Surgical Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA Guideline Amendment 2019.

PURPOSE: Male lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) is common in men and can have negative effects on quality of life (QoL). It is the hope that this Guideline becomes a reference for effective evidence-based surgical management of LUTS/BPH. MATERIALS AND METHODS: The evidence team searched Ovid MEDLINE, the Cochrane Library, and the Agency for Healthcare Research and Quality database to identify studies indexed between January 2007-September 2017. Following initial publication, this guideline was amended in 2019 and reflects relevant literature published through January 2019. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table 1 in supplementary unabridged guideline, https://www.jurology.com). RESULTS: This Guideline provides evidence-based recommendations regarding management of LUTS/BPH utilizing surgery and minimally invasive surgical therapies (MIST). Additional statements are made regarding diagnostic and pre-operative tests. Clinical statements are made in comparison to what is generally accepted as the gold standard (i.e. transurethral resection of the prostate [TURP] monopolar and/or bipolar). This guideline is designed to be used in conjunction with the associated treatment algorithm (see figure).[Figure: see text]Conclusions:The prevalence and the severity of LUTS increases as men age and is an important diagnosis in the healthcare of patients and the welfare of society. This document will undergo updating as knowledge regarding treatments and future surgical options continues to expand.

Surgical Management of Lower Urinary Tract Symptoms Attributed to Benign Prostatic Hyperplasia: AUA Guideline.

PURPOSE: Male lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) is common in men and can have negative effects on quality of life (QoL). It is the hope that this Guideline becomes a reference on the effective evidence-based surgical management of LUTS/BPH. MATERIALS AND METHODS: The evidence team searched Ovid MEDLINE, the Cochrane Library, and the Agency for Healthcare Research and Quality (AHRQ) database to identify studies indexed between January 2007 and September 2017. When sufficient evidence existed, the body of evidence was assigned a strength rating of A (high), B (moderate), or C (low) for support of Strong, Moderate, or Conditional Recommendations. In the absence of sufficient evidence, additional information is provided as Clinical Principles and Expert Opinions (table 1 in supplementary unabridged guideline, http://jurology.com/). RESULTS: This Guideline provides updated, evidence-based recommendations regarding management of LUTS/BPH utilizing surgery and minimally invasive surgical therapies; additional statements are made regarding diagnostic and pre-operative tests. Clinical statements are made in comparison to what is generally accepted as the gold standard (i.e. transurethral resection of the prostate [TURP]-monopolar and/or bipolar). This guideline is designed to be used in conjunction with the associated treatment algorithm. CONCLUSIONS: The prevalence and the severity of LUTS increases as men age and is an important diagnosis in the healthcare of patients and the welfare of society. This document will undergo additional literature reviews and updating as the knowledge regarding current treatments and future surgical options continues to expand.

Use of vanilloids in urologic disorders.

The bladder is an organ rich in vanilloid targets: dense unmyelinated c-fibers partially responsible for bladder sensation and response to noxious stimuli. Drugs such as capsaicin and resiniferatoxin (RTX) interact with the VR1 vanilloid receptor subtype to initially excite then subsequently desensitize the c-fibers. This chapter examines the literature describing the use of vanilloid receptor agonists in the treatment of the following urological disorders: neurogenic bladder (NGB), overactive bladder (OAB), and interstitial cystitis/painful bladder syndrome (IC/PBS). Review of the literature was performed using Pubmed and the following key words "capsaicin," "resiniferatoxin (RTX)," and "neurogenic bladder," "overactive bladder (OAB)," and "interstitial cystitis," "painful bladder syndrome." Articles focusing on randomized trials comparing intravesical administration of a vanilloid receptor agonist to placebo and those in English were reviewed. We conclude that capsaicin and RTX do appear to provide some acceptable treatment results in patients with neurogenic bladder, though larger studies are needed to confirm this. Although efficacy has been shown in some studies, currently the use of vanilloids cannot be recommended for routine use in patients with OAB as the need for catheterization may cause the risk to outweigh the benefit of treatment. Similarly, for the treatment of BPS, vanilloid receptor agonists lack strong evidence for efficacy or tolerability; larger studies are needed to define their role. Understanding how vanilloids are able to impact these disorders, however, may help further elucidate their underlying pathophysiological processes.

