Unveiling the Impact of Morphine on Tamoxifen Metabolism in Mice in vivo

Background- Tamoxifen is used to treat breast cancer and cancer recurrences. After administration, tamoxifen is converted into two more potent antitumor compounds, 4OH-tamoxifen and endoxifen by the CYP3A4/5 and 2D6 enzymes in human. These active compounds are inactivated by the same UDP-glucuronosyltransferases isoforms as those involved in the metabolism of morphine. Importantly, cancer-associated pain can be treated with morphine, and the common metabolic pathway of morphine and tamoxifen suggests potential clinically relevant interactions. Methods- Mouse liver microsomes were used to determine the impact of morphine on 4OH-tamoxifen metabolism in vitro. For in vivo experiments, female mice were first injected with tamoxifen alone and then with tamoxifen and morphine. Blood was collected, and LC-MS/MS was used to quantify tamoxifen, 4OH-tamoxifen, N-desmethyltamoxifen, endoxifen, 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Results- In vitro, we found increased Km values for the production of 4OH-tamoxifen-glucuronide in the presence of morphine, suggesting an inhibitory effect on 4OH-tamoxifen glucuronidation. Conversely, in vivo morphine treatment decreased 4OH-tamoxifen levels in the blood while dramatically increasing the formation of inactive metabolites 4OH-tamoxifen-glucuronide and endoxifen-glucuronide. Conclusions- Our findings emphasize the need for caution when extrapolating results from in vitro metabolic assays to in vivo drug metabolism interactions. Importantly, morphine strongly impacts tamoxifen metabolism in mice. It suggests that tamoxifen efficiency could be reduced when both drugs are co-administered in a clinical setting, e.g. to relieve pain in breast cancer patients. Further studies are needed to assess the potential for tamoxifen-morphine metabolic interactions in humans

Comparison of common perioperative blood loss estimation techniques: a systematic review and meta-analysis

Estimating intraoperative blood loss is one of the daily challenges for clinicians. Despite the knowledge of the inaccuracy of visual estimation by anaesthetists and surgeons, this is still the mainstay to estimate surgical blood loss. This review aims at highlighting the strengths and weaknesses of currently used measurement methods. A systematic review of studies on estimation of blood loss was carried out. Studies were included investigating the accuracy of techniques for quantifying blood loss in vivo and in vitro. We excluded nonhuman trials and studies using only monitoring parameters to estimate blood loss. A meta-analysis was performed to evaluate systematic measurement errors of the different methods. Only studies that were compared with a validated reference e.g. Haemoglobin extraction assay were included. 90 studies met the inclusion criteria for systematic review and were analyzed. Six studies were included in the meta-analysis, as only these were conducted with a validated reference. The mixed effect meta-analysis showed the highest correlation to the reference for colorimetric methods (0.93 95% CI 0.91-0.96), followed by gravimetric (0.77 95% CI 0.61-0.93) and finally visual methods (0.61 95% CI 0.40-0.82). The bias for estimated blood loss (ml) was lowest for colorimetric methods (57.59 95% CI 23.88-91.3) compared to the reference, followed by gravimetric (326.36 95% CI 201.65-450.86) and visual methods (456.51 95% CI 395.19-517.83). Of the many studies included, only a few were compared with a validated reference. The majority of the studies chose known imprecise procedures as the method of comparison. Colorimetric methods offer the highest degree of accuracy in blood loss estimation. Systems that use colorimetric techniques have a significant advantage in the real-time assessment of blood loss

A Political Economy of Positions in Climate Change Negotiations: Economic, Structural, Domestic, and Strategic Explanations

After the disappointing outcome of the Copenhagen climate summit, it still remains to be explained why the participating states chose irreconcilable negotiation positions that reflected very diverse domestic interests in spite of a publicly displayed wish for cooperation. While environmental studies have intensely investigated national climate policies and their determinants over the last few decades, little attention has been paid to the bargaining positions the same governments assume in climate negotiations. We argue that their bargaining positions reflect structural, economic, and domestic factors, but less so strategic factors. A country’s vulnerability to climate change, its power and its democratic status are among the best predictors of its choice of negotiation position; its international interconnectedness, on the other hand, does not seem to have an influence. By comparing two negotiation issues – reducing emissions and financing climate mitigation – we can show that democracies choose rather different negotiation positions. When it comes to compensation mechanisms, democracies do not commit to substantial emission reduction targets due to pressure from industry at home. They are, however, more prepared than other states to pay for projects that help to reduce emissions. By understanding the choice of negotiation positions we can thus explain why the more or less cooperative bargaining positions adopted by states led to a breakdown of the Copenhagen negotiations. We investigated this question using a novel dataset on the UNFCCC negotiations, in which the positions of all participating governments were collected by hand-coding protocols from the negotiations as well as expert interviews with negotiators