Tadalafil-loaded PLGA microspheres for pulmonary administration: preparation and evaluation

Tadalafil, a long-acting PED-5 inhibitor, is commonly used for the treatment of pulmonary arterial hypertension (PAH). However, its efficacy and clinical application are severely limited by the poor water solubility, low bioavailability and a series adverse effects (e.g. headaches, indigestion). In this study, tadalafil was prepared and loaded into biodegradable PLGA (poly(lactic-co-glycolic acid)) microspheres (TDF-PLGA-MS) via emulsification-solvent evaporation. The resulting microspheres were processed into pulmonary inhalant by freeze drying. The TDF-PLGA-MS was spherical and uniform, with an average particle diameter ~10.29 μm. The encapsulation efficiency and drug loading yield of TDF‑PLGA‑MS were 81.68% and 8.52%, respectively. The investigation of micromeritics showed that the TDF‑PLGA‑MS had low moisture content. The fluidity of powders was relatively good. The aerodynamic diameter and emptying rate of microspheres powders were 3.92 μm and 95.41%, respectively. Therefore, the microspheres powders were easy to be atomized, and can meet the requirements of pulmonary administration. In vitro release results showed that the microspheres group released slowly. The cumulative release in 24 h and 10 d was 46.87% and 84.06%, respectively. The in vitro release profile of TDF‑PLGA‑MS was in accordance with the Weibull model. The results of Pharmacokinetics showed that tadalafil from microspheres slowly released into the blood after intratracheal instillation. The pulmonary drug residue in 0.5 h was 3.5 times compared with solution group. The residual concentration in lung after 10d was still higher than that of solution group in 48 h. The t1/2β and MRT0-∞ were 3.10 times and 3.96 times that of solution group, respectively. Moreover, the Cmax and AUC of drug residues in lung were 3.48 times and 16.36 times that of solution group, respectively. The results of tissue distribution showed that the Re in lung was 16.358, which indicated the lung targeting. In conclusion, the TDF-PLGA-MS for pulmonary administration in this study can significantly improve the pulmonary targeting, increase efficacy of tadalafil and reduce other non-target organs toxicity. This study will have an important clinical significance for PAH patients who need long-term drug therapy

Liposomes for systematic delivery of vancomycin hydrochloride to decrease nephrotoxicity: Characterization and evaluation

AbstractVancomycin hydrochloride （VANH）, the first glycopeptide antibiotic, is a water-soluble drug for the treatment of acute osteomyelitis. Liposomal formulations of VANH have already been manipulated and characterized, which was a mean of increasing their therapeutic index, reducing their toxicity and altering drug biodistribution. One of the challenges for preparing VANH-Lips is their low encapsulation efficiency (EE). In the present study, we aim to improve the liposomal formulation of VANH for higher EE, longer systemic circulation, reduced nephrotoxicity and enhanced antimicrobial activities. Vancomycin hydrochloride-loaded liposomes (VANH-Lips) were formulated by the method of modified reverse phase evaporation. Based on the optimization of formulation with orthogonal experimental design, the average drug encapsulation efficiency and the mean particle size of VANH-Lips were found to be 40.78 ± 2.56% and 188.4 ± 2.77 nm. In vitro drug release of VANH-Lips possessed a sustained release characteristic and their release behavior was in accordance with the Weibull equation. After intravenous injection to mice, the mean residence time (MRT) of VANH-Lips group was significantly prolonged in vivo and the AUC value was improved as well compared with the vancomycin hydrochloride solution (VANH-Sol) group. Furthermore, the biodistribution results in mice showed that VANH-Lips decreased the accumulation of VANH in kidney after intravenous injection. In conclusion, VANH-Lips may be a potential delivery system for VANH to decrease nephrotoxicity in the treatment of osteomyelitis

A new data-enabled intelligence framework for evaluating urban space perception

The urban environment has a great impact on the wellbeing of citizens and it is of great significance to understand how citizens perceive and evaluate places in a large scale urban region and to provide scientific evidence to support human-centered urban planning with a better urban environment. Existing studies for assessing urban perception have primarily relied on low efficiency methods, which also result in low evaluation accuracy. Furthermore, there lacks a sophisticated understanding on how to correlate the urban perception with the built environment and other socio-economic data, which limits their applications in supporting urban planning. In this study, a new data-enabled intelligence framework for evaluating human perceptions of urban space is proposed. Specifically, a novel classification-then-regression strategy based on a deep convolutional neural network and a random-forest algorithm is proposed. The proposed approach has been applied to evaluate the perceptions of Beijing and Chengdu against six perceptual criteria. Meanwhile, multi-source data were employed to investigate the associations between human perceptions and the indicators for the built environment and socio-economic data including visual elements, facility attributes and socio-economic indicators. Experimental results show that the proposed framework can effectively evaluate urban perceptions. The associations between urban perceptions and the visual elements, facility attributes and a socio-economic dimension have also been identified, which can provide substantial inputs to guide the urban planning for a better urban space

Case report: Abolishing primary resistance to PD-1 blockade by short-term treatment of lenvatinib in a patient with advanced metastatic renal cell carcinoma

