Retinoic acid metabolism blocking agents (RAMBAs) to treat osteoarthritis of the hand: A 2-arm double-blind randomised controlled proof of concept study

开始日期2024-01-04

申办/合作机构

University of Oxford

NCT00719121 / Completed临床1期

Placebo-Controlled, Investigator Blinded, Explorative Trial to Evaluate the Anti-inflammatory Effect of Multiple Topical Applications of R115866 Gel (0.35%) in Two Models of Cutaneous Inflammation in Healthy Male Subjects

The purpose of this exploratory trial is to assess the anti-inflammatory effect(s) of topical R115866 in a model of UVB-induced inflammation and in a model of cutaneous irritation.

开始日期2006-11-01

申办/合作机构

Stiefel Laboratories, Inc.

NCT00716144 / Completed临床2期

A Randomized, Evaluator-Blind, Placebo-Controlled, Parallel-Group Dose-Ranging Study of the Safety and Efficacy of Oral R115866 and R115866 Placebo in the Treatment of Plaque Psoriasis

Eligible subjects will be randomly assigned to one of three dose regimens of oral R115866 or placebo for the treatment of severe plaque psoriasis for 12 twelve weeks. The safety and efficacy of R115866 will be evaluated during the treatment period and the 8-week post treatment follow-up period.

开始日期2006-06-01

申办/合作机构

Stiefel Laboratories, Inc.

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100 项与他拉罗唑相关的临床结果

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100 项与他拉罗唑相关的转化医学

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100 项与他拉罗唑相关的专利（医药）

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项与他拉罗唑相关的文献（医药）

2024-10-01·ANTICANCER RESEARCH

Enhancing Retinoic Acid-mediated Effects Through Inhibition of CYP26A1, CYP26B1 and HGF Signaling in Neuroblastoma Cells

Article

作者: KAEHLER, MEIKE ; CASCORBI, INGOLF ; ISSA, REEMA SAMI ; POMMERT, NINA SOPHIE ; WAETZIG, VICKI ; Kaehler, Meike ; Waetzig, Vicki ; Cascorbi, Ingolf ; Issa, Reema Sami ; Pommert, Nina Sophie

BACKGROUND/AIM:

Retinoic acid (RA) induces tumor cell differentiation in diseases like acute promyelocytic leukemia or high-risk neuroblastoma. However, the formation of resistant cells, which results from dysregulation of different signaling pathways, limits therapy success. The present study aimed to characterize basic regulatory processes induced by the application of RA in human neuroblastoma cells, to identify therapeutic targets independent of the often amplified oncogene MYCN.

MATERIALS AND METHODS:

In MYCN-amplified Kelly and MYCN non-amplified SH-SY5Y cells, different assays were employed to quantify the viability and cytotoxicity, while RA-mediated expression changes were examined using genome-wide gene expression analysis followed by quantitative PCR. Enzyme-linked immunoabsorbent assays (ELISA) and western blots were used to determine the levels or activation of the examined proteins.

RESULTS:

In Kelly cells, treatment with 5 μM RA for 3 days significantly reduced the cell number due to attenuated proliferation, while SH-SY5Y cells were less responsive. An up-regulation of the RA-metabolizing enzymes CYP26A1 and CYP26B1 was observed in both cell lines, and co-treatment with the selective CYP26 inhibitor talarozole markedly decreased cell viability. When RA and ketoconazole, which inhibits CYP26 as well as RA-degrading CYP3A enzymes, were co-administered, not only cell survival was impaired in both cell lines, but also the release of hepatocyte growth factor (HGF). Accordingly, co-application of the c-Met inhibitor tepotinib and RA or ketoconazole substantially decreased cell viability.

CONCLUSION:

Independent of MYCN amplification, inhibitors of RA metabolism or HGF signaling might prevent the emergence of RA-resistant neuroblastoma cells when co-applied with RA.

