Triclabendazole is a benzimidazole compound used as a systemic antihelmintic in veterinary practice. Triclabendazole is considered to be a second-line drug for parasites and is used when other preferred agents cannot be used because they are ineffective or because adverse reactions limit their use. Although Triclabendazole is widely used in developing countries for the treatment of parasites it is not approved by the FDA for this treatment in the US. It is currently being distributed in the US through a special arrangement with the FDA and the manufacturer on an individual patient approval basis. This arrangement requires that a single patient Investigational New Drug (IND) be obtained from FDA for each patient requiring Triclabendazole. Upon approval by FDA, the manufacturer (Novartis) will ship the drug directly to the prescribing physician.

开始日期-

申办/合作机构

University of Colorado Denver

JPRN-jRCTs071190020 / Recruiting临床2/3期IIT

Efficacy and safety of triclabendazole for the treatment of fasciolosis - Egaten study

开始日期2019-08-30

申办/合作机构-

100 项与三氯苯达唑相关的临床结果

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100 项与三氯苯达唑相关的转化医学

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100 项与三氯苯达唑相关的专利（医药）

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602

项与三氯苯达唑相关的文献（医药）

2024-12-06·Journal of Biomolecular Structure and Dynamics

Network pharmacology and molecular docking study-based approach to explore mechanism of benzimidazole-based anthelmintics for the treatment of lung cancer

Article

作者: Nidhi ; Khan, Imran A. ; Khan, Mohd Ashif ; Reeta ; Garg, Aakriti ; Karhana, Sonali ; Bano, Aysha

Emerging studies have reported the potential anticancer activity of benzimidazole-based anthelmintics (BBA) against lung cancer (LC). However, mechanism underlying the anticancer activity of BBA is unclear. Therefore, in the current study, network pharmacology and molecular docking-based approach were used to explore the potential molecular mechanism for the treatment of LC. The potential targets for BBA were obtained from multiple databases including SwissTargetPrediction, Drug Bank, Therapeutic Target Database, and Comparative Toxicogenomics Database while LC targets were collected from DisGeNet gene discovery platform, Integrated Genomic Database of NSCLC, Catalogue of Somatic Mutations in Cancer and Online Mendelian Inheritance in Man database. Protein-protein interaction (PPI) diagram of common targets was constructed using STRING online platform. Topological analysis was performed using Cytoscape and gene enrichment analysis was conducted using FunRich software. Highest degree targets were then confirmed using molecular docking and molecular dynamics simulations. The BBA were prioritized according to their S scores, with ricobendazole ranking highest followed by flubendazole, fenbendazole, mebendazole, triclabendazole, albendazole, oxibendazole, parbendazole, thiabendazole and oxfendazole. The potential targets of BBA identified using topological analysis and molecular docking were found to be CCND1 (cyclin D1), EGFR (Epidermal Growth Factor Receptor), ERBB2 (Erb-B2 Receptor Tyrosine Kinase 2/CD340), PTGS2 (Prostaglandin-endoperoxide synthase 2), and SRC (Proto-oncogene tyrosine-protein kinase). Furthermore, molecular dynamics confirmed that CCND1 and EGFR are the potential targets of ricobendazole for the treatment of LC. BBA can be further explored as a therapeutic strategy for the treatment of lung cancer under in vitro and in vivo studies.Communicated by Ramaswamy H. Sarma.

2024-11-01·Experimental Parasitology

Fosfatriclaben: Effective dose determination and comparative efficacy assessment with closantel, triclabendazole+ivermectin, triclabendazole+albendazole in artificially infected cattle

Article

作者: Flores-Ramos, Miguel ; Ezeta-Miranda, Alonso ; Leyva-Gómez, Gerardo ; Ibarra-Velarde, Froylán ; Francisco-Márquez, Gerardo ; Vera-Montenegro, Yolanda ; Arias-García, Rosa ; Rojas-Campos, Tania ; Castillo, Rafael ; Cruz-Mendoza, Irene ; Hernández-Campos, Alicia ; Tovar-Escobar, David

