Intravesical drug delivery for dysfunctional bladder

The bladder is a hollow organ that can be treated locally by transurethral catheter for intravesical drug instillation or cystoscopy for intravesical drug injection. With advancing technology, local organ‐specific therapy and drug delivery is of expanding interest for treating dysfunctional bladder, including interstitial cystitis/bladder pain syndrome, overactive bladder and sterile hemorrhagic cystitis after chemotherapy or pelvic radiation. Intravesical therapy has shown varying degrees of efficacy and safety in treating interstitial cystitis/bladder pain syndrome, overactive bladder and hemorrhagic cystitis with new modalities being developed. Intravesical (regional) therapy has several advantages than oral (systemic) therapy, including high local concentration and less systemic toxicity. In recent years, intravesical delivery of biotechnological products including neurotoxins and immunosuppressive agents, and delivery platform including liposomes has shown promise for lower urinary tract symptoms. This review considers the current status of intravesical therapy in dysfunctional bladder including interstitial cystitis/bladder pain syndrome, overactive bladder and hemorrhagic cystitis with special attention to lipid based novel drug‐delivery.     

Pathology and pathophysiology of painful bladder diseases

Painful bladder disease is an ill-defined disease presenting with chronic cystitis symptoms, despite sterile urine. This report includes only patients with painful bladder diseases of unknown etiology and pathogenesis. We have chosen to classify these patients pathoanatomically as follows: interstitial cystitis, detrusor myopathy, chronic unspecific cystitis and eosinophilic cystitis. The pathoanatomical appearance of the four groups of patients are described in details and certain clinical differences appear between the groups. The etiology and pathogenesis to the inflammatory reactions and muscle changes found in the detrusor biopsies are unknown, but many theories exist. It is suggested that something in the urine gains access to the bladder wall and initiates the pathoanatomical changes through a defective urothelium and glycosaminoglycans layer. In the interstitial cystitis patients, the inflammatory process and mast cell degranulation might be monitored by the urinary excretion of 1,4-methyl-imidazole-acetic acid and eosinophil cationic protein. It is concluded that no specific therapy for the disease exists, since etiology and pathogenesis are still unknown and therefore future research in this field is very important.     

The combination therapy of prednisolone and tacrolimus for severe painful bladder syndrome/interstitial cystitis

A 47-year-old woman visited our hospital with complaints of frequent urination and intensive pelvic pain. Painful bladder syndrome/interstitial cystitis (PBS/IC) was suspected based on her symptoms. Hydrodistention was performed, and crack and petechial hemorrhage were found, and she was treated with tricyclic antidepressants and antihistamine. However, these treatments were ineffective. An allergy or autoimmune reaction was suspected as the pathogenesis due to eosinophilia and elevation of serum IgE levels. The patient was then treated with immunosuppressive agents. Although her symptoms were not sufficiently improved by single-agent therapy with prednisolone or tacrolimus, they were completely improved by their combined administration. This is the first case to report the effectiveness of combination therapy consisting of prednisolone and tacrolimus to treat PBS/IC.     

Symptoms of interstitial cystitis, painful bladder syndrome and similar diseases in women: a systematic review

PURPOSE: In women symptoms of interstitial cystitis are difficult to distinguish from those of painful bladder syndrome and they appear to overlap with those of urinary tract infection, chronic urethral syndrome, overactive bladder, vulvodynia and endometriosis. This has led to difficulties in formulating a case definition for interstitial cystitis, and complications in the treatment and evaluation of its impact on the lives of women. We performed a systematic literature review to determine how best to distinguish interstitial cystitis from related conditions. MATERIALS AND METHODS: We performed comprehensive literature searches using the terms diagnosis, and each of interstitial cystitis, painful bladder syndrome, urinary tract infection, overactive bladder, chronic urethral syndrome, vulvodynia and endometriosis. RESULTS: Of 2,680 screened titles 604 articles were read in full. The most commonly reported interstitial cystitis symptoms were bladder/pelvic pain, urgency, frequency and nocturia. Interstitial cystitis and painful bladder syndrome share the same cluster of symptoms. Chronic urethral syndrome is an outdated term. Self-reports regarding symptoms and effective antibiotic use can distinguish recurrent urinary tract infections from interstitial cystitis in some but not all women. Urine cultures may also be necessary. Pain distinguishes interstitial cystitis from overactive bladder and vulvar pain may distinguish vulvodynia from interstitial cystitis. Dysmenorrhea distinguishes endometriosis from interstitial cystitis, although many women have endometriosis plus interstitial cystitis. CONCLUSIONS: In terms of symptoms interstitial cystitis and painful bladder syndrome may be the same entity. Recurrent urinary tract infections may be distinguished from interstitial cystitis and painful bladder syndrome via a combination of self-report and urine culture information. Interstitial cystitis and painful bladder syndrome may be distinguished from overactive bladder, vulvodynia and endometriosis, although identifying interstitial cystitis and painful bladder syndrome in women with more than 1 of these diseases may be difficult.     