2024-05-01·TOXICOLOGY AND APPLIED PHARMACOLOGY

In silico and in vitro assessment of drugs potentially causing adverse effects by inhibiting CYP17A1

Article

作者: Jäger, Marie-Christin ; Naeem, Sadaf ; Odermatt, Alex ; Smieško, Martin ; Kędzierski, Jacek

Cytochrome P450 enzymes (CYPs) play a crucial role in the metabolism and synthesis of various compound classes. While drug-metabolizing CYP enzymes are frequently investigated as anti-targets, the inhibition of CYP enzymes involved in adrenal steroidogenesis is not well studied. The steroidogenic enzyme CYP17A1 is a dual-function enzyme catalyzing hydroxylase and lyase reactions relevant for the biosynthesis of adrenal glucocorticoids and androgens. Inhibition of CYP17A1-hydroxylase leads to pseudohyperaldosteronism with subsequent excessive mineralocorticoid receptor activation, hypertension and hypokalemia. In contrast, specific inhibition of the lyase function might be beneficial for the treatment of prostate cancer by decreasing adrenal androgen levels. This study combined in silico and in vitro methods to identify drugs inhibiting CYP17A1. The most potent CYP17A1 inhibitors identified are serdemetan, mocetinostat, nolatrexed, liarozole, and talarozole. While some of these drugs are currently under investigation for the treatment of various cancers, their potential for the treatment of prostate cancer is yet to be explored. The DrugBank database was screened for CYP17A1 inhibitors, to increase the awareness for the risk of drug-induced pseudohyperaldosteronism and to highlight drugs so far unknown for their potential to cause side effects resulting from CYP17A1 inhibition.

2024-03-01·Neuroscience bulletin

Cytochrome P450 26A1 Contributes to the Maintenance of Neuropathic Pain

Article

作者: Gao, Yong-Jing ; Jiang, Bao-Chun ; Ma, Ling-Jie ; Cao, De-Li ; Gu, Qiang

Abstract:

The cytochrome P450 proteins (CYP450s) have been implicated in catalyzing numerous important biological reactions and contribute to a variety of diseases. CYP26A1, a member of the CYP450 family, carries out the oxidative metabolism of retinoic acid (RA), the active metabolite of vitamin A. Here we report that CYP26A1 was dramatically upregulated in the spinal cord after spinal nerve ligation (SNL). CYP26A1 was mainly expressed in spinal neurons and astrocytes. HPLC analysis displayed that the content of all-trans-RA (at-RA), the substrate of CYP26A1, was reduced in the spinal cord on day 7 after SNL. Inhibition of CYP26A1 by siRNA or inhibition of CYP26A1-mediated at-RA catabolism by talarozole relieved the SNL-induced mechanical allodynia during the maintenance phase of neuropathic pain. Talarozole also reduced SNL-induced glial activation and proinflammatory cytokine production but increased anti-inflammatory cytokine (IL-10) production. The RA receptors RARα, RXRβ, and RXRγ were expressed in spinal neurons and glial cells. The promoter of Il-10 has several binding sites for RA receptors, and at-RA directly increased Il-10 mRNA expression in vitro. Finally, intrathecal IL-10 attenuated SNL-induced neuropathic pain and reduced the activation of astrocytes and microglia. Collectively, the inhibition of CYP26A1-mediated at-RA catabolism alleviates SNL-induced neuropathic pain by promoting the expression of IL-10 and suppressing glial activation. CYP26A1 may be a potential therapeutic target for the treatment of neuropathic pain.

