vehicles. After a long period of research and development efforts, liposome-formulated drugs have now entered the clinics to treat cancer and systemic or local fungal infections, mainly because they are biologically inert and biocompatible and practically do not cause unwanted toxic or antigenic reactions. A novel, up-coming and promising therapy approach for the treatment of solid tumors is the depletion of macrophages, particularly tumor associated macrophages with bisphosphonate-containing liposomes. In the advent of the use of genetic material as therapeutic molecules the development of delivery systems to target such novel drug molecules to cells or to target organs becomes increasingly important. Liposomes, in particular lipid-DNA complexes termed lipoplexes, compete successfully with viral gene transfection systems in this field of application. Future DDS will mostly be based on protein, peptide and DNA therapeutics and their next generation analogs and derivatives. Due to their versatility and vast body of known properties liposome-based formulations will continue to occupy a leading role among the large selection of emerging DDS