Pathophysiology of interstitial cystitis

Interstitial cystitis/bladder pain syndrome is a chronic pain syndrome whose causes remains elusive with no generally accepted treatment. A hallmark of functional pain syndromes such as interstitial cystitis/bladder pain syndrome is pain in the absence of demonstrable pathology of the viscera or associated nerves. Patients with chronic pain experience a greater impairment in quality of life than healthy controls. In addition, interstitial cystitis/bladder pain syndrome symptoms can frequently overlap with other conditions including irritable bowel syndrome, fibromyalgia, chronic fatigue syndrome, anxiety disorders, and a number of other syndromes not directly related to the urinary bladder. Because of the complex pathophysiology, a number of animal models have been studied over the years to better understand mechanisms underlying patient symptoms. These models can include: bladder centric, complex mechanisms and psychological and physical stress models. Such animal models can aid in the investigation of aspects of interstitial cystitis/bladder pain syndrome that cannot be pursued in humans as well as to develop and test potential therapies. In addition, the search for urinary factors that may be a cause of interstitial cystitis/bladder pain syndrome has resulted in the discovery of a number of potential targets that could serve as predictive biomarkers which can aid in early diagnosis and treatment of this chronic disorder.     

Pregnancy and interstitial cystitis/painful bladder syndrome

Painful bladder syndrome (PBS) and interstitial cystitis (IC) often affect women of child-bearing age. This article includes information of interest to PBS/IC patients who are pregnant or contemplating pregnancy, and to the clinicians who care for them. One topic is how pregnancy affects PBS/IC symptoms, although little is known at this time. The article also describes the pregnancy risks associated with the most commonly used PBS/IC treatments. Finally, the current knowledge regarding genetic factors in IC is discussed.     

Clinical guidelines for interstitial cystitis/bladder pain syndrome

The clinical guidelines for interstitial cystitis and related symptomatic conditions were revised by updating our previous guidelines. The current guidelines define interstitial cystitis/bladder pain syndrome as a condition with chronic pelvic pain, pressure or discomfort perceived to be related to the urinary bladder accompanied by other urinary symptoms, such as persistent urge to void or urinary frequency in the absence of confusable diseases. The characteristic symptom complex is collectively referred as hypersensitive bladder symptoms. Interstitial cystitis/bladder pain syndrome is divided into Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis and bladder pain syndrome represent interstitial cystitis/bladder pain syndrome with Hunner lesions and interstitial cystitis/bladder pain syndrome without Hunner lesions, respectively. So-called non-Hunner-type interstitial cystitis featured by glomerulations or bladder bleeding after distension is included in bladder pain syndrome. The symptoms are virtually indistinguishable between Hunner-type interstitial cystitis and bladder pain syndrome; however, Hunner-type interstitial cystitis and bladder pain syndrome should be considered as a separate entity of disorder. Histopathology totally differs between Hunner-type interstitial cystitis and bladder pain syndrome; Hunner-type interstitial cystitis is associated with severe inflammation of the urinary bladder accompanied by lymphoplasmacytic infiltration and urothelial denudation, whereas bladder pain syndrome shows little pathological changes in the bladder. Pathophysiology would also differ between Hunner-type interstitial cystitis and bladder pain syndrome, involving interaction of multiple factors, such as inflammation, autoimmunity, infection, exogenous substances, urothelial dysfunction, neural hyperactivity and extrabladder disorders. The patients should be treated differently based on the diagnosis of Hunner-type interstitial cystitis or bladder pain syndrome, which requires cystoscopy to determine the presence or absence Hunner lesions. Clinical studies are to be designed to analyze outcomes separately for Hunner-type interstitial cystitis and bladder pain syndrome.     

