Effect of X-ray radiation on the pharmacokinetics of apatinib in vivo in rats.

Purpose: The "radiotherapy-pharmacokinetic" ("RT-PK") phenomenon refers to the fact that radiation can significantly alter the pharmacokinetic behavior of a drug. At present, it is not clear whether there is an "RT-PK" phenomenon that can affect apatinib during concurrent chemoradiotherapy. In this study, we used a rat irradiation model to study the effects of X-ray radiation on absorption, tissue distribution, and excretion of apatinib. Method: Healthy Sprague-Dawley (SD) rats were randomly divided into control and radiation groups. The radiation group was given an appropriate dose of abdominal X-ray radiation, while the control group was not given irradiation. After 24 h of recovery, both groups were given apatinib solution 45 mg/kg by gavage. A quantitative LC-MS/MS method was developed to determine the concentration of apatinib in the rats, so as to compare the differences between the control and radiation groups and thus investigate the modulating effect of radiation on the pharmacokinetics of apatinib in rats. Results: After abdominal X-ray irradiation, the area under the curve (AUC0-t) of apatinib in rat plasma decreased by 33.8% and 76.3% at 0.5 and 2 Gy, respectively. Clearance (CL) and volume of distribution (Vd) increased and were positively correlated with radiation dose. X-ray radiation significantly reduced the concentration of apatinib in the liver and small intestine, and there was no tissue accumulation. In excretion studies, we found that X-ray radiation reduced the cumulative excretion of apatinib in feces and urine by 11.24% and 86.17%, respectively. Conclusion: Abdominal X-ray radiation decreased plasma exposure, tissue distribution, and excretion of apatinib in rats, suggesting that the RT-PK phenomenon affects apatinib. We speculate that this RT-PK phenomenon is closely related to changes in metabolic enzymes in vivo. In clinical practice, when apatinib is combined with radiotherapy, attention should be paid to adjusting the dose of apatinib and optimizing the treatment plan to alleviate the adverse effects of this RT-PK phenomenon.

[Identification of chemical constituents in Zhachong Shisanwei Pills by UPLC-Q-TOF-MS/MS].

Zhachong Shisanwei Pills, composed of 13 Chinese medicinal materials, are used for treating the diseases such as hemiplegia, pain of muscles and bones, rheumatism, and joint pain. The chemical composition and pharmacodynamics of Zhachong Shisanwei Pills have not been reported. Ultra-performance liquid chromatography/quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS) was employed to quickly identify the chemical components of Zhachong Shisanwei Pills, which was performed with Shim-pack GIST C_(18) column(4.6 mm×150 mm, 5 µm). The gradient elution was conducted with methanol-0.05% acetic acid as the mobile phase. Electrospray ionization mass spectrometry(ESI-MS) was carried out in both positive and negative ion modes. The compounds were identidied based on accurate relative molecular weight, fragment ion species, and the MS data of reference substances and in literature. In conclusion, a total of 98 compounds were identified, including 19 organic acids, 36 flavonoids, 13 volatile oils, 8 tannins, 5 2-(2-phenylethyl)chromones, 5 amino acids, 3 sesquiterpenoids, 3 alkaloids, and 2 other compounds. This study characte-rized the chemical components of Zhachong Shisanwei Pills rapidly for the first time, laying a foundation for further research on the pharmacodynamic material basis and quality evaluation.

Investigation of the metabolites of five major constituents from Berberis amurensis in normal and pseudo germ-free rats.

