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Background: The trough concentration (Cmin) of Imatinib (IM) is closely related to the treatment outcomes and adverse reactions of patients with gastrointestinal stromal tumors (GIST). However, the drug plasma level has great inter- and intra-individual variability, and therapeutic drug monitoring (TDM) is highly recommended. Objective: To develop a novel, simple, and economical two-dimensional liquid chromatography method with the ultraviolet detector (2D-LC-UV) for simultaneous determination of IM and its major active metabolite, N-desmethyl imatinib (NDIM) in human plasma, and then apply the method for TDM of the drug. Methods: The sample was processed by simple protein precipitation. Two target analytes were separated on the one-dimension column, captured on the middle column, and then transferred to the two-dimension column for further analysis. The detection was performed at 264 nm. The column temperature was maintained at 40˚C and the injection volume was 500 μL. Totally 32 plasma samples were obtained from patients with GIST who were receiving IM. Results: IM and NDIM were separated well from other impurities and the entire analytical time for each run was 12.0 min. The calibration curves had good linearity in the range of 33.5-2678.4 ng/mL for IM, and 20.0-1600.0 ng/mL for NDIM, respectively. The extraction efficiency was more than 95%. The acceptable accuracy, precision, recovery and stability were also obtained. The Cmin of the drug in patients was measured with the validated method. Conclusion: The novel 2D-LC-UV method is simple, stable, highly automated and independent of specialized technicians, which greatly increases the real-time capability of routine TDM for IM in hospital.

This study aimed to evaluate the label compliance of DOACs in the Chinese AF population and explore the relationship between inappropriate DOACs dosage and clinical results.This is a retrospective multicenter cohort study conducted in 14 centers in China. According to the China Food and Drug Administration(CFDA) label and the recommendations of international guidelines, we divided patients into on-label dosage and off-label dosage. We then compared the clinical results after propensity score matching. We collect demographic information through the hospital information system and obtain clinical events through follow-up of patients or their families. Clinical results include major, minor, total bleeding, thrombosis, and all-cause death. 4191 patients with non-valvular AF (NVAF) were included, and approximately 55.6% and 1.7% of AF patients received off-label underdose and off-label overdose of DOACs, respectively. Compared with the on-label dose, DOACs with off-label underdose were associated with a significantly reduced risk of major bleeding (P = 0.004, OR = 0.23,95% CI: 0.08-0.69) and all-cause death (P0.001, OR = 0.49,95% CI: 0.33-0.73). However, there was no significant difference in thrombotic events (P = 0.865 OR = 1.06,95% CI: 0.54-2.07) and minor bleeding (P = 0.465, OR = 1.10,95% CI: 0.85-1.43) risk.About 57.3% of Asian AF patients received an off-label dose of DOACs in daily practice. Off-label underdose DOACs were associated with significantly lower risks of major bleeding, all-cause death, and similar risks of minor bleeding, thrombotic events compared with on-label dose DOACs. Further prospective randomized trials are needed to determine the optimal dose of DOACs in Asian patients with AF at high bleeding risk.

This study observes a previously neglected pharmacological phenomenon and investigates its mechanism of that the continuous low-dose administration of some antineoplastic agents in certain dose ranges can promote tumorigenesis and tumor progression in vitro and in vivo, through stimulation of tumor cell functions directly as well as enhancement of tumor angiogenesis by BMDCs recruitment indirectly. The results alert to a potential risk in current empirically based continuous low-dose chemotherapy regimens such as metronomic chemotherapy.There are indications that certain antineoplastic agents at low dosages may exhibit abnormal pharmacological actions, such as promoting tumor growth. However, the phenomenon still needs to be further confirmed, and its underlying mechanisms have not yet been fully elucidated.Gemcitabine (GEM) and cisplatin (CDDP) were employed as representative antineoplastic agents to observe effects of continuous low-dose chemotherapy with GEM or GEM combined with CDDP (GEM+CDDP) on tumor formation and growthin xenograft tumor models in vivo. Tumor and endothelial cell functions, apoptosis, cell cycle analysis, as well as bone marrow derived cells (BMDCs) mobilization, were evaluated with transwell, MTT or flow cytometry analysis in vitro, respectively. Histological methods were employed to assess angiogenesis in tumor tissues.The results showed that tumor formation and growth were both significantly promoted by GEM or GEM+CDDP at as low as half of the metronomic dosages, which were accompanied by enhancements of angiogenesis in tumor tissues and the release of proangiogenic BMDCs in the circulating blood. Additionally, GEM or GEM+CDDP at low concentrations dramatically facilitated the proliferation, migration, and invasion of tumor cells in vitro. Cell-cycle arrest, activation of associated apoptotic proteins, and inhibition of apoptosis were also observed in tumor cells.These findings indicate that, the continuous low-dose administration of GEM and GEM+CDDP can promote tumorigenesis and tumor progression in vivo by inhibiting apoptosis, mobilizing BMDCs, and promoting angiogenesis in certain dose ranges. These findings urge further investigations to avoid the potential risks in current empiric continuous low-dose chemotherapy regimens with antineoplastic agents.

