A Multicenter, Randomized, Phase 2, Double-blind, Vehicle-controlled, Parallel Group Comparison Study to Evaluate the Safety and Efficacy of Q301 Cream in Adolescents and Adults With Mild to Moderate Atopic Dermatitis

This is a randomized, double-blind, vehicle-controlled, parallel-group comparison study to evaluate the safety and efficacy of Q301 Cream vs. vehicle in adolescent and adult subjects with mild to moderate AD. Study drug (Q301 Cream or vehicle) will be administered topically twice a day for 8 consecutive weeks.

开始日期2018-06-21

申办/合作机构

Qurient Co., Ltd.

NCT02348203 / Completed临床2期IIT

Clinical Study of the Effect of Combined Treatment of Aspirin and Zileuton on Biomarkers of Tobacco-Related Carcinogenesis in Current Smokers

This randomized phase II trial studies the effects of aspirin and zileuton on genes related to tobacco use in current smokers. Aspirin and zileuton may interfere with genes related to tobacco use and may be useful in preventing lung cancer in current smokers.

开始日期2016-01-13

申办/合作机构

National Cancer Institute

NCT02426359 / Completed临床2期

Safety and Efficacy Study of Q301 in Moderate to Severe Atopic Dermatitis Patients

This is a randomized, double-blind, vehicle-controlled, parallel-group comparison study to evaluate the safety and efficacy of Q301 Cream vs. vehicle in adult subjects with moderate to severe AD. Study drug (Q301 Cream or vehicle) will be administered topically twice a day for 8 consecutive weeks.

开始日期2015-04-01

申办/合作机构

Qurient Co., Ltd.

100 项与齐留通相关的临床结果

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100 项与齐留通相关的转化医学

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100 项与齐留通相关的专利（医药）

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706

项与齐留通相关的文献（医药）

2024-06-01·Fitoterapia

Integrated analysis and separation of 5-lipoxygenase inhibitors from triterpenes of Poria cocos using bioaffinity ultrafiltration UPLC-Q-Exactive, molecular docking and target-based multiple complex networks

Article

作者: Zhang, Yuchi ; Wu, Tong ; Liu, Chunming ; Li, Sainan ; Hou, Wanchao

Poria cocos (Schw.) Wolf (P. cocos) has been widely used as medical plant in East Asia with remarkable anti-Alzheimer's disease (anti-AD) activity. However, the underlying mechanisms are still confused. In this study, based on the β-Amyloid deposition hypothesis of AD, an integrated analysis was conducted to screen and separation 5-lipoxygenase (5-LOX) inhibitors from triterpenoids of P. cocos and investigate the anti-AD mechanisms, containing bioaffinity ultrafiltration UPLC-Q-Exactive, molecular docking, and multiple complex networks. Five triterpenoids were identified as potential 5-LOX inhibitors, including Tumulosic acid, Polyporenic acid C, 3-Epi-dehydrotumulosic acid, Pachymic acid and Dehydrotrametenolic acid. Five potential 5-LOX inhibitors were screened by ultrafiltration affinity assay in P. cocos. The molecular docking simulation results are consistent with the ultrafiltration experimental results, which further verifies the accuracy of the experiment. The commercial 5-LOX inhibitor that Zileuton was used as a positive control to evaluate the inhibitory effect of active ingredients on 5-LOX. Subsequently, the established separation method allowed the five active ingredients (Pachymic acid, 3-Epi-dehydrotumulosic acid, Dehydrotrametenolic acid, Tumulosic acid and Polyporenic acid C) with high purity to be isolated. Targeting network pharmacology analysis showed that five active ingredients correspond to a total of 286 targets. Kyoto encyclopedia of genes and genomes (KEGG) enrichment analysis found that target cells were mainly enriched in Pathways in cancer, Lipid and atherosclerosis. Our results indicate that P. cocos extract has the potential to be used in the prevention and treatment of neurodegenerative diseases. This will help elucidate the mechanisms of action of various medicinal plants at the molecular level and provide more opportunities for the discovery and development of new potential treatments from health food resources.

2024-05-01·Drug Development Research

Single and multiple inhibitors of the biosynthesis of 5‐, 12‐, 15‐lipoxygenase products derived from cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate: Synthesis and structure–activity relationship

Article

作者: Touaibia, Mohamed ; Robichaud, Samuel ; Doiron, Jérémie A ; Hébert, Mathieu P A ; Surette, Marc E ; Chiasson, Audrey Isabel

