Poly(ortho ester) nanoparticles targeted for chronic intraocular diseases: ocular safety and localization after intravitreal injection

Treatment of posterior eye diseases is more challenging than the anterior segment ailments due to a series of anatomical barriers and physiological constraints confronted by drug delivery to the back of the eye. In recent years, concerted efforts in drug delivery have been made to prolong the residence time of drugs injected in the vitreous humor of the eye. Our previous studies demonstrated that poly(ortho ester) (POE) nanoparticles were biodegradable/biocompatible and were capable of long-term sustained release. The objective of the present study was to investigate the safety and localization of POE nanoparticles in New Zealand white rabbits and C57BL/6 mice after intravitreal administration for the treatment of chronic posterior ocular diseases. Two concentration levels of POE nanoparticles solution were chosen for intravitreal injection: 1.5?mg/ml and 10?mg/ml. Our results demonstrate that POE nanoparticles were distributed throughout the vitreous cavity by optical coherence tomography (OCT) examination 14 days post-intravitreal injection. Intraocular pressure was not changed from baseline. Inflammatory or adverse effects were undetectable by slit lamp biomicroscopy. Furthermore, we demonstrate that POE nanoparticles have negligible toxicity assessed at the cellular level evidenced by a lack of glia activation or apoptosis estimation after intravitreal injection. Collectively, POE nanoparticles are a novel and nontoxic as an ocular drug delivery system for the treatment of posterior ocular diseases.     

白鲜皮多糖的分离纯化及抗银屑病作用

目的:对白鲜皮粗多糖(DDP)进行分离纯化,并研究其抗银屑病作用。方法:DDP经膜分离技术截留相对分子质量小于10 k Da的组分(DDP-UF),采用DEAE-52纤维素柱分离纯化得到4种组分(DDP-UF-1,DDP-UF-2,DDP-UF-3,DDPUF-4);并通过红外光谱法,高效凝胶渗透色谱法(HPGPC),高效液相色谱法(HPLC),扫描电镜(SEM)测定其理化性质及结构特征。选用咪喹莫特乳膏诱导银屑病小鼠模型,己烯雌酚诱导雌鼠阴道上皮细胞增殖,酶联免疫吸附测定法(ELISA)检测各组小鼠血清白细胞介素(IL)-17与IL-23含量,苏木精-伊红(HE)染色法观察小鼠背部皮肤组织病理变化、阴道上皮细胞有丝分裂指数变化。结果:DDP-UF-1～4均具有多糖特征吸收峰,DDP-UF-1～4相对分子质量分别为10 948,40 148,32 222,19 943 Da;单糖组成及摩尔比分别为甘露糖-葡萄糖-半乳糖(32. 45∶11. 35∶8. 69),甘露糖-鼠李糖-葡萄糖醛酸-葡萄糖-木糖(25. 68∶23. 44∶21. 62∶18. 86∶3. 68),甘露糖-鼠李糖-葡萄糖醛酸-半乳糖醛酸-木糖-半乳糖(18. 68∶4. 61∶3. 89∶1. 65∶5. 36∶6. 21),葡萄糖醛酸-半乳糖醛酸-葡萄糖-木糖-半乳糖(11. 63∶15. 26∶5. 32∶2. 08∶3. 46);扫描电镜(SEM)显示DDP-UF-1～4形态结构为片状或海绵状结构。DDP-UF-1与DDP-UF-3可改善银屑病小鼠背部皮损状态、抑制雌鼠阴道上皮细胞有丝分裂、明显降低血清IL-17,IL-23含量(P 0. 05,P 0. 01)。结论:DDP-UF-1与DDP-UF-3均具有良好的抗银屑病作用,其作用可能与抑制IL-23/IL-17信号通路有关。     

Ospemifene plus fractional CO2 laser: a powerful strategy to treat postmenopausal vulvar pain

Abstract

This study is a single-center, retrospective analysis of postmenopausal women presenting with dyspareunia and vulvar pain, aiming to evaluate relative effectiveness of vestibular CO₂ laser therapy as a treatment. Three monthly sessions of laser were performed to each patient and thereafter a three-months follow-up was stablished. A total number of 72 patients undergoing vestibular laser treatment were recruited from patient files in the period between 2016 and 2018. Among these, 39 women also received a concomitant treatment with ospemifene (60?mg/day) during the study period. There was a statistically significant reduction of all the symptoms in both groups up to the three month follow-up. Regarding dryness and dyspareunia, the relief tent to be more prominent in the ospemifene?+?laser group at all follow-ups and remained statistically significant at three-month follow-up. Specifically, vestibular dryness was significantly lower in the ospemifene?+?laser group compared with the laser treatment group (?87% vs???34%, respectively), and the vestibular health score started declining faster in the ospemifene?+?laser group. Although, additional research is needed to understand the mechanism of action, our data shows that a combination regimen of laser and ospemifene may improve clinical effectiveness for long-term treatment of symptoms associated with the under-recognized genitourinary syndrome of menopause.     

User experiences with second-generation 32-gauge × 4 mm vs. thinner comparator pen needles: prospective randomized trial

Abstract

Objective

Two similarly designed studies compared user experiences with a second-generation extra-thin-wall, 5-bevel 32?G?×?4?mm pen needle (PN) with redesigned hub versus four thinner commercially available PNs.     

Barriers to vaccination service delivery within general practice: opportunity to make a sustainable difference in Aboriginal child health?

