A Pharmacokinetic Interaction and Safety and Efficacy Phase II, Open Label Study With a Safety Lead-in Evaluating Docetaxel Plus Tesmilifene (YMB1002) in Patients With Metastatic Breast Cancer Suitable for Treatment With Docetaxel

This is a Phase II study designed to evaluate whether the co-administration of a fixed dose of tesmilifene and a standard regimen of docetaxel alters the plasma pharmacokinetics of docetaxel. This study will also assess the safety and efficacy of the tesmilifene/docetaxel combination in metastatic breast cancer patients.

开始日期2006-06-01

申办/合作机构

YM BioSciences, Inc.

EUCTR2004-001263-22-EE / Not yet recruitingN/A

A Phase III study of DPPE (Temilifene) combined with Epirubicin and Cyclophosphamide versus Epirubicin and Cyclophosphamide alone as First – line Treatment in Metastatic/Recurrent Cancer - The DEC Trial

开始日期2005-01-07

申办/合作机构

YM BioSciences, Inc.

NCT00099281 / Terminated临床3期

A Phase III Study of DPPE Combined With Epirubicin and Cyclophosphamide vs Epirubicin and Cyclophosphamide Alone as First Line Treatment in Metastatic/Recurrent Breast Cancer

The purpose of this trial is to study DPPE combined with epirubicin and cyclophosphamide in patients with metastatic and/or recurrent breast cancer who may have received previous hormone treatment but have not had exposure to anthracycline treatment. Stratification allocation will be within the following subgroups:
Prior cytotoxic treatment;
Estrogen receptor status;
ECOG performance status;
Number of cycles of chemotherapy.

开始日期2004-05-01

申办/合作机构

YM BioSciences, Inc.

100 项与替米利芬相关的临床结果

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100 项与替米利芬相关的转化医学

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100 项与替米利芬相关的专利（医药）

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项与替米利芬相关的文献（医药）

2024-01-10·ACS applied materials & interfaces

Enhanced Performance and High Resistance to Efficiency Degradation of Blue Quantum-Dot Light-Emitting Diodes Using the Lewis Base Blended Hole-Transporting Layers

Article

作者: Zhang, Yong ; Qin, Ziyu ; He, Hongwei ; Yan, Minming ; Shu, Jia ; Liu, Yuyu ; Wang, Zi ; Wang, Yunwei

The distinctive characteristics of blue quantum dots (QDs) such as their deep valence band and large bandgap give rise to an elevated hole injection barrier between the hole transport layers (HTLs) and the QD active layer. This results in an imbalance of carrier transport and injection across the device, leading to a degrading performance in QD light-emitting diodes (QLEDs). In this paper, high-efficiency and low-efficiency degradation blue CdSe/CdS/ZnS QLEDs were fabricated by using the Lewis base, 1,2-bis(diphenylphosphino)ethane (DPPE), blended with poly(9-vinylcarbazole) (PVK) (DPPE:PVK) as HTLs. The device performance of blue QLEDs can be finely adjusted by manipulating the blending ratio between DPPE and PVK. When 4 wt % DPPE was blended with PVK (4 wt % DPPE:PVK) as the HTL, the device achieved its optimal performance. Compared to the device with neat PVK as the HTL, the turn-on voltage of blue QLEDs with the 4 wt % DPPE:PVK HTL is reduced from 3.21 to 2.9 V. The maximum current efficiency (CE) and external quantum efficiency (EQE) of blue QLEDs increase from 2.92 cd A^-1 and 5.89% in neat PVK to 5.75 cd A^-1 and 11.75% for the 4 wt % DPPE:PVK HTL. Furthermore, the QLEDs incorporating DPPE:PVK HTLs exhibited exceptional resistance to efficiency degradation (EQE = 8.83%@L = 12,000 cd m^-2 for 4 wt % DPPE:PVK as the HTL and EQE = 2.80%@L = 12,000 cd m^-2 for neat PVK as the HTL). A more in-depth analysis reveals that enhanced device performance results from the chelating and bridging effect of the bidentate ligand Lewis base DPPE. These effects strengthen the binding of free metal ions in the blue QDs, reduce the charge barriers, enhance the contact between the HTLs and the QD active layer, and ultimately improve hole injection.

