Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer

Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation

Toxicity of abamectin to the terrestrial isopod Porcellio scaber (Isopoda, Crustacea).

To determine effects of the antiparasitic veterinary drug abamectin on the isopod Porcellio scaber, animals were exposed for 21 days to Lufa 2.2 soil spiked at concentrations of 3-300 mg/kg dry soil. After exposure, abamectin residues in the isopods were analysed using a novel analytical method. Toxicity was evaluated on different levels of biological organisation: biochemical, cellular and the individual organism. Measurements included glutathione S-transferase (GST) activity and stability of cell membranes in the digestive gland, animal mass gain or loss, food consumption, behaviour and mortality. LC50 for the effect of abamectin on survival of P. scaber was 71 mg/kg dry soil. The most obvious sublethal effects were reduced food consumption and decreased body mass (NOEC 3 mg/kg dry soil). Additionally, loss of digging activity and reduced GST activity (NOEC 30 mg/kg dry soil) and cell membrane destabilization (NOEC 10 mg/kg dry soil) were recorded. Abamectin only slightly accumulated in the isopods, with bioaccumulation factors always being <0.1. Based on these results and current information on environmental levels of abamectin, it is not likely that isopods will be affected by abamectin, but further studies with exposure through faeces are recommended. © 2010 Springer Science+Business Media, LLC

Untargeted Metabolomics Reveals a Lack Of Synergy between Nifurtimox and Eflornithine against Trypanosoma brucei

A non-targeted metabolomics-based approach is presented that enables the study of pathways in response to drug action with the aim of defining the mode of action of trypanocides. Eflornithine, a polyamine pathway inhibitor, and nifurtimox, whose mode of action involves its metabolic activation, are currently used in combination as first line treatment against stage 2, CNS-involved, human African trypanosomiasis (HAT). Drug action was assessed using an LC-MS based non-targeted metabolomics approach. Eflornithine revealed the expected changes to the polyamine pathway as well as several unexpected changes that point to pathways and metabolites not previously described in bloodstream form trypanosomes, including a lack of arginase activity and N-acetylated ornithine and putrescine. Nifurtimox was shown to be converted to a trinitrile metabolite indicative of metabolic activation, as well as inducing changes in levels of metabolites involved in carbohydrate and nucleotide metabolism. However, eflornithine and nifurtimox failed to synergise anti-trypanosomal activity in vitro, and the metabolomic changes associated with the combination are the sum of those found in each monotherapy with no indication of additional effects. The study reveals how untargeted metabolomics can yield rapid information on drug targets that could be adapted to any pharmacological situation

Waiting time-based staff capacity and shift planning at blood collection sites

Sanquin, the organization responsible for blood collection in the Netherlands, aims to be donor-friendly. An important part of the perception of donor-friendliness is the experience of waiting times. At the same time, Sanquin needs to control the costs for blood collection. A significant step to shorten waiting times is to align walk-in arrivals, and staff capacity and shifts. We suggest a two-step procedure. First, we investigate two methods from queuing theory to compute the minimum number of staff members required for every half hour. Next, these minimum numbers of staff members will be used to determine optimal lengths and starting times of shifts with an Integer Linear Program. Finally, the practical implications of the method are shown with numerical results. These results show that the presented approach can bring significant savings while at the same time guaranteeing a waiting time-based service level for blood donors