A Phase 1, Single Center, Randomized, Double-Blind, Placebo-Controlled Single Ascending Dose Study to Assess the Safety, Tolerability and Pharmacokinetic Profiles of Oral CPSI-2364 in Healthy Subjects

This study will be conducted in healthy male or female subjects using a double-blind, randomized, placebo-controlled, single-dose design. Up to 30 subjects will be enrolled; 3 healthy subjects in Cohorts 1 and 2 (2 active, 1 placebo) and 8 healthy subjects in Cohorts 3 to 5 (6 active, 2 placebo). The following CPSI-2364 doses are proposed: 1 mg, 10 mg, 30 mg, 90 mg, and 270 mg.Safety will be evaluated throughout the study and include physical examinations, vital signs assessments, 12-lead electrocardiograms (ECGs), routine clinical laboratory tests (including blood chemistry, hematology, coagulation, and urinalysis), and adverse event (AE) assessments. Vital sign assessments and 12-lead ECGs will be performed repeatedly over the 24-hour observation period. Venous blood samples will be taken at specified intervals and tested for the presence of CPSI-2364.

开始日期2009-07-01

申办/合作机构

Ferring Pharmaceuticals A/S

NCT00741910 / Completed临床2期

Extension Study of CNI-1493 for Treatment of Moderate to Severe Crohn's Disease

Study CNI-1493-CD06 is an open, single-arm extension studies to CD03 and CD05. CDAI is the only efficacy measure assessed in this study. The safety of multiple courses of semapimod is to be determined by the incidence of clinical and laboratory adverse events.

开始日期2003-07-01

申办/合作机构

Ferring Pharmaceuticals A/S

NCT00740103 / Completed临床2期

Long-term Study of Semapimod (CNI-1493) for Treatment of Moderate to Severe Crohn's Disease With Reference to Study CNI-1493-CD-04, 1 or 3 Days' Treatment vs. Placebo

CNI-1493-CD05 is an open-label extension study of CNI-1493-CD04. In the CD05 study, patients are eligible for up to 5 courses of semapimod 60 mg IV x 3 days every 6 - 8 weeks. Primary objective is assessment of the efficacy of cumulative doses of semapimod measured by decrease in Crohn's Disease Activity Index (CDAI).

开始日期2002-12-01

申办/合作机构

Ferring Pharmaceuticals A/S

100 项与塞马莫德相关的临床结果

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100 项与塞马莫德相关的转化医学

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100 项与塞马莫德相关的专利（医药）

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项与塞马莫德相关的文献（医药）

2024-04-01·Cell chemical biology

Discovery of antibiotics that selectively kill metabolically dormant bacteria

Article

作者: Herneisen, Alice ; Valeri, Jacqueline A ; Krishnan, Aarti ; Collins, James J ; Zheng, Erica J ; Linnehan, Brooke ; Renner, Lars D ; Wong, Felix ; Bandyopadhyay, Parijat ; Schulte, Fabian ; Anahtar, Melis N ; Stokes, Jonathan M ; Lourido, Sebastian ; Andrews, Ian W

There is a need to discover and develop non-toxic antibiotics that are effective against metabolically dormant bacteria, which underlie chronic infections and promote antibiotic resistance. Traditional antibiotic discovery has historically favored compounds effective against actively metabolizing cells, a property that is not predictive of efficacy in metabolically inactive contexts. Here, we combine a stationary-phase screening method with deep learning-powered virtual screens and toxicity filtering to discover compounds with lethality against metabolically dormant bacteria and favorable toxicity profiles. The most potent and structurally distinct compound without any obvious mechanistic liability was semapimod, an anti-inflammatory drug effective against stationary-phase E. coli and A. baumannii. Integrating microbiological assays, biochemical measurements, and single-cell microscopy, we show that semapimod selectively disrupts and permeabilizes the bacterial outer membrane by binding lipopolysaccharide. This work illustrates the value of harnessing non-traditional screening methods and deep learning models to identify non-toxic antibacterial compounds that are effective in infection-relevant contexts.

2023-04-20·Pharmaceutics

Multicomponent Lipid Nanoparticles for RNA Transfection.

