This is a multicenter, interventional, non-randomized study among patients with a relapsed or refractory Wilms tumor. The study will aim to assess efficacy of metronomic chemotherapy, in terms of disease control after two cycles of metronomic chemotherapy.

开始日期2022-09-14

申办/合作机构

Centre Oscar Lambret

KCT0006687

/ Completed临床4期IIT

A multicenter, open-label, single-arm, investigator-initiated clinical trial to evaluate the efficacy and safety of alitretinoin in patients with chronic hand eczema in real patient encounter

开始日期2022-01-28

申办/合作机构-

NCT05077813

/ Unknown status临床2期IIT

Utilizing the Crosstalk Among Chicoric Acid, 13-Cis Retinoic Acid(Aerosolized), Minocycline and Vitamin D as a Potent Quadrate Therapy for Treating Patients With Multidrug-resistant TB and Patient With Both Multidrug-resistant TB and COVID-19

Utilizing the Crosstalk Among Chicoric Acid, 13-Cis Retinoic Acid(Aerosolized), Minocycline and Vitamin D as a Potent Quadrate Therapy for treating patients with Multidrug-resistant TB and patient with both Multidrug-resistant TB and COVID-19 . A double-edged sword Clinical Study
I)Part of Tuberculosis
Tuberculosis (TB) is a major infectious disease killer globally. It affected 10 million and killed 1.4 million people in 2019 alone. The predicted impact of the COVID-19 pandemic is an additional 190,000 TB deaths in 2020, and it is expected in the next 5 y that there will be up to a 20% increase in the global TB disease burden , stressing the critical need for new safe and effective drugs against Mycobacterium tuberculosis (Mtb). In addition, controlling multidrug-resistant TB (MDR-TB) presents a huge public health challenge . New drug discovery could require several years with no guarantee but repurposing established may be useful to treat patients with tuberculosis . Here we demonstrate that we could utilize the crosstalk among Chicoric Acid, 13-Cis Retinoic Acid, Minocycline , and vitamin D as a novel quadrate therapy against TB.Drug-resistant tuberculosis represents a global emergency, requiring new drugs. Recently Minocycline was found to be highly potent in laboratory strains of Mycobacterium TB, and 30 drug-sensitive and multidrug/extensively drug-resistant clinical strains were susceptible to clinically attainable dosages. The lung concentration-time profiles of a 7 mg/kg/day human-equivalent minocycline dosage yielded bacterial kill rates comparable to first-line antituberculosis drugs. Extracellular bacilli were destroyed directly by minocycline. Minocycline also killed intracellular bacilli indirectly through granzyme A-driven apoptosis. Furthermore, minocycline showed dose-dependent antiinflammatory effect, suggesting that it may protect tuberculosis patients against immunopathology. A study showed that M. tuberculosis induced the expression of indoleamine 2,3-dioxygenase (IDO), an enzyme involved in tryptophan catabolism, in macrophages and in the lungs of animals (mice and macaque) with active disease. In a macaque model of inhalation TB, suppression of IDO activity reduced bacterial burden, pathology, and clinical signs of TB disease, leading to increased host survival. This increased protection was accompanied by increased lung T cell proliferation, induction of inducible bronchus-associated lymphoid tissue and correlates of bacterial killing . A recent study showed that Minocycline-induced significantly inhibition of IDO expression. But Minocycline-induced inhibition of IDO expression is retinoid-dependent. The combined treatment with minocycline and retinol, however, resulted in a striking, statistically significant decrease in IDO. Co-treatment with minocycline and retinol again resulted in decreased TNF-α and IL-6 levels. A study showed that IL-6 inhibits IFN-γ induced autophagy in Mycobacterium (TB) H37Rv infected macrophages. As well as neutralization of endogenous IL-6 by anti-IL-6 antibody significantly enhances the IFN-γ mediated killing of the intracellular bacteria. Minocycline's anti-inflammatory effects are mediated through RAR signaling. Therefore, The combined treatment with minocycline and retinol is expected to effectively inhibit (TB) and its inflammatory complication, Fortunately, Retinoic Acid significantly inhibits the in vivo growth of M. tuberculosis and the development of tuberculosis. In addition to, 13-Cis RA and Chicoric Acid ( CA ) enhanced the cell surface expression of HLA-DR and CD14 molecules on U937 macrophages and prevented the growth of Mtb within macrophages. Moreover, 13-cis RA and CA, have increased NO generation compared to untreated control macrophages, significantly . Both drugs have a significant inhibitory effect on Mtb growth but CA at the highest concentration was more potent than 13-cis RA . Therefore we will use retinoic acid to induce the effect of Minocycline as well as its ability to inhibit tuberculosis in combination with CA .Recent data showed that Vitamin D support innate immune responses to Mycobacterium TB and Low vitamin D levels were associated with a 5-fold increased risk for progression to tuberculosis. Deficiency of vitamin D has long been implicated in activation of (TB) . Serum vitamin D in TB patients are lower than in healthy controls . Vitamin D has been found to speed up the clearance of (TB) bacteria from the lungs of people with multi-drug resistant TB, according to a study of 1,850 patients. It was showed that Vitamin D receptor (VDR) must form a heterodimer complex with retinoid X receptor (RXR) to regulate gene transcription. Retinol plays a crucial role in lung development and signaling the vitamin D pathway. 9-cis-retinoic acid, an active vitamin A metabolite and the ligand of RXR, assists VDR signaling and suppresses the degradation of circulating vitamin D.