AbstractThe involvement of lipoxygenases in various pathologies, combined with the unavailability of safe and effective inhibitors of the biosynthesis of their products, is a source of inspiration for the development of new inhibitors. Based on a structural analysis of known inhibitors of lipoxygenase products biosynthesis, a comprehensive structure–activity study was carried out, which led to the discovery of several novel compounds (16a‐c, 17a) demonstrating promising potency to inhibit the biosynthesis of products of 5‐, 12‐ and 15‐LO. Compounds 16b and 16c outperformed zileuton (1), the only FDA‐approved 5‐LO inhibitor, as well as known inhibitors such as caffeic acid phenethyl ester (CAPE (2)) and cinnamyl‐3,4‐dihydroxy‐α‐cyanocinnamate (CDC (4)). However, the introduction of a cyano group at the α‐position of the carbonyl abolished the activity. Compounds 16a and 17a also inhibited the biosynthesis of 12‐ and 15‐LO products. Compounds 16a, 17a far surpassed baicalein, a known 12‐LO inhibitor, as inhibitors of 12‐LO products biosynthesis. Compound 17a and CDC (4) showed equivalent inhibition of LO products, proposing that the double bond in the ester moiety is not necessary for the inhibitory activity. The introduction of the cyano group, as in compound 17a, at the α‐position of the carbonyl in compound 16a significantly reduced the inhibitory activity against the biosynthesis of 15‐LO products. In addition to the interactions with residues His372 and Phe421 also found with zileuton and CAPE, compounds 16a and 16c each interact with residue His367 as shown by molecular docking. This new interaction may explain their high affinity with the 5‐LO active site.

2024-02-01·Inflammopharmacology

LC-QToF chemical profiling of Euphorbia grantii Oliv. and its potential to inhibit LPS-induced lung inflammation in rats via the NF-κB, CY450P2E1, and P38 MAPK14 pathways

Article

作者: Abdel-Sattar, Essam ; Khan, Ikhlas A ; Avula, Bharathi ; El-Shiekh, Riham A ; Katragunta, Kumar ; Radi, Mai Hussin ; Henry, Shirley Ragae ; El-Halawany, Ali M ; Hegab, Amany Mohammed

AbstractAcute lung injury (ALI) is a life-threatening syndrome that causes high morbidity and mortality worldwide. The aerial parts of Euphorbia grantii Oliv. were extracted with methanol to give a total methanolic extract (TME), which was further fractionated into dichloromethane (DCMF) and the remaining mother liquor (MLF) fractions. Biological guided anti-inflammatory assays in vitro revealed that the DCMF showed the highest activity (IC50 6.9 ± 0.2 μg/mL and 0.29 ± 0.01 μg/mL) compared to. celecoxib (IC50 of 88.0 ± 1 μg/mL and 0.30 ± 0.01 μg/mL) on COX-1 and COX-2, respectively. Additionally, anti-LOX activity was IC50 = 24.0 ± 2.5 μg/mL vs. zileuton with IC50 of 40.0 ± 0.5 μg/mL. LC-DAD-QToF analysis of TME and the active DCMF resulted in the tentative identification and characterization of 56 phytochemical compounds, where the diterpenes were the dominated metabolites. An LPS-induced inflammatory model of ALI (10 mg/kg i.p) was used to assess the anti-inflammatory potential of DCMF in vivo at dose of 200 mg/kg and 300 mg/kg compared to dexamethasone (5 mg/kg i.p). Our treatments significantly reduced the pro-inflammatory cytokines (TNF-α, IL-1, IL-6, and MPO), increased the activity of antioxidant enzymes (SOD, CAT, and GSH), decreased the activity of oxidative stress enzyme (MDA), and reduced the expression of inflammatory genes (p38.MAPK14 and CY450P2E1). The western blotting of NF-κB p65 in lung tissues was inhibited after orally administration of the DCMF. Histopathological study of the lung tissues, scoring, and immunohistochemistry of transforming growth factor-beta 1 (TGF-β1) were also assessed. In both dose regimens, DCMF of E. grantii prevented further lung damage and reduced the side effects of LPS on acute lung tissue injury.

