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Ganesh Thiagamoorthy, Linda Cardozo, Dudley Robinson
INTRODUCTION: Drugs which prevent acetylcholine mediated involuntary detrusor contractions are the mainstay of overactive bladder(OAB) treatment but there are now several alternative therapeutic options available. AREAS COVERED: Current and future drug therapies for OAB are highlighted. These include novel antimuscarinic molecules (imidafenacin and tarafenacin); novel combination therapies with β3-adrenoceptor agonists or muscarinic agonists (tolenix) and a novel vaginal delivery method for oxybutynin...
July 2016: Expert Opinion on Pharmacotherapy
Martin C Michel, Stavros Gravas
INTRODUCTION: We have reviewed the safety and tolerability of β3-adrenoceptor agonists, specifically mirabegron and solabegron, a newly emerging drug class for the treatment of the overactive bladder syndrome. We discuss them mechanistically in the context of expression and other preclinical data. AREAS COVERED: Based on a systematic PubMed search, incidence of overall adverse events, hypertension, dry mouth, and constipation are comparable between mirabegron or solabegron and placebo...
May 2016: Expert Opinion on Drug Safety
Cedric K Olivera, Kate Meriwether, Sherif El-Nashar, Cara L Grimes, Chi Chiung Grace Chen, Francisco Orejuela, Danielle Antosh, Jon Gleason, Shunaha Kim-Fine, Thomas Wheeler, Brook McFadden, Ethan M Balk, Miles Murphy
The purpose of the study was to determine the efficacy and safety of nonantimuscarinic treatments for overactive bladder. Medline, Cochrane, and other databases (inception to April 2, 2014) were used. We included any study design in which there were 2 arms and an n > 100, if at least 1 of the arms was a nonantimuscarinic therapy or any comparative trial, regardless of number, if at least 2 arms were nonantimuscarinic therapies for overactive bladder. Eleven reviewers double-screened citations and extracted eligible studies for study: population, intervention, outcome, effects on outcome categories, and quality...
July 2016: American Journal of Obstetrics and Gynecology
Martin C Michel, Cees Korstanje
β3-Adrenoceptor agonists were originally considered as a promising drug class for the treatment of obesity and/or type 2 diabetes. When these development efforts failed, they were repositioned for the treatment of the overactive bladder syndrome. Based on the example of the β3-adrenoceptor agonist mirabegron, but also taking into consideration evidence obtained with ritobegron and solabegron, we discuss challenges facing a translational pharmacology program accompanying clinical drug development for a first-in-class molecule...
March 2016: Pharmacology & Therapeutics
Helena Burden, Paul Abrams
INTRODUCTION: Urinary incontinence in men is a significant and often underappreciated problem. Men can have urgency and or stress incontinence. Urgency incontinence as part of the overactive bladder (OAB) syndrome and can often coexist with benign prostatic obstruction (BPO) in men and the initial treatment of this is conservative lifestyle changes and then medical therapy. AREAS COVERED: This literature review aims to cover synthetic drugs currently utilised to treat urinary incontinence in men that are phase III and onwards...
2016: Expert Opinion on Pharmacotherapy
Ganesh Thiagamoorthy, Ilias Giarenis, Linda Cardozo
INTRODUCTION: Antimuscarinic drugs form the mainstay of medical treatment for Overactive bladder Syndrome (OAB). With a proven efficacy but poor tolerability, other treatment modalities have been sought. Recent concerns regarding cumulative anticholinergic load and risk of dementia have provided further impetus to find novel OAB treatments. β3-adrenoceptor (β3-AR) agonists improve OAB symptoms by relaxing bladder tissue. As such, the search is underway to develop β3-AR agonist drugs for the treatment of OAB...
2015: Expert Opinion on Investigational Drugs
Ganesh Thiagamoorthy, Ilias Giarenis, Linda Cardozo
Antimuscarinic drugs form the mainstay of medical treatment for Overactive bladder Syndrome (OAB). With a proven efficacy but poor tolerability, other treatment modalities have been sought. Recent concerns regarding cumulative anticholinergic load and risk of dementia have provided further impetus to find novel OAB treatments. β3-adrenoceptor (β3-AR) agonists improve OAB symptoms by relaxing bladder tissue. As such, the search is underway to develop β3-AR agonist drugs for the treatment of OAB. Areas covered: The authors discuss studies on the only approved β3-AR agonist, mirabegron, followed by reports on β3-AR agonists in development, namely ritobegron and solabegron...
August 14, 2015: Expert Opinion on Investigational Drugs
Robin Hertzberg, Guillermo Monreal Santiago, Christina Moberg
A novel methodology to produce highly enantioenriched N-(2-ethylamino)-β-amino alcohols was developed. These compounds were obtained from O-(α-bromoacyl) cyanohydrins, which were synthesized by the minor enantiomer methodology employing a Lewis acid and a biocatalyst, followed by nucleophilic substitution with amines and reduction. The importance of the developed methodology was demonstrated by completing a highly enantioselective total synthesis of the β3-adrenergic receptor agonist Solabegron.