项与他拉罗唑相关的新闻（医药）

2024-04-07

·今日头条

100分综述详解：短链脂肪酸链起饮食、菌群和免疫

04月07日的《热心肠日报》，我们解读了 15 篇文献，关注：SCFA，膳食纤维，脑健康，生酮饮食，老年人，社交孤立，丙酮酸，性别差异，橄榄油，人造甜味剂，模拟禁食饮食，Enhertu，司美格鲁肽生物类似药，REVIV Global，Affinity Biosensors，世和基因。该篇日报由R·AI辅助创作生成，人工审核校对。 Nature Reviews：短链脂肪酸——连接饮食、肠菌和免疫的纽带（综述） Nature Reviews Immunology——[100.3] ① 短链脂肪酸（SCFAs）如丁酸、丙酸和乙酸在调节肠道及全身免疫中发挥着关键作用，同时它们也与饮食、微生物群和抗生素使用密切相关；② SCFAs通过G蛋白偶联受体信号传导或组蛋白去乙酰化酶活性影响上皮屏障功能及粘膜和系统性免疫；③ 丁酸通过直接作用于肠上皮细胞、吞噬细胞、B细胞、浆细胞以及调节性和效应性T细胞的分化发挥抗炎作用；④ SCFAs还能直接或间接影响肠外部位如肝脏、肺部、生殖道和大脑的免疫反应，并与多种疾病相关；⑤ 本文强调了通过生态学理解微生物群及其代谢状态以及工程化丁酸生成菌的重要性，为预防和治疗免疫介导疾病提供了以SCFA为焦点的干预策略。【原文信息】 Short-chain fatty acids: linking diet, the microbiome and immunity 2024-04-02 , doi: 10.1038/s41577-024-01014-8 膳食纤维调节肠道菌群及其代谢物，降低糖尿病风险 Circulation Research——[20.1] ① 本研究包括11394名参与者，结果表明，较高的膳食纤维摄入量与肠道微生物群分类特征、微生物功能酶及循环代谢物的有益模式有关，这与较低的2型糖尿病（T2D）风险相关；② 对于某些与膳食纤维相关的菌群如Butyrivibrio和Faecalibacterium，对T2D风险的潜在有益影响可以通过微生物相关的代谢物来解释，即吲哚丙酸盐、3-苯基丙酸盐和肉桂酰甘氨酸；③ 这些发现有助于我们理解膳食纤维摄入、肠道微生物群和循环代谢物之间的复杂关系，并为它们在T2D发展中的潜在作用提供了见解。【原文信息】 Gut Microbiota and Blood Metabolites Related to Fiber Intake and Type 2 Diabetes 2024-03-28 , doi: 10.1161/CIRCRESAHA.123.323634 生酮饮食可改善精神疾病患者的代谢异常 Psychiatry Research——[11.3] ① 本研究探讨了生酮饮食对患有精神分裂症和双相情感障碍且存在代谢异常的个体的代谢和精神健康的影响，发现该饮食干预具有积极效果；② 23名参与者在遵循生酮饮食后，代谢健康得到改善，研究结束时没有参与者符合代谢综合征的标准，体重（12%）、BMI（12%）、腰围（13%）和内脏脂肪（36%）显著减少；③ 生物标志物方面，胰岛素抵抗指数（HOMA-IR）降低了27%，甘油三酯水平下降了25%；④ 在精神健康方面，精神分裂症患者的简明精神病评定量表得分降低了32%，整体临床总体印象严重程度平均改善了31%，79%的参与者在临床总体印象评分上至少改善了1分；⑤ 参与者的生活满意度提高了17%，睡眠质量提高了19%；⑥ 这项试点试验强调了辅助生酮饮食治疗在与严重精神疾病作斗争的个体中的潜在优势。【原文信息】 Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial 2024-03-20 , doi: 10.1016/j.psychres.2024.115866 复旦大学Nature子刊：均衡饮食对老年人大脑健康至关重要！ Nature Mental Health——[0] ① 复旦大学类脑智能科学与技术研究院冯建峰和程炜与团队研究发现，老年人中“更健康”的均衡饮食模式与更好的心理健康状况、更高水平的认知功能和更少的精神障碍风险有关，并且这些饮食模式背后存在遗传关联；② 纳入英国生物银行超18万名平均年龄70岁以上老年人的食物喜好数据，识别出四种饮食亚型：无淀粉或低淀粉（亚型1）、素食（亚型2）、高蛋白低纤维（亚型3）和均衡饮食（亚型4）；③ 亚型4与其他亚型相比，心理健康问题较少，幸福感得分较高，亚型2表现出相对较高的心理健康评分水平和相对较低的幸福感评分，亚型3幸福感得分低于其他亚型，与亚型4相比，亚型3患焦虑、抑郁和卒中的风险更高；④ 与其他亚型相比，亚型2对一系列精神障碍表现出更高的遗传易感性，而亚型4对大多数精神障碍和相关疾病表现出相对较低的多基因风险评分；⑤ 与亚型4相比，亚型3在11个脑区的灰质体积显著降低，而亚型2在丘脑和楔前叶区域显示出较高的灰质体积；⑥ 全基因组关联分析确定了亚型3和亚型4之间的16个不同基因，这些基因在与心理健康和认知相关的生物学过程中富集。