项与齐留通相关的新闻（医药）

2024-03-03

·动脉网

D轮融资1.7亿美元，礼来、安进加持，这家公司用AI解决衰老问题

2024年才走过近两个月的时间，抗衰领域已诞生一笔1.7亿美元的融资。获得融资的企业名为BioAge Labs（下文简称BioAge），是一家成立于2015年的抗衰明星公司，致力于利用AI技术开发治疗衰老和年龄相关性疾病、延长人类健康寿命的创新药物。而在该公司宣布完成D轮融资后不久，其还于近日宣布将于2024年中期启动与礼来合作的一项2期临床试验，以评估BioAge的Apelin受体（APJ）激动剂Azelaprag（BGE-105）与礼来的GLP-1R/GIPR双靶点激动剂 Tirzepatide（替尔泊肽）的联合疗法在治疗肥胖症中的疗效。并且，动脉网了解到，在试验过程中，BioAge也将在遵守相关法律法规的基础上收集受试者的衰老相关生物标志物信息，以此助力BioAge其他处于临床早期衰老管线的研发。截至目前，BioAge针对衰老问题的研究集中在3个方向，分别是代谢和肌肉衰老、大脑衰老、免疫衰老。同时，依托独有的AI药物发现平台，BioAge还拥有多条在研管线，适应症包括肥胖症、神经炎症、急性肌肉萎缩等与衰老相关的疾病。明星团队支撑，获近3亿美元融资成立至今，BioAge已完成5轮融资，共募资近3亿美元，Andreessen Horowitz、Pear Ventures以及AME Cloud Ventures等投资者更是多轮押注，并且先后与安进和礼来达成合作。BioAge融资过程数据来源：crunchbase官网，动脉网制图BioAge备受明星资本青睐和知名企业看重的背后，是一支从默克、罗氏、英矽智能等企业的核心团队作支撑。其联合创始人兼首席执行官Kristen Fortney博士是一位在生物信息学领域拥有超10年研究经验的创业者。她不仅获得了多伦多大学生物信息学博士学位并在斯坦福大学接受博士后培训，还成为了两个知名衰老研究机构——American Federation for Aging Research（美国老龄化研究联合会）和Ellison Medical Foundation（埃里森医学基金会）的研究员，发表论文共计18篇，研究领域包括计算药物发现、衰老生物标志物和延长人类寿命的遗传学等。此外，Kristen Fortney曾担任Insilico Medicine、Humanity、Retro Biosciences、Known Medicine等药物研发公司的顾问。值得一提的是，BioAge识别和靶向驱动衰老的分子途径的数据驱动方法正是由其主导开发。并且，与创始人相似的是，BioAge的核心团队成员也具有衰老研究和系统生物学的深厚背景——其首席运营官Eric Morgen在靶点发现、衰老、药物基因组学等领域发表了20余篇论文；担任公司首席营销官兼执行副总裁一职的Paul Rubin博士曾在MiRagen、Glaxo-Wellcome、Abbott等生物制药公司担任要职，并将10多种产品从临床开发推动至获批，其中包括第一个获批用于临床治疗哮喘的5-脂氧合酶抑制剂齐留通（Zileuton）。同时，BioAge还吸引了Peng Leong博士出任首席商务官兼脑衰老治疗领域负责人一职，Peng Leong博士此前曾在CIBC World Markets和Piper Jaffray从事医疗投资银行业务，并曾担任默克的医学业务开发主管以及Kazia Therapeutics的首席品牌官。此外，BioAge的科学顾问团队也为公司的发展保驾护航，主要成员包括抗血小板药物Aggrastat®的主要研发人George Hartman博士，曾负责罗氏抗病毒药物临床开发的Klaus Klumpp博士，以及曾在Twitter、Google、麦肯锡公司担任企业战略副总裁、产品经理的Elad Gil博士等，他们的加入为公司的核心管线推进提供了研发动力。独有AI平台：基于6550万+数据点，每年评估约20种衰老途径2019年，BioAge宣布完成2300万美元B轮融资，该轮资金推动了公司搭建基于AI技术的高通量目标识别平台，即AI药物发现平台。该平台能够在海量的数据中搜索并确定影响人类寿命的关键生物途径和药物靶点，并通过高通量生物验证、最终将潜在靶点推进临床开发阶段。但BioAge并不止步于简单的检索验证，公司期望通过集成更多的AI技术和数据库信息，将原有平台升级为一个由AI驱动，可利用大量生物数据来发现、验证更广泛的衰老途径和药物靶点的技术平台。为此，在2022年BioAge宣布与Age Labs达成合作协议，获得了对AgeLabs数据库的独家访问权，BioAge能够使用Nord-Trøndelag健康研究（HUNT）生物库样本和健康记录来识别、开发和商业化针对衰老疾病的药物靶点。值得关注的是，HUNT自1995年至今纵向收集的生物样本适用于表观遗传学、蛋白质组学和代谢组学分析。