Renal tract ultrasonography for routine surveillance in spinal cord injury patients.

OBJECTIVES: To report the efficacy of a urinary tract surveillance regime based on annual renal tract ultrasound without routine use of urodynamic testing (UDS) in our population of spinal cord injury (SCI) patients managed with clean intermittent catheterization (CIC). METHODS: Data was gathered retrospectively from the records of 48 SCI patients (40 males and 8 females). After establishing a safe system with initial urodynamics, renal ultrasonography was done annually for surveillance. UDS was repeated only when patients presented with new symptoms. The primary endpoint was the report of ultrasound findings at last follow-up. Findings of dilatation, calculi, scarring, and reflux were noted. RESULTS: Mean follow-up was 6.8 years. By final follow-up, pelvicaliectasis was present in 4 (8%) subjects. Mild-moderate hydronephrosis was present in 3 (6%) subjects: 1 stable and 2 (4%) new compared to initial assessment. No severe cases of hydronephrosis were noted. Six (13%) subjects had renal/ureteral calculi. No new cases of renal cortical scarring or thinning were noted. One (2%) subject had high-grade reflux on UDS secondary to a double J stent. CONCLUSIONS: Data relating to the efficacy of sequential surveillance studies in SCI patients are scarce, thus there is great variability in urologic surveillance methods worldwide. Upper tract abnormalities detected in our patients were early consequences of acute obstruction rather than late manifestations of detrusor changes and could not have been prevented with more regular urodyamic testing. These results suggest that annual ultrasound monitoring without routine urodynamic testing is an effective surveillance strategy in SCI patients managed with CIC.

Intermittent catheterization and recurrent urinary tract infection in spinal cord injury.

PURPOSE: To study the association of recurrent symptomatic urinary tract infections (UTIs) with the long-term use of clean intermittent catheterization (CIC) for the management of neurogenic bladder in patients with spinal cord injury (SCI). METHODS: Retrospective study of 61 SCI patients with neurogenic bladder managed by CIC. Subjects were selected from 210 SCI patients seen at the Yale Urology Medical Group between 2000 and 2010. Medical UTI prophylaxis (PRx) with oral antimicrobials or methenamine/ascorbic acid was used to identify patients with recurrent UTI. The number of positive cultures (≥10(3) cfu/mL) within a year prior to starting PRx was used to confirm the recurrence of UTI. RESULTS: Fifty-one male and 10 female subjects were managed with CIC. Forty-one (67%) subjects were placed on medical PRx for symptomatic recurrent UTI. Seventeen (28%) subjects had at least 3 positive cultures within the year prior to starting PRx. Fifteen of 20 (75%) subjects not on PRx had no complaints of UTI symptoms in the final year of follow-up. CONCLUSION: Recurrent symptomatic UTIs remain a major complication of long-term CIC in SCI patients. Although CIC is believed to have the fewest number of complications, many SCI patients managed with long-term CIC are started on medical PRx early in the course of management. Future studies are needed to determine the efficacy of routine UTI PRx in these patients as well as determine what factors influence why many patients on CIC experience frequent infections and others do not.

Suprapubic cystostomy for neurogenic bladder using Lowsley retractor method: a procedure revisited.

OBJECTIVE: To report our experience with the Lowsley retractor method for suprapubic cystostomy (SPC) in patients with neurogenic bladder (NGB). METHODS: A retrospective study was performed of 44 patients with NGB who underwent SPC with the Lowsley retractor method. The subjects were selected from 90 patients undergoing SPC by 1 surgeon from 1995 to 2010. The age, sex, indication, anesthesia type, catheter type, blood loss, fluids administered, and duration and complications were recorded. RESULTS: A total of 49 primary catheter placements were performed in 44 patients. A total of 23 men and 21 women were included. The etiology of NGB was spinal cord injury and multiple sclerosis in 38 subjects (86%). The mean age was 44 years (range 18-86). The cases were performed under general anesthesia, except for 8 (16%) that were successfully performed with local and monitored anesthesia. The operation time documented in 19 cases (39%) was 20.2 ± 5.5 minutes (range 11-31). The Foley catheter size ranged from 16F to 22F. The blood loss was minimal, and there were no intraoperative complications or incorrect catheter placements. One patient returned with significant hematuria 1 day after the procedure. No other minor or major complications were noted. CONCLUSION: Patients with NGB have been shown to have a greater risk of complication during percutaneous suprapubic catheter placement. SPC using the Lowsley retractor was described by Zeidman et al in 1988. Their report did not detail the patient characteristics or operative experience. To our knowledge, no other institutional experience with the technique has been reported. The present report describes the Lowsley retractor method as a quick and safe ambulatory procedure for patients with NGB.

