Marietta Kirchner

Expression of CYP3A5 protein is a basal and acquired resistance mechanism of pancreatic ductal adenocarcinoma cells conferring protection against the CYP3A and CYP2C8 substrate paclitaxel through metabolic degradation. Inhibition of CYP3A isozymes restores the cells sensitivity to paclitaxel. The combination of gemcitabine and nab‐paclitaxel is an established regimen for the treatment of metastasized or locally advanced inoperable pancreatic cancer. Cobicistat is a CYP3A inhibitor developed for the pharmacoenhancement of protease inhibitors. The addition of cobicistat to gemcitabine and nab‐paclitaxel may increase the antitumor effect. We will conduct a phase I dose escalation trial with a classical 3 + 3 design to investigate the safety, tolerability, and pharmacokinetics (PKs) of gemcitabine, nab‐paclitaxel, and cobicistat. Although the doses of gemcitabine (1000 mg/m 2 ) and cobicistat (150 mg) are fixed, three dose levels of nab‐paclitaxel (75, 100, and 125 mg/m 2 ) will be explored to account for a potential PK drug interaction. After the dose escalation phase, we will set the recommended dose for expansion (RDE) and treat up to nine patients in an expansion part of the trial. The trial is registered under the following identifiers EudraCT‐Nr. 2019‐001439‐29, drks.de: DRKS00029409, and ct.gov : NCT05494866. Overcoming resistance to paclitaxel by CYP3A5 inhibition may lead to an increased efficacy of the gemcitabine and nab‐paclitaxel regimen. Safety, efficacy, PK, and RDE data need to be acquired before investigating this combination in a large‐scale clinical study.

The mechanisms underlying the altered postural control and risk of falling in patients with osteoporosis are not yet fully understood. The aim of the present study was to investigate postural sway in women with osteoporosis and a control group. The postural sway of 41 women with osteoporosis (17 fallers and 24 non-fallers) and 19 healthy controls was measured in a static standing task with a force plate. The amount of sway was characterized by traditional (linear) center-of-pressure (COP) parameters. Structural (nonlinear) COP methods include spectral analysis by means of a 12-level wavelet transform and a regularity analysis via multiscale entropy (MSE) with determination of the complexity index. Patients showed increased body sway in the medial–lateral (ML) direction (standard deviation in mm: 2.63 ± 1.00 vs. 2.00 ± 0.58, p = 0.021; range of motion in mm: 15.33 ± 5.58 vs. 10.86 ± 3.14, p = 0.002) and more irregular sway in the anterior–posterior (AP) direction (complexity index: 13.75 ± 2.19 vs. 11.18 ± 4.44, p = 0.027) relative to controls. Fallers showed higher-frequency responses than non-fallers in the AP direction. Thus, postural sway is differently affected by osteoporosis in the ML and AP directions. Clinically, effective assessment and rehabilitation of balance disorders can benefit from an extended analysis of postural control with nonlinear methods, which may also contribute to the improvement of risk profiles or a screening tool for the identification of high-risk fallers, thereby prevent fractures in women with osteoporosis.