Treatment of stress urinary incontinence with duloxetine hydrochloride

Currently, there are no approved medications for the treatment of stress urinary incontinence (SUI) in the United States. The effectiveness of duloxetine in the treatment of SUI is linked to its inhibition of presynaptic neuronal reuptake of serotonin and norepinephrine in the central nervous system, resulting in elevated levels of serotonin and norepinephrine in the synaptic cleft. In animal studies, this agent leads to an increase in nerve stimulation to the urethral striated sphincter muscle. A similar mechanism in women is believed to result in stronger urethral contractions, with improved sphincter tone during urine storage and physical stress. In 3 randomized, placebo-controlled clinical trials, patients receiving duloxetine had a statistically significant and clinically relevant reduction in the number of incontinence episodes and a corresponding improvement in quality of life. If this use of duloxetine is approved by the U.S. Food and Drug Administration, as it has been by the European regulatory agencies, it will be the first drug indicated for the treatment of SUI. This pharmacologic therapy is an additional option for women and is likely to become an integral component of patient management.     

Duloxetine: a summary of published clinical experience

Effective oral therapy for genuine stress urinary incontinence (SUI) in women has, to date, been an unattainable goal. Although oral pharmacologic agents have been used for this condition, none has ultimately been successful, because of side effects, lack of efficacy, or problematic compliance with drug ingestion. The availability of an effective oral agent for SUI would increase the range of therapeutic options for symptom management and possibly make treatment accessible to more women who otherwise feel that surgical therapy is not an option because of social, personal, or medical reasons. Duloxetine is a selective serotonin (5-HT) and norepinephrine reuptake inhibitor that has been shown to increase rhabdosphincter activity. Rhabdosphincter contractility changes are thought to occur as the result of increased stimulation of alpha(1)-adrenergic and 5-HT(2) receptors in the sacral spinal cord, resulting in increased efferent pudendal nerve activity, producing increased pelvic floor tonus. Two large-scale studies have been completed employing subjective and objective outcomes to assess the therapeutic index of duloxetine as a therapy for SUI.     

Duloxetine: a new pharmacologic therapy for stress urinary incontinence

The dual serotonin (5-HT)/norepinephrine (NE) reuptake inhibitor duloxetine shows promise as a pharmacologic therapy for stress urinary incontinence. This agent modulates lower urinary tract function through selective inhibition of 5-HT and NE receptor sites. It works centrally at Onuf's nucleus to increase activity of the pudendal nerve. Duloxetine facilitates sphincter activity during urine storage but not during voiding, maintaining the bladder-sphincter synergy. Because it inhibits both 5-HT and NE reuptake, duloxetine appears to offer an advantage over agents that inhibit reuptake of a single neurotransmitter.     

Expectations of Stress Urinary Incontinence Surgery in Patients With Mixed Urinary Incontinence

Mixed urinary incontinence is estimated to affect 30% of all women who have urinary incontinence, and it has been shown to be more bothersome to women than pure stress incontinence. Given the degree of bother, many women will undergo surgical correction for incontinence. Patients have high expectations about the success of these interventions. Understanding mixed incontinence and the effects of our interventions can help guide therapeutic choices and manage patients’ expectations.Key words: Urodynamics, Mixed urinary incontinence, Sling, Anti-incontinence surgery, Urgency incontinenceIt has been estimated that approximately 30% of women with urinary incontinence have mixed urinary incontinence (MUI). Degree of bother is higher among women with MUI compared with those who have pure stress urinary incontinence (SUI).¹ MUI can be a very challenging and costly condition to treat.^2,3 Patients with MUI are often offered conservative therapy such as physical therapy, weight-loss strategies, and behavioral modification. Some patients also benefit from treatments aimed directly at urgency, frequency, and urgency incontinence (overactive bladder), which currently include pharmacologic therapy (antimuscarinic or β-3 agonists), chemodenervation (botulinum toxin), or neuromodulation (sacral or posterior tibial nerves).⁴ However, many patients with MUI progress to surgical therapies for treatment of SUI. This article reviews the literature available that can help clinicians manage expectations of SUI surgeries on patients with MUI.     

