STAT3 rs4796793 contributes to lung cancer risk and clinical outcomes of platinum-based chemotherapy.

BACKGROUND: Signal transducer and activator of transcription (STAT) 3 plays a vital role in carcinogenesis and drug response. Platinum-based chemotherapy is the first-line treatment for lung cancer patients, especially those in advanced stages. In the present study, we investigated the association of STAT3 polymorphism rs4796793 with lung cancer susceptibility, platinum-based chemotherapy response, and toxicity. METHODS: A total of 498 lung cancer patients and 213 healthy controls were enrolled in the study. 467 of them received at least 2-cycle platinum-based chemotherapy. Unconditional logistical regression analysis was used to assess the associations. RESULTS: STAT3 rs4769793 G allele carriers had an increased susceptibility of lung cancer [additive model: adjusted OR (95% CI) 1.376 (1.058-1.789), P = 0.017; recessive model: adjusted OR (95% CI) 1.734 (1.007-2.985), P = 0.047]. Rs4769793 was not significantly associated with platinum-based chemotherapy response in lung cancer patients. STAT3 rs4796793 was associated with an increased risk of severe overall toxicity [additive model: adjusted OR (95% CI) 1.410 (1.076-1.850), P = 0.013; dominant model: adjusted OR (95% CI) 1.638 (1.091-2.459), P = 0.017], especially hematological toxicity [additive model: adjusted OR (95% CI) 1.352 (1.001-1.826), P = 0.049]. CONCLUSIONS: STAT3 rs4796793 may be considered as a potential candidate biomarker for the prediction of susceptibility and prognosis in Chinese lung cancer patients. However, well-designed studies with larger sample sizes are required to verify the results.

Insight into the phenolics and antioxidant activity of Indian jujube (Ziziphus mauritiana Lamk) peel and pulp subjected to the simulated digestion.

To evaluate the release and activity of Indian jujube phenolics in vivo, its peel and pulp were subjected to simulated digestions. The phenolics content and antioxidant activity of the digested samples were determined. The results showed that the total phenolics/flavonoids in the peel were respectively 4.63 and 4.48 times higher than that in the pulp. The release of phenolics and flavonoids respectively increased by 79.75% and 39.98% in the peel and 86.34% and 23.54% in the pulp after the intestinal digestion. The correlation between the total phenolics/flavonoids and antioxidant activity was higher in the peel (r > 0.858, p < 0.01) than that in the pulp. The phenolics profiles of the peel were almost the same after the digestion, and four phenolics including naringenin tri-glycoside, quercetin-3-O-[(2-hexosyl)-6-rhamnosyl] -hexoside, quercetin-3-O-pentosylhexoside and quercetin-3-O-(2-pentosyl -rhamnoside)-4'-O-rhamnoside were found to be the main flavonoids of Indian jujube peel, and they showed high recovery (>89.88%) during the digestion, implying that these phenolics may play a vital role in the function of Indian jujubes.

Prediction of response and adverse drug reaction of pemetrexed plus platinum-based chemotherapy in lung adenocarcinoma by serum metabolomic profiling.

BACKGROUND: Pemetrexed plus platinum doublet chemotherapy regimen remains to be the standard first-line treatment for lung adenocarcinoma patients. However, few biomarkers can be used to identify potential beneficiaries with maximal efficacy and minimal toxicity. This study aimed to explore potential biomarker models predictive of efficacy and toxicity after pemetrexed plus platinum chemotherapy based on metabolomics profiling. METHODS: A total of 144 patients who received at least two cycles of pemetrexed plus platinum chemotherapy were enroled in the study. Serum samples were collected before initial treatment to perform metabolomics profiling analysis. Logistic regression analysis was performed to establish prediction models. RESULTS: 157 metabolites were found to be differentially expressed between the response group and the nonresponse group. A panel of Phosphatidylserine 20:4/20:1, Sphingomyelin d18:1/18:0, and Phosphatidic Acid 18:1/20:0 could predict pemetrexed and platinum chemotherapy response with an Area Under the Receiver Operating Characteristic curve (AUROC) of 0.7968. 76 metabolites were associated with hematological toxicity of pemetrexed plus platinum chemotherapy. A panel incorporating triglyceride 14:0/22:3/22:5, 3-(3-Hydroxyphenyl) Propionate Acid, and Carnitine C18:0 was the best predictive ability of hematological toxicity with an AUROC of 0.7954. 54 differential expressed metabolites were found to be associated with hepatotoxicity of pemetrexed plus platinum chemotherapy. A model incorporating stearidonic acid, Thromboxane B3, l-Homocitrulline, and phosphoinositide 20:3/18:0 showed the best predictive ability of hepatotoxicity with an AUROC of 0.8186. CONCLUSIONS: This study established effective and convenient models that can predict the efficacy and toxicity of pemetrexed plus platinum chemotherapy in lung adenocarcinoma patients before treatment delivery.