2023-01-01·Food science & nutrition

Active food packaging films from alginate and date palm pit extract: Physicochemical properties, antioxidant capacity, and stability

Article

作者: M'Rabet, Yassine ; Boulila, Abdennacer ; Khwaldia, Khaoula

Abstract:

Date palm pits are highly available and inexpensive palm date by‐products, representing a valuable source of natural antioxidants, particularly phenolic compounds. Date palm pit extract (DPPE) was prepared from these waste products and characterized for its phenolic content and in vitro antioxidant activity. Profiling DPPE by liquid chromatography coupled with mass spectrometry (LC/MS) showed the presence of dimers and trimers of (epi)catechin as the main constituents. Alginate‐based films with four increasing concentrations of DPPE (10%, 20%, 30%, and 40% w/w) were prepared by the casting method. DPPE incorporation reduced solubility values of alginate films by 37%–64% and their surface wettability by 72%–111%. The incorporation of 10% DPPE improved water vapor barrier properties and increased tensile strength (TS) and elongation at break (%E) of alginate films by more than 23%, 50%, and 45%, respectively. The film containing 40% DPPE showed the lowest loss of phenolic content (32%), DPPH (1,1‐diphenyl‐2‐picrylhydrazyl) scavenging activity (38%), and ferric reducing antioxidant power (FRAP) (30%) after storage for 3 months.

2023-01-01·Surgical neurology international

Minimizing blood loss with direct percutaneous polymethylmethacrylate embolization before corpectomy for vascular spinal tumors.

Article

作者: Carnevale, Joseph Anthony ; Jayaraman, Mahesh ; Oyelese, Adetokunbo ; Anderson, Matthew ; Torabi, Radmehr ; Abdulrazeq, Hael ; Moldovan, Krisztina ; Gokaslan, Ziya

Background:

Standard surgical treatment for vascular spinal tumors, including renal cell carcinomas and hemangiomas, may result in significant blood loss despite preoperative arterial tumor embolization.

Methods:

This is a retrospective review of 12 patients who underwent direct percutaneous polymethylmethacrylate embolization (DPPE) with or without feeding artery embolization before partial or complete corpectomy for the resection of vascular spinal tumors (2013-2018). Estimated blood loss (EBL) was compared to the blood loss reported in the literature and to patients receiving standard arterial embolization before surgery.

Results:

The mean EBL for 12 patients was 1030 mL; three of 12 patients required blood transfusions. For the single level corpectomies, the EBL ranged from 100 mL to 3900 mL (mean 640 mL). This mean blood loss was not increased in patients receiving only DPPE preoperatively versus those patients receiving preoperative arterial embolization in addition to DPPE (1005 vs. 1416 mL); in fact, the EBL was significantly reduced for those undergoing DPPE alone.

Conclusion:

In this initial study, nine patients treated with DPPE embolization alone before spinal tumor resection demonstrated reduction of intraoperative blood loss compared to three patients having arterial embolization with DDPE.