开始日期2021-12-01

申办/合作机构

Kafrelsheikh University

100 项与阿利维A酸相关的临床结果

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100 项与阿利维A酸相关的转化医学

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100 项与阿利维A酸相关的专利（医药）

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2,687

项与阿利维A酸相关的文献（医药）

2025-03-01·FOOD CHEMISTRY

Unraveling key non-volatiles responsible for taste differences of Pixian broad bean paste based on sensory analysis and untargeted metabolomics

Article

作者: Yang, Aiping ; Wei, Yilan ; Xiang, Qin ; Liu, Ping ; Zhou, Wenjing ; Xu, Min

Besides aroma, the tastes of Pixian Broad Bean Paste (PBBP) are also important, however, they have not yet been thoroughly elucidated. Therefore, this study employed sensory and untargeted metabolomics approaches to investigate taste characteristics, molecular basis and their metabolic pathways of PBBP from three different manufacturers and two grades. Results showed PBBP was predominantly characterized by strong sour, umami and salty tastes, and significant differences were observed in samples from different manufacturers and grades (p < 0.05), especially higher sourness, saltiness and umami in premium PBBP. Based on non-volatiles, 55 key differential metabolites were identified through orthogonal partial least square discriminant analysis (OPLS-DA, P value<0.05, VIP value>1.0) and Pearson correlation analysis (|ρ| > 0.7). These key differential metabolites responsible for taste differences were metabolized by 36 crucial KEGG pathways (P value<0.05, impact value>0.05). These results could expand our understandings of PBBP taste compounds and their metabolisms, and provide theoretical evidences for further quality improvement.

2025-02-19·ACS bio & med chem Au

Simulations Reveal Unique Roles for the FXR Hinge in the FXR–RXR Nuclear Receptor Heterodimer

Article

作者: Dube, Namita ; Biswas, Arumay ; Okafor, C. Denise ; Yu, Tracy

Nuclear receptors are multidomain transcription factors whose full-length quaternary architecture is poorly described and understood. Most nuclear receptors bind DNA as heterodimers or homodimers, which could encompass a variety of arrangements of the individual domains. Only a handful of experimental structures currently exist describing these architectures. Given that domain interactions and protein-DNA interactions within transcriptional complexes are tightly linked to function, understanding the arrangement of nuclear receptor domains on DNA is of utmost importance. Here, we employ modeling and molecular dynamics (MD) simulations to describe the structure of the full-length farnesoid X receptor (FXR) and retinoid X receptor alpha (RXR) heterodimer bound to DNA. Combining over 100 μs of atomistic MD simulations with enhanced sampling simulations, we characterize the dynamic behavior of eight FXR-RXR-DNA complexes, showing that these complexes support a range of quaternary architectures. Our simulations reveal critical roles for the hinge in the DNA-bound dimer in facilitating interdomain allostery, mediating DNA binding and driving the dynamic flexibility of the complex. These roles have been hard to appreciate previously due to experimental limitations in studying the flexible hinge. These studies provide a much-needed framework that will enable the field to obtain a complete understanding of nuclear receptor quaternary architectures.

2025-02-01·iScience

Microbiota-derived β carotene is required for strobilation of Aurelia aurita by impacting host retinoic acid signaling

Article

作者: Chibani, Cynthia Maria ; Jensen, Nadin ; Schmitz, Ruth Anne ; Weiland-Bräuer, Nancy

The strobilation process, an asexual reproduction mechanism in Aurelia aurita, transitions from the sessile polyp to the pelagic medusa stage. This study explored the essential role of the microbiome in strobilation, particularly through bacterial beta carotene's impact on the host's retinoic acid signaling pathway. Experiments demonstrated that native polyps undergo normal strobilation while sterile polyps exhibit morphological defects. Supplementing sterile polyps with provitamin A beta carotene or the vitamin A metabolite 9-cis retinoic acid (RA) remedied these defects, underscoring their crucial role in strobilation. Transcriptional analysis revealed that beta carotene and 9-cis RA restored expression of strobilation genes in sterile polyps to native levels. Inhibition of key enzymes in the RA pathway disrupted strobilation, further confirming its importance. The expression of bacterial β-carotenoid synthesis genes in the native microbiome, contrasted with tremendously reduced expression in antibiotic-treated polyps, emphasizes the microbiome's pivotal role in beta carotene provision, facilitating A. aurita's strobilation through RA signaling.

