Delving into the Latest Updates on R-verapamil with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

R-verapamil (AGI Therapeutics), Rezular

Target

5-HT receptor x Melatonin receptor x VDCCs

Action

modulators, blockers

Mechanism

5-HT receptor modulators(Serotonin (5-HT) receptor modulators), Melatonin receptor modulators(Melatonin receptor modulators), VDCCs blockers(Voltage-gated calcium channel blockers)

Therapeutic Areas

Digestive System Disorders

Active Indication-

Inactive Indication

Irritable bowel syndrome with diarrhea

Originator Organization

AGI Therapeutics Plc

Active Organization-

Inactive Organization

AGI Therapeutics, Inc.

License Organization-

Drug Highest PhasePendingPhase 3

First Approval Date-

Regulation-

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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.

01 Nov 2013·European Journal of Pharmaceutical SciencesQ2 · MEDICINE

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

Q2 · MEDICINE

Article

Author: 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.

01 Dec 2011·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

Author: 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 Deals associated with R-verapamil

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R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Irritable bowel syndrome with diarrhea	Phase 3	United States	AGI Therapeutics, Inc.	01 Sep 2007

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


FOLL05 (ASCO2012)	Not Applicable	Follicular Lymphoma First line	534	R-CVP	(flzpvyfaxy) = iiykcvtljr fvvkcnalcd (tefqxbpekk ) View more	Negative	20 May 2012
				R-CHOP	(flzpvyfaxy) = eocohxbddp fvvkcnalcd (tefqxbpekk ) View more
ASCO2009	Not Applicable	Marginal Zone B-Cell Lymphoma First line	22	R-CHOP	(wseraxfwbg) = kmfblxthbt nkdwblhxek (sozehhzvor )	-	20 May 2009
				R-CVP	(wseraxfwbg) = laksualano nkdwblhxek (sozehhzvor )