March 6, 2015: Journal of Organic Chemistry
Pamela Ellsworth, Jennifer Fantasia
INTRODUCTION: Overactive bladder (OAB) affects many women and men worldwide and has a significant adverse effect on a person's quality of life. Historically, behavioral therapy and anti-muscarinic agents have been the primary therapies used in the management of OAB. However, persistence with anti-muscarinic therapy has been limited. The role of β-3 agonists is established in the management of OAB with the first β-3 agonist recently approved by the FDA. Solabegron is one such selective β-3 agonist currently under investigation...
March 2015: Expert Opinion on Investigational Drugs
Yasuhiko Igawa, Martin C Michel
β(3)-Adrenoceptor agonists are an emerging drug class for the treatment of the overactive bladder syndrome, and clinical proof-of-concept data have been obtained for three representatives of this class, mirabegron, ritobegron, and solabegron. We review here the pharmacological profile of these three drugs and discuss the potential clinical relevance of differences between them. In the absence of direct comparative studies, it appears that all three are strong agonists selective for β(3)- vs. β(1)- and β(2)-adrenoceptors in studies with cloned receptor subtypes...
March 2013: Naunyn-Schmiedeberg's Archives of Pharmacology
Eliot H Ohlstein, Alexander von Keitz, Martin C Michel
BACKGROUND: β-Adrenoceptor agonists are effective in animal models of bladder dysfunction, and the human bladder primarily expresses the β3 receptor subtype. OBJECTIVE: To evaluate the efficacy and tolerability of the highly selective and potent β3-adrenoceptor agonist solabegron in a clinical proof-of-concept study in incontinent women with overactive bladder (OAB). DESIGN, SETTING, AND PARTICIPANTS: This was a randomized, double-blind trial in adult women with OAB (one or more 24-h incontinence episodes and eight or more average 24-h micturitions)...
November 2012: European Urology
Pamela Ellsworth
Overactive bladder (OAB) is a common syndrome that affects both men and women. First-line therapies for the management of OAB symptoms consist of antimuscarinic agents and behavioral therapy, ideally used in combination. Although effective in improving OAB symptoms, the use of antimuscarinic therapy may be limited by side effects, contraindications, and insufficient response. Current second-line therapies include sacral nerve stimulation and percutaneous tibial nerve stimulation. These therapies have been shown to be useful in treating OAB symptoms, but are more invasive and time-consuming than medical therapy...
May 2012: Postgraduate Medicine
Michael Schemann, Nadia Hafsi, Klaus Michel, Olivia I Kober, Jutta Wollmann, Qin Li, Florian Zeller, Rupert Langer, Kevin Lee, Selim Cellek
BACKGROUND & AIMS: beta3 Adrenoceptor (beta3-AR) is expressed on adipocytes and enteric neurons. GW427353 is a human selective beta3-AR agonist with visceral analgesic effects. Some of its effects may involve release of somatostatin (SST) and actions on enteric neurons. The aim of this study was to investigate the mode of action of GW427353 in human submucous neurons. METHODS: Voltage sensitive dye imaging was used to record from human submucous neurons. SST release from human primary adipocytes was measured with enzyme-linked immunoabsorbent assay...
January 2010: Gastroenterology
Pradeep Tyagi, Catherine A Thomas, Naoki Yoshimura, Michael B Chancellor
PURPOSE: We investigated the presence of functional Beta1, Beta2 and Beta3-adrenoceptor in urothelium and detrusor muscle of human bladder through in vitro pharmacology of selective Beta3 adrenoceptor agonist solabegron. MATERIALS AND METHODS: Expression of these adrenoceptors in surgically separated human urothelium and detrusor muscle were investigated using RT-PCR. The effects of activating these receptors were studied by determining the relaxation produced by Beta-adrenoceptors agonist in pre-contracted human detrusor strips...
January 2009: International Braz J Urol: Official Journal of the Brazilian Society of Urology
April B M Grudell, Michael Camilleri, Kim L Jensen, Amy E Foxx-Orenstein, Duane D Burton, Michael D Ryks, Kari L Baxter, Donna S Cox, George E Dukes, Dennis L Kelleher, Alan R Zinsmeister
beta(3)-Adrenoceptors(beta(3)-AR) are expressed by cholinergic myenteric neurons and beta(3)-AR agonists are effective in experimental models of diarrhea. Our aim was to explore the effects of a beta(3)-AR agonist, solabegron, on gastrointestinal transit, safety, bowel function, plasma somatostatin, and solabegron pharmacokinetics (PK) following single and multiple doses. In a single-center, double-blind, parallel-group trial, 36 healthy volunteers were randomized to oral solabegron (50 or 200 mg twice daily) or placebo...
May 2008: American Journal of Physiology. Gastrointestinal and Liver Physiology
Alexandra Hicks, Gerald P McCafferty, Erin Riedel, Nambi Aiyar, Mark Pullen, Christopher Evans, Trudy D Luce, Robert W Coatney, Gian C Rivera, Timothy D Westfall, J Paul Hieble
Functional studies have demonstrated that adrenoceptor agonist-evoked relaxation is mediated primarily by beta3-adrenergic receptors (ARs) in human bladder. Thus, the use of selective beta3-AR agonists in the pharmacological treatment of overactive bladder is being explored. The present studies investigated the effects of a novel selective beta3-AR agonist, (R)-3'-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1'-biphenyl]-3-carboxylic acid (GW427353; solabegron) on bladder function in the dog using in vitro and in vivo techniques...
October 2007: Journal of Pharmacology and Experimental Therapeutics
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