【原文信息】 Associations of dietary patterns with brain health from behavioral, neuroimaging, biochemical and genetic analyses 2024-04-01 , doi: 10.1038/s44220-024-00226-0 JAMA子刊：社交孤立与饮食行为及心理健康有关？ JAMA Network Open——[13.8] ① 从加利福尼亚州洛杉矶社区招募了健康的绝经前女性参与者，探究社会孤立与食物线索的大脑反应、不良饮食行为、肥胖和心理健康症状之间的关联；② 在社交孤立感更强的参与者中，其脂肪质量百分比更高、饮食质量更低、不适应性进食行为和较差的心理健康增加；③ 社会孤立感较强的个体默认模式网络、执行控制网络和视觉注意网络的大脑区域对食物线索的反应发生改变，并与不良饮食行为和心理症状相关；④ 大脑对食物线索的改变反应在社会孤立与不良饮食行为、增加的体脂比例和减少的积极情感间起到中介作用。【原文信息】 Social Isolation, Brain Food Cue Processing, Eating Behaviors, and Mental Health Symptoms 2024-04-01 , doi: 10.1001/jamanetworkopen.2024.4855 丙酮酸——抑制炎症、减肥的新希望 Protein & Cell——[21.1] ① 本研究揭示了丙酮酸通过靶向细胞质磷脂酶A2（cPLA2）减轻小鼠肥胖和炎症的新机制，为肥胖治疗提供了潜在的营养干预策略；② 丙酮酸能显著抑制体外脂肪生成分化，并在高脂饮食诱导的小鼠模型中有效预防体重增加、白色脂肪组织炎症和代谢紊乱；③ 通过药物亲和性响应靶蛋白稳定性分析、蛋白质组学、细胞热位移实验和等温药物反应检测，明确cPLA2为丙酮酸的新靶标；④ 丙酮酸以cPLA2依赖性的方式抑制饮食诱导的肥胖、白色脂肪组织炎症和肝脏脂肪变性；⑤ 通过体内和体外实验证明，cPLA2的缺乏会阻断丙酮酸的保护作用，证实丙酮酸-cPLA2相互作用在丙酮酸抑制炎症和肥胖中的重要性。【原文信息】 Dietary pyruvate targets cytosolic phospholipase A2 to mitigate inflammation and obesity in mice 2024-03-21 , doi: 10.1093/procel/pwae014 国内团队：关注性别差异——钠钾摄入与早死风险的关联 BMC Medicine——[9.3] ① 中南大学的黄佳琦团队与合作者，通过前瞻性分析和系统评价，揭示了钠和钾摄入量与总体及特因死亡率之间的关联，以及其中的性别差异；② 在追踪期间，高钠摄入量（每日≥2000毫克）与总体和心血管疾病（CVD）死亡率显著正相关，女性的钠钾比与死亡率关联更强；③ 高钾摄入量和较低的钠钾比与降低的死亡率相关，在女性中这一关联更为显著；④ 钠、钾摄入和钠钾比与整体死亡率的关联在人群风险因素亚组中基本相似，唯一的例外是钾死亡率的负相关在体重指数较低或水果消费较少的男性中更强；⑤ 基于42个风险估计、2,085,904名参与者和80,085例心血管事件的更新队列研究的荟萃分析，结果非常相似；⑥ 每日钠摄入量（在2,000至7,500毫克/天的范围内）、钠钾比和CVD风险以及总体死亡率之间存在显著正相关，女性的钠钾比-死亡率关联比男性更强。【原文信息】 Sex-specific associations between sodium and potassium intake and overall and cause-specific mortality: a large prospective U.S. cohort study, systematic review, and updated meta-analysis of cohort studies 2024-03-22 , doi: 10.1186/s12916-024-03350-x 橄榄油代替猪油，或可降低胆固醇？ American Journal of Clinical Nutrition——[7.1] ① 开展一项随机、双盲对照交叉试验，招募18名与胰岛素抵抗相关的血脂异常受试者，分为富含饱和脂肪酸和单不饱和脂肪酸饮食组；② 将饱和脂肪酸（SFAs）替换成单不饱和脂肪酸（MUFAs），未发现对甘油三酯富集脂蛋白（TRL）载脂蛋白B-48的分解率和产生率有显著影响，但可减少VLDL载脂蛋白B-100的池大小；③ 这种替代还降低了LDL胆固醇（LDL-C）、非高密度脂蛋白胆固醇水平和LDL载脂蛋白B-100池；④ MUFA饮食也可降低鞘脂类浓度，提高磷脂类水平；⑤ 本研究表明MUFAs替代SFAs能够通过提高LDL载脂蛋白B-100的分解率来降低LDL-C水平，对胰岛素抵抗引起的血脂异常患者具有积极影响。【原文信息】 Substitution of dietary monounsaturated fatty acids from olive oil for saturated fatty acids from lard increases LDL apolipoprotein B-100 fractional catabolic rate in subjects with dyslipidemia associated with insulin resistance: a randomized controlled trial 2024-03-20 , doi: 10.1016/j.ajcnut.2024.03.015 人造甜味剂如何影响超重/肥胖成年人的食欲和内分泌反应？ EBioMedicine——[11.1] ① 本研究发现与使用蔗糖相比，使用StRebM和Neotame替代糖制成的饼干对超重/肥胖成人饥饿感和内分泌反应方面没有明显差异，但能降低餐后胰岛素和血糖反应；② 纳入53名超重/肥胖健康成年人在为期两周的干预期间使用含有水果馅的饼干，其中1）含有蔗糖，或者经过改良的2）甜菊糖甙M（StRebM）或3）Neotame，共3个干预期，每个干预期间之间有两周的洗脱期；③ 在三小时内，三种饼干对饥饿感的降低效果相似；④ 相比蔗糖，Neotame和StRebM能显著降低餐后两小时的胰岛素水平，且StRebM还能降低血糖水平，而Neotame不能；⑤ 胃饥饿素、胰高血糖素样肽1或胰腺多肽在三种饼干间无差异；⑥ 短期（1天）与长期（两周）摄入这些替代甜味剂的饼干，在饥饿感和内分泌反应上没有显著差异。【原文信息】 Acute and two-week effects of neotame, stevia rebaudioside M and sucrose-sweetened biscuits on postprandial appetite and endocrine response in adults with overweight/obesity-a randomised crossover trial from the SWEET consortium 2024-03-25 , doi: 10.1016/j.ebiom.2024.105005 模拟禁食饮食助糖尿病患者控糖减药 Diabetologia——[8.2] ① 本研究探讨了每月接受5天模拟禁食饮食（FMD）辅助2型糖尿病常规治疗，发现其能显著减少患者对降糖药物的需求并改善血糖控制；② 在为期12个月的随机对照试验中，与常规治疗相比，FMD组患者在降糖药物使用效果评分、糖化血红蛋白水平和体重上均有显著改善；③ FMD组有53%的参与者血糖管理改善，而对照组仅有8%，同时FMD组血糖管理恶化的比例也显著低于对照组；④ 将FMD计划整合入常规初级保健中，对于仅使用二甲双胍或饮食控制血糖的2型糖尿病患者而言是一种安全有效的辅助治疗策略。【原文信息】 Integration of a fasting-mimicking diet programme in primary care for type 2 diabetes reduces the need for medication and improves glycaemic control: a 12-month randomised controlled trial 2024-03-28 , doi: 10.1007/s00125-024-06137-0 不限癌种，重磅ADC药物Enhertu获FDA加速批准 ① 4月6日，美国FDA宣布，加速批准了由第一三共和阿斯利康联合开发的抗体偶联药物（ADC）Enhertu用于治疗不可切除或转移性HER2阳性实体瘤成年患者，这些患者已接受过先前治疗且缺乏满意的替代治疗选项；② Enhertu是首款不限癌种适应症的HER2靶向ADC疗法，对罹患HER2阳性罕见癌症的患者尤为重要；③ 批准基于192名患者参加的三项多中心试验（DESTINY-PanTumor02、DESTINY-Lung01和DESTINY-CRC02）的疗效评估结果；④ Enhertu的主要疗效结果指标是确认客观缓解率（ORR），在三项试验中ORR分别为51.4%、52.9%和46.9%；⑤ 第一三共和阿斯利康还在开发其他ADC疗法；⑥ 第一三共与其他公司（如默沙东、罗氏）也达成了ADC疗法相关合作协议。