The purpose of this study is to learn more about why some people are at greater risk for oral emergency contraceptive failure while others are not. The investigators want to learn if genetic differences impact the risk of emergency contraception failure.

开始日期2023-01-09

申办/合作机构

Oregon Health & Science University

100 项与醋酸乌利司他相关的临床结果

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100 项与醋酸乌利司他相关的转化医学

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100 项与醋酸乌利司他相关的专利（医药）

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项与醋酸乌利司他相关的文献（医药）

2025-03-01·Brain Research

Long-term impact of congenital Zika virus infection on the rat hippocampus: Neuroinflammatory, glial alterations and sex-specific effects

Article

作者: Roehe, Paulo Michel ; Dos Santos, Adriana Souza ; de Aguiar, Gabrielle Batista ; Rieder, Alessandra Schmitt ; Pereira, Lenir Orlandi ; de Almeida, Wellington ; Dalmaz, Carla ; Netto, Carlos Alexandre ; Carvalho, Andrey Vinicios Soares ; Bohn, Anna Luísa Lothhammer ; da Costa, Meirylanne Gomes ; Teixeirad, Thais Fumaco ; Wyse, Angela Terezinha de Souza ; Martini, Ana Paula Rodrigues ; Varelad, Ana Paula Muterle ; Smaniotto, Thiago Ângelo

Congenital Zika Syndrome (CZS) is a condition that arises when a neonate presents with abnormalities resulting from Zika virus infection during gestation. While microcephaly is a prominent feature of the syndrome, other forms of brain damage are also observed, often accompanied by significant neurological complications. It is therefore essential to investigate the long-term effects of CZS, with special attention to sex differences, particularly concerning hippocampal function, given its vulnerability to viral infections. The aim of this study was to evaluate the long-term impacts on cognitive and memory functions, as well as neuroinflammatory and glial alterations in the hippocampus, in offspring of both sexes exposed to a model of congenital Zika virus infection. Pregnant rats were subcutaneously inoculated with ZIKV-BR at a dose of 1 × 10^7 plaque-forming units (PFU mL^-1) of ZIKV isolated in Brazil (ZIKV-BR) on gestational day 18 (G18). From postnatal day 70, the animals underwent behavioral tests. On postnatal day 80, the animals were euthanized, and hippocampal samples were collected for biochemical and histological analyses. In the open field test, females displayed more exploratory behavior and less grooming, while no significant differences in locomotion were observed between the sexes. Additionally, ZIKV-exposed females showed a reduction in grooming behavior compared to ZIKV-exposed males. In the memory test, males in the ZIKV group exhibited greater memory impairment, spending more time to locate the correct quadrant, while females showed relatively better performance. Neuroinflammatory markers, such as TNF-α, were significantly elevated in the hippocampus of ZIKV-exposed animals, regardless of sex. However, microglial and astrocytic responses, indicated by higher IBA1 and GFAP density, were only observed in male ZIKV rats. In conclusion, our findings suggest that congenital ZIKV exposure leads to sex-specific behavioral and neuroinflammatory alterations. While both males and females exhibited some behavioral changes, males were more significantly impacted in memory performance. Additionally, increased neuroinflammatory markers and glial activation were observed in the hippocampus of ZIKV-exposed animals, with a pronounced response in males. These results highlight the long-term impact of ZIKV infection on neurodevelopment, emphasizing the importance of considering sex differences in studies of congenital ZIKV syndrome.

2025-03-01·Theriogenology

Foals born alive from mares with ultrasonographically assessed placental abnormalities: Neonatal health and development up to weaning compared to foals from healthy mares

Article

作者: Debes, Leonie ; Blanco, Miguel ; Venner, Monica ; Sieme, Harald ; Sielhorst, Jutta ; Koether, Karoline ; Vervuert, Ingrid

Little is known about the health status of foals born alive from mares treated for placental disease. The aims of the present study were (1) to compare the neonatal health status and health development during the rearing period of foals born from mares treated for ultrasonographically assessed placental abnormalities (UPA) to age-matched healthy foals from the same warmblood stud and (2) analyze the influence of mare's placental health on colostrum quality. Foals (n = 127) born from mares with UPA (UPA group; P) in 2017-2019 were compared to 127 foals born from healthy mares (control group; C). Sixty-six UPA mares showed subclinical placental abnormalities (PSc1) and 61 mares showed clinical placental abnormalities (PSc2). The colostrum quality assessed by refractometry showed that healthy mares had 42 excellent (>30 %), 73 good (20-30 %) and 6 poor (<20 %) colostrum, whereas UPA mares showed 29 excellent, 66 good and 26 poor colostrum quality (P < 0.001). The administration of high-quality colostrum was more frequent in the UPA group (17.5 %) than in C (7.9 %; P = 0.024). The mean (±SD) gestation length of UPA mares was shorter (330 ± 11 days) and foal birth weight lower (54.2 ± 7.3 kg) compared to the healthy pregnancies (335 ± 11 days; P = 0.002 and 57.0 ± 6.6 kg; P < 0.001). The number of foals with a reduced immunoglobin G concentration 14 h postpartum was significantly higher in PSc2 (P = 0.007). Foals born from UPA mares received foreign plasma (P 25.4 % vs C 4.2 %; P = 0.028) more frequently. Premature placental separation, the occurrence of the retention of fetal membranes, placental weight, foal vitality and the white blood cell count did not differ between groups. Regarding the health status of the foal in the neonatal period (1-14 days postpartum), 10 foals (8.1 %) born from UPA pregnancies showed maladjustment syndrome, whereas none of the foals in the control group showed this condition (P < 0.001). Foals from UPA mares developed diarrhea more often (P 31.4 % vs C 19.9 %; P = 0.042), whereas omphalitis, pneumonia, sepsis, meconium obstipation and contracted tendons did not differ between the groups. Multimorbidity and treatment were more frequent in foals born from UPA pregnancies (P 12.8 % vs C 4.7 %; P = 0.004 and 59.6 % vs 40.4 %; P = 0.007). In conclusion, foals born alive from UPA mares face decreased immunity and an increased risk of disease during the first 14 days postpartum. The study underlines that colostrum supplementation from a healthy mare seems essential in UPA pregnancies.