Comparison of the effects of serotonin selective,norepinephrine selective,and dual serotonin and norepinephrine reuptake inhibitors on lower urinary tract function in cats

Previous studies showed that the dual serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) reuptake inhibitor, duloxetine, increases bladder capacity and urethral sphincter electromyographic (EMG) activity in a cat model of acetic acid-induced bladder irritation. The present study aimed to determine the relative importance of 5-HT versus NE reuptake inhibition for mediating these effects by examining drugs that are selective for either the 5-HT or NE system or both. Similar to duloxetine, venlafaxine (0.1 to 10 mg/kg), also a dual serotonin and norepinephrine reuptake inhibitor, produced marked increases in bladder capacity and EMG activity that were reversed by methiothepin (0.3 mg/kg). S-norfluoxetine (0.01 to 10 mg/kg), a serotonin selective reuptake inhibitor, produced small but significant increases in bladder capacity and EMG activity at doses of 3 and 10 mg/kg. Thionisoxetine (0.01 to 3.0 mg/kg), a NE selective reuptake inhibitor, produced no effects on bladder capacity or sphincter EMG activity. Surprisingly, co-administration of thionisoxetine and s-norfluoxetine up to doses of 1 mg/kg of each compound produced no effect on lower urinary tract function. These doses were the maximum that could be administered in combination due to drug-induced emergence of skeletal muscle activity in chloralose-anesthetized animals. These results indicate that there are unexplained pharmacological differences between the effects of single compounds that exhibit dual NE and 5-HT reuptake inhibition and a combination of compounds that exhibit selective NE and 5-HT reuptake inhibition on lower urinary tract function.     

Neurophysiology of stress urinary incontinence

Stress urinary incontinence (SUI) involves involuntary leakage of urine in response to abdominal pressure caused by activities such as sneezing and coughing. The condition affects millions of women worldwide, causing physical discomfort as well as social distress and even social isolation. Until recently, SUI was approached by clinicians as a purely anatomic problem requiring behavioral or surgical therapy. Over the past several years, extensive basic and clinical research in the field of neurourology has enhanced our understanding of the complex neural circuitry regulating normal function of the lower urinary tract. As a result, novel concepts have emerged regarding possible neurologic dysfunctions that might underlie the development of SUI, as well as potential novel strategies for pharmacologic therapy. This article reviews the normal neurophysiologic control of lower urinary tract function and considers potential pharmacologic approaches to correcting SUI.     

The definition, prevalence, and risk factors for stress urinary incontinence

Stress urinary incontinence (SUI) has an observed prevalence of between 4% and 35%. Whereas the clinical definition of SUI has been established by the International Continence Society, the epidemiologic definition has not been established, leading to a broad disparity in reported prevalence rates. Numerous risk factors for SUI have been identified. Aging, obesity, and smoking appear to have consistent causal relationships with the condition, whereas the roles of pregnancy and childbirth remain controversial. The prevalence of many of these risk factors is increasing in the adult female population of the United States. These population changes, combined with increasing physician awareness and the availability of nonsurgical therapy, will likely increase the number of women receiving care for SUI over the next 3 decades.     

Effect of co-administration of varenicline and antidepressants on extracellular monoamine concentrations in rat prefrontal cortex

Since a substantial proportion of smokers have comorbid mood disorders, the smoking cessation aid varenicline might occasionally be prescribed to patients who are simultaneously treated with antidepressants. Given that varenicline is a selective nicotinic acetylcholine receptor partial agonist and not a substrate or inhibitor of drug metabolizing enzymes, pharmacokinetic interactions with various classes of antidepressants are highly unlikely. It is, however, conceivable that varenicline may have a pharmacodynamic effect on antidepressant-evoked increases in central monoamine release. Interactions resulting in excessive transmitter release could cause adverse events such as serotonin syndrome, while attenuation of monoamine release could impact the clinical efficacy of antidepressants. To investigate this we examined whether varenicline administration modulates the effects of the selective serotonin reuptake inhibitor sertraline and the monoamine oxidase inhibitor clorgyline, given alone and combined, on extracellular concentrations of the monoamines serotonin, dopamine, and norepinephrine in rat brain by microdialysis. Given the important role attributed to cortical monoamine release in serotonin syndrome as well as antidepressant activity, the effects on extracellular monoamine concentrations were measured in the medial prefrontal cortex. Responses to maximally effective doses of sertraline or clorgyline and of sertraline plus clorgyline were the same in the absence as in the presence of a relatively high dose of varenicline, which by itself had no significant effect on cortical monoamine release. This is consistent with the binding profile of varenicline that has insufficient affinity for receptors, enzymes, or transporters to inhibit or potentiate the pharmacologic effects of antidepressants. Since varenicline neither diminished nor potentiated sertraline- or clorgyline-induced increases in neurotransmitter levels, combining varenicline with serotonergic antidepressants is unlikely to cause excessive serotonin release or to attenuate antidepressant efficacy via effects on cortical serotonin, dopamine or norepinephrine release.     