Phenotyping of interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome is a chronic, potentially debilitating condition characterized by pain perceived to be related to the bladder in conjunction with lower urinary tract symptoms, and includes a wide variety of clinical phenotypes with diverse etiologies. Currently the only clinically relevant proven phenotype of interstitial cystitis/bladder pain syndrome is the Hunner lesion. Whether the presence of Hunner lesions is a hallmark of a distinct disease cohort or a potentially transient feature of non‐Hunner lesion phenotype has been debated but remains controversial. There are few documented examples of a patient converting between the two forms. Growing clinical and basic evidence supports eliminating the Hunner lesion phenotype from the bladder pain syndrome umbrella and considering it a distinct disease. The Hunner lesion phenotype is characterized by distinct bladder histology, including subepithelial chronic inflammatory changes and epithelial denudation, and specific clinical characteristics (older onset age, severe bladder‐centric symptoms, reduced bladder capacity, and favorable response to the lesion‐targeted therapies). To define the Hunner lesion phenotype, it is necessary to develop an atlas of standardized images of cystoscopic (and, if possible, pathological) appearances of Hunner lesions. A true potential and clinically relevant phenotype of interstitial cystitis/bladder pain syndrome may be patients with non‐bladder‐centric symptoms, characterized by the affect dysregulation and somatic symptoms, and a greater bladder capacity in absence of Hunner lesions. In the present workshop, we concluded that the Hunner lesion is a valid phenotype and can reasonably be considered a disease in its own right. Assessment of bladder capacity and the extent of symptoms (bladder beyond or bladder centric) may help phenotyping of interstitial cystitis/bladder pain syndrome. Proper phenotyping is essential for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome, and for facilitating research.     

A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease

Painful bladder disease, sensory bladder disease, chronic abacterial cystitis and interstitial cystitis are ill-defined conditions of unknown etiology and pathogenesis, and, therefore, they are without any rational therapy. Pathogenetic theories concerning defects in the epithelium and/or mucous surface coat (including glycosaminoglycans) of the bladder, and theories concerning immunological disturbances predominate. Sodium pentosanpolysulfate (Elmiron) acts by substituting a defective glycosaminoglycan layer and inhibits complement reactions in inflammatory processes. We compared sodium pentosanpolysulfate versus placebo in a prospective double-blind, clinically controlled multicenter trial of 115 patients with painful bladder disease. Two protocols were used. Protocol A included 43 patients with clinically and pathologically anatomically verified interstitial cystitis (28 or more mast cells per mm.2), and protocol B included 72 patients with a painful bladder and unspecific histological findings. The patients were randomized to receive either sodium pentosanpolysulfate (200 mg. twice daily) or placebo capsules for 4 months. Before and after the trial the patients were evaluated with symptom grading, urodynamics and cystoscopy with distension and deep bladder biopsies. The results showed no difference between the pre-trial and post-trial values in the sodium pentosanpolysulfate and placebo groups in both protocols in regard to symptoms, urodynamic parameters, cystoscopic appearance and mast cell counts. A significant increase in the cystoscopically determined bladder capacity in the sodium pentosanpolysulfate group in protocol A was found. We conclude that no statistically or clinically significant effect of sodium pentosanpolysulfate was found compared to placebo in patients with painful bladder disease.     