【原文信息】首款！不限癌种，重磅ADC获FDA加速批准 2024-04-06 , 药明康德司美格鲁肽生物类似药减重适应证临床研究将有指导原则 ① 近日，国家药监局药品审评中心（CDE）发布《司美格鲁肽注射液生物类似药体重管理适应症临床试验设计指导原则（征求意见稿）》，为今后指导我国司美格鲁肽注射液生物类似药的临床研发，提供可参考的技术标准；② 司美格鲁肽注射液是丹麦诺和诺德公司开发的一种长效（每周一次给药）人胰高血糖素样肽-1（GLP-1）受体激动剂；③ 司美格鲁肽的减重适应证产品已在国内递交上市申请，预计今年将获批；④ 国内多家企业如联邦制药、华东医药等正在研发司美格鲁肽生物类似药。【原文信息】司美格鲁肽生物类似药减重适应症临床研究将有指导原则 2024-04-06 , 新京报 Cardone Ventures投资REVIV Global，助力精准营养 ① 4月1日，Grant Cardone旗下公司Cardone Ventures宣布，投资REVIV Global公司，并与其达成战略合作；② 该战略合作将把REVIV Global的技术与全球增长最快的健康品牌10X Health System相结合，以推出一个全新的精准营养测试；③ 新的精准营养测试将分析超过50种与体重和营养相关的遗传因素，并提供一份长达400页的个性化报告；④ 10X Health System也是Cardone Ventures投资的公司之一。【原文信息】 Grant Cardone's Cardone Ventures Leads A Strategic Investment And Partnership With REVIV To Launch World's First Patented Precision Nutrition System With 10X Health 2024-04-01 , Yahoo Affinity Biosensors旗下分析仪获FDA批准，用于指导菌血症治疗 ① 4月3日，Affinity Biosensors宣布，其台式分析仪LifeScale AST获得FDA市场许可，用于指导菌血症治疗；② LifeScale AST使用微流控传感器来测量数千种细菌，并可进行快速的表型抗生素敏感性测试，结果包括碳青霉烯类耐药菌和多重耐药菌的鉴定；③ 该系统能在5小时内得到结果，可有效帮助临床医师确定哪些抗生素最有可能对血流感染有效；④ LifeScale AST无需化学样品制备和处理，具有成本效益的高通量操作，室温耗材存储，并与现有的微生物鉴定系统兼容。【原文信息】菌血症快速药敏鉴定！仅需5小时！ 2024-04-05 , IVD从业者网世和基因IPO上市终止 ① 近日，世和基因宣布撤回在科创板的IPO申请，上海证券交易所终止审核；② 世和基因成立于2013年，专注于高通量基因测序技术的临床转化应用；③ 公司主要为肿瘤患者提供基因检测服务，已累计检测肿瘤样本数十万例；④ 世和基因是国家级高新技术企业，检测实验室具备CAP/CLIA/ISO15189资质。【原文信息】重磅！世和基因IPO上市终止 2024-04-02 , IVD体外诊断网感谢本期日报的审核者：九卿臣，注册营养师陈彬林，章台柳，RZN，617 点击阅读过去10天的日报： 0406 | 贾伟/刘铁民/郑晓皎Cell子刊新发现：改善抑郁症的肠菌代谢物 0405 | 高分Cell子刊：中国农大团队详解后生元 0404 | 顶刊双发：肠菌相关神经发育和肠道免疫研究均有新发现 0403 | 今日Cell肠道研究双发：代谢胆固醇的肠菌+肠炎细胞图谱 0402 | 保肠护关节：高分研究揭示抵御关节炎的肠道因子 0401 | 3月，最值得关注的35篇肠道健康要闻！ 0331 | 聚焦特殊人群：老年人和孕妈妈的饮食新知 0330 | Akk菌或是免疫性肾病帮凶？Science子刊揭示机制 0329 | 33页综述纵论：超加工食品健康转型的新策略 0328 | Science子刊：锁定肠道中让病毒逃脱免疫的"避风港"

