Development and validation of individualized tacrolimus dosing software for Chinese pediatric liver transplantation patients: a population pharmacokinetic approach.

OBJECTIVE: We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4 years old after liver transplantation and to develop individualized tacrolimus dosing software. METHODS: A total of 663 blood concentrations from 85 patients aged 4.57 months to 3.97 years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed. RESULTS: A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%). CONCLUSIONS: A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.

Simultaneous quantitative analysis of nine triterpenoid saponins for the quality control of Stauntonia obovatifoliola Hayata subsp. intermedia stems.

Stauntonia obovatifoliola Hayata subsp. intermedia is used in China to treat rheumatic arthralgia, hernia pain, and traumatic pain. An accurate and reliable method based on high-performance liquid chromatography with diode array detection has been developed and validated for the quantitative determination of nine triterpenoid saponins in this herb. By using a Kromasil 100-5 C18 column (250 mm × 4.6 mm, 5 µm), nine analytes were separated by gradient elution over a running time of 45.0 min. All standard calibration curves demonstrated satisfactory linearity (R(2) ≥ 0.9995) within a relatively wide range. The precision was evaluated by intra- and interday tests, which revealed relative standard deviation values within the ranges of 0.20-2.83 and 0.51-2.79%, respectively. The recoveries for the nine target compounds were between 84.6 and 103% with relative standard deviation values less than 2.67%. The samples were also analyzed on a linear trap quadrupole Orbitrap Velos Pro mass spectrometer equipped with an electrospray ionization source in negative mode to confirm the quantification results. In conclusion, the present high-performance liquid chromatography with diode array detection method could serve as an accurate and reliable method for the quality evaluation of Stauntonia obovatifoliola Hayata subsp. intermedia stems.

[Study on pharmacological ingredients of wuzhuyu tang treating migraine by correlating absorption ingredients in everted intestinal sac and pharmacodynamics].

Wuzhuyu Tang is a classical formula for treating migraine, but its' pharmacological ingredients is unclear yet. Present study employed the everted intestinal sac model to collect the absorption samples of 10 kinds of Wuzhuyu decoction, and then analyzed the contents of 9 ingredients in Wuzhuyu Tang and absorption samples quantitatively or semi-quantitatively by HPLC-DAD method. Reserpine was used to establish the mice model of migraine, and then the contents and activities of 5-hydroxytryptamine, noradrenaline, dopamine, nitric oxide and nitricoxide synthase in brain tissues and serums were determined respectively after oral administration of Wuzhuyu Tang. Using the partial least squares regression method to correlate the total absorption quantity of 9 ingredients and pharmacodynamics. The result shows that limocitrin-3-O-beta-D-glucoside, ginsenoside Rg1 and Rb1, rutaevine, limonin, evodiamine and rutaecarpine are the main ingredients influenced the effects in absorption samples in everted intestinal sacs, especially ginsenoside Rg1, rutaevine, evodiamine and rutaecarpine among them have obvious improving effects to most pharmacodynamics index, might be the pharmacological ingredients influenced the therapeutical effects of Wuzhuyu Tang treating migraine.

LINC02532 by Mediating miR-541-3p/HMGA1 Axis Exerts a Tumor Promoter in Breast cancer.

The newly discovered LINC02532 is abnormally expressed in a variety of cancers and promotes cancer progression. The research proposed to discover the biological and molecular mechanisms of LINC02532 in breast cancer (BCa). In the resected BCa tissue samples and adjacent normal tissues, LINC02532, miR-541-3p, and High Mobility Group A1 (HMGA1) levels were determined. Cell function experiments were carried out on the premise of cell transfection with relevant plasmids. Based on that, the influence of LINC02532, miR-541-3p, and HMGA1 on MCF-7 cell activities (proliferation, migration, invasion, cell cycle, and apoptosis) was determined, as well as on EMT. Additionally, animal experiments were allowed to support cell experimental conclusions on LINC02532. Finally, the mechanistic network of LINC02532, miR-541-3p, and HMGA1 was identified. It was BCa tissues highly expressing LINC02532 and HMGA1, while lowly expressing miR-541-3p. Functionally, LINC02532 depletion repressed the activities and EMT process of MCF-7 cells. Silencing LINC02532 delayed tumor growth in mice. In terms of mechanism, LINC02532 mainly existed in the cytoplasm and could mediate HMGA1 expression by absorbing miR-541-3p. The findings offer new insights into the molecular mechanisms of LINC02532 in BCa and, more importantly, new strategies for the clinical treatment of BCa.

Association of Physical Activity Intensity with All-Cause Mortality in Cancer Survivors: A National Prospective Cohort Study.