项与阿利维A酸相关的新闻（医药）

2025-02-04

·Business Wire

LEO Pharma Achieves Positive DELTA TEEN Trial Results with Anzupgo® (delgocitinib) Cream in Adolescents with Moderate to Severe Chronic Hand Eczema (CHE)

BALLERUP, Denmark--( BUSINESS WIRE )-- NOT FOR UK USE – NOT INTENDED FOR UK MEDIA LEO Pharma A/S, a global leader in medical dermatology, today announced the positive results of the DELTA TEEN trial. DELTA TEEN is a pivotal phase 3 clinical trial with Anzupgo ® (delgocitinib) 20mg/g cream, a topical pan-Janus kinase (JAK) inhibitor, for the potential treatment of adolescents (aged 12-17) with moderate to severe Chronic Hand Eczema (CHE) for whom topical corticosteroids are inadequate or inappropriate. 1 This is the fifth phase 3 Anzupgo trial to achieve primary and all key secondary endpoints, validating the results of the previous clinical trials from the DELTA program. 1,3-10 DELTA TEEN expands LEO Pharma’s growing portfolio of scientific evidence for the treatment of moderate to severe CHE, offering insight into a new patient population. Currently, no treatment options are approved specifically for moderate to severe CHE in the adolescent population. " Research on adolescents with CHE has revealed that the condition can considerably affect their quality of life, including psychosocial well-being, school performance and leisure activities," said Professor Sonja Molin, Academic Dermatologist at Charite Universitätsmedizin Berlin and Adjunct Associate Professor of Dermatology at Queen’s University and coordinating investigator. " These findings further our understanding of how moderate to severe CHE manifests in adolescents and how to support this underserved patient group." The trial met the primary endpoint with a statistically significant improvement in CHE symptoms after 16 weeks of treatment with Anzupgo compared to cream vehicle. 1 Furthermore, the safety profile of Anzupgo was consistent with previous pivotal trials. 1 “ The positive results from DELTA TEEN are encouraging and in line with LEO Pharma’s purpose of serving more and more people living with this debilitating condition,” said Christophe Bourdon, Chief Executive Officer, LEO Pharma . “ Anzupgo is already available to adults in some markets, including Germany, and it is a critical next step to address the unmet need in this younger patient population.” Currently, Anzupgo is approved for adults in the European Union, United Kingdom, Switzerland and the United Arab Emirates for the treatment of moderate to severe CHE for whom topical corticosteroids are inadequate or inappropriate, and is under investigation in other markets, including the United States. Detailed results from DELTA TEEN are planned to be submitted for scientific presentation and publication at a later date. For more information on the DELTA TEEN trial (NCT05355818) go to clinicaltrials.gov . Notes to editors About Anzupgo ® (delgocitinib) cream Anzupgo is currently approved in the European Union, United Kingdom, Switzerland and the United Arab Emirates for the treatment of moderate to severe chronic hand eczema (CHE) in adults for whom topical corticosteroids are inadequate or inappropriate. Anzupgo is under investigation in other markets, including the United States. Anzupgo ® (delgocitinib) cream is a topical pan-Janus kinase (JAK) inhibitor for the treatment of moderate to severe CHE. It inhibits the activation of JAK-STAT signaling, which plays a key role in the pathogenesis of CHE. 11 The pathophysiology is characterized by skin barrier dysfunction, inflammation of the skin, and alterations of the skin microbiome. 12 In 2014, LEO Pharma A/S and Japan Tobacco Inc. (JT) entered into a license agreement in which LEO Pharma gained exclusive rights to develop and commercialize delgocitinib cream for topical use in dermatological indications worldwide, excluding Japan, where JT retains rights. About the DELTA TEEN Trial DELTA TEEN was a 16-week, phase 3, randomized, double-blind, vehicle-controlled, parallel group, multi-site trial to evaluate the efficacy and safety of twice-daily applications of Anzupgo compared with cream vehicle in adolescents 12-17 years of age with moderate to severe CHE. 1 The primary endpoint of DELTA TEEN was the Investigator’s Global Assessment for chronic hand eczema treatment success (IGA-CHE TS) at Week 16. Treatment success was defined as an IGA-CHE score of 0 (clear) or 1 (almost clear) with at least a two-step improvement from baseline. 1 About Chronic Hand Eczema Chronic Hand Eczema (CHE) is defined as hand eczema (HE) that lasts for more than three months or relapses twice or more within a year. 13,14 HE is the most common skin disorder of the hands 15 with a prevalence rate of approximately 4.7%. 16 In a substantial number of patients, HE can develop into a chronic condition. 15 CHE is a fluctuating disorder characterized by itch and pain, and patients may experience signs such as erythema, scaling, lichenification, hyperkeratosis, vesicles, edema, and fissures on hands and wrists. 17 CHE has been shown to cause psychological and functional burdens that impact patient quality of life, 18 with approximately 70% of individuals who live with severe CHE admitting to problems in performing everyday activities, and suffering disruption in their daily life due to the condition. 