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  • br Disclosure statement br Acknowledgements This research wa


    Disclosure statement
    Acknowledgements This research was supported by grants from the National Institutes of Health, NS046400 and AG022971 (SD), and a fellowship from the Korea Research Foundation, KRF-2007-357-E00016 (YTK). The authors thank Dr. Barbara Crain for assistance with the immunological procedures, and Claire Levine and all laboratory team members for their insightful comments and generous assistance.
    bladder syndrome is a symptom complex defined by urinary urgency with or without UUI and usually accompanied by frequency and nocturia in the absence of urinary tract infection or another obvious pathological condition. Antimuscarinics are the mainstay therapy for OAB even if the site and mechanisms of action of these drugs have not been definitively established. These agents competitively inhibit the effects of acetylcholine at post-junctional muscarinic receptors on detrusor muscle cells as well as on other structures in the AZD1390 wall, such as the urothelium, interstitial cells and afferent nerves. It is now widely accepted that effects on afferent signaling are important for their clinical efficacy. Afferent activity can be inhibited by antimuscarinics at the low concentrations achieved by doses recommended for clinical use for OAB and within this therapeutic window the drugs may increase OAB symptoms without affecting voiding contraction. Clinically, large meta-analyses of studies of the currently most widely used drugs clearly show that antimuscarinics have significant clinical benefit. However, treatment with antimuscarinics leads only to a modest reduction in the number of micturitions and urgency incontinence episodes while long-term adherence to therapy is conspicuously low., , Administration of antimuscarinics can be limited by their less than optimal tolerability profile with frequently reported adverse effects, such as dry mouth, blurred vision and urinary retention. Thus, new agents with a different mode of action from that of antimuscarinics may offer greater efficacy for treating OAB syndrome and show an improved tolerability profile. The micturition reflex involves complex interplay between the bladder efferent and afferent pathways. However, the degree to which the afferent pathway contributes to the pathophysiology of OAB symptoms remains unknown. Clinical and nonclinical studies indicate that PGE2 and its receptor EP1 have a role in OAB pathogenesis. Evidence suggests that PGE2 controls bladder function via afferent signaling in physiological and pathological conditions. In healthy women intravesical instillation of PGE2 led to detrusor overactivity, urgency and decreased bladder capacity. In patients with detrusor underactivity intravesical PGE2, particularly combined with bethanechol, may improve bladder emptying., Urinary levels of PGE2 were also increased in patients with OAB compared with controls., , A study in knockout mice lacking EP1 indicated that the receptor may have a role in the development of PGE2 induced detrusor overactivity and in bladder outlet obstruction. Furthermore, in bladder outlet obstructed rats the EP1 receptor antagonist PF-2907617-02 increase bladder capacity, micturition volume and the micturition interval. Therefore, EP1 receptor antagonism may provide symptomatic relief of OAB. ONO-8539 is a potent, selective EP1 receptor antagonist that was effective for decreasing ATP induced detrusor overactivity in monkeys, including reductions in nonvoiding contractions and voiding duration, and for increasing the uroflow rate. ONO-8539 also did not affect salivation in rats (Okada, unpublished data). ONO-8539 was well tolerated after twice daily repeat administration in young (up to 600 mg) or elderly (up to 300 mg) subjects with no safety issues observed.
    Introduction Prostaglandin E2 (PGE2) is produced by arachidonic acid metabolism and is synthesized via the cyclooxygenase (COX) and prostaglandin synthase pathways. COX-2/PGE2 signaling mediates both physiological and pathological effects in a vast array of tissue types, including bone [1], [2], [3], [4]. The broad effects of PGE2 are attributed to the four prostanoid receptors which bind PGE2: EP1, EP2, EP3 and EP4. These four receptors differ in tissue distribution, ligand binding affinity and activation of downstream signaling pathways [1], [3], [5]. EP2, EP3 and EP4 modulate cAMP levels [3], [5]. EP2 and EP4 activation stimulates the production of cAMP through Gαs. In contrast, EP3 activation results in decreased cAMP levels through Gαi, Gαq, or Gαs, depending on the EP3 isoform. Less is known about the EP1 receptor. While the EP1 receptor is involved in regulating intracellular calcium levels, the G protein to which it couples remains to be identified.