Population pharmacokinetics and pharmacogenetics of apatinib in adult cancer patients.

AIMS: Apatinib is widely used in Chinese cancer patients. As the in vivo drug disposition of apatinib has large individual differences, adverse events are prone to occur. Cytochrome P450 (CYP)3A5 and cancer types maybe the main factors affecting this individual differences. The objective of our study was to establish a population pharmacokinetics (PK) model of apatinib in adult cancer patients, and to explore optimal dosage regimens for individualized treatment. METHODS: Adult patients with various types of cancer treated with apatinib were enrolled. The concentration of apatinib in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. CYP3A5 genotype was determined using TaqMan allelic discrimination technique. The population PK model was developed by NONMEM V7.4. The dosing regimen was optimized based on Monte Carlo simulations. RESULTS: A population PK model of apatinib in adult cancer patient was established. CYP3A5 genotype and systemic cancer type (digestive system cancers, nondigestive system cancers) were the most significant covariates for PK parameters. Patients with CYP3A5*1 expressers (CYP3A5*1/*1 and CYP3A5*1/*3) had lower apparent clearance and apparent volume of distribution than patients who do not express CYP3A5*1 (CYP3A5*3/*3). Patients with nondigestive system cancer had higher apparent volume of distribution and absorption rate constant than digestive system cancer. The results of dose simulation suggest that the apatinib dose in patients who do not express CYP3A5*1 should be 33.33-50.00% higher than that in CYP3A5*1 expressers. CONCLUSIONS: A population PK model of apatinib in adult cancer patients was established. CYP3A5 genotype and systemic cancer type had concurrent effects on PK parameters. CYP3A5 patients who do not express CYP3A5*1 required higher doses.

Drug Elimination Alteration in Acute Lymphoblastic Leukemia Mediated by Renal Transporters and Glomerular Filtration.

PURPOSE: Drug elimination alteration has been well reported in acute lymphoblastic leukemia (ALL). Considering that transporters and glomerular filtration influence, to different extents, the drug disposition, and possible side effects, we evaluated the effects of ALL on major renal transporters and glomerular filtration mediated pharmacokinetic changes, as well as expression of renal drug transporters. METHODS: ALL xenograft models were established and intravenously injected with substrates of renal transporters and glomerular filtration separately in NOD/SCID mice. The plasma concentrations of substrates, after single doses, were determined using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). RESULTS: With the development of ALL, protein expression of MDR1, OAT3 and OCT2 were increased by 2.62-fold, 1.70-fold, and 1.45-fold, respectively, whereas expression of MRP2 and MRP4 were significantly decreased by 30.98% and 45.28% in the kidney of ALL groups compared with control groups. Clearance of MDR1-mediated digoxin, OAT3-mediated furosemide, and OCT2-mediated metformin increased by 3.04-fold, 1.47-fold, and 1.26-fold, respectively. However, clearance of MRPs-mediated methotrexate was reduced by 39.5%. These results are consistent with mRNA expression. Clearance of vancomycin and amikacin, as markers of glomerular filtration rate, had a 2.14 and 1.64-fold increase in ALL mice, respectively. CONCLUSIONS: The specific alteration of renal transporters and glomerular filtration in kidneys provide a rational explanation for changes in pharmacokinetics for ALL.

Co-existent choroidal neovascular membrane and macular hole in pathologic myopia: a long follow-up clinical outcome and literature review.

Choroidal neovascularization (CNV) is an uncommon complication associated with a macular hole. In this case report of a rare condition, we present a pathologic myopia patient with a co-existent macular hole and choroidal neovascular membrane. The patient was treated with photodynamic therapy for CNV, and then vitreous surgery for the retinal detachment and macular hole. At the end of 4 years follow-up, her visual acuity was improved to 0.1 while the macular hole remained open. Optical coherence tomography is a useful inspection method of the diagnosis of CNV and macular hole.

Conductive keratoplasty: an approach for the correction of residual hyperopia in post-lasik pseudophakia.

