Treatment of refractory interstitial cystitis/painful bladder syndrome with CystoProtek--an oral multi-agent natural supplement.

OBJECTIVES: Interstitial cystitis/Painful bladder syndrome (IC/PBS) is a chronic bladder condition of unknown etiology and pathogenesis. However, there is evidence of bladder surface mucosal and glycosaminoglycans (GAG) dysfunction in IC/PBS and GAG replacement therapy has been used to treat the condition. The results of an open label, uncontrolled study of a dietary supplement designed to improve GAG mucopolysaccharides integrity (glucosamine sulfate, sodium hyaluronate and chondroitin sulfate) and reduce bladder wall inflammation (quercetin, rutin) are presented herein. METHODS: Two hundred fifty two IC/PBS patients (25 men, 227 women; 18-69 years old), who had failed other treatments, took four CystoProtek capsules /day (mg/capsule: glucosamine sulfate, 120; chondroitin sulfate, 150; hyaluronate sodium, 10; quercetin, 150; rutin, 20). Symptoms were evaluated using a visual analogue scale (VAS) (severity range from 1-10) before and after treatment (< 6, 6-12 or > 12 months). The women were divided into two severity groups--a more severe A group with a baseline mean VAS score greater than or equal to 5 and a less severe B group with a mean score < 5. RESULTS: Male patients (55.72 +/- 9.53 years, n = 25) had a mean VAS score at baseline of 7.6 +/- 1.63 which fell 51.8% to 3.94 +/- 2.46 (p < 0.0001) after 12.46 +/- 8.76 months of treatment. The women (n = 227) experienced a 48.8% reduction in the mean VAS score (p < 0.0001) after 11.2 +/- 8.7 months. The mean VAS score in Group A (49.72 +/- 11.39 years, n = 207) fell 52.1% from 7.91 +/- 1.55 to 3.79 +/- 2.37 (p < 0.0001) after 11.06 +/- 8.18 months and in Group B (52.40 +/- 10.19 years, n = 20) fell 43.5% from 3.15 +/- 0.92 to 1.78 +/- 1.63 (p = 0.013) after 10.10 +/- 5.80 months. Patients in Group A and B were further subdivided into Groups A1, B1 (> 12 months), A2, B2 (6-12 months) and A3, B3 (< 6 months treatment); improvement was statistically significant in all the more severe Group A treatment duration subgroups. CONCLUSIONS: Dietary supplements targeting the bladder GAGs (chondroitin, glucosamine, hyaluronate) and bladder inflammation (quercetin, rutin) are useful in the treatment of refractory IC/PBS. Prospective randomized trials of such supplements are warranted in both treatment refractory and treatment naïve patients.

A pilot open label study of Cystoprotek in interstitial cystitis.

Interstitial cystitis (IC) is a disorder of the urinary bladder characterized by urgency, frequency, nocturia and suprapubic pain. IC occurs primarily in women and symptoms are exacerbated by stress, ovulatory hormones and certain foods. IC pathogenesis is unknown, but the most consistent findings involve some dysfunction of the bladder glycosaminoglycan (GAG) protective layer and a high number of activated bladder mast cells. There is no effective therapy even through intravesical administration of dimethylsulfoxide (DMSO) or oral pentosanpolysulfate (PPS) have had variable success. A dietary supplement, CystoProtek, was formulated with the natural GAG components chondroitin sulfate and sodium hyaluronate to provide urothelial cytoprotection, together with the flavonoid quercetin that has anti-inflammatory properties and inhibits activation of mast cells. Thirty-seven female patients diagnosed by the NIDDK criteria who had failed all forms of therapy took six softgel CystoProtek capsules per day for 6 months. Global assessment scale was reduced from 9.0 +/- 2.9 to 4.3 +/- 2.1 (p < 0.05); moreover, the O'Leary/Sant Symptom Index decreased from 15.3 +/- 3.1 to 6.9 +/- 4.2 (p < 0.05) and the Problem Index from 13.1 +/- 3.7 to 5.4 +/- 4.0 (p <0.05). These results are very promising and warrant a larger study that may permit further analyses with respect to other, especially atopic, comorbid diseases.

New agents for the medical treatment of interstitial cystitis.

