呋咯地辛(Forodesine Hydrochloride) - 药物靶点：PNP_在研适应症：外周T细胞淋巴瘤_专利_临床

概要

基本信息

药物类型

小分子化药

别名

(1S)-1,4-dideoxy-4-imino-(9-deazahypoxanthin-9-yl)-D-ribitol、1,4-Dideoxy-4-aza-1-(S)-(9-deazahypoxanthin-9-yl)-D-ribitol、FDS

+ [10]

靶点

PNP

作用机制

PNP抑制剂(嘌呤核苷磷酸化酶抑制剂)、免疫抑制剂

治疗领域

肿瘤免疫系统疾病血液及淋巴系统疾病+ [1]

在研适应症

外周T细胞淋巴瘤

非在研适应症

急性淋巴细胞白血病CD19阳性B细胞急性淋巴细胞白血病CD30-Positive recurrent or refractory Cutaneous T-Cell Lymphoma+ [10]

原研机构

BioCryst Pharmaceuticals, Inc.Mundipharma KK

在研机构

Mundipharma KK

非在研机构

Mundipharma Research Ltd.

BioCryst Pharmaceuticals, Inc.

Mundipharma International Ltd.

最高研发阶段批准上市

首次获批日期

日本 (2017-03-31),

外周T细胞淋巴瘤

最高研发阶段(中国)-

特殊审评孤儿药 (日本)

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结构/序列

分子式C11H15ClN4O4

InChIKeyWEIAMZKHBCLFOG-QPAIBFMUSA-N

CAS号284490-13-7

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关联

21

项与呋咯地辛相关的临床试验

NCT01776411

/ Completed临床1/2期

Phase I/II Clinical Study of Forodesine in Japanese Recurrent/Refractory Peripheral T-cell Lymphoma Patients

Phase I portion:
To confirm safety and tolerability in recurrent/refractory peripheral T-cell lymphoma patients during repeated oral administration of forodesine 300 mg twice daily (600 mg/day) for 28 days, and determine the recommended dose. Also, to evaluate pharmacokinetics.
Phase II portion:
To evaluate the efficacy, safety, and pharmacokinetics of the recommended dosage regimen determined in the phase I portion. The primary efficacy endpoint shall be objective response rate (ORR).

开始日期2013-01-01

申办/合作机构

Mundipharma KK

JPRN-JapicCTI-121985

/ Unknown status临床1/2期

Phase 1/2 clinical study of forodesine in Japanese recurrent/refractory peripheral T-cell lymphoma

开始日期2012-11-01

申办/合作机构

Mundipharma KK

JPRN-jRCT2080221940

/ Unknown status临床1/2期

Phase 1/2 clinical study of forodesine in Japanese recurrent/refractory peripheral T-cell lymphoma

开始日期2012-10-12

申办/合作机构

Mundipharma KK

100 项与呋咯地辛相关的临床结果

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100 项与呋咯地辛相关的转化医学

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100 项与呋咯地辛相关的专利（医药）

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221

项与呋咯地辛相关的文献（医药）

2024-12-01·Annals of Neurology

Guanylate Kinase 1 Deficiency: A Novel and Potentially Treatable Mitochondrial DNA Depletion/Deletions Disease

Article

作者: Saneto, Russell P. ; Tort, Frederic ; Dorschner, Michael O. ; Comi, Giacomo Pietro ; Shintaku, Jonathan ; Ronchi, Dario ; Hirano, Michio ; Marti, Ramon ; Sciacco, Monica ; Gort, Laura ; Hidalgo‐Gutierrez, Agustin ; Ramon, Javier ; Meneri, Megi ; Pesini, Alba ; Matas‐Garcia, Ana ; Gu, Yue ; Koganti, Lahari ; Barriocanal‐Casado, Eliana ; Milisenda, Jose Cesar ; Tadesse, Saba ; Garrabou, Gloria ; Horwitz, Marshall S. ; Ribes, Antonia ; Mansukhani, Mahesh ; Ugarteburu, Olatz ; Wang, Tian ; Tanji, Kurenai ; Wang, Shuang

