Ionic liquids as the effective technology for enhancing transdermal drug delivery: Design principles, roles, mechanisms, and future challenges

Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs;as novel solvents for improving the solubility of drugs in carriers;as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs;and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structure-activity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs.

Dose-response relationship between risk factors and incidence of COVID-19 in 325 hospitalized patients:A multicenter retrospective cohort study

BACKGROUND The epidemiological and clinical characteristics of coronavirus disease 2019(COVID-19)patients have been widely reported,but the assessment of doseresponse relationships and risk factors for mortality and severe cases and clinical outcomes remain unclear.AIM To determine the dose-response relationship between risk factors and incidence of COVID-19.METHODS In this retrospective,multicenter cohort study,we included patients with confirmed COVID-19 infection who had been discharged or had died by February 6,2020.We used multivariable logistic regression and Cox proportional hazard models to determine the dose-response relationship between risk factors and incidence of COVID-19.RESULTS It clarified that increasing risk of in-hospital death were associated with older age(HR:1.04,95%CI:1.01-1.09),higher lactate dehydrogenase[HR:1.04,95%confidence interval(CI):1.01-1.10],C-reactive protein(HR:1.10,95%CI:1.01-1.23),and procalcitonin(natural log-transformed HR:1.88,95%CI:1.22-2.88),and D-dimer greater than 1μg/m L at admission(natural log transformed HR:1.63,95%CI:1.03-2.58)by multivariable regression.D-dimer and procalcitonin were logarithmically correlated with COVID-19 mortality risk,while there was a linear dose-response correlation between age,lactate dehydrogenase,D-dimer and procalcitonin,independent of established risk factors.CONCLUSION Higher lactate dehydrogenase,D-dimer,and procalcitonin levels were independently associated with a dose-response increased risk of COVID-19 mortality.

A Study on the Dose-Response Relationship between Asbestos Exposure Level and Asbestosis among Workers in a Chinese Chrysotile Product Factory

The dose-response relationship for asbestos exposure in a chrysotile product factory was studied. The past gravimetric dust concentration values, obtained from different worksites, were converted into fiber concentration values according to conversion factors that were worked out by simultaneous sampling in this study. The conversions were made so that exposure could be expressed in fiber-years (f-yr). Asbestosis was diagnosed on the basis of chest radiographs and occupational histories. Cumulative dust exposure (f-yr) was calculated up to the date of diagnosis for asbestosis patients, and up to September 1982 for the remaining workers. A dose-response relationship expressed as fiber-years exposed vs cumulative prevalence of asbestosis was established by the life table method on the basis of these data. Predicted 3 and 1% prevalence of asbestosis corresponded to 43 and 22 f-yr exposure, respectively. Considering that a worker can work for 35 years, these doses are commensurate with dust concentrations of 1.22 and 0.63 f/ml, respectively. It is recommended that 1 f/ml be taken as the maximum allowable concentration of airborne asbestos dust for the workplace with an anticipated prevalence of about 2% asbestosis after 35 years of exposure. 1990 Academic Press, Inc.

Structure-Property Relationships and Models of Controlled Drug Delivery of Biodegradable Poly (D, L-lactic acid) Microspheres

An oil-in-water (O/W) solvent evaporation method was used to prepare biodegradable microspheresbased on poly(D,L-lactic acid) (PLA). Nifedipine, a hydrophobic drug, was chosen as a model molecule in the studyof drug entrapment and release. Effect of preparation conditions on the size, morphology, drug loading, and releaseprofiles of micropheres was investigated. Based on in vitro release experimental findings, a diffusion/dissolutionmodel was presented for quantitative description of the resulting release behaviors and drug release kinetics fromPLA microspheres analyzed. The mathematical models were used to predict the effect of microstructure on theresulting drug release. It provided an approach to determine the suitable structure parameters for microspheres toachieve desired drug release behaviors.