Interstitial cystitis (IC) is a painful, sterile, disorder of the urinary bladder characterised by urgency, frequency, nocturia and pain. IC occurs primarily in women but also in men with recent findings indicating that chronic, abacterial prostatitis may be a variant of this condition. The prevalence of IC has ranged from about 8 - 60 cases/100,000 female patients depending on the population evaluated. About 10% of patients have severe symptoms that are associated with Hunner's ulcers on bladder biopsy; the rest could be grouped in those with or without bladder inflammation. Symptoms of IC are exacerbated by stress, certain foods and ovulatory hormones. Many patients also experience allergies, irritable bowel syndrome (IBS) and migraines. There have been various reports indicating dysfunction of the bladder glycosaminoglycan (GAG) protective layer and many publications showing a high number of activated bladder mast cells. Increasing evidence suggests that neurogenic inflammation and/or neuropathic pain is a major component of IC pathophysiology. Approved treatments so far include intravesical administration of dimethylsulphoxide (DMSO) or oral pentosanpolysulphate (PPS). New treatments focus on the combined use of drugs that modulate bladder sensory nerve stimulation (neurolytic agents), inhibit neurogenic activation of mast cells, or provide urothelial cytoprotection, together with new drugs with anti-inflammatory activity.

Interstitial cystitis: a neuroimmunoendocrine disorder.

Interstitial cystitis (IC) is a sterile bladder condition occurring primarily in females. It is characterized by frequency, nocturia, and suprapubic pain. IC symptoms are exacerbated during ovulation and under stress, thus implicating neurohormonal processes. The most prevalent theories to explain the pathophysiology of IC appear to be altered bladder lining and increased number of activated bladder mast cells. A defective bladder glycosaminoglycan (GAG) layer could allow penetration of allergic triggers, as well as chemicals, food preservatives, drugs, toxins, and adherent bacteria, all of which can activate bladder mast cells. Vasoactive, nociceptive, and proinflammatory molecules released can lead to immune cell infiltration and can sensitize neurons to secrete neurotransmitters or neuropeptides that can further activate mast cells. Mast cell-derived proteases can directly cause tissue damage, and it is noteworthy that urine tryptase is elevated in IC. Bladder mast cells are located close to neuronal processes, which are increased in IC, and they can be activated in situ by acetylcholine (ACh) and substance P (SP). Such activation is augmented by estradiol, which acquires significance in view of the fact that human bladder mast cells express estrogen receptors, but few progesterone receptors, which may explain the worsening of IC symptoms during ovulation. Finally, acute psychological stress in rats leads to mast cell activation that can be reduced by depletion of SP or neutralization of peripheral immune corticotropin-releasing hormone (CRH). These findings suggest that IC could be a syndrome with neural, immune, and endocrine components, in which activated mast cells play a central role.

Rupture of the corpus cavernosum of the penis.

Rupture of the corpus cavernosum ("fracture" of the penis) is an uncommon injury that occurs in an erect penis. The tunica albuginea is torn during coitus or as a result of external forces, resulting in sudden pain, swelling, and discoloration of the penis. Urethral rupture is associated with the cavernous injury in approximately 10% of cases. Treatment of the injury aims at full functional and cosmetic recovery. Nonoperative treatment results in a 10% incidence of penile deformity and requires a substantial hospital stay. However, surgical repair eliminates resultant deformity and allows for earlier hospital discharge. Three patients had fractured penises, including one penis associated with a torn urethra. Early surgical repair was performed in each patient, and the results were excellent. Prompt surgical repair should be given to all patients with a fractured penis.

Hydroxyzine therapy for interstitial cystitis.

OBJECTIVES: To determine the usefulness of oral hydroxyzine for the treatment of symptomatic interstitial cystitis. METHODS: This study was an open-label, nonconsecutive case series of patients treated by their local physicians, in consultation with the authors. A case-report form using visual analog scales was used to assess outcomes. RESULTS: Out of 140 patients, 90 (65%) returned the case-report forms. A 40% reduction in symptom scores was reported. This rose to 55% in patients with a history of allergies. CONCLUSIONS: Hydroxyzine is a useful drug for the symptomatic treatment of IC, especially in patients with documented allergies and/or evidence of bladder mast cell activation.

Intravesical dimethyl sulfoxide (DMSO) for interstitial cystitis--a practical approach.

OBJECTIVES: To provide a brief overview of intravesical dimethly sulfoxide (DMSO) therapy for interstitial cystitis and offer a practical approach to patient treatment. METHODS: A review of the literature and a summation of the experience with treatment of > 300 patients with DMSO at the Interstitial Cystitis Clinic, New England Medical Center. RESULTS: DMSO is helpful in a significant number of patients and it has acceptable morbidity and an excellent safety profile. CONCLUSIONS: Intravesical DMSO (singly or in combination) is one of the mainstays in the pharmacologic treatment of interstitial cystitis.

Renal immunoblastic sarcoma complicating immunosuppressive therapy for Wegener granulomatosis.

A renal tumor developing in a patient receiving cyclophosphamide (Cytoxan) therapy for Wegener granulomatosis is reported. The tumor was similar histologically to the "immunoblastic" sarcoma that develops in renal allograft recipients as a complication of immunosuppressive therapy. This case report strengthens the cause and effect relationship between immunosuppressive drug usage and the subsequent development of neoplasia.