Article

作者: Fomina-Ageeva, Elena ; Bezuglov, Vladimir ; Gretskaya, Nataliya ; Belitskaya, Ekaterina ; Mikhalyov, Ilya ; Akimov, Mikhail ; Zalygin, Anton ; Vodovozova, Elena ; Zinchenko, Galina ; Andreev, Dmitry

Despite the wide variety of available cationic lipid platforms for the delivery of nucleic acids into cells, the optimization of their composition has not lost its relevance. The purpose of this work was to develop multi-component cationic lipid nanoparticles (LNPs) with or without a hydrophobic core from natural lipids in order to evaluate the efficiency of LNPs with the widely used cationic lipoid DOTAP (1,2-dioleoyloxy-3-[trimethylammonium]-propane) and the previously unstudied oleoylcholine (Ol-Ch), as well as the ability of LNPs containing GM3 gangliosides to transfect cells with mRNA and siRNA. LNPs containing cationic lipids, phospholipids and cholesterol, and surfactants were prepared according to a three-stage procedure. The average size of the resulting LNPs was 176 nm (PDI 0.18). LNPs with DOTAP mesylate were more effective than those with Ol-Ch. Core LNPs demonstrated low transfection activity compared with bilayer LNPs. The type of phospholipid in LNPs was significant for the transfection of MDA-MB-231 and SW 620 cancer cells but not HEK 293T cells. LNPs with GM3 gangliosides were the most efficient for the delivery of mRNA to MDA-MB-231 cells and siRNA to SW620 cells. Thus, we developed a new lipid platform for the efficient delivery of RNA of various sizes to mammalian cells.

2016-06-15·Journal of immunology (Baltimore, Md. : 1950)2区 · 医学

Experimental Anti-Inflammatory Drug Semapimod Inhibits TLR Signaling by Targeting the TLR Chaperone gp96

2区 · 医学

Article

作者: Grishin, Anatoly V. ; Ford, Henri R. ; Wang, Jin

Abstract:

Semapimod, a tetravalent guanylhydrazone, suppresses inflammatory cytokine production and has potential in a variety of inflammatory and autoimmune disorders. The mechanism of action of Semapimod is not well understood. In this study, we demonstrate that in rat IEC-6 intestinal epithelioid cells, Semapimod inhibits activation of p38 MAPK and NF-κB and induction of cyclooxygenase-2 by TLR ligands, but not by IL-1β or stresses. Semapimod inhibits TLR4 signaling (IC50 ≈0.3 μmol) and acts by desensitizing cells to LPS; it fails to block responses to LPS concentrations of ≥5 μg/ml. Inhibition of TLR signaling by Semapimod is almost instantaneous: the drug is effective when applied simultaneously with LPS. Semapimod blocks cell-surface recruitment of the MyD88 adapter, one of the earliest events in TLR signaling. gp96, the endoplasmic reticulum–localized chaperone of the HSP90 family critically involved in the biogenesis of TLRs, was identified as a target of Semapimod using ATP-desthiobiotin pulldown and mass spectroscopy. Semapimod inhibits ATP-binding and ATPase activities of gp96 in vitro (IC50 ≈0.2–0.4 μmol). On prolonged exposure, Semapimod causes accumulation of TLR4 and TLR9 in perinuclear space, consistent with endoplasmic reticulum retention, an anticipated consequence of impaired gp96 chaperone function. Our data indicate that Semapimod desensitizes TLR signaling via its effect on the TLR chaperone gp96. Fast inhibition by Semapimod is consistent with gp96 participating in high-affinity sensing of TLR ligands in addition to its role as a TLR chaperone.