Pharmacotherapy for stress urinary incontinence

The purpose of this review article is to highlight new pharmacotherapies on the horizon for the treatment of stress urinary incontinence. Although behavioral and surgical therapies are currently the mainstay of treatment for this condition, we are hopeful that pharmacotherapy will one day take center stage of the various treatment options. Currently, there are no medications approved by the US Food and Drug Administration for the treatment of stress urinary incontinence. However, exciting clinical data are becoming available about an oral medication for the treatment of stress urinary incontinence that appears to be clinically safe and efficacious. In addition to discussing medications currently under development, this article also discusses pharmacologic targets that could be suitable future targets to treat stress urinary incontinence.     

Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake

A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta™) has proven to be effective in clinical trials for the treatment of depression.     

A biomechanical model to assess the contribution of pelvic musculature weakness to the development of stress urinary incontinence

A biomechanical model of the female pelvic support system was developed to explore the contribution of pelvic floor muscle defect to the development of stress urinary incontinence (SUI). From a pool of 135 patients, clinical data of 26 patients with pelvic muscular defect were used in modelling. The model was employed to estimate the parameters that describe the stiffness properties of the vaginal wall and ligament tissues for individual patients. The parameters were then implemented into the model to evaluate for each patient the impact of pelvic muscular defect on the vaginal apex support and the bladder neck support, a factor that relates to the onset of SUI. For the modelling analysis, the compromise of pelvic muscular support was demonstrated to contribute to vaginal apex prolapse and bladder neck prolapse, a condition commonly seen in SUI patients, while simulated conditions of restored muscular support were shown to help re-establish both vaginal apex and bladder neck supports. The findings illustrate the significance of pelvic muscle strength to vaginal support and urinary continence; therefore, the clinical recommendation of pelvic muscle strengthening, such as Kegel exercises, has been shown to be an effective treatment for patients with SUI symptoms.     

Synthesis and activity of a new class of dual acting norepinephrine and serotonin reuptake inhibitors: 3-(1H-indol-1-yl)-3-arylpropan-1-amines

Compounds with a combination of norepinephrine and serotonin reuptake inhibition have been approved in the US and Europe for a number of indications, including major depressive disorder and pain disorders such as diabetic neuropathy and fibromyalgia. Efforts to design selective norepinephrine reuptake inhibitors based on SAR from the aryloxypropanamine series of monoamine reuptake inhibitors have led to the identification of a potent new class of dual acting norepinephrine and serotonin reuptake inhibitors, namely the 3-(1H-indol-1-yl)-3-arylpropan-1-amines.     

HPLC analysis of the novel antidepressant duloxetine in human plasma after an original solid-phase extraction procedure

Duloxetine is the most recent serotonin and norepinephrine reuptake inhibitor (SNRI) drug introduced for the therapy of depression. Thus, it is evident that there is a need for having on hand new reliable analytical methods for the determination of duloxetine plasma levels in depressed patients. The present paper deals with the development of a rapid and sensitive high-performance liquid chromatographic method for duloxetine analysis in human plasma. The assays were carried out using a C8 reversed-phase column and a mobile phase composed of 60% aqueous phosphate buffer containing triethylamine at pH 3.0 and 40% acetonitrile. The UV detector was set at 230 nm and loxapine was used as the internal standard. An original pre-treatment of plasma samples was developed, based on solid-phase extraction (SPE) with mixed-mode reversed phase-strong cation exchange cartridges (30 mg, 1 mL). The extraction yields values were higher than 90%. Linearity was found in the 2-200 ng mL(-1) duloxetine concentration range; the limit of quantitation was 2.0 ng mL(-1) and the limit of detection was 0.7 ng mL(-1). The method was applied to plasma samples from depressed patients undergoing therapy with duloxetine. Precision data and accuracy results were satisfactory and no interference from other drugs was found. Thus, the method seems to be suitable for the therapeutic drug monitoring of duloxetine in depressed patients' plasma.     