项与替米利芬相关的新闻（医药）

2023-08-20

·生物制品圈

吸入式核酸纳米递送载体 : 挑战与对策

吸入式核酸纳米递送系统在呼吸系统疾病治疗中显示出良好的临床应用前景,但也因肺部的特殊结构等原因面临种种挑战。呼吸系统疾病如肺炎、呼吸合胞病毒(RSV)感染、肺纤维化、哮喘、过敏性鼻炎、慢性阻塞性肺病(COPD)等已成为中国第三大疾病死因，仅次于心脑血管疾病和恶性肿瘤。呼吸系统疾病病程长、用药技术壁垒高、可供选择的有效治疗药品有限，未满足巨大的临床需求。mRNA 技术凭借其研发周期短、预防效果好、安全性好、理论上可表达任意抗原等优势在新冠疫苗开发中得到迅速应用，显示了核酸药物在呼吸系统疾病预防和治疗领域中的巨大应用潜力。与传统药物（小分子、多肽、蛋白等）相比，核酸药物在高特异性和高效性方面表现出独特优势，且有望攻克“不可成药”靶点的局限性，具有广泛的临床应用前景。吸入递送为呼吸系统疾病治疗的最佳给药方式，具有无创性、可直接将治疗剂递送到肺部、增加药物局部浓度和减少全身系统毒性等优势。此外，肺泡巨大的表面积有利于药物快速吸收、避免直接代谢。然而，裸露的核酸具有电负性大分子的固有属性，易降解、细胞摄取和转染效率低，因此亟待开发安全有效的核酸递送载体，不仅能够保护核酸药物不被降解和促进细胞摄取，而且能够承受雾化过程中产生的剪切力，经吸入给药后能够克服多重生理屏障将核酸治疗分子递送至肺组织疾病部位。吸入式核酸递送面临的挑战抗雾化剪切力雾化过程会产生一定的剪切力，剪切力可以通过设计优化递送载体、粒径及分布、分散体系以及雾化装置等参数降低，保护药物结构不被破坏。近期，上海交通大学章雪晴团队利用类脂质G0-C14构建吸入式核酸纳米药物。该纳米颗粒可有效包载小干扰核糖核酸(siRNA)，具有良好的雾化稳定性，并保持雾化前后纳米颗粒的粒径、形貌、包封率及转染效率不变，在肺纤维化小鼠模型上显著改善了肺组织损伤和功能损伤。另有研究表明，振动网筛雾化器在雾化过程中产生的剪切力较低，可以实现温和的气溶胶产生过程。此外，有文献报道粒径较小的单层脂质体（通常小于 200 nm）在雾化过程中不易受到剪切力的影响。克服黏液屏障呼吸道中高度分支的支气管结构对药物在肺部特定位置的富集形成障碍，这要求吸入式气溶胶制剂具有高分散性和气动性能。核酸纳米药物雾化形成的雾滴直径需控制在1～ 5μm，才可通过重力沉降机制沉积在肺组织深处的呼吸区域。气道内壁黏液 - 纤毛清除是气道的主要防御机制，也是吸入式核酸纳米药物面临的主要生理屏障之一。研究表明，黏蛋白是黏液主要成分，呈负电性，分子骨架中周期性的疏水裸蛋白球状结构域可以结合并束缚外来疏水分子。聚乙二醇(PEG)因其亲水性和屏蔽纳米颗粒表面电荷的性质，能增强纳米颗粒在黏液层的渗透能力，在纳米颗粒表面修饰PEG可避免其被黏液纤毛清除。采用多粒子跟踪(MPT)技术对表面分别修饰有可控密度的胺、羧基和PEG的二氧化硅纳米颗粒(SNP)库进行研究，结果显示，SNP表面高密度修饰的聚乙二醇形成一种刷状构象，可以屏蔽纳米颗粒 - 黏蛋白的相互作用，表现出更强的黏液渗透能力。逃避巨噬细胞清除肺泡巨噬细胞吞噬介导的免疫清除是吸入式核酸纳米药物面临的另一个主要生理屏障。纳米颗粒在呼吸道中沉积后首先与肺表面活性剂(PS)层接触，随后肺泡巨噬细胞内化外来颗粒并在充满溶菌酶的囊泡中将其消化、运送至黏膜纤毛或淋巴系统进行清除。PS 影响纳米颗粒的保留时间并决定药物的肺部生物利用度。