Medical management of patients with refractory carcinoma in situ of the bladder

Bladder cancer is a common genitourinary malignancy and carcinoma in situ (CIS) of the bladder exists as a potentially aggressive variant of the superficial form of the disease. Treatment must reflect the unpredictable nature of this disease entity. In 1976, the use of intravesical Bacillus Calmette-Guerin (BCG) was described for the management of early stage bladder cancer. A subsequent report demonstrated efficacy in a cohort of patients with CIS of the bladder. Since this time, intravesical BCG has been recognised as the initial therapy for CIS of the bladder. Although a 6-week treatment with intravesical BCG has been established as standard therapy in patients with CIS, there has been no consensus as to the subsequent treatment for patients in the setting of failure to initial management with BCG. In addition, a number of reports have demonstrated an increased potential of adverse effects after repeated treatment with intravesical BCG. A variety of alternative immunological and chemotherapeutic agents have been developed in response to the limitations of BCG for patients with refractory CIS of the bladder. At present, valrubicin remains the only agent that is approved by the US Food and Drug Administration for the specific indication of CIS of the bladder unresponsive to intravesical BCG. Although these agents appear promising, the most efficacious therapy remains to be determined. The specific treatment protocol for refractory CIS of the bladder remains elusive. It is ultimately the combined decision of the clinician and patient to determine which course of management is most beneficial.     

Intravesical Treatments of Bladder Cancer: Review

For bladder cancer, intravesical chemo/immunotherapy is widely used as adjuvant therapies after surgical transurethal resection, while systemic therapy is typically reserved for higher stage, muscle-invading, or metastatic diseases. The goal of intravesical therapy is to eradicate existing or residual tumors through direct cytoablation or immunostimulation. The unique properties of the urinary bladder render it a fertile ground for evaluating additional novel experimental approaches to regional therapy, including iontophoresis/electrophoresis, local hyperthermia, co-administration of permeation enhancers, bioadhesive carriers, magnetic-targeted particles and gene therapy. Furthermore, due to its unique anatomical properties, the drug concentration-time profiles in various layers of bladder tissues during and after intravesical therapy can be described by mathematical models comprised of drug disposition and transport kinetic parameters. The drug delivery data, in turn, can be combined with the effective drug exposure to infer treatment efficacy and thereby assists the selection of optimal regimens. To our knowledge, intravesical therapy of bladder cancer represents the first example where computational pharmacological approach was used to design, and successfully predicted the outcome of, a randomized phase III trial (using mitomycin C). This review summarizes the pharmacological principles and the current status of intravesical therapy, and the application of computation to optimize the drug delivery to target sites and the treatment efficacy.     

Bladder,bowel and sexual dysfunction in multiple sclerosis: management strategies

Although patients with multiple sclerosis (MS) are likely to have problems with bladder, bowel and sexual function, these problems have often been neglected in the past. Bladder dysfunction produces symptoms of urgency, frequency and urge incontinence (due to bladder overactivity and incomplete emptying), and is found in up to 75% of patients with MS. The mainstay of drug treatment for neurogenic bladder overactivity is anticholinergic medication, although intravesical treatments have also been proposed, such as the vanilloids and botulinum toxin, as well as sublingual cannibanoids. There has been much progress with pro-erectile agents in recent years, notably the use of sildenafil citrate, which has been shown to be particularly efficacious in these patients. Other agents include apomorphine hydrochloride and newer phosphodiesterase 5 inhibitors; however, the efficacy of these drugs in patients with MS remains to be proven. Research in female sexual dysfunction is also progressing, although this aspect of patient well being has only recently been addressed; the reported development of a classification system for the condition is likely to help categorise future treatments. Unlike bladder and sexual dysfunction, there have been rather limited advances in the treatment of faecal incontinence and constipation specifically for patients with MS, despite a prevalence of up to 50%. This review highlights the strategies for these types dysfunction commonly seen in patients with MS, with report of recent pharmacological developments.     