Two controlled efficacy studies were conducted to determine the effective dose of fosfatriclaben (FTCB) and compare its fasciolicidal efficacy with that of three commercial products against eggs and adult stages of Fasciola hepatica in artificially infected cattle. In study 1, 20 trematode-free Holstein Friesian steers were infected on day 0 with 500 F. hepatica metacercariae. Ten weeks after infection and the steers were confirmed to be positive for trematode eggs through a modified sedimentation method. On day 75, they were divided into five groups of four animals each for treatment. Group 1 (G1) served as the untreated control; G2, G3, and G4 received FTCB at 4, 6, and 8 mg/kg/intramuscularly (IM), respectively. G5 received a combined treatment of triclabendazole (TCBZ) (12 mg/kg IM + ivermectin (0.2 mg/kg IM). Individual faecal analyses were performed on days -8, 0, 70, 75, and 105 to evaluate the reduction in trematode eggs. Four weeks after treatment, the steers were humanely slaughtered to harvest the livers and remove the parasites present in the bile ducts. Efficacy was evaluated by the reduction in fecal egg counts or in number of adult parasites, compared to the untreated control. The effective FTCB dose was 6 mg/kg. Once the effective dose was determined, study 2 was conducted on another 20 steers infected with 500 F. hepatica metacercariae, to compare the effectiveness of FTCB with three commercials fasciolicides. All procedures were performed as described in study 1, and treatments were as follows: Group 1 (G1), closantel (5 mg/kg subcutaneously (SC)); G2, TCBZ (12 mg/kg IM) + ivermectin (0.2 mg/kg IM); G3, FTCB (6 mg/kg IM); G4, triclabendazole (12 mg/kg) + albendazole (5 mg/kg/PO (orally); and G5 served as an untreated control. The results indicated that all tested compounds were highly effective in the reduction of faecal egg excretion (99.7-100%) and adult parasites (98.9-100%), except closantel, which exhibited low efficacy (74.4%) when tested against adult trematodes. We concluded that the effective dose of FTCB for cattle was 6 mg/kg IM, which is half the recommended clinical dose of the commercial combination of TCBZ and ivermectin. The fasciolicidal efficacy of FTCB was like the other three flukicides in reducing adult F. hepatica and Fasciola eggs; however, closantel was not sufficiently efficient against adult flukes.

2024-11-01·Journal of Clinical and Experimental Hepatology

Characteristics of Hepatobiliary Fascioliasis and the Role of Endoscopic Retrograde Cholangiopancreatography in Management: A Single Center Experience

Article

作者: Bahcecioglu, Ibrahim H ; Cicek, Sedat ; Madkour, Ahmad ; Tawheed, Ahmed ; Tunc, Nurettin ; Yalniz, Mehmet ; Artas, Hakan

BackgroundHepatobiliary fascioliasis has two phases, each requiring specific management approaches. Triclabendazole has been widely effective in treating the two phases of clinical fascioliasis and endoscopic retrograde cholangiopancreatography (ERCP) in the biliary phase. We aimed to characterize presentations of hepatobiliary fascioliasis and highlight the role of ERCP in management.Subjects and methodsThis retrospective cohort includes patients diagnosed with clinical hepatobiliary fascioliasis between January 2013 and December 2022. Demographic data, clinical presentation, laboratory and radiological investigations, treatment, and endoscopy reports were collected from the records of 62 participants. Patients were divided into two groups: acute hepatic and chronic biliary phases.ResultsThirty-six patients were in the biliary phase, and 26 were in the hepatic phase. All patients were from rural areas, and females were predominant (76%). Hypereosinophilia was detected in 92% of acute cases and 58% of chronic biliary cases. In chronic biliary cases, the levels of liver biochemicals, including alanine transaminase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), and bilirubin, were higher at levels of 189 ± 76, 127 ± 47, 268 ± 77, and 2.4 ± 0.7 respectively, compared to acute hepatic cases, 35.6 ± 8.2, 32.7 ± 4.3, 69.2 ± 45.45, and 0.58 ± 0.01. The corresponding P-values were 0.003, 0.001, <0.001, and <0.001, respectively. Triclabendazole effectively cured 93.5% of patients and was used in combination with ERCP in biliary-phase cases where the fluke was extracted from the biliary system in 34 patients (94.4%). Three patients (8.8%) were diagnosed with post-ERCP pancreatitis. None of the patients experienced bleeding, perforation, or required biliary stenting.ConclusionClinical fascioliasis could manifest in acute hepatic or chronic biliary phases. Hypereosinophilia was more evident in the hepatic phases, while ALT, AST, GGT, and bilirubin were higher in the biliary phase. Triclabendazole is effective in the hepatic phase and when combined with ERCP in the biliary phase. ERCP is highly effective for relieving obstruction and treating biliary fascioliasis.