PS 由 II 型肺泡细胞产生，主要由90%脂质（如磷脂酰胆碱、磷脂酰甘油和胆固醇）以及 10% 表面活性蛋白（如亲水蛋白SP-A和SP-D及疏水蛋白SP-B和SP-C）组成。研究表明，吸入制剂的表面和理化性质（如尺寸）会影响纳米颗粒与PS之间的相互作用，对其被肺泡巨噬细胞吞噬的过程有较大影响。经PS组分修饰的纳米颗粒可在其表面形成生物分子冕，进而调节其与肺泡巨噬细胞之间的相互作用。研究者利用二棕榈酰磷脂酰胆碱(DPPC)、二棕榈酰磷脂胺(DPPE)、二棕榈酰磷脂酰甘油(DPPG)以及二棕榈酰磷脂酰丝氨酸(DPPS)分别修饰负载紫杉醇(PTX)的聚乳酸 - 羟基乙酸共聚物(PLGA)纳米颗粒，结果显示不同的磷脂修饰可以赋予纳米颗粒不同的黏液渗透和细胞摄取性质。吸入式核酸递送载体分类目前，吸入式核酸递送载体包括病毒载体、脂质纳米颗粒、脂质-聚合物杂化纳米颗粒、纳米结构脂质载体、阳离子聚合物、外泌体纳米囊泡，以及蛋白载体等。病毒载体病毒载体在疫苗领域已经得到了广泛研究。2022年5月19日，全球首款吸入用重组新型冠状疫苗（5 型腺病毒载体）克威莎® 雾优® 被正式列入世界卫生组织紧急使用清单。2022年12月5日，北京万泰生物与厦门大学、香港大学合作研发的鼻喷流感病毒载体新冠疫苗也获批紧急使用。相较于肌肉注射疫苗主要产生IgG抗体来保护下呼吸道和肺，吸入疫苗可以利用黏膜免疫产生更多的IgA抗体，从而保护上呼吸道免受病毒入侵。需要注意的是，病毒作为核酸递送载体具有转染效率高且基因表达持续时间较长等优点，但也存在尺寸限制、整合宿主基因组所带来的潜在风险等问题。除此以外，有文献报道腺相关病毒(AAV)衣壳的免疫原性触发中和抗体和T细胞反应，限制了基于AAV治疗的重复给药。关于优化病毒载体的安全性研究仍在持续进行中。基于脂质的吸入式核酸纳米载体（1）脂质纳米颗粒(LNP)新兴的非病毒载体因其免疫反应低、载体容量大、化学结构可控、无整合宿主基因组风险等优势被认为是病毒载体的更安全的替代品。LNP 是目前临床使用的核酸纳米载体，由可电离脂质、胆固醇、辅助型脂质和PEG-脂质自组装形成。使用LNP的上市核酸药物包括首款上市的siRNA药物ONPATTRO®(Patisiran) 和 5 款新冠病毒mRNA疫苗制剂。近年来，吸入式mRNA递送系统的研究也不断取得进展。例如，美国化学和生物工程师詹姆斯·达尔曼(James Dahlman)等通过对大量 LNP 制剂处方的评价和筛选，对LNP组分及组分比例进行迭代优化，获得经雾化吸入递送mRNA的最优 LNP。该LNP以吸入式气溶胶的方式递送编码治疗性抗体FI6的mRNA，可以有效结合血凝素，中和流感病毒亚型。全球现已有至少4个吸入式 mRNA 纳米载体应用到人体临床试验。美国mRNA 疗法研发公司Translate Bio 研发的MRT5005于2018年获批进入临床试验治疗囊性纤维化，是全球首个以可雾化气溶胶制剂进入临床试验的LNP-mRNA纳米药物。出自美国RNA 制药公司 Arcturus、生物制药公司Vertex Pharmaceuticals和基因疗法公司ReCode Therapeutics的吸入式 LNP-mRNA 药物（ARCT-032、VX-522 和 RCT1100）于2023 年先后获批进入临床试验，分别用于治疗囊性纤维化肺病和原发性纤毛运动障碍(PCD)。遗憾的是，目前尚无吸入式 LNP-mRNA 候选药物成功完成临床试验。（2）脂质 - 聚合物杂化纳米颗粒(LPN)脂质-聚合物杂化纳米颗粒由脂质和聚合物组成，在体内外显示出良好的核酸递送潜能。LPN中的可离子化脂质与核酸通过静电相互作用结合，促进细胞摄取、内体逃逸和胞质递送。