Evaluation of specific immune responses to BoNT/A and tetanus toxoid in patients undergoing treatment for neurologic disorders

Botulinum neurotoxins (BoNTs) are used in the treatment of many neurological disorders. The primary structure of BoNTs shows a high degree of homology with the tetanus neurotoxin, the toxoid of which is used as a vaccine. Because of the potential cross-reactivity between these toxins, we investigated the effects of Botulinum neurotoxin A (BoNT/A) and tetanus toxoid on peripheral blood mononuclear cells (PBMC) and the corresponding serum antibody levels, in twenty patients who had been treated with BoNT/A. We observed very low PBMC immunostimulation by BoNT/A at the tested dose (15 units/ml), as demonstrated by the low lymphocyte proliferation, and the absence of detectable antibodies cross-reacting with tetanus. However, exposure of PBMC from tetanus-sensitized patients to both neurotoxins showed that BoNT/A exerted a co stimulatory effect on tetanus-stimulated cells. Interestingly, in flow cytometry analysis, BoNT/A seemed to also alter the ratio of na?ve (CD45RA) : memory/effector (CD45RO) T lymphocyte subsets, in favour of CD45RO. These preliminary data give a new insight on the potential immune crossreactivity between the two antigens. In view of the wide use of both neurotoxins, these immunotoxic effects merit a more detailed investigation.     

Use of botulinum toxin A in adult neurological disorders: efficacy, tolerability and safety

The protein botulinum neurotoxin A (BoNT/A) is one of seven distinct neurotoxins produced by Clostridium botulinum. BoNT/A blocks cholinergic synapses with an extremely high specificity and potency. Appropriately purified and diluted, BoNT/A serves as a reliable and well tolerated drug that is applied by local injection.The efficacy of BoNT/A is evident in the symptomatic therapy of disorders in which muscular hyperactivity plays a prominent role, such as focal dystonias and hemifacial spasm; in these disorders, BoNT/A is considered first-line therapy. BoNT/A is also beneficial in the treatment of both adults and children with spasticity of various causes. The pain that frequently accompanies these conditions is effectively reduced by BoNT/A. A genuine analgesic effect for BoNT/A unrelated to skeletal muscle spasmolysis has been suggested on the basis of in vitro and in vivo (animal) data. However, studies in humans designed to detect such an effect were negative, as were controlled studies of BoNT/A in patients with primary headache disorders.BoNT/A also acts on cholinergic synapses of the autonomic nervous system, and injection of BoNT/A into salivary glands significantly decreases the production of saliva. This may be beneficial for patients with Parkinson's disease, in whom the excessive production of saliva may be problematic.Overall, BoNT/A has been confirmed as an efficacious, predictable and well tolerated drug in an ever-increasing number of neurological disorders.     

BoNT/A in the Urinary Bladder—More to the Story than Silencing of Cholinergic Nerves

Botulinum neurotoxin (BoNT/A) is an FDA and NICE approved second-line treatment for overactive bladder (OAB) in patients either not responsive or intolerant to anti-cholinergic drugs. BoNT/A acts to weaken muscle contraction by blocking release of the neurotransmitter acetyl choline (ACh) at neuromuscular junctions. However, this biological activity does not easily explain all the observed effects in clinical and non-clinical studies. There are also conflicting reports of expression of the BoNT/A protein receptor, SV2, and intracellular target protein, SNAP-25, in the urothelium and bladder. This review presents the current evidence of BoNT/A’s effect on bladder sensation, potential mechanisms by which it might exert these effects and discusses recent advances in understanding the action of BoNT in bladder tissue.     

Investigational therapies for non-muscle invasive bladder cancer

Importance of the field: Bacillus Calmette–Guérin (BCG) is currently the most effective adjuvant intravesical agent at preventing disease recurrence and the only therapy shown to inhibit disease progression in non-muscle invasive bladder cancer (NMIBC). However, recurrence rates as high as 30% and significant local/systemic toxicity have resulted in an increased interest in the use of alternative intravesical agents.

Areas covered in the review: Our aim is to discuss recent clinical trial evidence utilizing novel intravesical agents for treatment of NMIBC. A systematic literature review was performed via the National Center for Biotechnology Information databases to identify pertinent studies from 2000 – 2009.

What the reader will gain: A durable response has been demonstrated with alternative agents in patients refractory to or intolerant of BCG. This review compares the merits and shortcomings of these emerging agents, focusing on clinical trial safety and efficacy results.