Functional consequences of homo- but not hetero-oligomerization between transporters for the biogenic amine neurotransmitters

Before this study, the human norepinephrine transporter (hNET) was the only member of the biogenic amine neurotransmitter transporter family that had not been demonstrated to be a functional homo-oligomer. Here, using two forms of the transporter, I155C and hNET-myc, with distinct antigenicity and inhibitor sensitivity, we demonstrated that hNET exists as a homo-oligomer. hNET I155C is a functional mutant and is sensitive to inactivation by the sulfhydryl reagent [2-(trimethylammonium)ethyl]methanethiosulfonate, while hNET-myc is resistant to inactivation by this reagent. Coimmunoprecipitation of these two forms demonstrated that a physical interaction exists between norepinephrine transporter monomers. Further characterization of this physical interaction has revealed that the activity of norepinephrine transporters depends on interactions between monomers. Because norepinephrine transporters and serotonin transporters are the only two members of the neurotransmitter transporter family endogenously expressed in the cell membrane of the same cells, placental syncytiotrophoblasts, we tested the ability of norepinephrine transporters and serotonin transporters to associate and function in a hetero-oligomeric form. Similarly, coexpression of hNET-myc with serotonin transporter-FLAG showed a physical interaction in coimmunoprecipitation assays. However, coexpression of serotonin and norepinephrine transporters did not sensitize norepinephrine transporter activity to inhibition by citalopram, a selective serotonin transport inhibitor. Thus, the norepinephrine transporter-serotonin transporter physical association did not produce functional consequences. Based on this, we propose that the transporters for biogenic amine neurotransmitters interact functionally in homo- but not hetero-oligomeric forms.     