2025-02-01·Life Sciences

Progesterone signaling in uterine fibroids: Molecular mechanisms and therapeutic opportunities

Review

作者: Segars, James H ; Macri, Valeria I ; Ploumaki, Ioanna ; Islam, Md Soriful

Progesterone (P4) is a vital female sex hormone involved in various physiological processes, including the maintenance of the endometrium, mammary gland development, and bone health. Beyond its reproductive roles, P4 is implicated in the pathogenesis of hormone-dependent conditions like uterine fibroids, the most common benign tumors in women, which can severely affect quality of life and fertility. Traditionally, estrogen was considered the primary driver of fibroid growth, but recent research highlights the significant role of P4 in fibroid growth. P4 interacts with progesterone receptors (PRs) and non-genomic membrane receptors (mPRs and PGRMCs) to activate signaling pathways that enhance tumor growth and survival. P4 promotes vascular changes that improve the blood supply to fibroids and modifies the extracellular matrix, a key component of fibroid structure. This understanding has led to the investigation of selective progesterone receptor modulators (SPRMs) as potential therapies for fibroids. Clinical trials have demonstrated the effectiveness of SPRMs like mifepristone, asoprisnil, and ulipristal acetate in reducing fibroid size and symptoms, though concerns about safety, particularly with long-term use, remain. Newer SPRMs, such as vilaprisan, show promise, but further research is necessary to assess the long-term safety and effectiveness. This review discusses the mechanisms by which progesterone contributes to fibroid growth and examines clinical effectiveness of SPRMs as potential treatments for uterine fibroids.

项与醋酸乌利司他相关的新闻（医药）

2025-01-15

·药时空

Arcturus启动H5N1禽流感自复制mRNA疫苗1期临床试验

2025年1月10日，Arcturus Therapeutics（“Arcturus”）宣布，已启动自复制mRNA（sa-mRNA）疫苗ARCT-2304（LUNAR-H5N1）的1期临床试验研究（NCT06602531），用于预防由H5N1病毒引起的大流行性流感疾病。该临床试验正在美国的多个地点进行，旨在招募大约200名健康成年人（120名18-59岁的参与者；80名60-80岁的参与者），第一批参与者于2024年12月接种，中期研究数据预计将于2025年下半年公布。该临床研究由生物医学高级研究与发展局（BARDA）全额资助。 ARCT-2304，也称为LUNAR-H5N1，是一种sa-mRNA候选疫苗，采用Arcturus专有的LUNAR®递送技术和STARR® mRNA平台技术配制而成。sa-mRNA候选疫苗旨在肌肉注射后在宿主细胞内制造许多mRNA拷贝，以增强血凝素（HA）和神经氨酸酶（NA）抗原的表达，从而实现比传统mRNA疫苗更低的剂量。该技术可能比基于鸡蛋和细胞的技术更快地提供疫苗。冻干疫苗制剂在冰箱中稳定，从而简化了冷链储存并降低了分销风险。该初步临床试验的主要目的是评估ARCT-2304疫苗的三种不同剂量水平和两种不同疫苗接种方案的安全性和免疫反应。通过血凝抑制（HAI）、病毒微量中和（MN）和神经氨酸酶联凝集素测定（ELLA）来测量免疫反应。 Arcturus Therapeutics总裁兼首席执行官Joseph Payne表示：“在H5N1流感中临床验证我们的低剂量STARR® mRNA技术是迈向大流行准备的关键一步，我们的团队正在与我们在美国和全球的合作伙伴BARDA和CSL加紧合作。” 识别微信二维码，可添加药时空小编请注明：姓名+研究方向！

疫苗信使RNA临床1期临床结果

2024-08-27

·PRNewswire

ScaleReady announces the inaugural G-Rex® Grant has been awarded to Stanford Medicine Laboratory for Cell and Gene Medicine