19 Furthermore, careers and earning potential have also been shown to be impacted by the burden of living with CHE. 20 About LEO Pharma LEO Pharma is a global company dedicated to advancing the standard of care through innovation for the benefit of people with skin conditions. LEO Pharma is co-owned by majority shareholder the LEO Foundation and, since 2021, Nordic Capital. LEO Pharma offers a broad portfolio of treatments, serving 100 million patients annually. Headquartered in Denmark, LEO Pharma has a global team of 4,000 people. In 2023, the company generated net sales of EUR 1.5 billion. References ClinicalTrials.gov. National Library of Medicine (U.S.). Efficacy and Safety of Delgocitinib Cream in Adolescents 12-17 Years of Age With Moderate to Severe Chronic Hand Eczema (DELTA TEEN). Identifier: NCT05355818. https://clinicaltrials.gov/study/NCT05355818 . Haft MA, Park HH, Lee SS, Sprague JM, Eichenfield LF. Pediatric chronic hand eczema: Epidemiology, clinical presentation, and management. JAAD Int. 2023;11:165-173. ClinicalTrials.gov. National Library of Medicine (U.S.). Efficacy and Safety of Delgocitinib Cream in Adults With Moderate to Severe Chronic Hand Eczema (DELTA 1). Identifier: NCT04871711. https://clinicaltrials.gov/ct2/show/NCT04871711 . ClinicalTrials.gov. National Library of Medicine (U.S.). Efficacy and Safety of Delgocitinib Cream in Adults With Moderate to Severe Chronic Hand Eczema (DELTA 2). Identifier: NCT04872101. https://clinicaltrials.gov/ct2/show/NCT04872101 . ClinicalTrials.gov. National Library of Medicine (U.S.). Open-label Multi-site Extension Trial in Subjects Who Completed the DELTA 1 or DELTA 2 Trials (DELTA 3). Identifier: NCT04949841 https://clinicaltrials.gov/ct2/show/NCT04949841 . Bissonnette R, Warren RB, Pinter A, et al. Efficacy and safety of delgocitinib cream in adults with moderate to severe chronic hand eczema (DELTA 1 and DELTA 2): results from multicentre, randomised, controlled, double-blind, phase 3 trials. Lancet. 2024;404(10451):461-473. doi:10.1016/S0140-6736(24)01027-4. Schliemann S, et al. Efficacy and safety of delgocitinib cream in adults with moderate to severe chronic hand eczema: results of the Phase 3 DELTA 2 trial. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2023. Berlin, Germany. 11– 14 October. Poster Presentation #P0395. Bissonnette R, et al. Efficacy and safety of delgocitinib cream in adults with moderate to severe chronic hand eczema: results of the Phase 3 DELTA 1 trial. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2023. Berlin, Germany. 11– 14 October. Poster Presentation #P0369. ClinicalTrials.gov. National Library of Medicine (U.S.). A 24 Week Trial to Compare the Efficacy and Safety of Delgocitinib Cream 20 mg/g Twice-daily With Alitretinoin Capsules Once-daily in Adult Participants With Severe Chronic Hand Eczema. Identifier: NCT05259722. https://clinicaltrials.gov/study/NCT05259722 . Giménez-Arnau AM, Pinter A, Sondermann W et al. DELTA FORCE trial: 24-week Phase 3 trial comparing the efficacy and safety of topical delgocitinib cream with oral alitretinoin capsules in adults with severe CHE. Presented at the European Academy of Dermatology and Venereology (EADV) Congress 2024. Amsterdam, Netherlands. 25-28 September. Late Breaking News Session. D1T01 Dubin C, Del Duca E, Guttman-Yassky E. Drugs for the Treatment of Chronic Hand Eczema: Successes and Key Challenges. Ther Clin Risk Manag. 2020;16:1319-1332. Erratum in: Ther Clin Risk Manag. 2021 Mar 18;17:233. Lee GR, Maarouf M, Hendricks AK, Lee DE, Shi VY. Current and emerging therapies for hand eczema. Dermatol Ther. 2019;32(3):e12840. Diepgen TL, Andersen KE, Chosidow O, et al. Guidelines for diagnosis, prevention and treatment of hand eczema. J Dtsch Dermatol Ges. 2015;13(1):e1-e22. Lynde C, Guenther L, Diepgen TL, et al. Canadian hand dermatitis management guidelines. J Cutan Med Surg. 2010;14(6):267-284. Erratum in: J Cutan Med Surg. 2011 Nov-Dec;15(6):360. Bissonnette R, Diepgen TL, Elsner P, et al. Redefining treatment options in chronic hand eczema (CHE). J Eur Acad Dermatol Venereol. 2010;24 Suppl 3:1-20. Apfelbacher C, Bewley A, Molin S, et al. Prevalence of Chronic Hand Eczema in adults: A cross-sectional multi-national study of 60,000 respondents in the general population. Presented at the 2024 European Society of Contact Dermatitis (ESCD) congress; September 04-07 2024; Dresden, Germany. Poster presentation #3. Thyssen JP, Schuttelaar MLA, Alfonso JH, et al. Guidelines for diagnosis, prevention, and treatment of hand eczema. Contact Dermatitis. 2022;86(5):357-378. Grant L, Seiding Larsen L, Burrows K, et al. Development of a Conceptual Model of Chronic Hand Eczema (CHE) Based on Qualitative Interviews with Patients and Expert Dermatologists. Adv Ther. 2020;37(2):692-706. Cortesi PA, Scalone L, Belisari A, et al. Cost and quality of life in patients with severe chronic hand eczema refractory to standard therapy with topical potent corticosteroids. Contact Dermatitis. 2014;70(3):158-168. Voorberg AN, Loman L, Schuttelaar MLA. Prevalence and Severity of Hand Eczema in the Dutch General Population: A Cross-sectional, Questionnaire Study within the Lifelines Cohort Study. Acta Derm Venereol. 2022;102:adv00626. MAT-79328 February 2025

