February 29, 2016

Promising effects of a novel EP2 and EP3 receptor dual agonist, ONO-8055, on neurogenic underactive bladder in a rat lumbar canal stenosis model.

Promising effects of a novel EP2 and EP3 receptor dual agonist, ONO-8055, on neurogenic underactive bladder in a rat lumbar canal stenosis model.
J Urol. 2016 Feb 12;
Authors: Sekido N, Kida J, Mashimo H, Wakamatsu D, Okada H, Matsuya H
Abstract
PURPOSE: We investigated whether a novel EP receptor agonist, ONO-8055, improved the lower urinary tract dysfunctions of neurogenic underactive bladder in a rat lumbar spinal canal stenosis (LCS) model.
MATERIALS AND METHODS: First, the agonistic effect of ONO-8055 on EP receptors was studied in EP receptor-expressing Chinese hamster ovary (CHO) cells using the increase in intracellular calcium level and intracellular cAMP production as indicators of receptor activation. Then, the effects of ONO-8055 on bladder and urethral strips from normal rats were investigated. Finally, the effects of ONO-8055 on the bladder and urethral function in LCS rats were evaluated by awake cystometry and intraurethral perfusion pressure, respectively. The effects of tamsulosin and distigmine on urethral pressure were also evaluated.
RESULTS: ONO-8055 is a highly potent and selective agonist for both EP2 and EP3 receptors on CHO cells. While this compound contracted bladder strips, it relaxed urethral strips. Awake cystometry showed that ONO-8055 significantly decreased bladder capacity, residual urine, and voiding pressure. Compared with the vehicle, tamsulosin and ONO-8055 significantly decreased urethral pressure.
CONCLUSIONS: ONO-8055 decreased residual urine, probably through decreasing bladder capacity The decrease in voiding pressure probably resulted from the lowered urethral pressure due to its relaxation of the urethra. Thus, ONO-8055, a novel EP2 and EP3 receptor dual agonist, has potential to improve neurogenic underactive bladder.
PMID: 26880410 [PubMed - as supplied by publisher]
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February 26, 2016

Underactive Bladder.

Underactive Bladder.
Curr Urol Rep. 2016 Mar;17(3):17
Authors: Aggarwal H, Zimmern PE
Abstract
Underactive bladder (UAB) is a very common condition leading to disabling lower urinary tract symptoms. There has been an increasing interest in this condition as there is no effective treatment currently available. UAB has been described in many ways, but there is no agreed upon consensus on its terminology. The prevalence of UAB may be underestimated. This review focuses on the terminology, pathophysiology, common causes, its treatment, and future areas of research.
PMID: 26874529 [PubMed - as supplied by publisher]
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February 25, 2016

Detrusor underactivity and the underactive bladder: Symptoms, function, cause-what do we mean? ICI-RS think tank 2014.

Detrusor underactivity and the underactive bladder: Symptoms, function, cause-what do we mean? ICI-RS think tank 2014.
Neurourol Urodyn. 2016 Feb;35(2):312-7
Authors: Smith PP, Birder LA, Abrams P, Wein AJ, Chapple CR
Abstract
Impaired bladder emptying is a well-recognized cause of lower urinary tract symptoms. However, the symptoms produced do not always relate to voiding, and may include frequency, urgency and incontinence. Conversely, the etiology of symptoms of disturbed voiding is not necessarily dependent upon objectively impaired voiding. Terms including underactive bladder, detrusor underactivity, and impaired contractility describe aspects of these problems, and have been used somewhat interchangeably. It is possible that the present lack of effective therapy in many cases relates to both etiologic and diagnostic uncertainty stemming from terminologic imprecision. Detrusor underactivity has a standardized definition, unlike underactive bladder and impaired contractility. The relationships of symptoms, function, and cause were the focus of a 2014 ICI-RS Think Tank entitled Does Detrusor Underactivity Exist, and if so it is neurogenic, myogenic, or both? This review presents a summary of the problem and the Think Tank conclusions. A terminologic hierarchy and specific research goals are presented. Neurourol. Urodynam. 35:312-317, 2016. © 2016 Wiley Periodicals, Inc. 
PMID: 26872574 [PubMed - in process]
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February 10, 2016