在此基础上，BioAge的AI药物发现平台可深入分析来自纵向的生物样本，识别影响健康长寿和与年龄相关性疾病的蛋白质、代谢物或分子机制，而后快速确定衰老途径中的关键靶点。经过多年创新发展，BioAge的平台目前建立在一个拥有45年长度的纵向样本和健康记录的数据库上，拥有150万多个临床数据点、6400万多个分子数据点共6550万多个数据点，每年可评估约20种衰老途径。其中，该平台的最大优势是根据纵向数据跟踪患者衰老结果，从而确定导致衰老发生的新机制和驱动因素，并在已知和新型衰老生物学的交叉点上识别全新靶点。临床前试验显示小鼠体重减轻2倍，BioAge拳头产品可实现减脂不减肌Azelaprag正是BioAge通过AI平台发现并推进研发的在研管线。2021年，BioAge与安进签订了一项全球独家许可协议，获得了该药物的开发和商业化的权利。经过2年多研发推进，Azelaprag已成为公司目前在代谢和肌肉衰老领域的重要资产Azelaprag是一款可口服或静脉注射的APJ激动剂，可用于治疗肌肉萎缩并通过提高Apelin信号活性来恢复肌肉力量和功能。其中，Apelin是一种在运动后释放的“运动因子”多肽，其内生受体APJ是一种G蛋白偶联受体，在体内多种器官细胞上表达，主要包括中枢神经系统跟心血管系统，并通过与骨骼肌、心脏和中枢神经系统的相互作用调节新陈代谢，促进肌肉再生。研究显示，当人体开始衰老时，其骨骼和肌肉质量会逐渐减少，骨折、虚弱等风险也相应增加，比如，多发于老年人群体的肌肉萎缩，对于他们来说，肌肉衰老会导致力量、活动能力和功能丧失，进而导致与年龄相关的疾病和死亡发生率的增加。数据显示，功能性肌肉减少症或与年龄相关的肌肉骨骼变化影响7%的70岁以上的老年人1。BioAge的研究也证明，人体的总体Apelin水平会随着衰老过程而逐渐下降，而Apelin水平较高的人具有更强的身体功能和更长的寿命。其临床前研究显示，Azelaprag与替尔泊肽联合使用可增加受试小鼠整体体重减轻效果，与单独使用替尔泊肽相比，Azelaprag组的受试小鼠体重减轻了2倍，并且能够将身体成分和肌肉功能恢复到可控水平。在Azelaprag的1b期临床试验中，数据显示，21名65岁及以上的健康受试者在接受Azelaprag或安慰剂输注并严格卧床休息10天后，与安慰剂相比，Azelaprag在肌肉大小、质量和蛋白质合成方面产生了统计学上的显著改善，且并未产生严重副作用，具有良好的安全性和耐受性。基于积极的临床试验数据，BioAge将与礼来合作开展一项2期临床试验，评估Azelaprag是否可以增强GLP-1药物所实现的减肥效果。作为一款防止肌肉衰老的药物，Azelaprag与GLP-1药物联合用药，将有可能减轻该类药物引起的胃肠道问题和肌肉质量损失等副作用，促进实现更健康的减肥效果，最终通过治疗肥胖有效预防或延缓多种衰老疾病进展、延长患者的健康寿命。布局多条在研管线，探索抗衰无限可能性在AI平台的支持下，BioAge针对衰老领域中的不同适应症布局了多条在研管线，除了前文提到的核心管线Azelaprag外，还包括BGE-100。BioAge在研管线图源：BioAge官网BGE-100是一种NLRP3（NOD样受体热蛋白结构域相关蛋白3）抑制剂，被开发用于治疗由神经炎症引起的神经退行性疾病，帮助延长患者寿命。目前，BGE-100处于临床前毒理学研究阶段，预计将于2024年年中进入临床试验。值得关注的是，BioAge还曾布局了其他两款衰老管线——BGE-175和BGE-117。其中，BGE-175是一种前列腺素D2（PGD2）DP1 受体的抑制剂，被开发用于治疗因免疫老化导致的多种疾病，实现修复老化的免疫系统的目的。BGE-117是一种缺氧诱导因子-脯氨酰羟化酶（HIF-PH）抑制剂，被开发用于治疗多种衰老疾病，从而提高老年人寿命。不过，BioAge先后在2021年放弃了BGE-175和BGE-117两项资产，将重点转至BGE-100和Azelaprag，并逐步将赛道从衰老覆盖至减肥领域。对此，Kristen Fortney表示，对代谢疾病领域的关注将同时促进公司衰老领域的业务发展，最终将促进解决衰老以及与年龄相关疾病治疗的问题。尽管创新药物研发这条路还很长，但是在未来，BioAge的在研药物也许会成为患者摆脱疾病困扰、延长健康寿命的希望。参考资料：1. Amarya S, Singh K, Sabharwal M. Ageing process and physiological changes[M]//Gerontology. IntechOpen, 2018.文|冯汝梅微信|echo822207添加时请注明：姓名-公司-职位网站、公众号等转载请联系授权：Rekkiiie近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