ST. PAUL, Minn., Aug. 27, 2024 /PRNewswire/ -- ScaleReady™, in collaboration with Wilson Wolf Manufacturing, Bio-Techne Corporation (NASDAQ: TECH) and CellReady™, today announced that Dr. Steve Feldman, Scientific Director and Site Head of Stanford Medicine's Laboratory for Cell and Gene Medicine (LCGM), has been awarded the inaugural G-Rex® Grant. Dr. Feldman's $300,000 G-Rex Grant will enable expeditious development of Stanford Medicine's LCGM's G-Rex platform for CAR-T cell therapy manufacturing, which will be offered to internal investigators and external developers who are seeking its development and manufacturing services. "Stanford's LCGM anticipates a need to support a greater number of clinical trials and the G-Rex Grant will be used to help meet that need," said Dr. Feldman. "We are honored to award the inaugural G-Rex Grant to Dr. Feldman and his team at Stanford Medicine LCGM. Stanford University is a world-class institution with faculty who have a reputation for innovative and ground-breaking achievements. Their work aligns with Wilson Wolf's mission of bringing hope to cancer patients, one G-Rex at a time" said John Wilson, CEO of Wilson Wolf and co-inventor of G-Rex. As part of the G-Rex Grant, Stanford Medicine LCGM will deploy their G-Rex-centric manufacturing process in an upcoming Phase 1 trial for GPC2+ pediatric neuroblastoma and medulloblastoma. Previously, the FDA had recommended sponsors develop and implement potency assays earlier in the clinical trial process. With that objective, Stanford Medicine LCGM plans to implement Bio-Techne's leading automated multiplexing immunoassay platform, Ella™, as a potency assay for final drug product release. Furthermore, Stanford Medicine LCGM will collaborate with CellReady, the world's first and only G-Rex based contract development and manufacturing organization (CDMO), to leverage their proven capacity to quickly create G-Rex master batch records that establish manufacturing simplicity, efficiency, and repeatability. Additionally, Stanford Medicine LCGM plans to further develop a novel technology (developed by Wilson Wolf) that enables closed-system T cell purification to be done directly in a G-Rex device, without the need for expensive ancillary equipment. ScaleReady's G-Rex Grant Program is a $20M initiative to advance the state of cell and gene-modified cell therapy (CGT) development and manufacturing by awarding individual Grant Awards worth up to $300,000. G-Rex Grant Recipients also gain access to exclusive support from ScaleReady's growing consortium of G-Rex Grant Partners who bring best-in-class tools and technologies as well as unparalleled knowledge and expertise in the areas of cGMP manufacturing, quality and regulatory affairs, CGT business operations, and more. About ScaleReady ScaleReady provides the field of cell and gene-modfied cell therapy (CGT) with a G-Rex centric manufacturing platform that enables the world's most practical, flexible, scalable, and affordable CGT drug product development and manufacturing. The G-Rex manufacturing platform is currently used by a rapidly growing list of over 800 organizations and is producing drug products for approximately 50% of CGT clinical trials as well as 4 commercially approved CGT drugs. CGT entities relying on the breadth and scope of ScaleReady's expertise can expect to save years of time and millions of dollars on the path to CGT commercialization. For more information about the ScaleReady G-Rex® Grant Program, please contact [email protected]. About Wilson Wolf Manufacturing Wilson Wolf () is dedicated to simplifying cell and gene-modified cell (CGT) therapy research, process development, and manufacturing. This is being accomplished through its scalable G-Rex® technology, which is used throughout the world in CGT applications ranging from basic research to commercial drug production. Wilson Wolf's mission is to create hope for cancer patients, one G-Rex® device at a time. About Bio-Techne Corporation Bio-Techne Corporation (NASDAQ: TECH) is a global life sciences company providing innovative tools and bioactive reagents for the research and clinical diagnostic communities. Bio-Techne, in partnership with Wilson Wolf, is creating products such as media and cytokines that are specifically tailored to G-Rex® Bioreactors, including right-sized reagent quantities in containers that are tailored to high throughput closed-system manufacturing. For more information on Bio-Techne and its brands, please visit or follow the Company on social media at: Facebook, LinkedIn, Twitter or YouTube. Contact: David Clair, Vice President, Investor Relations & Corporate Development [email protected] 612-656-4416 About CellReady LLC CellReady is the world's first and only G-Rex® centric contract development and manufacturing organization (CDMO) specializing in G-Rex® based cell and gene-modified cell therapy development and manufacturing. The company offers a wide range of services to support the development and commercialization of these therapies. CellReady's mission is to create hope for cancer patients, one G-Rex® process at a time. SOURCE Bio-Techne Corporation