Interstitial cystitis and systemic autoimmune diseases

The cause of interstitial cystitis, a chronic disease that affects the bladder, is unknown. Autoantibodies, such as those against nuclear and bladder epithelium antigens, have been found in patients with interstitial cystitis, but these are likely to be secondary to the disease. No data support a direct causal role of autoimmune reactivity in the pathogenesis of interstitial cystitis. Indirect evidence, however, does support a possible autoimmune nature of interstitial cystitis, such as the strong female preponderance and the clinical association between interstitial cystitis and other known autoimmune diseases within patients and families. The strongest association occurs between interstitial cystitis and Sj?gren's syndrome. Increasing evidence suggests a possible role of autoantibodies to the muscarinic M3 receptor in Sj?gren's syndrome. The M3 receptor is also located on the detrusor muscle cells of the bladder and mediates cholinergic contraction of the urinary bladder and other smooth muscle tissues. Autoantibodies to the M3 receptor might be important in both the early noninflammatory and the late inflammatory features of interstitial cystitis.     

Interstitial cystitis: how should we diagnose it and treat it in 2004?

PURPOSE OF REVIEW: During the last 2 years, two international and two European meetings have taken place and a European Society formed dealing only with interstitial cystitis. A separate committee for interstitial cystitis was formed during the last WHO International Consensus Meeting on urinary incontinence. As a consequence, new concepts and recommendations are evolving, for example the nomenclature is changing from interstitial cystitis to painful bladder syndrome/interstitial cystitis. RECENT FINDINGS: At an international meeting in Kyoto, the scientific basis for diagnosis and treatment of painful bladder syndrome/interstitial cystitis was reviewed, confirming the poor evidence for many diagnostic procedures and treatments. There are two main reasons for this: an internationally accepted definition is lacking and the disease is rare, making clinical trials difficult. A meeting in Copenhagen resulted in a standardization of the procedures for evaluation and the creation of a European Society for the Study of Interstitial Cystitis. Increased concentration of nitric oxide in the urine of patients with Hunner's ulcer may help to separate ulcer from non-ulcer patients. A prospective, randomized, placebo-controlled multicenter study failed to show a statistically significant effect of the antihistamine hydroxine or pentosan polysulfate sodium compared with placebo. The study confirmed the difficulties in recruiting patients for large-scale trials, which could be one of the reasons for the negative result. The effect of the traditional treatment with amitriptyline was confirmed in a prospective, placebo-controlled study. SUMMARY: Standardized evaluation of patients with painful bladder syndrome/interstitial cystitis will benefit both patients and science. An internationally accepted definition of the condition appears to be in sight, which will make epidemiological and research studies easier.     

Review of intravesical therapies for bladder pain syndrome/interstitial cystitis

Bladder pain syndrome/interstitial cystitis (BPS/IC) is a chronic pain condition characterised by urinary frequency, urgency and pain or discomfort which the patient attributes to the bladder. It is a complex condition to manage and treat and requires a multi-disciplinary and multi-modal approach. As well as lifestyle and behavioural modifications, physical therapy and oral medications, intravesical treatments can be used in the treatment algorithm for BPS/IC. A number of intravesical agents are reviewed in this paper along with the available evidence for their use.     

Effect of comestibles on symptoms of interstitial cystitis

PURPOSE: Anecdotal evidence suggests that patients with painful bladder syndrome/interstitial cystitis report symptom exacerbation after consuming particular foods, beverages and/or supplements. We determined the prevalence of the effect of comestibles on painful bladder syndrome/interstitial cystitis symptoms and identified particular comestible items more likely to affect such symptoms. MATERIALS AND METHODS: A validated questionnaire designed to detect whether food, beverages and/or supplements have an effect on bladder symptoms was administered to 104 patients meeting National Institute for Diabetes and Digestive and Kidney Diseases criteria for interstitial cystitis. In addition to answering general questions about the effect of comestibles on painful bladder syndrome/interstitial cystitis symptoms, subjects were asked to indicate whether each of 175 individual items worsened, improved or had no effect on symptoms. Each response was numerically scored on a scale of -2 to 2 and mean values were generated for each comestible item. RESULTS: Of the surveyed patients with painful bladder syndrome/interstitial cystitis 90.2% indicated that the consumption of certain foods or beverages caused symptom exacerbation. There was no correlation between allergies and the effect of comestibles on symptoms. Patients who reported that specific foods worsened symptoms tended to have higher O'Leary-Sant interstitial cystitis symptom index and problem index, and/or pelvic pain and urgency/frequency patient symptom scale scores. A total of 35 comestible items had a mean score of lower than -1.0, including caffeinated, carbonated and alcoholic beverages, certain fruits and juices, artificial sweeteners and spicy foods. CONCLUSIONS: There is a large cohort of patients with painful bladder syndrome/interstitial cystitis in whom symptoms are exacerbated by the ingestion of specific comestibles. The most frequently reported and most bothersome comestibles were coffee, tea, soda, alcoholic beverages, citrus fruits and juices, artificial sweeteners and hot pepper.     