临床3期引进/卖出临床结果上市批准

2024-12-31

·医学新视点

瘙痒、糜烂、水疱……《柳叶刀》：4大类措施，早日摆脱手部湿疹

▎药明康德内容团队编辑手部红斑、丘疹、水疱、糜烂、渗出等，伴或不伴有瘙痒等症状的手部湿疹皮炎样改变，临床称为手部湿疹或手部皮炎，终生患病率约为15%。多达2/3的手部湿疹会演变为慢性病，即持续3个月以上或在12个月内复发2次及以上。近期，《柳叶刀》（The Lancet）发表一项关于手部湿疹的综述，阐述了手部湿疹的主要影响因素、临床症状和诊断以及当前相关治疗措施的进展，以期为临床管理慢性手部湿疹提供参考。截图来源：The Lancet 特应性皮炎和皮肤干燥是导致手部湿疹的主要影响因素手部湿疹常见于成人，平均发病年龄在20岁左右。特应性皮炎和皮肤干燥是导致手部湿疹的主要影响因素。特应性皮炎、暴露于刺激物（如摩擦）和接触过敏原（如某些香料、橡胶添加剂等）是导致手部湿疹的主要外在因素，而有些职业可能需要长期接触某些刺激物（如理发师、美容师等），也会增加手部湿疹的发生风险。 ▲手部湿疹通常由内源性因素和刺激性或接触过敏原等因素共同导致（图片来源：参考文献[1]）手部湿疹的症状和临床诊断手部湿疹通常表现为手掌发红、水肿和浸润、水疱、糜烂、鳞屑、角化过度和裂纹。手部湿疹急性期以渗出、水疱和结痂为主，而慢性期以浸润和鳞屑为主，主要症状为皮肤瘙痒和疼痛。值得注意的是，高达30%的慢性手部湿疹患者同时存在足部湿疹。如下图所示，图A为角化过度-裂隙型手部湿疹，表现为红斑斑块伴鳞屑，可覆盖整个手掌，有裂隙或皲裂；图B为复发水疱型手部湿疹，表现为手掌、手指掌侧和外侧出现瘙痒、复发性、对称性、深层、1~2 mm的充满液体的水疱，水疱迅速破裂，数周后消退。水疱周围通常很少或没有红斑。 ▲手部湿疹的不同表现（图片来源：参考文献[1]）手部湿疹的诊断需考虑到病史、临床特征，同时排除其他诊断。询问患者病史时应详细了解发病时间、病程（发作-复发性或持续性）、有无潜在刺激物及特应性皮炎病史等。慢性手部湿疹，特别是疑似有接触性过敏时，可采用斑贴试验。若斑贴试验结果为阳性，表明患者接触了致敏性物质，需结合患者病史、暴露情况和临床病程来评估。皮肤点刺、抓挠试验或测量过敏原特异性IgE浓度对诊断手部湿疹通常价值不大，但在某些特殊情况可能是有用的，如疑似患者患有罕见接触性荨麻疹综合征，对植物或动物来源的乳胶或蛋白质过敏，在持续或重复暴露的情况，可能会引起手部湿疹。几种皮肤病症状表现类似手部湿疹，临床需注意加以鉴别，如银屑病、手掌角化病、掌跎脓疱病、皮肤癣菌感染等。目前已有各种工具可用于测量手部湿疹严重程度，但由于多数评估工具并未得到有效验证，因此临床实际使用的频率并不高，相对常用的临床评估工具有：手部湿疹严重程度指数（HECSI）、皮肤病生活质量指数。手部湿疹的治疗和管理慢性手部湿疹的管理核心在于做好患者教育，识别和避免接触外源性触发饮食，改善症状，实现长期疾病控制。临床可选择的治疗方式较多，如使用润肤剂持续修复表皮屏障、外用糖皮质激素、钙调磷酸酶抑制剂等治疗，以及额外的光疗或全身治疗等。外用治疗尽管相关支持性证据较少，但适当使用润肤剂（保湿剂）是慢性手部湿疹管理的重要组成部分。润肤剂有助于保持和补充皮肤表皮水分，减少瘙痒，延长疾病发作间隔。对于急性和渗出性手部湿疹，可首选具有抗菌作用的亲水性乳膏或凝胶，而慢性手部湿疹可能更适合选择油包水型软膏剂。外用糖皮质激素是慢性手部湿疹的主要替代疗法，短期使用证据等级较低，而中长期使用证据等级为中等。短期内急性干预治疗，可使用传统外用糖皮质激素，如丙酸氯倍他索或曲安奈德。如果需长期使用，为了减少可能出现的不良反应，如表皮屏障修复受损，可考虑使用治疗指数更高的外用糖皮质激素，如糠酸莫米松乳膏。钙调磷酸酶抑制剂是非甾体抗炎药，有软膏（0.03%和0.1%的他克莫司软膏适用于成人，0.03%适用于年龄≥2岁的儿童）和乳膏（1%的吡美莫司乳膏适用于年龄≥2岁的患者）两种类型，被批准用于治疗特应性皮炎，但不用于治疗其他原因引起的手部湿疹。尽管目前只有少部分短期试验证据支持使用0.1%的他克莫司软膏，但其仍被推荐用于外用糖皮质激素难治性或需要长期治疗的手部湿疹患者的二线短期治疗，因为从现有证据来看用药具备安全性，不会干扰表皮屏障修复。尚无令人信服的证据表明，吡美莫司乳膏适用于治疗手部湿疹。病情缓解后，通常以每周2~3次的频率，使用外用糖皮质激素或钙调磷酸酶抑制剂作为二级预防策略应该是可行的。 Delgocitinib属于外用泛JAK抑制剂，已被日本监管局批准用于治疗特应性皮炎。鉴于其在两项随机双盲对照试验中展现出的良好疗效和安全性，最近被欧盟委员会（EC）推荐用于治疗无法使用外用糖皮质激素或外用糖皮质治疗效果不佳的成人严重慢性手部湿疹。Delgocitinib的批准主要是基于包括DELTA 1和DELTA 2临床3期试验的结果，这些试验评估了delgocitinib相较于安慰剂的安全性和疗效。两项试验均达到了其主要和所有次要终点，详细试验结果发布于今年7月的《柳叶刀》。两项试验的主要终点是第16周时研究者整体评估的慢性手部湿疹治疗成功（IGA-CHE TS）。治疗成功定义为IGA-CHE评分为0（皮损清除）或1（皮损几乎清除），且较基线至少提高两级。试验数据显示，在第16周时，delgocitinib治疗组比对照组有更高比例的患者达到IGA-CHE治疗成功的标准。DELTA 1中delgocitinib治疗组患者达到治疗成功标准的患者比例为20%，对照组为10%。