Effect of a Bicyclic Pyrimidine Derivative (KRP-103), a Novel Selective Tachykinin NK1 Receptor Antagonist, on Bladder Function in Guinea Pigs

AbstractWe evaluated the pharmacological characteristics of KRP-103, chemically named as ((2-(4-acetylpiperazin-1-yl)-6-[3,5-bis(trifluorometheyl)-phenylmethyl]-4- (2-methylphenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one), and its effects on lower urinary tract function in guinea pigs. In radioligand binding assay, KRP-103 showed higher selectivity for human NK1 receptor (hNK1R) than for human NK2 receptor (hNK2R) and human NK3 receptor (hNK3R) (Ki for hNK1R, hNK2R and hNK3R=0.126 nM, > 10 000 nM and > 10 000 nM). In distention-induced rhythmic bladder contractions (RBCs) in urethane-anesthetized guinea pigs, intravenous administration of KRP-103 dose-dependently increased the shutdown time of RBCs and slightly decreased the amplitude of RBCs (only about 20%). In acutely spinalized guinea pig cystometory, intraduodenal administration of KRP-103 dose-dependently increased the effective bladder capacity with a minimum effective dose of 1 mg/kg. Furthermore, to clarify the site of action of KRP-103, we evaluated the inhibitory effects of KRP-103 on bladder contractions induced by electrical stimulation (ES) of the central or peripheral cut end of the pelvic nerve (PN). KRP-103 inhibited the bladder contractions induced by ES of the central cut end of PN but not those induced by ES of the peripheral cut end of PN. These results indicate that KRP-103 enhances bladder storage function by inhibiting sensory transmission from the bladder at the level of spinal cord without affecting bladder efferent function, suggesting that KRP-103 may be a suitable therapeutic drug for treatment of overactive bladder.

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L'enterocistoplastica nel recupero della funzione vescicale gravemente compromessa nella donna non neurologica. Nostra esperienza

Urologia Journal ◽

10.1177/039156039406101s68 ◽

1994 ◽

Vol 61 (1_suppl) ◽

pp. 243-244

Author(s):

F. Catanzaro ◽

M. Pizzoccaro ◽

F. Cappellano ◽

F. Torelli ◽

M. Baruffi ◽

...

Keyword(s):

Urinary Tract ◽

Radical Hysterectomy ◽

Surgical Procedure ◽

Bladder Capacity ◽

Upper Urinary Tract ◽

Bladder Function ◽

Ureteral Reimplantation ◽

Female Patients ◽

Tract Function

The Authors report their experience in the recovery of bladder function in 8 female patients (5 of whom had undergone radical hysterectomy + CHT + RT for gynecological tumours) by means of ileovesicoplasty and bilateral ureteral reimplantation. They underline the improvement of bladder capacity (7/7), continence (7/7), voiding (good results in 5/7) and upper urinary tract function (5/7). All patients are satisfied at a mean follow-up of 31 months. The Authors propose this surgical procedure as an alternative to external diversion.

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Pharmacotherapy for female nocturia

Journal of Korean Medical Association ◽

10.5124/jkma.2021.64.6.449 ◽

2021 ◽

Vol 64 (6) ◽

pp. 449-454

Author(s):

Soo Rim Kim

Keyword(s):

Bladder Capacity ◽

Steering Committee ◽

Positive Pressure ◽

Nocturnal Polyuria ◽

Obstructive Sleep ◽

Lower Urinary Tract Function ◽

Tract Function ◽

Continuous Positive Pressure ◽

Limited Usefulness ◽

Consensus Report

Background: In 2018, nocturia and nocturnal lower urinary tract function definitions were updated in a clinically and practically based consensus report by the International Continence Society Standardization Steering Committee. Previous research has suggested that the pathophysiology of nocturia has a multifactorial etiology, including obstructive sleep apnea, overactive bladder syndrome, diabetes mellitus, sleep disturbance, congestive heart failure, primary polydipsia, and other factors.Current Concepts: Three main mechanisms have been identified: low functional bladder capacity, nocturnal polyuria, and diurnal polyuria (24-hour polyuria). Multifactorial pathophysiology implies multiple possible targets for therapeutic intervention, and suggests that it is unlikely that one treatment modality, including drugs, will be successful in all patients. The bladder diary is the most important diagnostic tool.Discussion and Conclusion: Strong evidence supports the efficacy of desmopressin and continuous positive pressure breathing. Antimuscarinic drugs for treating nocturia display limited usefulness because of their low efficacy for nocturnal polyuria. Management of nocturia may require a multidisciplinary approach to visualization and phenotyping of patients for diagnosis and therapy.

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Is it possible to improve elderly male bladder function by having them drink more water? A randomized trial of effects of increased fluid intake/urine output on male lower urinary tract function

Urology ◽

10.1016/j.urology.2006.07.010 ◽

2006 ◽

Vol 68 (5) ◽

pp. 1031-1036 ◽

Cited By ~ 12

Author(s):

Mark Spigt ◽

Onno van Schayck ◽

Paul Knipschild ◽

Klaas Westerterp ◽

Cees van de Beek ◽

...