We designed this study to investigate the associations between physical activity (PA) and the risk of all-cause mortality in cancer survivors using a nationally representative cohort of US adults. This cohort study included 13 cycles of the National Health Interview Surveys, and by matching participants with the National Death Index (2015), survival status was determined. The main outcome was all-cause mortality during follow-up. A total of 20,088 participants aged 62.2 (15.9) years (62.4% women) were analyzed. After an average follow-up of 117.5 months, 7214 (35.9%) participants died. Compared with inactive cancer survivors, we observed a 25% lower all-cause mortality risk among participants performing PA 10 min to 1 h/week (hazard ratio [HR] = 0.75, 95% confidence interval [CI] = 0.67-0.85), a 28% lower risk among those performing PA 1-2.5 h/week (HR = 0.72, 95% CI = 0.67-0.78), a 34% lower risk among those performing PA 2.5-5 h/week (HR = 0.66, 95% CI = 0.60-0.72), a 37% lower risk among those performing PA 5-7.5 h/week (HR = 0.63, 95% CI = 0.56-0.70), a 47% lower risk among those performing PA 7.5-13.3 h/week (HR = 0.53, 95% CI = 0.47-0.61), and a 43% lower risk among those performing PA 13.3-24 h/week (adjusted HR = 0.53, 95% CI = 0.49-0.66). In cancer survivors, leisure-time PA was associated with a lower all-cause mortality. Inactive cancer survivors should be encouraged to perform more PA to reduce the risk of all-cause mortality.

Optimization of combinations of ginsenoside-Rg1, ginsenoside-Rb1, evodiamine and rutaecarpine for effective therapy of mouse migraine.

Wuzhuyu decoction (WZYD) is a classic traditional Chinese medicine (TCM) formula. It has been extensively used for treating migraine for thousands of years in TCM. Four potential active ingredients from WZYD, ginsenoside-Rg1 (Rg1), ginsenoside-Rb1 (Rb1), evodiamine (Ev) and rutaecarpine (Ru), were found to have positive correlations with pharmacodynamic indicators involving mouse migraine in our previous study. To find a better therapeutic effect on migraine, this research was carried out to optimize the combinations of Rg1, Rb1, Ev and Ru using the uniform design method. The results showed that Rb1 and Ev played key roles in improving the therapeutic effect on mouse migraine by strongly ameliorating pharmacodynamic indicators associated with migraine. They significantly increased the contents of 5-hydroxytryptamine, noradrenaline and dopamine in brain tissues, and reduced the content of nitric oxide in brain tissues and the activities of nitric oxide synthase in both brain tissues and blood serum. The optimal concentrations of Rb1 and Ev were 1057.4 mg/L and 312.5 mg/L, respectively. Rg1 and Ru contributed less to the overall desirability, suggesting that they had reverse effects on some pharmacodynamic indicators of this type of migraine. The verification test demonstrated by the immunohistochemical method that the optimal combination inhibited the expression of c-fos and c-jun in periaqueductal gray of mice, and strongly ameliorated pharmacodynamic indicators. These results suggested that the therapeutic effect of the optimal combination of the four ingredients was strong, and the optimal results were proven to be reliable and accurate.

Identification of active ingredients in Wuzhuyu decoction improving migraine in mice by spectral efficiency association.

Wuzhuyu decoction is a traditional Chinese medicine used for the effective treatment of migraines, termed 'Jueyin headache', in China. However, there have been few investigations to clarify the composition of Wuzhuyu decoction for the treatment of migraines. In the present study, 10 types of Wuzhuyu decoction were analyzed by chromatograms. 5-hydroxytryptamine (5-HT)-depletion mouse models of migraine were prepared by subcutaneous injection of reserpine and placement of autologous blood clots in the cerebral cortex. The levels of 5-HT, noradrenaline (NE), dopamine (DA), nitric oxide (NO) and nitric oxide synthase (NOS) in the brain tissues and sera of the mice were determined. The ingredients and pharmacodynamic indices of the Wuzhuyu decoctions were analyzed using spectral efficiency association by partial least squares regression. The levels of 5-HT, NE and DA in the mouse brain tissues were reduced to 337.785 ± 84.504, 171.173 ± 65.172 and 242.075 ± 158.621 mg/g brain tissue, respectively. The level of NO in the brain tissues increased to 0.425 ± 0.184 µmol/g protein and the activities of NOS in the brain tissues and sera increased to 0.719 ± 0.477 U/mg and 50.688 ± 8.132 U/ml, respectively. Regarding the ingredients of the Wuzhuyu decoction, those with significant regression coefficients were ginsenoside-Rg1, Re, Rb1, rutaevine (Rv), limonin (Li), evodiamine (Ev), rutaecarpine (Ru) and substance X (awaiting identification). Rg1, Re, Rb1, Rv, Li, Ev, Ru and X in the Wuzhuyu decoction were observed to yield the pharmacological effects, whereas Rb1, Rv and Ev were important in index improvement.