Von der Endorganerkrankung zum klassifizierbaren Blasenschmerzsyndrom

Growing clinical and scientific data imply that the condition currently called interstitial cystitis is not just a mere bladder end-organ disease but that the symptoms perceived to be related to the bladder are rather one aspect of a complex pelvic pain syndrome. The term bladder pain syndrome/interstitial cystitis (BPS/IC) suggested by the European Society for the Study of IC/PBS (ESSIC) for this condition is currently the only one strictly consistent with the taxonomy guidelines of the European Association of Urology and the International Association for the Study of Pain. BPS would be diagnosed on the basis of chronic pelvic pain, pressure, or discomfort perceived to be related to the urinary bladder, accompanied by at least one other urinary symptom such as persistent urge to void or urinary frequency. Confusable diseases as the cause of the symptoms must be excluded. Classification of BPS types might be performed according to findings at cystoscopy with hydrodistention and morphologic findings in bladder biopsies. The end-organ condition interstitial cystitis has thus become a chronic pain syndrome with a predominantly neurovisceral pathophysiology. In daily practice, therapeutic approaches aiming at both the peripheral bladder urothelium and central nervous targets should be combined. A multimodal treatment strategy, such as the combination of tricyclic antidepressants with instillation therapy, still appears reasonable and justified.     

Interstitial cystitis,bladder pain syndrome,hypersensitive bladder,and interstitial cystitis/bladder pain syndrome – clarification of definitions and relationships

Interstitial cystitis and interstitial cystitis‐related conditions such as bladder pain syndrome and hypersensitive bladder have a similar symptomatic profile but probably different etiologies. A meaningful classification of these diseases/conditions is mandatory for clinical and investigational progress. The condition with Hunner lesions (Hunner type interstitial cystitis) is distinct from other categories in terms of histopathology, gene expression, and clinical management. Classification should clearly differentiate the presence or absence of Hunner lesions. The term covering patients as a whole should contain interstitial cystitis, since interstitial cystitis is historically a well‐known name and used for insurance reimbursement. The proposed taxonomy features an umbrella term (interstitial cystitis/bladder pain syndrome) and two subgroups, Hunner type interstitial cystitis (with Hunner lesions) and bladder pain syndrome (without Hunner lesions). Interstitial cystitis/bladder pain syndrome is convenient for initial management, and subgroups can categorize the patients for specific management. The characteristic symptom profile is to be collectively termed as hypersensitive bladder symptoms.     

What’s new in the diagnosis and management of painful bladder syndrome/interstitial cystitis?

Painful bladder syndrome/interstitial cystitis (PBS/IC) is a controversial subject. Despite its many controversies, recent data on diagnostics show that cystoscopy and hydrodistension findings may not be sensitive or specific. Diagnosis is suggested primarily on the basis of history. Antiproliferative factor and Tamm-Horsfall protein are novel tests that may prove to be worthwhile pending future studies. Currently, there is no single diagnostic gold standard. Recent data on therapeutics show that, among oral therapies, amitriptyline and pentosan are efficacious. For best response, pentosan should be initiated early and used for a minimum of 6 months. Immune-modulating agents show promise but are limited by side effects. Intravesical alkalinized lidocaine with heparin may be effective for rapid symptom relief, pending results of prospective randomized trials. Intravesical botulinum toxin A, bacille Calmette-Guérin, and sacral neuromodulation may have a role in select patients.     