Vaginal calculus in female with myelodysplasia.

A case report of vaginal calculus formation in a nine-year-old girl with myelodysplasia is presented. Etiologic factors in the formation of such calculi include fistulous communication between the vagina and the bladder, neuropathic urethrovesical dysfunction, anatomic conditions causing vaginal outlet obstruction, and/or vaginal pooling of urine and urease-producing bacterial infection. A correct preoperative diagnosis can be made by using oblique x-ray films and cystoscopy. Surgical treatment is simple and successful.

Bladder detrusor endometriosis mimicking interstitial cystitis.

Endometriosis involving the muscular wall of the bladder may cause symptoms similar to those of interstitial cystitis. Vesical endometriosis should be considered in the differential diagnosis of interstitial cystitis, especially in patients with a history of prior gynecologic or pelvic surgery.

Multicentric angiomyolipoma: renal and lymph node involvement.

A retrospective review of 6 patients with renal angiomyolipoma treated surgically revealed regional lymph node involvement in 2--an incidence of 33 per cent. The clinical behavior in these patients suggests that nodal involvement is an expression of multicentricity rather than metastatic disease.

Spurious azotemia associated with 5-fluorocytosine therapy.

A patient with false elevation of serum creatinine level due to 5-fluorocytosine (5-FC) is reported. 5-FC interferes with the enzymatic method used for creatinine determination in the Kodak Ektachem analyzer. Clinicians should be aware of the potential for spurious azotemia in patients receiving 5-FC therapy for fungal urinary tract infections.

Infected urachal cysts.

Infected urachal cysts present with protean clinical manifestations. Diagnosis is frequently difficult in spite of the use of modern genitourinary radiologic imaging techniques. Patients with intra-abdominal or pelvic symptoms are frequently misdiagnosed. Surgical excision is the treatment of choice for infected urachal cysts.

Testicular microlithiasis occurring in postorchiopexy testis.

Testicular microlithiasis occurring in a postorchiopexy testis is described. The histologic characteristics of this uncommon entity are presented, and its etiology and clinical significance are briefly reviewed.

Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study.

Pentosan polysulfate sodium (PPS) was compared with placebo for the symptomatic therapy of interstitial cystitis in a double-blind, multicenter study. A total of 110 patients were enrolled and treated for three months. In this study, overall improvement of greater than 25 percent was reported by 28 percent of the PPS-treated patients and by 13 percent of the placebo-treated patients (p = 0.03). The investigators' overall evaluation provided similar results, 26 percent vs 11 percent in favor of PPS (p = 0.04). Improvement in pain and pressure to urinate also favored PPS over placebo and approached statistical significance (p = 0.07 and 0.08). The incidence of adverse reactions was 6 percent in the PPS-treated group and 13 percent in the placebo-treated group. All adverse reactions were minor, and treatment was discontinued by 1 patient in the PPS group and 2 in the placebo group. In this study, PPS was found to be significantly more effective than, and equally as safe as, placebo.

Computed tomographic findings in renal angiomyolipoma: an histologic correlation.

Accurate preoperative diagnosis of renal angiomyolipomas is essential if conservative resection or angiographic embolization is to be used. Computed tomographic (CT) scanning failed to diagnose angiomyolipoma preoperatively in 2 patients, and this led to a retrospective review of 6 patients to define the limits of CT scanning in preoperative diagnosis. The CT findings were correlated with the histology of the tumors. Two tumors with positive attenuation coefficients suggestive of renal adenocarcinoma had significant amounts of immature "fetal" fat, and one of these had a virtual absence of mature fat. The relative inability of CT scanning to identify immature "fetal" fat, especially in the presence of abundant vessel and muscle elements, is a limitation to its use in the preoperative diagnosis of angiomyolipoma. A negative attenuation coefficient is highly characteristic of renal angiomyolipoma with mature fat elements. A positive attenuation coefficient, although suggestive of renal cell carcinoma, may be found in angiomyolipomas with paucity of mature fat or high proportions of immature fat.

The interstitial cystitis symptom index and problem index.

OBJECTIVES: To develop 2 brief self-administered indices for measuring lower urinary tract symptoms and their impact in patients with interstitial cystitis (IC). METHODS: An initial set of questions was developed and evaluated in focus groups. The index was revised, shortened, and validated with patients diagnosed in 3 large urologic practices with experience in interstitial cystitis (N = 45). Controls were recruited from a group of healthy volunteers in a gynecology clinic (N = 67). Internal consistency, construct validity, and test-retest reliability were evaluated. RESULTS: The IC symptom index and the IC problem index measure urinary and pain symptoms and assesses how problematic symptoms are for patients with interstitial cystitis. Psychometric performance of both instruments is good, with the symptom index demonstrating excellent ability to discriminate characteristics between patients and controls. CONCLUSION: Both indices should be useful in the evaluation and management of patients with IC and should be particularly useful in clinical trials of new therapies for this condition, where reliable, validated, and reproducible outcome measures are critically important.