Berberis amurensis (Berberidaceae) is a traditional Chinese medicine, which is often used to treat hypertension, inflammation, dysentery and enteritis. It contains alkaloids, mainly including berberine, berbamine, magnoflorine, jatrorrhizine and palmatine. Berberis amurensis extracts (BAEs) is often orally taken. Oral herbs might be metabolized by intestinal bacteria in the small intestine. However, the interaction between the herb and the gut microbiota is still unknown. In the current study, UPLC/Q-TOF-MS/MS combined with Metabolitepilot and Peakview software was used to identify the metabolites of BAEs in anti-biotic cocktail induced pseudo germ-free rats and normal rats. As a result, a total of 46 metabolites in normal rats were detected and its main metabolic pathways include demethylation, dehydrogenation, methylation, hydroxylation, sulfation and glucuronidation. Only 29 metabolites existed in pseudo germ-free rats. Dehydrogenated metabolites (M29, M30, M34 and M36), methylated metabolites (M33, M41 and M46) and other metabolites were not detected in pseudo germ-free rats. The result implied that the intestinal bacteria have an influence on the metabolism of BAEs. Furthermore, this investigation might contribute to the understanding of the metabolism of BAEs, and further promote its clinical application.

Clinicopathologic and Prognostic Significance of Body Mass Index (BMI) among Breast Cancer Patients in Western China: A Retrospective Multicenter Cohort Based on Western China Clinical Cooperation Group (WCCCG).

INTRODUCTION: Clinicopathologic and prognostic significance of body mass index (BMI) in breast cancer (BC) patients remained conflicting. We aimed to investigate and modify the impact of BMI on clinicopathological significance and survival in western Chinese BC patients. MATERIALS AND METHODS: 8,394 female BC patients from Western China Clinical Cooperation Group (WCCCG) between 2005 and 2015 were identified. Multivariable logistic regression and Cox proportion hazard regressions were used to examine the difference of clinicopathologic and survival characteristics between BMI categories. RESULTS: For the premenopausal, overweight and obese (OW) patients tended to have large tumor size (>5cm) (odds ratio [OR], 1.30, P<0.01) and triple-negative BC (OR, 1.31; P=0.01) compared with normal weight (NW) patients. Premenopausal underweight (UW) patients had a significantly higher risk of HER2 positive (OR, 1.71; P=0.02) and distant metastasis (OR, 2.59; P=0.01). For postmenopausal patients, OW patients showed higher risks of large tumor size (>5cm) (OR, 1.46; P=0.01), nuclear grade III (OR, 1.24; P=0.04), and lymphovascular invasion (OR, 1.46; P=0.01) compared with NW patients. An "U" shaped relationship between BMI and DFS was found (UW versus NW, adjusted hazard ratio (HR), 2.80, P<0.001; OW versus NW, adjusted HR, 1.40, P=0.02), whereas no significant difference of disease-free survival (DFS) between OW and NW premenopausal patients (adjusted HR=1.34, P=0.18) was revealed. CONCLUSION: We concluded that UW and OW were associated with aggressively clinicopathological characteristics, regardless of menopausal status. An "U" shaped association of BMI and DFS was revealed, and no significant difference of DFS between OW and NW in postmenopausal subgroup was revealed.

Predictors of internal mammary lymph nodes (IMLN) metastasis and disease-free survival comparison between IMLN-positive and IMLN-negative breast cancer patients: Results from Western China Clinical Cooperation Group (WCCCG) database (CONSORT).

Limited studies performed a comprehensive assessment of risk factors for internal mammary lymph nodes (IMLN) metastasis, and disease-free survival (DFS) difference between IMLN-positive and IMLN-negative breast cancer (BC) patients undergoing IMLN dissection and systemic therapies was not clear.A retrospective study included 1977 BC patients from Western China Clinical Cooperation Group between January 2005 and December 2012. The impact of clinicopathological factors on the occurrence of IMLN metastasis was assessed in univariate and multivariate logistic regression analyses, and a nomogram (model) was constructed to predict the IMLN status. DFS difference was evaluated in univariate and multivariate Cox regression analyses between IMLN-negative and IMLN-positive patients, and univariate analysis was performed to compare DFS between individuals with high and low IMLN metastasis risk defined by proposed nomogram.Of 1977 enrolled patients, 514 cases underwent IMLN dissection and 1463 cases did not undergo IMLN irradiation or dissection. We found that initial disease symptoms and signs, mammographic calcification, tumor site, number of positive axillary lymph nodes (ALNs), American Joint Committee on Cancer pT stage, and human epidermal growth factor receptor 2 status were associated with IMLN metastasis (all P < .05). Those variables were included in nomogram, whose predictive ability was better than that of ALN classification (area under the curve: 0.82 vs 0.76, P < .001). Univariate cox proportional hazards model indicated that better DFS was observed in IMLN-negative patients than IMLN-positive group (hazard ratio [HR] = 1.87, 95% confidence interval [CI] = 1.05-3.34; P = .04), whereas no significant differences in DFS (HR = 0.99, 95% CI = 0.49-2.00; P = .97) were found after adjusting patient-, disease-, and treatment-related factors.Nipple inversion, mammographic calcification, larger tumor size, medial tumor site, negative HER-2 status, and more positive ALNs are independent risk factors for IMLN metastasis, and the individualized nomogram is a feasible tool to predict the status of IMLN. Equivalent DFS was found between positive and negative IMLN patients who all accepted IMLN dissection and systemic therapies.