Prediction of tacrolimus dosage in the early period after heart transplantation: a population pharmacokinetic approach.

AIM: The aim of this study was to evaluate tacrolimus population pharmacokinetics and investigate factors that explain tacrolimus variability in adult heart transplant patients. METHODS: A total of 707 tacrolimus concentrations from 107 adult heart transplant patients were included in model development. The effects of demographic, clinical factors and CYP3A5 genotype on tacrolimus clearance were evaluated using a nonlinear mixed-effects modeling. 24 patients with 106 tacrolimus concentrations were used for external validation. RESULTS: The pharmacokinetic data were adequately described by a one-compartment model with first-order absorption and elimination. The estimated apparent clearance and volume of distribution of tacrolimus were 13.7 l/h and 791 l, respectively. Tacrolimus apparent clearance was significantly reduced in CYP3A5 nonexpressers (CYP3A5*3/*3), concomitant with azole antifungal drugs and Wuzhi capsule (WZ). A predictive performance was further confirmed in an external validation by Bayesian estimation. Recommended dose regimens were obtained by simulations based on the established model. CONCLUSION: This is the first population pharmacokinetic study conducted in Chinese heart transplant recipients. These findings are of great importance with regards to tacrolimus dose optimization in heart transplantation patients.

[Pharmacokinetics and distribution of 5-Fu magnetic albumin deuto-microsphere in normal and tumor-bearing mice].

To observe the pharmacokinetic and tissue-distribution characters of 5-flourouracil magnetic albumin deuto-microsphere (5-Fu-MAD) in normal and tumor-bearing mice, HPLC method for the determination of 5-Fu in plasma and tissues was established and applied to determine 5-Fu in mouse plasma and tissue samples. A Flame atomic absorption spectrometer was used to detect the iron concentration in mouse tissue. Plasma concentration-time curves of free 5-Fu, 5-Fu-MAD and 5-Fu-MAD plus the magnetic frame (MF) conformed to two compartment model of first order absorption and they had C(max) of 34.9, 7.95 and 5.97 mg x L(-1); T1/2 (Ke) of 22.26, 76.0 and 124.6 min, V(d) of 3.28, 30.7 and 66.1 L x kg; AUC(0-t), of 233.9, 78.3 and 50.2 mg x min x L(-1); AUC(0-infinity) of 237.2, 89.3 and 68.1 mg x min x L(-1), respectively. The distribution of 5-Fu and iron was the highest in the plenty blood perfusion organs like the liver, tumor, spleen and lung, while lower in the kidney and heart and lowest in brain and muscle. The tissue distribution of muscle and tumor increased significantly when a magnetic frame was inserted there. The pharmacokinetics and tissue distribution of 5-Fu-MAD exhibited sustained-release and target characteristics.

[Determination of daurisoline in rabbit plasma and study on its pharmacokinetics].

AIM: To establish an HPLC method for the determination of daurisoline (DS) in rabbit plasma and investigate its pharmacokinetic characteristics after intravenous administration. METHODS: Dauricine was used as internal standard. The plasma samples were deproteinated with acetonitrile and extracted with two-step dichloromethane. Acetonitrile-water-triethylamine (18:82:0.28, pH 3) was used as mobile phase at a flow rate of 1.0 mL.min-1. The UV-detector was set at 284 nm. RESULTS: The linear range was 0.05-20.00 micrograms.h.mL-1 with correlation coefficients 0.9996. The limit of quantitation (LOQ) was 0.05 mg.L-1 of plasma. The absolute and relative recoveries were above 80% and (101 +/- 5)%, respectively. The intra- and inter-assay coefficient of variation were 1.9%-5.6% and 3.5%-6.5%, respectively. The plasma concentration-time profiles were adequately described by a two-compartment open model. CONCLUSION: A sensitive, precise and accurate method for the determination of DS in plasma was described, which can be used in its pharmacokinetic studies.

Pharmacokinetic-pharmacodynamic modeling of daurisoline and dauricine in beagle dogs.

AIM: To study the combined pharmacokinetic-pharmacodynamic (PK-PD) model of daurisoline and dauricine, and compare their effects on cardiac electrophsiology, blood pressure, and hemodynamics in beagle dogs. METHODS: The plasma drug concentration was determined by the reversed-phase HPLC method and the effects on cardiac and hemodynamics were recorded by polygraph. The pharmacokinetic and PK-PD model parameters were calculated. RESULTS: The pharmacokinetics were best fitted to a two-compartment open model, and the relationship between effect and effect compartment concentration of both drugs could be represented by the sigmoid-E(max) model. There were no significant differences in main pharmacokinetics and PK-PD parameters between the two drugs. CONCLUSION: No statistically different kinetic disposition characteristics and potencies of inhibitory effects on myocardial function of daurisoline and dauricine were found in beagle dogs.