Effect of increasing doses of saw palmetto extract on lower urinary tract symptoms: a randomized trial.

CONTEXT: Saw palmetto fruit extracts are widely used for treating lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH); however, recent clinical trials have questioned their efficacy, at least at standard doses (320 mg/d). OBJECTIVE: To determine the effect of saw palmetto extract (Serenoa repens, from saw palmetto berries) at up to 3 times the standard dose on lower urinary tract symptoms attributed to BPH. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, multicenter, placebo-controlled randomized trial at 11 North American clinical sites conducted between June 5, 2008, and October 10, 2010, of 369 men aged 45 years or older, with a peak urinary flow rate of at least 4 mL/s, an American Urological Association Symptom Index (AUASI) score of between 8 and 24 at 2 screening visits, and no exclusions. INTERVENTIONS: One, 2, and then 3 doses (320 mg/d) of saw palmetto extract or placebo, with dose increases at 24 and 48 weeks. MAIN OUTCOME MEASURES: Difference in AUASI score between baseline and 72 weeks. Secondary outcomes included measures of urinary bother, nocturia, peak uroflow, postvoid residual volume, prostate-specific antigen level, participants' global assessments, and indices of sexual function, continence, sleep quality, and prostatitis symptoms. RESULTS: Between baseline and 72 weeks, mean AUASI scores decreased from 14.42 to 12.22 points (-2.20 points; 95% CI, -3.04 to -1.36) [corrected]with saw palmetto extract and from 14.69 to 11.70 points (-2.99 points; 95% CI, -3.81 to -2.17) with placebo. The group mean difference in AUASI score change from baseline to 72 weeks between the saw palmetto extract and placebo groups was 0.79 points favoring placebo (upper bound of the 1-sided 95% CI most favorable to saw palmetto extract was 1.77 points, 1-sided P = .91). Saw palmetto extract was no more effective than placebo for any secondary outcome. No clearly attributable adverse effects were identified. CONCLUSION: Increasing doses of a saw palmetto fruit extract did not reduce lower urinary tract symptoms more than placebo. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00603304.

Recruitment of participants to a clinical trial of botanical therapy for benign prostatic hyperplasia.

OBJECTIVES: The timely recruitment of study participants is a critical component of successful trials. Benign prostatic hyperplasia (BPH), a common nonmalignant urologic condition among older men, is characterized by lower urinary tract symptoms (LUTS). Successful recruitment methods for a trial of medical therapy for BPH, Medical Therapy of Prostate Symptoms (MTOPS), were mass mailing and advertising. The Complementary and Alternative Medicines Trial for Urological Symptoms (CAMUS) was designed to evaluate a botanical therapy, saw palmetto, for the treatment of BPH. The objective of this study was to evaluate recruitment strategies for CAMUS and to contrast the baseline characteristics of CAMUS participants with those recruited to a similar trial using conventional medical therapy. DESIGN: CAMUS is a randomized, double-blind, placebo-controlled trial designed to evaluate the effects of saw palmetto given at escalating doses over an 18-month period on relief from LUTS. SUBJECTS: The target enrollment goal was 350 men with LUTS from 11 clinical centers over a 12-month period. The recruitment techniques used and participants contacted, screened, and randomized through each technique were obtained from the clinical centers. Baseline characteristics of the CAMUS participants were compared with participants in the MTOPS trial who met the CAMUS eligibility criteria for LUTS. RESULTS: The target enrollment goal was achieved in 11 months. The overall monthly recruitment rate per site was 3.7 and ranged from 2.4 to 8.0. The most successful recruitment methods were mass mailing and advertising, which accounted for 39% and 35% of the study participants, respectively. In comparison to MTOPS participants, CAMUS participants were younger, more highly educated, more diverse, and had less severe urinary symptoms. CONCLUSIONS: Successful recruitment methods for CAMUS were similar to those in MTOPS. The use of botanical therapy attracted a less symptomatic and more educated study population.