细胞疗法免疫疗法基因疗法

2024-08-15

·精准药物

一文深度解析特应性皮炎新兴药物

来源：药渡撰文：踏雪编辑：维他命特应性皮炎（Atopic Dermatitis，简称AD）是一种由免疫系统在背后“操纵”的皮肤疾病，特征是慢性复发，发病机制复杂多样。该病的发病率非常高，全球约有15-20%的儿童和1-3%的成年人患有该病。在以往传统观念里，认为AD是一种2型免疫被激活导致的疾病。然而，最新研究发现AD具有高度的异质性，可以根据临床表现、流行病学或分子特征分类为不同的表型。长久以来，对于中度至重度的AD，传统的免疫抑制药物一直是唯一的治疗选项。然而，近些年来，AD治疗有了令人瞩目的发展，许多新药物已经上市、获得许可，或处于临床开发的最后阶段。生物制剂和小分子药物的登场大大丰富了中度至重度AD的治疗武器库。例如，靶向IL-4/13通路的单克隆抗体（如dupilumab、tralokinumab、lebrikizumab）和JAK抑制剂（如abrocitinib、upadacitinib、baricitinib）等新药物。目前，AD的治疗模式主要分为两大类：一是靶向IL-4/13轴，二是瞄准JAK/STAT通路。这两种方式都成效显著，并且在临床前和临床试验中都拥有着坚实有力的证据。正因如此，在这二者之间抉择治疗方法往往让人倍感棘手，这对于皮肤科医生而言，无疑是一项重大的挑战。这样的选择当中，必须要斟酌一些关键因素，比如AD的异质性、表型特征、患者所患的其他病症、年龄以及个人的偏好等。 1 AD的表型 AD的主要表型根据年龄相关的临床表现、IgE水平、疾病阶段和身体部位进行分类。此外，各种种族群体中AD的表型和免疫学差异也很重要（图1）。图1. AD所涉及的复杂且异质性的致病途径、疾病表型、内型和免疫学途径年龄相关的表型 AD的表现随着年龄的变化而有所不同，可以分为以下几个阶段：在婴儿期（1岁以下），AD常常局限于面部区域，呈现出红色的斑块和强烈的瘙痒。皮肤常常会出现潮湿和渗出的丘疹，有时会形成痂或鳞屑。面部尤其是口周、脸颊和头皮是主要受累部位。随着年龄增长进入儿童期，AD的表现变得更加局限，通常影响到肘部、膝盖等屈侧表面。这些区域的皮肤容易出现渗出和结痂现象。这一阶段的AD表现出明显的免疫学特征，特别是Th2细胞因子的强烈表达，如IL-5和IL-13，这些因子与嗜酸性粒细胞的增加和IgE水平升高有关。在青少年和成人期，AD的表现可能会更加局限化。有些人可能只经历慢性手部湿疹，而其他人则可能出现头颈部、上胸部和肩部的皮炎。此阶段的皮损可能呈现出急性渗出和苔藓样病变。随着年龄的增加，AD患者的Th1和Th17相关标志物（如IFNG和IL17A）的表达逐渐增加，反映出免疫反应的复杂性。在老年期，AD的皮肤表现与成人期相似，但“反向苔藓化”现象更为常见，尤其是在未受影响的肘部和膝盖褶皱周围。外在性和内在性AD AD还可以根据血清IgE水平分为外在性和内在性两种类型。外在性AD是最常见的表型，占AD病例的80%。这种类型的特征是血清IgE水平升高、嗜酸性粒细胞增多，以及个人和家族过敏背景。此外，外在性AD患者通常具有更高的FLG突变率，这是AD发病的最强遗传风险因素。相比之下，内在性AD较为少见，占AD病例的20%。内在性AD患者的IgE水平正常，女性患者居多，并且通常在成年后期发病。内在性AD与金属接触过敏增加有关。尽管两种类型的AD患者均表现出Th2标志物的增加，但内在性AD患者表现出更显著的Th1信号和Th17/Th22活化，甚至显示出与银屑病免疫特征的重叠。根据疾病阶段的表型 AD的表现随着疾病阶段的变化而有所不同，可以分为急性和慢性两个阶段。急性AD病变通常呈现为红斑、水样和高度炎症性的皮肤表现。基因表达谱显示，急性阶段与Th22和Th2细胞因子显著增加相关，而IL-17的增加较小。急性期的免疫反应主要通过IL-22的作用引发，IL-17和IFN-γ的贡献较小。随着疾病的进展，急性病变逐渐变干、苔藓化、增厚，并出现色素沉着，表现为慢性阶段。慢性AD病变中观察到Th1相关产物的显著增加。此外，慢性期还伴随着Th2和Th22细胞因子的进一步增加，以及Th1和Th17反应的更高活化。种族相关的表型新的研究表明，AD在不同种族背景下表现出不同的临床、遗传和免疫病理学特征。与白人AD患者中的经典临床表现相比，亚洲AD患者通常表现为边界更加明确的病变，有时与银屑病斑块非常相似，并伴有较多的鳞屑和苔藓化。这种表现与亚洲AD患者中强烈的Th17特征有关，具有类似银屑病的临床和组织学特征。非洲AD患者的表现主要集中在伸肌表面，有时伴有毛囊周围的突出和躯干上的明显丘疹。免疫反应表现为强烈的Th2/Th22偏向，Th2和Th22标志物与疾病严重程度显著相关。相比之下，Th1和Th17轴在欧洲裔美国人中有所减弱。 2 市场新兴药物概览随着研究的进展，一些新的药物作为中度至重度AD的治疗方法已被开发和批准。当前批准的药物主要属于两大类，具有不同的作用机制：靶向IL-4/13通路的单克隆抗体和广谱小分子抑制剂（JAK抑制剂）。靶向IL4/IL-13轴的生物药物由于IL-4和IL-13在AD病理生理学中的多种作用，包括破坏皮肤屏障、招募炎症细胞等，使这些细胞因子和及其受体成为理想的治疗靶标。目前，三种靶向IL4/IL-13轴的单克隆抗体获批用于治疗AD：Dupilumab 、Tralokinumab和Lebrikizumab（图2）。图2. 获批用于治疗AD的靶向IL4/IL-13轴的单克隆抗体示意图 1 Dupilumab：首个突破性治疗药物 Dupilumab是一种完全人源化的单克隆抗体，通过结合IL-4Rα来阻断IL-4和IL-13的信号传导。它是第一个被批准用于中度至重度AD成年和青少年的特定药物，并已在全球多个国家获得批准。真实世界的数据支持其在III期临床试验中的疗效。作为首个获批治疗AD的药物，dupilumab的长期疗效和安全性数据也被广泛研究。在长达76周的III期开放标签扩展研究中，该药物显示出持续的疗效，并且没有发现新的安全信号，最常见的不良事件为咽喉炎、结膜炎和注射部位反应。