Dose-response effect of a β<sub>3</sub>-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health

Grudell, April; Camilleri, Michael; Jensen, Kimberly L.; Foxx‐Orenstein, Amy E.; Burton, Duane D.; Ryks, Michael; Baxter, Kari; Cox, Donna S.; Dukes, George E.; Kelleher, Dennis; Zinsmeister, Alan R.

doi:10.1152/ajpgi.00051.2008

Cited by 28 publications

(24 citation statements)

References 25 publications

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“…Given the differential role of β 3 -adrenoceptors in glucose and lipid metabolism between rodents and humans (Arch 2008), the relevance of such findings for OAB patients is difficult to predict. In a placebo-controlled, double-blind study in 36 healthy volunteers, oral administration of solabegron doses of 50 or 200 mg twice daily for 7 days did not significantly alter gastrointestinal or colonic transit or bowel function (Grudell et al 2008). In propofol-anesthetized female dogs, bladder irritation was induced by intravesical acetic acid instillation; in this model, i.v.…”

Section: In Vivo Animal Studiesmentioning

confidence: 78%

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Igawa

Michel

2012

Naunyn-Schmiedeberg's Arch Pharmacol

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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. The potency of these agonists may be species-dependent, with all three having high potency in the human detrusor. All three agonists were effective in one or more animal models of bladder dysfunction, which typically involved reductions of micturition frequency. Agonist doses effective for bladder function lowered blood pressure in some cases, but the relevance of this for clinical use is difficult to determine due to species differences in the importance of cardiovascular β 3 -adrenoceptors. While limited effects on other organ systems are expected for β 3 -adrenoceptor agonists, this requires further investigation.

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Section: In Vivo Animal Studiesmentioning

confidence: 78%

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Igawa

Michel

2012

Naunyn-Schmiedeberg's Arch Pharmacol

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“…Equally important, the colonic transit measurement has correctly predicted lack of efficacy of medications to alter bowel dysfunction in IBS in clinical trials when there were no significant effects of the drug on colonic transit. Examples include a CRF1-antagonist (99) and solabegron, a β3-adrenergic agonist (100). …”

Section: Evaluation Of Colon Transitmentioning

confidence: 99%

Methods for the Assessment of Small-Bowel and Colonic Transit

Szarka

Camilleri

2012

Seminars in Nuclear Medicine

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“…For example, the efficacy of lubiprostone (63) in improving colonic transit and stool form in pharmacodynamic studies in healthy volunteers accurately predicted clinical efficacy in patients with IBS-C (66). At present, the only discrepancy between results of scintigraphic transit (111) and phase IIB clinical trial data pertains to the drug, solabegron (preliminary data, in press); results of larger phase II trials are eagerly awaited. Nonetheless, GI transit assessment can be a useful biomarker for predicting the effects of a test article on bowel habits and overall response in patients with IBS.…”

Section: Approaches To Proof Of Concept For Novel Ibs Drugsmentioning

confidence: 99%

Challenges to the Therapeutic Pipeline for Irritable Bowel Syndrome: End Points and Regulatory Hurdles

Camilleri

Chang

2008

Gastroenterology

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Recent advances in our understanding of basic neuroenteric mechanisms and the role of effectors and transmitters in the brain-gut axis have provided opportunities to develop new therapeutic agents for irritable bowel syndrome (IBS). Furthermore, human pharmacodynamic studies utilizing transit, colonic or rectal sensitivity, and brain imaging have been useful in determining therapeutic efficacy (particularly for drugs that act on motor function). This review provides an overview of medications that have not yet been approved for treatment of patients with IBS, yet have shown promise in phase IIB trials. These include drugs that act on the serotonin receptor and transporter system, antidepressants, norepinephrine reuptake inhibitors, opioids, cholecystokinin antagonists, neurokinin-antagonists, chloride channel activators, guanylate cyclase C agonists, atypical benzodiazepines, probiotics and antibiotics. The changing landscape in the regulatory approval process has impacted the development of IBS drugs. Guidance documents from regulatory agencies in Europe and the United States have focused on patients' reported outcomes and associated quality of life. After a decade of experience with different endpoints that have generated some data on psychometric validation and unprecedented information about responsiveness of the binary or global endpoints to drug therapy, it is necessary to pursue further validation studies before or during pivotal phase IIB or III trials. The hope of providing relief to patients should galvanize all parties to achieve these goals.

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Dose-response effect of a β₃-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health

Abstract: DL, Zinsmeister AR. Dose-response effect of a ␤ 3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health.

Cited by 28 publications

References 25 publications

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Methods for the Assessment of Small-Bowel and Colonic Transit

Challenges to the Therapeutic Pipeline for Irritable Bowel Syndrome: End Points and Regulatory Hurdles

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Dose-response effect of a β3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health

Abstract: DL, Zinsmeister AR. Dose-response effect of a ␤ 3-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health.

Cited by 28 publications

References 25 publications

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Pharmacological profile of β3-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome

Methods for the Assessment of Small-Bowel and Colonic Transit

Challenges to the Therapeutic Pipeline for Irritable Bowel Syndrome: End Points and Regulatory Hurdles

Contact Info

Product

Resources

About

Dose-response effect of a β₃-adrenergic receptor agonist, solabegron, on gastrointestinal transit, bowel function, and somatostatin levels in health