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Aims: The objectives were to investigate the pharmacokinetics, pharmacodynamics and safety of ilaprazole infusion in healthy subjects and patients with esomeprazole as positive control, and then recommend the dosage regimen for Phase 2b/3 studies. Methods: Three clinical studies were performed. First, 16 healthy subjects received infusion of ilaprazole 30 mg or esomeprazole 80 mg. Second, 12 healthy subjects received ilaprazole 20 mg followed by 10 mg once daily for 2 days. Finally, 20 patients with duodenal ulcers received ilaprazole 20 mg followed by 10 mg for 2 days or esomeprazole 40 mg twice daily for 3 days. Serial blood samples were collected and intragastric pH was recorded. Results: The mean percentages time of intragastric pH >6 was 63.6 and 51.7% for healthy subjects after receiving ilaprazole 30 mg and esomeprazole 80 mg. Linear pharmacokinetics was observed when the dose was increased to 30 mg but the effect was saturated. Ilaprazole 20 mg followed by 10 mg for 2 days provided higher plasma exposure in healthy subjects than patients, but the effect was comparable. After multiple administrations, ilaprazole provided similar effect to esomeprazole. Ilaprazole infusion was safe and well tolerated without serious adverse events. Conclusions: Ilaprazole provided comparable effect of pH control to esomeprazole, with lower dose and fewer times of administration. There was no significant difference of ilaprazole between healthy subjects and patients regarding intragastric acid inhibition. A loading dose of ilaprazole 20 mg followed by 10 mg once daily for 2 days was recommended for Phase 2b/3 studies. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to standard chemo- and radiotherapy. Recently, a new class of non-platinum-based halogenated molecules (called FMD compounds) was discovered that selectively kills cancer cells. Here, we investigate the potential of 1,2-Diamino-4,5-dibromobenzene (2Br-DAB) in combination with standard chemotherapy and radiotherapy in murine and human PDAC. Methods: Cell viability and colony formation was performed in human (Panc1, BxPC3, PaTu8988t, MiaPaCa) and three murine LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) pancreatic cancer cell lines. In vivo, preclinical experiments were conducted in LSL-KrasG12D/+;p48-Cre (KC) and KPC mice using 2Br-DAB (7 mg/kg, i.p.), +/- radiation (10 × 1.8 Gy), gemcitabine (100 mg/kg, i.p.), or a combination. Tumor growth and therapeutic response were assessed by high-resolution ultrasound and immunohistochemistry. Results: 2Br-DAB significantly reduced cell viability in human and murine pancreatic cancer cell lines in a dose-dependent manner. In particular, colony formation in human Panc1 cells was significantly decreased upon 25 µM 2Br-DAB + radiation treatment compared with vehicle control (p = 0.03). In vivo, 2Br-DAB reduced tumor frequency in KC mice. In the KPC model, 2Br-DAB or gemcitabine monotherapy had comparable therapeutic effects. Furthermore, the combination of gemcitabine and 2Br-DAB or 2Br-DAB and 18 Gy irradiation showed additional antineoplastic effects. Conclusions: 2Br-DAB is effective in killing pancreatic cancer cells in vitro. 2Br-DAB was not toxic in vivo, and additional antineoplastic effects were observed in combination with irradiation. [ABSTRACT FROM AUTHOR]

Powder plasma arc additive manufacturing (PPA-AM) is a promising method for the preparation of high-entropy alloys (HEAs), and has the advantages of low cost, high efficiency, and high quality. In this study, the CoCrFeNiW x (x = 0, 0.2, 0.5, 0.7, and 1.0) HEAs were successfully prepared via the PPA-AM technique. Microstructure and mechanical properties of alloys with different W content were investigated. The results showed that the microstructure changed from a single FCC phase (x = 0) to the dual-phase FCC + µ (x = 0.2 and 0.5), and then to a three-phase combination of FCC + µ + BCC (x = 0.7 and 1.0) with the addition of W. The volume fraction of the µ phase and BCC phase increases with the increase in W content, while the size of FCC columnar grain is significantly reduced. The solid-solution strengthening of the FCC phase and the second phase strengthening were mainly responsible for the increase in the microhardness (136–413 HV) and yield strength (187–567 MPa) while the brittleness of the μ phase contributes to the expansion of the crack, which leads to a decrease in the ductility (50.8% to 0.3%). These results can provide a systematic understanding of the phase transformation of PPA-AM HEAs with different W content and its effects on the mechanical properties. • Powder plasma arc additive manufacturing (PPA-AM) of CoCrFeNiWx high-entropy alloys. • PPA-AM can produce high-entropy alloys with lower cost and high efficiency. • The microstructure and mechanical properties of the CoCrFeNiWx HEAs were investigated. • W element can promote the phase transformation from FCC phase to µ and BCC phase. • The strength of the HEAs was significantly improved with addition of W. [ABSTRACT FROM AUTHOR]