A targeted neurotransmitter quantification and nontargeted metabolic profiling method for pharmacometabolomics analysis of olanzapine by using UPLC-HRMS

Neurotransmitters (NTs) are specific endogenous metabolites that act as “messengers” in synaptic transmission and are widely distributed in the central nervous system. Olanzapine (OLZ), a first-line antipsychotic drug, plays a key role in sedation and hypnosis, but, it presents clinical problems with a narrow therapeutic window, large individual differences and serious adverse effects, as well as an unclear mechanism in vivo. Herein, a simultaneous targeted NT quantification and nontargeted metabolomics method was developed and validated for pharmacometabolomics analysis of OLZ by using ultra-high-performance liquid chromatography coupled with high-resolution mass spectrometry (UPLC-HRMS). Considering the low physiological concentrations of NTs, a full MS scan and target selective ion monitoring (tSIM) scan were combined for nontargeted metabolomics and targeted NT quantification, respectively. By using this strategy, NTs at a very low physiological concentration can be accurately detected and quantified in biological samples by tSIM scans. Moreover, simultaneously nontargeted profiling was also achieved by the full MS scan. The newly established UPLC-HRMS method was further used for the pharmacometabolomics study of OLZ. Statistical analysis revealed that tryptophan, 5-hydroxytryptophan, 5-hydroxytryptamine, γ-aminobutyric acid etc. were significantly downregulated, while tyrosine was significantly upregulated, which suggested that OLZ could promote the downstream phase II reaction of 5-hydroxytryptamine, inhibit tyrosine hydroxylase activity, and increase the activity of γ-aminobutyric acid transaminase. In conclusion, this method could provide novel insights for revealing the pharmacodynamic effect and mechanism of antipsychotic drugs.

We developed a method that would provide novel insights for revealing the pharmacodynamic effect and mechanism of antipsychotic drugs (olanzapine).     

Ursolic acid derivatives are potent inhibitors against porcine reproductive and respiratory syndrome virus

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most devastating viral pathogens of swine and has a substantial economic impact on the global pork industry. Currently, vaccination strategies provide very limited protection against PRRSV transmission. Therefore, there is an urgent need to develop new antiviral strategies to prevent PRRSV pandemics. In this study, we showed that 3-O-β-chacotriosyl ursolic acid (1) and its ester analogs possessed anti-PRRSV activity in vitro, of which bioisosteric surrogates 7–15 were further generated with the aim of enhancing the selective index. Our results showed that amidation of the 17-COOH group of UA could significantly reduce cytotoxicity and enhance anti-PRRSV activity in MARC-145 cells. Among them, compound 9 displayed the strongest anti-PRRSV activity with the least cytotoxicity. Potent inhibition of representative compounds 9 and 12 on PRRSV infection was observed not only in MARC-145 cells, but also in primary porcine alveolar macrophages, PRRSV-target cells in vivo. Furthermore, compounds 8, 9, 12 and 14 exhibited broad-spectrum inhibitory activities in vitro against high pathogenic type 2 PRRSV NADC30-like and GD-XH strains as well as classical CH-1a and VR2332 strains. Mechanistically, compounds 9 and 12 inhibited PRRSV replication by directly inactivating virions and therefore affecting all tested stages of the virus life cycle, including viral entry, replication and progeny virus release, but did not affect cellular susceptibility to PRRSV. Our findings suggest that compound 9 could be a hit PRRSV inhibitor and deserves further in vivo studies in swine.

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most devastating viral pathogens of swine and has a substantial economic impact on the global pork industry.     