Update on AUA guideline on the management of benign prostatic hyperplasia.

PURPOSE: To revise the 2003 version of the American Urological Association's (AUA) Guideline on the management of benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: From MEDLINE® searches of English language publications (January 1999 through February 2008) using relevant MeSH terms, articles concerning the management of the index patient, a male ≥45 years of age who is consulting a healthcare provider for lower urinary tract symptoms (LUTS) were identified. Qualitative analysis of the evidence was performed. Selected studies were stratified by design, comparator, follow-up interval, and intensity of intervention, and meta-analyses (quantitative synthesis) of outcomes of randomized controlled trials were planned. Guideline statements were drafted by an appointed expert Panel based on the evidence. RESULTS: The studies varied as to patient selection; randomization; blinding mechanism; run-in periods; patient demographics, comorbidities, prostate characteristics and symptoms; drug doses; other intervention characteristics; comparators; rigor and intervals of follow-up; trial duration and timing; suspected lack of applicability to current US practice; and techniques of outcomes measurement. These variations affected the quality of the evidence reviewed making formal meta-analysis impractical or futile. Instead, the Panel and extractors reviewed the data in a systematic fashion and without statistical rigor. Diagnosis and treatment algorithms were adopted from the 2005 International Consultation of Urologic Diseases. Guideline statements concerning pharmacotherapies, watchful waiting, surgical options and minimally invasive procedures were either updated or newly drafted, peer reviewed and approved by AUA Board of Directors. CONCLUSIONS: New pharmacotherapies and technologies have emerged which have impacted treatment algorithms. The management of LUTS/BPH continues to evolve.

Early termination of a trial of mycophenolate mofetil for treatment of interstitial cystitis/painful bladder syndrome: lessons learned.

PURPOSE: We evaluated the efficacy and tolerability of mycophenolate mofetil in patients with treatment refractory interstitial cystitis/painful bladder syndrome. MATERIALS AND METHODS: A total of 210 patients with interstitial cystitis/painful bladder syndrome were to be randomized into a multicenter, placebo controlled trial using a 2:1 randomization. Participants in whom at least 3 interstitial cystitis/painful bladder syndrome specific treatments had failed and who had at least moderately severe symptoms were enrolled in a 12-week treatment study. The primary study end point was the global response assessment. Secondary end points were general and disease specific symptom questionnaires, and voiding diaries. RESULTS: Only 58 subjects were randomized before a black box warning regarding mycophenolate mofetil safety was issued by the manufacturer in October 2007. The trial was halted, and interim analysis was performed and presented to an independent data and safety monitoring board. Six of the 39 subjects (15%) randomized at study cessation were considered responders for mycophenolate mofetil compared to 3 of 19 controls (16%, p=0.67). Secondary outcome measures reflected more improvement in controls. CONCLUSIONS: In a randomized, placebo controlled trial that was prematurely halted mycophenolate mofetil showed efficacy similar to that of placebo to treat symptoms of refractory interstitial cystitis/painful bladder syndrome. The results of this limited study cannot be used to confirm or refute the hypothesis that immunosuppressive therapy may be beneficial to at least a subgroup of patients with interstitial cystitis/painful bladder syndrome. Despite study termination lessons can be gleaned to inform future investigations.

Effect of amitriptyline on symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome.

PURPOSE: Amitriptyline is frequently used to treat patients with interstitial cystitis/painful bladder syndrome. The evidence to support this practice is derived mainly from a small, single site clinical trial and case reports. MATERIALS AND METHODS: We conducted a multicenter, randomized, double-blind, placebo controlled clinical trial of amitriptyline in subjects with interstitial cystitis/painful bladder syndrome who were naïve to therapy. Study participants in both treatment arms received a standardized education and behavioral modification program. The drug dose was increased during a 6-week period from 10 up to 75 mg once daily. The primary outcome was a patient reported global response assessment of symptom improvement evaluated after 12 weeks of treatment. RESULTS: A total of 271 subjects were randomized and 231 (85%) provided a global response assessment at 12 weeks of followup. Study participants were primarily women (83%) and white (74%), with a median age of 38 years. In an intent to treat analysis (271) the rate of response of subjects reporting moderate or marked improvement from baseline in the amitriptyline and placebo groups was 55% and 45%, respectively (p = 0.12). Of the subgroup of subjects (207) who achieved a drug dose of at least 50 mg, a significantly higher response rate was observed in the amitriptyline group (66%) compared to placebo (47%) (p = 0.01). CONCLUSIONS: When all randomized subjects were considered, amitriptyline plus an education and behavioral modification program did not significantly improve symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. However, amitriptyline may be beneficial in persons who can achieve a daily dose of 50 mg or greater, although this subgroup comparison was not specified in advance.

