托那博沙(Tonabersat) - 药物靶点：GJA1_在研适应症：糖尿病性黄斑水肿，癫痫_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

GJA1

作用机制

GJA1抑制剂(缝隙连接蛋白α1抑制剂)

治疗领域

心血管疾病内分泌与代谢疾病眼部疾病+ [1]

在研适应症

糖尿病性黄斑水肿癫痫

非在研适应症

偏头痛先兆偏头痛无先兆偏头痛

原研机构

GSK Plc

在研机构

Jaeb Center For Health Research Foundation, Inc.

Upsher-Smith Laboratories LLC

非在研机构

Minster Research LtdProximagen Group Plc

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

登录后查看时间轴

结构

分子式C20H19ClFNO4

InChIKeyXLIIRNOPGJTBJD-ROUUACIJSA-N

CAS号175013-84-0

关联

9

项与托那博沙相关的临床试验

NCT06437223 / Recruiting临床2期

A Phase 2 Study to Compare the Efficacy and Safety of Orally Administered Xiflam™ Therapy With Orally Administered Placebo in Patients With Ocular and Systemic Manifestations of Post COVID Sequelae Known as "Long" COVID

The primary objective of this study is to evaluate the safety and efficacy of Xiflam versus Placebo in patients who present with signs and symptoms of Long COVID.
Xiflam (n=10) or placebo (n=5) will be administered orally once a day (QD) for 12 weeks.

开始日期2024-03-12

申办/合作机构

InflammX Therapeutics, Inc.

NCT05727891 / Recruiting临床2期IIT

A Phase 2 Evaluation of Tonabersat for Diabetic Macular Edema (Protocol AN)

This randomized clinical trial will evaluate the effect of tonabersat compared with placebo on central subfield thickness (CST) in eyes with center-involved diabetic macular edema (CI-DME) and good visual acuity.

开始日期2023-05-02

申办/合作机构

Jaeb Center For Health Research Foundation, Inc.

[+3]

NL-OMON35227 / CompletedN/A

A PHASE 1, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND, MULTIPLE DOSE, PARALLEL ARM STUDY TO EVALUATE THE EFFECT OFMEAL TIMING AND FOOD- VERSUS THE FASTED STATE ON THE SAFETY, TOLERABILITY AND PHARMACOKINETICS OF REPETITIVE DAILY DOSES OF TONABERSAT (USL260) IN HEALTHY SUBJECTS - FE Tonabersat

开始日期2011-10-24

申办/合作机构-

100 项与托那博沙相关的临床结果

登录后查看更多信息

100 项与托那博沙相关的转化医学

登录后查看更多信息

100 项与托那博沙相关的专利（医药）

登录后查看更多信息

51

项与托那博沙相关的文献（医药）

2024-11-01·Methods

Development and validation of a stability-indicating HPLC method for assay of tonabersat in pharmaceutical formulations

Article

作者: Agarwal, Priyanka ; Rupenthal, Ilva D ; Bhujbal, Santosh ; Rupenthal, Ilva D.

A stability-indicating reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed to assay tonabersat and assess its stability in pharmaceutical formulations. Chromatographic separation was achieved using a Kinetex® C18 column (2.6 µm, 150 x 3 mm, 100 Å) at 50 °C, with a 20 µL injection volume. A linear gradient of acetonitrile in water (5 - 33.5 %) was applied for 1 min, followed by a gradual increase to 100 % over 26 min at a flow rate of 0.5 mL/min. Tonabersat and its degradation products were detected at 275 nm and 210 nm, respectively. The optimized method was used to evaluate the stability of tonabersat in lipid-based pharmaceutical formulations at 5 ± 3 °C, 25 ± 2°C/60 ± 5 % RH, and 40 ± 2 °C/75 ± 5 % RH over 3 months. The method was validated as per ICH guidelines and demonstrated linearity in the range of 5 - 200 µg/mL (R² = 0.99994) with good accuracy (98.25 - 101.58 % recovery) and precision (% RSD < 2.5 %). The limits of detection and quantitation were 0.8 µg/mL and 5 µg/mL, respectively. Forced degradation studies showed significant degradation on exposure to alkaline (90.33 ± 0.80 %), acidic (70.60 ± 1.57 %), and oxidative stress (33.95 ± 0.69 %) at 70 °C, but no degradation was observed on exposure to thermal or photolytic stress. No chemical degradation was observed in either formulation on storage. Thus, the method was sensitive, specific, and suitable for stability testing of tonabersat in pharmaceutical formulations.

2024-01-01·Experimental Neurology

Blockade of connexin hemichannels with tonabersat protects against mild hypoxic ischemic brain injury in neonatal rats

Article

作者: Dean, Justin M ; Zhou, Kelly Q ; Wassink, Guido ; Ranasinghe, Sumudu ; Davidson, Joanne O ; McDouall, Alice ; Karunasinghe, Rashika N

