Population Pharmacokinetics and Initial Dosage Optimization of Tacrolimus in Pediatric Hematopoietic Stem Cell Transplant Patients.

Background: There is a substantial lack of tacrolimus pharmacokinetic information in pediatric hematopoietic stem cell transplant (HSCT) patients. This study aimed to develop population pharmacokinetics (PopPK) of tacrolimus in pediatric HSCT patients and to devise model-guided dosage regimens. Methods: A retrospective analysis was performed on 86 pediatric HSCT patients who received tacrolimus intravenously or orally. A total of 578 tacrolimus trough concentrations (C0) were available for pharmacokinetic analysis using a non-linear mixed-effects modeling method. Demographic and clinical data were included and assessed as covariates via the stepwise method. Bayesian estimators were used to devise pediatric dosage regimens that targeted C0 of 5-15 ng mL-1. Results: A one-compartment model with first-order absorption adequately described the tacrolimus pharmacokinetics. Clearance (CL), volume of distribution (V), and typical bioavailability (F) in this study were estimated to be 2.42 L h-1 (10.84%), 79.6 L (16.51%), and 19% (13.01%), respectively. Body weight, hematocrit, post-transplantation days, and caspofungin and azoles concomitant therapy were considered significant covariates for tacrolimus CL. Hematocrit had a significant impact on the V of tacrolimus. In the subgroup cohort of children (n = 24) with CYP3A5 genotype, the clearance was 1.38-fold higher in CYP3A5 expressers than in non-expressers. Simulation indicated that the initial dosage optimation of tacrolimus for intravenous and oral administration was recommended as 0.025 and 0.1 mg kg-1 d-1 (q12h), respectively. Conclusion: A PopPK model for tacrolimus in pediatric HSCT patients was developed, showing good predictive performance. Model-devised dosage regimens with trough tacrolimus concentrations provide a practical strategy for achieving the therapeutic range.

Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway.

Lung cancer is one of the leading causes of cancer deaths worldwide. Recent evidences indicated that bisphenol A (BPA), a wide contaminant with endocrine disrupting activity, could enhance the susceptibility of carcinogenesis. Although there are increasing opportunities for lung cells exposure to BPA via inhalation, there is no study concerning the effects of BPA on the development of lung cancer. The present study revealed that BPA less than 10(-4)M had limited effects on the proliferation of lung cancer A549 cells, however, BPA treatment significantly stimulated the in vitro migration and invasion of cells combing with the morphological changes and up regulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. G-protein-coupled estrogen receptor (GPER), while not estrogen receptor α/ß (ERα/ß), mediated the BPA induced up regulation of MMPs. Further, BPA treatment induced rapid activation of ERK1/2 via GPER/EGFR. GPER/ERFR/ERK1/2 mediated the BPA induced upregulation of MMPs and in vitro migration of lung cancer A549 cells. In summary, our data presented here revealed for the first time that BPA can promote the in vitro migration and invasion of lung cancer cells via upregulation of MMPs and GPER/EGFR/ERK1/2 signals, which mediated these effects. This study suggested that more attention should be paid on the BPA and other possible environmental estrogens induced development of lung cancer.

Reconstruction of total degloving injuries of the foot in children.

BACKGROUND: The aim of this study is to introduce experiences of reconstruction of total degloving injuries of the foot in children. METHODS: Seven children, five male and two female, were treated for total degloving injury of the foot at our medical institution between January 2002 and December 2008. Patients were between 5 years and 9 years of age with a mean age of 7 years. All injuries involved the total foot. In cases 1-3, the foot was covered by intermediate split-thickness skin graft. In cases 4-7, the dorsal aspect of the foot was covered by full-thickness skin graft obtained from the degloving flap in emergency operation and the planta aspect of the foot was covered by posteriortibial artery flap in the second operation. RESULTS: The mean time to wound healing was 29 days to 50 days in cases 1-3 and 21 days to 28 days in cases 4-7. The posteriortibial artery flaps in cases 4-7 all survived. Both the donor and the recipient site healed successfully. All patients were followed for at least 12 months (range, 12-24 months; mean, 17.9 months). All patients showed insensitivity at the recipient sites. No patient complained of cold intolerance in the foot. Cases 1-3 had pain, deformity, and dysfunction to some extent at follow-up. Cases 4-7 did not exhibit pain, deformity, or dysfunction. All toes were amputated in all cases. Patients 1-3 scored fair or poor on the Maryland Foot Score (two fair, one poor), and patients 4-7 scored either good or fair (three good, one fair). CONCLUSION: This method, the dorsal aspect of the foot covered by full-thickness skin and the planta aspect of the foot covered by posteriortibial artery flap, is a good choice for treatment of total degloving injury of foot in children. At the same time, the early exercise should be emphasized for the functional recovery. LEVEL OF EVIDENCE: Therapeutic study, level IV.