Take home message: Despite recent enthusiasm for novel agents, radical cystectomy remains the treatment of choice for patients with NMIBC who have failed intravesical therapy. However, evidence is accumulating that novel agents provide an efficacious alternative in patients refractory or intolerable to BCG or unfit for cystectomy. Further randomized prospective data are required to demonstrate a recurrence- and progression-free benefit compared with BCG.     

Botulinum toxin A for the Treatment of Overactive Bladder

The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder.     

Intravesical drug delivery. Pharmacokinetic and clinical considerations.

Intravesical drug administration is widely used in the treatment of patients with superficial bladder cancer, and aims to optimise drug delivery in the vicinity of the tumour and reduce systemic availability. The most commonly employed intravesical agents in patients with superficial bladder cancer are mitomycin (mitomycin C), thiotepa, ethoglucid (ethoglucid), anthracyclines such as doxorubicin, bacille Calmette-Guérin (BCG) and, more recently, taxol and the new mitomycin derivative KW-2149. Recurrence rates in patients with superficial bladder cancer have been substantially reduced by combined transurethral resection and intravesical pharmacotherapy. The high concentration of cytotoxics in urine and tumour tissue explain the high efficacy rates. Furthermore, the low systemic availability of most intravesical agents is consistent with the low frequency of acute and delayed systemic adverse effects. Systemic toxicity is almost negligible, except in the case of thiotepa, and local toxicity is transient and tolerable. Pharmacokinetic models of drug absorption from the bladder have been developed, both in animals and humans. These have led to the identification of optimal intravesical treatment regimens.     

Preliminary Exploration of a New Therapy for Interstitial Cystitis/Bladder Pain Syndrome: Botulinum Toxin A Combined with Sapylin

Interstitial cystitis/bladder pain syndrome (IC/BPS) is an intractable disease without long-term effective therapy. This study aims to evaluate the efficacy and safety of botulinum toxin A (BoNT/A) plus Sapylin, which might modulate the immune response of the bladder in the treatment of IC/BPS patients. We retrospectively investigated the clinical outcomes among 34 patients who accepted repeated Sapylin instillations after 200 U of BoNT/A submucosally injected into bladder walls (Mix group) and 28 patients who received BoNT/A alone (Control group). Each of the bladder walls (left, right, anterior and posterior) was injected six times with 8 U of BoNT/A per injection. The primary outcome measure was the global response assessment. The results showed that at 6 months post-injection, the response rate in the Mix group was remarkably higher than that in the Control group (58.8% vs. 28.6%, p < 0.05). The mean effective duration of the responders in the Mix group was apparently better than that in the Control group (27.5 (range 0–89) vs. 4.9 (range 0–11) months, p < 0.05). None of the patients experienced serious adverse events. In conclusion, repeated intravesical instillations of Sapylin after BoNT/A injection can produce significantly better clinical outcomes than BoNT/A alone in IC/PBS patients.     

Botulinum toxin in the treatment of OAB, BPH, and IC

Botulinum neurotoxins (BoNTs) are well known for their ability to potently and selectively disrupt and modulate neurotransmission. BoNT is currently undergoing regulatory evaluation for urological disorders in the United States and the European Union and is not FDA approved for urologic use. Overactive bladder (OAB) and benign prostatic hyperplasia (BPH) are common urologic conditions characterized by urinary frequency, urgency, nocturia, urge incontinence and, in the case of BPH, decreased urine flow that are currently being evaluated in clinical trials with BoNT-A. Interstitial cystitis (IC) is a chronic condition in which patients describe urinary frequency, urgency and associated bladder/pelvic pain. In the two former conditions, BoNT-A is currently being evaluated in Phase II or Phase III clinical trials as a therapeutic agent. Evidence for BoNT in the treatment of IC is limited to small case series. The purpose of this article is to provide up to date clinical evidence regarding the use of BoNT to treat these three urologic problems. For the sake of clarity, BoNT-A describes the use of Botox^® unless otherwise specified. In addition, when describing OAB, two sub-populations exist: those with OAB of neurogenic origin (NDO) and those with OAB of unknown (idiopathic) origin (IDO).     

