Is the combinational administration of doxorubicin and glutathione a reasonable proposal?

The combinational administration of antioxidants and chemotherapeutic agents during conventional cancer treatment is among one of the most controversial areas in oncology. Although the data on the combinational usage of doxorubicin (DOX) and glutathione (GSH) agents have been explored for over 20 years, the duration, administration route, and authentic rationality have not yet been fully understood yet. In the current study, we systematically investigated the pharmacokinetics (PK) and pharmacodynamics (PD) with both in vivo and in vitro models to elucidate the influence of GSH on the toxicity and efficacy of DOX. We first studied the cardioprotective and hepatoprotective effects of GSH in Balb/c mice, H9c2, and HL7702 cells. We showed that coadministration of exogenous GSH (5, 50, and 500 mg/kg per day, intragastric) significantly attenuated DOX-induced cardiotoxicity and hepatotoxicity by increasing intracellular GSH levels, whereas the elevated GSH concentrations did not affect the exposure of DOX in mouse heart and liver. From PK and PD perspectives, then the influences of GSH on the chemotherapeutic efficacy of DOX were investigated in xenografted nude mice and cancer cell models, including MCF-7, HepG2, and Caco-2 cells, which revealed that administration of exogenous GSH dose-dependently attenuated the anticancer efficacy of DOX in vivo and in vitro, although the elevated GSH levels neither influenced the concentration of DOX in tumors in vivo, nor the uptake of DOX in MCF-7 tumor cells in vitro. Based on the results we suggest that the combined administration of GSH and DOX should be contraindicated during chemotherapy unless DOX has caused serious hepatotoxicity and cardiotoxicity.

Pharmacokinetic and pharmacodynamic evidence for developing an oral formulation of octreotide against gastric mucosal injury.

Among the somatostatin analogues, octreotide (OCT) is the most commonly used in clinic via intravenous or subcutaneous injection to treat various diseases caused by increased secretion of growth hormone, gastrin or insulin. In order to assesse the feasibility of developing oral formulations of OCT, we conducted systematical pharmacokinetic and pharmacodynamic analyses of OCT in several animal models. The pharmacokinetic studies in rats showed that intragastric administration of OCT had extremely low bioavailability (<0.5%), but it could specifically distribute to the gastric mucosa due to the high expression of somatostatin receptor 2 (SSTR2) in the rat stomach. The pharmacodynamic studies revealed that intragastric administration of OCT dose-dependently protected against gastric mucosal injury (GMI) in mice with WIRS-induced mouse gastric ulcers, which were comparable to those achieved by intravenous injection of OCT, and this effect was markedly attenuated by co-administration of CYN-154806, an antagonist of SSTR2. In pyloric ligation-induced ulcer mice, we further demonstrated that OCT significantly reduced the secretion of gastric acid via down-regulating the level of gastrin, which was responsible for the protective effect of OCT against GMI. Overall, we have provided pharmacokinetic and pharmacodynamic evidence for the feasibility of developing an oral formulation of OCT. Most importantly, the influence of SSTR2 on the pharmacokinetics and pharmacodynamics of OCT suggested that an oral formulation of OCT might be applicable for other clinical indications, including neuroendocrine neoplasms and pituitary adenoma due to the overexpression of SSTR2 on these tumor cells.

[Transient Storage Characteristics of Artificial Pool Geomorphic Structure in an Agricultural Headwater Stream].

From November 2015 to February 2016, five short-term tracer injections were performed with a conservative tracer (NaCl) in an agricultural headwater stream, Lake Chaohu basin. Thus the data sets of tracer experiments were finally employed for calculating the physical characteristics and transient storage metrics. Through the comparisons between the artificial pool reach and straight reach, characteristics of transient storage for the artificial pool geomorphic structure were interpreted and explored. Study results showed that: ① The ratio of As/A in artificial pool was larger than that in straight reach, whereas its value of exchange coefficient α was lower by an order of magnitude than that of straight reach. ② Artificial pool geomorphic structure had greater influence of transient storage on solute retention than that in straight reach, but its solute retention capacity of flowing water was weaker than that of straight reach. ③ It had a large ratio of As/A for the pool geomorphic structure, whereas its impact on the migration and transformation of solutes was less than that of straight reach. ④ Based on the Fmed200 metric, the transient storage accounted for 18.86% to 26.05% of travel time in artificial pool. For the straight reach, the Fmed200 metric had a range of 5.28% to 33.87%. In most cases, the values of Fmed200 metric in straight reach were higher than those in artificial pool. ⑤ Significant differences existed between artificial pool geomorphic structure and straight reach in the values of φw, φA and Ts, however, the differences were not significant in other indicators.

Monitoring of flow field based on stable isotope geochemical characteristics in deep groundwater.

The water circulation in deep aquifers controls not only chemical composition of the groundwater, but also stable isotope composition. In order to analyze the flow field in the process of the deep groundwater circulation in different aquifers, specimens belonging to the fourth aquifer in the Quaternary (the fourth aquifer for short), the coal and sandstone cranny aquifer in the Permian, and Carboniferous (the coal catena aquifer for short), the Taiyuan group limestone aquifer in the Carboniferous (the Taiyuan limestone aquifer for short), and the limestone aquifer in the Ordovician (the Ordovician limestone aquifer for short) were gained from the top down in Renlou colliery and local Linhuan coalmine district, northern Anhui, China, in the study. δD, δ(18)O, and the content of tall dissolve solids (TDS for short) of these specimens were tested. The experimental results had revealed that the groundwater in the fourth aquifer and the Taiyuan limestone aquifer takes on (18)O excursion and the coal catena aquifer takes on D excursion in Linhuan coalmine district, while excursion characteristic in the Ordovician limestone aquifer is not evident in the coalmine district. By analysis, δ(18)O and the content of TDS are in negative relationship in the groundwater of the fourth aquifer and the Taiyuan limestone aquifer in Linhuan coalmine district, yet δD and the content of TDS are in positive relationship in the coal catena aquifer. Mining greatly influences the fourth aquifer and the coal catena aquifer so the groundwater in the fourth aquifer flows from northwest and southeast to mining areas and the groundwater in the coal catena aquifer flows from around to mining areas. However, mining does not influence the Taiyuan limestone aquifer evidently so the groundwater flows from east to west still.