然而，尽管dupilumab在AD治疗中是一个重要里程碑，但只有35%至40%的患者在使用dupilumab时能够达到清晰或几乎清晰的皮肤状态（IGA评分0/1），因此仍需额外的治疗选择。 2 Tralokinumab：靶向IL-13的新选择在dupilumab进入市场几年后，tralokinumab被批准用于治疗中度至重度AD。这是一种完全人源化的IgG4单克隆抗体，特异性结合IL-13，从而抑制其与IL-13受体复合物的相互作用，进而中和IL-13的生物活性。在两个设计相同的52周多国随机双盲安慰剂对照试验（ECZTRA 1和2）中，第16周达到IGA评分0或1和EASI 75的患者比例显著高于安慰剂组。在ECZTEND开放标签扩展试验中，长期疗效和安全性数据表明，tralokinumab能够在为期两年的治疗中长期控制AD的症状和体征。 3 Lebrikizumab：另一个针对IL-13的具有不同MOA的单克隆抗体最近，lebrikizumab被批准用于治疗中度至重度AD。这是一种高亲和力的IgG4单克隆抗体，靶向IL-13。该药物的批准是基于两个III期临床试验（ADvocate 1和ADvocate 2）的结果。在这些试验中，患者按2:1比例随机接受lebrikizumab 250 mg（基线和第2周的500 mg负荷剂量）或安慰剂，每两周皮下注射一次。结果显示，ADvocate 1中lebrikizumab组43.1%的患者达到IGA 0或1，而安慰剂组为12.7%；ADvocate 2中lebrikizumab组为33.2%，安慰剂组为10.8%。尽管tralokinumab和lebrikizumab都与IL-13结合，但其作用机制略有不同。具体而言，tralokinumab阻止其与IL-13Rα1和IL-13Rα2的接触，而lebrikizumab则只干扰IL-13与IL-13Rα1的结合，而不干扰IL-13Rα2，从而通过IL-13Rα2的内源性调节保持体内IL-13水平。这两个不同作用机制的治疗药物谁更胜一筹尚待阐明。批准的JAK抑制剂 JAK/STAT通路是受体介导的信号转导范式，参与许多关键的生物过程，如细胞增殖、分化、凋亡和免疫调节。该通路已在多种慢性炎症性皮肤病中扮演了重要角色，并在一些疾病中通过抑制该通路取得了成功的治疗效果，如AD、银屑病、白癜风和斑秃。许多参与AD病理生理学的关键细胞因子，如IL-4、IL-13、IL-31和TSLP都通过激活JAK/STAT通路发挥作用。此外，JAK/STAT通路还与皮肤免疫中的其他关键通路（如TNFα信号传导）相互作用。目前，批准了三种不同选择性的JAK抑制剂用于治疗AD：upadacitinib、abrocitinib和baricitinib（图3）。图3. JAK/STAT通路的主要细胞因子和获准用于治疗AD的JAK抑制剂示意图 1 Upadacitinib（UPA）：高度选择性的JAK1抑制剂 UPA是一种口服选择性JAK1抑制剂，专门用于治疗中度至重度AD。这种药物是一种可逆的ATP竞争性抑制剂，对JAK1的选择性远高于对JAK2、JAK3和TYK2。在MeasureUp 1和MeasureUp 2这两项III期临床试验中，患者被随机分配接受UPA 15mg、UPA 30mg或安慰剂，每日一次，持续16周。结果显示，第16周时UPA组达到主要终点IGA0/1的患者比例显著高于安慰剂组： MeasureUp 1：UPA 15mg（48%）；UPA 30mg（62%）vs安慰剂（8%） MeasureUp 2：UPA 15mg（39%）；UPA 30mg（52%）vs安慰剂（5%）长期治疗UPA显示其在52周内具有持续的疗效反应。此外，来自III期临床试验的安全性数据表明，UPA治疗期间不良事件（AE）的发生率较低，显示出良好的风险收益比。 2 Abrocitinib（ABRO）：另一个选择性的JAK1抑制剂 ABRO是一种口服选择性JAK1抑制剂，最近获得EMA和FDA的批准，用于治疗中度至重度AD成人患者。在JADE MONO-1和JADE MONO-2这两项III期临床试验中，ABRO在第12周时均达到主要终点： JADE MONO-1：ABRO 100mg（24%）；ABRO 200mg（44%）vs安慰剂（8%） JADE MONO-2：ABRO 100mg（28.4%）；ABRO 200mg（38.1%）vs安慰剂（9.1%） 48周疗效和安全性数据表明，ABRO在AD治疗中具有持续的临床反应和可控的安全性。 3 Baricitinib（BARI）：JAK1和JAK2的双重抑制剂 BARI是一种口服选择性JAK1和JAK2抑制剂，最近在欧洲和日本获批用于治疗中度至重度AD成人患者，口服每日剂量为4 mg和2 mg。在III期临床试验项目中，BARI的疗效和安全性得到了充分验证。在BREEZE-AD1和BREEZE-AD2试验中，BARI单药治疗（4mg、2mg或1mg）与安慰剂在年龄≥18岁的中度至重度AD成人中进行了比较。结果显示： BREEZE-AD1：BARI 4mg（16.8%）；BARI 2mg（11.4%）vs安慰剂（4.8%） BREEZE-AD2：BARI 4mg（13.8%）；BARI 2mg（10.6%）vs安慰剂（4.5%） Baricitinib联合外用皮质类固醇（TCS）的长期疗效显示，在连续治疗68周内，两种剂量的BARI均具有临床意义的持续疗效。此外，对八项BARI临床试验数据的综合分析表明，治疗AD患者的3.9年期间未发现新的安全信号，显示其安全性良好。 3 选择IL-4/13单克隆抗体还是JAK抑制剂？随着中度至重度AD治疗选择的增加，需要对特定患者群体选择全身药物提供更精确的指导。然而，选择最适合用于中度至重度AD管理的全身药物并不容易，必须考虑几个重要因素，如AD的异质性及其表型分类、患者的共病、年龄和个人偏好等因素（图4）。图4. 影响AD人群选择IL-4/13抗体和JAK抑制剂的主要因素 AD的临床表型与安全性考虑 AD的临床表型多种多样。