Efficacy and Safety of a Neurokinin-1 Receptor Antagonist in Postmenopausal Women With Overactive Bladder With Urge Urinary Incontinence

Green, Stuart A.; Alon, Achilles; Ianus, Juliana; McNaughton, Kristin S.; Tozzi, Carol A.; Reiss, Theodore F.

doi:10.1016/j.juro.2006.08.018

Cited by 88 publications

(46 citation statements)

References 20 publications

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“…Various parts of the genitourinary tract, such as the urinary bladder or the kidney, also exhibit neurokinin 1 receptor expression (Meini et al 1994;Chen and Hoover 1995). Application of NK1 receptor antagonists may be effective for the treatment of urge incontinence (Green et al 2006).…”

Section: Oryctolagus Cuniculus Nk2r Sus Scrofa Nk2rmentioning

confidence: 99%

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

Jakimiuk¹,

Podlasz²,

Chmielewska-Krzesińska³

et al. 2017

Vet. Med.

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Substance P is involved in many physiological and pathophysiological processes. This functional diversity is mediated by three neurokinin receptor subtypes (NK1R, NK2R and NK3R) encoded by the TACR1, TACR2 and TACR3 genes, respectively. Despite the increasing interest in using pigs (Sus scrofa) to study human disease mechanisms, the sequences of these receptors are still unconfirmed or in the case of the NK1 receptor, not yet even unpredicted. We employed in silico analysis to define the localisation of the porcine tachykinin receptor genes, and to predict the structures and amino acid sequences of the respective proteins. A reverse transcription polymerase chain reaction (RT-PCR) assay was performed to analyse the expression of tachykinin receptor genes in different porcine tissues. The data show that the TACR1 gene is located on chromosome 3, TACR2 on chromosome 14 and TACR3 on chromosome 8. All three genes encode proteins with structures that incorporate features of G-protein-coupled receptors with sizes of 407, 381 and 464 amino acids, respectively. The receptors display a high degree of similarity to other mammalian neurokinin receptors. The NK1R subtype is expressed in both the central nervous system and peripheral tissues, while NK2R expression seems to be localised mostly to peripheral tissues. The expression of NK3R is found mainly in the central nervous system. This report provides for the first time the results of a comprehensive analysis of the structure and distribution of porcine NK1R, as well as other porcine neurokinin receptors and their genes. We hope that our data may offer an invaluable foundation for the future studies on the function of diverse tachykinin peptides in the central nervous system and peripheral tissues.

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Section: Oryctolagus Cuniculus Nk2r Sus Scrofa Nk2rmentioning

confidence: 99%

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

Jakimiuk¹,

Podlasz²,

Chmielewska-Krzesińska³

et al. 2017

Vet. Med.

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“…Thus, NK-1 receptors could play a key role in a positive feedback, amplification mechanism that enhances sensory input from the bladder and contributes to abnormal reflex bladder activity in guinea pigs. Clinical studies showing that NK-1 antagonists (aprepitant and serlopitant) are effective in treating overactive bladder symptoms (Green et al, 2006;Frenkl et al, 2010) raise the possibility that similar mechanisms exist in humans.…”

Section: Downloaded Frommentioning

confidence: 99%

“…The contribution of NK-1 receptors to the pathophysiology of bladder dysfunction, has attracted the most interest because clinical studies revealed that NK-1 receptor antagonists, aprepitant (Green et al, 2006) and serlopitant (Frenkl et al, 2010), reduce overactive bladder (OAB) symptoms. These agents also reduce normal bladder reflexes in guinea pig, rat, or cat (Doi et al, 1999(Doi et al, , 2000Kamo and Doi, 2001) as well as hyperactive bladder reflexes induced by spinal cord injury (Doi et al, 2000), systemic administration of L-DOPA (Ishizuka et al, 1995), or application of irritant chemicals to the bladder in the rat (Abdel-Gawad et al, 2001) or guinea pig (Doi et al, 1999(Doi et al, , 2000.…”

Section: Introductionmentioning

confidence: 99%

Activation of Neurokinin-1 Receptors Increases the Excitability of Guinea Pig Dorsal Root Ganglion Cells

