R-verapamil(R-verapamil) - 药物靶点：5-HT receptor x Melatonin receptor x VDCCs_专利_临床

概要

基本信息

药物类型

小分子化药

别名

R-verapamil (AGI Therapeutics)、Rezular

靶点

5-HT receptor x Melatonin receptor x VDCCs

作用方式

调节剂、阻滞剂

作用机制

5-HT receptor调节剂(5-羟色胺受体调节剂)、Melatonin receptor调节剂(褪黑激素受体家族调节剂)、VDCCs阻滞剂(电压门控性钙通道复合体阻滞剂)

治疗领域

消化系统疾病

在研适应症-

非在研适应症

腹泻型肠易激综合征

原研机构

AGI Therapeutics Plc

在研机构-

非在研机构

AGI Therapeutics, Inc.

权益机构-

最高研发阶段无进展临床3期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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关联

4

项与 R-verapamil 相关的临床试验

NCT02209155

/ Terminated临床2期

A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Phase 2 Study to Evaluate the Safety and Efficacy of R-Verapamil in the Prophylaxis of Episodic Cluster Headache

This is a double-blinded, randomized, parallel, placebo-controlled phase 2 study to evaluate the safety and efficacy of R-verapamil in the prophylaxis of episodic cluster headache.

开始日期2013-11-01

申办/合作机构

晟德大药厂股份有限公司

EUCTR2012-003729-62-GB

/ Not yet recruiting临床2期

A Randomized, Placebo-Controlled, Double-Blind, Parallel-Group, Phase 2 Study to Evaluate the Safety and Efficacy of R-Verapamil in the Prophylaxis of Episodic Cluster Headache - R-Verapamil in the Prophylaxis of Episodic Cluster Headache V.1

开始日期2013-01-16

申办/合作机构

晟德大药厂股份有限公司

NCT00552565

/ Completed临床3期

A Randomized, Double-Blind, Placebo-Controlled Study of Rezular (Arverapamil) in the Treatment of Irritable Bowel Syndrome With Diarrhea (IBS-D)

The purpose of the study is to determine the efficacy and safety of Rezular (arverapamil) in the treatment of IBS-D.

开始日期2007-09-01

申办/合作机构

AGI Therapeutics, Inc.

100 项与 R-verapamil 相关的临床结果

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100 项与 R-verapamil 相关的转化医学

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100 项与 R-verapamil 相关的专利（医药）

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61

项与 R-verapamil 相关的文献（医药）

2014-08-01·The Journal of Infectious Diseases2区 · 医学

Verapamil, and Its Metabolite Norverapamil, Inhibit Macrophage-induced, Bacterial Efflux Pump-mediated Tolerance to Multiple Anti-tubercular Drugs

2区 · 医学

Article

作者: Szumowski, John D. ; Ramakrishnan, Lalita ; Adams, Kristin N.

Drug tolerance likely represents an important barrier to tuberculosis treatment shortening. We previously implicated the Mycobacterium tuberculosis efflux pump Rv1258c as mediating macrophage-induced tolerance to rifampicin and intracellular growth. In this study, we infected the human macrophage-like cell line THP-1 with drug-sensitive and drug-resistant M. tuberculosis strains and found that tolerance developed to most antituberculosis drugs, including the newer agents moxifloxacin, PA-824, linezolid, and bedaquiline. Multiple efflux pump inhibitors in clinical use for other indications reversed tolerance to isoniazid and rifampicin and slowed intracellular growth. Moreover, verapamil reduced tolerance to bedaquiline and moxifloxacin. Verapamil's R isomer and its metabolite norverapamil have substantially less calcium channel blocking activity yet were similarly active as verapamil at inhibiting macrophage-induced drug tolerance. Our finding that verapamil inhibits intracellular M. tuberculosis growth and tolerance suggests its potential for treatment shortening. Norverapamil, R-verapamil, and potentially other derivatives present attractive alternatives that may have improved tolerability.

