Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome (original) (raw)
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European Urology, 2016
Context: Mirabegron, the first b 3-adrenoceptor agonist in clinical practice, is approved for treatment of overactive bladder (OAB) syndrome symptoms. Because b 3-adrenoceptors are expressed in cardiovascular (CV) tissues, there are concerns that OAB treatment with b 3-adrenoceptor agonists may affect the heart and vasculature. Objective: To provide a summary of CV effects of b 3-adrenoceptor agonists in clinical studies. Evidence acquisition: A systematic literature search from inception until November 2014 was performed on studies in PubMed and Medline. Evidence synthesis: 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. Conclusions: 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. Patient summary: In this review we looked at the cardiovascular (CV) effects of b 3adrenoceptor agonists used for the treatment of overactive bladder (OAB). The CV safety of mirabegron (the only clinically approved b 3-adrenoceptor agonist) appears to be acceptable at therapeutic doses and comparable with that of antimuscarinic agents, the current first-line therapy for OAB.
Beta3-Adrenoceptor Agonists: Possible Role in the Treatment of Overactive Bladder
Korean Journal of Urology, 2010
In the present review article, we present an overview of beta-adrenoceptor (β-AR) subtype expression at the mRNA and receptor protein levels in the human detrusor, the in vitro and in vivo bladder function of the β3-AR, the in vivo effect of β3-AR agonists on detrusor overactivity in animal models, and the available results of clinical trials of β3-AR agonists for treating overactive bladder (OAB). There is a predominant expression of β3-AR mRNA in human bladder, constituting 97% of total β-AR mRNA. Also, functionally, the relaxant response of human detrusor to catecholamines is mainly mediated through the β3-ARs. Moreover, the presence of β1-, β2-, and β3-AR mRNAs in the urothelium and suburothelial layer of human bladder has been identified. Stimulation of urothelial β-ARs results in the release of nitric oxide and an unknown substance inhibiting detrusor contractions from the urothelium. Intravenous application of CL316,243, a selective β3-AR agonist, in rats selectively inhibits mechano-sensitive Aδ-fiber activity of the primary bladder afferents. A number of selective β3-AR agonists are currently being evaluated in clinical trials for OAB with promising preliminary results. In conclusion, the β3-AR agonists are the most notable alternative class of agents to antimuscarinics in the pharmacological treatment of OAB. The β3-AR agonists act to facilitate bladder storage function probably through at least two mechanisms: first, direct inhibition of the detrusor, and second, inhibition of bladder afferent neurotransduction.
On the Site and Mechanism of Action of β3-Adrenoceptor Agonists in the Bladder
International Neurourology Journal, 2017
The clinical success of mirabegron as the first β3-adrenoceptor (AR) agonist for treatment of the overactive bladder (OAB) syndrome, has resulted in substantial interest in its site and mechanism of action. Even if the adrenergic innervation of the bladder and urethra has been well studied, the location(s) of β3-ARs in different structures within the bladder wall and urethra, and the mode(s) of action of β3-AR stimulation have still not been established. The recent demonstration of β3-ARs on cholinergic nerve terminals with no immunoreactivity in urothelium or detrusor smooth muscle, is not in agreement with previous morphological studies, and functional data strongly suggest that β3-ARs can be found these structures. However, recent studies suggest that the β3-ARs on detrusor smooth muscle may not be the functionally most relevant. The assumption that β3-AR activation during bladder filling inhibits acetylcholine release from parasympathetic neurons by a prejunctional mechanism and that this decreases bladder micromotions that generate afferent activity, is an attractive hypothesis. It does not exclude that other mechanisms may be contributing, and supports combined approaches to reduce afferent activity for treatment of the OAB syndrome.
Clinical use of the β3 adrenoceptor agonist mirabegron in patients with overactive bladder syndrome
Therapeutic advances in urology, 2015
Mirabegron is a β3 adrenoceptor agonist licensed for the treatment of overactive bladder symptoms, such as urinary urgency or urgency incontinence. β3 adrenoceptor activation causes detrusor muscle relaxation, but mirabegron may also act by binding other targets in the bladder, and it may also reduce activity in sensory nerves. Phase III clinical trials (SCORPIO, ARIES, and CAPRICORN) evaluated mirabegron at various doses, demonstrating reduction from baseline to endpoint in mean incontinence episodes and mean number of micturitions per 24 h (coprimary endpoints), along with health-related quality of life and a range of secondary measures. Efficacy was seen in many patients who had previously discontinued antimuscarinic therapy on the grounds of lack of efficacy or poor tolerability. Treatment emergent adverse effects were documented in a long-term study (TAURUS), mostly being of mild or moderate severity. The most frequent adverse effects were hypertension, dry mouth, constipation,...