Functional effects of imipramine on the rabbit urinary bladder: an in-vitro study

Imipramine is a tricyclic antidepressant that has been demonstrated to be useful in the treatment of certain voiding dysfunctions. Imipramine has a variety of pharmacological effects including direct antimuscarinic activity, inhibition of catecholamine reuptake, direct muscle relaxant, and calcium antagonism. Using the in-vitro whole bladder model we have studied the effect of imipramine on the rate and magnitude of both intravesical pressure generation and bladder emptying in response to field stimulation. The results can be summarized as follows: at concentrations as low as 1 mumol/l imipramine causes a significant inhibition of volume expulsion without significantly affecting pressure generation. Imipramine produced a dose-dependent inhibition of both pressure development and percent volume emptying; however, it was substantially more potent in inhibiting the ability of the bladder to empty than to generate pressure.     

Oxidative stress of red blood cells during Bacillus Calmette-Guerin intravesical instillations

Although Bacillus Calmette-Guerin (BCG) intravesical instillation is widely accepted as a very effective modality in treating bladder carcinoma in situ, and in preventing superficial bladder cancer recurrence, its mechanism of action is not yet fully understood. The antitumor effects of BCG are mostly related to local immunological events but a systemic activation of the immune system cannot be excluded. The objective of the present study was to estimate the systemic production of oxidants during intravesical BCG treatment. Systemic production of oxidants was estimated by assessing the red blood cells (RBC) oxidative stress in twelve patients undergoing BCG immunotherapy for bladder carcinoma in situ. RBC oxidative stress induced by peroxynitrite was determined by luminol-enhanced chemiluminescence. During the treatment period, the RBC oxidative stress revealed a biphasic curve of changes: after an initial 5-fold increase, it dropped to pretreatment levels following the 4th instillation. Intravesical BCG administration induced systemic production of oxygen free radicals that may reflect a systemic activation of the immune system.     

Current concepts in the treatment of disorders of micturition

Disorders of micturition may be divided into disturbances of the storage function of the bladder, and disturbances of the emptying function. The main symptoms of disturbances of storage function are frequency, urgency and incontinence. Hyperactivity of the bladder may lead to urge incontinence, and incompetence of the urethral closure mechanism to stress incontinence. There are many drugs available for treating bladder hyperactivity, but their efficacy as judged from controlled clinical trials (when available) is often limited. Bladder contraction in man is mediated by stimulation of muscarinic receptors, and when given parenterally anticholinergic drugs have been shown to depress bladder hyperactivity irrespective of the underlying cause. Clinically, however, treatment of urge incontinence with anticholinergic drugs is often unsatisfactory. Lack of effect of oral treatment and systemic side effects limit the use of available agents. Drugs with "mixed" actions (anticholinergic and 'direct' muscle effects), for example oxybutynin and terodiline, have well-documented efficacy in bladder hyperactivity. Side effects are common with oxybutynin; terodiline seems to be well tolerated. The aim of drug treatment of stress incontinence is to increase outflow resistance. Although there is only limited possibility of improving the condition with drugs, beneficial effects can be obtained in some patients by use of orally active alpha-adrenoceptor agonists (e.g. phenylpropanolamine) and/or oestrogens. The main symptom of disturbed bladder emptying is urinary retention. Drug therapy is aimed at improving the contractile activity of the detrusor or reducing urethral outflow resistance. Drugs used for improving bladder contractility include parasympathomimetic agents, e.g. bethanechol or carbachol, and intravesical instillation of prostaglandins. Although the efficacy of both types of treatment is open to question, bethanechol seems to be widely used. Increased outflow resistance may be seen in patients with parasympathetic decentralization of the lower urinary tract or in patients with benign prostatic hypertrophy. These patients may respond favourably to alpha-adrenoceptor blockers such as phenoxybenzamine or prazosin.     

非肌层浸润性膀胱癌的免疫治疗

膀胱癌是泌尿生殖系统常见的恶性肿瘤,中、高危非肌层浸润性膀胱癌的标准治疗方式为单纯经尿道膀胱肿瘤切除术＋膀胱灌注治疗。在众多膀胱灌注药物中,BCG膀胱灌注以其明显的抗肿瘤疗效得到广泛使用。但部分高危患者即使进行了BCG标准灌注治疗,仍会发生膀胱癌复发和/或进展,且后续可供选择的治疗方式很少。近几年随着肿瘤免疫学研究的进展,新型免疫治疗药物的开发为膀胱癌的治疗带来了重大突破。此文对非肌层浸润性膀胱癌TURBT术后BCG等免疫调节剂膀胱灌注及其失败后的免疫治疗方法进行综述。     

