Harris E. Foster

Effect of amitriptyline on symptoms in treatment naive 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.

Urinary Nitric Oxide Synthase Activity and Cyclic GMP Levels are Decreased with Interstitial Cystitis and Increased with Urinary Tract Infections

PURPOSE Since urinary nitric oxide synthase (NOS) activity correlates with certain disease process affecting the urinary tract and since nitric oxide increases cyclic GMP levels by activating guanylyl cyclase, urinary particulate NOS activity and cyclic GMP levels are evaluated in female patients with interstitial cystitis (IC) and compared with those from female controls and female patients with urinary tract infections (UTIs). MATERIALS AND METHODS Urinary NOS activity is measured as the formation of [(14)C]-L-citrulline from [(14)C]-L-arginine, and urinary cyclic GMP levels are measured by an [(125)I]-radioimmunoassay. RESULTS Female patients with IC have significantly less NOS activity in their urine pellet particulate fractions than female control females UTIs, 2.3 +/- 1.0, 14 +/- 3.0, and 120 +/- 10 pmol. citrulline formed/min./mg. protein. Urinary cyclic GMP levels are significantly lower in IC patients than in female controls or females with UTIs: 0.50 +/- 0.06, 0.82 +/- 0.14. and 3.72 +/- 0.81 micromol. cyclic GMP/g. creatinine. CONCLUSIONS Regulation of urinary NOS activity with subsequent changes in nitric oxide and cyclic GMP may be an important determinant of symptoms and immunologic responses to UTIs and IC.

Detection of urethral diverticula in women : Comparison of a high resolution fast spin echo technique with double balloon urethrography

PURPOSE We compared a rapid high resolution magnetic resonance imaging (MRI) technique to contrast urethrography for the detection of urethral diverticula in women. MATERIALS AND METHODS During a 19-month interval 13 patients with clinically suspected urethral diverticula were evaluated with MRI and contrast urethrography. All patients were referred by a urologist, and had clinical signs and symptoms suggesting the presence of a urethral diverticulum. Double balloon urethrography was performed in 12 patients and voiding cystourethrography was done in 1. MRI was performed using a fast spin echo T2-weighted pulse sequence and a dedicated pelvic multicoil. Following a sagittal localizer sequence 3 mm. thick axial sections were obtained from the bladder base through the entire urethra. Total imaging time was 15 minutes. RESULTS In 7 patients MRI and urethrography were negative for urethral diverticula, and in 3 cystourethroscopy was negative. In 1 patient MRI revealed a vaginal inclusion cyst confirmed by surgery. Three patients had no other studies or procedures performed. In 6 patients MRI was positive for urethral diverticula, including 4 in whom the diverticulum was confirmed at surgery, 1 who declined surgery and 1 who was lost to followup. Of the 4 patients (75%) with a surgically confirmed diverticulum double balloon urethrogram was negative in 3. CONCLUSIONS MRI is a valuable noninvasive technique for determining the presence of urethral diverticula as well as detecting other abnormalities. In our study MRI had a higher sensitivity for detecting diverticula and a much higher negative predictive rate.

Improvement in Interstitial Cystitis Symptom Scores During Treatment With Oral L-Arginine

PURPOSE Urinary nitric oxide synthase activity is decreased in patients with interstitial cystitis. Since nitric oxide may be an important determinant of the symptoms and immunological responses associated with interstitial cystitis, patients with this disease were treated with oral L-arginine, the substrate for nitric oxide synthase. MATERIALS AND METHODS Ten patients took 1.5 gm. L-arginine orally daily for 6 months. Interstitial cystitis symptoms were surveyed before and during the 6-month trial. RESULTS Oral L-arginine treatment resulted in a significant decrease in urinary voiding discomfort, lower abdominal pain and vaginal/urethral pain. Urinary frequency during the day and night also significantly decreased. CONCLUSIONS This self-controlled study provides evidence that long-term oral L-arginine improves interstitial cystitis related symptoms.

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.

EFFECT OF LONG-TERM ORAL L-ARGININE ON THE NITRIC OXIDE SYNTHASE PATHWAY IN THE URINE FROM PATIENTS WITH INTERSTITIAL CYSTITIS

PURPOSE We attempted to determine whether oral L-arginine, the substrate for nitric oxide synthase, increases nitric oxide synthase activity and cyclic guanosine monophosphate (cGMP) levels in the urine from interstitial cystitis patients. Nitric oxide and cGMP are decreased in urine from interstitial cystitis patients and both induce smooth muscle relaxation and immunological responses. Increasing urinary nitric oxide and cGMP may ameliorate interstitial cystitis symptoms. MATERIALS AND METHODS Eight patients with interstitial cystitis were given L-arginine (1,500 mg. a day) orally for 6 months. Before and during treatment nitric oxide synthase activity and inducible nitric oxide synthase protein, cGMP, nitrate plus nitrite and interleukin 8 (IL-8) levels were measured in urine. RESULTS After 2 weeks to 1 month of oral L-arginine treatment, urinary levels of nitric oxide synthase related enzymes and products increased significantly, while levels of the cytokine IL-8 were not changed significantly. IL-8 was significantly elevated in interstitial cystitis patients with leukocyte esterase positive urine. CONCLUSIONS Long-term oral administration of L-arginine increases nitric oxide related enzymes and metabolites in the urine of patients with interstitial cystitis, which is associated with a decrease in interstitial cystitis related symptoms.