Role of liposome in treatment of overactive bladder and interstitial cystitis

Intravesical (local) therapy of agents has been effective in delaying or preventing recurrence of superficial bladder cancer. This route of drug administration has also shown tremendous promise in the treatment of interstitial cystitis/painful bladder syndrome (IC/PBS) and overactive bladder without systemic side effects. Liposomes are lipid vesicles composed of phospholipid bilayers surrounding an aqueous core. They can incorporate drug molecules, both hydrophilic and hydrophobic, and show greater uptake into cells via endocytosis. Intravesical liposomes have therapeutic effects on IC/PBS patients, mainly because of their ability to form a protective lipid film on the urothelial surface. Recent studies have shown the sustained efficacy and safety of intravesical instillation of botulinum toxin formulated with liposomes (lipo-BoNT) for the treatment of refractory overactive bladder This review considers the current status of intravesical liposomes or liposomal mediated drug delivery for the treatment of IC/PBS and overactive bladder.     

Bladder necrosis following hydrodistention in patients with interstitial cystitis

PURPOSE: Bladder hydrodistention is used to diagnose and treat patients with interstitial cystitis. This procedure has been shown to have minimal morbidity and provide symptomatic relief in a subset of patients with interstitial cystitis. We report our experience with almost total bladder necrosis after hydrodistention at 2 institutions. To our knowledge this rare complication has not been previously reported in the literature. We also reviewed the literature regarding complications of hydrodistention and discuss their possible etiology. MATERIALS AND METHODS: We report 3 cases of bladder necrosis after therapeutic hydrodistention for interstitial cystitis at 2 institutions. All records were reviewed, and the clinical presentation, findings and treatments are discussed. A literature review was performed to evaluate the effectiveness and complications of hydrodistention for interstitial cystitis. RESULTS: There were 2 female and 1 male patient between ages 29 and 46. All patients had a previous diagnosis of interstitial cystitis and had been previously treated with hydrodistention. All patients presented with severe abdominal pain and had necrosis of the entire bladder wall with sparing of the trigone. Two patients were treated with supratrigonal cystectomy. A review of the literature revealed little data on the effectiveness of hydrodistention for interstitial cystitis. CONCLUSIONS: Vesical necrosis is a rare but devastating complication of hydrodistention. It can occur in young patients in the absence of a contracted bladder and it usually presents as severe postoperative abdominal pain. At exploration bladder necrosis with sparing of the trigone was observed. All patients required enterocystoplasty.     

Chronic pelvic pain syndrome and the overactive bladder: The inflammatory link

Although the causes of chronic prostatitis/chronic pelvic pain syndrome, painful bladder syndrome/interstitial cystitis, and overactive bladder remain unclear, inflammation may explain some of the causative and propagating features. Cytokines may play a role by recruiting inflammatory cells and ultimately in inducing symptoms. This paper reviews the role of cytokines in the pathophysiology of chronic prostatitis/chronic pelvic pain syndrome, overactive bladder, and painful bladder syndrome/interstitial cystitis.     

Epidural spinal cord stimulation for interstitial cystitis

INTRODUCTION: Interstitial cystitis, a chronic inflammatory disorder of the bladder wall, is highly painful and incapacitating. Urinary frequency and urgency develop, as well as nocturia, dysuria, perineal pain and reduction of bladder capacity. The condition seems to arise from a variety of factors with multiple and diverse pathogenic mechanisms and is refractory to medical and surgical treatment. Because treatments are ineffective and recent studies have implicated an inflammatory neurogenic mechanism in the pathogenesis of interstitial cystitis, neuromodulation by epidural spinal cord stimulation has been suggested for treating patients in whom other measures have failed. CASE DESCRIPTION: A 66-year-old woman with a 9-year history of urinary incontinence, urinary urgency and suprapubic pain was diagnosed of interstitial cystitis. She was referred to our pain clinic with persistent symptoms after repeated attempts to treat the condition medically. After implantation of a cephalocaudal (retrograde) epidural spinal cord stimulator, pain decreased 80% and the improvement has been maintained with no complications. CONCLUSION: Results from this and previous reports allow us to state that retrograde epidural spinal cord stimulation seems to be a relatively non-invasive therapeutic approach for treating interstitial cystitis that is refractory to conventional treatments.