Keyword(s):

Urinary Tract ◽

Randomized Trial ◽

Urine Output ◽

Lower Urinary Tract ◽

Fluid Intake ◽

Bladder Function ◽

Elderly Male ◽

Lower Urinary Tract Function ◽

Tract Function ◽

Lower Urinary

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Stimulation of the pelvic nerve increases bladder capacity in the prostaglandin E2 rat model of overactive bladder

AJP Renal Physiology ◽

10.1152/ajprenal.00116.2017 ◽

2017 ◽

Vol 313 (3) ◽

pp. F657-F665 ◽

Cited By ~ 9

Author(s):

Christopher L. Langdale ◽

James A. Hokanson ◽

Arun Sridhar ◽

Warren M. Grill

Keyword(s):

Urinary Tract ◽

Overactive Bladder ◽

Rat Model ◽

Lower Urinary Tract ◽

Bladder Capacity ◽

Pelvic Nerve ◽

Lower Urinary Tract Function ◽

Tract Function ◽

Stimulation Of ◽

Lower Urinary

Overactive bladder (OAB) syndrome is a highly prevalent condition that may lead to medical complications and decreased quality of life. Emerging therapies focusing on selective electrical stimulation of peripheral nerves associated with lower urinary tract function may provide improved efficacy and reduced side effects compared with sacral neuromodulation for the treatment of OAB symptoms. Prior studies investigating the effects of pelvic nerve (PelN) stimulation on lower urinary tract function were focused on promoting bladder contractions, and it is unclear whether selective stimulation of the PelN would be beneficial for the treatment of OAB. Therefore our motivation was to test the hypothesis that PelN stimulation would increase bladder capacity in the prostaglandin E2 (PGE2) rat model of OAB. Cystometry experiments were conducted in 17 urethane-anesthetized female Sprague-Dawley rats. The effects of intravesical PGE2 vs. vehicle and PelN stimulation after intravesical PGE2 on cystometric parameters were quantified. Intravesical infusion of PGE2 resulted in decreased bladder capacity and increased voiding efficiency without a change in bladder contraction area under the curve, maximum contraction pressure, or contraction duration. Bladder capacity was also significantly decreased compared with vehicle (1% ethanol in saline) confirming that the change in bladder capacity was mediated by PGE2. PelN stimulation reversed the PGE2-induced change in bladder capacity and increased the external urethral sphincter electromyogram activity at a specific stimulation condition (amplitude of 1.0 times threshold at 10 Hz). These results confirm that the urodynamic changes reported in conscious rats are also observed under urethane anesthesia and that PelN stimulation is a novel and promising approach for the treatment of the symptoms of OAB.

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Involvement of tachykinin receptors in sensitisation to cow’s milk proteins in guinea pigs

Gut ◽

10.1136/gut.44.4.497 ◽

1999 ◽

Vol 44 (4) ◽

pp. 497-503 ◽

Cited By ~ 9

Author(s):

J Gay ◽

J Fioramonti ◽

R Garcia-Villar ◽

X Emonds-Alt ◽

L Bueno

Keyword(s):

Receptor Antagonist ◽

Guinea Pigs ◽

Milk Proteins ◽

Cow’S Milk ◽

Nk1 Receptor ◽

Receptor Antagonists ◽

Tachykinin Receptors ◽

Antigenic Challenge ◽

Nk1 Receptor Antagonist ◽

Nk3 Receptor

BACKGROUNDThere is growing evidence for a pivotal role for tachykinins in gut neuroimmune interactions.AIMSTo determine whether NK1, NK2, and NK3 tachykinin receptors are involved in milk protein induced allergic sensitisation.METHODSEight groups of 12 Dunkin-Hartley guinea pigs (250–300 g) were used. Four groups were sensitised to milk proteins for three weeks. During this period, these animals were injected intraperitoneally each day with NK1 (SR 140333; 0.3 mg/kg), NK2 (SR 48968; 5 mg/kg), or NK3 (SR 142801; 5 mg/kg) receptor antagonist or vehicle. The fifth group had water available instead of milk and was used as a non-sensitised control. The three other groups received the NK receptor antagonists for three weeks but were not sensitised to milk proteins.RESULTSSensitised animals treated with NK1 and NK3 receptor antagonists had both lower IgE and IgG serum titres, evaluated by passive cutaneous anaphylaxis, and lower specific IgG serum titres, determined by enzyme linked immunosorbent assay (ELISA), than vehicle treated animals. Sensitisation induced an increase in intestinal mast cell number which was abolished by treatment with the NK1 receptor antagonist. Antigenic challenge-induced jejunal hypersecretion was also blocked by treatment with the NK1 receptor antagonist.CONCLUSIONIn guinea pigs, NK1 and NK3 but not NK2 receptors are involved in sensitisation to cow’s milk. However, NK1 but not NK3 receptor antagonists abolish both the hypermastocytosis induced by food allergy and the hypersecretion induced by antigenic challenge, suggesting different roles for NK1 and NK3 receptors in the mechanisms of sensitisation to β-lactoglobulin.

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