ObjectiveMitochondrial DNA (mtDNA) depletion/deletions syndrome (MDDS) comprises a group of diseases caused by primary autosomal defects of mtDNA maintenance. Our objective was to study the etiology of MDDS in 4 patients who lack pathogenic variants in known genetic causes.MethodsWhole exome sequencing of the probands was performed to identify pathogenic variants. We validated the mitochondrial defect by analyzing mtDNA, mitochondrial dNTP pools, respiratory chain activities, and GUK1 activity. To confirm pathogenicity of GUK1 deficiency, we expressed 2 GUK1 isoforms in patient cells.ResultsWe identified biallelic GUK1 pathogenic variants in all 4 probands who presented with ptosis, ophthalmoparesis, and myopathic proximal limb weakness, as well as variable hepatopathy and altered T‐lymphocyte profiles. Muscle biopsies from all probands showed mtDNA depletion, deletions, or both, as well as reduced activities of mitochondrial respiratory chain enzymes. GUK1 encodes guanylate kinase, originally identified as a cytosolic enzyme. Long and short isoforms of GUK1 exist. We observed that the long isoform is intramitochondrial and the short is cytosolic. In probands’ fibroblasts, we noted decreased GUK1 activity causing unbalanced mitochondrial dNTP pools and mtDNA depletion in both replicating and quiescent fibroblasts indicating that GUK1 deficiency impairs de novo and salvage nucleotide pathways. Proband fibroblasts treated with deoxyguanosine and/or forodesine, a purine phosphatase inhibitor, ameliorated mtDNA depletion, indicating potential pharmacological therapies.InterpretationPrimary GUK1 deficiency is a new and potentially treatable cause of MDDS. The cytosolic isoform of GUK1 may contribute to the T‐lymphocyte abnormality, which has not been observed in other MDDS disorders. ANN NEUROL 2024;96:1209–1224

2024-11-01·World Neurosurgery

Telescoping Flow Diverters for the Treatment of Brain Aneurysms: Indications and Outcome

Article

作者: Jabbour, Pascal M ; Momin, Arbaz A. ; Lan, Matthews ; Winiker, Sarah ; Musmar, Basel ; Teichner, Eric M ; Momin, Arbaz A ; Roy, Joanna M. ; El Naamani, Kareem ; Ghanem, Marc ; Gooch, Michael R. ; Rosenwasser, Robert H. ; Tjoumakaris, Stavropoula I ; Ghosh, Ritam ; Ahmed, Meah T. ; Gooch, Michael R ; Zarzour, Hekmat ; Schmidt, Richard F ; Teichner, Eric M. ; Rosenwasser, Robert H ; Schmidt, Richard F. ; Roy, Joanna M ; Ahmed, Meah T ; Jabbour, Pascal M. ; Tjoumakaris, Stavropoula I.

OBJECTIVEFew studies have reported the impact of telescoping flow diverters (FDs) in intracranial aneurysm treatment. Our study compared aneurysms treated using telescoping FDs to those treated with a single FD and identified predictors of telescoping.METHODSThis was a single-center retrospective review of a prospectively maintained database of aneurysms treated with FDs between 2011 and 2023. All patients who were treated with FDs for intracranial aneurysms were included in the study.RESULTSThe study comprised 750 patients with 750 aneurysms treated using 871 FDs. The study cohort was divided into 85 patients requiring telescoping FDs and 655 who did not. Rates of hemorrhage (7.1% vs. 1.8%, P < 0.001), symptomatic stroke (5.9% vs. 2.6, P < 0.001), and asymptomatic stroke (1.2% vs. 0.8%, P < 0.001) were significantly higher in the telescoping cohorts. At final follow-up, the rate of nonocclusion (9.8% vs. 5.1%, P = 0.029) and the rate of complete occlusion (88.5% vs. 81.1%, P = 0.029) were significantly higher in the telescoping cohort. On multivariate analysis, fusiform morphology (odds ratio [OR]: 2.4, 95% confidence interval [CI] 1.0-5.0, P = 0.03), increasing aneurysm height (OR: 1.0, 95% CI 1.0-1.1, P= 0.034), and the use of the Pipeline Embolization Device FD (OR: 2.4, 95% CI 1.3-4.4, P = 0.005) were independent predictors of telescoping.CONCLUSIONSAneurysms with fusiform morphology, increasing aneurysm height and those that underwent flow diversion using Pipeline Embolization Device had higher odds for telescoping. Significantly higher rates of angiographic occlusion with the use of telescoping FD add to the literature on its efficacy in treating aneurysms of varying morphology.