We conducted a multicenter real-world study in China to assess the association between body mass index (BMI) and clinical outcomes in patients with atrial fibrillation (AF) taking direct oral anticoagulants (DOACs).This is a retrospective multicenter cohort study conducted in 15 centers in China. We collected demographic information through the hospital information system and obtained clinical events through follow-up visits to patients or relatives. Clinical outcomes include major, minor, total bleeding, thromboembolism, and all-cause death.A total of 6164 patients with non-valvular AF (NVAF) were included in this study. The incidence of major bleeding in patients with NVAF differed significantly by BMI category (P0.001), with 5.2% in the underweight group, 2.6% in the normal group, 1.4% in the overweight group, 1.1% in the obese I group, and 1.3% in the obese II group. There was no significant difference in minor, total bleeding, and thrombosis in the five groups (P = 0.493; P = 0.172; P = 0.663). All-cause death was significantly different among the five groups (P0.001), with 8.9% in the underweight group, 6.3% in the normal group, 4.8% in the overweight group, 2.2% in the obese I group, and 0.4% in the obese II group. High BMI was negatively associated with major bleeding (OR = 0.353, 95% CI 0.205-0.608), total bleeding (OR = 0.664, 95% CI 0.445-0.991), and all-cause death (OR = 0.370, 95% CI 0.260-0.527).In patients with NVAF treated with DOACs, higher BMI was associated with lower major bleeding and better survival. BMI was a negative correlate of total bleeding, but not minor bleeding and thrombosis.

There is emerging evidence that antineoplastic agents and the cytotoxic effects on tumor tissues attenuate the benefits of chemotherapy due to tumor microenvironment changes. Nevertheless, the actual relationship between chemotherapy and recurrent tumors in which the genotypes differ from the original tumor after chemotherapy is unclear.Bone marrow transplantation, flow cytometer, immune inhibition and immunofluorescence will be utilized to investigate the effect of antineoplastic agents on bone-marrow-derived cells (BMDCs) release and recruitment, and to explore the pathways and mechanisms of antineoplastic agents in promoting tumor growth.Tumor growth and angiogenesis were significantly enhanced in the mouse model after treatment with antineoplastic agents such as cyclophosphamide, 5-fluorouracil, or cisplatin, along with large increases in proangiogenic vascular endothelial growth factor receptor-2 (VEGFR2The results suggested that antineoplastic-agent treatment augmented the tumor microenvironment by mobilizing proangiogenic BMDCs, enhancing BMDC recruitment and angiogenesis, and increasing BMDC-mediated tumor and EC functions. These results led to tumor growth and angiogenesis aggravation. It is paramount to elucidate the potential mechanism by which the cellular and molecular effects triggered by the antineoplastic agents attenuate the effects of cancer therapy, and thereafter to explore possible methods for improving tumor treatment efficacy.