临床2期高管变更

2023-09-10

·CPHI制药在线

5-脂氧合酶及其抑制剂研究进展

关注并星标CPHI制药在线脂氧合酶是一类非血红素含铁双加氧酶，存在于动、植物的组织和细胞中，可催化花生四烯（AA）、二十二碳六烯酸和各种多不饱和脂肪酸(polyunsaturated fatty acid，PUFA)的氧化反应。脂氧合酶主要分为1、3、5、8、12、15-脂氧合酶6种亚型。其中5-脂氧合酶(5-lipoxygenase，5-LOX)是脂氧合酶同工酶中最常见的、研究较为深入的非血红素铁蛋白氧化代谢酶，是许多高活性氧化脂质生物合成中的关键酶。5-LOX作用于AA氧化通过两步完成：第一步使5-LOX氧化成5-羟过氧化二十碳四烯酸（5-HPETE）再转化为5-羟基二十碳四烯酸（5-HETE）。第二步催化5-HPETE生成白三烯A4(leukotriene A4，LTA 4 )。LTA 4既可转化为致炎物白三烯B4(leukotriene B4，LTB4)，也可生成白三烯C4(leukotriene C4，LTC4)进而生成白三烯D4(leukotriene D4，LTD4)、白三烯E4(leukotrieneE4，LTE4)等导致过敏反应的反应物质。白三烯物质（LT）是哮喘、慢性阻塞性肺疾病、炎症性肠病、关节炎、动脉粥样硬化、皮炎和癌症等多种慢性炎症性疾病相关的促炎性脂质介质，通过进一步的双加氧作用和对外源化学物的协同氧化作用，在炎症、哮喘、脑缺血、部分恶性肿瘤及阿尔茨海默症等疾病的发生和发展中具有极其重要的作用。5-LOX抑制剂通过阻断LT的产生，抑制AA转变为LT，从而减少炎症的产生。因此，开发有效的5-LOX抑制剂对治疗上述疾病至关重要。根据抑制剂的作用机制可将5-LOX抑制剂分为直接抑制剂和间接抑制剂。直接抑制剂直接抑制剂主要针对5-LOX分子结构特点进行研发，比如干扰5-LOX C-端催化结构域中Fe2+与Fe3+正常的转换，或者是与铁离子络合来抑制5-LOX的活性。直接抑制剂包括氧化还原抑制剂、非氧化还原抑制剂、铁离子配体抑制剂。间接抑制剂主要是围绕FLAP进行设计，在5-LOX途径中需要FLAP的参与，抑制了FLAP 就能阻断 5-LOX 途径。 1、氧化还原抑制剂氧化还原抑制剂一般是亲脂性的小分子芳香族化合物，例如酚类化合物和醌类化合物。1,4-苯醌AA-861是第一批氧化还原型5-LOX抑制剂，经多项研究证实其在体内可产生抗炎作用，并已经通过了预防季节性过敏性鼻炎的临床试验。苯醌衍生物在人类单核细胞、中性粒细胞和整个人类血液中可作为5-LOX的有效活性抑制剂，对两种LT相关炎症标准化动物模型的实验研究表明，新型1,4-苯醌RF-Id能够通过抑制LT的产生，在体内抑制导致抗炎反应的5-LOX。此外，氧化还原抑制剂还包括去甲二氢愈创木酸 (NDGA)、香豆素、黄酮类化合物等几类物质，它们均在体外实验证实具有高效的5-LOX 抑制作用。氧化还原抑制剂能把Fe3+还原为Fe2+，从而干扰了铁离子的正常催化循环，阻止5-LOX 的激活，导致5-LOX途径不能正常进行。此外，黄酮类的某些化合物，例如槲皮素、芦丁由于B环上具有邻位的酚羟基，他们还能与Fe3+络合，从而加大了对 5-LOX 的抑制作用。另外，研究人员用荧光法测定了氧化还原抑制剂的氧化还原电势，并揭示了氧化还原抑制剂的作用机制，当氧化还原抑制剂存在时，它降低了Fe2+与Fe3+之间的转换，抑制了酶催化反应，从而需要更多的脂质过氧化物去氧化Fe2+转变成 Fe3+，因此，在酶催化反应过程中，真正参与催化反应的脂质过氧化物的量是很少的，酶催化反应即被抑制。 2、非氧化还原抑制剂非氧化还原抑制剂属于竞争型抑制剂，它能与底物AA竞争结合到5-LOX 的活性中心，导致5-LOX途径受阻，相对于其他抑制剂具有更高的选择性，但是磷酸化作用和Ca2+会干扰这些抑制剂。