Followup of patients with interstitial cystitis responsive to treatment with intravesical bacillus Calmette-Guerin or placebo.

PURPOSE: We evaluated the longer term response in patients with interstitial cystitis who initially responded to intravesical bacillus Calmette-Guerin or placebo in a randomized clinical trial. MATERIALS AND METHODS: Patients with interstitial cystitis who responded positively to treatment with bacillus Calmette-Guerin or placebo after 34 weeks of followup in a double-blind clinical trial were followed for an additional 34 weeks in an observational study to assess response durability. Outcomes at 68 weeks included a patient reported global response assessment, 24-hour voiding diary, and pain, urgency and validated interstitial cystitis symptom indexes. RESULTS: Of responders to bacillus Calmette-Guerin or placebo in the clinical trial 38 continued extended followup in the observational study. A total of 12 (75%) responders who received placebo and 19 (86%) who received bacillus Calmette-Guerin considered themselves to remain moderately or markedly improved at week 68. Improved symptom outcomes were also generally maintained during followup in the 2 groups. CONCLUSIONS: Most patients who respond to therapy with intravesical bacillus Calmette-Guerin or placebo maintain improved symptoms for up to 68 weeks after the initiation of therapy. However, initial response rates are low and placebo responders demonstrated essentially the same durability of response as bacillus Calmette-Guerin responders. These results argue against the routine use of bacillus Calmette-Guerin in this patient group.

Did patients with interstitial cystitis who failed to respond to initial treatment with bacillus Calmette-Guerin or placebo in a randomized clinical trial benefit from a second course of open label bacillus Calmette-Guerin?

PURPOSE: We evaluated safety and efficacy outcomes in a case series of subjects who received open label intravesical bacillus Calmette-Guerin after failing to respond to bacillus Calmette-Guerin or intravesical placebo in a randomized clinical trial. MATERIALS AND METHODS: Subjects who met National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases criteria for IC and reported at least moderate pain and frequency were initially randomized to 6 weekly intravesical instillations of bacillus Calmette-Guerin or placebo and followed for a total of 34 weeks. At 34 weeks subjects who reported that they had not responded to treatment were offered treatment with open label bacillus Calmette-Guerin, using the same course of treatment and followup. Outcomes included a patient reported global response assessment, a 24-hour voiding diary, pain, urgency, validated interstitial cystitis symptom indexes and adverse events. RESULTS: A total of 156 subjects elected open label bacillus Calmette-Guerin, of whom 18 (12%) withdrew during the open label series. The response rate based on the global response assessment was 18% and it was identical between those initially randomized to placebo (first course of bacillus Calmette-Guerin in the open label series) and those initially randomized to bacillus Calmette-Guerin (second course). Small improvements were observed for most secondary efficacy outcomes. Most participants reported at least 1 adverse event, primarily pain, genitourinary symptoms and gastrointestinal disturbances. However, there was no difference in adverse events between those who received the first course of bacillus Calmette-Guerin in this series compared to those who received 2 courses. CONCLUSIONS: The low response rate for bacillus Calmette-Guerin in this open label case series further argues against the routine use of bacillus Calmette-Guerin as treatment for interstitial cystitis.

Sexual function is a determinant of poor quality of life for women with treatment refractory interstitial cystitis.