Background: There are indications that certain antineoplastic agents at low dosages may exhibit abnormal pharmacological actions, such as promoting tumor growth. However, the phenomenon still needs to be further confirmed, and its underlying mechanisms have not yet been fully elucidated.Methods: Gemcitabine (GEM) and cisplatin (CDDP) were employed as representative antineoplastic agents to observe effects of continuous low-dose chemotherapy with GEM or GEM combined with CDDP (GEM+CDDP) on tumor formation and growthin xenograft tumor models in vivo. Tumor and endothelial cell functions, apoptosis, cell cycle analysis, as well as bone marrow derived cells (BMDCs) mobilization, were evaluated with transwell, MTT or flow cytometry analysis in vitro, respectively. Histological methods were employed to assess angiogenesis in tumor tissues.Results: The results showed that tumor formation and growth were both significantly promoted by GEM or GEM+CDDP at as low as half of the metronomic dosages, which were accompanied by enhancements of angiogenesis in tumor tissues and the release of proangiogenic BMDCs in the circulating blood. Additionally, GEM or GEM+CDDP at low concentrations dramatically facilitated the proliferation, migration, and invasion of tumor cells in vitro. Cell-cycle arrest, activation of associated apoptotic proteins, and inhibition of apoptosis were also observed in tumor cells. Conclusions: These findings indicate that, the continuous low-dose administration of GEM and GEM+CDDP can promote tumorigenesis and tumor progression in vivo by inhibiting apoptosis, mobilizing BMDCs, and promoting angiogenesis in certain dose ranges. These findings urge further investigations to avoid the potential risks in current empiric continuous low-dose chemotherapy regimens with antineoplastic agents.

Objective To observe the differences in curative effects between prophylactic and therapeutic administrations of Gliclazide (GLZ) or Methylcobalamin (MCA) on diabetic peripheral neuropathy in rats. Methods GLZ (25 mg/kg/day) or MCA (175 μg/kg/day) was orally administrated prophylactically to streptozotocin-induced diabetic rats for 8 weeks before diabetic peripheral neuropathy developed or administrated therapeutically after diabetic peripheral neuropathy developed, respectively. The motor nerve conduction velocities (MNCV), aldose reductase (AR) activities, the polyol contents and antioxidative enzyme activities in the sciatic never tissues were determined. The morphology of sciatic never tissues was observed. Results In comparison to vehicle, most of the changes in the sciatic nerves of the diabetic rats (e. g., delayed MNCV, altered/damaged nerve structure, enhanced AR activity, increased polyol contents, altered Cu, Zn-superoxide dismutase, glutathione-peroxidase activities, and elevated malondialdehyde level) were significantly ameliorated by prophylactic administration with either GLZ or MCA. In contrast, only few of above-mentioned parameters were alleviated in DPN rats by therapeutic administration with GLZ or MCA as compared to vehicle. The curative effects of GLZ or MCA prophylactic administration on MNCV, AR activity, polyol contents and antioxidative enzyme activities were markedly stronger than therapeutic administration. Conclusion Prophylactic administration of GLZ or MCA was superior to the therapeutic administration in alleviation of diabetic neuropathy in STZ-rats, suggesting that pharmacotherapy should be initiated at a much earlier stage before diabetic neuropathy developed, but not at a later stage after never damage reached.

Objective To determine the health risks of antineoplastic drugs (ADs) occupational exposure in nurses and to evaluate the effects of implementing a pharmacy intravenous admixture service (PIVAS) in two Chinese hospitals. Methods The laboratory findings were collected from annual staff physical examination data. Reproductive toxicity and clinical manifestations were self-reported via a questionnaire. Results Hematotoxicity, organ damage, reproductive toxicity, and clinical manifestations associated with AD exposure were markedly higher in oncology nurses than unexposed nurses. Application of PIVAS led to a significant restoration of the blood cell counts and kidney function, and a reduction in adverse reproductive outcomes among oncology nurses. Pronounced symptoms related to AD exposure were alleviated as well. Conclusion Oncology nurses who work with AD's experienced more adverse health outcomes than unexposed nurses. The health risks to AD were significantly alleviated by implementing a pharmacy intravenous admixture service. Am. J. Ind. Med. © 2016 Wiley Periodicals, Inc.