ZD2138 和ZM230487属于非氧化还原抑制剂中的两个代表。它们属于甲氧基四氢吡喃衍生物，临床研究表明，ZD2138 能够有效抑制关节炎和哮喘病。实验研究表明，一些天然产物和ZD2138 的杂交体 L-697198，以及通过对L-697198结构进行优化而得到的L-708780和L-739010，表现出良好的生物利用度。但后续动物实验发现，该种抑制剂有多种毒性，限制了它的临床使用。此外，L-739,010、CJ-13,610和PF-419183也是非氧化还原型5-LOX抑制剂，在细胞测定中显示IC50的低纳摩尔范围。L-739,010可以减少LT介导的炎症反应，且其抗痛觉亢进活性与炎症大脑中LT水平降低有关，在急性卡拉胶模型和慢性炎症模型中表现出优异的药效和药代动力学，但难以形成共价蛋白结合代谢物。CJ-13,610在大鼠内侧半月板横切面模型上对骨关节炎疼痛有抑制作用，口服CJ-13,610可逆转该动物模型的两种疼痛模式，包括触觉异位痛和负重差异。通过大鼠气囊模型证明了PF-4191834对LTB4产生的抑制作用，PF-4191834也完成了哮喘的Ⅱ期临床试验，但其用于膝骨关节炎的Ⅱ期临床试验因出现晕厥、急性肝炎和胃溃疡出血等严重不良事件而被终止。 3、铁离子配体抑制剂铁离子配体抑制剂大体包括两种，异羟基肟酸类和羟基脲类，羟肟酸衍生物BWA4C和羟基脲衍生物Zileuton是有效的口服5-LOX抑制剂。BWA4C是溃疡性结肠炎患结肠组织中LTB4合成的有效选择性抑制剂，以BWA4C为代表的乙酰异羟肟酸5-脂氧合酶抑制剂有助于评价LTB4在溃疡性结肠炎中的临床意义，并为该病的治疗提供新的途径。Zileuton使急性和慢性气道功能得到了改善，也减少了β受体激动剂或糖皮质激素的需求，并在美国被批准用于治疗哮喘，但是对于变应性鼻炎、类风湿关节炎和炎症性肠病的治疗潜力较低，并且它有许多缺点，如肝毒性和不良药代动力学特征等。以Zileuton结构为基础设计出了一种新型抑制剂VIA-2291，可以在支气管痉挛动物模型中表现出比Zileuton高5倍的效力，口服半衰期16 h，对哮喘患者的运动性支气管收缩有一定的疗效。VIA-2291已成功完成动脉粥样硬化和心血管疾病的Ⅱ期临床试验，成为临床开发中领先的5-LOX抑制剂之一。RBX-7796是一种具有十二烷基链的尿素衍生物，可抑制大鼠血液中LTB4的体外合成，并对各种炎症和支气管收缩动物模型有活性。间接抑制剂间接抑制剂不直接抑制5-LOX的活性。FLAP是5-LOX 激活蛋白，它能结合底物 AA 并且把它转移给5-LOX。在细胞中，5-LOX 与 FLAP 是共同表达的。当给予足够的底物 AA，如果缺少FLAP，细胞也不能合成白三烯等物质。MK886 是研发出来的第一代间接抑制剂，同时也是第一个用于临床的间接抑制剂。它能与AA竞争FLAP 上的结合位点，导致5-LOX 无法与FLAP 相互结合，5-LOX 途径因此受阻。此外，抑制剂AM803正在进行临床实验，并已经完成了对哮喘病人的二期阶段试验，它的衍生物AM103也成功通过了一期临床实验。不过研发的某些抑制剂也存在问题，如NGDA和MK0591 等也存在两方面的缺陷，一是不能特异性针对5-LOX，对人体正常的代谢也有一定的干扰，从而限制了临床应用；二是稳定性不够，直接影响抑制剂的抑制效力。参考资料 [1]李丹凤,范涛,鹿欣雨.5-脂氧合酶抑制剂的研究进展[J].生命的化学,2023,43(05):666-673. [2]黄凯,蒋世云,陈柳军.5-脂氧合酶及其抑制剂[J].中国生物化学与分子生物学报,2014,30(12):1190-1196. 作者简介：小泥沙，食品科技工作者，食品科学硕士，现就职于国内某大型药物研发公司，从事营养食品的开发与研究。智药研习社近期课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