可生物降解的聚合物如PLGA构成LPN基质骨架，实现负载核酸的持续释放。丹麦和瑞典的研究团队利用PLGA和L5N12制备负载肿瘤坏死因子(TNF)-α siRNA的LPN干粉吸入制剂，并通过亮氨酸等辅料的引入提高该干粉吸入制剂耐受喷雾干燥过程的热稳定性和气溶胶性能。上海交通大学章雪晴研究团队基于类脂质G0-C14构建吸入式LPN，通过雾化吸入给药方式将靶向IL-11的siRNA有效递送至小鼠肺部，在肺纤维化小鼠模型中展示出良好的抗纤维化治疗效果。（3）纳米结构脂质载体(NLC)纳米结构脂质载体是另一类由固体脂质和液体脂质的混合物组成的脂质纳米载体，具有避免药物在储存过程中析出的优势。美国新泽西州立罗格斯大学药剂学系教授塔玛拉·明科(Tamara Minko)等以Precirol® ATO 5作为固体脂质，角鲨烯作为液体脂质制备 NLC，单次吸入及静脉注射非靶向 NLC 24 小时后的器官分布结果显示，吸入方式递送的非靶向 NLC 在肺部富集的总量为83%，比静脉注射(23%)高出 3.5 倍以上。进一步对NLC进行靶向修饰，实验结果证明，表面修饰LHRH肽的NLC经吸入方式递送后主要富集在肺部肿瘤中，而未在健康肺组织中检出，该NLC共递送化疗药物以及靶向MRP1和Bcl2 mRNA的siRNA可以显著增强纳米颗粒的抗肿瘤细胞作用。阳离子聚合物阳离子聚合物是另一类得到关注的吸入式核酸载体。美国麻省理工学院教授丹尼尔·安德森(Daniel Anderson)等使用超支化聚β氨基酯(hPBAEs)hDD90-118 包载编码荧光素酶的mRNA，经吸入给药后可以实现荧光素酶在5个肺叶中的均匀分布，且未在其他组织中观察到荧光素酶表达，重复给药hPBAE-mRNA未产生局部或全身毒性。此外，美国佐治亚理工学院和埃默里大学的研究团队报道了一种基于聚 β- 氨基硫代酯的聚合物纳米载体，该载体对于所负载核酸的大小和复杂性没有限制，可经吸入给药方式将不同类型的核酸分子输送到多个动物种属的肺部。所获最优聚合物载体经吸入递送编码Cas13a蛋白的mRNA，在极低的剂量下产生的疗效与高于其20倍剂量的中和抗体相似。外泌体纳米囊泡外泌体是由体内细胞主动分泌的纳米级(30 ～ 150 nm)细胞外囊泡，通常由双层脂质膜形成，富含多种生物成分，包括来自其亲本细胞的蛋白质、核酸和脂质。因其表达来自亲本细胞的表面蛋白和受体，在靶向相同的组织受体细胞方面具有独特优势，是一类新兴的靶向药物递送载体。美国北卡罗来纳州立大学程柯团队报道的人肺球细胞来源的外泌体经雾化吸入给药后能将mRNA递送至细支气管和肺泡中，提高mRNA在肺组织中的分布、保留及蛋白表达。然而，外泌体载体在临床转化上存在工艺复杂、可放大性差的技术挑战。蛋白载体近年来，蛋白载体也被探索用作吸入式核酸纳米递送载体。山东大学研究团队采用内源性核糖体蛋白包载基质金属蛋白酶 13的mRNA，并在该核糖体蛋白纳米结构表面修饰RGD肽和角化细胞生长因子(KGF)，经雾化吸入给药方式将纳米药物靶向递送至特发性肺纤维化小鼠肺部富含整合素的肌成纤维细胞和受损的上皮细胞，从而加速细胞外基质的降解和促进肺泡上皮再生。 3结语吸入式核酸药物在呼吸系统疾病的预防和治疗领域具有广阔的临床应用前景。合理设计和开发吸入式核酸纳米递送系统，使其具备良好的生物安全性和耐受雾化剪切的性能，并能穿透黏液屏障和减少肺泡巨噬细胞吞噬清除，继而促进靶细胞摄取和实现溶酶体逃逸，是提高mRNA纳米药物肺部递送效率及其靶向转染特定细胞效率的关键。