Journal of Pharmacology and Experimental Therapeutics, 2007
Functional studies have demonstrated that adrenoceptor agonist-evoked relaxation is mediated primarily by  3-adrenergic receptors (ARs) in human bladder. Thus, the use of selective  3-AR agonists in the pharmacological treatment of overactive bladder is being explored. The present studies investigated the effects of a novel selective  3-AR agonist, (R)-3Ј-[[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]ethyl]amino]-[1,1Ј-biphenyl]-3carboxylic 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  3-AR, with an EC 50 value of 22 Ϯ 6 nM and an intrinsic activity 90% of isoproterenol. At concentrations of 10,000 nM, GW427353 produced a minimal response in cells expressing either  1-ARs or  2-ARs (maximum response Ͻ10% of that to isoproterenol). In dog isolated bladder strips, GW427353 evoked relaxation that was attenuated by the nonselective -AR antagonist bupranolol and 1-(2-ethylphenoxy)-3-[[(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]-(2S)-2-propanol (SR59230A) (reported to have  3-AR antagonist activity). The relaxation was unaffected by atenolol, a selective  1-AR antagonist, or (Ϯ)-1-[2,3-(dihydro-7-methyl-1H-inden-4yl)oxy]-3-[(1-methylethyl)amino]-2-butanol (ICI 118551), a selective  2-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  3-AR with GW427353 evokes bladder relaxation and facilitates bladder storage mechanisms in the dog. Overactive bladder is a syndrome characterized by symptoms of urinary frequency, urgency, nocturia, and urgency incontinence in which there is a need for alternative therapies with novel mechanisms of action (Andersson and Wein, 2004). The activities of the urinary bladder during urine storage and voiding are governed by a complex neural control system, involving both sympathetic and parasympathetic input. During bladder filling, sympathetic nerve activity to bladder smooth muscle results in -adrenergic receptor (AR)mediated relaxation (Andersson and Wein, 2004). Several subtypes of -ARs have been identified, namely,  1 ,  2 , and  3-ARs (Bylund et al., 1994). Evidence suggests that species differences exist in the distributions and roles of -ARs in the bladder (for comprehensive review, see Michel and Vrydag, 2006). Bladder relaxation evoked by -AR agonists is mediated mainly via  1-ARs in cats (Nergardh et al., 1977) and guinea pigs (Li et al., 1992), by  2-ARs in rabbits, by both  2and  3-ARs in rats (Yamazaki et al., 1998) and pigs (Yamanishi et al., 2002), and by  3-ARs in the ferrets (Takeda et al., 2000), dogs (Yamazaki et al., 1998), and primates (Takeda et al., 2002a). Based on mRNA expression, at least 95% of the adrenoceptor message in human bladder comprises the  3-AR subtype (Nomiya and Yamaguchi, 2003). Further-Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
European Urology, 2012
Background: b-Adrenoceptor agonists are effective in animal models of bladder dysfunction, and the human bladder primarily expresses the b3 receptor subtype. Objective: To evaluate the efficacy and tolerability of the highly selective and potent b3adrenoceptor 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). Interventions: Solabegron 50 mg (n = 88), solabegron 125 mg (n = 85), or placebo (n = 85)-all twice daily-were administered. Outcome measurements and statistical analysis: 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. Results and limitations: Solabegron 125 mg produced a statistically significant difference in percent change from baseline to week 8 in incontinence episodes over 24 h 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. Conclusions: 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. b3-Adrenoceptor agonists may represent a new therapeutic approach for treating OAB symptoms.
Mirabegron for overactive bladder: a novel, first-in-class β3-agonist therapy
Urology journal, 2013
PURPOSE To discuss the pharmacotherapeutic aspects of Mirabegron which is a first-in class novel β3 receptor agonist drug recently approved by the food and drug administration (FDA) for the treatment of overactive bladder (OAB). MATERIALS AND METHODS We conducted a computerized search of the MEDLINE/PUBMED databases with the word Mirabegron, β3 receptor agonist and overactive bladder. RESULTS Effect of Mirabegron on β3 adrenergic receptor purportedly releases nitric oxide(NO) by an increase in intracellular Ca2+ through accumulation of cyclic adenosine monophosphate (cAMP). Along with NO which relaxes the detrusor muscle, it also releases an urothelial-derived inhibiting factor (UDIF) that inhibits contractions. It increases the bladder capacity by causing bladder relaxation during the storage phase. CONCLUSION Mirabegron appears to be a promising treatment in OAB patients by shifting its management from reducing detrusor over-activity to inducing relaxation. Also it lacks the troub...