Brain ischemia, including cerebral ischemia and cerebrovascular ischemia, leads to poor oxygen supply or cerebral hypoxia, and causes brain tissue death or cerebral infarction/ischemic stroke. The troxerutin and cerebroprotein hydrolysate injection (TCHI), is widely applied in China to improve blood supply in ischemic brain tissues and to enhance neuroprotective effects in clinical practice. However, the benefits and detailed underlying mechanism elaborating the effectiveness of TCHI in cerebrovascular diseases require further investigation. Therefore, in the present study, experimental in vivo and in vitro models were employed to investigate the potential mechanisms of TCHI on cerebral ischemic injury. The results demonstrated that TCHI increased the lactate dehydrogenase levels in the brain homogenate and conversely decreased lactic acid levels. TCHI was further observed to significantly increase superoxide dismutase activity and decrease malondialdehyde levels in ischemic brain tissues. In addition, TCHI significantly induced vascular maturation processes, including proliferation, adhesion, migration and tube formation in cultured human umbilical vein endothelial cells. Additionally, TCHI significantly stimulated microvessel formation in the rat aortic ring and chick chorioallantoic membrane assays. Taken together, these results provided strong evidence that TCHI stimulated angiogenesis at multiple steps, and indicated that TCHI attenuated cerebral ischemic damage through the amelioration of oxidative stress and promotion of angiogenesis.

Granulocyte-macrophage colony-stimulating factor has been widely used as an adjuvant therapy for cancer patients exhibiting myelosuppression induced by chemotherapy or radiotherapy. However, the effects of granulocyte-macrophage colony-stimulating factor on tumor growth, as well as its precise mechanism, are still controversial due to inconsistent evidence. This study investigated the effect of exogenous granulocyte-macrophage colony-stimulating factor on the growth of B16 melanoma, S180 sarcoma, and U14 cervical carcinoma in mice. The angiogenesis and recruitment of bone-marrow-derived cells were analyzed in tumor tissues. Interactions among granulocyte-macrophage colony-stimulating factor, bone-marrow-derived cells, and B16 tumor cells were investigated in vitro. Proangiogenic types of bone-marrow-derived cells in blood were assessed both in vivo and in vitro. The results showed that granulocyte-macrophage colony-stimulating factor markedly facilitated the growth of B16 and S180 tumors, but not U14 tumors. Granulocyte-macrophage colony-stimulating factor increased the densities of blood vessels and the number of bone-marrow-derived cells in B16 tumor tissues. The granulocyte-macrophage colony-stimulating factor–induced enhancement of tumor cell proliferation was mediated by bone-marrow-derived cells in vitro. Meanwhile, a distinct synergistic effect on endothelial cell function between granulocyte-macrophage colony-stimulating factor and bone-marrow-derived cells was observed. After separating two types of bone-marrow-derived cells, granulocyte-macrophage colony-stimulating factor–induced enhancement of tumor growth and angiogenesis in vivo was mediated by proangiogenic cells in granulocytes, but not monocytes, with CD11b+, vascular endothelial growth factor receptor 2, and C-X-C chemokine receptor 4 granulocytes possibly involved. These data suggest that granulocyte-macrophage colony-stimulating factor contributes to the growth and angiogenesis of certain types of tumor, and these mechanisms are probably mediated by proangiogenic cells in granulocytes. Applying granulocyte-macrophage colony-stimulating factor may attenuate the antitumor effects of chemotherapy and radiotherapy in certain types of tumor.

Aims This study investigated the efficacies of gliclazide (GLZ), methylcobalamin (MCA), and GLZ + MCA combination therapy on DPN by evaluating the treatment-related changes in peripheral nerve function, the polyol pathway, and oxidative stress in the sciatic nerve of streptozotocin-induced diabetic rats. Materials and methods The rat model of streptozotocin-induced diabetes was orally given GLZ (25 mg/kg/day), MCA (175 μg/kg/day), and GLZ + MCA (25 mg/kg/day + 175 μg/kg/day) combination therapy for 8 weeks, in order to observe its effects on the motor nerve conduction velocity (MNCV), on the activities of Na + , K + -ATPase, aldose reductase(AR), AR mRNA expression, on the polyol contents, antioxidative enzyme activities and peroxidation products in the sciatic never tissue. Key findings Most of the indicators of DPN, such as delayed MNCV, altered/damaged nerve structure, inhibited Na + ,K + -ATPase activity, enhanced AR activity and AR mRNA expression, increased polyol contents, altered Cu,Zn-superoxide dismutase, catalase, and glutathione-peroxidase activities, and elevated malondialdehyde level in the sciatic nerves of the diabetic rats, were significantly ameliorated by treatment with either GLZ or MCA. Moreover, the combination of GLZ and MCA was found to enhance the curative effect on DPN in parts of above-mentioned parameters as compared to monotherapy. Significance Monotherapy with GLZ or MCA, and especially the combined application of GLZ and MCA, could be efficient therapeutic strategies for combating experimental DPN in diabetic rats.