在DELTA 2中delgocitinib治疗组达标的患者比例为29%，对照组为7%（两项试验均P≤0.0055）。报告不良事件的患者比例在delgocitinib治疗组和对照组中相似，发生率至少为2%的最常见不良事件（如鼻咽炎）在两组中相似。光疗如果外用措施无法控制病情，则可考虑短期光疗（通常为4~8周），但需要考虑到光疗相对周期较长，且长期应用可能存在不良反应，如皮肤癌风险（非黑色素瘤）。系统治疗若外用治疗和支持性措施均无法充分控制疾病时，可能需要系统治疗。阿利维A酸是首个在欧洲获准用于治疗手部湿疹的口服药物，鉴于其高质量的临床试验证据和真实世界证据，最近的欧洲指南将其作为一线系统性治疗选择。常规治疗周期长达24周，若用药后症状有所改善但未完全“治愈”，可考虑延长用药时长。对于用药效果良好，但停药后复发的患者，重新开启治疗可能是有效的。需要注意的是，阿利维A酸具有致畸性，在治疗前、治疗期间和治疗后1个月内均需做好避孕措施。用药后可能出现的不良反应是短暂性头痛、胆固醇、甘油三酯、转氨酶升高和甲状腺功能水平降低，因此需要定期抽血检查相关指标。目前尚未有系统性糖皮质激素用于治疗慢性手部湿疹治疗的临床试验证据，根据相关指南建议，仅在严重手部湿疹急性干预时可考虑短期使用，通常为0.5~1.0 mg/kg/d泼尼松龙，而后2~3周逐步减量。此外，部分系统性治疗被批准用于治疗中重度特应性皮炎，如短期和长期使用的全身性JAK抑制剂abrocitinib、baricitinib和upadacitinib，以及长期应用的生物制剂，如dupilumab、tralokinumab和lebrikizumab，可能是特应性皮炎伴手部湿疹或重度特应性手部湿疹患者的全身性治疗替代选择。一些小规模的观察性研究和相关特应性皮炎研究的事后分析显示，应用dupilumab、upadacitinib和abrocitinib具有一定的有效性。目前正在开展相关临床试验中。辅助治疗健康教育有助于加强人们自我管理意识，这是慢性病护理的重要组成部分。一般初级预防指提高人们意识和做出行为改变，以及对于高风险人群（如特应性皮炎患者）采取相关保护皮肤措施。二级预防可包含：面对面教育和实践研讨会、提供个人防护措施（如防护手套、避免接触过敏原和刺激物、手部清洁、使用润肤剂等）。对于严重和顽固性手部湿疹，采取三级预防措施是必要的，如在门诊或住院时选择专科治疗中心。仍有待解决的问题由于不同手部湿疹患者的症状、病程和治疗反应存在较大差异，因此在疾病分类上尚缺乏普遍可接受的分类标准，也因此影响了后续的诊断、疾病活动评估和选择合理治疗方案。类似地，尽管有较多的慢性手部湿疹的评估工具，但不同评估工具之间也存在较大差异，未来需要整合现有证据，将不同类型手部湿疹划分到合理的亚型分类中，开发基于指南共识核心而衍生的合理评估工具，制定针对预防和治疗措施的标准化评价标准，这也有利于未来开展更多临床试验，解决慢性手部湿疹患者未竟需求。小结手部湿疹是一种非常普遍的皮肤病，多达2/3的患者可能发展为慢性病，严重影响个人正常生活。慢性手部湿疹的临床症状随着时间的推移，在严重程度和皮肤外观表现上会有所不同。影响其发病的因素也较多，主要是当前或既往患有特应性皮炎，或是长期暴露于过敏原。治疗策略包括患者教育、避免接触过敏原、采取一级至三级预防措施，合理使用外用糖皮质激素、钙调磷酸酶抑制剂或泛JAK抑制剂等，必要时可考虑光疗、阿利维A酸全身治疗等措施。未来仍需开展更多研究，以了解慢性手部湿疹的亚型和潜在发病机制，以及比较不同治疗的有效性和安全性。点击文末“阅读原文/Read more”，即可访问The Lancet官网阅读完整论文。推荐阅读欢迎投稿：学术成果、前沿进展、临床干货等主题均可，点此了解投稿详情。参考资料（可上下滑动查看） [1] Weidinger S, Novak N. Hand eczema. Lancet. 2024 Dec 14;404(10470):2476-2486. doi: 10.1016/S0140-6736(24)01810-5. Epub 2024 Nov 29. PMID: 39615508. [2] European Commission Approves LEO Pharma’s Anzupgo® (delgocitinib) Cream for Adults with Moderate to Severe Chronic Hand Eczema (CHE). Retrieved September 23, 2024 from https://www.businesswire.com/news/home/20240923751725/en [3] LEO Pharma Announces Positive Phase 3 Head-to-head Data Results from DELTA FORCE Trial Comparing Delgocitinib Cream With Alitretinoin Capsules in Adults With Severe Chronic Hand Eczema (CHE). Retrieved January 24, 2024 from https://www.businesswire.com/news/home/20240123989016/en 免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医学新视点」微信公众号留言联系。如有其他合作需求，请联系wuxi_media@wuxiapptec.com 分享，点赞，在看，传递医学新知