项与三氯苯达唑相关的新闻（医药）

2024-05-22

·药精通Bio

美国FDA批准的38个小分子药合成路线汇总

深度聚焦多肽、多肽偶联药物研发、质控、工艺开发，联系电话181 1603 6798文章来源：有机合成路线这里小编和大家分享美国食品药品监督管理局 (FDA) 批准上市的38个化学小分子药合成路线，以飨化学和药化从业者，学生和爱好者。第一类（1.1）：抗肿瘤药物1.1.1 Erdafitinib (1)1.1.2 Alpelisib (2)1.1.3 Selinexor (3)1.1.4 Darolutamide (4)1.1.5 Pexidartinib (5)1.1.6 Entrectinib(6)1.1.7 Fedratinib (7)第二类（1.2）：抗菌药1.2.1 亚胺培南/西拉司丁/relebactam (9)1.2.2 Pretomanid (10)1.2.3 Lefamulin (11)1.2.4 Cefiderocol(12)第三类（1.3）：偏头痛治疗药物1.3.1 Lasmiditan (13)1.3.2 Ubrogepant(14)第四类（1.4）：其它治疗药物1.4.1 三氯苯达唑 (triclabendazole, 15)1.4.2 Brexanolone (16)1.4.3 Solriamfetol(17)1.4.4 Siponimod (18)1.4.5 Tafamidis(19) 和tafamidis meglumine1.4.6 Bremelanotide (20)1.4.8 替洛利生 (pitolisant, 22)1.4.9 Upadacitinib (23)1.4.10 Istradefylline (24)1.4.11Tenapanor(25)1.4.12 Trifarotene (26)1.4.13 阿法诺肽 (afamelanotide，27)1.4.14 Elexacaftor(28)/tezacaftor/ivacaftort1.4.15 Givosiran (29)1.4.16 Cenobamate (30)1.4.17 Voxelotor (31)1.4.18 Golodirsen (32)1.4.19Lemborexant (33)1.4.20 Lumateperone tosylate (34)2.1 Ga-68-DOTATOC(35)2.2 Fluorodopa (36)2.3 Air polymer-type A(37)是一种无菌透明凝胶 [polymer-type A(80.97 mg羟乙基纤维素 )，434.80 mg甘油 (85％)和纯净水 ]2.4 Brilliant blue G ophthalmic solution (38)参考文献：中国医药工业杂志Chinese Journal of Pharmaceuticals 2020, 51(1), 吕训磊，周伟澄，林快乐. 免责声明：本文信息来源于网络，本文仅作知识交流与分享及科普目的，不涉及商业宣传，不作为相关医疗指导或用药建议。文章如有侵权请联系删除。END深度聚焦多肽、多肽偶联药物研发、质控、工艺开发，7月相约苏州，联系电话18116036798戳“阅读原文”立即报名多肽药物论坛吧!