2013-11-01·European Journal of Pharmaceutical Sciences2区 · 医学

A semi-physiologically-based pharmacokinetic model characterizing mechanism-based auto-inhibition to predict stereoselective pharmacokinetics of verapamil and its metabolite norverapamil in human

2区 · 医学

Article

作者: Dawei Wang ; Weifang Xue ; Jian Wang ; Xiaodong Liu ; Sumei Xia ; Yang Sai ; Li Liu

Verapamil and its major metabolite norverapamil were identified to be both mechanism-based inhibitors and substrates of CYP3A and reported to have non-linear pharmacokinetics in clinic. Metabolic clearances of verapamil and norverapmil as well as their effects on CYP3A activity were firstly measured in pooled human liver microsomes. The results showed that S-isomers were more preferential to be metabolized than R-isomers for both verapamil and norverapamil, and their inhibitory effects on CYP3A activity were also stereoselective with S-isomers more potent than R-isomers. A semi-physiologically based pharmacokinetic model (semi-PBPK) characterizing mechanism-based auto-inhibition was developed to predict the stereoselective pharmacokinetic profiles of verapamil and norverapamil following single or multiple oral doses. Good simulation was obtained, which indicated that the developed semi-PBPK model can simultaneously predict pharmacokinetic profiles of S-verapamil, R-verapamil, S-norverapamil and R-norverapamil. Contributions of auto-inhibition to verapamil and norverapamil accumulation were also investigated following the 38th oral dose of verapamil sustained-release tablet (240mg once daily). The predicted accumulation ratio was about 1.3-1.5 fold, which was close to the observed data of 1.4-2.1-fold. Finally, the developed semi-PBPK model was further applied to predict drug-drug interactions (DDI) between verapamil and other three CYP3A substrates including midazolam, simvastatin, and cyclosporine A. Successful prediction was also obtained, which indicated that the developed semi-PBPK model incorporating auto-inhibition also showed great advantage on DDI prediction with CYP3A substrates.

2011-12-01·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids

Identification and characterization of ABCB1-mediated and non-apoptotic sebum secretion in differentiated hamster sebocytes

Article

作者: Akira Ito ; Takayuki Ogura ; Hirokazu Kurihara ; Noriko Akimoto ; Takashi Sato

Sebaceous glands secrete sebum onto the skin surface in a holocrine manner and as such a thin lipid layer is formed as a physiological barrier. In the present study, extracellular level of triacylglycerols (TG), a major sebum component, as well as intracellular TG accumulation was augmented in insulin-differentiated hamster sebocytes (DHS). The DHS exhibited phosphatidylserine exposure in an apoptosis-independent manner. In addition, intracellular ATP level and membrane-transporter activity using a substrate, Rhodamine 123, were highly detectable in the DHS rather than in the undifferentiated hamster sebocytes. A membrane-transporter activating reagent, 2'(3')-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP), enhanced transporter activity, extracellular TG level, and phosphatidylserine exposure in the DHS. Both transporter activity and TG secretion were suppressed by R-verapamil, a potent membrane-transporter inhibitor, in the BzATP-treated and untreated DHS. Furthermore, the gene expression and production of ATP-binding cassette subfamily B member 1 (ABCB1) were augmented in the DHS. ABCB1 was also detectable in sebaceous glands in the skin of hamsters. Moreover, the cell-differentiation- and BzATP-augmented transporter activity and TG secretion were dose-dependently inhibited by adding not only an ABCB1 antibody but also a selective inhibitor of ABCB1, PSC833. Thus, these results provide novel evidence that ABCB1 is involved in sebum secretion in the DHS, which is associated with non-apoptotic phosphatidylserine exposure and the increased level of intracellular ATP. These findings should accelerate the understanding of sebum secretion occurring in a holocrine-independent manner in sebaceous glands, and may contribute to the development of therapies for sebaceous gland disorders such as acne, seborrhea, and xerosis.

100 项与 R-verapamil 相关的药物交易

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研发状态

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
腹泻型肠易激综合征	临床3期	美国	AGI Therapeutics, Inc.	2007-09-01

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临床结果

适应症

分期

评价

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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


FOLL05 (ASCO2012)	N/A	滤泡性淋巴瘤一线	534	R-CVP	(網範築膚醖衊顧衊構鏇) = 淵鏇構鹹繭簾齋網鑰繭願鏇壓艱膚窪膚憲夢簾 (繭窪齋範夢夢繭簾遞繭 ) 更多	不佳	2012-05-20
				R-CHOP	(網範築膚醖衊顧衊構鏇) = 觸衊憲製簾遞簾觸簾構願鏇壓艱膚窪膚憲夢簾 (繭窪齋範夢夢繭簾遞繭 ) 更多
ASCO2009	N/A	边缘区B细胞淋巴瘤一线	22	R-CHOP	(鏇鏇積夢獵衊網築壓網) = 選夢選醖鏇鏇願膚鹽網衊築鹹積醖鬱範選艱構 (鏇範淵遞鹹鏇繭選鏇餘 )	-	2009-05-20
				R-CVP	(鏇鏇積夢獵衊網築壓網) = 艱顧築鹽蓋窪廠醖淵觸衊築鹹積醖鬱範選艱構 (鏇範淵遞鹹鏇繭選鏇餘 )