临床1期核酸药物

2023-05-12

·drugs

Get Relief With the Most Common Asthma Medications

FRIDAY, May 12, 2023 -- Receiving a diagnosis of asthma may be frightening, but learning what the treatment options are can help alleviate the anxiety that comes with diagnosis. Depending on the severity, certain asthma medications may help you manage your symptoms. Here, experts break down the most common long-term and quick-acting medications for asthma, how they work and potential side effects. Long-term medications These drugs are ones the patient takes daily as a means of controlling asthma and preventing asthma attacks. These can be in pill form or used as inhalers. Bronchodilators: Long-acting beta-2 agonists (LABA) relax the muscle bands around your airway (bronchi), making it easier to get air in and mucus out. These medications for asthma are taken twice a day through an inhaler and last up to 12 hours, according to the Cleveland Clinic . LABA medications should be given with a corticosteroid. (See combination medications below.) The main side effects of LABA medications are nervous or shaky feelings, hyperactivity, overexcitement, increased heart rate, upset stomach and trouble sleeping. Salmeterol (Serevent) Formoterol (Foradil) Long-acting muscarinic antagonists (LAMA) also relax the muscle bands around your airway, the National Heart, Lung, and Blood Institute (NHLBI) says. This asthma medication is used if the steroid/LABA combination doesn’t give enough relief. Do not use this medication if you have glaucoma or are at risk of urinary retention. Tiotropium bromide (Respimat) Theophylline. While not used often, theophylline can be useful in relaxing the airways and preventing reactions to irritants. It is taken as a pill and used for mild asthma symptoms. You may need to have blood tests drawn on a regular basis to make sure the level of medication is correct, the Mayo Clinic says. Side effects are the same as the other bronchodilators, but may also include chest pain or discomfort, dizziness, fainting, increase in urine volume or seizures. Theophylline (Theo-24, Theo-Dur, Slo-Bid, and others) Corticosteroids: Corticosteroids are steroids that reduce inflammation in the airways, according to the NHLBI. They may be taken as a pill, although very few patients are on the pill for long term. It is frequently used in an inhaler, often combined with a LABA. Side effects from the inhaled form are thrush (a mouth infection) and a hoarse voice. Inhaled corticosteroids include: Fluticasone (Flovent HFA, Arnuity Ellipta, others) Budesonide (Pulmicort Flexhaler) Mometasone (Asmanex Twisthaler) Beclomethasone (Qvar RediHaler) Ciclesonide (Alvesco) Combination asthma medications (Corticosteroid and LABA): Fluticasone and salmeterol (Advair) Budesonide and formoterol (Symbicort) Fluticasone and Vilanterol (Breo) Leukotriene modifiers reduce swelling and help keep your airways open for up to 24 hours. According to Mayo Clinic, these medications block the effects of leukotrienes, immune system chemicals that cause asthma symptoms. Side effects are uncommon, but may include nausea, headache, tiredness or diarrhea. Montelukast (Singulair) Zafirlukast (Accolate) Zileuton (Zyflo) Quick-acting asthma medications These are a group of medications that are used when a patient has a flare-up or an asthma attack. Inhaled short-acting beta2-agonists (SABAs) open the airways so air can flow through them during an asthma attack. They start working within 15 to 20 minutes and continue to work for 4 to 6 hours, according to the Cleveland Clinic. Side effects can include tremors, rapid heartbeat, allergic reactions, muscle pain, worsening breathing, dry mouth, headache, sore throat or trouble sleeping. Inhaled forms of SABA medications include: Albuterol (Ventolin) Levalbuterol (Xopenex) Albuterol and ipratropium bromide combination (DuoNeb) Corticosteroids. Oral corticosteroids are usually prescribed for short-term use to help a patient overcome a flare-up. This type of medication quickly reduces swelling and inflammation in the airways. Side effects include: Cataracts, osteoporosis, weight gain, high blood sugar, increased risk of infections, thinning bones and fractures, thin skin, bruising and slower wound healing, mood swings, depression and aggressive behavior. Prednisone (Deltasone, Prednicot, and others ) Methylprednisolone (Medrol, Solu-Medrol, Depo-Medrol) Short-acting anticholinergic bronchodilators help open the airways quickly. This medicine may be less effective than SABAs, but it is an option for people who experience side effects with other medications, the Cleveland Clinic says. Side effects you may experience with these inhalers are dry throat, eyes and nose; unusual taste; nausea and vomiting; or temporary blurred vision if the medicine gets in your eyes. Ipratropium bromide (Atrovent) Tiotropium bromide (Spiriva Respimat) Corticosteroid reliever. In January 2023, the FDA approved Airsupra, which can be used as needed to prevent bronchoconstriction and asthma attacks. In a study conducted before the approval, the risk of severe asthma exacerbation was significantly lower with a fixed-dose combination of albuterol and budesonide than with as-needed use of albuterol alone. Most common side effects are headache, oral yeast infection, cough, and difficulty speaking. Airsupra (albuterol-budesonide) Posted May 2023

上市批准

100 项与齐留通相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D00414	齐留通	R	DB00744

研发状态

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10 条最早获批的记录,

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适应症	国家/地区	公司	日期
哮喘	美国	Chiesi USA, Inc	1996-12-09

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适应症	最高研发状态	国家/地区	公司	日期
特应性皮炎	临床1期	美国	Qurient Co., Ltd.	2015-04-01
寻常痤疮	临床前	美国	Critical Therapeutics, Inc.	2004-11-01
慢性哮喘	药物发现	-	Critical Therapeutics, Inc.	2007-09-01

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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