2024-12-19

·FiercePharma

Sanofi and Regeneron's Dupixent, Leo Pharma's Anzupgo could help close treatment gap in chronic hand eczema: GlobalData

GlobalData highlighted a handful of therapeutics currently under investigation as chronic hand eczema treatments including Leo Pharma's delgocitinib cream, Sanofi and Regeneron's blockbuster biologic Dupixent and new molecules from clinical-stage biotechs Asana BioSciences and Afecta Pharmaceuticals. Current treatments for chronic hand eczema (CHE) generally fall into two buckets: Either they battle inflammation but lead to unwanted side effects with long-term use or they soothe external symptoms without solving underlying inflammation.The lack of any approved treatments that are helpful in managing both the disease and its symptoms without tacking on any major side effects has created a significant gap in the CHE space that may be filled by up-and-coming treatments, according to a new report from GlobalData.“Overall, current treatment options for CHE, such as topical corticosteroids, emollients, immunosuppressants, and phototherapy, may improve the condition, but all have limitations,” Filippos Maniatis, a healthcare analyst for the firm, said in a statement. “Nevertheless, to address the unmet needs in CHE treatment, further research and clinical trials that focus on safety and the patient’s [quality of life] are essential.”To that end, GlobalData highlighted a handful of therapeutics currently under investigation as CHE treatments that might fit the bill. Sanofi and Regeneron are in the process of testing out blockbuster biologic Dupixent in the indication, for one, and clinical-stage biotechs Asana BioSciences and Afecta Pharmaceuticals are both studying new molecules in the CHE arena.Leo Pharma, meanwhile, announced this fall that it had submitted its delgocitinib cream for FDA approval as a treatment for adults with moderate to severe CHE for whom topical corticosteroids either have been inadequate or are not advisable. At the same time, the company shared that the treatment had been approved in the indication in Europe, where it’s now marketed under the name Anzupgo.If approved by the FDA, Anzupgo would become the first treatment specifically indicated for CHE in the U.S. GSK previously attempted to earn that title with alitretinoin, the exclusive global rights to which it had purchased from Basilea Pharmaceutica in 2012. Before that, the drug had raked in several international approvals as Toctino for severe CHE.By 2016, however, GSK had given up on attempting to bring Toctino to the U.S., abruptly announcing in January of that year that it was bailing on its stateside goals for the drug.Toctino, which remains available in more than two dozen countries outside the U.S., has been proven in studies to offer “good efficacy in eczema clearance,” per GlobalData, but “research investigating new therapeutic agents, including biologics and small molecules targeting specific inflammatory pathways, may provide better alternatives to the current standard of care for CHE.”As Maniatis pointed out in the report, Leo’s Anzupgo outperformed Toctino in a recent head-to-head study. The DELTA FORCE phase 3 trial pitted the Anzupgo cream against oral alitretinoin capsules; after 12 weeks, those who received Leo’s treatment demonstrated a “significantly greater least squares mean decrease” in their hand eczema severity index (HECSI) scores compared to those who took alitretinoin, achieving the study’s primary endpoint, according to a September release from the company. The Anzupgo group saw their HECSI scores drop an average 67.6 points on the 360-point scale, compared to 51.5 points among the Toctino group.Those on Anzupgo also reported “sizable” improvements in their health-related quality of life over the course of the study and experienced fewer treatment-related adverse events than the alitretinoin group, per Leo.