Although there are many formulae for the calculation of intraocular lens power in the eyes with previous kerato-refractive surgeries, unexpected refractive bias still exists. Hyperopic bias is particularly disliked because it affects both uncorrected distance and near visual acuity. Surgical treatment of the residual hyperopia for the eyes with both laser in situ keratomileusis and cataract surgery remains to be a big problem. Conductive keratoplasty has been shown to be an effective, safe and predictable method for low and moderate hyperopia in the pseudophakic eyes or in the eyes with kerato-refractive surgeries. However, the efficacy and safety of conductive keratoplasty in the correction of residual hyperopia after both corneal and lens refractive surgeries has not been reported. Herein, we reported the surgical correction with conductive keratoplasty for cases of residual hyperopia with/without astigmatism after previous laser in situ keratomileusis for high myopia and following phacoemulsification combined with posterior intraocular lens implantation for complicated cataract.

[Conductive keratoplasty for presbyopia and two years follow-up].

OBJECTIVE: To investigate the effect of conductive keratoplasty (CK) for presbyopia and 2 years follow-up. METHODS: This study is prospective clinical trial. CK was performed on 34 patients for presbyopia, in which 26 hyperopic patients underwent binocular operations and 8 emmetropic patients underwent monocular operation. The following-up time was 24 months. RESULTS: At 24 months postoperatively, for the hyperopia group, binocular uncorrected near visual acuity (33 cm) (5-logMAR) (4.63 ± 0.12) was increased significantly (t = 9.237, P < 0.001) compared pre-operatively (4.06 ± 0.15); binocular uncorrected distance visual acuity (4.99 ± 0.02) was significantly increased (t = 6.718, P < 0.05) compared pre-operatively (4.82 ± 0.21); for the emmetropia group, binocular uncorrected near visual acuity (33 cm) (5-logMAR) (4.68 ± 0.16) was increased significantly (t = 10.413, P < 0.001) compared pre-operatively (4.13 ± 0.18); binocular uncorrected distance visual acuity was same as pre-operative one; compared pre-operatively (+0.97 ± 0.63D), manifest refractive spherical equivalent was decreased significantly (P < 0.001) to peak value (-1.21 ± 1.00) D at 1 week, and then regressed to a relative plateau (-0.40 ± 0.70) D at 24 months; the regressive rate was decreased from (+0.35 ± 0.44) D/month at 1 month postoperatively to (+0.01 ± 0.01) D/months at 24 months postoperatively. Contrast sensitivity and glare sensitivity, intraocular pressure, tear break-up time, endothelial cell count, central corneal thickness, stereopsis function and best corrected visual acuity were not significantly changed. CONCLUSIONS: For treatment of presbyopia, CK appeared to be safe, effective, refractive-predictable and controllable, and relatively stable at 24 months post-operatively. More long-time follow-up is necessary for further evaluation.

[Advances and prospects in studies of cataract in the past five years in China].

In the past five years, the cataract surgery rate increased in China. Cataract researches has made significant achievements and has gradually geared international standard. Along with the trend of increasing visual quality requirement to a higher level, studies of cataract face new opportunities and challenges. This article reviews the progress and problems of cataract studies in the past five years in China in order to make further development in this field.

Protective effect of magnolol against hydrogen peroxide-induced oxidative stress in human lens epithelial cells.

Oxidative stress plays a significant role in the progression of cataract. We aimed to investigate the protective effect of magnolol, a compound extracted from the Chinese herb Magnolia officinalis, against oxidative stress in human lens epithelial (HLE) cells as well as the possible molecular mechanism involved. In this study, magnolol was observed to protect against H2O2-induced cytotoxicity in HLE B-3 cells. Magnolol inhibited the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (Delta psi m) and release of cytochrome c from mitochondria caused by H2O2 into cytosol in HLE B-3 cells. Magnolol also inhibited H2O2-induced expressions of caspase-9 and caspase-3 and reduction of Bcl-2/Bax ratio. Moreover, magnolol attenuated the deactivation of ERK/MAPK (extracellular signal-regulated kinase/mitogen activated protein kinase) and the enhanced activation of p38, JNK (c-Jun N-terminal kinase) induced by H2O2. Magnolol could be useful in protecting against oxidative stress in HLE cells, suggesting a potential protective effect against cataractogenesis effect against cataractogenesis.

[Clinical evaluation on the bimanual microincision cataract surgery].