2024-11-01·Journal of NeuroInterventional Surgery

Two year follow-up of distal unruptured intracranial aneurysms treated with a surface modified flow diverter under prasugrel monotherapy

Article

作者: Abud, Thiago Giansante ; Machado, João Paulo ; de Oliveira, Ricardo Santos ; de Castro-Afonso, Luis Henrique ; Abud, Daniel Giansante ; Nakiri, Guilherme Seizem ; Monsignore, Lucas Moretti ; Colli, Benedicto Oscar ; Freitas, Rafael Kiyuze

BackgroundA new generation of modified surface flow diverters (FDs) and monotherapy using new antiplatelets may reduce both ischemic and hemorrhagic complications during the treatment of intracranial aneurysms. Previous preliminary safety analysis of distal unruptured intracranial aneurysms treated with the FD p48 MW HPC (phenox-Wallaby, Bochum, Germany) under antiplatelet monotherapy with prasugrel showed promising results. However, the long term outcomes of distal intracranial aneurysms treated with FDs under antiplatelet monotherapy are not known.MethodsThis was a single center, prospective, pivotal, open single arm study. The primary (safety) endpoint was absence of any new neurological deficits after treatment until the 24 month follow-up. The primary (efficacy) endpoint was the incidence of complete aneurysm occlusion 24 months after treatment. The secondary (efficacy) endpoints were any incidence of aneurysm dome reduction 24 months after treatment.Results21 patients harboring 27 distal aneurysms of the anterior circulation were included. No patient had neurologic deficits in the time from treatment to the 24 month follow-up. Complete aneurysm occlusion occurred in 20 (74%) of 27 aneurysms at the 24 month follow-up. Four aneurysms (14.8%) had dome reduction, and three aneurysms (11.1%) remained unchanged.ConclusionsIn this pilot trial, treatment of distal unruptured intracranial aneurysms with an FD under monotherapy with prasugrel, followed by monotherapy with aspirin, appeared to be safe and effective. Randomized studies with long term follow-up are needed to confirm these results.

1

项与呋咯地辛相关的新闻（医药）

2023-02-01

·生物谷

BJP：急性T淋巴细胞白血病的发病机制及靶向药物的研究进展

急性淋巴细胞性白血病(ALL)是一种恶性增殖的淋巴样细胞，早期分化受阻。淋巴细胞的异常增殖会在骨髓中积聚，并抑制正常的造血功能。成人ALL在确诊时往往有更高的风险因素，并有更多的共病。急性淋巴细胞性白血病(ALL)是一种恶性增殖的淋巴样细胞，早期分化受阻。淋巴细胞的异常增殖会在骨髓中积聚，并抑制正常的造血功能。成人ALL在确诊时往往有更高的风险因素，并有更多的共病。在T-ALL发病期间，淋巴细胞的异常增殖会破坏正常的免疫反应，扰乱免疫系统的功能。患者可能会出现药物不良反应(ADR)，如发热、体重意外减轻、盗汗、感染、出血和中枢神经系统(CNS)受累。在癌症治疗过程中，这些严重的并发症甚至可能危及患者的生命。图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/36623836/ 近日，来自安徽医科大学的研究者们在Br J Pharmacol杂志上发表了题为“The pathogenesis and development of targeted drugs in acute T lymphoblastic leukemia”的综述性文章，在这篇综述中，研究者旨在介绍T-ALL病因学中最新和最经典的信号通路，并阐明T-ALL治疗的潜在靶向药物。急性淋巴细胞白血病(ALL)按其淋巴细胞来源主要分为急性T淋巴细胞白血病(T-ALL)和急性B淋巴细胞白血病(B-ALL)。其中，成人T-ALL的发病率约占成人ALL的25%，但恶性程度高，治愈率和预后差。现阶段针对T-ALL的靶向药物很少，常用的广谱化疗药物疗效差、不良反应多。了解T-ALL的发病机制，寻找介入治疗的发病机制，对于进一步开发新的T-ALL靶向药物和改进现有药物具有重要意义。信号通路异常是T的主要致病因素，在促进肿瘤的发生、发展、药物设计和治疗反应等方面起着至关重要的作用。这主要是因为信号通路在许多细胞生物学过程中是不可或缺的，包括肿瘤的生长、迁移、侵袭、转移等。因此，针对信号通路主要蛋白的小分子抑制剂受到了广泛的关注，并在临床前模型和临床试验中得到了开发和评估。已经上市的药物也正在作为联合疗法开发，以进一步提高疗效和克服肿瘤细胞耐药性。传统抗癌药物与靶向抗癌药物利弊比较图片来源：https://pubmed-ncbi-nlm-nih-gov.libproxy1.nus.edu.sg/36623836/ 本文综述了目前的研究现状，阐明信号通路异常是T-ALL发病机制中的关键因素，也是T-ALL治疗的关键。Forodesine、Nelarabine、ruxolitinib、cerulatinib、everolimus和temsirolimus等药物是公认的治疗白血病的抗癌药物，用于治疗ALL、AML和复发/难治性套细胞淋巴瘤。唯一已被批准上市并明确指明用于治疗T-ALL的药物是奈拉滨。总而言之，靶向治疗是个性化癌症医学的核心，并促进了诊断。靶向药物在T-ALL治疗中的应用仍然是一个困难的挑战，需要更多的关注。（生物谷 Bioon.com）参考文献 Zhaoying Chen et al. The pathogenesis and development of targeted drugs in acute T lymphoblastic leukemia. Br J Pharmacol. 2023 Jan 9. doi: 10.1111/bph.16029.