BACKGROUND AND PURPOSEThere is growing evidence that infants with mild hypoxic-ischemic (HI) encephalopathy have increased risk of brain injury and adverse neurodevelopmental outcomes. Currently, there is no approved treatment for these infants. It was previously shown that blocking connexin 43 hemichannels is neuroprotective in models of moderate to severe HI injury. However, it is yet to be established whether these channels play a role in the evolution of mild HI brain injury, and whether blocking these channels after mild HI is neuroprotective.METHODSHI was induced in postnatal day 10 rats of both sexes by right carotid artery ligation followed by 80 min of hypoxia in 8% oxygen. Pups receiving HI were randomised to receive intraperitoneal injections of either saline, vehicle (2-hydroxypropyl-beta-cyclodextrin polyethylene glycol-400), or tonabersat (2 mg/kg), at 60 min, 24 h, and 48 h after hypoxia. Seven days after HI, brains were harvested for measurement of volume loss and histological analysis.RESULTSHI resulted in a significant reduction in hemispheric, hippocampal, and white matter volumes, which were significantly attenuated after treatment with tonabersat. HI was also associated with a significant reduction in numbers of neurons in the CA1 and CA3 hippocampal regions, a reduction in the numbers of oligodendrocytes in the corpus callosum, and an increase in the number of astrocytes in both regions, which were significantly attenuated by tonabersat treatment. There were no differences in rectal temperatures between tonabersat- and vehicle-treated rat pups.CONCLUSIONSBlockade of connexin hemichannels with tonabersat significantly reduced mild HI injury in the hippocampus and white matter, without causing hypothermia.

2022-12-01·Diabetic Medicine

Blocking connexin 43 hemichannel‐mediated ATP release reduces communication within and between tubular epithelial cells and medullary fibroblasts in a model of diabetic nephropathy

Article

作者: Hills, Claire E. ; Williams, Bethany M. ; Squires, Paul E. ; Demirel, Isak ; Cliff, Chelsy L.

AbstractIntroductionFibrosis of renal tubules is the final common pathway in diabetic nephropathy and develops in the face of tubular injury and fibroblast activation. Aberrant connexin 43 (Cx43) hemichannel activity has been linked to this damage under euglycaemic conditions, however, its role in glycaemic injury is unknown. This study investigated the effect of a Cx43 blocker (Tonabersat) on hemichannel activity and cell–cell interactions within and between tubular epithelial cells and fibroblasts in an in vitro model of diabetic nephropathy.MethodsHuman kidney (HK2) proximal tubule epithelial cells and medullary fibroblasts (TK173) were treated in low (5 mM) or high (25 mM) glucose ± transforming growth factor beta‐1 (TGFβ1) ± Tonabersat in high glucose. Carboxyfluorescein dye uptake and ATPlite luminescence assessed changes in hemichannel‐mediated ATP release, while immunoblotting determined protein expression. Co‐incubation with the ATP‐diphosphohydrolase apyrase or a P2X7R inhibitor (A438079) assessed ATP‐P2X7R signalling. Indirect co‐culture with conditioned media from the alternate cell type evaluated paracrine‐mediated heterotypic interactions.ResultsTonabersat partially negated glucose/TGFβ1‐induced increases in Cx43 hemichannel‐mediated ATP release and downstream changes in adherens junction and extracellular matrix (ECM) protein expression in HK2 and TK173 cells. Apyrase and A438079 highlighted the role for ATP‐P2X7R in driving changes in protein expression in TK173 fibroblasts. Indirect co‐culture studies suggest that epithelial cell secretome increases Tonabersat‐sensitive hemichannel‐mediated dye uptake in fibroblasts and downstream protein expression.ConclusionTonabersat‐sensitive hemichannel‐mediated ATP release enhances TGFβ1‐driven heterotypic cell–cell interaction and favours myofibroblast activation. The data supports the potential benefit of Cx43 inhibition in reducing tubulointerstitial fibrosis in late‐stage diabetic nephropathy.

100 项与托那博沙相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB06578

研发状态

10 条进展最快的记录,

登录

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
糖尿病性黄斑水肿	临床2期	美国	Jaeb Center For Health Research Foundation, Inc.	2023-05-02
先兆偏头痛	临床1期	英国	Minster Research Ltd	2006-04-01
先兆偏头痛	临床1期	丹麦	Minster Research Ltd	2006-04-01
先兆偏头痛	临床1期	匈牙利	Minster Research Ltd	2006-04-01
先兆偏头痛	临床1期	南非	Minster Research Ltd	2006-04-01
无先兆偏头痛	临床1期	英国	Minster Research Ltd	2006-04-01
无先兆偏头痛	临床1期	丹麦	Minster Research Ltd	2006-04-01
无先兆偏头痛	临床1期	南非	Minster Research Ltd	2006-04-01
无先兆偏头痛	临床1期	匈牙利	Minster Research Ltd	2006-04-01
偏头痛	临床前	-	Upsher-Smith Laboratories LLC	-

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT00332007 (Pubmed \| Lancet Neurol)	临床2期	先兆偏头痛	39	Tonabersat 40 mg	(襯簾遞網積壓衊範衊膚) = Tonabersat was well tolerated but overall had more side-effects than placebo 餘窪衊夢製範醖觸鑰蓋 (簾蓋餘蓋簾糧鹽憲齋遞 )	积极	2009-08-01
				Placebo
NCT00311662 (Pubmed \| Cephalalgia)	临床2期	偏头痛	124	Tonabersat 20 mg	(繭獵蓋鹹憲醖網廠願積) = 繭衊網壓襯積選網淵鬱選範衊艱窪獵淵簾膚衊 (襯餘鬱積鏇範築淵衊簾 )	-	2009-07-01
				Placebo	(繭獵蓋鹹憲醖網廠願積) = 艱艱夢選積顧憲醖選鹽選範衊艱窪獵淵簾膚衊 (襯餘鬱積鏇範築淵衊簾 )