Chovatiya等人在最近的一项研究中，根据瘙痒和病变的严重程度，将AD分为四种表型：轻度至中度瘙痒和病变（MI-ML）、轻度至中度瘙痒和严重病变（MI-SL）、严重瘙痒和轻度至中度病变（SI-ML）、严重瘙痒和病变（SI-SL）。针对瘙痒主导型AD的研究显示，JAK1抑制剂如Abrocitinib（ABRO）和Upadacitinib（UPA）在改善瘙痒症状方面表现优异。特别是在与Dupilumab的对比试验中，UPA和ABRO都在起效速度和皮肤清除水平上显示出更高的优势。对于需要快速缓解瘙痒的患者，JAK抑制剂也可能是更好的选择。尽管尚无JAK抑制剂之间的直接比较试验，但现有分析显示，UPA 30mg每日的疗效最高，其次是ABRO 200mg每日。然而，由于这些分析存在局限性，需谨慎解读结果。另一方面，JAK抑制剂的安全性仍是关注的重点。虽然选择性JAK1抑制剂在AD患者中的安全性尚未被全面验证，但在其他免疫介导疾病中的应用数据提示，其可能带来感染、静脉血栓和恶性肿瘤风险。特别是在65岁以上、心血管疾病患者中，应优先选择IL-4/13单克隆抗体，如Dupilumab。Dupilumab已被证实在老年AD患者中是安全有效的。此外，研究显示，与JAK1抑制剂相比，Dupilumab在中度至重度AD患者中引起带状疱疹的风险较低。身体部位影响值得注意的是，AD在“头颈部”表现出对Dupilumab的治疗抵抗性。一项长达104周的研究发现，Dupilumab治疗后，头颈部AD症状仍然在较高比例的患者中存在。然而，当患者转用JAK抑制剂后，症状有所改善。此外，Dupilumab可能引发面部红斑，而这一副作用在使用JAK抑制剂后得到缓解。因此，对于主要局限于头颈部的AD患者，JAK抑制剂可能是更好的选择。共病的影响对于肿瘤或心血管共病，临床医生倾向于选择单克隆抗体治疗，如Dupilumab。而当AD与其他免疫介导的皮肤病（如银屑病、斑秃、白癜风、化脓性汗腺炎）共存时，JAK抑制剂可能是更好的选择，因为JAKi在这些疾病中也显示了疗效。例如，除了AD外，Upadacitinib（UPA）还被批准用于治疗类风湿关节炎（RA）、轴性脊柱关节炎、克罗恩病（CD）和溃疡性结肠炎（UC）。类似的，Baricitinib（BARI）已用于治疗斑秃和RA，因此在AD与这些疾病共存时，JAK抑制剂可能是最佳选择。另一方面，AD常与过敏性疾病（如哮喘）相关联，在这种情况下，Dupilumab应优先被选择。Dupilumab已被批准用于哮喘、伴鼻息肉的慢性鼻窦炎等多种疾病，并在这些共病患者中表现良好。患者的内型分层 AD的异质性不仅体现在临床特征上，还在分子特征上有所体现。临床表型不一定与疾病的机制或分子标志物相关，因此，识别不同分子内型的生物标志物有助于更好地表征和分层AD患者，并指导治疗选择。研究表明，通过血清和组织生物标志物可以识别AD患者的内型。例如，Thijs等人通过血清生物标志物将成年AD患者分为四个群体。Bakker等人的蛋白质组学分析也识别了四个群体，包括"皮肤趋向趋化因子/IL-1R1主导、“Th1/Th2/Th17主导”、“Th2/Th22/PARC主导”和“Th2/嗜酸性粒细胞劣性”群体。 Sekita等人通过对115名AD患者和14名健康对照的皮肤和外周血单个核细胞样本的RNA-seq数据分析，发现了AD皮肤表现与不同免疫特征之间的相关性，并描述了三种患者群体，表现出不同的疾病进程和病史。此外，组织或血液生物标志物可能有助于预测患者对某种疗法的反应。Glickman等人发现，AD患者皮肤中Th17相关细胞因子CXCL2的基线基因表达水平与Dupilumab治疗反应之间存在强关联性，提出该分子可作为预测性生物标志物。这些研究表明，内型信息对个性化治疗选择具有重要意义。例如，IL-4/IL-13抗体可能对Th2主导的AD亚型，如外在性AD、欧裔美国人AD或儿童AD有效，而内在性AD、亚洲和非洲裔美国人AD患者可能更适合广谱的JAK抑制剂。尽管目前临床实践中尚缺乏验证的生物标志物，但基于当前研究可以做出一些假设。未来的研究将帮助验证这些假设，并促进更精准地分层AD患者以及识别新的表型-内型关联。 4 小结随着中度至重度AD治疗选择的增加，了解疾病的异质性和患者分层成了个性化医学诊疗的关键任务。靶向IL4/13的抗体和JAK抑制剂不仅是治疗的突破，还为AD发病机制提供了新的见解。由于AD的临床进程和治疗反应高度异质，某些疾病亚型可能对某种疗法反应更好，从而指导临床实践。此外，AD的共病情况也可能影响药物选择。目前的研究和临床试验数据表明，瘙痒主导型AD、头颈部AD、OSD或免疫介导的共病患者可能更适合JAK抑制剂；而老年人、肿瘤、心血管或过敏共病、复发性带状疱疹感染或痤疮的患者则可能更适合IL4/13抗体。下一步的方向将是基于患者的分子特征在IL-4/IL-13抗体或JAK抑制剂之间做出选择。随着我们进入更精准的治疗时代，分子生物标志物将帮助更好地表征和分层患者，从而定制基于内型的治疗方案。近年来还研究了各种新的机制针对多种T细胞群体，如Th1、Th2、Th17和Th22。例如，靶向OX40受体（如rocatinlimab）及其配体OX40L（如amlitelimab）的单克隆抗体在II期研究中显示出优异的疗效，目前正在进行III期临床试验用于中度至重度AD治疗。无疑，我们正走向一个更精准、个性化的治疗时代，有望使每位AD患者都能得到最适合的治疗方案。参考资料： 1. Blocking the IL-4/IL-13 Axis versus the JAK/STAT Pathway inAtopic Dermatitis: How Can We Choose? 2. Biomarkers in atopic dermatitis. 3. Targeting Interleukin 13 for the Treatment of Atopic Dermatitis. 4.The Epidemiology and Global Burden of Atopic Dermatitis: A Narrative Review. 声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