Diagnosis,Evaluation, and Treatment of Mixed Urinary Incontinence in Women

Mixed urinary incontinence (MUI) is a common clinical problem in the community and hospital setting. The broad definition of the term makes it difficult to diagnose, as well as determine effective treatment strategies. There are no current guidelines recommended for physicians. The estimated prevalence of this condition is approximately 30% in all women with incontinence. It has also been suggested that patients with MUI report more bothersome symptoms than either stress or urge incontinence; approximately 32% of 40- to 64-year-olds with MUI report symptoms of depression. The authors examine the diagnosis, evaluation, and treatment of patients with MUI.Key words: Mixed urinary incontinence, Detrusor overactivity, Stress incontinence, Urge incontinence, Urodynamic stress incontinence, Pelvic organ prolapse, Transvaginal tapeMixed urinary incontinence (MUI) is the leading cause of incontinence in the community and hospital setting.¹ The term refers to a combination of symptoms, with the patient exhibiting features of both stress urinary incontinence (SUI) and urge urinary incontinence (UUI); it may also refer to a combination of features of urodynamic SUI and detrusor hyperactivity.¹ The current International Continence Society guidelines define MUI as a complaint of the involuntary loss of urine during exertion, sneezing, or coughing, as well as leakage associated with urgency.²The term MUI is extremely broad because it may refer to equal stress and urge symptoms, stress-predominant symptoms, urge-predominant symptoms, urodynamic SUI (USUI) with detrusor overactivity (DO), or USUI with clinical urge symptoms but no DO.³ The challenge of this broad definition is that it leads to inconsistencies when evaluating treatment options and outcomes. In an attempt to validate diagnostic questions that could later be used in an epidemiological survey, Sandvik and colleagues⁴ defined MUI based on subjective answers to a structured questionnaire designed for their study.⁴ SUI was presumed if a positive answer was given to the question: “Do you lose urine during sudden physical exertion, lifting, coughing, or sneezing?” If the patient responded positively to the question: “Do you experience such a strong and sudden urge to void that you leak before reaching the toilet?” then a diagnosis of UUI was presumed. MUI was considered if a positive answer was given to both questions. In contrast, Brubaker and colleagues⁵ reported that strict definitions based on self-reported symptoms do not properly categorize patients as having MUI. Their group believed that patients should be broken down into MUI subgroups of SUI and UUI rather than describing it as a single entity. However, without a precise definition or understanding of the role of these stress and urge subcomponents, the assessment of an intervention for SUI or UUI is challenging.⁶The prevalence rates of MUI vary widely in the literature. In a secondary analysis of the Stress Incontinence Surgical Treatment Efficacy Trial (SISTEr), Brubaker and colleagues⁵ evaluated 655 women for the presence of incontinence and their response to treatment. They found that 50% to 93% of women fell into the category of MUI based on patient-reported answers to the Medical Epidemiologic and Social Aspects of Aging (MESA) and Urinary Distress Inventory (UDI) questionnaires. However, when objective criteria such as urodynamic findings were used, only 8% of women were categorized with MUI. Dooley and associates⁷ compared physical examination findings and responses to the MESA and UDI questionnaires in 551 women with a mean age of 56 ± 16 years. They estimated a prevalence rate of 30% of MUI in all women with urinary incontinence.According to Dooley and associates,⁷ in their cohort, MUI was more bothersome to patients than either pure SUI or UUI. In a cross-sectional population-based study across 6 European countries that included over 300 patients, the effects of overactive bladder (OAB) symptoms on employment, social interactions, and emotional well-being were evaluated by direct interview or a telephone-conducted interview. Irwin and associates⁸ found 32% of patients aged 40 to 64 years reported being depressed. In addition, they determined that symptoms of OAB have a statistically significant negative impact on emotional well-being both at home and at work.We sought to examine the existing literature on MUI and better understand the role urodynamic testing (UDS) plays in its diagnosis. In addition, we sought to examine treatment methods so that better treatment outcomes may be achieved.     

Conservative Management of Urinary Incontinence in Women

Urinary incontinence in women has a high prevalence and causes significant morbidity. Given that urinary incontinence is not generally a progressive disease, conservative therapies play an integral part in the management of these patients. We conducted a nonsystematic review of the literature to identify high-quality studies that evaluated the different components of conservative management of stress urinary incontinence, including behavioral therapy, bladder training, pelvic floor muscle training, lifestyle changes, mechanical devices, vaginal cones, and electrical stimulation. Urinary incontinence can have a severe impact on our healthcare system and patients’ quality of life. There are currently a wide variety of treatment options for these patients, ranging from conservative treatment to surgical treatment. Although further research is required in the area of conservative therapies, nonsurgical treatments are effective and are preferred by some patients.Key words: Urinary incontinence, Women, Conservative managementUrinary incontinence (UI) is a significant cause of decrease in quality of life, especially among women.¹ The prevalence of UI in women is estimated to range from 13% to 46%,^2,3 and studies have shown that incontinence increases with age.⁴ In addition to the significant social impact that UI has on a woman’s quality of life, this condition has a significant financial burden on individual and national healthcare dollars. It has been estimated that the total annual direct and indirect cost for UI in the United States alone is $19.5 billion.⁵UI is defined according to patients’ symptoms. Although definitions vary in the literature, the International Continence Society defines three major subtypes of UI: (1) stress urinary incontinence (SUI) is the complaint of involuntary leakage on effort or exertion, or on sneezing or coughing; (2) urgency urinary incontinence (UUI) is the complaint of involuntary leakage accompanied by or immediately preceded by urgency; and (3) mixed urinary incontinence (MUI) is the complaint of involuntary leakage associated with urgency and also with exertion, effort, sneezing, or coughing.^6,7Although there is a plethora of treatment options, conservative management is the first-line option for most patients with UI. The rationale for conservative treatment is that UI is not necessarily a progressive disease, and that conservative therapies can be effective, well tolerated, and safe. Furthermore, a moderate delay in surgical therapy does not make treatment more difficult or less effective. One of the recommendations of the 1992 Agency for Health Care Policy and Research guideline states that “surgery, except in very specific cases, should be considered only after behavioral and pharmacologic interventions have been tried.”⁸ Similarly, the European Association of Urology guidelines advocate a stepwise approach regarding management of UI, which begins with addressing underlying medical or cognitive issues, progressing to lifestyle modifications, behavioral therapy, and mechanical devices.⁹ In addition, conservative therapies are frequently preferred by many patients. Taking into account the patient’s goals and preferences, it is appropriate to recommend conservative management as an initial approach.     

