Safety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies.

BACKGROUND: YN968D1 (Apatinib) selectively inhibits phosphorylation of VEGFR-2 and tumor angiogenesis in mice model. The study was conducted to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetic variables, and antitumor activity in advanced solid malignancies. METHODS: This dose-escalation study was conducted according to the Chinese State Food and Drug Administration (SFDA) recommendations in patients with advanced solid tumors to determine the MTD for orally administered apatinib. Doses of continuously administered apatinib were escalated from 250 mg. Treatment continued after dose-escalation phase until withdrawal of consent, intolerable toxicities, disease progression or death. RESULTS: Forty-six patients were enrolled. Hypertension and hand-foot syndrome were the two dose-limiting toxicities noted at dose level of 1000 mg. MTD was determined to be 850 mg once daily. Pharmacokinetic analysis showed early absorption with a half-life of 9 hours. The mean half-life was constant over all dose groups. Steady-state conditions analysis suggested no accumulation during 56 days of once-daily administration. The most frequently observed drug-related adverse events were hypertension (69.5%, 29 grade 1-2 and 3 grade 3-4), proteinuria (47.8%, 16 grade 1-2 and 6 grade 3-4), and hand-foot syndrome (45.6%, 15 grade 1-2 and 6 grade 3-4). Among the thirty-seven evaluable patients, PR was noted in seven patients (18.9%), SD 24 (64.9%), with a disease control rate of 83.8% at 8 weeks. CONCLUSIONS: The recommended dose of 750 mg once daily was well tolerated. Encouraging antitumor activity across a broad range of malignancies warrants further evaluation in selected populations. TRIAL REGISTRATION: ClinicalTrials.gov unique identifier: NCT00633490.

[Effect of different N, P and K fertilizers on soil pH and available Cd under waterlogged conditions].

In order to tackle the problem of Cd pollution in paddy soils and investigate soil available Cd as affected by different fertilizers, incubation experiments were carried out to study the effects of different N, P and K fertilizers and pH by adding acid or base on soil available Cd under waterlogged conditions. Results revealed that soil pH increased sharply after the soil was flooded, especially at the beginning of incubation, and gradually decreased with incubation time and finally tended to approach the neutral values. The patterns of soil pH change were just opposite to those of soil available Cd, a negative correlation observed between the two. Soil flooding made the soil available Cd drop by 58.2%-84.1%. There were significant differences between different fertilizer types/varieties on soil available Cd, being most complex with N fertilizers and followed by K and P fertilizers. Among the fertilizers studied, ammonium chloride showed the unique ability in reducing soil pH and enhancing soil available Cd, and urea, single super phosphate and potassium chloride also promoted to a less extent amounts of Cd extracted from the soil. Ammonium sulfate, potassium sulfate and mono-ammonium phosphate significantly decreased soil available Cd compared to the CK treatment. Whether or not the soil was flooded, soil available Cd was highly negatively correlated with soil pH after adding acid or base (R = - 0.994 without incubation and R = - 0.919 after incubation for 60 d). The results further suggest that in the Cd polluted paddy soil, use of ammonium chloride should be avoided, S bearing fertilizers in combination with alkaline materials can be adopted, and the rice field should be flooded all the time during growing season, all the these practices can effectively lower soil available Cd.

[Anti-angiogenesis targeting drugs: a review].

The dependence of tumor growth and metastasis on blood vessels makes tumor angiogenesis a rational target for cancer therapy. One of the key mediators of angiogenesis is vascular endothelial growth factor (VEGF), which is an appealing target for anticancer therapy. The development of anti-VEGF/VEGFR agents and the latest clinical data are reviewed, including bevacizumab as a monoclonal antibody to VEGF, sunitinib and sorafenib as VEGFR tyrosine kinase inhibitors, and IMC-1C11 as VEGFR monoclonal antibody.