Pharmacokinetics, safety and tolerability of L-3-n-butylphthalide tablet after single and multiple oral administrations in healthy Chinese volunteers

L-3-n-butylphthalide (L-NBP) is a naturally occurring antioxidant, which can be used for the treatment of acute ischemic stroke and vascular dementia. This study evaluated the safety, tolerability and pharmacokinetics of L-NBP tablets in healthy Chinese volunteers. This was a single-center, randomized, double-blind, placebo-controlled, single- and multiple-dose study. Subjects were assigned to receive a single dose of L-NBP tablet at either 80, 160, 320, or 480 mg (n=40), or multiple doses of 160 mg twice daily for 7 days (n=12). Plasma samples were analyzed with LC-MS/MS. Pharmacokinetic parameters of L-NBP were calculated using non-compartmental analysis with WinNonlin software. Statistical analysis was performed using SPSS software. All adverse events (AEs) were mild and of limited duration; AEs in this study occurred less frequently and more mildly than AEs listed for the DL-NBP soft capsule. No serious adverse event (SAE), death or withdrawal from the study was observed. In the single-dose study, Cmax was reached at about 1 h, and the mean t1/2 was approximately 13.76 h. Area under curve (AUC) and Cmax increased with dose escalation, but dose proportionality was not observed over the range of 160 to 480 mg. In the multiple-dose study, the steady-state was reached within 3 days with slight accumulation. In summary, the L-NBP tablet was well tolerated in healthy Chinese subjects. Slight accumulation appeared after repeated doses.L-3-n-butilftalida (L-NMP) é um antioxidante natural, que pode ser utilizado para o tratamento do acidente isquêmico agudo e demência vascular. Este estudo avaliou segurança, tolerância e farmacocinética de comprimidos de L-NBP em chineses voluntários sadios. Este foi um estudo monocêntrico, randomizado, duplo cego, com controle por placebo e doses única e múltipla. Os indivíduos receberam dose única de comprimido de L-NBP de 80, 160, 320 ou 480 mg (n=40) e doses múltiplas de 160 mg duas vezes ao dia, por sete dias (n=12). Amostras de plasma foram analisadas com LC-MS/MS. Os parâmetros farmacocinéticos do L-NBP foram calculados utilizando análise não compartimental, com o programa WinNonlin. A análise estatística foi realizada utilizando-se o programa SPSS. Todos os eventos adversos (EAs) foram moderados e de duração limitada. EAs nesse estudo ocorreram menos frequentemente e mais moderadamente do que os EAs relacionados para cápsulas moles de DL-NBP. Não se observaram eventos adversos graves (EAG), morte ou abandono do estudo. Com dose única, atingiu-se o Cmax em cerca de 1 hora e o t1/2 médio foi de, aproximadamente, 13,76 h. A área sob a curva (ASC) e o Cmax aumentaram com o aumento da dose, mas não se observou proporcionalidade na faixa acima de 160 a 480 mg. No estudo de dose múltipla, o equilíbrio foi alcançado em três dias, com pequeno acúmulo. Em resumo, o comprimido de L-NMP foi bem tolerado em indivíduos chineses saudáveis. O acúmulo pequeno apareceu após doses repetidas

An autonomous ultra-wide band-based attitude and position determination technique for indoor mobile laser scanning

Mobile laser scanning (MLS) has been widely used in three-dimensional (3D) city modelling data collection, such as Google cars for Google Map/Earth. Building Information Modelling (BIM) has recently emerged and become prominent. 3D models of buildings are essential for BIM. Static laser scanning is usually used to generate 3D models for BIM, but this method is inefficient if a building is very large, or it has many turns and narrow corridors. This paper proposes using MLS for BIM 3D data collection. The positions and attitudes of the mobile laser scanner are important for the correct georeferencing of the 3D models. This paper proposes using three high-precision ultra-wide band (UWB) tags to determine the positions and attitudes of the mobile laser scanner. The accuracy of UWB-based MLS 3D models is assessed by comparing the coordinates of target points, as measured by static laser scanning and a total station survey

The signal transduction pathway of PKC/NF-κB/c-fos may be involved in the influence of high glucose on the cardiomyocytes of neonatal rats