Mast cell and substance P-positive nerve involvement in a patient with both irritable bowel syndrome and interstitial cystitis.

Many patients with interstitial cystitis (IC) also have irritable bowel syndrome (IBS), both of which occur overwhelmingly in women, are characterized by pain, and worsen under stress. Bladder and colon biopsies of a female patient with both IC and IBS were evaluated immunohistochemically. There were 40 +/- 10 mast cells (MC)/mm2 (normal, less than 10) in the bladder, which were degranulated. The colon contained 148 +/- 11 MC/mm2 (normal, less than 50), mostly close to numerous substance P (SP)-positive nerves. Histamine, methylhistamine, and the unique MC enzyme tryptase were evaluated in 24-hour urine during two flare-ups. These results may help explain the concurrent presentation and the painful nature of these syndromes.

Neurotensin mediates rat bladder mast cell degranulation triggered by acute psychological stress.

OBJECTIVES: An increased number of activated mast cells have been documented in interstitial cystitis (IC), a painful bladder disorder occurring primarily in women and exacerbated by stress. Mast cells in the bladder and in the intestine are often found in juxtaposition to neurons, where they are activated by neuropeptides and neurotransmitters as well as by acute psychological stress. This work was undertaken to investigate whether the neuropeptide neurotensin (NT) is involved in the activation of bladder mast cells by acute psychological stress. METHODS: Male 300-g Sprague-Dawley rats were either kept on the bench in a quiet procedure room or stressed by confining them one at a time for 30 minutes in a clear Plexiglas immobilizer and then killed with carbon dioxide. The bladder was removed and fixed with 4% paraformaldehyde. Frozen sections were either stained with acidified toluidine blue or processed for NT immunocytochemical analysis. An immunosorbent assay was used to also measure NT in bladder homogenate before and after stress. RESULTS: Bladder mast cell activation in control rats was 37.3 +/- 1.4%, as judged by extrusion of granule contents. Degranulation in stressed animals increased to 75.3 +/- 5.5% (P = 0.0003). Treatment of the animals neonatally with capsaicin decreased mast cell degranulation to 48.9 +/- 7.5% (P = 0.008), a 35.1% inhibition. Intraperitoneal administration of the nonpeptide NT receptor antagonist SR48692 sixty minutes before stress decreased bladder mast cell degranulation to 25.2 +/- 3.6% (P = 0.00007), a 66.5% inhibition. This value is 32.5% below control levels, indicating that NT is involved in basal mast cell degranulation. Stress also reduced the total bladder NT content. CONCLUSIONS: The present results indicate that NT mediates the effect of acute, nontraumatic psychological stress on bladder mast cell degranulation. They further suggest that NT receptor antagonists may be useful in subpopulations of patients with IC in whom symptoms worsen under stress.

Carbachol-induced bladder mast cell activation: augmentation by estradiol and implications for interstitial cystitis.

OBJECTIVES: Interstitial cystitis (IC) is a painful, sterile bladder disorder that occurs primarily in women, many of whom also experience allergies with symptoms that worsen perimenstrually. Increased numbers of activated bladder mast cells have recently been implicated in the pathophysiology of IC. These mast cells express high-affinity estrogen receptors and are located close to increased bladder nerves, many of which contain the neuropeptide substance P (SP). We therefore investigated whether the neurotransmitter acetylcholine (ACh) and SP could activate bladder mast cells and whether estradiol could influence this effect. METHODS: Bladder pieces from male Sprague-Dawley rats were perfused with carbachol (the stable analogue of ACh), SP, or the mast cell secretagogue compound 48/80 (C48/80) with or without preincubation with beta-estradiol. The effect of carbachol was also investigated after pretreatment with the muscarinic antagonist atropine. Mast cell activation was assessed by release of 3H-serotonin and morphologic evidence of secretion by light and electron microscopy. RESULTS: Carbachol triggered rat bladder mast cell serotonin release in a dose-dependent manner, an effect increased by tissue pretreatment with estradiol and blocked by atropine. The effect of carbachol was accompanied by ultrastructural evidence of mast cell activation and was stronger than that obtained by either C48/ 80 or SP. CONCLUSIONS: Bladder mast cell activation is neurogenically mediated and augmented by estradiol, findings that could possibly explain the painful symptoms of IC and its prevalence in women, as well as the worsening of symptoms perimenstrually.