上市批准临床结果

2024-03-22

·奇点网

《科学》：抗生素遭“背刺”！科学家发现，与抗生素抗菌机制没有交集的非抗生素，竟也可导致细菌对抗生素耐药丨科学大发现

*仅供医学专业人士阅读参考没想到有一天，抗生素竟然遭到了非抗生素的“背刺”。近期，马萨诸塞大学医学院Amir Mitchell团队发表了一项重要研究成果，他们在分析了186种抗生素和非抗生素药物后发现，非抗生素与抗生素之间很多时候呈正交关系，即它们通过不同的机制作用于细菌。值得注意的是，药物输送相关基因的分析显示，虽然非抗生素与抗生素对细菌的作用机制不同，但他们却都受到了细菌外排（细菌耐药的一个重要机制）的影响。这也就意味着，细菌在对非抗生素产生耐药性的同时，也会不小心引发抗生素交叉耐药。研究发表在顶级期刊《科学》上。论文首页截图抗生素耐药是全球健康的最大问题之一，据估计，到2050年，每年将会有1000万人死于耐药性感染。更让人头疼的是，从1990年以来，人类发现新的抗生素种类相当有限。而近年来，非抗生素展现出的抗菌活性让人们看到了新的希望。然而更大的问题是，我们对非抗生素的抗菌活性还存在很多未知，比如非抗生素是如何作用于细菌的，是否和抗生素一样？它是否会导致细菌耐药？等等，总之这些问题都有待解答。Amir Mitchell团队为了搞清楚非抗生素作用于细菌的机制，他们选取了1280种药物，这些药物包括市面上已经获批了的，还有一些是正在研发中的药物，其中226种为抗生素，1054种为非抗生素。通过观察每个药物对大肠杆菌的影响，研究人员最终选取了186种可以显著抑制大肠杆菌生长的药物（103种抗生素和83种非抗生素）。药物筛选接下来，研究人员想知道，非抗生素的抑菌作用是否可以归咎于与抗生素有着一致的化学相似性。通过计算Tanimoto系数（0.8以上就是高度相似了），研究人员发现，同类抗生素，即对细菌有着相同作用机制的抗生素们通常具有很高的化学相似性，但不同类型的抗生素、抗生素和非抗生素，以及非抗生素之间化学相似性较低。这一发现表明，非抗生素显示出的抗菌活性，并不能归咎于它们在化学特征上类似于抗生素，而更可能是它们通过不同的机制来抑制细菌生长。随后，研究人员利用混合基因筛选方法捕获了90种抗生素对细菌的作用机制，并生成了针对抗生素的药物相关性网络。在将非抗生素加入到抗生素的药物相关性网络中后，研究人员发现，非抗生素与抗生素之间呈正交关系，也就是说，大多数非抗生素与抗生素作用机制的确不同（如果存在一样的机制，网络模块会聚集在一起）。药物相关性网络不过意外的是，一些非抗生素之间却存在相关性。于是研究人员又构建了非抗生素的药物相关性网络，结果共发现九个独立的网络模块，共涉及如生物合成和代谢过程，脂多糖生物合成相关的过程等多种生物功能。接下来，研究人员观察了一些参与细菌膜通透性和转运的基因对药物抗菌活性的影响，结果发现删除细菌的某些基因会增加药物的敏感性（尤其是一些编码抗性-结瘤-分裂家族转运蛋白、Tol-Pal系统和外膜蛋白的基因）。敲除编码膜通透性和转运的基因，会增加抗生素和非抗生素的抗菌活性此外，研究还发现，有26种包括抗生素和非抗生素在内药物都会受到五种或更多不同转运系统的影响。根据以上结果，研究人员推测，尽管大多数非抗生素与抗生素作用机制不同，但若因为非抗生素相关膜通透性和转运途径导致的耐药，那么细菌也可能通过同样途径对抗生素产生耐药。为了证明这一猜想，研究人员打算做一个药物抗性演化实验。研究人员从非抗生素的药物相关性网络的不同模块中选取了链脲佐菌素（Streptozotocin）、三氯苯达唑（Triclabendazole）和舍曲林（sertraline）这三种非抗生素，并将其放置于5种独立进化的大肠杆菌中。结果发现，对链脲佐菌素、三氯苯达唑适应的演化细菌完全耐药，而对舍曲林适应的演化细菌竟然增加了两倍以上的抗药性。通过对演化细菌进行基因组测序，研究人员发现了三种的非抗生素导致细菌耐药的机制。对链脲佐菌素耐药的细菌进化出了让nagE基因失活（这一基因编码葡萄糖-6－磷酸运输体，负责把药物运输到细菌内）的本事，总结就是谁都别想进来。对三氯苯达唑耐药的细菌让编码翻译起始因子IF2的基因突变了（非抗生素可与IF2结合可组织细菌蛋白质生成），总结就是细菌换了个锁芯，主打一个让你有钥匙也打不开。对舍曲林耐药的细菌让调节外排泵的基因（marR、acrR和lon）发生了突变，增加了多种外排途径，总结就是谁来都得给撵出去。鉴于细胞外排也是细菌对抗生素耐药的主要机制，研究人员认为对舍曲林耐药细菌也可能无意间促进了其对抗生素的耐药（围绕舍曲林耐药菌的抗生素耐药性实验也证实了这一点）。这就好比抗生素和细菌要打架，非抗生素巴巴地冲过去给细菌送了一份装备经验大礼包，这让抗生素怎么玩，纯纯背刺。总之，该研究通过遗传筛选和网络分析，发现一些非抗生素药物可能存在与抗生素不同的抑菌机制，这为开发新型抗菌药物提供了新的方向。不过在抗生素使用过程中导致的抗生素耐药也是一个亟须关注的问题。参考文献：[1]Guillen M N, Li C, Rosener B, et al. Antibacterial activity of nonantibiotics is orthogonal to standard antibiotics[J]. Science, 2024: eadk7368.本文作者丨张金旭