Anti-PD-1 immunotherapy has been extensively used in treatment of patients with advanced metastatic renal cell carcinoma (mRCC). Several prospective clinical trials showed that the combined treatment of anti-PD-1 antibody plus lenvatinib, a potent receptor tyrosine kinase inhibitor (TKI), exhibited high response rate compared with single-agent sunitinib. However, whether the patients with primary resistance to PD-1 blockade could benefit from the addition of lenvatinib is still unclear. Herein, we reported a patient with mRCC who was primary resistant to pembrolizumab and achieved a durable complete response after a short-term treatment with lenvatinib. This case report indicates that the patients with primary resistance to anti-PD-1 therapy could benefit from the short-term lenvatinib in combination with anti-PD-1 therapy, and provides a useful paradigm worthy of establishing a clinical trial for mRCC patients with primary resistance to anti-PD-1 therapy

Social Development with Public Value: An International Comparison

10.1007/s11205-021-02805-5Social Indicators Researc

Effects of chronic sleep deprivation on the extracellular signal-regulated kinase pathway in the temporomandibular joint of rats.

OBJECTIVES: To examine the possible involvement and regulatory mechanisms of extracellular signal-regulated kinase (ERK) pathway in the temporomandibular joint (TMJ) of rats subjected to chronic sleep deprivation (CSD). METHODS: Rats were subjected to CSD using the modified multiple platform method (MMPM). The serum levels of corticosterone (CORT) and adrenocorticotropic hormone (ACTH) were tested and histomorphology and ultrastructure of the TMJ were observed. The ERK and phospho-ERK (p-ERK) expression levels were detected by Western blot analysis, and the MMP-1, MMP-3, and MMP-13 expression levels were detected by real-time quantitative polymerase chain reaction (PCR) and Western blotting. RESULTS: The elevated serum CORT and ACTH levels confirmed that the rats were under CSD stress. Hematoxylin and eosin (HE) staining and scanning electron microscopy (SEM) showed pathological alterations in the TMJ following CSD; furthermore, the p-ERK was activated and the mRNA and protein expression levels of MMP-1, MMP-3, and MMP-13 were upregulated after CSD. In the rats administered with the selective ERK inhibitor U0126, decreased tissue destruction was observed. Phospho-ERK activation was visibly blocked and the MMP-1, MMP-3, and MMP-13 mRNA and protein levels were lower than the corresponding levels in the CSD without U0126 group. CONCLUSION: These findings indicate that CSD activates the ERK pathway and upregulates the MMP-1, MMP-3, and MMP-13 mRNA and protein levels in the TMJ of rats. Thus, CSD induces ERK pathway activation and causes pathological alterations in the TMJ. ERK may be associated with TMJ destruction by promoting the expression of MMPs

Sensitivity analysis of log interpretation parameters of through casing reservoir saturation logging

In the middle and late stages of oilfield production and development, the increase of production measures has resulted in a greater difference in reservoir physical properties between layers and a complex oil-water relationship. Most of the main reservoirs are highly flooded, the distribution of formation water salinity is complex, and the accuracy of remaining oil evaluation is relatively low. In order to solve the problem of inaccurate evaluation of remaining oil in high temperature, high pressure, low formation water salinity and low porosity reservoirs, it is necessary to improve the existing logging interpretation and evaluation technology of remaining oil saturation. It can provide a powerful basis for accurately finding oil layers with development potential, and for adjustment and judgment of potential layers in the middle and late stages of oilfield development. In this paper, the parameter sensitivity is calculated by normalizing the parameter change amplitude, which can better compare the sensitivity of water saturation interpretation of each parameter at different depths. It can also be obtained which factor has the greatest influence on the interpretation of water saturation at different depths. Calculating the partial derivative value corresponding to the capture cross-section value of shale and formation water can specifically compare the sensitivity of parameters to the results and find out the direction of parameter adjustment

Correlation analysis.

Based Correctly handling the creativity of employees who have not been adopted is not only conducive to continuously stimulating employees’ creativity and improving individual innovation performance, but also conducive to making the best use of organizational resources. This study integrates conservation of resource theory (COR) and social information processing theory to explore the influence of bootleg innovation behavior in organizations on individual innovation performance, as well as the mediating role of cognitive flexibility and the moderating role of leadership emotional intelligence. A three-stage time-lagged research design is used to obtain a valid sample of 327 employees from China. The PROCESS macro for SPSS was applied to test the hypothesized relationships. Findings demonstrated that bootleg innovation is positively related to individual innovation performance; cognitive flexibility mediates the relationship between bootleg innovation and individual innovation performance. Moreover, leadership emotional intelligence moderates the relationship between bootleg innovation and individual innovation performance and between bootleg innovation and cognitive flexibility and between cognitive flexibility and individual innovation performance respectively. The conclusion of the study not only provides a theoretical basis for individuals and leaders to deal with employees’ creative abortion, but also provides a new thinking mode for how to maximize the effectiveness of unaccepted ideas and promote individual innovation performance.</div