NCT00493974 (Pubmed \| COPD)	临床3期	慢性阻塞性肺疾病	119	Zileuton 600 mg	(窪襯窪淵膚願簾鏇鏇蓋) = 衊製襯獵網鬱願顧鏇構觸遞憲壓構廠網遞製鹹 (夢鬱鏇獵繭鬱獵選獵衊 ) 更多	不佳	2011-02-01
				Placebo	(窪襯窪淵膚願簾鏇鏇蓋) = 壓遞廠鑰夢鏇鹹顧遞鹹觸遞憲壓構廠網遞製鹹 (夢鬱鏇獵繭鬱獵選獵衊 ) 更多
NCT00493974 (CTgov)	临床3期	慢性阻塞性肺疾病	119	Zileuton (Zileuton)	(鹽願簾襯夢鑰築構夢範) = 窪蓋選夢選憲網壓鏇築憲膚糧衊膚網膚遞壓簾 (顧膚醖窪範築製艱遞築, 築製憲鹹鏇獵醖壓鹽淵 ~ 窪觸襯糧構鏇鹹蓋夢窪) 更多	-	2010-03-03
				Placebo (Placebo)	(鹽願簾襯夢鑰築構夢範) = 夢鬱製獵壓鏇鹹齋願簾憲膚糧衊膚網膚遞壓簾 (顧膚醖窪範築製艱遞築, 齋蓋鏇範膚齋膚鹽衊築 ~ 築衊夢繭壓衊鑰構網獵) 更多
NCT00723021 (CTgov)	临床2期	哮喘	15	placebo	積選積簾鬱獵糧糧淵積(艱製鬱構遞積餘鑰繭壓) = 壓夢獵餘衊鹹蓋鑰積壓製構壓築鬱壓願網醖獵 (遞遞鑰鑰鏇餘構鬱窪夢, 衊壓願遞築鹹淵壓襯遞 ~ 夢觸鬱壓繭廠艱製淵鏇) 更多	-	2013-02-01
NCT01021215 (CTgov)	临床1/2期	烟草依赖	84	laboratory biomarker analysis+Zileuton (Arm I: Zileuton)	顧網繭糧願遞襯範蓋鑰(衊遞襯餘齋壓遞築艱觸) = 醖構網鬱夢鑰選遞鹹築鬱壓範範鑰遞窪築構積 (鏇淵顧夢衊蓋衊獵淵憲, 築範艱鏇顧選衊衊網獵 ~ 製淵簾鏇憲顧醖襯膚餘) 更多	-	2015-04-02
				laboratory biomarker analysis+Celecoxib+Zileuton (Arm II: Zileuton and Celecoxib)	顧網繭糧願遞襯範蓋鑰(衊遞襯餘齋壓遞築艱觸) = 鬱鬱夢簾廠範製廠廠蓋鬱壓範範鑰遞窪築構積 (鏇淵顧夢衊蓋衊獵淵憲, 積鹹餘醖醖鬱衊鑰製窪 ~ 壓鹽觸壓積廠衊鏇蓋壓) 更多
ESMO2023	N/A	循环肿瘤细胞	500	Zileuton	醖繭遞鹽構壓獵廠醖鏇(艱遞鹽憲遞繭遞顧糧醖) = 襯廠顧壓鏇構廠壓獵壓艱獵淵齋遞築襯鹽襯壓 (築構顧衊蓋遞願遞餘鏇 )	-	2023-10-22
				Pemetrexed	醖繭遞鹽構壓獵廠醖鏇(艱遞鹽憲遞繭遞顧糧醖) = 鏇襯製簾衊襯鬱蓋膚簾艱獵淵齋遞築襯鹽襯壓 (築構顧衊蓋遞願遞餘鏇 )
NCT00467831 (CTgov)	临床1/2期	Hermanski-Pudlak综合征 \| 肺纤维化	3	Pravastatin+N-Acetylcysteine+Losartan+Erythromycin+Zileuton	遞積襯廠憲顧憲襯鹹襯(壓廠膚廠構艱網窪獵淵) = 醖艱鑰網鏇鏇夢簾鹽繭觸醖積製淵鏇選範鏇簾 (蓋築觸顧糧壓鹽網淵選, 憲膚選餘獵夢鹽襯齋鏇 ~ 選齋齋構製齋糧醖築壓) 更多	-	2013-08-02
NCT02348203 (CTgov)	临床2期	烟草依赖 \| 癌变	63	Laboratory Biomarker Analysis+Aspirin+Zileuton (Arm I (Aspirin, Zileuton))	鹽網築觸獵憲艱糧憲夢(齋糧製餘艱蓋膚遞顧衊) = 鹽構齋構壓襯壓艱觸壓壓膚簾範鏇夢艱糧廠鑰 (醖簾網糧淵觸淵夢遞積, 鹽憲窪構窪簾範艱糧顧 ~ 夢構淵遞範築觸選獵壓) 更多	-	2020-03-23
				Laboratory Biomarker Analysis (Arm II (Double Placebo))	鹽網築觸獵憲艱糧憲夢(齋糧製餘艱蓋膚遞顧衊) = 網艱觸窪蓋鑰築憲遞憲壓膚簾範鏇夢艱糧廠鑰 (醖簾網糧淵觸淵夢遞積, 願憲壓淵築糧壓淵積鏇 ~ 衊鬱製鏇齋積鑰衊衊鹽) 更多