Redesigning a large-scale clinical trial in response to negative external trial results: the CAMUS study of Phytotherapy for Benign Prostatic Hyperplasia

Background Benign prostatic hyperplasia (BPH), a common condition among older men, confers its morbidity through potentially bothersome lower urinary tract symptoms. Treatments for BPH include drugs such as alpha-adrenergic receptor blockers and 5-alpha reductase inhibitors, minimally invasive therapies that use heat to damage or destroy prostate tissue, and surgery including transurethral resection of the prostate. Complementary and alternative medicines are gaining popularity in the US. Two phytotherapies commonly used for BPH are extracts of the fruit of Serenoa repens, the Saw palmetto dwarf palm that grows in the Southeastern US, and extracts of the bark of Pygeum africanum, the African plum tree. Purpose The objective of the Complementary and Alternative Medicines for Urological Symptoms (CAMUS) clinical trial is to determine if phytotherapy is superior to placebo in the treatment of BPH. Methods CAMUS was originally designed as a 3300-participant, four-arm trial of S. repens, P. africanum, an alpha-adrenergic blocking drug, and placebo with time to clinical progression of BPH, a measure of long-term efficacy, as the primary endpoint. Before enrollment started, a randomized, double-blind, placebo-controlled, single institution clinical trial showed that S. repens at the usual dose did not demonstrate any benefit over placebo with respect to symptom relief at 1 year. Consequently, the focus of CAMUS shifted from evaluating long-term efficacy to determining if any short-term (6—18 months) symptom relief could be achieved with increasing doses of S. repens, the phytotherapy most commonly used in the US for BPH. Results Results are anticipated in 2011. Conclusions Trial design occurs in an environment of continually evolving information. In this case, emerging results from another trial suggested that a study of long-term efficacy was premature, and that an effective dose and preparation of S. repens had to be established before proceeding to a long-term clinical trial. Clinical Trials 2009; 6: 628—636. http://ctj.sagepub.com

Cystic pelvic pathology presenting as falsely elevated postvoid residual urine measured by portable ultrasound bladder scanning: report of 3 cases and review of the literature

Dedicated portable ultrasound devices generally offer a rapid, noninvasive, largely operator-independent means of assessing post-void residual urine (PVR) volume. In most published series, PVR measured by portable ultrasound correlates well with catheterized urine volume. We report 3 cases in which follow-up of falsely elevated PVR measurements on ultrasound resulted in comparatively low catheterized volumes. In all 3 cases, the elevated readings were due to cystic ovarian pathology, which was diagnosed by formal radiologic evaluation and ultimately confirmed operatively in 2 cases. Cystic pathology of the pelvis or lower abdomen may present as an elevated PVR on ultrasound and low urine volume on subsequent catheterization and should prompt further evaluation.

Developmental changes in the functional, biochemical and molecular properties of rat bladder endothelin receptors

The effect of aging on functional, biochemical, anatomical and molecular properties of endothelin (ET) receptors in bladder smooth muscle of the 3-week-, 3-month- and 22-month-old rats was examined using isolated muscle bath techniques, radioligand binding on membrane particulates and slide mounted tissue sections, and real-time reverse transcription polymerase chain reaction (RT-PCR). ET-1 induced significantly larger contractile responses in bladder dome muscle strips from 3-week- than from 3-month- and 22-month-old rats. The expression level of total ET receptors, determined by saturation binding experiments with [125I]ET-1, was higher in detrusor from 3-week- than 22-month-old rats. Inhibition studies with BQ123, a selective ETA receptor antagonist, indicated the predominance of the ETA receptor subtype and a similar proportion of ETA to ETB receptor subtypes in the rat detrusor at all ages studied. Autoradiographic data support the age-dependent decrease in the density of ET receptors and also indicate that the ETA receptor subtype is primarily located in the smooth muscle layer, whereas the ETB receptor subtype is located in both the urothelial and smooth muscle layers. Determined by real-time RT-PCR, ET 1, ET-3, ECE-1 and ET receptor subtype (ETA and ETB) mRNAs were shown to be higher in bladders of 3-week- compared to 3-month- or 22-month-old rats. This study indicates age-dependent alterations in the ET receptor system at both gene transcript and protein levels in the Fischer rat detrusor.

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.