微生物疗法临床研究

2023-03-24

·药时代

FDA批准药物的关键专利特征

专利保护，是新药开发者阻止仿制药竞争，并获取高额回报的保证。从美国食品药品管理局（FDA）橙皮书列表中提取了专利，并评估了专利申请的时间、专利涵盖药物的特征以及其他国家是否获得类似的专利，寻找原研药物关键专利特征。FDA在2019-2020年批准的78个药物中，有10个没有专利，其余68个药物列出了322个不同的专利（中位数为4个）。根据受保护发明的性质，最常见的专利类别是化合物（201；62%），其次是使用方法（195；61%）。从原始药物批准到最终专利到期日的中位时间为10.3年。大约五分之一的专利在世界其他主要司法管辖区没有对应的专利。涵盖新批准药物的专利在很大程度上保护了产品及其用途；专利（而不是非专利排他性）是确保及时阻止仿制药进入市场的关键。FDA于2019-2020年批准的78个小分子药物（2019年48个药物和2020年53个药物）：2019年，有5个药物没有专利：artesunate，copper Cu-64 dotatate (Detectnet)，gallium Ga 68 PSMA-11，nifurtimox (Lampit)，和fluoroestradiol F18 (Cerianna)。2020年，有5个药物没有专利：brilliant blue G ophthalmic solution (TissueBlue)，fluorodopa F18，Ga-68-DOTATOC (Ga-68-DOTATOC)，pretomanid,和triclabendazole (Egaten)。其余68个药物获得了322件专利。每种药物的专利数量中位数为4。最常见的专利申请类别是化合物（n=201；62%），其次是使用方法（n=195；61%）、制造工艺（n=32；10%）和制剂（n=173；54%）或复合制剂（n=13；4%）（图表1）。结果是非互斥的，超过一半（n=188；58%）的专利拥有属于一个以上类别的权利要求。在FDA批准之前，专利的申请时间中位数为5.6年（IQR:3.3–9.2），公告时间中位数为4.5年（IQR:1.3–6.1）。专利申请到药物批准的时间范围从芦比替定/lurbinectedin（在FDA批准前17.6年提交）到塞普替尼/selpercatinib（在FDA审批前2年提交）。在大量专利中，专利申请时间通常与药物开发过程一致，因为化合物权利要求（n=201）在FDA批准药物前的中位数为6.5年（IQR:4-10），而使用方法权利要求（n=195）的专利在FDA批准之前的中位数为5.1年（IQR=3.2-8.4）。在FDA批准药物之前，仅有化合物权利要求专利的申请时间中值为5.7年（IQR:2-8）。图 2019-2020年FDA批准药物的批准日期与最后一项到期专利的到期日期之间的时间差基于所列专利的最新到期日，这些药物的预期专利保护市场独占期为药物批准后10.3年的中位数（IQR:7.2-13.8）。药物批准与专利最新到期日之间的最低时间差为3.7年，而最高时间差为20.3年。队列中的68个药物中有39个（57%）被指定为“孤儿药（Orphan Drug）”，在FDA批准时，39个药物中的33个（85%）的专利保护超过了法规规定的额外的7年市场排他性。所有29个非孤儿药指定药物（100%）的初始专利期超过了五年的哈奇-瓦克斯曼法案新药非专利市场独占期。在批准时，孤儿药指定的药物和普通条件指定药物之间的专利保护期限没有重大差异。在FDA橙皮书列出的322件专利中，有22件（7%）最初颁发给了非公司研究机构。例如，与5件专利相关的一个机构是非美国学术中心（西澳大利亚大学）。大约一半的专利（n=149；46%）的原始专利受让人与FDA列出的申请新药的发起人不同。17件（5%）专利有多名受让人。在322件专利中，52件（16%）在其简单专利家族中没有授予外国专利，因此仅为美国专利。在这52件专利中，34件（65%）在简单专利家族没有外国未决专利申请。在剩余的未决专利申请中（52件中的18件；35%），有5件外国专利申请在欧洲、加拿大或日本被撤回或拒绝。其他13件专利申请仍在审理中。FDA列出的与外国授予的同等专利最常见的国家是日本（n=243；75%），其次是欧洲（n=232；72%）和加拿大（n=183；57%）。没有外国授予专利等效物的专利包括化合物权利要求（55%）、使用方法权利要求（65%）、工艺权利要求（8%）、制剂权利要求（52%）和复合制剂权利要求的专利（2%）。FDA在2019年和2020年批准的涵盖小分子药物的专利大多涵盖了活性成分和使用方法，但也涵盖了多种其他发明。这些专利的有效期通常已经超过了《Hatch-Waxman Act》和《孤儿药法案》的排他性期限。我们预计有些药物未来将申请更多的专利，涵盖药物的次要方面。参考资料：Van de Wiele VL, Torrance AW, Kesselheim AS. Characteristics Of Key Patents Covering Recent FDA-Approved Drugs. Health Aff (Millwood). 2022 Aug;41(8):1117-1124. doi: 10.1377/hlthaff.2022.00002. PMID: 35914209.封面图来源：123rf推荐阅读4轮临床试验结果全矛盾，这减肥药，把积极结果做毁了……3年前，百济神州为了一个冷门靶点花了800万美金，如今......10年时间，临床成功率翻10倍！辉瑞的成功之道在哪里？点击在看，共济新药研发浪潮

专利到期专利无效

100 项与三氯苯达唑相关的药物交易

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