PURPOSE: Interstitial cystitis significantly negatively impacts quality of life. The demographic and clinical factors associated with decreased quality of life in these patients have not been well studied. MATERIALS AND METHODS: Women with moderate/severe interstitial cystitis enrolled in a clinical trial of intravesical bacillus Calmette-Guerin were studied. Demographic data and responses to questionnaires were evaluated at baseline, including the O'Leary-Sant Interstitial Cystitis Symptom Index and Problem Index, University of Wisconsin Interstitial Cystitis Inventory, Medical Outcomes Study sexual functioning scale, and the physical composite and mental composite scales of the Medical Outcomes Study Short Form Health Status Survey. Three composite indexes were constructed (from the O'Leary-Sant Interstitial Cystitis Symptom Index, O'Leary-Sant Interstitial Cystitis Problem Index, pain/urgency Likert scales and 24-hour voiding diary) to document the severity, frequency and bother of pain, urinary urgency and frequency (frequency composite index). Linear and multivariate regression models were used to examine predictors of the physical composite and mental composite scales of the Medical Outcomes Study Short Form Health Status Survey. Medical Outcomes Study sexual functioning scale data were available for 163 of the 217 women in the trial. RESULTS: Physical composite scale (median 36) and mental composite scale (median 42) were lower than the standard population value of 50. Multivariate models showed that employment, pain composite index and Medical Outcomes Study sexual functioning scale (all p<0.001) predicted physical composite scale, while only Medical Outcomes Study sexual functioning scale (p<0.001) remained a strong predictor of mental composite scale. CONCLUSIONS: Sexual functioning, employment and pain issues predict mental and physical quality of life. In particular, this study identifies sexual functioning as a primary predictor of mental quality of life in women with long-standing interstitial cystitis. It is suggested that sexual functioning may be a salient therapeutic target in the multifaceted treatment of patients with interstitial cystitis.

Age related changes in the functional, biochemical and molecular properties of alpha1-adrenoceptors in the rat genitourinary tract.

PURPOSE: Because age related changes occur in the properties of alpha(1)-adrenoceptor in several mammalian tissues and alpha(1)-adrenoceptor antagonists are extensively used to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia, we investigated age related changes in the functional, biochemical and molecular properties of alpha(1)-adrenoceptor in the rat genitourinary tract. MATERIALS AND METHODS: The characteristics of alpha(1)-adrenoceptor in the ventral and dorsolateral prostate, and bladder base and dome of 3 and 22-month-old rats were determined using an isolated muscle bath, radioligand receptor binding and real-time reverse transcriptase-polymerase chain reaction techniques. RESULTS: Old rats had significantly higher body weight, lower testosterone, a smaller ventral prostate and a larger bladder dome than young rats. Although there was no significant age dependent difference in the properties of alpha(1)-adrenoceptor in the bladder base and dome, total alpha(1)-adrenoceptor density, mRNA expression of all 3 alpha(1)-adrenoceptor subtypes (alpha(1A), alpha(1B) and alpha(1D)) and the maximum contractile responses to phenylephrine were significantly lower in the ventral and dorsolateral prostate of 22 vs 3-month-old rats. CONCLUSIONS: Age related differences in the molecular, biochemical and functional properties of alpha(1)-adrenoceptors in the rat genitourinary tract may indicate potential differences in the response to alpha(1)-adrenoceptor antagonists with aging, ie a decrease in the therapeutic response in old vs young rats in the response to alpha(1)-adrenoceptor antagonists when used to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia.

The management of interstitial cystitis: an update.

Treating interstitial cystitis (IC) is one of the greatest challenges facing physicians and other health care providers who manage patients with this condition. The symptoms of urinary frequency and urgency, dysuria, and chronic pelvic pain characterize IC, but it is the debilitating pelvic pain associated with IC that is most difficult to control. The pathophysiology of IC pain is poorly understood, but is thought to be a complex entity including nociceptive, visceral, and neuropathic components. There are currently no universally effective therapies available. Oral treatments, however, are frequently used, including nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, gabapentin, and pentosan polysulfate, all of which have shown varying degrees of efficacy. Recognition that IC pain is multifactorial, and probably has a neuropathic component, has led to the use of some of these agents, previously prescribed for other neurologic conditions associated with chronic pain. Intravesical and surgical options are also available, which expands the armamentarium for those who treat pain secondary to IC. Treating IC requires managing all of the symptoms of this disease. This review aims to cover standard and novel treatment options, while concentrating on the management of pain.

Molecular classification of doxazosin-induced alterations in the rat prostate using gene expression profiling.