Liposome-Encapsulated Botulinum Toxin A in Treatment of Functional Bladder Disorders

Botulinum toxin A (BoNT-A) intravesical injections have been used to treat patients with refractory functional bladder disorders such as overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS), but the risk of adverse events and the need for repeated injections continue to prevent widespread application of this treatment. Liposomes are vesicles that comprise concentric phospholipid layers and an aqueous core; their flexible compositions enable them to adsorb and fuse with cell membranes and to deliver drugs or proteins into cells. Therefore, liposomes have been considered as promising vehicles for the less invasive delivery of BoNT-A. In previous placebo-controlled trials including patients with OAB refractory to medical treatment, it was shown that liposomal BoNT-A could significantly decrease the frequency and urgency of urination. In patients with IC/BPS, it was shown that liposomal BoNT-A could also improve bladder pain, but the therapeutic efficacy was not superior to that of the placebo. As the therapeutic mechanisms of BoNT-A include the decreased expression of nerve growth factors, P2X3 receptors, and vanilloid receptors on C-fibers, liposomal BoNT-A might play a more promising role in the treatment of bladder oversensitivity. This article features the contemporary literature regarding BoNT-A, liposomes, and liposomal BoNT-A treatment for functional bladder disorders and potential clinical applications in the future.     

Use of botulinum toxins in cancer therapy

A recent study has demonstrated for the first time that botulinum neurotoxin (BoNT) briefly opens tumour vessels, allowing more effective destruction of cancer cells by radiotherapy and chemotherapy. This review discusses the implications of BoNTs in cancer treatment. After briefly reviewing the different BoNT serotypes, their pharmacological activities and their general use in medicine, the authors focus on their possible application in cancer and describe how BoNTs have been used so far to treat spasm related to tumour or to therapies. By dissecting the mechanisms of action leading to a potentiation of anticancer therapy, it can be seen that BoNTs act by an effect on the tumour microenvironment rather than by a direct cytotoxic effect on tumour cells.     

Pharmacotherapy of hormone refractory prostate cancer: new developments and challenges

Hormone refractory prostate cancer (HRPC) remains a challenge in the management of prostate cancer patients. With the widespread use of PSA (prostate specific antigen), recurrent disease after local treatment for localised prostate cancer is usually diagnosed long before evidence of metastatic disease. In many cases, hormonal manipulations are started at the time of biochemical relapse and therefore, patients become ‘hormone refractory’ earlier in the course of their disease, frequently with a good performance status, often with no evidence of metastatic disease, and they still face a considerably long life expectancy. Despite these changes, the need for more options in the treatment of HRPC is obvious. The pharmacological treatments that are in use and those that are under investigation for this group of patients will be discussed and include: cytotoxic agents including the microtubule inhibitors, alone and in combination with other conventional or experimental therapies such as calcitriol or thalidomide; treatment with epothilone analogues; endothelin receptor antagonists; palliative therapy with bisphosphonates, bone-targeted radiopharmaceuticals and other developing treatments such as vaccines, gene therapies and monoclonal antibodies.     

Kinetic model of drug distribution in the urinary bladder wall following intravesical instillation

Intravesical administration of cytotoxic agents is commonly used in urological practice for treatment of superficial bladder cancer. The leading motive is optimisation of drug delivery near the site of action and reduction of systemic toxicity. Bladder pharmacokinetics is complicated by several mechanisms. The objectives of this work were to develop a kinetic model of drug distribution in the bladder wall following intravesical instillation and to study the effect of various parameters on tissue and systemic drug exposure and explore the potential benefits of permeability enhancing effects of chitosan (CH) and polycarbophil (PC) through simulation. Key elements of the model are variable urinary drug concentration due to urine formation and voiding, biphasic diffusion in the bladder tissue and systemic absorption. Model parameters were estimated from bladder-tissue concentration profiles obtained in previous in vitro experiments with pipemidic acid (PPA) as a model drug. The results support further investigations on application of CH and PC in intravesical drug delivery. Both polymers increase permeability of the bladder wall by diffusion enhancement in the urothelium and presumably by improving the contact with the bladder surface. The developed mathematical model could serve for optimisation of intravesical drug delivery and future development of intravesical drug delivery systems.