Serum Ferritin and the Risk of Metabolic Syndrome:A Systematic Review and Dose-Response Meta-Analysis of Cross-sectional Studies

Objective This study aims to assess the dose-response relationship between serum ferritin(SF)and metabolic syndrome(MetS)in the two sexes.Methods We searched for articles on PubMed,the Cochrane Library,EMBASE,and the Web of Science databases that were published from 1950 to 2020.The summary odds ratio(OR)and 95%confidence interval(CI)of the association between SF and MetS were estimated using a random-effects model through a meta-analysis.Based on the methods described by Greenland and Longnecker,we explored the dose-response relationship between the two sexes.Results This study included 14 studies and 74,710 samples.The results of the classical meta-analysis showed that SF was positively associated with MetS(OR=1.77,95%CI:1.59–1.98).Regarding the components of MetS(8 studies included),the results showed that SF was positively associated with abdominal obesity(OR=1.42,95%CI:1.24–1.62),elevated fasting plasma glucose(OR=1.84,95%CI:1.50–2.25),elevated blood pressure(OR=1.17,95%CI:1.08–1.26),elevated triglycerides(OR=2.09,95%CI:1.72–2.54),and reduced high-density lipoprotein cholesterol(OR=1.33,95%CI:1.19–1.49).In the linear dose-response meta-analysis,the ORs of males,females,and postmenopausal females were 1.14(95%CI:1.13–1.16),1.32(95%CI:1.26–1.39),and 1.34(95%CI:1.22–1.47),respectively.Conclusions Our study shows that SF is significantly and positively associated with MetS,and the risk in the male population is higher than that in the female population.This finding also supports the recommendation of using SF as an early warning marker of MetS.

Quantitative Structure Activity Relationship Studies of Benzoxazinone Derivative Antithrombotic Drug Using New Three-dimensional Structure Descriptors

A novel three-dimensional holographic vector of atomic interaction field（3D-HoVAIF） was used to describe the chemical structures of 23 benzoxazinone derivatives as antithrombotic drugs.Here a quantitative structure activity relationship（QSAR） model was built by partial least-squares（PLS） regression.The estimation stability and prediction ability of the model were strictly analyzed by both internal and external validations.The correlation coefficients of established PLS model,leave-one-out（LOO） cross-validation,and predicted values versus experimental ones of external samples were R2=0.899,RCV2=0.854 and Qext2=0.868,respectively.These values indicated that the built PLS model had both favorable estimation stability and good prediction capabilities.Furthermore,the satisfactory results showed that 3D-HoVAIF could preferably express the information related to the biological activity of benzoxazinone derivatives.

Analysis on Epidemiology Causality Relationship Theory under Food and Drug Safety Context

Violation of food and drug safety and other hazard crimes have the features of long latency and multiple factors. Traditional criminal law causality theory is no controversy to determine causality of criminal responsibility, thus it is necessary to introduce the epidemiology causality theory-it is a kind of causality theory based on epidemic diseases, and it is the high degree of probability in the determination of causality in criminal laws so as to solve the traditional attribution problem, but the theory also exists applicable restriction conditions in judicial practice.

药物的定量结构色谱保留关系研究

采用人工神经网络(ANN)建立了110种药物的结构与色谱保留之间的定量关系(QSRR)模型,并将其与偏最小二乘回归(PLSR)模型进行比对.110种药物的ANN模型自相容能力的复相关系数(R^(2))为0.9191,泛化能力的复相关系数(R^(2))为0.9365;而PLSR模型的复相关系数(R^(2))为0.8275和0.8514.结果表明,ANN模型的自相容能力、泛化能力优于PLSR模型.采用集内集和集外集对模型进行检验时,ANN模型的复相关系数(R^(2))为0.9105,也优于PLSR模型,且ANN预测精密度和准确度更高.