We investigated molecular changes that occurred during chronic administration of doxazosin, an alpha1-adrenoceptor (AR) antagonist, using Affymetrix GeneChip analysis of gene expression. Rats were treated with doxazosin (4 mg/kg/day subcutaneously, supplemented with 4 mg/kg/day orally) for 12 weeks. Labeled cRNA was prepared and the subsequent hybridization to rat 230A arrays was performed. The alterations in gene expression levels of candidate genes identified by microarray analysis with potential biological relevance were verified by real-time reverse transcription polymerase chain reaction (RT-PCR) using SYBR Green I. Doxazosin treated rats had significantly heavier prostates compared to control rats. Microarray analysis revealed that chronic doxazosin treatment caused changes in the expression levels of 625 genes, of which 39 were related to cell death, necrosis, growth, proliferation and G-protein signalling pathways in the rat prostate. Furthermore, RT-PCR experiments, in accord with the microarray analysis, indicated that chronic doxazosin treatment caused an up-regulation in the mRNA expression level of clusterin, an antiapoptotic mediator, and epiregulin, a mitogen, in the ventral and dorsolateral prostate, respectively. These findings, that demonstrate chronic doxazosin administration causes significant changes in the expression of several hundred genes in the rat prostate, may provide insight into the long-term efficacy of alpha1-AR antagonists in the treatment of benign prostatic hyperplasia.

A randomized controlled trial of intravesical bacillus calmette-guerin for treatment refractory interstitial cystitis.

PURPOSE: We compared intravesical bacillus Calmette-Guerin (BCG) to placebo instillations in patients with treatment refractory interstitial cystitis (IC). MATERIALS AND METHODS: Subjects who met the National Institutes of Health-National Institute for Diabetes and Digestive and Kidney Diseases criteria for IC, and reported at least moderate pain and frequency for a minimum of 6 months before study entry, were randomized to 6 weekly double-blinded intravesical instillations of either BCG or placebo, and then followed for a total of 34 weeks. The primary outcome was a patient reported global response assessment at week 34, supplemented with medications for IC during weeks 31 to 34. Secondary outcomes included a 24-hour voiding diary, pain, urgency, validated IC symptom indexes and adverse events. The target sample size was 260 participants, designed to detect a difference in response rates between placebo and BCG of 30% and 50%, respectively. RESULTS: A total of 265 participants were randomized and 17 (6%) patients withdrew from study. The response rates for the primary outcome were 12% for placebo and 21% for BCG (p = 0.062). Small improvements were observed for all secondary outcomes, some more so with BCG, but these differences were of borderline statistical significance. Although a large number of adverse events were reported in the BCG arm, there was no statistically significant difference between the treatment arms in overall adverse event rates. CONCLUSIONS: Although the BCG safety profile was acceptable, the response rate for the primary outcome was low. Effective medical treatment for patients with moderate to severe interstitial cystitis remains elusive.

Doxazosin-induced up-regulation of alpha 1A-adrenoceptor mRNA in the rat lower urinary tract.

Alpha1-adrenoceptor (AR) antagonists can provide effective treatment of symptoms caused by benign prostatic hyperplasia. However, their mechanisms of action have not been fully elucidated. We previously reported that chronic administration of doxazosin causes an up-regulation in the mRNA expression of all three alpha1-AR subtypes in the rat prostate. As alpha1-AR antagonists might also affect the properties of alpha1-ARs in the lower urinary tract, we examined the effects of doxazosin (2 or 4 mg/kg daily subcutaneously, supplemented with 4 mg/kg daily orally for 8 or 12 weeks) on alpha1-AR subtype mRNAs in the rat bladder dome, bladder base, and urethra using real-time reverse transcription PCR. Rats that received the highest doses of doxazosin had significantly heavier bladder base and prostatic urethra than controls. PCR data showed that all three alpha1-AR subtypes were expressed in all tissues studied. Doxazosin treatment caused an up-regulation in the mRNA levels of alpha1A-AR in the rat bladder base and prostatic urethra, indicating that chronic doxazosin treatment may cause an alteration in the properties of alpha1A-AR subtype mRNA in these two areas. Furthermore, the heavier bladder base and prostatic urethra in the doxazosin-treated rats suggest that alpha1-AR antagonist treatment might also influence the growth process in these areas of the rat lower urinary tract.