项与塞马莫德相关的新闻（医药）

2024-06-17

·AIDD Pro

Cell Chemical Biology | 休眠细菌的抗生素研发

简介新型抗生素药物的研发是当今的热点话题。今天介绍一篇发表在Cell Chemical Biology的抗生素研发的文章，传统抗生素多针对细菌活跃代谢时期，而作者针对于代谢不活跃的细菌(休眠细菌)进行药物设计。本文结合静止期筛选方法、深度学习和细胞毒性实验，发现了一种名为semapimod的药物，对静止期的大肠杆菌和鲍曼不动杆菌有效。研究表明，semapimod通过结合脂多糖，选择性破坏细菌外膜，增加外膜通透性。此研究展示了非传统筛选方法和深度学习模型在发现新型抗菌化合物中的潜力。休眠细菌当细菌进入人体并迅速繁殖时，如果食物耗尽，它们会进入休眠状态以节省能量。部分细菌在抗生素治疗期间保持休眠，从而避免被杀死，并在治疗结束后苏醒并再次繁殖，导致疾病复发。研究发现，细菌群体中少数休眠细菌的存在是其长期生存和适应环境压力的一种策略。这种机制使得抗生素耐药性问题变得更加复杂，需采取新的治疗方法来应对。休眠细菌是指处于一种低代谢或不活动状态的细菌。与活跃生长和繁殖的细菌不同，休眠细菌在这种状态下几乎不进行分裂和繁殖，代谢活动非常低。它们通过降低新陈代谢来适应不利的环境条件，例如营养缺乏、抗生素压力或其他应激条件。休眠状态的细菌在以下几个方面具有显著特征：抗药性：休眠细菌对传统抗生素具有很强的耐药性，因为大多数抗生素是针对活跃分裂和代谢旺盛的细胞设计的。休眠细胞由于代谢活动低，对这些药物不敏感。持久存在：这些细菌能够在宿主体内长期存活，导致慢性感染和反复发作。这是许多慢性和难治性细菌感染的根源。应激反应：代谢休眠是细菌应对不利环境的一种生存策略。当环境条件改善时，这些细胞可以重新恢复活跃的生长和分裂。生物膜形成：代谢休眠细菌常常形成生物膜，这是一种细菌聚集在一起并包裹在自身产生的保护性基质中的结构。生物膜使细菌更加难以被抗生素和免疫系统清除。理解和研究代谢休眠细菌对于开发新的抗菌策略，特别是针对慢性和顽固性细菌感染，具有重要意义。作者作者的研究方向包括以下两个主要领域：合成生物学：利用工程原理来建模、设计和构建合成基因网络和可编程细胞，目的是创造新型治疗手段。同时，使用深度学习方法发现新的基因元件并改进合成生物学设计过程。抗生素与人工智能（AI）：在抗生素-AI项目中，利用人工智能的力量发现新型抗生素，并快速了解它们的作用机制。同时，使用深度学习方法进行新抗生素的从头设计和开发。文章1. 基于稀释再生的筛选方法识别化合物作者开发了一种基于稀释和再生的方法来识别对休眠细菌具有致死性的化合物，使用静止期大肠杆菌BW25113，这种细菌在1% LB培养基中生长，从而进入代谢休眠状态，对常规抗生素具有耐受性。将上述静止期细菌经化合物处理24小时后，将少量样本接种到新鲜的100% LB培养基中，再生长24小时，识别出具有活性的 “Hit” 化合物。 2. 机器学习方法加速研发作者使用筛选数据训练了一个模型，用于预测抗生素。尽管许多预测方法使用分子表示方式比较固定，如SMILES字符串、化学指纹和特征描述符，但这些模型的表现通常不如直接从分子图中学习的表示。分子图将键和原子表示为图中的节点和边，这些分子图通常输入到图神经网络（GNNs）中，GNNs是将图表示转换为向量表示的神经网络。GNNs在药物性质预测中是非常强大的工具，可以准确地预测化合物的性质。 3.哺乳动物细胞毒性测试作者挑选了105种能够杀死休眠细菌的化合物：其中84种来自初级筛选，21种来自机器学习驱动的虚拟筛选。鉴于许多针对休眠细菌有效的抗生素具有较高毒性，作者设计了一个三步毒性过滤系统，目的是找到对代谢休眠细菌细胞具有选择性致命作用的化合物。首先，使用人肝细胞癌（HepG2）和胚胎肾（HEK293）细胞进行了单剂量细胞毒性测试，使用瑞沙星作为细胞活力的检测指标。将在任何一种细胞系中细胞活力表现低于50%的化合物分类为有毒，作者移除了56种化合物，最终保留了49种化合物。 4. Semapimod：一种靶向革兰氏阴性菌且无毒的抗生素 Semapimod通过了细胞毒性筛选。此外，semapimod在含有10% FBS或BSA的培养基中，其抗菌效力没有下降。Semapimod作为一种免疫调节药物曾用于治疗克罗恩病，并在临床试验中表现良好。总结在抗生素发现的“黄金时代”，大多数常用抗生素是在细菌生长时期发现的。然而，随后的研究揭示了感染微环境之间的多样性，其中许多情况涉及营养匮乏和代谢休眠。值得注意的是，细菌病原体的休眠状态对抗生素的耐受性和持久性会有很大影响，这一现象会导致治疗周期延长和反复发作感染。作者设计了一种筛选方法，结合了实验性化合物测试、基于机器学习的虚拟筛选和毒性评估。这种方法筛选出了多种针对代谢休眠的细菌，具有低毒性的抗菌化合物。参考 https://hms.harvard.edu/news/how-dormant-bacteria-return-life https://kids.frontiersin.org/articles/10.3389/frym.2019.00045 https://be-mit-edu.libproxy1.nus.edu.sg/directory/james-j-collins https://www-cell-com.libproxy1.nus.edu.sg/cell-chemical-biology/abstract/S2451-9456(23)00387-2?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2451945623003872%3Fshowall%3Dtrue 关注我，更多资讯早知道↓↓↓

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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
克罗恩病	临床2期	美国	Ferring Pharmaceuticals A/S	2002-06-01
HIV感染	临床2期	德国	GPC Biotech AG	-
胰腺炎	临床2期	荷兰	Cytokine PharmaSciences, Inc.	-
银屑病	临床2期	美国	Cytokine PharmaSciences, Inc.	-
化疗引起的损伤	临床1期	美国	Cytokine PharmaSciences, Inc.	-
炎症	临床1期	美国	Cytokine PharmaSciences, Inc.	-