他汀类药物与骨密度:一项药物靶向孟德尔随机化分析

背景:观察性研究表明他汀类药物可能对骨密度具有保护作用,这使其成为潜在的骨质疏松症治疗药物之一。目的:通过孟德尔随机化方法来评估药物靶点介导的脂质表型与骨密度之间的因果关系。方法:从IEU Open GWAS数据库获取了与他汀类药物相关的单核苷酸多态性以及骨密度相关数据。主要分析方法是逆方差加权法,同时也使用了加权中位数法、简单中位数法、加权中值方法和MR-Egger回归法。使用β值和95%CI来评估他汀类药物与骨密度之间的因果关系;另外,进行敏感性分析以验证结果的可靠性,使用Cochran’s Q检验来评估异质性,使用MR-Egger截距检验是否存在水平多效性。使用留一法分析确定是否有单个或多个单核苷酸多态性影响了结果。结果与结论:他汀类药物作用靶点——3-羟基-3-甲基戊二酰辅酶A还原酶介导的低密度脂蛋白胆固醇与足跟定量超声骨密度(β=-0.086,95%CI:-0.117至-0.055,P=5.42×10^(-8))和全身骨密度(β=-0.193,95%CI:-0.288至-0.098,P=7.35×10^(-5))呈显著相关。该研究结果支持了他汀类药物对骨密度的保护作用。这些发现不仅加深了对胆固醇相关基因和骨骼健康关系的理解,还揭示了改善骨密度的潜在治疗靶点。

β-咔啉杂合咪唑类化合物的合成及体外抗肿瘤活性

以L-色氨酸为原料,经Pictet-Spengler环化反应、氧化脱羧、N^(9)-烷基化等反应步骤,合成了一系列β-咔啉杂合咪唑类化合物。目标化合物经1HNMR、13CNMR和HRMS确证结构。采用MTT(噻唑蓝)法检测了目标化合物对肺癌细胞(A-549)、胃癌细胞(BGC-823)、结肠癌细胞(CT-26)、肝癌细胞(Bel-7402)和乳腺癌细胞(MCF-7)的体外抗肿瘤活性。结果表明,大部分化合物对这5种肿瘤细胞株表现出了中等及优良的抑制活性。特别是3-苄基-11-(3-苯基丙基)-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴr)对CT-26、Bel-7402和MCF-7细胞株的体外抗肿瘤活性较高,对应的半数抑制浓度(IC_(50))分别为(9.5±0.4)、(7.4±0.3)和(8.8±0.6)µmol/L。分子对接结果表明,3-苄基-11-甲基-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴa)、3-苄基-11-丁基-11H-咪唑并[1',5':1,2]吡啶并[3,4-b]吲哚(Ⅴf)和Ⅴr与VEGFR^(2)激酶的多个氨基酸残基具有良好的结合作用。

Research progress on the mechanism of exercise against depression

The substantial global health burden of depression encourages the development of innovative and broadly effective interventions.This paper aimed to examine recent advancements by which exercise works as an antidepressant and recommends optimal types and quantity of exercise as supplemental therapies in treating depression.Sedentary behavior and low physical activity significantly influence the onset of depression.Being an effective treatment option,exercise can significantly reduce depression risk.Exercise exerts antidepressant effects as it modulates neurotransmitters,neuroplasticity,the immune system,and hormone levels.Effective exercise forms include yoga,strength training,and walking/jogging.Tailored exercise regimens that consider individual preferences and tolerability can improve outcomes.Regular exercise enhances general well-being and reduces depressive symptoms.Additional research is needed to understand the complex basis of exercise's effects on depression.Exercise is a cost-effective and accessible intervention for depression management that needs additional exploration.Thus,customized exercise programs,as per each patient’s needs,are essential for their successful implementation clinically.