微生物疗法生物类似药

2022-12-30

·生物谷

Science子刊：新研究表明他拉罗唑有望能够预防骨关节炎

在一项新的研究中，来自英国牛津大学的研究人员发现作为一种已知能增加视黄酸水平的药物，他拉罗唑（Talarozole）能够在疾病模型中预防骨关节炎。在一项新的研究中，来自英国牛津大学的研究人员发现作为一种已知能增加视黄酸（retinoic acid）水平的药物，他拉罗唑（Talarozole）能够在疾病模型中预防骨关节炎（osteoarthritis）。相关研究结果发表在2022年12月21日的Science Translational Medicine期刊上，论文标题为“Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis”。论文通讯作者、牛津大学纳菲尔德骨科、风湿病学与肌肉骨骼科学系肌肉骨骼生物学教授Tonia Vincent说，“手骨关节炎（hand osteoarthritis）是一种常见的、令人衰弱的疾病，主要影响女性，尤其是在更年期前后。我们目前还没有有效的治疗方法来改变她们的疾病。” 这些作者首先研究了一个与严重的手骨关节炎有关的常见ALDH1A2基因变体。利用在常规手部手术时收集的患者样本，以及一些实验模型，他们能够确定一种在“高危”个体中浓度特别低的关键分子，即视黄酸。超过40%的人在其一生中会患上骨关节炎。手骨关节炎是一种极其常见的骨关节炎形式，目前还没有有效缓解症状或阻止关节变形和僵硬的疾病缓解疗法。 Vincent教授补充说，“这个项目之所以能够实现，是因为我们采取了多学科的方法；与我们的手外科同事、遗传学家、数据科学家和生物学家合作。” 由于他拉罗唑在人类受试者中具有可接受的安全性，一项小型的概念验证临床研究正在进行中，以了解这种药物是否可能代表一种新的疾病缓解疗法。图示软骨损伤后全反式视黄酸(atRA)的抗炎作用。图片来自Science Translational Medicine, 2022, doi:10.1126/scitranslmed.abm4054。慈善机构Versus Arthritis研究与健康情报主任Neha Issar-Brown博士说，“在英国，大约有850万人患有骨关节炎。尽管经常被认为只是一些疼痛，但骨关节炎会对生活产生深远的影响，影响人们上班工作、照顾家庭或独立生活的能力。现在迫切需要疾病缓解疗法，以防止或逆转骨关节炎的痛苦症状。这项新的研究揭示了对手骨关节炎原因的新认识，这可能会导致确定新的生物靶标来干预手骨关节炎。” Issar-Brown博士总结说，“这项新的研究仍处于早期阶段，但有了这些令人鼓舞的发现，我们离能够开发出一类新的疾病缓解药物来治疗骨关节炎、预防慢性疼痛并使人们能够带着这种疾病好好生活又近了一大步。”（生物谷 Bioon.com）参考资料： Linyi Zhu et al. Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis. Science Translational Medicine, 2022, doi:10.1126/scitranslmed.abm4054.