To determine the health risks of antineoplastic drugs (ADs) occupational exposure in nurses and to evaluate the effects of implementing a pharmacy intravenous admixture service (PIVAS) in two Chinese hospitals.The laboratory findings were collected from annual staff physical examination data. Reproductive toxicity and clinical manifestations were self-reported via a questionnaire.Hematotoxicity, organ damage, reproductive toxicity, and clinical manifestations associated with AD exposure were markedly higher in oncology nurses than unexposed nurses. Application of PIVAS led to a significant restoration of the blood cell counts and kidney function, and a reduction in adverse reproductive outcomes among oncology nurses. Pronounced symptoms related to AD exposure were alleviated as well.Oncology nurses who work with AD's experienced more adverse health outcomes than unexposed nurses. The health risks to AD were significantly alleviated by implementing a pharmacy intravenous admixture service.

Aim: This study aimed to investigate the specificity and potency of curcumin derivative 64PH in inhibiting the proliferation of HepG2 human hepatoma cells in vitro. Methods: Various concentrations of 64PH were administrated to HepG2 hepatoma cells and HL7702 hepatic cells. The viability of cells was evaluated by methyl thiazolyl tetrazolium assay. The concentration-inhibition rates in the two cell lines were calculated, and the accumulation normal distribution function was adopted to fit their rate curves. The differences of the rates between the two cells were observed on the 3rd day of 64PH treatment. The maximum difference and the 95% credibility interval of the corresponding 64PH concentration were evaluated. Results: 64PH inhibited the proliferation of HepG2 and HL7702 cells in vitro. To fit the concentration-effect curves on the 3rd day, the determination coefficients (γ2) were more than 0.99, the half maximal inhibitory concentration (IC50) was 3.07 and 4.28 μg/mL of 64PH, respectively, and their ratio was 1.39. To fit the normal distribution function of the differences of concentration-inhibition rates between HepG2 and HL7702 cells (s2 = 0.9861), the maximum difference of inhibition rates was 33.58%, and the corresponding concentration of 64PH and the 95% credibility interval were 2.65 and 3.52 μg/mL, respectively. Conclusion: In vitro, HepG2 cells are more sensitive than HL7702 cells due to the presence of 64PH. The inhibition of cell proliferation induced by 64PH is stronger in HepG2 than in HL7702 at concentrations between 2.65 and 3.52 μg/mL. 64PH has the potential to be a therapeutic approach in hepatocellular carcinoma and to achieve the desired efficacy and safety.

Previous studies have found that Danhong injection (DHI), an extensively used herbal extract preparation in China, might be a powerful vasodilator. The aims of this study were to determine the vascular activity of DHI and its effects on arteries of different sizes. The results showed that DHI significantly inhibited rat-hindquarters and rabbit-ear vasoconstriction elicited by norepinephrine (NE) perfusion and markedly relaxed KCl-contracted and NE-contracted rat abdominal aortic and mesenteric artery rings. The endothelium made only a minor contribution to the vasorelaxant effect of DHI on artery segments. The vasorelaxant effect of DHI varied with the artery size, with larger arteries exhibiting a more sensitive and potent vasodilator response. DHI relaxed NE-induced vasoconstriction probably through inhibition of the intracellular Ca2+ release through the inositol triphosphate receptor system in the abdominal aorta and mesenteric artery, along with blockage of extracellular Ca2+ influx through the receptor-linked Ca2+ channels in the mesenteric artery. In addition, DHI completely relaxed KCl-induced contraction in both of the arteries, suggesting that inhibition of Ca2+ influx through voltage-gated Ca2+ channels is involved in the vasorelaxant effect of DHI. This elucidation of the vascular effects of DHI and the underlying mechanisms could lead to improved clinical applications.