白芥子穴位给药配伍对延胡索乙素药效动力学影响的研究

目的:探讨“冬病夏治”全方配伍和无白芥子配伍延胡索乙素在模型家兔“肺俞”穴皮下药代动力学特征及药代动力学-药效动力学(PK-PD)模型的相关性。方法:支气管哮喘模型家兔随机分成延胡索单方组、缺白芥子组、全方组,微透析技术收集14 h穴位皮下透析液,液相色谱-质谱法(Liquid Chromatography Mass Spectrometry,LCMS)法检测方中君药延胡索主要成分延胡索乙素浓度,获得药代动力学参数;酶联免疫吸附试验(ELISA)法检测对应时间点模型动物血清中IgE水平,获得药效学参数;对药动学、药效学参数进行PK-PD模型拟合。结果:白芥子配伍后的药峰浓度(C_(max))、药时曲线下面积(AUC_(0-t))、平均滞留时间(MRT_(0-t))均显著增加(P<0.01,P<0.01,P<0.05),达峰时间(T_(max))提前(P<0.01);“浓度-时间-效应”三维曲线表明,方中有白芥子配伍时,药效出现更快、消退更慢,起效时间晚于峰浓度,具有一定滞后性。结论:动力学参数、PK-PD模型结果表明,白芥子配伍能够改变“方中君药”——延胡索的主要成分延胡索乙素穴位局部的皮下分布,促进方中君药有效成分快速吸收,延长滞留时间,在方剂中起到主药、改善其他药物分布的“双重”作用。

菊科橐吾属植物中艾里莫芬烷型倍半萜化合物细胞毒性研究进展

艾里莫芬烷型倍半萜是由15个碳原子组成的双环倍半萜,主要从菊科植物橐吾属植物中提取,具有抗肿瘤、抗菌、抗炎等生物活性。艾里莫芬烷型倍半萜的基本结构类型主要包括内酯环、二聚体、呋喃环、降碳型和C19等。本文综述了艾里莫芬烷型倍半萜的相关结构及其潜在的细胞毒性,阐述其特定化学结构特点对抗肿瘤活性的影响,以期为研究其抗肿瘤的临床治疗效果提供参考。

不同体位对膝关节镜手术患者蛛网膜下腔阻滞罗哌卡因ED50的影响

目的研究不同体位对膝关节镜手术患者蛛网膜下腔阻滞罗哌卡因半数有效剂量(ED50)的影响。方法选取90例需要进行择期单侧膝关节镜手术的患者,年龄18~64岁,ASA分级为I或Ⅱ级,体质量指数(BMI)为18~24 kg/m^(2),根据不同的体位,这些患者被分为三组,分别是头高脚低0°组、10°组和20°组。试验采用序贯法,每组第1例患者均获得蛛网膜下腔注射0.75%罗哌卡因11.25 mg,接下来根据前1例患者蛛网膜下腔阻滞是否有效,决定下一位患者的剂量是否减少或增加0.75 mg。使用概率单位回归分析法,计算罗哌卡因在不同体位下的蛛网膜下腔阻滞ED50。结果三组的ED50分别为:0°组为11.625 mg(95%CI:11.259~11.991 mg);10°组为11.325 mg(95%CI:10.968~11.669 mg);20°组为9.373 mg(95%CI:8.963~9.765 mg)。与0°组比较,10°组和20°组运动阻滞恢复时间缩短,20°组ED50降低、最高感觉阻滞平面下降、运动阻滞起效时间延长(P<0.05);与10°组比较,20°组ED50降低、运动阻滞恢复时间缩短(P<0.05)。三组术中低血压和恶心呕吐发生率比较差异无统计学意义(P>0.05)。结论膝关节镜手术患者在保持头高脚低0°、10°、20°体位时,蛛网膜下腔阻滞罗哌卡因的ED50分别为11.625 mg、11.325 mg和9.373 mg。通过头高脚低20°的姿势可以降低蛛网膜下腔阻滞的罗哌卡因ED50。

An Analysis of Specific Categories of Birth Defects and Developmental Disabilities for Children of Participants of the Air Force Health Study