Zhang

Pietra

Lovati

et al. 2012

J Pharmacol Exp Ther

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The suppression of overactive bladder symptoms in patients and overactive bladder reflexes in animal models by neurokinin (NK)-1 receptor antagonists raises the possibility that these drugs target sensory neurons. This mechanism was evaluated by examining the interactions between a specific NK-1 agonist, [Sar 9 ,Met(O 2 )(11)]-substance P (Sar-Met-SP), and a potent NK-1 antagonist, netupitant (NTP), on small size (20 -30 m) dissociated L6 and S1 dorsal root ganglion (DRG) neurons from female guinea pigs. Current-clamp recording revealed that SarMet-SP (1 M) elicited membrane depolarization (average 8.05 Ϯ 1.38 mV) in 27% (18 of 65) of DRG neurons. In 74% of the remaining neurons (35 of 47) Sar-Met-SP decreased the rheobase for action potential (AP) generation and increased the response to a suprathreshold stimulus (3 times rheobase) without changing the membrane potential. Sar-Met-SP also induced changes in the action potential (AP) wave form, including 1) an increase in overshoot (average 5 mV, n ϭ 35 neurons), 2) a prolongation of AP duration (from 4.64 to 5.29 ms, n ϭ 34), and 3) a reduction in the maximal rate of AP repolarization. NTP (200 nM) reversed the Sar-Met-SP-induced changes. Ca 2ϩ imaging showed that application of Sar-Met-SP (1 M) decreased the tachyphylaxis induced by repeated application of capsaicin (0.5 M), an effect blocked by pretreatment with NTP (200 nM). These results raise the possibility that activation of NK-1 receptors in primary sensory neurons plays a role in the generation of overactive bladder and that block of NK-1 receptors in these neurons may contribute to efficacy of NK-1 antagonists in the treatment of overactive bladder symptoms.

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“…Aprepitant, an NK-1-receptor antagonist used for treatment of chemotherapy-induced nausea and vomiting (33) significantly improved symptoms of OAB in postmenopausal women with a history of urgency incontinence or mixed incontinence (with predominantly urgency urinary incontinence), as shown in a well-designed pilot randomized controlled trials (34).…”

Section: Pharmacotherapymentioning

confidence: 87%

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology and Pharmacotherapy of Overactive Bladder

Yoshida¹,

Masunaga

Nagata

et al. 2010

J Pharmacol Sci

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J Pharmacol Sci 112, 128 -134 (2010) Definition and prevalence of overactive bladder (OAB)OAB is a symptom complex that is comprised of the storage symptoms of urgency with or without urgency incontinence, frequency, and nocturia (1). These symptoms are suggestive but not diagnostic of detrusor overactivity (urodynamically demonstrable involuntary bladder contractions) if there is no proven infection or other obvious pathology. OAB is, therefore, clearly distinct from urodynamically proven detrusor overactivity, although the majority of people with OAB are thought to have this underlying diagnosis. The prevalence of OAB increases with age. From the epidemiological studies conducted to date, it can be concluded that of those patients with OAB, approximately one-third are troubled Abstract. Overactive bladder (OAB) syndrome, which is characterized by a complex of storage symptoms (urinary urgency, frequency, nocturia, and urgency incontinence) is highly prevalent within the general population, causing major distress to patients in terms of their psychosocial and physical functioning. Muscarinic receptors of bladder smooth muscles are involved in both normal and disturbed bladder contraction. The muscarinic receptor functions may change in bladder disorders associated with OAB, implying that mechanisms, which normally have little clinical importance, may be up-regulated and contribute to the pathophysiology of OAB. In addition, several reports have suggested that various stimulations release many substances, including adenosine triphosphate, prostaglandins, nitric oxide, and acetylcholine, from bladder urothelium, which contribute to pathophysiology of the increased bladder sensation, OAB symptoms, and detrusor overactivity. Bladder urothelium possesses a non-neuronal cholinergic system and high density of muscarinic receptors. The roles and functions of the non-neuronal cholinergic system in OAB are now being evaluated. In the pharmacotherapy of OAB, antimuscarinic agents are the first choice drugs. Furthermore, new therapeutic targets at the levels of the urothelium, detrusor muscles, autonomic and afferent pathways, spinal cord, and brain are proposed. In this review, the pathophysiology of OAB, especially the role of non-neuronal acetylcholine, is discussed. In addition, new drugs with new action mechanisms will be introduced.

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Efficacy and Safety of a Neurokinin-1 Receptor Antagonist in Postmenopausal Women With Overactive Bladder With Urge Urinary Incontinence

Abstract: Results of this initial study suggest that neurokinin-1 receptor antagonism may represent a novel therapeutic approach to treating overactive bladder syndrome.

Cited by 88 publications

References 20 publications

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

Characterisation, localisation and expression of porcine TACR1, TACR2 and TACR3 genes

Activation of Neurokinin-1 Receptors Increases the Excitability of Guinea Pig Dorsal Root Ganglion Cells

The Forefront for Novel Therapeutic Agents Based on the Pathophysiology of Lower Urinary Tract Dysfunction: Pathophysiology and Pharmacotherapy of Overactive Bladder

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