临床3期临床结果上市批准

100 项与阿利维A酸相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D02815	阿利维A酸	L01XX22 D11AH04	DB00523

研发状态

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适应症	国家/地区	公司	日期
艾滋病相关性卡波西肉瘤	美国	Advanz Pharma Corp. Ltd.	1999-02-02

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适应症	最高研发状态	国家/地区	公司	日期
急性早幼粒细胞白血病	临床3期	美国	Ligand Pharmaceuticals, Inc.	1999-06-30
支气管疾病	临床2期	美国	Ligand Pharmaceuticals, Inc.	2001-01-01
骨髓增生异常综合征	临床2期	美国	Ligand Pharmaceuticals, Inc.	1998-03-26
乳腺癌	临床2期	美国	Ligand Pharmaceuticals, Inc.	1997-05-23
前列腺癌	临床2期	美国	Ligand Pharmaceuticals, Inc.	1997-05-23
头颈部肿瘤	临床2期	美国	Ligand Pharmaceuticals, Inc.	1996-08-27
卵巢癌	临床2期	美国	Ligand Pharmaceuticals, Inc.	1996-08-27
鳞状细胞癌	临床2期	美国	Ligand Pharmaceuticals, Inc.	1996-08-27
肾肿瘤	临床2期	加拿大	Ligand Pharmaceuticals, Inc.	1995-05-23
非霍奇金淋巴瘤	临床2期	美国	Ligand Pharmaceuticals, Inc.	1995-05-23

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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


NCT00817063 (HANDEL, CTgov)	临床3期	慢性湿疹	599	Placebo	範觸選繭夢鬱鹽壓簾鏇 = 窪糧鹹鹹齋鹽鏇壓選鏇願鹽繭衊艱糧蓋憲觸廠 (淵鬱廠選淵網獵壓繭選, 夢製選淵壓廠遞衊鹹艱 ~ 選淵淵鏇醖窪壓獵糧襯) 更多	-	2017-11-09
NCT01245140 (CTgov)	临床2期	脓疱型银屑病	33	placebo (Matching Placebo)	願艱構淵網廠製鹹繭鑰(憲構積鏇獵膚製膚鬱顧) = 鑰範鏇獵襯艱願襯顧糧簾醖構願願網鏇範鑰鑰 (築構製簾願觸壓遞觸構, 45.9) 更多	-	2017-04-04
NCT01245140 (CTgov)	临床2期	脓疱型银屑病	33	Alitretinoin (Alitretinoin 30 mg)	願艱構淵網廠製鹹繭鑰(憲構積鏇獵膚製膚鬱顧) = 廠築淵選憲製構餘網廠簾醖構願願網鏇範鑰鑰 (築構製簾願觸壓遞觸構, 32.8) 更多	-	2017-04-04
NCT00817063 (Pubmed)	临床3期	湿疹	596	Alitretinoin 30 mg	鬱鏇築鹹積鑰鏇鹹積糧(廠築獵壓襯鹹憲餘糧憲) = 夢夢夢網選餘鏇簾構繭鹽構繭餘鬱構簾憲鬱襯 (鬱膚構淵鏇鏇遞鏇艱鬱 ) 更多	积极	2014-10-01
NCT00817063 (Pubmed)	临床3期	湿疹	596	Placebo	醖憲糧廠膚壓構觸衊顧(齋觸艱網蓋鹹簾齋鹽醖) = 鏇淵積鑰蓋構構顧壓醖鬱壓襯選顧顧襯繭觸觸 (窪襯鬱壓醖積鏇衊淵觸 )	积极	2014-10-01
NCT00609739 (CTgov)	临床1/2期	幼年型骨髓单核细胞白血病	1	umbilical cord blood transplantation+methylprednisolone+Cis-Retinoic acid+cyclosporine+Filgrastim+mitoxantrone hydrochloride+methotrexate+Cytarabine	願醖積鏇夢艱壓選衊襯 = 醖願鬱鬱艱夢襯顧餘遞膚積窪遞鹽鑰構衊壓觸 (憲遞簾鏇衊鹹觸簾願獵, 醖遞糧網餘餘壓壓夢製 ~ 醖製範簾艱範醖鬱鹹醖) 更多	-	2012-03-02