Background: The Air Force Health Study collected reproductive outcomes for live-born children of male Air Force veterans of the Vietnam War. Methods: Dioxin values for participants were obtained from blood samples. Analyses were conducted of occurrence of 16 specific categories of birth defects and developmental disabilities. Children were categorized as conceived before and after the start of participants’ Vietnam War service. Children conceived before the start of Vietnam War service were treated as being conceived when their fathers had unquantifiable dioxin values. Children conceived after the start of Vietnam War service for participants with missing dioxin values were excluded from primary analyses, but were used to assess the impact of their exclusion on conclusions. Correlation between values for specific categories for multiple children fathered by the same participant was accounted for. The dose-response relationship was treated as a step function increasing for dioxin values larger than adaptively identified individual thresholds changing with the specific category. Results: For 15 of 16 specific categories, the probability of occurrence increased substantially for a sufficiently high dioxin level above identified thresholds. Exclusion of children due to missing dioxin likely did not affect these results. Conclusions: Results supported the conclusion of substantial adverse effects on a wide variety of specific categories of birth defects and developmental disabilities due to sufficiently high exposures to dioxin, a toxic contaminant of Agent Orange used for herbicide spraying in the Vietnam War. Results may hold more generally, but might also have been affected by a variety of limitations.

阿司匹林对认知功能的影响

阿司匹林是预防心脑血管事件的常用药物,有多个专家共识推荐使用低剂量阿司匹林(75~150 mg/d)对心脑血管疾病进行二级预防。该文旨在探讨阿司匹林发挥对心脑血管事件预防作用以及对认知功能的影响。

通过语义三元组和网络药理学发现抑郁症药物

基于抑郁症相关医学文献信息挖掘潜在抗抑郁药并揭示其抗抑郁相关机制和通路,为抑郁症药物的研发提供方向。通过SemRep提取与抑郁症相关的语义三元组,限定语义关系和语义类型确定潜在药物。从PubChem、GeneCards等数据库获取潜在药物和抑郁症的靶点并取二者的交集后,构建交集靶点的蛋白相互作用(protein-protein interaction,PPI)网络。通过Cytoscape分析PPI网络,确定核心靶点。通过R软件对核心靶点进行GO(gene ontology)和KEGG(kyoto encyclopedia of genes and genomes)分析。最后,通过AutodockTool软件对核心靶点与潜在药物进行分子对接分析。结果表明Hydrocortisone、Benzodiazepine、Curcumin、Metformin、Nicotine、Risperidone等6种药物为潜在抗抑郁药,这些药物通过炎症、神经递质的调节等生物过程以及MAPK(mitogen activated protein kinase)、TNF(tumor necrosis factor)等信号通路发挥抗抑郁作用,并且与抑郁症核心靶点间结合性能良好。此外,Benzodiazepine和Nicotine在临床实践中存在成瘾和滥用的风险,在抑郁症治疗中的作用可能有限。可见基于语义三元组和网络药理学发现抑郁症药物新知识,可以节约时间和经济成本,也能为临床药物使用提供新的方向。

可电离脂质及其对载核酸药物脂质纳米粒转染效率和安全性的影响研究进展

可电离脂质构成的脂质纳米粒(LNP)是目前临床上最具应用前景的非病毒核酸药物递送载体之一,在递送基因治疗药物和疫苗等方面具有巨大潜力。LNP的主要成分可电离脂质对LNP的内涵体逃逸率、转染效率、器官靶向性和安全性等起决定性作用。可电离脂质的亲水头基含有叔胺基,可提高LNP缓冲能力,进而改变其p Ka值,并含有咪唑,可增强mRNA-LNP的稳定性和转染活性;连接体含有酯基能够高效诱导基因沉默并可提高其降解速率和安全性;疏水尾数量在3~4个,具有1~2个不饱和度和8~18个碳链长度时,LNP能够高效诱导基因沉默,同时含有分支或不对称的疏水尾时可提高LNP的转染效率。本综述从可电离脂质的化学结构出发,总结了其结构对载核酸药物LNP的转染效率和安全性的影响,并总结归纳其构效关系,为新型可电离脂质的研究提供借鉴。

