solabegron and Urinary-Bladder--Overactive

Mirabegron, the first β3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms. Because β3-adrenoceptors are expressed in cardiovascular (CV) tissues, there are concerns that OAB treatment with β3-adrenoceptor agonists may affect the heart and vasculature.. To provide a summary of CV effects of β3-adrenoceptor agonists in clinical studies.. A systematic literature search from inception until November 2014 was performed on studies in PubMed and Medline.. Twenty papers, published between 1994 and 2014, were identified: mirabegron (16), solabegron (2), AK-677 (1), and BRL35135 (1). More detailed CV data from mirabegron studies were available in online regulatory documents filed with the US Food and Drug Administration and the UK National Institute for Health and Care Excellence.. The CV safety of mirabegron appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, currently first-line therapy for OAB.. In this review we looked at the cardiovascular (CV) effects of β3-adrenoceptor agonists used for the treatment of overactive bladder (OAB). The CV safety of mirabegron (the only clinically approved β3-adrenoceptor agonist) appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, the current first-line therapy for OAB.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Benzoates; Biphenyl Compounds; Blood Pressure; Cardiovascular Diseases; Electrocardiography; Heart Rate; Humans; Thiazoles; Urinary Bladder, Overactive

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.. Based on a systematic PubMed search, incidence of overall adverse events, hypertension, dry mouth, and constipation are comparable between mirabegron or solabegron and placebo. Hypertension is the most frequently observed adverse event, but has a similar incidence with mirabegron and placebo. Nevertheless, severe uncontrolled hypertension has become a contraindication for use of mirabegron based on observation of severe hypertension in association with mirabegron exposure. The overall incidence of adverse events is also similar between mirabegron and the muscarinic receptor antagonist tolterodine, but the incidence of dry mouth is much lower with mirabegron.. The high β3-adrenoceptor mRNA expression in the human ovaries is not associated with reproductive side effects. Generally, β3-adrenoceptors exhibit a rather restricted expression in human tissues, which may explain the overall good tolerability of agonists acting on this receptor. We propose that expression profiles and functional preclinical studies can be important tools in the prediction of adverse event profiles in first-in-class drugs.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Animals; Benzoates; Biphenyl Compounds; Gene Expression Profiling; Humans; Receptors, Adrenergic, beta-3; Thiazoles; Urinary Bladder, Overactive

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.. In this review, the authors discuss animal studies, in vitro human bladder strip and Phase II studies, which suggest a role for solabegron in the management of OAB. The authors also discuss its potential role in combination therapy.. Phase II studies with solabegron support its potential future role in the management of OAB. However, further studies are needed to establish its efficacy and safety as well as to allow its clinical comparison with current therapies.

Topics: Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Animals; Benzoates; Biphenyl Compounds; Drug Therapy, Combination; Female; Humans; Male; Muscarinic Antagonists; Quality of Life; Urinary Bladder, Overactive

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. Onabotulinum toxin A is currently under investigation for idiopathic OAB, as well as the β-3-adreno-renoreceptor agonists mirabegron and solabegron. The role of these agents, with different mechanisms of action, in the pharmacologic management of OAB remains to be determined, although they appear to be promising alternatives and possible adjuncts to current pharmacologic and behavioral therapy. This article discusses second-line and current and future therapies for the management of OAB symptoms.

Topics: Acetanilides; Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Behavior Therapy; Benzoates; Biphenyl Compounds; Botulinum Toxins, Type A; Clinical Trials as Topic; Electric Stimulation Therapy; Humans; Muscarinic Antagonists; Neuromuscular Agents; Sacrum; Thiazoles; Tibial Nerve; Urinary Bladder, Overactive

β-Adrenoceptor agonists are effective in animal models of bladder dysfunction, and the human bladder primarily expresses the β3 receptor subtype.. 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).. 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).. Solabegron 50 mg (n=88), solabegron 125 mg (n=85), or placebo (n=85)-all twice daily-were administered.. The primary efficacy end point was percentage change from baseline to week 8 in the number of incontinence episodes over 24 h. Secondary end points included actual change and percentage change from baseline to week 4 and week 8 in micturitions per 24 h, urgency episodes per 24 h, and volume voided per micturition. Adverse events (AEs) were assessed, as well.. Solabegron 125 mg produced a statistically significant difference in percent change from baseline to week 8 in incontinence episodes over 24h when compared with placebo (p=0.025). Solabegron 125 mg treatment also showed statistically significant reductions from baseline to weeks 4 and 8 in micturitions over 24 h and a statistically significant increase from baseline to week 8 in urine volume voided. Solabegron was well tolerated, with a similar incidence of AEs in each treatment group. There were no significant treatment differences for mean changes from baseline to week 8 in systolic blood pressure (BP), diastolic BP, mean arterial pressure (MAP), or heart rate during the 24-h ambulatory measurement.. Solabegron significantly reduced the symptoms of OAB in women with moderate to severe OAB. Solabegron was safe, well tolerated, and did not demonstrate significant differences in AEs as compared to placebo. β3-Adrenoceptor agonists may represent a new therapeutic approach for treating OAB symptoms.

Topics: Adrenergic beta-3 Receptor Agonists; Adult; Aged; Aniline Compounds; Argentina; Australia; Benzoates; Biphenyl Compounds; Double-Blind Method; Drug Administration Schedule; Europe; Female; Humans; Linear Models; Middle Aged; New Zealand; Republic of Korea; South Africa; Taiwan; Time Factors; Treatment Outcome; Urinary Bladder; Urinary Bladder, Overactive; Urinary Incontinence; Urination; Urodynamics; Young Adult

Topics: Adrenergic beta-3 Receptor Agonists; Aniline Compounds; Benzoates; Biphenyl Compounds; Female; Humans; Urinary Bladder; Urinary Bladder, Overactive; Urinary Incontinence

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. GW427353 stimulated cAMP accumulation in Chinese hamster ovary cells expressing the human beta3-AR, with an EC50 value of 22 +/- 6 nM and an intrinsic activity 90% of isoproterenol. At concentrations of 10,000 nM, GW427353 produced a minimal response in cells expressing either beta1-ARs or beta2-ARs (maximum response <10% of that to isoproterenol). In dog isolated bladder strips, GW427353 evoked relaxation that was attenuated by the nonselective beta-AR antagonist bupranolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol (SR59230A) (reported to have beta3-AR antagonist activity). The relaxation was unaffected by atenolol, a selective beta1-AR antagonist, or (+/-)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118551), a selective beta2-AR antagonist. GW427353 increased the volume required to evoke micturition in the anesthetized dog following acetic acid-evoked bladder irritation, without affecting the ability of the bladder to void. GW427353-evoked effects on bladder parameters in vivo were inhibited by bupranolol. The present study demonstrates that selective activation of beta3-AR with GW427353 evokes bladder relaxation and facilitates bladder storage mechanisms in the dog.

Topics: Acetic Acid; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-Agonists; Aniline Compounds; Animals; Benzoates; Biphenyl Compounds; CHO Cells; Cricetinae; Cricetulus; Cyclic AMP; Disease Models, Animal; Dogs; Female; Humans; Muscle Relaxation; Muscle, Smooth; Reflex; Urinary Bladder; Urinary Bladder, Overactive; Urination