<p>Abstract</p> <p>Background</p> <p>High glucose could induce structure and function change in cardiomyocytes, PKC plays a core effect in the onset and progression of diabetic cardiomyopathy, but its underlying downstream signal transduction pathway is still not completely understood.</p> <p>Objectives</p> <p>To study the influence of high glucose on the structure, function and signal transduction pathway of PKC (Protein Kinase C)/NF-κB(Nuclear factor-κB)/c-fos in cultured cardiomyocytes.</p> <p>Methods</p> <p>Using cultured cardiomyocytes of neonatal Sprague-Dawley rats as a model, groups were divided into: control group (glucose: 5 mmol/L); high glucose group (glucose: 10 mmol/L, 15 mmol/L, 20 mmol/L, 25.5 mmol/L); equimolar mannital group (5 mmol/L glucose + 20.5 mmol/L maninital); high glucose(25.5 mmol/L) add PKC inhibitor (Ro-31-8220, 50 nmol/L); high glucose (25.5 mmol/L) add NF-κB inhibitor (BAY11-7082, 5 μmol/L). The cellular contracting frequency and volumes were measured and the expression of PKC-α, PKC-β2, p-PKC-α, p-PKC-β2, NF-κB, p-NF-κB, TNF-α (tumor necrosis factor-α) and c-fos were measured by western blot or RT-PCR.</p> <p>Results</p> <p>Cardiomyocytes cultured in high glucose level, but not iso-osmotic mannital, showed an increased pulsatile frequency and higher cellular volumes consistent with the increased glucose levels, and also higher expression of PKC-α, PKC-β2, p-PKC-α, p-PKC-β2, NF-κB, p-NF-κB, TNF-α and c-fos. The addition of Ro-31-8220 and BAY11-7082 could partly reverse these changes induced by high glucose level.</p> <p>Conclusion</p> <p>High glucose significantly increased the pulsatile frequency and cellular volumes of cultured cardiomyocytes via PKC/NF-κB/c-fos pathway, which might lead to diabetic cardiomyopathy.</p

Original Article Downregulation of miR-129 in peripheral blood mononuclear cells is a diagnostic and prognostic biomarker in prostate cancer

Abstract: Objective: The present study was designed to explore the clinical values of microRNA-129 (miR-129) expression in peripheral blood mononuclear cells for prostate cancer patients and the role of miR-129 in the proliferation of prostate cancer. Methods: The peripheral blood mononuclear cells were isolated form blood simple from 98 patients confirmed with prostate cancer and 56 matched healthy volunteers. Reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the expression level of miR-129 in peripheral blood mononuclear cells. Cox proportional hazards regression models and Kaplan-Meier analysis were used to evaluate the association of miR-129 expression with clinical and pathological characteristics of prostate cancer patients. The effect of miR-129 on the proliferation of prostate cancer cells in vitro was also determined. Results: Reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR) results showed that the expression of miR-129 was dramatically down-regulated in peripheral blood mononuclear cells for prostate cancer patients in comparison with healthy controls (P&lt;0.05). The decrease in miR-129 expression in peripheral blood mononuclear cells was significantly associated with aggressive clinical pathological features such as histological grade (P=0.010), high preoperative PSA level (P=0.002), pathological stage (P=0.011), high Gleason score (P=0.005), lymph node metastasis (P=0.002), angiolymphatic invasion (P=0.004), biochemical recurrence (P=0.001). The prostate cancer patients with a low miR-129 expression in peripheral blood mononuclear cells had an obviously shorter BCR-free survival compared with high miR-129 expression (P&lt;0.001). The Cox multivariate analysis established that the miR-129 expression may be an independent prognostic factor for biochemical recurrence (BCR)-free survival prostate cancer patients (P=0.000). The results of in vitro CCK-8 assays, as well as proliferating cell nuclear antigen (PCNA) and phosphorylated histone-3 (P-H3) (markers of proliferation) indicated that miR-129 overexpression markedly retarded the proliferation of PC-3 and DU-145 cells. Conclusions: Our results provide the first evidence that the miR129is significantly downregulated in prostate cancer patients and multivariate analysis confirmed that miR-129 is a novel independent prognostic factor for prostate cancer. Overexpression of miR-129 exerts tumor suppressive functions and abrogates prostate cancer growth

Boolean Game on Scale-free Networks

Inspired by the local minority game, we propose a network Boolean game and investigate its dynamical properties on scale-free networks. The system can self-organize to a stable state with better performance than random choice game, although only the local information is available to the agent. By introducing the heterogeneity of local interactions, we find the system has the best performance when each agent's interaction frequency is linear correlated with its information capacity. Generally, the agents with more information gain more than those with less information, while in the optimal case, each agent almost has the same average profit. In addition, we investigate the role of irrational factor and find an interesting symmetrical behavior.Comment: 12 pages and 6 figure

Forecasting the Short-Term Passenger Flow on High-Speed Railway with Neural Networks

Short-term passenger flow forecasting is an important component of transportation systems. The forecasting result can be applied to support transportation system operation and management such as operation planning and revenue management. In this paper, a divide-and-conquer method based on neural network and origin-destination (OD) matrix estimation is developed to forecast the short-term passenger flow in high-speed railway system. There are three steps in the forecasting method. Firstly, the numbers of passengers who arrive at each station or depart from each station are obtained from historical passenger flow data, which are OD matrices in this paper. Secondly, short-term passenger flow forecasting of the numbers of passengers who arrive at each station or depart from each station based on neural network is realized. At last, the OD matrices in short-term time are obtained with an OD matrix estimation method. The experimental results indicate that the proposed divide-and-conquer method performs well in forecasting the short-term passenger flow on high-speed railway