吲哚芳砜类化合物定量构效关系研究

从文献中选取76种具有抗人类免疫缺陷病毒(HIV)活性的吲哚芳砜类化合物,采用分子结构描述符对其进行结构表征。通过逐步回归分析法,从28个结构参数中筛选出10个参数作为回归方程的最终变量,构建了吲哚芳砜类化合物的分子结构与抗HIV活性之间的定量关系模型。所建模型的复相关系数R为0.904 9,表明该模型的拟合效果较好,可以反映吲哚芳砜类化合物分子结构与生物活性之间的相关关系。留一法(LOO)交互检验结果表明,R为0.856 7,标准偏差(Std)为0.445 5,说明所建模型具有较好的稳定性和可靠性,可以用于预测吲哚芳砜类化合物的抗HIV活性。

血浆蛋白与骨质疏松症的关系及潜在治疗靶点:基于国际UK Biobank数据库信息

背景:骨质疏松症是全球范围内增加疾病负担和致残率的重要因素。血浆蛋白参与体内复杂的生物过程,在揭示疾病机制和发现潜在治疗靶点方面起着关键作用。尽管已有研究显示血浆蛋白与骨质疏松症之间存在关联,但这些关联的因果性质尚未得到充分阐明。因此,利用大规模的血浆蛋白数据探究与骨质疏松症相关的因果蛋白并识别潜在的药物靶点,对于骨质疏松症的防治至关重要。目的:运用两样本孟德尔随机化分析,以国际UK Biobank数据库为来源信息,评估血浆蛋白与骨质疏松症之间的因果关联。方法:从UK Biobank数据库获取1001种血浆蛋白相关的全基因组显著性水平(P<5×10-8)的蛋白质数量性状位点作为工具变量,并排除连锁不平衡。骨质疏松症的汇总数据来自FinnGen数据库,共涉及438872名欧洲血统个体。研究采用逆方差加权、MR-Egger回归、加权中位数等方法进行分析,并进行多项敏感性分析以确保结果的稳健性。进一步构建蛋白-蛋白互作网络,结合基因本体富集分析和京都基因与基因组百科全书通路分析,探索血浆蛋白的功能相关性及潜在作用机制。结果与结论:①孟德尔随机化逆方差加权法结果显示有50种血浆蛋白与骨质疏松症存在因果关系(P<0.05),包括染色体19开放阅读框12(chromosome 19 open reading frame 12,C19orf12;OR=0.610,95%CI:0.483-0.769,P=2.967×10-5)、表皮生长因子(OR=0.877,95%CI:0.770-0.999,P=0.049)等20种血浆蛋白可能与骨质疏松症的风险降低相关,有CCL18(OR=1.091,95%CI:1.037-1.147,P=0.001)、CD209(OR=1.036,95%CI:1.003-1.070,P=0.034)等30种血浆蛋白可能增加骨质疏松症的风险,经Bonferroni校正后,只有C19orf12与骨质疏松症存在显著的因果关联。②多项敏感性分析显示研究不存在多效性和异质性,说明结果具有稳健性。③通过构建蛋白-蛋白互作网络明确了表皮生长因子、CCL5、CXCL13、CXCL5、血管内皮生长因子C、CCL18、CCL17、TEK受体酪氨酸激酶、含免疫球蛋白样和表皮生长因子样结构域的酪氨酸激酶1(TIE1)和CCL23为核心蛋白。④基因本体富集分析和京都基因与基因组百科全书通路分析表明这些血浆蛋白在免疫系统中具有重要作用,通过参与信号传导、细胞迁移和趋化等过程影响骨质疏松症。⑤文章结果揭示了1001种血浆蛋白与骨质疏松症的潜在因果关联,这种基于大规模数据驱动的分析方法有助于在中国人群中识别新的生物标志物和药物靶点;其次,文章结果表明,免疫系统信号传导、细胞迁移和趋化等过程在骨质疏松症发病机制中发挥重要作用,这为特定遗传背景和环境因素下的骨质疏松症研究提供了新的方向;最后,研究中识别的核心蛋白(如表皮生长因子、CCL5及CXCL13等)有望成为新的生物标志物或药物靶点,为骨质疏松症的精准防治提供新的依据。