Aims: Endostatin is a type of human vascular endostatin with more stable and higher activity. This study sought to evaluate pharmacokinetics (PK), safety and preliminary efficacy between treatment with endostatin 4 hours intravenous infusion and 72 hours or 168 hours intravenous pump infusion in patients with advanced non-small cell lung cancer (NSCLC). Methods: A total of 24 patients with advanced NSCLC were randomly assigned to group A and B. All patients received a standard 21 days treatment cycle of platinum-based doublet chemotherapy (paclitaxel or pemetrexed) and endostatin. Endostatin was administered at 7.5 mg/m2/day for 4 hours from day 1 to day 14 of cycle 1. Starting from day 1 of cycle 2, endostatin was administered at 105 mg/m2/cycle for 72 hours (group A) or 168 hours (group B), respectively. The total treatment duration was 4 cycles, with the option to extend up to 6 cycles. Results: The PK exposure per cycle of endostatin 4 hours infusion and 72 hours or 168 hours pump infusion were comparable between group A and group B. The majority of adverse events during pump infusion were consistent with those observed during infusion and no endostatin-related serious adverse events were reported. The overall objective response rate (ORR) was 37.5%. Conclusion: The PK exposure between intravenous infusion and intravenous pump infusion at the same total cycle dose is similar. Both 72 hours and 168 hours intravenous pump infusion endostatin were well tolerated, and no new unexpected safety signals were observed.

Background and Purpose: Emerging studies indicated that Klotho is a marker of renal injury and owns a protective effect on different kinds of kidney diseases. However, the role of Klotho in vancomycin (Van)-induced acute kidney injury (AKI) is largely unclear. Hence this study aimed to explore the regulatory mechanism of Klotho in Van-AKI. Experimental Approach: The mRNA expression of Klotho and the JAK2/STAT3/GPx3 axis was assessed by RNA sequence analysis after the Van challenging; the mechanism action of Klotho was examined in vitro by Klotho small interfering RNA and recombinant Klotho. The expression of reactive oxygen species and antioxidant enzymes was detected by flow cytometry and spectrophotometry. Transmission electron microscopy was performed to scan the structural damage of mitochondria. Western blot, qPCR, and immunofluorescence were applied to further explore the function of the JAK2/STAT3/GPx3 axis in Van-AKI. Key Results: RNA sequence analysis indicated that Van challenging reduced the expression of Klotho and GPx3, but increased JAK2/STAT3. In vitro, Klotho siRNA enhanced the production of reactive oxygen species and the cell apoptosis ratio by regulating the JAK2/STAT3/GPx3 axis, while the decrease of GPx3 was prevented by specific inhibitors of JAK2/STAT3. In contrast, recombinant human Klotho showed the opposite function to Klotho siRNA. In vivo, recombinant mouse Klotho improved the anti-oxidative enzyme level and mitochondria damage as well as renal dysfunction and histological damage via upregulating anti-oxidative ability. Conclusion and Implications: To conclude, the study evidenced that recombinant Klotho ameliorated Van-induced AKI via the JAK2/STAT3/GPx3 signaling axis by upregulating anti-oxidative ability.