细胞疗法免疫疗法

100 项与呋咯地辛相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D04245	呋咯地辛	L01XX	DB06185

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
外周T细胞淋巴瘤	日本	Mundipharma KK	2017-03-31

未上市

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适应症	最高研发状态	国家/地区	公司	日期
皮肤T细胞淋巴瘤	临床2期	瑞士	BioCryst Pharmaceuticals, Inc.	2007-07-01
T细胞白血病	临床2期	美国	BioCryst Pharmaceuticals, Inc.	2004-03-01
T细胞白血病	临床2期	格鲁吉亚	BioCryst Pharmaceuticals, Inc.	2004-03-01
CD30-Positive recurrent or refractory Cutaneous T-Cell Lymphoma	临床2期	美国	BioCryst Pharmaceuticals, Inc.	2003-02-01
皮肤T细胞淋巴瘤	临床1期	澳大利亚	BioCryst Pharmaceuticals, Inc.	2007-07-01
皮肤T细胞淋巴瘤	临床1期	奥地利	BioCryst Pharmaceuticals, Inc.	2007-07-01
复发性T淋巴母细胞淋巴瘤	临床1期	美国	BioCryst Pharmaceuticals, Inc.	2006-07-01
慢性淋巴细胞白血病	临床申请	美国	BioCryst Pharmaceuticals, Inc.	2005-06-01
CD19阳性B细胞急性淋巴细胞白血病	临床申请	美国	BioCryst Pharmaceuticals, Inc.	2004-09-01
前体B细胞成淋巴细胞白血病淋巴瘤	药物发现	美国	BioCryst Pharmaceuticals, Inc.	2004-09-01

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临床结果

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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


NCT01776411 (Pubmed \| Ann Hematol) 人工标引	临床2期	外周T细胞淋巴瘤二线	48	forodesine	(築廠鏇範淵齋鏇壓夢積) = 壓鏇廠選餘醖餘顧獵遞遞壓淵淵鏇築積獵積夢 (醖繭襯鏇鬱蓋膚觸蓋齋, 14 ~ 38) 更多	积极	2019-01-01
NCT01776411 (ASCO2016)	临床1/2期	复发性T细胞淋巴瘤	44	Forodesine 300 mg BID	(艱淵窪齋鑰構夢憲齋願) = 蓋壓鏇壓遞淵顧觸顧構遞繭壓膚醖夢構襯艱餘 (範簾獵廠艱餘艱齋艱壓, 12.0 ~ 35.3) 更多	积极	2016-05-20
NCT00501735 (Pubmed \| Ann Oncol)	临床2期	皮肤T细胞淋巴瘤 \| 蕈样真菌病 \| 塞扎里综合征	144	Forodesine	(鑰顧窪獵觸範願襯糧蓋) = 願築醖選襯築繭鹹醖鑰壓選鑰醖鏇醖鬱膚積構 (遞鹹構餘顧願獵構構蓋 ) 更多	-	2014-09-01
ASCO2009	N/A	皮肤T细胞淋巴瘤	64	Forodesine	(鑰選蓋鏇積積襯壓蓋觸) = 築網鏇壓艱廠廠鏇蓋築遞鑰顧夢積選壓選製鹹 (遞獵願範艱構觸觸鏇鬱 ) 更多	-	2009-05-20