麻醉前使用右美托咪定或咪达唑仑临床效果的比较

目的探讨右美托咪定与咪达唑仑作为麻醉前用药的镇静效果及对患者记忆功能的影响。方法选择择期手术患者40例,年龄20～60岁,ASAⅠ或Ⅱ级,随机均分为右美托咪定组(A组)和咪达唑仑组(B组)。麻醉前20minA组静脉泵注右美托咪定0.7μg/kg,持续10min;B组静注咪达唑仑0.07mg/kg,所有患者在用药前、用药后10min均观看了内容不同的两张水果图片。记录用药前5min、用药后10min患者OAA/S评分,焦虑视觉模拟/焦虑状态问卷(AVA/SAI)评分和BIS,记录MAP、HR和SpO2,术后24h随访患者对用药前后水果图片的记忆情况。结果用药后10min两组MAP明显低于、HR明显慢于用药前5min(P<0.05或P<0.01),A组HR明显慢于B组(P<0.05)。用药后10min两组OAA/S、AVA/SAI评分和BIS明显低于用药前5min(P<0.05),A组OAA/S评分明显低于B组(P<0.05)。术后24h随访,两组患者对给药前图片西瓜记忆率均为100%,A组对给药后图片香蕉记忆率为95%,明显高于B组的0%(P<0.01)。两组患者未出现寒战和躁动。结论作为麻醉前用药,右美托咪定和咪达唑仑具有良好的镇静作用。右美托咪定对记忆功能几乎无影响,但对HR的干扰更明显。     

东方女性综合鼻整形术

目的：探讨适合于东方女性的鼻综合整形手术方法并评价其-陆床效果。方法：80例东方女性根据外鼻形态的具体缺陷情况,同时采用假体隆鼻、鼻头缩小、鼻翼缩小、耳软骨鼻尖延长、鼻小柱延长、鼻孔缩小等多项术式中的二项以上进行鼻整形手术。结果：2008年3月-2011年3月对80例患者采用上述方法行鼻整形术,术后随访6个月-2年,除2例鼻尖软组织增生导致效果不满意外,其余患者对效果均感满意,形态自然,切口瘢痕不明显。结论：鼻综合整形能从全方位改善外鼻不良形态,据东方女性的外鼻形态特点,应用综合手术方法能取得良好的效果。     

Adenoid Cystic Carcinoma of the Nasal Cavity and Paranasal Sinuses: A Meta-Analysis

Objectives To identify independent predictors of outcome in patients with adenoid cystic carcinoma (ACC) of the paranasal sinuses and skull base.Design Meta-analysis of the literature and data from the International ACC Study Group.Setting University-affiliated medical center.Participants The study group consisted of 520 patients, 99 of them from the international cohort. The median follow-up period was 60 months (range, 32 to 100 months).Main Outcome Measures Overall survival (OS) and disease-specific survival (DSS).Results The 5-year OS and DSS of the entire cohort were 62% and 67%, respectively. The local recurrence rate was 36.6%, and the regional recurrence rate was 7%. Distant metastasis, most commonly present in the lung, was recorded in 106 patients (29.1%). In the international cohort, positive margins and ACC of the sphenoid or ethmoidal sinuses were significant predictors of outcome (p < 0.001). Perineural invasion and adjuvant treatment (radiotherapy or chemoradiation) were not associated with prognosis.Conclusion Tumor margin status and tumor site are associated with prognosis in ACC of the paranasal sinuses, whereas perineural invasion is not. Adjuvant treatment apparently has no impact on outcome.     

Influence of hyaluronic acid on wound healing using composite porcine acellular dermal matrix grafts and autologous skin in rabbits

This study aims to explore the influence of hyaluronic acid (HA) on wound healing during xenogeneic porcine acellular dermal matrix (PADM) composite skin grafting. The results will facilitate the development of methods for improving graft contracture and poor elasticity of composite transplantation. Exogenous HA was added to composite PADM grafts and to thin autologous skin grafts during rabbit full‐thickness skin wound repair. The influence of HA on wound healing was evaluated according to its contracture rate and its expression of collagen types I and III. The possible mechanism was then explored based on HA metabolism and vascularisation in the skin graft. The results show that exogenous HA relieves graft contracture on rabbit wound surfaces, increases collagen I and III expression and decreases the ratio between collagen types. HA stimulates the generation of more CD44 receptors to strengthen its enzymolysis. The resulting metabolites promote the vascularisation of the wound surface, which are conducive for mitigating graft contracture, and further improve the composite grafting effect.