临床结果

2022-12-21

·Science Daily

New drug offers hope for people with hand osteoarthritis

A new study has identified that Talarozole, a drug that is known to increase retinoic acid, was able to prevent osteoarthritis (OA) in disease models. A new study, published in Science Translational Medicine by researchers at the University of Oxford has identified that Talarozole, a drug that is known to increase retinoic acid, was able to prevent osteoarthritis (OA) in disease models. Tonia Vincent, Professor of Musculoskeletal Biology & Honorary Rheumatologist at Oxford's Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), said: 'Hand osteoarthritis is a common and debilitating medical condition that affects mainly women, especially around the time of the menopause. We currently have no effective treatments that modify their disease.' The researchers started by investigating a common gene variant that had been linked to severe hand OA. Using patient samples collected at the time of routine hand surgery, as well as a number of experimental models, they were able to identify a key molecule that was especially low in 'at risk' individuals, called retinoic acid. More than 40% of individuals will develop osteoarthritis (OA) during their lifetime. Hand (OA) is an extremely common form of OA and there are currently no disease modifying treatments that effectively relieve symptoms or stop deformity and stiffness of the joints. Professor Vincent added: 'This project was only possible because of the multi-disciplinary approach that we took; working with our hand surgical colleagues, geneticists, data scientists and biologists.' As talarozole has an acceptable safety pro human subjects, a small proof of concept clinical study is underway to see whether this drug might represent a new disease modifying treatment in patients. Dr Neha Issar-Brown, Director of Research and Health Intelligence at the charity Versus Arthritis, which funded the research, said: 'Around 8.5 million people in the UK live with OA. Despite often being dismissed as just a few aches and pains, OA can have a profound and far-reaching impact on life, affecting people's ability to work, care for a family, or live independently. 'There is an urgent need for disease-modifying treatments designed to prevent or reverse the painful symptoms of OA. This study reveals a new understanding of the causes of hand osteoarthritis, which could lead to identifying new biological targets for intervention in hand OA. 'This research is still at an early stage, but with these encouraging findings we are a big step closer in being able to develop a new class of disease-modifying drugs to treat osteoarthritis, prevent chronic pain, and enable people to live well with the condition,' Dr Issar-Brown concludes.

100 项与他拉罗唑相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D09385	他拉罗唑	-	DB13083

研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
寻常痤疮	临床2期	比利时	Stiefel Laboratories, Inc.	2004-09-01
寻常痤疮	临床2期	荷兰	Stiefel Laboratories, Inc.	2004-09-01
斑块状银屑病	临床2期	荷兰	Stiefel Laboratories, Inc.	2004-04-01
银屑病	临床2期	欧洲	Stiefel Laboratories, Inc.	-
皮炎	临床1期	比利时	Stiefel Laboratories, Inc.	2006-11-01
炎症性皮肤病	临床1期	比利时	Stiefel Laboratories, Inc.	2006-11-01
骨关节炎	临床前	英国	University of Oxford	2022-12-21

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临床结果

适应症

分期

评价

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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


NCT00716144 (CTgov)	临床2期	斑块状银屑病	176	placebo+R115866 (Placebo)	繭鹹鹽積窪糧糧願壓廠(願襯繭築廠憲壓鑰獵艱) = 願顧艱築糧齋鏇壓願構糧築積觸觸製鬱廠齋餘 (鹹築夢鹹鏇糧製廠獵蓋, 遞鑰選獵襯醖廠糧夢築 ~ 獵憲壓艱願顧鬱糧積夢) 更多	-	2018-01-29
				R115866 (R115866 0.5 mg)	繭鹹鹽積窪糧糧願壓廠(願襯繭築廠憲壓鑰獵艱) = 蓋獵餘醖鏇遞顧淵艱築糧築積觸觸製鬱廠齋餘 (鹹築夢鹹鏇糧製廠獵蓋, 憲夢簾構蓋範鹹襯願鬱 ~ 積夢顧鹽繭構憲壓製觸) 更多