OBJECTIVE: To compare the outcomes of bimanual microincision phacoemulsification with conventional small incision cataract surgery. METHODS: A randomized prospective study of 280 consecutive cases (280 eyes) was conducted. All patients were randomly assigned to receive bimanual microincision cataract surgery (MICS group) or small incision cataract surgery (SICS group). The PHACO time (PT) and the average power (AP) were recorded, then absolute PHACO time (APT = PT x AP) was calculated. The differences in PT, AP, APT and BCVA between these two groups were compared. Visual acuity, anterior chamber flare value, thickened pachymetry and endothelial cells loss were recorded 1 day and 3 months after surgery. In addition, surgically induced astigmatism was analyzed. RESULTS: The mean PT, AP and APT of MICS group were significantly lower than those in the SICS group (0.76 +/- 0.36) min versus (0.87 +/- 0.49) min, 10.93% +/- 4.78% versus 16.09% +/- 7.38% and (8.99 +/- 7.23) min versus (15.27 + 12.10) min, respectively (P < 0.01). At 3 months, the vertical astigmatic changes of MICS group was statistically lower than that of the SICS group [(0.37 - 0.32) D versus (1.28 +/- 0.77) D, P = 0.000]. There were no significant differences in the visual acuity, anterior chamber flare value, endothelial cells loss and the thickened pachymetry at 1 day and 3 months after surgery between these two groups (P > 0.05). CONCLUSIONS: Bimanual microincision cataract surgery could significantly reduce PHACO power, enhance energy efficiency and reduce surgically induced astigmatism. However, MICS does not reduce surgical trauma and postoperative inflammation as compared to conventional SICS.

Involvement of PI3K/Akt pathway in TGF-beta2-mediated epithelial mesenchymal transition in human lens epithelial cells.

BACKGROUND: Epithelial mesenchymal transition (EMT) of postoperative remnants of lens epithelial cells (LECs) can lead to posterior capsule opacification. This study was designed to determine the effect of signaling pathways that contribute to TGF-beta2-mediated EMT in human lens epithelial B-3 cells (HLEB-3 cells). METHODS: The HLEB-3 cells were cultured and stimulated with TGF-beta2 at different concentrations for an indicated time. The effect of TGF-beta2 on cell cycle distribution was measured by flow cytometry. Western blot and immunofluorescence were used to analyze changes in connexin 43, fibronectin, desmin and integrin beta(1) protein expression associated with EMT in HLEB-3 cells. Activation of phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways was also detected by Western blot. RESULTS: The cell cycle progression of HLEB-3 cells was limited, and the cells underwent morphological alteration after treatment with TGF-beta2. Stimulation of HLEB-3 cells with TGF-beta(2) suppressed connexin 43 protein expression, increased fibronectin, desmin and integrin beta1 protein expression. TGF-beta2 activated PI3K/Akt in a time-dependent manner, but not extracellular signal-regulated kinase and p38 MAPK. The activation of PI3K/Akt was necessary for the TGF-beta(2)-stimulated downregulation of connexin 43, which in turn was necessary for TGF-beta2-induced EMT in HLEB-3 cells. CONCLUSIONS: TGF-beta(2) is a potent growth factor for LEC EMT. TGF-beta(2)-induced EMT in LECs is mediated by the downregulation of connexin 43, which is regulated through the PI3K/Akt pathway.

Reactive oxygen species mediates the apoptosis induced by transforming growth factor beta(2) in human lens epithelial cells.

Transforming growth factor beta(2) (TGF-beta(2)), a growth regulator of human lens epithelial cells (HLECs), also regulates the death of these cells. Dose-response analysis showed that the TGF-beta(2) concentration needed to induce HLECs death (100 pg/ml) was 10 times that needed to inhibit growth in these cells (10 pg/ml). TGF-beta(2)-induced apoptosis in HLECs was preceded by an induction of reactive oxygen species (ROS) and a decrease in glutathione in the intracellular content, indicating that this factor induces oxidative stress in HLECs. Studies performed to analyze the levels of c-fos mRNA, a gene whose expression is modulated by the redox state, demonstrated that only high, apoptotic concentrations of TGF-beta(2) (100 pg/ml) produced an increase in the mRNA levels of this gene, the level of induction being similar to that found when cells were incubated in the presence of hydrogen peroxide. Finally, the cell death induced by TGF-beta(2) in HLECs was partially blocked by radical scavengers, which decreased the percentage of apoptotic cells, whereas these agents did not modify the growth-inhibitory effect elicited by TGF-beta(2) in these cells. The results presented in this paper provide evidence for the involvement of an oxidative process in the apoptosis elicited by TGF-beta(2) in HLECs.