Objective: To identify behavioural barriers of service provision within general practice that may be impacting the vaccination coverage rates of Aboriginal children in Perth, Western Australia (WA). Methods: A purposive developed survey was distributed to 316 general practices across Perth and three key informant interviews were conducted using a mixed‐methods approach. Results: Of the surveyed participants (n=101), 67.4% were unaware of the low vaccination coverage in Aboriginal children; 64.8% had not received cultural sensitivity training in their workplace and 46.8% reported having inadequate time to follow up overdue child vaccinations. Opportunistic vaccination was not routinely performed by 30.8% of participants. Key themes identified in the interviews were awareness, inclusion and cultural safety. Conclusion: Inadequate awareness of the current rates, in association with a lack of cultural safety training, follow‐up and opportunistic practice, may be preventing greater vaccination uptake in Aboriginal children in Perth. Cultural safety is a critical component of the acceptability and accessibility of services; lack of awareness may restrict the development of strategies designed to equitably address low coverage. Implications: The findings of this study provide an opportunity to raise awareness among clinicians in general practice and inform future strategies to equitably deliver targeted vaccination services to Aboriginal children.     

Understanding the Influence of Nanocarrier-Mediated Brain Delivery on Therapeutic Performance Through Pharmacokinetic-Pharmacodynamic Modeling

This study aimed at evaluating how encapsulation in a regular nanocarrier (NC) (providing extended circulation time) or in a brain-targeting NC (providing prolonged circulation time and increased brain uptake) may influence the therapeutic index compared with the unformulated drug and to explore the key parameters affecting therapeutic performance using a model-based approach. Pharmacokinetic (PK) models were built with chosen PK parameters. For a scenario where central effect depends on area under the unbound brain concentration curve and peripheral toxicity relates to peak unbound plasma concentration, dose-effect and drug-side effect curves were constructed, and the therapeutic index was evaluated. Regular NC improved the therapeutic index compared with the unformulated drug due to reduced peripheral toxicity, while brain-targeting NC enhanced the therapeutic index by lowering peripheral toxicity and increasing central effect. Decreasing drug release rate or systemic clearance of NC with drug still encapsulated could increase the therapeutic index. Also, a drug with shorter half-life would therapeutically benefit more from a NC encapsulation. This work provides insights into how a NC for brain delivery should be optimized to maximize the therapeutic performance and is helpful to predict if and to what extent a drug with certain PK properties would obtain therapeutic benefit from nanoencapsulation.     

探讨绝经过渡期、育龄子宫肌瘤患者异常阴道出血相关因素分析

目的: 探讨育龄、绝经过渡期子宫肌瘤患者异常阴道出血危险因素，为异常阴道出血临床精准诊断、治疗提供理论依据。方法： 选取2017年06月—2020年06月于内蒙古医科大学附属医院住院行手术治疗的子宫肌瘤患者。实验组设为非月经期异常阴道出血的子宫肌瘤患者，对照组为无异常阴道流血子宫肌瘤患者。根据第9版教科书年龄18-43岁定为育龄组；44-54岁定为绝经过渡期组（我国妇女平均绝经年龄为49.5岁，80%在44-54岁之间〔1〕）。 应用Excel双录入，核对无误后进行统计分析。计数资料的比较用R×C列联表卡方检验、四格表卡方检验及两独立样本秩和检验。非条件Logistic回归模型用于子宫肌瘤阴道异常出血危险因素的分析，并分别得到OR值与相应95%的可信区间。在此模型中，OR值＞1认为是危险因素，OR值＜1认为是保护因素。统计学显著性水平设定为双侧p≤0.05，即认为差异有统计学意义。全部统计分析选用SPSS19.0软件进行统计学分析。结果：1.将与子宫肌瘤阴道异常出血相关的33项临床指标纳入单因素分析得出，月经周期异常、肌瘤位置（子宫颈肌瘤）、肌瘤直径≥9cm、血红蛋白异常、子宫内膜癌、核分裂像＞5个差异有统计学意义（P≤0.05），均是子宫肌瘤阴道异常出血的危险因素；2.子宫肌瘤异常阴道出血核分裂像＞5个与子宫内膜病理性改变和异常阴道出血差异有统计学意义（P=0.019）。结论：1. 子宫内膜发生病理改变是子宫肌瘤患者引起异常阴道出血的原因之一。2.月经周期异常、子宫颈肌瘤、肌瘤直径≥9cm、血红蛋白异常、子宫内膜病理改变均是子宫肌瘤阴道异常出血的危险因素；子宫肌瘤核分裂像＞5个是子宫平滑肌瘤出现异常阴道出血的独立高危因素；3.子宫肌瘤核分裂像＞5与阴道出血、子宫内膜病理改变有统计学意义。进行单因素分析后得知，月经周期、肌瘤位置、肌瘤大小、血红蛋白、子宫内膜病理变化均子宫肌瘤阴道异常出血的发生有关。 关键词育龄；绝经过渡期；子宫平滑肌瘤；异常阴道出血；危险因素     

Recent advances in construction of small molecule-based fluorophore-drug conjugates

As a powerful tool to advance drug discovery, molecular imaging may provide new insights into the process of drug effect and therapy at cellular and molecular levels. When compared with other detection methods, fluorescence-based strategies are highly attractive and can be used to illuminate pathways of drugs’ transport, with multi-color capacity, high specificity and good sensitivity. The conjugates of fluorescent molecules and therapeutic agents create exciting avenues for real-time monitoring of drug delivery and distribution, both in vitro and in vivo. In this short review, we discuss recent developments of small molecule-based fluorophore-drug conjugates, including non-cleavable and cleavable ones, that are capable of visualizing drug delivery.