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KEGG	Wiki	ATC	Drug Bank
D09687	醋酸乌利司他	G03XB02 G03AD02	DB08867

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适应症	国家/地区	公司	日期
怀孕	美国	Laboratoire HRA Pharma SA	2010-08-13
避孕	列支敦士登	Laboratoire HRA Pharma SA	2009-05-15
避孕	冰岛	Laboratoire HRA Pharma SA	2009-05-15
避孕	欧盟	Laboratoire HRA Pharma SA	2009-05-15
避孕	挪威	Laboratoire HRA Pharma SA	2009-05-15

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适应症	最高研发状态	国家/地区	公司	日期
平滑肌瘤	申请上市	欧盟	Gedeon Richter (UK) Ltd.	2012-02-22
平滑肌瘤	申请上市	列支敦士登	Gedeon Richter (UK) Ltd.	2012-02-22
平滑肌瘤	申请上市	冰岛	Gedeon Richter (UK) Ltd.	2012-02-22
平滑肌瘤	临床前	冰岛	Gedeon Richter (UK) Ltd.	2012-02-22
平滑肌瘤	临床前	列支敦士登	Gedeon Richter (UK) Ltd.	2012-02-22
平滑肌瘤	临床前	欧盟	Gedeon Richter (UK) Ltd.	2012-02-22
平滑肌瘤	临床前	挪威	Gedeon Richter (UK) Ltd.	2012-02-22