Effect of distigmine at 5 mg daily in patients with detrusor underactivity

[Effect of distigmine at 5 mg daily in patients with detrusor underactivity].
Nihon Hinyokika Gakkai Zasshi. 2014 Jan;105(1):10-6
Authors: Sugaya K, Kadekawa K, Onaga T, Ashitomi K, Mukouyama H, Nakasone K, Shimabukuro H, Shimabukuro S, Matayoshi Y, Hokama S, Touyama Y, Nishijima S
Abstract
PURPOSE: Since distigmine can cause the serious side effect of cholinergic crisis, its dosage regimen has been reduced to 5 mg/day for patients with difficulty in urination due to detrusor underactivity. Therefore, the efficacy and safety of add-on therapy with distigmine at 5 mg daily were examined in patients with persistent urination problems due to detrusor underactivity despite administration of alpha1-blockers.
PATIENTS AND METHODS: The subjects were 39 patients with underactive bladder (18 men and 21 women with an average age of 75 years) who showed no improvement of difficulty in urination or had a residual urine volume > or = 50 ml despite the administration of alpha1-blockers for more than 4 weeks. They received treatment with distigmine (5 mg daily after breakfast) in addition to their alpha1-blockers for 8 weeks. The international prostate symptom score (IPSS), quality-of-life (QOL) score, residual urine volume, blood pressure, and biochemistry tests were investigated before and after addition of distigmine.
RESULTS: After four and eight weeks of distigmine administration, all items of the IPSS and QOL score, as well as the residual urine volume, showed a significant decrease. In contrast, the pressure and pulse rate were unchanged. Serum creatinine showed a slight but significant decreased. As adverse events, frequent defecation, fecal incontinence, diarrhea, frequent urination and poor physical condition were recognized in 4 patients, but there was no serious event.
CONCLUSION: For difficulty in urination due to detrusor underactivity, the combination of an alpha1-blocker with distigmine at 5 mg daily showed early efficacy and good safety.
PMID: 24605581 [PubMed - in process]
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February 4, 2016

Excitatory effects of bombesin receptors in urinary tract of normal and diabetic rats in vivo.

Excitatory effects of bombesin receptors in urinary tract of normal and diabetic rats in vivo.
Life Sci. 2014 Feb 1;
Authors: Kullmann FA, Wells GI, McKenna D, Thor KB
Abstract
AIMS: Bombesin receptors (BB receptors) and bombesin related peptides are expressed in the lower urinary tract of rodents. Here we investigated whether in vivo activation of BB receptors can contract the urinary bladder and facilitate micturition in sham rats and in a diabetic rat model of voiding dysfunction.
MATERIAL AND METHODS: In vivo cystometry experiments were performed in adult female Sprague-Dawley rats under urethane anesthesia. Diabetes was induced by streptozotocin (STZ; 65mg/kg, i.p.) injection. Experiments were performed 9 and 20weeks post STZ-treatment. Drugs included neuromedin B (NMB; BB1 receptor preferring agonist), and gastrin-releasing peptide (GRP; BB2 receptor preferring agonist).
KEY FINDINGS: NMB and GRP (0.01 - 100μg/kg in sham rats; 0.1 - 300μg/kg in STZ-treated rats, i.v.) increased micturition frequency, bladder contraction amplitude and area under the curve dose dependently in both sham and STZ-treated rats. In addition, NMB (3, 10μg/kg i.v.) triggered voiding in >80% of STZ-treated rats when the bladder was filled to a sub-threshold voiding volume. NMB and GRP increased mean arterial pressure and heart rate at the highest doses, 100 and 300μg/kg.
SIGNIFICANCE: Activation of bombesin receptors facilitated neurogenic bladder contractions in vivo. Single applications of agonists enhanced or triggered voiding in sham rats as well as in the STZ-treated rat model of diabetic voiding dysfunction. These results suggest that BB receptors may be targeted for drug development for conditions associated with poor detrusor contraction such as underactive bladder.
PMID: 24496039 [PubMed - as supplied by publisher]
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