Second generation N-(1,2-diphenylethyl)piperazines as dual serotonin and noradrenaline reuptake inhibitors: Improving metabolic stability and reducing ion channel activity

New N-(1,2-diphenylethyl)piperazines 6 are disclosed as dual serotonin and noradrenaline reuptake inhibitors (SNRI) which may have potential in treating stress urinary incontinence (SUI). In this Letter, we present new data for SNRI PF-526014 (4) including performance in a canine in vivo model of SUI, cardiovascular assessment, pharmacokinetics in dog and determination of the primary routes of metabolism in vitro. Starting from 4, detailed structure activity relationships established that potent dual SNRIs could be achieved by appropriate substitution of the phenyl rings (6: R; R¹) combined with a preferred stereochemistry. From this set of compounds, piperazine (?)-6a was identified as a potent and selective dual SNRI with improved metabolic stability and reduced ion channel activity when compared to 4. Based on this profile, (?)-6a was selected for further evaluation in a preclinical model of SUI.     

Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study

This study assessed the effects of the serotonin (5-HT) and norepinephrine (NE) transporter inhibitor duloxetine on the effects of 3,4-methylenedioxy-methamphetamine (MDMA, ecstasy) in vitro and in 16 healthy subjects. The clinical study used a double-blind, randomized, placebo-controlled, four-session, crossover design. In vitro, duloxetine blocked the release of both 5-HT and NE by MDMA or by its metabolite 3,4-methylenedioxyamphetamine from transmitter-loaded human cells expressing the 5-HT or NE transporter. In humans, duloxetine inhibited the effects of MDMA including elevations in circulating NE, increases in blood pressure and heart rate, and the subjective drug effects. Duloxetine inhibited the pharmacodynamic response to MDMA despite an increase in duloxetine-associated elevations in plasma MDMA levels. The findings confirm the important role of MDMA-induced 5-HT and NE release in the psychotropic effects of MDMA. Duloxetine may be useful in the treatment of psychostimulant dependence. TRIAL REGISTRATION: Clinicaltrials.gov NCT00990067.     

电针阴部神经刺激疗法联合Kegel盆底康复训练对产后压力性尿失禁患者盆底肌力、尿流动力学和生活质量的影响

摘要 目的：探讨电针阴部神经刺激疗法联合Kegel盆底康复训练对产后压力性尿失禁（SUI）患者盆底肌力、尿流动力学和生活质量的影响。方法：选取2019年6月~2021年11月期间于我院就诊的产后SUI患者109例,按照入院就诊奇偶顺序分为两组,其中对照组54例,接受Kegel盆底康复训练,研究组55例,接受电针阴部神经刺激疗法联合Kegel盆底康复训练。对比两组疗效、漏尿量、尿失禁程度、盆底肌力、尿流动力学和生活质量。结果：研究组的临床总有效率高于对照组（P<0.05）。两组治疗后盆底肌肌力各指标（手测肌力和Ⅰ类肌纤维最大值、Ⅱ类肌纤维平均值）均升高,且研究组高于对照组（P<0.05）。两组治疗后漏尿量、尿失禁程度评分均下降,且研究组低于对照组（P<0.05）。两组治疗后尿流动力学相关指标[腹压漏尿点压（AL-PP）、最大尿流率（Qmax）和最大尿道闭合压力（MUCP）]均升高,且研究组高于对照组（P<0.05）。两组治疗后尿失禁生活质量量表（I-QOL）各维度（限制性行为、心理影响、社交活动受限）评分及总分均升高,且研究组高于对照组（P<0.05）。结论：电针阴部神经刺激疗法联合Kegel盆底康复训练可有效改善产后SUI患者的盆底肌肌力和尿失禁情况,减少漏尿量,同时可促进尿流动力学恢复,进而提高患者的生活质量。