核酸药物siRNA信使RNA疫苗

2022-11-21

·Science Daily

Simplified process shines light on new catalyst opportunities

Theory-guided development of an easier, more versatile process for synthesizing unsymmetric ligands provides new avenues of exploration in transitional metal catalysis. Theory-guided development of an easier, more versatile process for synthesizing unsymmetric ligands provides new avenues of exploration in transitional metal catalysis. Researchers at the Institute for Chemical Reaction Design and Discovery (WPI-ICReDD) have discovered the key to synthesizing a molecular tool that could greatly expand the variety of catalytic reactions possible with transition metals. The team has taken a well-established set of compounds that can be used to make transition metal catalysts and developed a simple, radical-based reaction for creating unsymmetric variants of these molecules using mild conditions. Easier access to a wider variety of these unsymmetric compounds opens a realm of new possibilities for designing transition metal catalysts. The focus of this research is on a class of compounds called 1,2-bis(diphenylphosphino)ethane derivatives (DPPEs). DPPEs are bidentate -- i.e., they attach to the metal center of a catalyst in two locations. However, DPPEs have typically been symmetric, with each attachment arm being the same, which limits the possible structural variety and reactivity. This study overcomes that limit, reporting a versatile method for developing unsymmetric DPPEs using ethylene, an abundantly available feedstock chemical. To guide their efforts, researchers initially performed quantum chemical computations via the artificial force induced reaction (AFIR) method to identify possible starting materials that could react to form DPPE. Computations showed a viable process whereby phosphine radicals reacted readily with ethylene to form DPPE. Based on this, the team experimentally verified a straightforward process for making symmetric DPPEs that forms phosphine radicals in solution simply by mixing three readily available compounds. This significantly improves upon previous methods that involved multiple steps and the use of unstable, highly reactive compounds. This process was then extended to unsymmetric DPPEs, mixing ethylene with both chlorophosphines and phosphine oxides that covered a wide range of electronic properties and sizes. The difference in sizes and electronic properties creates a push-pull effect that could lead to beneficial reactivity or selectivity. Optimization studies found the use of a photocatalyst with blue LED irradiation provided the best yield. As a test, the team then formed metal complexes using one of the unsymmetric DPPE derivatives. They compared the properties of palladium complexed with DPPE and with the unsymmetric DPPE derivative. The two complexes had significantly different properties, including color, absorption spectrum and molecular orbital energy, showing the potential for unsymmetric DPPE derivatives to enable different reactivity when used as ligands in catalysts. Researchers see both the application to catalyst design and the use of a low-cost, abundant material as advantages of this method. "We succeeded in synthesizing DPPE derivatives that are useful as ligands for transition metal catalysts, and we did this using cheap, readily-available ethylene," said lead author Hideaki Takano. "This result was realized due to the synergistic effect of using AFIR quantum chemical computations combined with the experimental skill and experience of organic chemists. Moving forward, I would like to develop new, revolutionary reactions using novel ligands synthesized by the method we reported here."

100 项与替米利芬相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D06084	-	-	DB04905

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
转移性乳腺癌	临床3期	英国	YM BioSciences, Inc.	2004-05-01
肿瘤转移	临床3期	英国	YM BioSciences, Inc.	2004-05-01
肝细胞癌	临床3期	-	Gilead Sciences, Inc.	-
胃癌	临床3期	-	Gilead Sciences, Inc.	-
前列腺癌	临床2期	美国	-	-
前列腺癌	临床2期	加拿大	-	-
乳腺癌	临床前	加拿大	London Health Sciences Centre	2007-05-01
头颈部鳞状细胞癌	临床前	加拿大	London Health Sciences Centre	2007-05-01