H2S protects against fatal myelosuppression by promoting the generation of megakaryocytes/platelets.

BACKGROUND: Our previous pilot studies aimed to examine the role of hydrogen sulfide (H2S) in the generation of endothelial progenitor cells led to an unexpected result, i.e., H2S promoted the differentiation of certain hematopoietic stem/progenitor cells in the bone marrow. This gave rise to an idea that H2S might promote hematopoiesis. METHODS: To test this idea, a mice model of myelosuppression and cultured fetal liver cells were used to examine the role of H2S in hematopoiesis. RESULTS: H2S promoted the generation of megakaryocytes, increased platelet levels, ameliorate entorrhagia, and improved survival. These H2S effects were blocked in both in vivo and in vitro models with thrombopoietin (TPO) receptor knockout mice (c-mpl(-/-) mice). In contrast, H2S promoted megakaryocytes/platelets generation in both in vivo and in vitro models with TPO knockout mice (TPO(-/-) mice). CONCLUSIONS: H2S is a novel promoter for megakaryopoiesis by acting on the TPO receptors but not TPO to generate megakaryocytes/platelets.

Quantum dynamics study of H + DBr and D + HBr reaction.

Time-dependent quantum wave packet calculations have been performed for the H + DBr and D + HBr reaction using the recent diabatic potential energy surfaces. Reaction probabilities, integral cross sections, and rate constants are obtained. The results show that the isotopic effects have an influence on the nonadiabatic effect which is generally inversely proportional to the atom mass. The calculated rate constants are in good overall agreement with experimental values, indicating that the ab initio surfaces are accurate to describe the isotopic effects.

Quantum dynamical study of the electronic nonadiabaticity in the D + DBr → Br(Br*) + D2 reaction on new diabatic potential energy surfaces.

A set of diabatic potential energy surfaces, that describe the D + DBr → Br(P(1/2,3/2)) + D(2) reaction, is constructed based on MRCI/aug-cc-pV5Z calculations at 29,526 grid points. Time-dependent wave packet calculations are performed for ground-state DBr initially with collision energies up to 2.0 eV to investigate possible electronic nonadiabaticity in this reaction. Reaction probabilities and integral cross sections are calculated. The results show negligible nonadiabatic effects for the title reaction in the energy range considered here, confirming experimental work of Zare and co-workers. In addition, the calculated thermal rate constants are in good agreement with experimental ones.

Full six-dimensional nonadiabatic quantum dynamics calculation for the energy pooling reaction O(2)(a (1)Delta)+O(2)(a (1)Delta)-->O(2)(b (1)Sigma)+O(2)(X (3)Sigma).

Six new potential energy surfaces of four singlet states and two triplet states for the title oxygen molecule reaction along with the spin-orbit coupling among them have been constructed from the complete active space second-order perturbation theory with a 6-311+G(d) basis. Accurate integral cross sections are calculated with a full six-dimensional nonadiabatic time-dependent quantum wave packet method. The thermal rate constant based on the integral cross sections agrees well with the result of the experimental measurements, and the intersystem crossing effects are also discussed in this electronic energy-transfer process.