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临床结果

适应症

分期

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT04291001 (CTgov)	早期临床1期	避孕	40	ENG implant (ENG Implant Alone)	遞鑰膚鹹鹹網廠糧製憲(艱網憲獵夢願築艱衊願) = 鬱鬱鑰構夢廠鹹鹽廠構觸遞襯構窪鹽遞獵鑰醖 (顧壓膚築蓋網醖積製憲, 壓淵顧餘糧壓餘衊鹽鑰 ~ 願齋築鹽憲築醖積鬱鹹) 更多	-	2024-07-12
				ENG implant+oral ulipristal acetate (ENG Implant Plus Oral UPA)	遞鑰膚鹹鹹網廠糧製憲(艱網憲獵夢願築艱衊願) = 廠夢鏇齋壓製壓鏇淵艱觸遞襯構窪鹽遞獵鑰醖 (顧壓膚築蓋網醖積製憲, 鏇鑰窪願繭蓋糧遞艱築 ~ 襯醖窪膚鹹壓網襯選觸) 更多
NCT02213081 (CTgov)	临床4期	子宫内膜异位症 \| 盆腔疼痛	1	Ulipristal	窪遞鹽顧廠鹹憲齋選餘(蓋積網願願醖遞糧糧蓋) = 構襯鏇淵鑰襯蓋餘選衊簾築鹹蓋選齋鑰窪繭鏇 (獵鏇餘鑰憲遞顧遞餘蓋, 構壓網鹹鑰簾積願築鏇 ~ 廠築範鏇衊鹽夢鹹餘製) 更多	-	2024-05-16
NCT00551616 (CTgov)	临床3期	避孕	2,221	CDB-2914 (CDB-2914)	簾網鏇顧夢鬱齋壓選壓(窪醖鹽顧襯遞顧積夢鹹) = 壓壓衊壓製鏇鹹鑰窪艱鑰製憲製醖遞壓襯鹹窪 (鹹衊鏇獵網選襯構膚膚, 艱憲窪鹽襯鹽襯憲蓋醖 ~ 鏇艱顧鬱範醖網淵糧鬱) 更多	-	2022-03-16
				Levonorgestrel (Levonorgestrel)	簾網鏇顧夢鬱齋壓選壓(窪醖鹽顧襯遞顧積夢鹹) = 鹽繭選網簾積齋願鏇膚鑰製憲製醖遞壓襯鹹窪 (鹹衊鏇獵網選襯構膚膚, 鏇齋醖壓簾鹽築觸網襯 ~ 窪構齋鬱夢積鏇窪餘積) 更多
ACR2021	临床3期	类风湿关节炎	905	UPA 15 mg + csDMARDs in bDMARD-IR patients	壓艱選製糧艱積積壓襯(鏇選憲憲醖廠廠餘窪鏇) = Among bDMARD-IR patients, the median (95% CI) time to 50% improvement in pain was longer in SELECT-BEYOND versus SELECT-CHOICE (16 [12, 20] versus 8 [8, 12] weeks) 壓鹽齋鏇憲獵窪醖廠選 (鹽糧築觸製蓋齋襯餘膚 ) 更多	积极	2021-11-07
				UPA 15 mg + csDMARDs in csDMARD-IR patients
EULAR2021	N/A	银屑病关节炎 \| 强直性脊柱炎	2,102	UPA 15 mg QD	膚鏇選積蓋繭願廠餘鑰(齋鬱襯選廠蓋餘憲齋鹽) = 壓顧憲觸積顧顧鬱餘鑰醖繭鹹蓋壓網獵窪觸觸 (鑰醖構糧膚遞蓋糧積鑰 )	-	2021-06-02
				UPA 30 mg QD	膚鏇選積蓋繭願廠餘鑰(齋鬱襯選廠蓋餘憲齋鹽) = 選夢衊艱製獵廠遞糧夢醖繭鹹蓋壓網獵窪觸觸 (鑰醖構糧膚遞蓋糧積鑰 )
NCT00411684 (CTgov)	临床3期	避孕	1,623	CDB-2914	(積選鬱窪鑰鏇淵壓願夢) = 壓簾糧繭蓋夢繭襯構鬱遞願夢憲構鹽願窪簾遞 (願糧顧襯積夢獵醖廠遞, 願憲糧糧選觸鑰憲窪範 ~ 廠鹹範壓觸膚憲艱憲衊) 更多	-	2021-05-03
NCT01629563 (PEARLIV \| PEARL IV, CTgov)	临床3期	平滑肌瘤	451	PGL4001 5 mg (Ulipristal Acetate (PGL4001) 5mg)	製鹽構淵衊衊鑰製壓獵(夢獵鹹製蓋齋鬱構憲醖) = 鬱艱廠齋鹽憲範構獵選簾選淵醖遞膚簾繭膚遞 (繭鏇鏇淵齋艱築願壓製, 構蓋繭淵夢網膚構遞網 ~ 鏇繭鏇糧築淵鹽醖鬱願) 更多	-	2019-09-04
				PGL4001 10 mg (Ulipristal Acetate (PGL4001) 10mg)	製鹽構淵衊衊鑰製壓獵(夢獵鹹製蓋齋鬱構憲醖) = 簾構構醖繭蓋窪範憲壓簾選淵醖遞膚簾繭膚遞 (繭鏇鏇淵齋艱築願壓製, 網觸獵繭鹹窪積餘鑰襯 ~ 鹹範鑰廠鏇憲選積鹽鬱) 更多
NCT02147197 (CTgov)	临床3期	异常子宫出血 \| 平滑肌瘤	157	Placebo (Placebo)	窪艱觸糧襯夢願齋壓繭(夢廠鑰築顧衊餘繭淵鏇) = 憲選網糧簾鹽襯觸淵顧壓醖壓壓觸網齋觸願選 (簾構齋遞壓繭簾顧顧淵, 簾齋糧鹽顧簾糧壓衊淵 ~ 糧選鹽積衊淵積繭繭鬱) 更多	-	2019-04-05
				Placebo+Ulipristal acetate (UPA) (UPA 5 mg)	窪艱觸糧襯夢願齋壓繭(夢廠鑰築顧衊餘繭淵鏇) = 窪鏇構廠壓壓襯襯膚繭壓醖壓壓觸網齋觸願選 (簾構齋遞壓繭簾顧顧淵, 膚齋鏇積襯糧糧憲遞鬱 ~ 蓋醖簾襯製衊蓋蓋選憲) 更多
NCT00290251 (Pubmed \| Fertil Steril)	临床2期	子宫肌瘤	72	Ulipristal acetate	蓋糧鬱窪製鹹範醖觸艱(鬱遞鑰築襯繭齋簾觸繭) = 艱選願願鬱範齋壓艱繭壓鬱膚憲鹽積艱觸觸廠 (窪鹽糧鬱鹽齋鬱繭艱壓 ) 更多	-	2019-04-01
				Placebo	鏇鏇窪窪構簾艱膚衊網(觸蓋夢積觸獵選積製鏇) = 選遞膚壓襯淵糧觸願壓齋糧遞選蓋糧獵淵壓獵 (艱夢鑰願淵構遞顧鹹鬱 ) 更多
NCT02147158 (Pubmed \| Obstet Gynecol)	临床3期	子宫肌瘤	432	5 mg ulipristal acetate	(鹽獵繭壓築糧繭齋襯觸) = 餘繭餘網鏇艱夢遞簾艱鏇範艱簾廠積壓獵遞製 (選願醖蓋積窪觸願網窪, 33.3 ~ 51.1) 更多	积极	2018-11-01
				10 mg ulipristal acetate	(鹽獵繭壓築糧繭齋襯觸) = 範網顧構積衊積製繭網鏇範艱簾廠積壓獵遞製 (選願醖蓋積窪觸願網窪, 45.5 ~ 63.8) 更多